Cad PVD

1850 pericardial effusions.
Angiography is rarely necessary but may help to statistics, it is worth noting that epidemiologic data show a decline in
delineate discrete myocardial lesions. the rate of deaths due to IHD, about half of which is attributable to
treatments and half to prevention by risk factor modification.
Obesity, insulin resistance, and type 2 diabetes mellitus are increas-
TREATMENT ing and are powerful risk factors for IHD. These trends are occurring in
Tumors Metastatic to the Heart the general context of population growth and as a result of the increase
PART 6
in the average age of the world’s population. With urbanization in

Most patients with cardiac metastases have advanced malignant countries with emerging economies and a growing middle class, ele-
disease; thus, therapy is generally palliative and consists of control- ments of the energy-rich Western diet are being adopted. As a result,
ling symptoms and treatment of the primary tumor. Symptomatic the prevalence of risk factors for IHD and the prevalence of IHD itself
malignant pericardial effusions should be drained by pericardio-
Disorders of the Cardiovascular System
are both increasing rapidly, so that in analyses of the global burden of

centesis. Prolonged drainage (3–5 days) and concomitant instillation disease, there is a shift from communicable to noncommunicable dis-
of a sclerosing agent (e.g., tetracycline or bleomycin) may delay or eases. Population subgroups that appear to be particularly affected are
prevent reaccumulation of the effusion, and creation of a pericardial men in South Asian countries, especially India and the Middle East. In
window allows drainage of the effusion to the adjacent pleural or light of the projection of large increases in IHD throughout the world,
peritoneal space. Given the overall poor prognosis of these patients, IHD is likely to become the most common cause of death worldwide
discussions regarding goals of care and involvement of palliative by 2020.
care services are often appropriate.
■■PATHOPHYSIOLOGY
■■FURTHER READING Central to an understanding of the pathophysiology of myocardial
Buckley O et al: Cardiac masses, part 1: Imaging strategies and techni- ischemia is the concept of myocardial supply and demand. In normal
cal considerations. AJR Am J Roentgenol 197:W837, 2011. conditions, for any given level of a demand for oxygen, the myocar-
Buckley O et al: Cardiac masses, part 2: Key imaging features for diag- dium will control the supply of oxygen-rich blood to prevent under-
nosis and surgical planning. AJR 1 Am J Roentgenol 97:W842, 2011. perfusion of myocytes and the subsequent development of ischemia
Bussani R et al: Cardiac metastases. J Clin Path 60:27, 2007. and infarction. The major determinants of myocardial oxygen demand
Shapira O et al: Tumors of the heart, in Sabiston and Spenser Surgery of (MVO2) are heart rate, myocardial contractility, and myocardial wall
the Chest, 9th ed, FW Sellke et al (eds). Philadelphia, Elsevier, 2016, tension (stress). An adequate supply of oxygen to the myocardium
pp 1849–1857. requires a satisfactory level of oxygen-carrying capacity of the blood
Tamin SS et al: Prognostic and bioepidemiologic implications of papil- (determined by the inspired level of oxygen, pulmonary function, and
lary fibroelastomas. J Am Coll Cardiol 65:2420, 2015. hemoglobin concentration and function) and an adequate level of coro-
nary blood flow. Blood flows through the coronary arteries in a phasic
fashion, with the majority occurring during diastole. About 75% of the
total coronary resistance to flow occurs across three sets of arteries:
(1) large epicardial arteries (Resistance 1 = R1), (2) prearteriolar vessels
(R2), and (3) arteriolar and intramyocardial capillary vessels (R3). In
Section 5 Coronary and Peripheral the absence of significant flow-limiting atherosclerotic obstructions, R1
is trivial; the major determinant of coronary resistance is found in R2
Vascular Disease and R3 (Fig. 267-1). The normal coronary circulation is dominated and
controlled by the heart’s requirements for oxygen. This need is met
by the ability of the coronary vascular bed to vary its resistance (and,
267 Ischemic Heart Disease

Elliott M. Antman, Joseph Loscalzo
therefore, blood flow) considerably while the myocardium extracts a
high and relatively fixed percentage of oxygen. Normally, intramyo-
cardial resistance vessels demonstrate a great capacity for dilation (R2
and R3 decrease). For example, the changing oxygen needs of the heart
with exercise and emotional stress affect coronary vascular resistance
Ischemic heart disease (IHD) is a condition in which there is an inade- and in this manner regulate the supply of oxygen and substrate to the
quate supply of blood and oxygen to a portion of the myocardium; myocardium (metabolic regulation). The coronary resistance vessels also
it typically occurs when there is an imbalance between myocardial adapt to physiologic alterations in blood pressure to maintain coronary
oxygen supply and demand. The most common cause of myocardial blood flow at levels appropriate to myocardial needs (autoregulation).
ischemia is atherosclerotic disease of an epicardial coronary artery By reducing the lumen of the coronary arteries, atherosclerosis
(or arteries) sufficient to cause a regional reduction in myocardial limits appropriate increases in perfusion when the demand for flow is
blood flow and inadequate perfusion of the myocardium supplied by augmented, as occurs during exertion or excitement. When the luminal
the involved coronary artery. Chapter 291e (from the 19th edition of reduction is severe, myocardial perfusion in the basal state is reduced.
Harrison’s) deals with the development and treatment of atherosclero- Coronary blood flow also can be limited by spasm (see Prinzmetal’s
sis. This chapter focuses on the chronic manifestations and treatment of angina in Chap. 268), arterial thrombi, and, rarely, coronary emboli as
IHD. The subsequent chapters address the acute phases of IHD. well as by ostial narrowing due to aortitis. Congenital abnormalities
such as the origin of the left anterior descending coronary artery from
■■EPIDEMIOLOGY AND GLOBAL TRENDS the pulmonary artery may cause myocardial ischemia and infarction in
IHD causes more deaths and disability and incurs greater infancy, but this cause is very rare in adults.
economic costs than any other illness in the developed world. Myocardial ischemia also can occur if myocardial oxygen demands
IHD is the most common, serious, chronic, life-threatening are markedly increased and particularly when coronary blood flow
illness in the United States, where 15.5 million persons have IHD, and may be limited, as occurs in severe left ventricular hypertrophy (LVH)
3.4 million people aged ≥40 years have angina pectoris. Although there due to aortic stenosis. The latter can present with angina that is indis-
is regional variation, about 4% of the population has sustained a myo- tinguishable from that caused by coronary atherosclerosis largely
cardial infarction. Genetic factors, a high-fat and energy-rich diet, owing to subendocardial ischemia (Chap. 256). A reduction in the
smoking, and a sedentary lifestyle are associated with the emergence of oxygen-carrying capacity of the blood, as in extremely severe anemia
IHD. In the United States and Western Europe, IHD is growing among or in the presence of carboxyhemoglobin, rarely causes myocardial
low-income groups, but primary prevention has delayed the disease to ischemia by itself but may lower the threshold for ischemia in patients
later in life across socioeconomic groups. Despite these sobering with moderate coronary obstruction.
Harrisons_20e_Part6_p1649-p1942.indd 1850 6/1/18 12:54 PM

1851
Macrocirculation Microcirculation
Segment Epicardial arteries >400 µm Small arteries <400 µm Arterioles <100 µm Capillaries <10 µm
and size
CHAPTER 267 Ischemic Heart Disease

Main stimulus
for vasomotion Flow Pressure Metabolites
Main
Transport Regulation Exchange
function
Percentage of
total resistance
to flow
FIGURE 267-1 Macrocirculation and microcirculation across segments and sizes of the arteries. The location and size of the arteries supplying blood to the heart
is shown at the top. Vasomotion of the arterial segments occurs in response to the stimuli shown. The main function of each of the arterial segments is shown next,
followed by a depiction of the relative resistance to antegrade flow. (Modified from B De Bruyne et al: J Am Coll Cardiol 67:1170, 2016.)
Not infrequently, two or more causes of ischemia coexist in a patient, Segmental atherosclerotic narrowing of epicardial coronary arter-
such as an increase in oxygen demand due to LVH secondary to ies is caused most commonly by the formation of a plaque, which is
hypertension and a reduction in oxygen supply secondary to coronary subject to rupture or erosion of the cap separating the plaque from
atherosclerosis and anemia. Abnormal constriction or failure of normal the bloodstream. Upon exposure of the plaque contents to blood, two
dilation of the coronary resistance vessels also can cause ischemia. important and interrelated processes are set in motion: (1) platelets
When it causes angina, this condition is referred to as microvascular are activated and aggregate, and (2) the coagulation cascade is acti-
angina. vated, leading to deposition of fibrin strands. A thrombus composed
of platelet aggregates and fibrin strands traps red blood cells and can
CORONARY ATHEROSCLEROSIS reduce coronary blood flow, leading to the clinical manifestations of
Epicardial coronary arteries are the major site of atherosclerotic dis- myocardial ischemia.
ease. The major risk factors for atherosclerosis (high levels of plasma The location of the obstruction influences the quantity of myocar-
low-density lipoprotein [LDL], low plasma high-density lipoprotein dium rendered ischemic and determines the severity of the clinical
[HDL], cigarette smoking, hypertension, and diabetes mellitus vary in manifestations. Thus, critical obstructions in vessels, such as the
their relative impact on disturbing the normal functions of the vascular left main coronary artery and the proximal left anterior descending
endothelium. These functions include local control of vascular tone, coronary artery, are particularly hazardous. Chronic severe coronary
maintenance of an antithrombotic surface, and control of inflamma- narrowing and myocardial ischemia frequently are accompanied by
tory cell adhesion and diapedesis. The loss of these defenses leads to the development of collateral vessels, especially when the narrow-
inappropriate constriction, luminal thrombus formation, and abnormal ing develops gradually. When well developed, such vessels can by
interactions between blood cells, especially monocytes and platelets, themselves provide sufficient blood flow to sustain the viability of the
and the activated vascular endothelium. Functional changes in the myocardium at rest but not during conditions of increased demand.
vascular milieu ultimately result in the subintimal collections of fat, With progressive worsening of a stenosis in a proximal epicardial
smooth muscle cells, fibroblasts, and intercellular matrix that define the artery, the distal resistance vessels (when they function normally) dilate
atherosclerotic plaque. Rather than viewing atherosclerosis strictly as a to reduce vascular resistance and maintain coronary blood flow. A pres-
vascular problem, it is useful to consider it in the context of alterations sure gradient develops across the proximal stenosis, and poststenotic
in the nature of the circulating blood (hyperglycemia; increased con- pressure falls. When the resistance vessels are maximally dilated, myo-
centrations of LDL cholesterol, tissue factor, fibrinogen, von Willebrand cardial blood flow becomes dependent on the pressure in the coronary
factor, coagulation factor VII, and platelet microparticles). The combi- artery distal to the obstruction. In these circumstances, ischemia, manifest
nation of a “vulnerable vessel” in a patient with “vulnerable blood” clinically by angina or electrocardiographically by ST-segment deviation,
promotes a state of hypercoagulability and hypofibrinolysis. This is can be precipitated by increases in myocardial oxygen demand caused
especially true in patients with diabetes mellitus. by physical activity, emotional stress, and/or tachycardia. Changes in
Atherosclerosis develops at irregular rates in different segments of the caliber of the stenosed coronary artery resulting from physiologic
the epicardial coronary tree and leads eventually to segmental reduc- vasomotion, loss of endothelial control of dilation (as occurs in athero-
tions in cross-sectional area, i.e., plaque formation. There is also a sclerosis), pathologic spasm (Prinzmetal’s angina), or small platelet-rich
predilection for atherosclerotic plaques to develop at sites of increased plugs also can upset the critical balance between oxygen supply and
turbulence in coronary flow, such as at branch points in the epicardial demand and thereby precipitate myocardial ischemia.
arteries. When a stenosis reduces the diameter of an epicardial artery
by 50%, there is a limitation of the ability to increase flow to meet ■■EFFECTS OF ISCHEMIA
increased myocardial demand. When the diameter is reduced by ~80%, During episodes of inadequate perfusion caused by coronary ath-
blood flow at rest may be reduced, and further minor decreases in the erosclerosis, myocardial tissue oxygen tension falls and may cause
stenotic orifice area can reduce coronary flow dramatically to cause transient disturbances of the mechanical, biochemical, and electrical
myocardial ischemia at rest or with minimal stress. functions of the myocardium (Fig. 267-2). Coronary atherosclerosis is a

1852
Repetitive/progressive manifestations of ischemia

Systolic dysfunction
Regional wall motion

PART 6
Decreased segmental perfusion
Diastolic dysfunction
Micro-infarction/myocardial fibrosis
Altered metabolism/abnormal ST segment
Decreased subendocardial perfusion
Endothelial and microvascular dysfunction
Near term Prolonged

Exposure time of mismatch in myocardial oxygen supply/demand
FIGURE 267-2 Cascade of mechanisms and manifestations of ischemia. (Modified from LJ Shaw et al: J Am Coll Cardiol 54:1561, 2009. Original figure illustration by
Rob Flewell.)
focal process that usually causes nonuniform ischemia. During ische- ■■ASYMPTOMATIC VERSUS SYMPTOMATIC IHD
mia, regional disturbances of ventricular contractility cause segmental Although the prevalence is decreasing, postmortem studies of accident
hypokinesia, akinesia, or, in severe cases, bulging (dyskinesia), which victims and military casualties in Western countries show that coronary
can reduce myocardial pump function. atherosclerosis can begin before age 20 and is present even among
The abrupt development of severe ischemia, as occurs with total or adults who were asymptomatic during life. Exercise stress tests in
subtotal coronary occlusion, is associated with almost instantaneous asymptomatic persons may show evidence of silent myocardial ische-
failure of normal muscle relaxation and then contraction. The relatively mia, i.e., exercise-induced ECG changes not accompanied by angina
poor perfusion of the subendocardium causes more intense ischemia pectoris; coronary angiographic studies of such persons may reveal
of this portion of the wall (compared with the subepicardial region). coronary artery plaques and previously unrecognized obstructions
Ischemia of large portions of the ventricle causes transient left ven- (Chap. 237). Coronary artery calcifications (CAC) may be seen on CT
tricular (LV) failure, and if the papillary muscle apparatus is involved, images of the heart, can be quantified in a CAC score, and may be used
mitral regurgitation can occur. When ischemia is transient, it may be as adjunctive information to support a diagnosis of IHD. However,
associated with angina pectoris; when it is prolonged, it can lead to they should not be used as the primary screening modality or as the
myocardial necrosis and scarring with or without the clinical picture of isolated basis on which to formulate therapeutic decisions. (See further
acute myocardial infarction (Chap. 269). discussion below.) Postmortem examination of patients with such
A wide range of abnormalities in cell metabolism, function, and obstructions without a history of clinical manifestations of myocardial
structure underlie these mechanical disturbances during ischemia. The ischemia often shows macroscopic scars secondary to myocardial
normal myocardium metabolizes fatty acids and glucose to carbon infarction in regions supplied by diseased coronary arteries, with or
dioxide and water. With severe oxygen deprivation, fatty acids cannot without collateral circulation. According to population studies, ~25%
be oxidized, and glucose is converted to lactate; intracellular pH is of patients who survive acute myocardial infarction may not come to
reduced, as are the myocardial stores of high-energy phosphates, i.e., medical attention, and these patients have the same adverse prognosis
ATP and creatine phosphate. Impaired cell membrane function leads as do those who present with the classic clinical picture of acute myo-
to the leakage of potassium and the uptake of sodium by myocytes as cardial infarction (Chap. 269). Sudden death may be unheralded and is
well as an increase in cytosolic calcium. The severity and duration of a common presenting manifestation of IHD (Chap. 299).
the imbalance between myocardial oxygen supply and demand deter- Patients with IHD also can present with cardiomegaly and heart
mine whether the damage is reversible (≤20 min for total occlusion in failure secondary to ischemic damage of the LV myocardium that may
the absence of collaterals) or permanent, with subsequent myocardial have caused no symptoms before the development of heart failure; this
necrosis (>20 min). condition is referred to as ischemic cardiomyopathy. In contrast to the
Ischemia also causes characteristic changes in the electrocardiogram asymptomatic phase of IHD, the symptomatic phase is characterized
(ECG) such as repolarization abnormalities, as evidenced by inversion by chest discomfort due to either angina pectoris or acute myocardial
of T waves and, when more severe, displacement of ST segments infarction (Chap. 269). Having entered the symptomatic phase, the
(Chap. 235). Transient T-wave inversion probably reflects nontransmu- patient may exhibit a stable or progressive course, revert to the asymp-
ral, intramyocardial ischemia; transient ST-segment depression often tomatic stage, or die suddenly.
reflects patchy subendocardial ischemia; and ST-segment elevation is
thought to be caused by more severe transmural ischemia. Another STABLE ANGINA PECTORIS
important consequence of myocardial ischemia is electrical instability, This episodic clinical syndrome is due to transient myocardial ische-
which may lead to isolated ventricular premature beats or even ventric- mia. Various diseases that cause myocardial ischemia and the numer-
ular tachycardia or ventricular fibrillation (Chaps. 249 and 250). Most ous forms of discomfort with which it may be confused are discussed
patients who die suddenly from IHD do so as a result of ischemia- in Chap. 11. Males constitute ~70% of all patients with angina pectoris
induced ventricular tachyarrhythmias (Chap. 299). and an even greater proportion of those aged <50 years. It is, however,

important to note that angina pectoris in women is often atypical in TABLE 267-1 Cardiovascular Disease Classification Chart 1853
presentation (see below).
NEW YORK HEART CANADIAN CARDIOVASCULAR
ASSOCIATION FUNCTIONAL SOCIETY FUNCTIONAL
■■HISTORY CLASS CLASSIFICATION CLASSIFICATION
The typical patient with angina is a man >50 years or a woman

I Patients have cardiac disease Ordinary physical activity, such
>60 years of age who complains of episodes of chest discomfort, usually but without the resulting as walking and climbing stairs,
described as heaviness, pressure, squeezing, smothering, or choking limitations of physical activity. does not cause angina. Angina
and only rarely as frank pain. When the patient is asked to localize the Ordinary physical activity does present with strenuous or rapid
sensation, he or she typically places a hand over the sternum, some- not cause undue fatigue, or prolonged exertion at work or
times with a clenched fist, to indicate a squeezing, central, substernal palpitation, dyspnea, or recreation.
anginal pain.
discomfort (Levine’s sign). Angina is usually crescendo-decrescendo in
nature, typically lasts 2–5 min, and can radiate to either shoulder and II Patients have cardiac disease Slight limitation of ordinary
resulting in slight limitation activity. Walking or climbing
to both arms (especially the ulnar surfaces of the forearm and hand). of physical activity. They are stairs rapidly, walking uphill,
It also can arise in or radiate to the back, interscapular region, root of comfortable at rest. Ordinary walking or stair climbing after
the neck, jaw, teeth, and epigastrium. Angina is rarely localized below physical activity results in meals, in cold, or when under
the umbilicus or above the mandible. A useful finding in assessing fatigue, palpitation, dyspnea, emotional stress or only during
a patient with chest discomfort is the fact that myocardial ischemic or anginal pain. the few hours after awakening.
discomfort does not radiate to the trapezius muscles; that radiation Walking more than two blocks
on the level and climbing more
pattern is more typical of pericarditis. than one flight of stairs at a
Although episodes of angina typically are caused by exertion (e.g., normal pace and in normal
exercise, hurrying, or sexual activity) or emotion (e.g., stress, anger, conditions.
fright, or frustration) and are relieved by rest, they also may occur at III Patients have cardiac disease Marked limitation of ordinary
rest (Chap. 268) and while the patient is recumbent (angina decubitus). resulting in marked limitation physical activity. Walking one
The patient may be awakened at night by typical chest discomfort of physical activity. They are to two blocks on the level and
and dyspnea. Nocturnal angina may be due to episodic tachycardia, comfortable at rest. Less climbing more than one flight of
than ordinary physical activity stairs in normal conditions.
diminished oxygenation as the respiratory pattern changes during causes fatigue, palpitation,
sleep, or expansion of the intrathoracic blood volume that occurs with dyspnea, or anginal pain.
recumbency; the latter causes an increase in cardiac size (end-diastolic IV Patients have cardiac Inability to carry on any physical
volume), wall tension, and myocardial oxygen demand that can lead to disease resulting in inability activity without discomfort—
ischemia and transient LV failure. to carry on any physical anginal syndrome may be
The threshold for the development of angina pectoris may vary by activity without discomfort. present at rest.
time of day and emotional state. Many patients report a fixed threshold Symptoms of cardiac
for angina, which occurs predictably at a certain level of activity, such insufficiency or of the anginal
syndrome may be present
as climbing two flights of stairs at a normal pace. In these patients, cor- even at rest. If any physical
onary stenosis and myocardial oxygen supply are fixed, and ischemia activity is undertaken,
is precipitated by an increase in myocardial oxygen demand; they are discomfort is increased.
said to have stable exertional angina. In other patients, the threshold Source: Modified from L Goldman et al: Circulation 64:1227, 1981.
for angina may vary considerably within any particular day and from
day to day. In such patients, variations in myocardial oxygen supply,
most likely due to changes in coronary vasomotor tone, may play an stroke, or transient ischemic attacks (Chap. 419). It is also important to
uncover a family history of premature IHD (<55 years in first-degree
important role in defining the pattern of angina. A patient may report
male relatives and <65 in female relatives) and the presence of diabetes
symptoms upon minor exertion in the morning (a short walk or shav-
mellitus, hyperlipidemia, hypertension, cigarette smoking, and other
ing) yet by midday be capable of much greater effort without symp-
risk factors for coronary atherosclerosis.
toms. Angina may also be precipitated by unfamiliar tasks, a heavy
The history of typical angina pectoris establishes the diagnosis of
meal, exposure to cold, or a combination of these factors.
IHD until proven otherwise. The coexistence of advanced age, male
Exertional angina typically is relieved in 1–5 min by slowing or
sex, the postmenopausal state, and risk factors for atherosclerosis
ceasing activities and even more rapidly by rest and sublingual nitro-
increase the likelihood of hemodynamically significant coronary dis-
glycerin (see below). Indeed, the diagnosis of angina should be sus-
ease. A particularly challenging problem is the evaluation and man-
pect if it does not respond to the combination of these measures. The
agement of patients with persistent ischemic-type chest discomfort but
severity of angina can be conveniently summarized by the Canadian
no flow-limiting obstructions in their epicardial coronary arteries. This
Cardiac Society functional classification (Table 267-1). Its impact on the
situation arises more often in women than in men. Potential etiologies
patient’s functional capacity can be described by using the New York
include microvascular coronary disease (detectable on coronary reac-
Heart Association functional classification (Table 267-1). tivity testing in response to vasoactive agents such as intracoronary
Sharp, fleeting chest pain or a prolonged, dull ache localized to the adenosine, acetylcholine, and nitroglycerin) and abnormal cardiac
left submammary area is rarely due to myocardial ischemia. However, nociception. Treatment of microvascular coronary disease should
especially in women and diabetic patients, angina pectoris may be atyp- focus on efforts to improve endothelial function, including nitrates,
ical in location and not strictly related to provoking factors. In addition, beta blockers, calcium antagonists, statins, and angiotensin-converting
this symptom may exacerbate and remit over days, weeks, or months. Its enzyme (ACE) inhibitors. Abnormal cardiac nociception is more diffi-
occurrence can be seasonal, occurring more frequently in the winter in cult to manage and may be ameliorated in some cases by imipramine.
temperate climates. Anginal “equivalents” are symptoms of myocardial
ischemia other than angina. They include dyspnea, nausea, fatigue, and ■■PHYSICAL EXAMINATION
faintness and are more common in the elderly and in diabetic patients. The physical examination is often normal in patients with stable angina
Systematic questioning of a patient with suspected IHD is impor- when they are asymptomatic. However, because of the increased
tant to uncover the features of an unstable syndrome associated with likelihood of IHD in patients with diabetes and/or peripheral arterial
increased risk, such as angina occurring with less exertion than in the disease, clinicians should search for evidence of atherosclerotic disease
past, occurring at rest, or awakening the patient from sleep. Since cor- at other sites, such as an abdominal aortic aneurysm, carotid arterial
onary atherosclerosis often is accompanied by similar lesions in other bruits, and diminished arterial pulses in the lower extremities. The
arteries, a patient with angina should be questioned and examined physical examination also should include a search for evidence of
for peripheral arterial disease (intermittent claudication [Chap. 275]), risk factors for atherosclerosis such as xanthelasmas and xanthomas.

1854 Evidence for peripheral arterial disease should be sought by evaluat- ECG, and arm blood pressure are monitored. Exercise duration is usu-
ing the pulse contour at multiple locations and comparing the blood ally symptom-limited, and the test is discontinued upon evidence of
pressure between the arms and between the arms and the legs (ankle- chest discomfort, severe shortness of breath, dizziness, severe fatigue,
brachial index). Examination of the fundi may reveal an increased light ST-segment depression >0.2 mV (2 mm), a fall in systolic blood pres-
reflex and arteriovenous nicking as evidence of hypertension. There sure >10 mmHg, or the development of a ventricular tachyarrhythmia.
also may be signs of anemia, thyroid disease, and nicotine stains on the This test is used to discover any limitation in exercise performance,
PART 6
fingertips from cigarette smoking. detect typical ECG signs of myocardial ischemia, and establish their
Palpation may reveal cardiac enlargement and abnormal contraction relationship to chest discomfort. The ischemic ST-segment response
of the cardiac impulse (LV dyskinesia). Auscultation can uncover arte- generally is defined as flat or downsloping depression of the ST seg-
rial bruits, a third and/or fourth heart sound, and, if acute ischemia or ment >0.1 mV below baseline (i.e., the PR segment) and lasting longer
previous infarction has impaired papillary muscle function, an apical than 0.08 s (Fig. 267-2). Upsloping or junctional ST-segment changes
systolic murmur due to mitral regurgitation. These auscultatory signs are not considered characteristic of ischemia and do not constitute a
are best appreciated with the patient in the left lateral decubitus position. positive test. Although T-wave abnormalities, conduction disturbances,
Aortic stenosis, aortic regurgitation (Chap. 256), pulmonary hyperten- and ventricular arrhythmias that develop during exercise should be
sion (Chap. 277), and hypertrophic cardiomyopathy (Chap. 254) must noted, they are also not diagnostic. Negative exercise tests in which the
be excluded, since these disorders may cause angina in the absence of target heart rate (85% of maximal predicted heart rate for age and sex)
coronary atherosclerosis. Examination during an anginal attack is use- is not achieved are considered nondiagnostic.
ful, since ischemia can cause transient LV failure with the appearance In interpreting ECG stress tests, the probability that coronary artery
of a third and/or fourth heart sound, a dyskinetic cardiac apex, mitral disease (CAD) exists in the patient or population under study (i.e.,
regurgitation, and even pulmonary edema. Tenderness of the chest wall, pretest probability) should be considered. Overall, false-positive or
localization of the discomfort with a single fingertip on the chest, or false-negative results occur in one-third of cases. However, a positive
reproduction of the pain with palpation of the chest makes it unlikely result on exercise indicates that the likelihood of CAD is 98% in males
that the pain is caused by myocardial ischemia. A protuberant abdomen who are >50 years with a history of typical angina pectoris and who
may indicate that the patient has the metabolic syndrome and is at develop chest discomfort during the test. The likelihood decreases if the
increased risk for atherosclerosis. patient has atypical or no chest pain by history and/or during the test.
The incidence of false-positive tests is significantly increased in
■■LABORATORY EXAMINATION patients with low probabilities of IHD, such as asymptomatic men age
Although the diagnosis of IHD can be made with a high degree of <40 or premenopausal women with no risk factors for premature athero-
confidence from the history and physical examination, a number of sclerosis. It is also increased in patients taking cardioactive drugs, such
simple laboratory tests can be helpful. The urine should be examined as digitalis and antiarrhythmic agents, and in those with intraventricular
for evidence of diabetes mellitus and renal disease (including microal- conduction disturbances, resting ST-segment and T-wave abnormal-
buminuria) since these conditions accelerate atherosclerosis. Similarly, ities, ventricular hypertrophy, or abnormal serum potassium levels.
examination of the blood should include measurements of lipids Obstructive disease limited to the circumflex coronary artery may result
(cholesterol—total, LDL, HDL—and triglycerides), glucose (hemoglo- in a false-negative stress test since the lateral portion of the heart that
bin A1C), creatinine, hematocrit, and, if indicated based on the physical this vessel supplies is not well represented on the surface 12-lead ECG.
examination, thyroid function. A chest x-ray is important as it may Since the overall sensitivity of exercise stress electrocardiography is only
show the consequences of IHD, i.e., cardiac enlargement, ventricular ~75%, a negative result does not exclude CAD, although it makes the
aneurysm, or signs of heart failure. These signs can support the diagno- likelihood of three-vessel or left main CAD extremely unlikely.
sis of IHD and are important in assessing the degree of cardiac damage. A medical professional should be present throughout the exercise test.
Evidence exists that an elevated level of high-sensitivity C-reactive It is important to measure total duration of exercise, the times to the onset
protein (CRP) (specifically, between 0 and 3 mg/dL) is an independent of ischemic ST-segment change and chest discomfort, the external work
risk factor for IHD and may be useful in therapeutic decision-making performed (generally expressed as the stage of exercise), and the internal
about the initiation of hypolipidemic treatment. The major benefit of cardiac work performed, i.e., by the heart rate–blood pressure product.
high-sensitivity CRP is in reclassifying the risk of IHD in patients in The depth of the ST-segment depression and the time needed for recov-
the “intermediate” risk category on the basis of traditional risk factors. ery of these ECG changes are also important. Because the risks of exercise
testing are small but real—estimated at one fatality and two nonfatal
■■ELECTROCARDIOGRAM complications per 10,000 tests—equipment for resuscitation should be
A 12-lead ECG recorded at rest may be normal in patients with typi- available. Modified (heart rate–limited rather than symptom-limited)
cal angina pectoris, but there may also be signs of an old myocardial exercise tests can be performed safely in patients as early as 6 days after
infarction (Chap. 235). Although repolarization abnormalities, i.e., uncomplicated myocardial infarction (Table 267-2). Contraindications to
ST-segment and T-wave changes, as well as LVH and disturbances of exercise stress testing include rest angina within 48 h, unstable rhythm,
cardiac rhythm or intraventricular conduction are suggestive of IHD, severe aortic stenosis, acute myocarditis, uncontrolled heart failure,
they are nonspecific, since they also can occur in pericardial, myocar- severe pulmonary hypertension, and active infective endocarditis.
dial, and valvular heart disease or, in the case of the former, transiently The normal response to graded exercise includes progressive
with anxiety, changes in posture, drugs, or esophageal disease. The increases in heart rate and blood pressure. Failure of the blood pressure
presence of LVH is a significant indication of increased risk of adverse to increase or an actual decrease with signs of ischemia during the test
outcomes from IHD. Of note, even though LVH and cardiac rhythm is an important adverse prognostic sign, since it may reflect ischemia-
disturbances are nonspecific indicators of the development of IHD, induced global LV dysfunction. The development of angina and/or
they may be contributing factors to episodes of angina in patients severe (>0.2 mV) ST-segment depression at a low workload, i.e., before
in whom IHD has developed as a consequence of conventional risk completion of stage II of the Bruce protocol, and/or ST-segment depres-
factors. Dynamic ST-segment and T-wave changes that accompany sion that persists >5 min after the termination of exercise increases the
episodes of angina pectoris and disappear thereafter are more specific. specificity of the test and suggests severe IHD and a high risk of future
adverse events.
■■STRESS TESTING
Cardiac Imaging (See also Chap. 236) When the resting ECG
Electrocardiographic The most widely used test for both the is abnormal (e.g., preexcitation syndrome, >1 mm of resting ST-
diagnosis of IHD and the estimation of risk and prognosis involves segment depression, left bundle branch block, paced ventricular
recording of the 12-lead ECG before, during, and after exercise, usually rhythm), information gained from an exercise test can be enhanced
on a treadmill (Fig. 267-3). The test consists of a standardized incremen- by stress myocardial radionuclide perfusion imaging after the intra-
tal increase in external workload (Table 267-2) while symptoms, the venous administration of thallium-201 or 99m-technetium sestamibi

during exercise (or with pharmacologic) stress. Contemporary data disease, exertional dyspnea, or deconditioning. In these circumstances, 1855
also suggest positron emission tomography (PET) imaging (with an intravenous pharmacologic challenge is used in place of exercise.
exercise or pharmacologic stress) using N-13 ammonia or rubidium-82 For example, dipyridamole or adenosine can be given to create a cor-
nuclide as another technique for assessing perfusion. Images obtained onary “steal” by temporarily increasing flow in nondiseased segments
immediately after cessation of exercise to detect regional ischemia are of the coronary vasculature at the expense of diseased segments. Alter-

compared with those obtained at rest to confirm reversible ischemia natively, a graded incremental infusion of dobutamine may be admin-
and regions of persistently absent uptake that signify infarction. istered to increase MVO2. A variety of imaging options are available to
A sizable fraction of patients who need noninvasive stress testing accompany these pharmacologic stressors (Fig. 267-3). The develop-
to identify myocardial ischemia and increased risk of coronary events ment of a transient perfusion defect with a tracer such as thallium-201
cannot exercise because of peripheral vascular or musculoskeletal or 99m-technetium sestamibi is used to detect myocardial ischemia.
Evaluation of the patient with known or suspected IHD
Possible indications for stress testing of patient:

1. Dx of IHD uncertain
2. Assess functional capacity of patient
3. Assess adequacy of treatment program for IHD
4. Markedly abnormal calcium score on EBCT
Can patient exercise adequately?
Yes No
Are confounding features

present on resting ECG?
No Yes
Perform treadmill An imaging study

exercise test should be performed
Nuclear Cardiac Cardiac

2-D perfusion MR PET
Echo scan scan scan
ECG ECHO MIBI CMR PET
A
FIGURE 267-3 Evaluation of the patient with known or suspected ischemic heart disease. On the left of the figure is an algorithm for identifying patients who
should be referred for stress testing and the decision pathway for determining whether a standard treadmill exercise with electrocardiogram (ECG) monitoring alone is
adequate. A specialized imaging study is necessary if the patient cannot exercise adequately (pharmacologic challenge is given) or if there are confounding features on
the resting ECG (symptom-limited treadmill exercise may be used to stress the coronary circulation). Panels B–E on the next page are examples of the data obtained
with ECG monitoring and specialized imaging procedures. CMR, cardiac magnetic resonance; EBCT, electron beam computed tomography; ECHO, echocardiography;
IHD, ischemic heart disease; MIBI, methoxyisobutyl isonitrite; MR, magnetic resonance; PET, positron emission tomography. A. Lead V4 at rest (top panel) and after
4.5 min of exercise (bottom panel). There is 3 mm (0.3 mV) of horizontal ST-segment depression, indicating a positive test for ischemia. (Modified from BR Chaitman,
in E Braunwald et al [eds]: Heart Disease, 8th ed, Philadelphia, Saunders, 2008.) B. A 45-year-old avid jogger who began experiencing classic substernal chest pressure
underwent an exercise echo study. With exercise the patient’s heart rate increased from 52 to 153 beats/min. The left ventricular chamber dilated with exercise,
and the septal and apical portions became akinetic to dyskinetic (red arrow). These findings are strongly suggestive of a significant flow-limiting stenosis in the
proximal left anterior descending artery, which was confirmed at coronary angiography. (Modified from SD Solomon, in E. Braunwald et al [eds]: Primary Cardiology,
2nd ed, Philadelphia, Saunders, 2003.) C. Stress and rest myocardial perfusion single-photon emission computed tomography images obtained with 99m-technetium
sestamibi in a patient with chest pain and dyspnea on exertion. The images demonstrate a medium-size and severe stress perfusion defect involving the inferolateral
and basal inferior walls, showing nearly complete reversibility, consistent with moderate ischemia in the right coronary artery territory (red arrows). (Images provided
by Dr. Marcello Di Carli, Nuclear Medicine Division, Brigham and Women’s Hospital, Boston, MA.) D. A patient with a prior myocardial infarction presented with recurrent
chest discomfort. On cardiac magnetic resonance (CMR) cine imaging, a large area of anterior akinesia was noted (marked by the arrows in the top left and right
images, systolic frame only). This area of akinesia was matched by a larger extent of late gadolinium-DTPA enhancements consistent with a large transmural myocardial
infarction (marked by arrows in the middle left and right images). Resting (bottom left) and adenosine vasodilating stress (bottom right) first-pass perfusion images
revealed reversible perfusion abnormality that extended to the inferior septum. This patient was found to have an occluded proximal left anterior descending coronary
artery with extensive collateral formation. This case illustrates the utility of different modalities in a CMR examination in characterizing ischemic and infarcted
myocardium. DTPA, diethylenetriamine penta-acetic acid. (Images provided by Dr. Raymond Kwong, Cardiovascular Division, Brigham and Women’s Hospital, Boston,
MA.) E. Stress and rest myocardial perfusion PET images obtained with rubidium-82 in a patient with chest pain on exertion. The images demonstrate a large and
severe stress perfusion defect involving the mid and apical anterior, anterolateral, and anteroseptal walls and the left ventricular apex, showing complete reversibility,
consistent with extensive and severe ischemia in the mid-left anterior descending coronary artery territory (red arrows). (Images provided by Dr. Marcello Di Carli, Nuclear
Medicine Division, Brigham and Women’s Hospital, Boston, MA.)

1856
PART 6
FIGURE 267-3 (Continued)

TABLE 267-2 Relation of Metabolic Equivalent Tasks (METs) to Stages in Various Testing Protocols 1857
FUNCTIONAL O2 COST
CLASS CLINICAL STATUS mL/kg/min METs TREADMILL PROTOCOLS
BRUCE Modified 3 min Stages BRUCE 3 min Stages

MPH %GR MPH %GR
6.0 22 6.0 22
5.5 20 5.2 20
HEALTHY, DEPENDENT ON AGE, ACTIVITY

5.0 18 5.0 18
56.0 16
NORMAL 52.5 15
AND 49.0 14
I 45.5 13 4.2 16 4.2 16
42.0 12
38.5 11 3.4 14 3.4 14
35.0 10
SEDENTARY HEALTHY
31.5 9
28.0 8
24.5 7 2.5 12 2.5 12
21.0 6
II
LIMITED
SYMPTOMATIC
17.5 5 1.7 10 1.7 10
14.0 4
III 10.5 3 1.7 5
7.0 2 1.7 0
IV 3.5 1
Note: The standard Bruce treadmill protocol (right hand column) begins at 1.7 MPH and 10% gradient (GR) and progresses every 3 min to a higher speed
and elevation. The corresponding oxygen consumption and clinical status of the patient are shown in the center and left hand columns.
Abbreviations: GR, grade; MPH, miles per hour.
Source: Modified from GF Fletcher et al: Circulation 104:1694, 2001.
Echocardiography is used to assess LV function in patients with plaques characteristically are scattered throughout the coronary tree,
chronic stable angina and patients with a history of a prior myo- tend to occur more frequently at branch points, and grow progressively
cardial infarction, pathologic Q waves, or clinical evidence of heart in the intima and media of an epicardial coronary artery at first without
failure. Two-dimensional echocardiography can assess both global encroaching on the lumen, causing an outward bulging of the artery—a
and regional wall motion abnormalities of the left ventricle that are process referred to as remodeling. Later in the course of the disease,
transient when due to ischemia. Stress (exercise or dobutamine) further growth causes luminal narrowing.
echocardiography may cause the emergence of regions of akinesis
or dyskinesis that are not present at rest. Stress echocardiography, Indications Coronary arteriography is indicated in (1) patients
like stress myocardial perfusion imaging, is more sensitive than exer- with chronic stable angina pectoris who are severely symptomatic
cise electrocardiography in the diagnosis of IHD. Cardiac magnetic despite medical therapy and are being considered for revasculariza-
resonance (CMR) stress testing is also evolving as an alternative to tion, i.e., a percutaneous coronary intervention (PCI) or coronary artery
radionuclide, PET, or echocardiographic stress imaging. CMR stress bypass grafting (CABG); (2) patients with troublesome symptoms that
testing performed with dobutamine infusion can be used to assess wall present diagnostic difficulties in whom there is a need to confirm or
motion abnormalities accompanying ischemia, as well as myocardial rule out the diagnosis of IHD; (3) patients with known or possible
perfusion. CMR can be used to provide more complete ventricular angina pectoris who have survived cardiac arrest; (4) patients with
evaluation using multislice magnetic resonance imaging (MRI) studies. angina or evidence of ischemia on noninvasive testing with clinical or
Atherosclerotic plaques become progressively calcified over time, laboratory evidence of ventricular dysfunction; and (5) patients judged
and coronary calcification in general increases with age. For this rea- to be at high risk of sustaining coronary events based on signs of severe
son, methods for detecting coronary calcium have been developed as ischemia on noninvasive testing, regardless of the presence or severity
a measure of the presence of coronary atherosclerosis. These meth- of symptoms (see below).
ods involve computed tomography (CT) applications that achieve Examples of other indications for coronary arteriography include
rapid acquisition of images (electron beam [EBCT] and multidetector the following:
[MDCT] detection). Coronary calcium detected by these imaging
techniques most commonly is quantified by using the Agatston score, 1. Patients with chest discomfort suggestive of angina pectoris but a
which is based on the area and density of calcification. Although negative or nondiagnostic stress test who require a definitive diag-
the diagnostic accuracy of this imaging method is high (sensitivity, nosis for guiding medical management, alleviating psychological
90–94%; specificity, 95–97%; negative predictive value, 93–99%), its stress, career or family planning, or insurance purposes.
prognostic utility has not been defined. Thus, its role in CT, EBCT, and 2. Patients who have been admitted repeatedly to the hospital for a
MDCT scans for the detection and management of patients with IHD suspected acute coronary syndrome (Chaps. 268 and 269), but in
has not been clarified. whom this diagnosis has not been established and in whom the
presence or absence of CAD should be determined.
■■CORONARY ARTERIOGRAPHY 3. Patients with careers that involve the safety of others (e.g., pilots,
(See also Chap. 237) This diagnostic method outlines the lumina of the firefighters, police) who have questionable symptoms or suspicious
coronary arteries and can be used to detect or exclude serious coronary or positive noninvasive tests and in whom there are reasonable
obstruction. However, coronary arteriography provides no informa- doubts about the state of the coronary arteries.
tion about the arterial wall, and severe atherosclerosis that does not 4. Patients with aortic stenosis or hypertrophic cardiomyopathy and
encroach on the lumen may go undetected. Of note, atherosclerotic angina in whom the chest pain could be due to IHD.

1858 5. Male patients >45 years and females >55 years who are to undergo a wall, thus exacerbating the manifestations of ischemia. The recent
cardiac operation such as valve replacement or repair and who may onset of symptoms, the development of severe ischemia during stress
or may not have clinical evidence of myocardial ischemia. testing (see above), and unstable angina pectoris (Chap. 268) all reflect
6. Patients after myocardial infarction, especially those who are at high episodes of rapid progression in coronary lesions.
risk after myocardial infarction because of the recurrence of angina With any degree of obstructive CAD, mortality is greatly increased
or the presence of heart failure, frequent ventricular premature con- when LV function is impaired; conversely, at any level of LV function,
PART 6
tractions, or signs of ischemia on the stress test. the prognosis is influenced importantly by the quantity of myocar-
7. Patients with angina pectoris, regardless of severity, in whom nonin- dium perfused by critically obstructed vessels. Therefore, it is essential
vasive testing indicates a high risk of coronary events (poor exercise to collect all the evidence substantiating past myocardial damage (evi-
performance or severe ischemia). dence of myocardial infarction on ECG, echocardiography, radioiso-
8. Patients in whom coronary spasm or another nonatherosclerotic tope imaging, or left ventriculography), residual LV function (ejection
cause of myocardial ischemia (e.g., coronary artery anomaly, Kawa- fraction and wall motion), and risk of future damage from coronary
saki disease) is suspected. events (extent of coronary disease and severity of ischemia defined
by noninvasive stress testing). The larger the quantity of established
Noninvasive alternatives to diagnostic coronary arteriography
myocardial necrosis is, the less the heart is able to withstand addi-
include CT angiography and CMR angiography (Chap. 236). Although
tional damage and the poorer the prognosis is. Risk estimation must
these new imaging techniques can provide information about obstruc-
include age, presenting symptoms, all risk factors, signs of arterial
tive lesions in the epicardial coronary arteries, their exact role in clinical
practice has not been rigorously defined. Important aspects of their use disease, existing cardiac damage, and signs of impending damage
that should be noted include the substantially higher radiation expo- (i.e., ischemia).
sure with CT angiography compared to conventional diagnostic arte- The greater the number and severity of risk factors for coronary
riography and the limitations on CMR imposed by cardiac movement atherosclerosis (advanced age [>75 years], hypertension, dyslipidemia,
during the cardiac cycle, especially at high heart rates. diabetes, morbid obesity, accompanying peripheral and/or cerebrovas-
cular disease, previous myocardial infarction), the worse the prognosis
■■PROGNOSIS of an angina patient. Evidence exists that elevated levels of CRP in
The principal prognostic indicators in patients known to have IHD are the plasma, extensive coronary calcification on electron beam CT (see
age, the functional state of the left ventricle, the location(s) and severity above), and increased carotid intimal thickening on ultrasound exami-
of coronary artery narrowing, and the severity or activity of myocardial nation also indicate an increased risk of coronary events.
ischemia. Angina pectoris of recent onset, unstable angina (Chap. 268),
early postmyocardial infarction angina, angina that is unresponsive
or poorly responsive to medical therapy, and angina accompanied TREATMENT
by symptoms of congestive heart failure all indicate an increased risk Stable Angina Pectoris
for adverse coronary events. The same is true for the physical signs
of heart failure, episodes of pulmonary edema, transient third heart Once the diagnosis of IHD has been made, each patient must be
sounds, and mitral regurgitation and for echocardiographic or radio- evaluated individually with respect to his or her level of under-
isotopic (or roentgenographic) evidence of cardiac enlargement and standing, expectations and goals, control of symptoms, and pre-
reduced (<0.40) ejection fraction. vention of adverse clinical outcomes such as myocardial infarction
Most important, any of the following signs during noninvasive test- and premature death. The degree of disability and the physical and
ing indicates a high risk for coronary events: inability to exercise for emotional stress that precipitates angina must be recorded carefully
6 min, i.e., stage II (Bruce protocol) of the exercise test; a strongly positive to set treatment goals. The management plan should include the fol-
exercise test showing onset of myocardial ischemia at low workloads lowing components: (1) explanation of the problem and reassurance
(≥0.1 mV ST-segment depression before completion of stage II, ≥0.2 mV about the ability to formulate a treatment plan, (2) identification
ST-segment depression at any stage, ST-segment depression for >5 min and treatment of aggravating conditions, (3) recommendations for
after the cessation of exercise, a decline in systolic pressure >10 mmHg adaptation of activity as needed, (4) treatment of risk factors that
during exercise, or the development of ventricular tachyarrhythmias will decrease the occurrence of adverse coronary outcomes, (5) drug
during exercise); the development of large or multiple perfusion therapy for angina, and (6) consideration of revascularization.
defects or increased lung uptake during stress radioisotope perfusion
imaging; and a decrease in LV ejection fraction during exercise on EXPLANATION AND REASSURANCE
radionuclide ventriculography or during stress echocardiography. Patients with IHD need to understand their condition and realize
Conversely, patients who can complete stage III of the Bruce exercise that a long and productive life is possible even though they have
protocol and have a normal stress perfusion scan or negative stress angina pectoris or have experienced and recovered from an acute
echocardiographic evaluation are at very low risk for future coronary myocardial infarction. Offering results of clinical trials showing
events. The finding of frequent episodes of ST-segment deviation on improved outcomes can be of great value in encouraging patients
ambulatory ECG monitoring (even in the absence of symptoms) is also to resume or maintain activity and return to work. A planned
an adverse prognostic finding. program of rehabilitation can encourage patients to lose weight,
On cardiac catheterization, elevations of LV end-diastolic pressure improve exercise tolerance, and control risk factors with more
and ventricular volume and reduced ejection fraction are the most confidence.
important signs of LV dysfunction and are associated with a poor
prognosis. Patients with chest discomfort but normal LV function IDENTIFICATION AND TREATMENT OF AGGRAVATING
and normal coronary arteries have an excellent prognosis. Obstruc- CONDITIONS
tive lesions of the left main (>50% luminal diameter) or left anterior A number of conditions may increase oxygen demand or decrease
descending coronary artery proximal to the origin of the first septal oxygen supply to the myocardium and may precipitate or exacer-
artery are associated with a greater risk than are lesions of the right bate angina in patients with IHD. LVH, aortic valve disease, and
or left circumflex coronary artery because of the greater quantity of hypertrophic cardiomyopathy may cause or contribute to angina
myocardium at risk. Atherosclerotic plaques in epicardial arteries and should be excluded or treated. Obesity, hypertension, and
with fissuring or filling defects indicate increased risk. These lesions hyperthyroidism should be treated aggressively to reduce the fre-
go through phases of inflammatory cellular activity, degeneration, quency and severity of anginal episodes. Decreased myocardial oxy-
endothelial dysfunction, abnormal vasomotion, platelet aggregation, gen supply may be due to reduced oxygenation of the arterial blood
and fissuring or hemorrhage. These factors can temporarily worsen the (e.g., in pulmonary disease or, when carboxyhemoglobin is present,
stenosis and cause thrombosis and/or abnormal reactivity of the vessel due to cigarette or cigar smoking) or decreased oxygen-carrying

capacity (e.g., in anemia). Correction of these abnormalities, if pres- reduced caloric intake to achieve optimal body weight are a corner- 1859
ent, may reduce or even eliminate angina pectoris. stone in the management of chronic IHD. It is especially important
to emphasize weight loss and regular exercise in patients with the
ADAPTATION OF ACTIVITY
metabolic syndrome or overt diabetes mellitus.
Myocardial ischemia is caused by a discrepancy between the demand Cigarette smoking accelerates coronary atherosclerosis in both sexes

of the heart muscle for oxygen and the ability of the coronary and at all ages and increases the risk of thrombosis, plaque instabil-
circulation to meet that demand. Most patients can be helped to ity, myocardial infarction, and death. In addition, by increasing
understand this concept and utilize it in the rational programming myocardial oxygen needs and reducing oxygen supply, it aggravates
of activity. Many tasks that ordinarily evoke angina may be accom- angina. Smoking cessation studies have demonstrated important
plished without symptoms simply by reducing the speed at which benefits with a significant decline in the occurrence of these adverse
they are performed. Patients must appreciate the diurnal variation outcomes. Noncombustible tobacco in the form of electronic ciga-
in their tolerance of certain activities and should reduce their energy rettes (nicotine delivery systems) may also increase the frequency of
requirements in the morning, immediately after meals, and in cold anginal episodes. The physician’s message must be clear and strong
or inclement weather. On occasion, it may be necessary to recom- and supported by programs that achieve and monitor abstinence of
mend a change in employment or residence to avoid physical stress. tobacco product use (Chap. 448).
Physical conditioning usually improves the exercise tolerance Hypertension (Chap. 271) is associated with an increased risk
of patients with angina and has substantial psychological benefits. of adverse clinical events from coronary atherosclerosis as well as
A regular program of isotonic exercise that is within the limits of the stroke. In addition, the LVH that results from sustained hyperten-
individual patient’s threshold for the development of angina pecto- sion aggravates ischemia. There is evidence that long-term effective
ris and that does not exceed 80% of the heart rate associated with treatment of hypertension can decrease the occurrence of adverse
ischemia on exercise testing should be strongly encouraged. Based coronary events (Chap. 271).
on the results of an exercise test, the number of metabolic equivalent Diabetes mellitus (Chap. 396) accelerates coronary and peripheral
tasks (METs) performed at the onset of ischemia can be estimated atherosclerosis and is frequently associated with dyslipidemias and
(Table 267-2) and a practical exercise prescription can be formulated increases in the risk of angina, myocardial infarction, and sudden
to permit daily activities that will fall below the ischemic threshold coronary death. Aggressive control of the dyslipidemia (target LDL
(Table 267-3). cholesterol <70 mg/dL) and hypertension (target blood pressure
TREATMENT OF RISK FACTORS 120/80 mmHg) that are frequently found in diabetic patients is
highly effective and therefore essential, as described below.
A family history of premature IHD is an important indicator of
increased risk and should trigger a search for treatable risk factors DYSLIPIDEMIA
such as hyperlipidemia, hypertension, and diabetes mellitus. Obesity The treatment of dyslipidemia is central in aiming for long-term
impairs the treatment of other risk factors and increases the risk of relief from angina, reduced need for revascularization, and reduc-
adverse coronary events. In addition, obesity often is accompanied tion in myocardial infarction and death. The control of lipids can be
by three other risk factors: diabetes mellitus, hypertension, and achieved by the combination of a diet low in saturated and trans-
hyperlipidemia. The treatment of obesity and these accompanying unsaturated fatty acids, exercise, and weight loss. Nearly always,
risk factors is an important component of any management plan. HMG-CoA reductase inhibitors (statins) are required and can lower
A diet low in saturated and trans-unsaturated fatty acids and a LDL cholesterol (25–50%), raise HDL cholesterol (5–9%), and lower
TABLE 267-3 Energy Requirements for Some Common Activities

LESS THAN 3 METs 3–5 METs 5–7 METs 7–9 METs MORE THAN 9 METs
Self-Care
Washing/shaving Cleaning windows Easy digging in garden Heavy shoveling Carrying loads up stairs
Dressing Raking Level hand lawn mowing Carrying objects (60–90 lb) (objects more than 90 lb)
Light housekeeping Power lawn mowing Carrying objects (30–60 lb) Climbing stairs (quickly)
Desk work Bed making/stripping Shoveling heavy snow
Driving auto Carrying objects (15–30 lb)
Occupational
Sitting (clerical/assembly) Stocking shelves (light objects) Carpentry (exterior) Digging ditches (pick and Heavy labor
Desk work Light welding/carpentry Shoveling dirt shovel)
Standing (store clerk) Sawing wood
Recreational
Golf (cart) Dancing (social) Tennis (singles) Canoeing Squash
Knitting Golf (walking) Snow skiing (downhill) Mountain climbing Ski touring
Sailing Light backpacking Vigorous basketball
Tennis (doubles) Basketball
Stream fishing
Physical Conditioning
Walking (2 mph) Level walking (3–4 mph) Level walking (4.5–5.0 mph) Level jogging (5 mph) Running more than 6 mph
Stationary bike Level biking (6–8 mph) Bicycling (9–10 mph) Swimming (crawl stroke) Bicycling (more than 13 mph)
Very light calisthenics Light calisthenics Swimming, breast stroke Rowing machine Rope jumping
Heavy calisthenics Walking uphill (5 mph)
Bicycling (12 mph)
Abbreviation: METs, metabolic equivalent tasks.
Source: Modified from WL Haskell: Rehabilitation of the coronary patient, in NK Wenger, HK Hellerstein (eds): Design and Implementation of Cardiac Conditioning
Program. New York, Churchill Livingstone, 1978.

1860 triglycerides (5–30%). A powerful treatment effect of statins on ath- TABLE 267-5 Properties of Beta Blockers in Clinical Use for Ischemic
erosclerosis, IHD, and outcomes is seen regardless of the pretreat- Heart Disease
ment LDL cholesterol level. Fibrates or niacin can be used to raise PARTIAL
HDL cholesterol and lower triglycerides (Chap. 400). Controlled AGONIST USUAL DOSE FOR
trials with lipid-regulating regimens have shown equal proportional DRUGS SELECTIVITY ACTIVITY ANGINA
benefit for men, women, the elderly, diabetic patients, and smokers. Acebutolol β1 Yes 200–600 mg twice daily
PART 6
Injectable monoclonal antibodies against PCSK9 are now available Atenolol β1 No 50–200 mg/d
and are capable of producing dramatic lowering of LDL cholesterol Betaxolol β1 No 10–20 mg/d
beyond that achieved with a statin alone.
Bisoprolol β1 No 10 mg/d
Compliance with the health-promoting behaviors listed above is
Esmolol β1 No 50–300 μg/kg/min
generally very poor, and a conscientious physician must not under-

(intravenous)a
estimate the major effort required to meet this challenge. Many
patients who are discharged from the hospital with proven coronary Labetalolb None Yes 200–600 mg twice daily
disease do not receive adequate treatment for dyslipidemia. In light Metoprolol β1 No 50–200 mg twice daily
of the proof that treating dyslipidemia brings major benefits, phy- Nadolol None No 40–80 mg/d
sicians need to establish treatment pathways, monitor compliance, Nebivolol β1 (at low doses) No 5–40 mg/d
and follow up regularly. Pindolol None Yes 2.5–7.5 mg 3 times daily
RISK REDUCTION IN WOMEN WITH IHD Propranolol None No 80–120 mg twice daily
The incidence of clinical IHD in premenopausal women is very low; Timolol None No 10 mg twice daily
however, after menopause, the atherogenic risk factors increase a
Esmolol is an ultra-short-acting beta blocker that is administered as a continuous
(e.g., increased LDL, reduced HDL) and the rate of clinical coronary intravenous infusion. Its rapid offset of action makes esmolol an attractive agent
to use in patients with relative contraindications to beta blockade. bLabetolol is a
events accelerates to the levels observed in men. Women have not combined alpha and beta blocker.
given up cigarette smoking as effectively as have men. Diabetes Note: This list of beta blockers that may be used to treat patients with angina
mellitus, which is more common in women, greatly increases the pectoris is arranged alphabetically. The agents for which there is the greatest
occurrence of clinical IHD and amplifies the deleterious effects of clinical experience include atenolol, metoprolol, and propranolol. It is preferable to
use a sustained-release formulation that may be taken once daily to improve the
hypertension, hyperlipidemia, and smoking. Cardiac catheteriza- patient’s compliance with the regimen.
tion and coronary revascularization are underused in women and
Source: Data from RJ Gibbons et al: J Am Coll Cardiol 41:159, 2003.
are performed at a later and more severe stage of the disease than
in men. When cholesterol lowering, beta blockers after myocardial
NITRATES
infarction, and CABG are applied in the appropriate patient groups,
women benefit to the same degree as men. The organic nitrates are a valuable class of drugs in the management
of angina pectoris (Table 267-4). Their major mechanisms of action
DRUG THERAPY include systemic venodilation with concomitant reduction in LV
The commonly used drugs for the treatment of angina pectoris
are summarized in Tables 267-4 through 267-6. Pharmacotherapy
for IHD is designed to reduce the frequency of anginal episodes, TABLE 267-6 Calcium Channel Blockers in Clinical Use for Ischemic
Heart Disease
myocardial infarction, and coronary death. Trial data emphasize
how important medical management is when added to the health- DURATION
DRUGS USUAL DOSE OF ACTION SIDE EFFECTS
promoting behaviors discussed above. To achieve maximum benefit
from medical therapy for IHD, it is frequently necessary to com- Dihydropyridines
bine agents from different classes and titrate the doses as guided Amlodipine 5–10 mg qd Long Headache, edema
by the individual profile of risk factors, symptoms, hemodynamic Felodipine 5–10 mg qd Long Headache, edema
responses, and side effects. Isradipine 2.5–10 mg bid Medium Headache, fatigue
Nicardipine 20–40 mg tid Short Headache, dizziness,
flushing, edema
TABLE 267-4 Nitrate Therapy in Patients with Ischemic Heart
Disease Nifedipine Immediate release:a Short Hypotension, dizziness,
30–90 mg daily orally flushing, nausea,
PREPARATION OF constipation, edema
AGENT DOSE SCHEDULE Slow release: 30–180
mg orally
Nitroglycerina
Nisoldipine 20–40 mg qd Short Similar to nifedipine
Ointment 0.5–2 in. Two or three times daily
Nondihydropyridines
Transdermal patch 0.2–0.8 mg/h Every 24 h; remove at
bedtime for 12–14 h Diltiazem Immediate release: Short Hypotension, dizziness,
30–80 mg 4 times flushing, bradycardia,
Sublingual tablet 0.3–0.6 mg As needed, up to three
daily edema
doses 5 min apart
Slow release: Long
Spray One or two sprays As needed, up to three
120–320 mg qd
doses 5 min apart
Verapamil Immediate release: Short Hypotension,
Isosorbide dinitratea
80–160 mg tid myocardial depression,
Oral 10–40 mg Two or three times daily heart failure, edema,
Slow release: Long
Oral sustained release 80–120 mg Once or twice daily 120–480 mg qd bradycardia
(eccentric schedules)
a
May be associated with increased risk of mortality if administered during acute
Isosorbide 5-mononitrate myocardial infarction.
Oral 20 mg Twice daily (given Note: This list of calcium channel blockers that may be used to treat patients
7–8 h apart) with angina pectoris is divided into two broad classes, dihydropyridines and
Oral sustained release 30–240 mg Once daily nondihydropyridines, and arranged alphabetically within each class. Among
the dihydropyridines, the greatest clinical experience has been obtained with
A 10- to 12-h nitrate-free interval is recommended.
a
amlodipine and nifedipine. After the initial period of dose titration with a short-
Source: Modified from DA Morrow, WE Boden: Stable ischemic heart disease. In acting formulation, it is preferable to switch to a sustained-release formulation
RO Bonow et al (eds): Braunwald’s Heart Disease: A Textbook of Cardiovascular that may be taken once daily to improve patient compliance with the regimen.
Medicine, 9th ed. Philadelphia, Saunders, 2012, p. 1224. Source: Data from RJ Gibbons et al: J Am Coll Cardiol 41:159, 2003.

end-diastolic volume and pressure, thereby reducing myocardial Because of differences in the dose-response relationship on cardiac 1861
wall tension and oxygen requirements; dilation of epicardial coro- electrical activity between the dihydropyridine and nondihydro-
nary vessels; and increased blood flow in collateral vessels. When pyridine calcium channel blockers, verapamil and diltiazem may
metabolized, organic nitrates release nitric oxide (NO) that binds produce symptomatic disturbances in cardiac conduction and
to guanylyl cyclase in vascular smooth muscle cells, leading to an bradyarrhythmias. They also exert negative inotropic actions and

increase in cyclic guanosine monophosphate, which causes relax- are more likely to aggravate LV failure, particularly when used
ation of vascular smooth muscle. Nitrates also exert antithrombotic in patients with LV dysfunction, especially if the patients are
activity by NO-dependent activation of platelet guanylyl cyclase, also receiving beta blockers. Although useful effects usually are
impairment of intraplatelet calcium flux, and platelet activation. achieved when calcium channel blockers are combined with beta
The absorption of these agents is rapid and complete through blockers and nitrates, individual titration of the doses is essential
mucous membranes. For this reason, nitroglycerin is most com- with these combinations. Variant (Prinzmetal’s) angina responds
monly administered sublingually in tablets of 0.4 or 0.6 mg. Patients particularly well to calcium channel blockers (especially members
with angina should be instructed to take the medication both to of the dihydropyridine class), supplemented when necessary by
relieve angina and also ~5 min before activities that are likely to nitrates (Chap. 268).
induce an episode. The value of this prophylactic use of the drug Verapamil ordinarily should not be combined with beta blockers
cannot be overemphasized. because of the combined adverse effects on heart rate and contrac-
Nitrates improve exercise tolerance in patients with chronic tility. Diltiazem can be combined with beta blockers in patients
angina and relieve ischemia in patients with unstable angina as well with normal ventricular function and no conduction disturbances.
as patients with Prinzmetal’s variant angina (Chap. 268). A diary of Amlodipine and beta blockers have complementary actions on cor-
angina and nitroglycerin use may be valuable for detecting changes onary blood supply and myocardial oxygen demands. Whereas the
in the frequency, severity, or threshold for discomfort that may sig- former decreases blood pressure and dilates coronary arteries, the
nify the development of unstable angina pectoris and/or herald an latter slows heart rate and decreases contractility. Amlodipine and
impending myocardial infarction. the other second-generation dihydropyridine calcium antagonists
Long-Acting Nitrates None of the long-acting nitrates is as effec- (nicardipine, isradipine, long-acting nifedipine, and felodipine) are
tive as sublingual nitroglycerin for the acute relief of angina. These potent vasodilators and are useful in the simultaneous treatment of
organic nitrate preparations can be swallowed, chewed, or admin- angina and hypertension. Short-acting dihydropyridines should be
istered as a patch or paste by the transdermal route (Table 267-4). avoided because of the risk of precipitating infarction, particularly
They provide effective plasma levels for up to 24 h, but the thera- in the absence of concomitant beta blocker therapy.
peutic response is highly variable. Different preparations and/or Choice Between Beta Blockers and Calcium Channel Blockers for
administration during the daytime should be tried only to prevent Initial Therapy Since beta blockers have been shown to improve
discomfort while avoiding side effects such as headache and dizzi- life expectancy after acute myocardial infarction (Chaps. 268 and
ness. Individual dose titration is important to prevent side effects. 269) and calcium channel blockers have not, the former may also
To minimize the effects of nitrate tolerance, the minimum effective be preferable in patients with angina and a damaged left ventricle.
dose should be used and a minimum of 8 h each day kept free of the However, calcium channel blockers are indicated in patients with
drug to restore any useful response(s). the following: (1) inadequate responsiveness to the combination
a-Adrenergic Blockers These drugs represent an important compo- of beta blockers and nitrates; many of these patients do well with a
nent of the pharmacologic treatment of angina pectoris (Table 267-5). combination of a beta blocker and a dihydropyridine calcium channel
They reduce myocardial oxygen demand by inhibiting the increases blocker; (2) adverse reactions to beta blockers such as depression,
in heart rate, arterial pressure, and myocardial contractility caused sexual disturbances, and fatigue; (3) angina and a history of asthma
by adrenergic activation. Beta blockade reduces these variables most or chronic obstructive pulmonary disease; (4) sick-sinus syndrome or
strikingly during exercise but causes only small reductions at rest. significant atrioventricular conduction disturbances; (5) Prinzmetal’s
Long-acting beta-blocking drugs or sustained-release formulations angina; or (6) symptomatic peripheral arterial disease.
offer the advantage of once-daily dosing (Table 267-5). The therapeu- A comparison of the common side effects, contraindications, and
tic aims include relief of angina and ischemia. These drugs also can potential drug interactions of many of the frequently presented
reduce mortality and reinfarction rates in patients after myocardial antianginal agents is shown in Table 267-7.
infarction and are moderately effective antihypertensive agents. Antiplatelet Drugs Aspirin is an irreversible inhibitor of platelet
Relative contraindications include asthma and reversible airway cyclooxygenase and thereby interferes with platelet activation.
obstruction in patients with chronic lung disease, atrioventricular Chronic administration of 75–325 mg orally per day has been shown
conduction disturbances, severe bradycardia, Raynaud’s phenome- to reduce coronary events in asymptomatic adult men over age
non, and a history of mental depression. Side effects include fatigue, 50, patients with chronic stable angina, and patients who have or
reduced exercise tolerance, nightmares, impotence, cold extremities, have survived unstable angina and myocardial infarction. There
intermittent claudication, bradycardia (sometimes severe), impaired is a dose-dependent increase in bleeding when aspirin is used
atrioventricular conduction, LV failure, bronchial asthma, worsen- chronically. It is preferable to use an enteric-coated formulation in
ing claudication, and intensification of the hypoglycemia produced the range of 81–162 mg/d. Administration of this drug should be
by oral hypoglycemic agents and insulin. Reducing the dose or even considered in all patients with IHD in the absence of gastrointestinal
discontinuation may be necessary if these side effects develop and bleeding, allergy, or dyspepsia. Clopidogrel (300–600 mg loading and
persist. Since sudden discontinuation can intensify ischemia, the 75 mg/d) is an oral agent that blocks P2Y12 ADP receptor–mediated
doses should be tapered over 2 weeks. Beta blockers with relative platelet aggregation. It provides benefits similar to those of aspirin in
β1-receptor specificity such as metoprolol and atenolol may be patients with stable chronic IHD and may be substituted for aspirin
preferable in patients with mild bronchial obstruction and insulin- if aspirin causes the side effects listed above. Clopidogrel combined
requiring diabetes mellitus. with aspirin reduces death and coronary ischemic events in patients
Calcium Channel Blockers Calcium channel blockers (Table 267-6) with an acute coronary syndrome (Chap. 268) and also reduces the
are coronary vasodilators that produce variable and dose- risk of thrombus formation in patients undergoing implantation
dependent reductions in myocardial oxygen demand, contractility, of a stent in a coronary artery (Chap. 270). Alternative antiplatelet
and arterial pressure. These combined pharmacologic effects are agents that block the P2Y12 platelet receptor such as prasugrel and
advantageous and make these agents as effective as beta block- ticagrelor have been shown to be more effective than clopidogrel
ers in the treatment of angina pectoris. They are indicated when for prevention of ischemic events after placement of a stent for an
beta blockers are contraindicated, poorly tolerated, or ineffective. acute coronary syndrome, but are associated with an increased risk

1862 TABLE 267-7 Antianginal Agents
AGENT COMMON SIDE EFFECTS CONTRAINDICATIONS POTENTIAL DRUG INTERACTIONS
Agents That Have a Physiological Effect
Short-acting and long-acting nitrates Headache, flushing, hypotension, Hypertrophic obstructive Phosphodiesterase type 5 inhibitors
syncope and postural hypotension, cardiomyopathy (sildenafil and similar agents), beta-
PART 6
reflex tachycardia, methemoglobinemia adrenergic blockers, calcium-channel

blockers
Beta blockers Fatigue, depression, bradycardia, Low heart rate or heart conduction Heart-rate-lowering calcium-channel
heart block, bronchospasm, peripheral disorder, cardiogenic shock, asthma, blockers, sinus-node or AV conduction
vasoconstriction, postural hypotension, severe peripheral vascular disease, depressors
impotence, masked signs of decompensated heart failure,

hypoglycemia vasospastic angina; use with caution
in patients with COPD (cardio-selective
beta blockers may be used if patient
receives adequate treatment with long-
acting beta agonists)
Calcium-channel blockers
Heart-rate-lowering agents Bradycardia, heart conduction defect, Cardiogenic shock, severe aortic CYP3A4 substrates (digoxin,
low ejection fraction, constipation, stenosis, obstructive cardiomyopathy simvastatin, cyclosporine)
gingival hyperplasia
Dihydropyridine Headache, ankle swelling fatigue, Low heart rate or heart rhythm Agents with cardiodepressant effects
flushing, reflex tachycardia disorder, sick sinus syndrome, (beta-blockers, flecainide), CYP3A4
congestive heart failure, low blood substrates
pressure
Agents That Affect Myocardial Metabolism
Ranolazine Dizziness, constipation, nausea, Liver cirrhosis CYP3A4 substrates (digoxin,
QT-interval prolongation simvastatin, cyclosporine), drugs that
prolong the corrected QT interval
Abbreviations: COPD, chronic obstructive pulmonary disease; CYP3A4, cytochrome P-450 3A4.
Source: Data from SE Husted: Lancet 386:691, 2015 and EM Ohman: N Engl J Med 374:1167, 2016.
of bleeding. Although combined treatment with clopidogrel and NSAID associated with the lowest risk of cardiovascular events, in
aspirin for at least a year is recommended in patients with an acute the lowest dose required, and for the shortest period of time.
coronary syndrome treated with implantation of a drug-eluting Another class of agents opens ATP-sensitive potassium channels
stent, studies have not shown any benefit from the routine addition in myocytes, leading to a reduction of free intracellular calcium ions.
of clopidogrel to aspirin in patients with chronic stable IHD. The major drug in this class is nicorandil, which typically is adminis-
tered orally in a dose of 20 mg twice daily for prevention of angina.
OTHER THERAPIES (Nicorandil is not available for use in the United States but is used
The ACE inhibitors are widely used in the treatment of survivors of in several other countries.)
myocardial infarction, patients with hypertension or chronic IHD Ivabradine (2.5–7.5 mg orally twice daily) is a specific sinus
including angina pectoris, and those at high risk of vascular diseases node inhibiting agent that may be helpful for preventing cardio-
such as diabetes. The benefits of ACE inhibitors are most evident in vascular events in patients with IHD who have a resting heart rate
IHD patients at increased risk, especially if diabetes mellitus or left ≥70 beats/min (alone or in combination with a beta blocker) and
ventricle dysfunction is present, and those who have not achieved LV systolic dysfunction. It does not appear to offer any benefit in
adequate control of blood pressure and LDL cholesterol on beta patients with IHD but who do not have clinical heart failure.
blockers and statins. However, the routine administration of ACE
Angina and Heart Failure Transient LV failure with angina can
inhibitors to IHD patients who have normal LV function and have
be controlled by the use of nitrates. For patients with established
achieved blood pressure and LDL goals on other therapies does not
congestive heart failure, the increased LV wall tension raises myo-
reduce the incidence of events and therefore is not cost-effective.
cardial oxygen demand. Treatment of congestive heart failure with
Despite treatment with nitrates, beta blockers, or calcium channel
an ACE inhibitor, a diuretic, and digoxin (Chap. 252) reduces heart
blockers, some patients with IHD continue to experience angina,
size, wall tension, and myocardial oxygen demand, which helps
and additional medical therapy is now available to alleviate their
control angina and ischemia. If the symptoms and signs of heart
symptoms. Ranolazine, a piperazine derivative, may be useful for
failure are controlled, an effort should be made to use beta blockers
patients with chronic angina despite standard medical therapy (see
not only for angina but because trials in heart failure have shown
Table 267-7). Its antianginal action is believed to occur via inhibition
significant improvement in survival. A trial of the intravenous ultra-
of the late inward sodium current (INa). The benefits of INa inhibition
include limitation of the Na overload of ischemic myocytes and short-acting beta blocker esmolol may be useful to establish the
prevention of Ca2+ overload via the Na+–Ca2+ exchanger. A dose of safety of beta blockade in selected patients. Nocturnal angina often
500–1000 mg orally twice daily is usually well tolerated. Ranolazine can be relieved by the treatment of heart failure.
is contraindicated in patients with hepatic impairment or with The combination of congestive heart failure and angina in
conditions or drugs associated with QTc prolongation and when patients with IHD usually indicates a poor prognosis and war-
drugs that inhibit the CYP3A metabolic system (e.g., ketoconazole, rants serious consideration of cardiac catheterization and coronary
diltiazem, verapamil, macrolide antibiotics, HIV protease inhibitors, revascularization.
and large quantities of grapefruit juice) are being used.
Nonsteroidal anti-inflammatory drug (NSAID) use in patients CORONARY REVASCULARIZATION
with IHD may be associated with a small but finite increased risk of Clinical trials have confirmed that with the initial diagnosis of stable
myocardial infarction and mortality. For this reason, they generally IHD, it is first appropriate to initiate a medical regimen as described
should be avoided in IHD patients. If they are required for symptom above. Revascularization should be considered in the presence of
relief, it is advisable to coadminister aspirin and strive to use an unstable phases of the disease, intractable symptoms, severe ischemia

or high-risk coronary anatomy, diabetes, and impaired LV function. PCI is more effective than medical therapy for the relief of angina. PCI 1863
Revascularization should be employed in conjunction with but not replace the improves outcomes in patients with unstable angina or when used
continuing need to modify risk factors and assess medical therapy. An algo- early in the course of myocardial infarction with and without cardio-
rithm for integrating medical therapy and revascularization options in genic shock. However, in patients with stable exertional angina, clinical
patients with IHD is shown in Fig. 267-4. trials have confirmed that PCI does not reduce the occurrence of death

or myocardial infarction compared to optimum medical therapy. PCI
■■PERCUTANEOUS CORONARY INTERVENTION can be used to treat stenoses in native coronary arteries as well as in
(See also Chap. 270) PCI involving balloon dilatation usually accompa- bypass grafts in patients who have recurrent angina after CABG.
nied by coronary stenting is widely used to achieve revascularization
of the myocardium in patients with symptomatic IHD and suitable Risks When coronary stenoses are discrete and symmetric, two and
stenoses of epicardial coronary arteries. Whereas patients with steno- even three vessels can be treated in sequence. However, case selection
sis of the left main coronary artery and those with three-vessel IHD is essential to avoid a prohibitive risk of complications, which are usu-
(especially with diabetes and/or impaired LV function) who require ally due to dissection or thrombosis with vessel occlusion, uncontrolled
revascularization are best treated with CABG, PCI is widely employed ischemia, and ventricular failure (Chap. 270). Oral aspirin, a P2Y12
in patients with symptoms and evidence of ischemia due to stenoses antagonist, and an antithrombin agent are given to reduce coronary
of one or two vessels and even in selected patients with three-vessel thrombus formation. Left main coronary artery stenosis generally is
disease (and, perhaps, in some patients with left main disease) and may regarded as a lesion that should be treated with CABG. In selected
offer many advantages over surgery. cases such as patients with prohibitive surgical risks, PCI of an unpro-
tected left main can be considered, but such a procedure should be
Indications and Patient Selection The most common clinical performed only by a highly skilled operator; importantly, there are
indication for PCI is symptom-limiting angina pectoris, despite medi- regional differences in the use of this approach internationally.
cal therapy, accompanied by evidence of ischemia during a stress test.
Efficacy Primary success, i.e., adequate dilation (an increase in
luminal diameter >20% to a residual diameter obstruction <50%) with
relief of angina, is achieved in >95% of cases. Recurrent stenosis of the
MANAGEMENT OF THE PATIENT WITH IHD dilated vessels occurs in ~20% of cases within 6 months of PCI with
bare metal stents, and angina will recur within 6 months in 10% of
Initiate medical therapy:
1. Decrease demand ischemia cases. Restenosis is more common in patients with diabetes mellitus,
2. Minimize IHD risk factors arteries with small caliber, incomplete dilation of the stenosis, long
3. ASA (clopidogrel if ASA intolerant) stents, occluded vessels, obstructed vein grafts, dilation of the left
anterior descending coronary artery, and stenoses containing thrombi.
In diseased vein grafts, procedural success has been improved by the
Any high-risk features? use of capture devices or filters that prevent embolization, ischemia,
Low exercise capacity or ischemia at low workload, large and infarction.
area of ischemic myocardium, EF <40%, ACS presentation It is usual clinical practice to administer aspirin indefinitely and a
P2Y12 antagonist for 1–3 months after the implantation of a bare metal
stent. Although aspirin in combination with a thienopyridine may help
No Yes
prevent coronary thrombosis during and shortly after PCI with stent-
ing, there is no evidence that these medications reduce the incidence
of restenosis.
Are exertional Refer for coronary The use of drug-eluting stents that locally deliver antiproliferative
symptoms controlled? arteriography drugs can reduce restenosis to much less than 10%. Advances in PCI,
especially the availability of drug-eluting stents, have vastly extended
Anatomy suitable the use of this revascularization option in patients with IHD. Of note,
Yes No for revascularization? however, the delayed endothelial healing in the region of a drug-eluting
stent also extends the period during which the patient is at risk for
subacute stent thrombosis. Aspirin administered indefinitely and a
Yes No
P2Y12 antagonist daily (dual antiplatelet therapy [DAPT]) for at least
1 year after implantation of a drug-eluting stent. Evidence exists of a
benefit of continuing DAPT for up to 30 months, albeit at the cost of
a higher risk of bleeding. When a situation arises in which temporary
Single vessel LM +/or multi Consider discontinuation of antiplatelet therapy is necessary, the clinical circum-
disease vessel disease unconventional stances should be reviewed with the operator who performed the PCI
treatments
and a coordinated plan should be established for minimizing the risk
of late stent thrombus; central to this plan is the discontinuation of
Assess:
PCI antiplatelet therapy for the shortest acceptable period. The risk of stent
PCI vs CABG
thrombosis is dependent on stent size and length, complexity of the
lesions, age, diabetes, and technique. However, compliance with DAPT
Continue medical therapy periodic stress assessment and individual responsiveness to platelet inhibition are very important
(see Fig. 267-3) factors as well.
Successful PCI produces effective relief of angina in >95% of cases.
FIGURE 267-4 Algorithm for management of a patient with ischemic heart The majority of patients with symptomatic IHD who require revascu-
disease. All patients should receive the core elements of medical therapy as larization can be treated initially by PCI. Successful PCI is less invasive
shown at the top of the algorithm. If high-risk features are present, as established and expensive than CABG and permits savings in the initial cost of
by the clinical history, exercise test data, and imaging studies, the patient should care. Successful PCI avoids the risk of stroke associated with CABG
be referred for coronary arteriography. Based on the number and location of the surgery, allows earlier return to work, and allows the resumption of
diseased vessels and their suitability for revascularization, the patient is treated
with a percutaneous coronary intervention (PCI) or coronary artery bypass graft an active life. However, the early health-related and economic benefit
(CABG) surgery or should be considered for unconventional treatments. See text of PCI is reduced over time because of the greater need for follow-up
for further discussion. ACS, acute coronary syndrome; ASA, aspirin; EF, ejection and the increased need for repeat procedures. When directly compared
fraction; IHD, ischemic heart disease; LM, left main. in patients with diabetes or three-vessel or left main CAD, CABG was

1864 superior to PCI in preventing major adverse cardiac or cerebrovascular life and has severe stenoses of two or three epicardial coronary arteries
events over a 12-month follow-up. with objective evidence of myocardial ischemia as a cause of the chest
discomfort. Congestive heart failure and/or LV dysfunction, advanced
■■CORONARY ARTERY BYPASS GRAFTING age (>80 years), reoperation, urgent need for surgery, and the presence
Anastomosis of one or both of the internal mammary arteries or a of diabetes mellitus are all associated with a higher perioperative mor-
radial artery to the coronary artery distal to the obstructive lesion is tality rate.
PART 6
the preferred procedure. For additional obstructions that cannot be LV dysfunction can be due to noncontractile or hypocontractile
bypassed by an artery, a section of a vein (usually the saphenous) is segments that are viable but are chronically ischemic (hibernating myo-
used to form a venous bypass conduit between the aorta and the coro- cardium). As a consequence of chronic reduction in myocardial blood
nary artery distal to the obstructive lesion. flow, these segments downregulate their contractile function. They can
Although some indications for CABG are controversial, certain areas
be detected by using radionuclide scans of myocardial perfusion and

of agreement exist: metabolism, PET, cardiac MRI, or delayed scanning with thallium-201
or by improvement of regional functional impairment provoked by
1. The operation is relatively safe, with mortality rates <1% in patients
low-dose dobutamine. In such patients, revascularization improves
without serious comorbid disease and normal LV function and
myocardial blood flow, can return function, and can improve survival.
when the procedure is performed by an experienced surgical team.
2. Intraoperative and postoperative mortality rates increase with the The Choice Between PCI and CABG All the clinical character-
severity of ventricular dysfunction, comorbidities, age >80 years, istics of each individual patient must be used to decide on the method
and lack of surgical experience. The effectiveness and risk of CABG of revascularization (e.g., LV function, diabetes, lesion complexity). A
vary widely depending on case selection and the skill and experi- number of randomized clinical trials have compared PCI and CABG in
ence of the surgical team. patients with multivessel CAD who were suitable technically for both
3. Occlusion of venous grafts is observed in 10–20% of patients during procedures. The redevelopment of angina requiring repeat coronary
the first postoperative year and in ~2% per year during 5- to 7-year angiography and repeat revascularization is higher with PCI. This is
follow-up and 4% per year thereafter. Long-term patency rates a result of restenosis in the stented segment (a problem largely solved
are considerably higher for internal mammary and radial artery with drug-eluting stents) and the development of new stenoses in
implantations than for saphenous vein grafts. In patients with left unstented portions of the coronary vasculature. It has been argued that
anterior descending coronary artery obstruction, survival is better PCI with stenting focuses on culprit lesions, whereas a bypass graft to
when coronary bypass involves the internal mammary artery rather the target vessel also provides a conduit around future culprit lesions
than a saphenous vein. Graft patency and outcomes are improved proximal to the anastomosis of the graft to the native vessel (Fig. 267-5).
by meticulous treatment of risk factors, particularly dyslipidemia. By contrast, stroke rates are lower with PCI.
4. Angina is abolished or greatly reduced in ~90% of patients after Based on available evidence, it is now recommended that patients
complete revascularization. Although this usually is associated with with an unacceptable level of angina despite optimal medical man-
graft patency and restoration of blood flow, the pain may also have agement be considered for coronary revascularization. Patients with
been alleviated as a result of infarction of the ischemic segment or a single- or two-vessel disease with normal LV function and anatomically
placebo effect. Within 3 years, angina recurs in about one-fourth of suitable lesions ordinarily are advised to undergo PCI (Chap. 270).
patients but is rarely severe. Patients with three-vessel disease (or two-vessel disease that includes
5. Survival may be improved by operation in patients with stenosis the proximal left descending coronary artery) and impaired global LV
of the left main coronary artery as well as in patients with three- or function (LV ejection fraction <50%) or diabetes mellitus and those
two-vessel disease with significant obstruction of the proximal left with left main CAD or other lesions unsuitable for catheter-based
anterior descending coronary artery. The survival benefit is greater procedures should be considered for CABG as the initial method of
in patients with abnormal LV function (ejection fraction <50%). revascularization. In light of the complexity of the decision-making, it
Survival may also be improved in the following patients: (a) patients is desirable to have a multidisciplinary team, including a cardiologist
with obstructive CAD who have survived sudden cardiac death or and a cardiac surgeon in conjunction with the patient’s primary care
sustained ventricular tachycardia; (b) patients who have undergone physician, provide input along with ascertaining the patient’s prefer-
previous CABG and have multiple saphenous vein graft stenoses, ences before committing to a particular revascularization option.
especially of a graft supplying the left anterior descending coronary
artery; and (c) patients with recurrent stenosis after PCI and high- ■■UNCONVENTIONAL TREATMENTS FOR IHD
risk criteria on noninvasive testing. On occasion clinicians will encounter a patient who has persistent
6. Minimally invasive CABG through a small thoracotomy and/or off- disabling angina despite maximally tolerated medical therapy and for
pump surgery can reduce morbidity and shorten convalescence in whom revascularization is not an option (e.g., small diffusely diseased
suitable patients but does not appear to reduce significantly the risk vessels not amenable to stent implantation or acceptable targets for
of neurocognitive dysfunction postoperatively. bypass grafting). In such situations, unconventional treatments should
7. Among patients with type 2 diabetes mellitus and multivessel be considered.
coronary disease, CABG surgery plus optimal medical therapy Enhanced external counterpulsation utilizes pneumatic cuffs on the
is superior to optimal medical therapy alone in preventing major lower extremities to provide diastolic augmentation and systolic
cardiovascular events, a benefit mediated largely by a significant unloading of blood pressure to decrease cardiac work and oxygen
reduction in nonfatal myocardial infarction. The benefits of CABG consumption while enhancing coronary blood flow. Clinical trials have
are especially evident in diabetic patients treated with an insulin- shown that regular application improves angina, exercise capacity, and
sensitizing strategy as opposed to an insulin-providing strategy. regional myocardial perfusion. Experimental approaches, such as stem
cell therapies and cardiac repair with small non-coding RNA molecules
CABG has also been shown to be superior to PCI (including the use
(miRNA), are also under active study.
of drug-eluting stents) in preventing death, myocardial infarction,
and repeat revascularization in patients with diabetes mellitus and
multivessel IHD.
ASYMPTOMATIC (SILENT) ISCHEMIA
Obstructive CAD, acute myocardial infarction, and transient myo-
Indications for CABG usually are based on the severity of symp- cardial ischemia are frequently asymptomatic. During continuous
toms, coronary anatomy, and ventricular function. The ideal candidate ambulatory ECG monitoring, the majority of ambulatory patients with
is male, <80 years of age, has no other complicating disease, and has typical chronic stable angina are found to have objective evidence
troublesome or disabling angina that is not adequately controlled by of myocardial ischemia (ST-segment depression) during episodes of
medical therapy or does not tolerate medical therapy. Great symptom- chest discomfort while they are active outside the hospital. In addi-
atic benefit can be anticipated if a patient wishes to lead a more active tion, many of these patients also have more frequent episodes of

PCI 1865

Stent Lesion
Coronary CABG
artery
Future
A culprit
lesion
Lesion
Bypass
graft
Future
culprit
lesion
B
FIGURE 267-5 Difference in the approach to the lesion with percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG). PCI is targeted at
the “culprit” lesion or lesions, whereas CABG is directed at the epicardial vessel, including the culprit lesion or lesions and future culprits, proximal to the insertion of
the vein graft, a difference that may account for the superiority of CABG, at least in the intermediate term, in patients with multivessel disease. (Reproduced from BJ
Gersh, RL Frye: N Engl J Med 352:2235, 2005.)
asymptomatic ischemia. Frequent episodes of ischemia (symptomatic the most appropriate approach in the large majority of patients for
and asymptomatic) during daily life appear to be associated with an whom the situation is less extreme. Asymptomatic patients with
increased likelihood of adverse coronary events (death and myocardial silent ischemia, three-vessel CAD, and impaired LV function may be
infarction). In addition, patients with asymptomatic ischemia after a considered appropriate candidates for CABG.
myocardial infarction are at greater risk for a second coronary event. The treatment of risk factors, particularly lipid lowering and
The widespread use of exercise ECG during routine examinations blood pressure control as described above, and the use of aspirin,
has also identified some of these previously unrecognized patients statins, and beta blockers after infarction have been shown to reduce
with asymptomatic CAD. Longitudinal studies have demonstrated an events and improve outcomes in asymptomatic as well as symp-
increased incidence of coronary events in asymptomatic patients with tomatic patients with ischemia and proven CAD. Although the inci-
positive exercise tests. dence of asymptomatic ischemia can be reduced by treatment with
beta blockers, calcium channel blockers, and long-acting nitrates, it
is not clear whether this is necessary or desirable in patients who
TREATMENT have not had a myocardial infarction.
Asymptomatic Ischemia
■■FURTHER READING
The management of patients with asymptomatic ischemia must be De Bruyne B et al: Microvascular (dys)function and clinical outcome in
individualized. When coronary disease has been confirmed, the stable coronary disease. J Am Coll Cardiol 67:1170, 2016.
aggressive treatment of hypertension and dyslipidemia is essential Fihn SD et al: 2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS
and will decrease the risk of infarction and death. In addition, the guideline for the diagnosis and management of patients with stable
physician should consider the following: (1) the degree of positivity of ischemic heart disease: A report of the American College of Cardiol-
the stress test, particularly the stage of exercise at which ECG signs ogy Foundation/American Heart Association task force on practice
of ischemia appear; the magnitude and number of the ischemic zones guidelines, and the American College of Physicians, American Asso-
of myocardium on imaging; and the change in LV ejection fraction ciation for Thoracic Surgery, Preventive Cardiovascular Nurses Asso-
that occurs on radionuclide ventriculography or echocardiography ciation, Society for Cardiovascular Angiography and Interventions,
during ischemia and/or during exercise; (2) the ECG leads showing a and Society of Thoracic Surgeons. Circulation 126:e354, 2012.
positive response, with changes in the anterior precordial leads indi- Levine GN et al: 2016 ACC/AHA guideline focused update on dura-
cating a less favorable prognosis than changes in the inferior leads; tion of dual antiplatelet therapy in patients with coronary artery
and (3) the patient’s age, occupation, and general medical condition. disease: A Report of the American College of Cardiology/American
Most would agree that an asymptomatic 45-year-old commercial Heart Association Task Force on Clinical Practice Guidelines: An
airline pilot with significant (0.4-mV) ST-segment depression in Update of the 2011 ACCF/AHA/SCAI Guideline for Percutaneous
leads V1 to V4 during mild exercise should undergo coronary arte- Coronary Intervention, 2011 ACCF/AHA Guideline for Coronary
riography, whereas an asymptomatic, sedentary 85-year-old retiree Artery Bypass Graft Surgery, 2012 ACC/AHA/ACP/AATS/PCNA/
with 0.1-mV ST-segment depression in leads II and III during SCAI/STS Guideline for the Diagnosis and Management of Patients
maximal activity need not. However, there is no consensus about with Stable Ischemic Heart Disease, 2013 ACCF/AHA Guideline

1866 for the Management of ST-Elevation Myocardial Infarction, 2014 (NSTEMI), who, by definition, have evidence of myocyte necrosis, and
AHA/ACC Guideline for the Management of Patients with Non-ST- those with unstable angina (UA), who do not (Fig. 268-1).
Elevation Acute Coronary Syndromes, and 2014 ACC/AHA Guide- The relative incidence of NSTEMI is rising due to the increasing
line on Perioperative Cardiovascular Evaluation and Management of burden of diabetes and chronic kidney disease in an aging population,
Patients Undergoing Noncardiac Surgery. Circulation 134:e123, 2016. while STEMI is declining due to greater use of aspirin, statins, and
Mody P et al: Antianginal agents for the management of stable ischemic less smoking. Among patients with NSTE-ACS, the proportion with
PART 6
heart disease: A review. Cardiol Rev 24:177, 2016. NSTEMI is rising while that with UA is falling because of the wider use
Mozaffarian D et al: Heart disease and stroke statistics—2016 of troponin assays with higher sensitivity to detect myocyte necrosis,
update: A report from the American Heart Association. Circulation thereby reclassifying UA as NSTEMI.
2016;133:e38, 2016.
Omland T, White HD: State of the art: Blood biomarkers for risk strat- ■■PATHOPHYSIOLOGY
ification in patients with stable ischemic heart disease. Clin Chem NSTE-ACS is caused by an imbalance between myocardial oxygen
63:165, 2017. supply and demand resulting from one or more of the following
Singh M, Arora R: Newer therapies for management of stable four processes that lead to thrombus formation : (1) disruption of an
ischemic heart disease with focus on refractory angina. Am J Ther unstable coronary plaque due to plaque rupture, erosion, or a calcified
23:e1842, 2016. protruding nodule that leads to intracoronary thrombus formation
(Fig. 268-2) and an inflammatory response; (2) coronary arterial vaso-
constriction; (3) gradual intraluminal narrowing; and (4) increased
myocardial oxygen demand produced by conditions such as fever,
tachycardia, and thyrotoxicosis in the presence of fixed epicardial
268 Non-ST-Segment Elevation coronary obstruction. While plaque rupture remains the most common
etiology of coronary thrombosis, erosion of an intracoronary plaque is
Acute Coronary Syndrome increasing in frequency, perhaps related to the above mentioned shifts
in the underlying risk factors for ACS.
(Non-ST-Segment Elevation Among patients with NSTE-ACS studied at angiography, ~10%
Myocardial Infarction and have stenosis of the left main coronary artery, 35% have three-vessel
CAD, 20% have two-vessel disease, 20% have single-vessel disease,
Unstable Angina) and 15% have no apparent critical epicardial coronary artery stenosis;
some of the latter may have obstruction of the coronary microcircula-
Robert P. Giugliano, Christopher P. Cannon, tion and/or spasm of the epicardial vessels. The so-called “vulnerable
Eugene Braunwald plaques” responsible for ischemia may show an eccentric stenosis with
scalloped or overhanging edges and a narrow neck on coronary angi-
ography. Vulnerable plaques are composed of a lipid-rich core with a
thin fibrous cap. Patients with NSTE-ACS frequently have multiple
Patients with acute coronary syndrome (ACS) commonly are classified
such plaques that are at risk of disruption.
into two groups to facilitate evaluation and management, namely patients
with acute myocardial infarction with ST-segment elevation (STEMI) on
■■CLINICAL PRESENTATION
their presenting electrocardiogram (ECG) (Chap. 269) and those with non-
ST-segment elevation acute coronary syndrome (NSTE-ACS). The latter Diagnosis The diagnosis of NSTE-ACS is based largely on the clin-
include patients with non-ST-segment elevation myocardial infarction ical presentation (Fig. 268-3).
Low likelihood High likelihood
1. Presentation
2. ECG
3. Troponin
4. Diagnosis Non-cardiac UA Other NSTEMI STEMI

cardiac
FIGURE 268-1 Assessment of patients with suspected acute coronary syndromes. The initial assessment is based on the integration of low-likelihood and/or high-
likelihood features derived from clinical presentation (i.e., symptoms, vital signs), 12-lead electrocardiogram and cardiac troponin. The proportion of the final diagnoses
derived from the integration of these parameters is visualized by the size of the respective boxes. (From Roffi M et al: 2015 European Society of Cardiology Guidelines
for the management of acute coronary syndromes. Eur Heart J 37:267, 2016.)

1867
Thrombus Plaque rupture
CHAPTER 268 Non-ST-Segment Elevation Acute Coronary Syndrome (Non-ST-Segment Elevation Myocardial Infarction and Unstable Angina)
*
*
A B
Plaque erosion Calcified nodule
*
*
C D
FIGURE 268-2 Intracoronary thrombosis and the three most common plaque morphologies resulting in acute coronary syndrome as visualized by optical coherence
tomography. A. Thrombus (arrow) is identified as a protruding mass attached to the arterial wall. B. Plaque rupture is identified as lipid plaque with fibrous cap
discontinuity (arrow) and cavity formation inside the plaque. C. Plaque erosion is confirmed by the presence of attached thrombus (arrows) overlying an intact and
visualized plaque. D. Calcified nodule appears on optical coherence tomography as a site with fibrous cap disruption (dotted arrow) and underlying plaque characterized
by protruding calcification, superficial calcium, and significant calcium adjacent to the lesion (arrows). The asterisks denote guidewire shadow artifact. (Modified from H
Jia et al: J Am Coll Cardiol 62:1748, 2013 and I Jang, D Ong: Optical coherence tomography and other emerging diagnostic procedures for vulnerable plaque, in D Morrow
(ed): Myocardial Infarction: A Companion to Braunwald’s Heart Disease. Philadelphia, Elsevier Health Sciences, 2017.)
Symptoms suggestive of ACS
Noncardiac diagnosis Chronic stable angina Possible ACS Definite ACS
Treatment as indicated See Chap. 267 No ST-segment ST-segment

by alternative diagnosis elevation elevation
Observe 12 h or more Nondiagnostic ECG ST- and/or T-

from symptom onset Normal initial cTn wave changes
Ongoing pain
or elevated cTn
No recurrent pain; Recurrent ischemic pain or Hemodynamic
negative positive follow-up studies abnormalities
follow-up studies Diagnosis of ACS confirmed
Stress study to provoke ischemia See Chap. 269

Consider evaluation of LV function
if ischemia is present
Negative Positive Admit to hospital

Potential diagnoses: nonischemic Diagnosis of ACS confirmed or Manage via acute
discomfort; low-risk ACS highly likely ischemia pathway
Outpatient follow-up
FIGURE 268-3 Algorithm for evaluation and management of patients with suspected acute coronary syndrome (ACS). Follow-up studies refer to ST deviation and
elevation of troponin levels. cTn, cardiac troponin; ECG, electrocardiogram; LV, left ventricular. (Modified from J Anderson et al: J Am Coll Cardiol 61:e179, 2013.)

1868 History and Physical Examination Typically, chest discom- ■■DIAGNOSTIC EVALUATION
fort is severe and has at least one of three features: (1) occurrence In addition to the clinical examination, three major noninvasive tools
at rest (or with minimal exertion), lasting >10 min; (2) of relatively are used in the evaluation of NSTEMI-ACS: the ECG, cardiac biomark-
recent onset (i.e., within the prior 2 weeks); and/or (3) a crescendo ers, and stress testing. In equivocal cases, coronary computed tomo-
pattern, i.e., distinctly more severe, prolonged, or frequent than pre- graphic angiography (CCTA) may be useful to improve the accuracy
vious episodes. The diagnosis of NSTEMI is established if a patient and speed of the diagnostic evaluation. The goals are to: (1) recognize
PART 6
with any of these features (without electrocardiographic ST segment or exclude myocardial infarction (MI) using cardiac biomarkers, pref-
elevations) develops evidence of myocardial necrosis, as reflected erably cTn; (2) detect rest ischemia (using serial or continuous ECGs);
in abnormally elevated levels of biomarkers (see below). The chest and (3) detect significant coronary obstruction at rest with CCTA and/
discomfort is typically located in the substernal region and radiates or myocardial ischemia using stress testing (Chap. 236).
to the left arm, left shoulder, and/or superiorly to the neck and jaw. Patients with a low likelihood of ischemia are usually managed in
Anginal equivalents such as dyspnea, epigastric discomfort, nausea, an emergency department or a dedicated “chest pain unit” follow-
or weakness may occur instead of chest discomfort. They appear to ing a critical pathway. Evaluation of such patients includes clinical
be more frequent in women, the elderly, and patients with diabetes monitoring for recurrent ischemic discomfort and continuous mon-
mellitus. The physical examination resembles that in patients with itoring of ECGs and cardiac markers, typically obtained at baseline
stable angina (Chap. 267) and may be unremarkable. However, if the and at 4–6 h and 12 h after presentation. If new elevations in cardiac
patient has a large area of myocardial ischemia or a large NSTEMI, markers or ST-T-wave changes on the ECG are noted, the patient
the physical findings can include diaphoresis; pale, cool skin; sinus should be admitted to the hospital. Patients who remain pain-free
tachycardia; a third and/or fourth heart sound; basilar rales; and, with negative markers may proceed to stress testing to determine the
sometimes, hypotension. presence of ischemia or CCTA to detect coronary luminal obstruction
(Fig. 268-3).
Electrocardiogram New ST-segment depression occurs in about The hs cTn assays permit a more rapid (3-h and even 1-h) rule-out
one-third of patients with NSTE-ACS. It may be transient but may MI determination and have been adopted by the 2015 European Guide-
persist for several days following NSTEMI. T-wave changes are more lines for the management of NSTE-ACS.
common but are less specific signs of ischemia, unless they are new and
deep T-wave inversions (≥0.3 mV). ■■RISK STRATIFICATION
Patients with documented NSTE-ACS exhibit a wide spectrum of early
Cardiac Biomarkers Patients with NSTEMI have elevated
(30 days) risk of death, ranging from 1 to 10%, and a recurrent ACS rate
biomarkers of necrosis, such as cardiac troponin (cTn) I or T, which are
of 5–15% during the first year. Assessment of risk can be accomplished
specific, sensitive, and the preferred markers of myocardial necrosis.
by clinical risk scoring systems such as that developed from the Throm-
The MB isoform of creatine kinase (CK-MB) is a less sensitive alter-
bolysis in Myocardial Infarction (TIMI) Trials, which includes seven
native. Elevated levels of any of these markers distinguish patients
independent risk factors (age ≥ 65 years, 3 or more of the traditional
with NSTEMI from those with UA. There is a characteristic temporal
risk factors for coronary heart disease, known history of coronary
rise and fall peaking 12–24 h post onset of symptoms of the plasma
artery disease or coronary stenosis of at least 50%, daily aspirin use
concentration of these markers and a direct relationship between the
in the prior week, more than one anginal episode in the past 24 h,
degree of elevation and mortality. However, in patients without a clear
ST segment deviation of at least 0.5 mm, and an elevated cardiac spe-
clinical history of myocardial ischemia, minor cTn elevations have been
cific biomarker above the upper limit of normal). Additional risk factors
reported and can be caused by heart failure, myocarditis, or pulmonary
include diabetes mellitus, left ventricular dysfunction, renal dysfunc-
embolism, or with high-sensitivity assays (hs cTn) may be observed in
tion, and elevated levels of B-type natriuretic peptides. Multibiomarker
ostensibly normal subjects. Thus, in patients with an unclear history,
strategies are now gaining favor, both to define more fully the patho-
small elevations of cTn, especially if they are persistent, may not be
physiologic mechanisms underlying a given patient’s presentation and
diagnostic of an ACS. In such cases, both cardiac and non-cardiac
to stratify the patient’s risk further. Patients with ACS without elevated
causes of an elevated cTn should be considered (Table 268-1).
levels of cTn (infrequently encountered with the new sensitive troponin
assays) are considered to have UA and have a more favorable prognosis
TABLE 268-1 Causes of Elevated Cardiac Troponin Reflecting Direct than those with cTn elevations (NSTEMI).
Myocardial Damage Other Than Spontaneous Myocardial Infarction Early risk assessment is useful in identifying patients who would
(Type 1) derive the greatest benefit from an early invasive strategy (see below).
CARDIAC NON-CARDIAC OR SYSTEMIC For example, in the TACTICS-TIMI 18 Trial, an early invasive strategy
Tachyarrhythmias Pulmonary embolism/pulmonary
conferred a 40% reduction in recurrent cardiac events in patients with
hypertension an elevated cTn level, whereas no benefit was observed in those with-
Congestive heart failure Trauma (e.g., electrical shock, burns, out detectable troponin.
blunt chest wall)
Hypertensive emergencies Hypo or hyperthyroidism
TREATMENT
Infection/inflammation (e.g., Toxicity (e.g., anthracyclines, snake
myocarditis, pericarditis) venom) Non-ST-Segment Elevation Acute Coronary
Stress cardiomyopathy (Tako-Tsubo Renal failure Syndrome (Non-ST-Segment Elevation Myocardial
cardiomyopathy)
Structural heart disease (e.g., aortic Sepsis, shock Infarction and Unstable Angina)
stenosis)
Aortic dissection Stroke or other acute neurologic MEDICAL TREATMENT
event Patients should be placed at bed rest with continuous ECG moni-
Coronary spasm Extreme endurance efforts (e.g., toring for ST-segment deviation and cardiac arrhythmias, preferably
ultra-marathon) on a specialized cardiac unit. Ambulation is permitted if the patient
Cardiac procedures (endomyocardial Rhabdomyolysis shows no recurrence of ischemia (symptoms or ECG changes) and
biopsy, ablation, CABG, PCI) does not develop an elevation of a biomarker of necrosis for 12–24 h.
Infiltrative diseases (e.g., amyloidosis, Medical therapy consists of an acute phase focused on the clinical
hemochromatosis, malignancy) symptoms and stabilization of the culprit lesion(s) and a longer-term
Source: Data from LK Newby et al: J Am Coll Cardiol 60:2427, 2012 and M Roffi: phase that involves therapies directed at the prevention of disease
Eur Heart J 37:267, 2016. progression and future plaque rupture/erosion.

ANTI-ISCHEMIC TREATMENT (TABLE 268-2) of intensive HMG-CoA reductase inhibitors (statins), such as ator- 1869
To provide relief and prevention of recurrence of ischemic dis- vastatin 80 mg/d, prior to percutaneous coronary intervention
comfort, initial treatment should include bed rest, nitrates, beta (PCI), and continued thereafter, has been shown to reduce peri-
adrenergic blockers, and inhaled oxygen in patients with arterial O2 procedural MI and recurrences of ACS. In patients who do not
have an adequate response to maximally tolerated statin (i.e., <50%
saturation (<90%) and/or in those with heart failure and rales.
decrease in LDL-C from untreated baseline or LDL-C on treatment
Nitrates These should first be given sublingually or by buccal >70 mg/dL), addition of ezetimibe 10 mg daily to reduce further
spray (0.3–0.6 mg) if the patient is experiencing ischemic discomfort. the LDL-C has been shown to reduce future cardiovascular events.
If symptoms persists after three doses given 5 min apart, intrave-
nous nitroglycerin (5–10 μg/min using nonabsorbing tubing) is rec- ANTITHROMBOTIC THERAPY (FIG. 268-4 AND TABLE 268-3)
ommended. The rate of the infusion may be increased by 10 μg/min Antithrombotic therapy consisting of antiplatelet and anticoagulant
every 3–5 min until symptoms are relieved, systolic arterial pressure drugs represent the second major cornerstone of treatment.
falls to <90 mmHg, or the dose reaches 200 μg/min. Topical or oral Antiplatelet Drugs (See Chap. 114) Initial treatment should begin
nitrates (Chap. 267) can be used when the pain has resolved, or they with the cyclooxygenase inhibitor aspirin with a dose of at least
may replace intravenous nitroglycerin when the patient has been 162 mg of a rapidly acting preparation (oral non-enteric coated
symptom-free for 12–24 h. The only absolute contraindications to or intravenous). Lower doses (75–100 mg/d) are recommended
the use of nitrates are hypotension or the recent use of a phosphodi- thereafter, since they maintain efficacy while causing less bleeding.
esterase type 5 (PDE-5) inhibitor, sildenafil or vardenafil (within Contraindications are severe active bleeding or aspirin allergy.
24 h), or tadalafil (within 48 h). In the absence of a high risk for bleeding, patients with NSTE-
Beta-Adrenergic Blockers and Other Agents Beta blockers are the ACS, irrespective of whether an invasive or conservative strategy
other mainstay of anti-ischemic treatment. They may be started by (see below) is selected, also should receive a platelet P2Y12 receptor
the intravenous route in patients with severe ischemia, but should blocker to inhibit platelet activation. There are now four oral and
be avoided in the presence of acute or severe heart failure, low car- one intravenous P2Y12 inhibitors to choose from (although the first in
diac output, hypotension, or contraindications to beta-blocker ther- class, ticlopidine, is rarely used due to poor tolerability); advantages
apy (e.g., high-degree atrioventricular block, active bronchospasm). for each of the others are noted below.
Ordinarily, oral beta blockade targeted to a heart rate of 50–60 beats/ The thienopyridine clopidogrel is an inactive prodrug that is
min is recommended. Heart rate–slowing calcium channel block- converted into an active metabolite that causes irreversible blockade
ers, e.g., verapamil or diltiazem, are recommended for patients of the platelet P2Y12 receptor. The loading dose of clopidogrel is 600
who have persistent symptoms or ECG signs of ischemia after or 300 mg while the maintenance dose is 75 mg daily. When clopido-
treatment with full-dose nitrates and beta blockers and in patients grel is added to aspirin, so-called dual antiplatelet therapy (DAPT),
with contraindications to either class of these agents. Additional has been shown to confer a 20% relative reduction in cardiovascular
medical therapy includes angiotensin-converting enzyme (ACE) death, MI, or stroke, compared to aspirin alone, but to be associated
inhibitors or angiotensin receptor blockers. Early administration with a moderate (absolute 1%) increase in major bleeding.
TABLE 268-2 Drugs Commonly Used in Intensive Medical Management of Patients with Unstable Angina and Non-ST-Segment Elevation
Myocardial Infarction
DRUG CATEGORY CLINICAL CONDITION WHEN TO AVOIDa DOSAGE
Nitrates Patients with ACS who have chest Hypotension Initially administer via sublingual or buccal route, and,
discomfort or an anginal equivalent if symptoms persist, intravenously.
Right ventricular infarction Topical or oral nitrates are acceptable alternatives for
Severe aortic stenosis patients without ongoing or refractory symptoms
Patient receiving a PDE-5 inhibitor 5–10 μg/min by continuous infusion titrated up to
75–100 μg/min until relief of symptoms or limiting
side effects (headache or hypotension with a
systolic blood pressure <90 mmHg or >30% below
starting mean arterial pressure levels if significant
hypertension is present)
Beta blockersb All patients with ACS PR interval (ECG) >0.24 s Metoprolol 25–50 mg by mouth every 6 h
2° or 3° atrioventricular block If needed, and no heart failure, 5-mg increments by
Heart rate <50 beats/min slow (over 1–2 min) IV administration
Systolic pressure <90 mmHg
Shock
Left ventricular failure
Severe reactive airway disease
Calcium channel Patients whose symptoms are not Pulmonary edema Dependent on specific agent
blockers relieved by adequate doses of nitrates Evidence of left ventricular dysfunction
and beta blockers, or in patients (for diltiazem or verapamil)
unable to tolerate adequate doses
of one or both of these agents, or in
patients with variant angina
Morphine sulfate Patients whose symptoms are not Hypotension 2–5 mg IV dose
relieved after three serial sublingual Respiratory depression May be repeated every 5–30 min as needed to relieve
nitroglycerin tablets or whose symptoms and maintain patient comfort
Confusion
symptoms recur with adequate anti-
ischemic therapy Obtundation
a
Allergy or prior intolerance is a contraindication for all categories of drugs listed in this chart. bChoice of the specific agent is not as important as ensuring that
appropriate candidates receive this therapy.
Source: Modified from J Anderson et al: J Am Coll Cardiol 61:e179, 2013.

1870 Initial Treatment DAPT and Anticoagulant therapy:
1. Aspirin (COR I, LOE A).
2. P2Y 12 inhibitor: clopidogrel or ticagrelor (COR I, LOE B).
3. Anticoagulant:
Enoxaparin (COR I, LOE A) or UFH (COR l, LOE B) or fondaparinux (COR I, LOE B)
or bivalirudin (for early invasive strategy, COR I, LOE B).
PART 6
4. Can consider GP Ilb/llla receptor inhibitors in high-risk patients stratified to early invasive
strategy (eptifibatide or tirofiban; COR IIb, LOE B).
Medically treated patients: PCI treated patients:

During
Hospitalization 1. Aspirin (COR I, LOE A). 1. Aspirin (COR I. LOE A).
2. P2Y 12 inhibitor: either ticagrelor or 2. P2Y 12: inhibitor: clopidogrel or ticagrelor or prasugrel
clopidogrel (COR I, LOE B). (COR I, LOE B).
3. Anticoagulant: 3. Anticoagulant:
Enoxaparin (COR I, LOE A) or UFH Enoxaparin (COR I, LOE A) or UFH (COR l, LOE B)
(COR l, LOE B) or fondaparinux (COR I, or fondaparinux* (COR I, LOE B) or bivalirudin (COR I,
LOE B). LOE B).
4. Can consider GP Ilb/llla receptor inhibitors in high-
risk patients not adequately per-treated with
clopidogrel (COR I, LOE A) or in high-risk patients
adequately pre-treated with clopidogrel
(COR IIa, LOE B).
Long-term Medically treated patients: PCI treated patients:

1. Aspirin indefinitely (COR I, LOE A). 1. Aspirin indefinitely (COR I, LOE A).
2. P2Y 12 inhibitor: clopidogrel or ticagrelor 2. P2Y 12 inhibitor: clopidogrel or ticagrelor or prasugrel
for up to 12 months (COR I, LOE B) for at least 12 months (COR I, LOE B).
(*Supplemental UFH or bivalirudin is required during PCI to prevent procedure-related thrombosis in patients treated with fondaparinux.)
FIGURE 268-4 Antiplatelet and anticoagulation treatment summary for NSTE-ACS according to the 2014 American Heart Association/American College of
Cardiology Practice Guideline. COR, classes of recommendation; DAPT, dual antiplatelet therapy; GP IIb/IIIa, glycoprotein IIb/IIIa; LOE, levels of evidence; NSTE-ACS,
non-ST-segment elevation acute coronary syndrome; PCI, percutaneous coronary intervention; UFH, unfractionated heparin. (From A Eisen, RP Giugliano: Cardiol Rev
24;170, 2016.)
Two newer P2Y12 inhibitors (prasugrel, ticagrelor) have been found

TABLE 268-3 Clinical Use of Antithrombotic Therapy
to be superior to clopidogrel in preventing recurrent cardiac ischemic
Oral Antiplatelet Therapy events in randomized double-blind studies although both increase
Aspirin Initial dose of 325 mg nonenteric formulation followed by bleeding. Prasugrel, also a thienopyridine, achieves a more rapid
75–100 mg/d of an enteric or a nonenteric formulation onset and higher level of platelet inhibition than clopidogrel. It has
Clopidogrel Loading dose of 300–600 mg followed by 75 mg/d been approved for ACS patients following angiography when PCI
Prasugrel Pre-PCI: Loading dose 60 mg followed by 10 mg/d is planned. It should be administered at a loading dose of 60 mg
Ticagrelor Loading dose of 180 mg followed by 90 mg twice daily followed by 10 mg/d. Compared to clopidogrel, prasugrel was
Intravenous Antiplatelet Therapy shown to significantly reduce by 19% the combined risk of cardio-
vascular death, MI, or stroke, and reduced stent thrombosis by 50%.
Abciximab 0.25 mg/kg bolus followed by infusion of 0.125 μg/kg per
min (maximum 10 μg/min) for 12–24 h Prasugrel is contraindicated in patients with prior stroke or transient
ischemic attack or at high risk for bleeding. It has not been found to
Eptifibatide 180 μg/kg bolus followed 10 min later by second bolus
of 180 μg with infusion of 2.0 μg/kg per min for 72–96 h be effective in patients treated by a conservative strategy prior to
following first bolus coronary angiography (see below).
Tirofiban 25 μg/kg per min followed by infusion of 0.15 μg/kg per Ticagrelor is a novel, potent, reversible platelet P2Y12 inhibitor that
min for 48–96 h was shown to reduce the risk of cardiovascular death, total mortality
Cangrelor 30 μg/kg bolus followed immediately by a 4 μg/kg per min or MI compared to clopidogrel across a broad spectrum patients with
infusion ACS. After a loading dose of 180 mg, 90 mg bid is administered as main-
Anticoagulantsa tenance. Unlike prasugrel, ticagrelor demonstrated benefit whether
patients were managed conservatively or with an early invasive strat-
Unfractionated b
Bolus 70–100 U/kg (maximum 5000 U) IV followed by
heparin (UFH) infusion of 12–15 U/kg per h (initial maximum 1000 U/h) egy. Some patients may develop dyspnea early after administration
titrated to ACT 250–300 s of ticagrelor, although the symptoms are most often transient and
Enoxaparin 1 mg/kg SC every 12 h; the first dose may be preceded by infrequently serious, and are not associated with clinical exacerbations
a 30-mg IV bolus; renal adjustment to 1 mg/kg once daily of chronic obstructive pulmonary disease or congestive heart failure.
if creatine clearance <30 mL/min DAPT should continue for at least 1 year in patients with NSTE-
Fondaparinux 2.5 mg SC qd ACS, especially those with a drug-eluting stent, to prevent stent
Bivalirudin Initial IV bolus of 0.75 mg/kg and an infusion of thrombosis. Up to one-third of patients have an inadequate response
1.75 mg/kg per h to clopidogrel, and a substantial proportion of these cases are related
to a genetic variant of the cytochrome P450 system involving the 2C19
a
Other low-molecular-weight heparins have been studied other than enoxaparin;
however there are less data to support their use. bIf no glycoprotein IIb/IIIa gene that leads to reduced conversion of clopidogrel into its active
inhibitor planned. metabolite. Thus, alternate P2Y12 blockers should be considered in
Abbreviations: ACT, activated clotting time for HemoTec; IV, intravenous; SC, patients with NSTE-ACS who develop a coronary event while receiv-
subcutaneous. ing clopidogrel and aspirin, who are hyporesponsive to clopidogrel,
Source: Modified from J Anderson et al: J Am Coll Cardiol 61:e179, 2013. or are at high risk for ischemic complications. Clinicians should select

the antiplatelet regimen that provides the best balance of efficacy TABLE 268-4 Factors Associated with Appropriate Selection of Early 1871
and safety based on the individual patient characteristics and clinical Invasive Strategy or Ischemia-Guided Strategy in Patients with
scenario. NSTE-ACS
More recently, an intravenous, direct and rapidly acting, P2Y12 Immediate invasive Refractory angina
inhibitor, cangrelor, was evaluated in three large outcome studies in (within 2 h)
Signs or symptoms of heart failure or new or worsening
>25,000 patients undergoing PCI across a broad spectrum of clini- mitral regurgitation
cal presentations (stable angina, UA, NSTEMI, STEMI). Among the Hemodynamic instability
14,282 patients who underwent PCI following a NSTE-ACS, cangrelor Recurrent angina or ischemia at rest or with low-level
reduced the risk of the primary composite outcome of death, MI, activities despite intensive medical therapy
ischemia-driven revascularization, and stent thrombosis at 48 h by 18% Sustained ventricular tachycardia or ventricular fibrillation
relative to control. There was an excess of 3 per 1000 major bleeding Early invasive None of the above, but GRACEa risk score >140
events with cangrelor. This drug is approved as an adjunct to PCI for (within 24 h) Temporal change in troponin
reducing the risk of periprocedural MI, repeat coronary revasculariza-
New or presumably new ST segment depression
tion, and stent thrombosis in patients who have not been treated with
a P2Y12 platelet inhibitor and are not being given a GP IIb/III inhibitor. Delayed invasive None of the above but diabetes mellitus
(within 25–72 h) Renal insufficiency (eGFR <60 mL/min per 1.73 m2)
In the 1990s and early 2000s several trials had shown the benefit of
intravenous glycoprotein IIb/IIIa inhibitors in patients with NSTE- Reduced left ventricular systolic function (ejection
ACS, with the majority of studies performed without concomitant fraction <0.40)
P2Y12 inhibition. The benefits, however, were modest (i.e., an ~1% Early postinfarction angina
absolute reduction in death or MI at 30 day) and counterbalanced Percutaneous coronary intervention within 6 months prior
by a 1% absolute increase in the rate of major bleeding. Two recent Prior coronary artery bypass graft surgery
studies failed to show a benefit of routine early initiation of a drug GRACEa risk score 109–140 or TIMIb risk score ≥2
in this class compared with their use only in patients who undergo Ischemia-guided Low-risk score (e.g., TIMIb [0 or 1], GRACEa [<109])
PCI. The addition of these agents to aspirin and a P2Y12 inhibitor strategy Low-risk, troponin-negative female patients
(i.e., triple antiplatelet therapy) should be reserved for unstable
Patient or clinician preference in the absence of high-
patients undergoing PCI. These include patients with recurrent rest risk features
pain, elevated cTn, and ECG changes, as well as those who have a
coronary thrombus evident on angiography.
a
See CB Granger (Arch Intern Med 163:2345, 2003). bSee EM Antman (JAMA
284:835, 2000).
Anticoagulants (See Chap. 114) Four options are available for Abbreviations: eGFR, estimated glomerular filtration rate; GRACE, Global Registry
anticoagulant therapy to be added to antiplatelet agents: (1) unfrac- of Acute Coronary Events; TIMI, Thrombolysis in Myocardial Infarction.
tionated heparin (UFH), long the mainstay of therapy; (2) the Source: Modified from EA Amsterdam et al: J Am Coll Cardiol 64:e139, 2014.
low-molecular-weight heparin (LMWH), enoxaparin, which has
been shown to be superior to UFH in reducing recurrent cardiac ■■LONG-TERM MANAGEMENT
events, especially in patients managed by a conservative strategy. The time of hospital discharge is a “teachable moment” for the patient
However, it is accompanied by a slight increase in bleeding com- with NSTE-ACS, when the physician can review and optimize the
pared to UFH; (3) bivalirudin, a direct thrombin inhibitor that is medical regimen. Risk-factor modification is key, and the caregiver
similar in efficacy to either UFH or LMWH but causes less bleeding should discuss with the patient the importance of smoking cessation,
and is used just prior to and/or during PCI; and (4) the indirect achieving optimal weight, daily exercise, blood-pressure control,
factor Xa inhibitor, fondaparinux, which is equivalent in efficacy following an appropriate diet, control of hyperglycemia (in diabetic
to enoxaparin but has a lower risk of major bleeding. While UFH patients), and lipid management as recommended for patients with
and enoxaparin have been widely studied in patients managed chronic stable angina (Chap. 267).
either with an early conservative or invasive strategy, the role of There is evidence of benefit with long-term therapy with five classes
bivalirudin in conservatively managed patients is less clear, while of drugs that are directed at different components of the atherothrom-
fondaparinux requires supplemental UFH or bivalirudin during botic process. Beta blockers, lipid lowering therapy (statins at high
PCI to prevent procedure-related thrombosis. dose, e.g., atorvastatin 80 mg/d, with ezetimibe if needed to achieve an
Excessive bleeding is the most important adverse effect of all LDL-C below 70 mg/dL), and ACE inhibitors or angiotensin receptor
antithrombotic agents, including both antiplatelet agents and antico- blockers are recommended. The recommended antiplatelet regimen
agulants. Therefore, attention must be directed to the doses of antith- consists of the combination of low-dose (75–100 mg/d) aspirin and a
rombotic agents, accounting for body weight, creatinine clearance, P2Y12 inhibitor (clopidogrel, prasugrel, or ticagrelor) for 1 year, with
and a previous history of excessive bleeding, as a means of reducing
aspirin continued thereafter. In selected patients at high ischemic risk
the risk of bleeding. Patients who have experienced a stroke are at
(e.g., those with prior MI, diabetes mellitus, vein graft stent, congestive
higher risk of intracranial bleeding with potent antiplatelet agents
heart failure) who are also at low risk of bleeding, continuation of
and combinations of antithrombotic drugs.
DAPT out to 3 years has been shown to be beneficial. These measures,
INVASIVE VERSUS CONSERVATIVE STRATEGY taken together, reduce the incidence of recurrent ACS.
In an invasive strategy, following initiation of anti-ischemic and Registries have shown that women and racial minorities, as well
antithrombotic agents, coronary arteriography is carried out within as patients with NSTE-ACS at high risk, including the elderly and
~48 h of presentation, followed by coronary revascularization (PCI patients with diabetes or chronic kidney disease, are less likely to
or coronary artery bypass grafting), depending on the coronary receive evidence-based pharmacologic and interventional therapies
anatomy. Multiple clinical trials have demonstrated the benefit of with resultant poorer clinical outcomes and quality of life. Special
this strategy in high-risk patients (i.e., patients with multiple clinical attention should be directed to these groups.
risk factors, ST-segment deviation, and/or positive biomarkers)
■■PRINZMETAL’S VARIANT ANGINA
(Table 268-4). In patients at low risk, the outcomes from an invasive
In 1959, Prinzmetal et al. described a syndrome of severe ischemic pain
strategy are similar to those obtained from a conservative strategy.
that usually occurs at rest and is associated with transient ST-segment ele-
The latter consists of anti-ischemic and antithrombotic therapy
vation. Prinzmetal’s variant angina (PVA) is caused by focal spasm of an
followed by a “selective invasive approach,” in which the patient
epicardial coronary artery with resultant transmural ischemia and abnor-
is closely observed and coronary arteriography is carried out if rest
malities in left ventricular function that may lead to acute MI, ventricular
pain or ST-segment changes recur, a biomarker of necrosis becomes
tachycardia or fibrillation, and sudden cardiac death. The cause of the
positive, or there is evidence of severe ischemia on a stress test.
spasm is not well defined, but it may be related to hypercontractility of

1872 vascular smooth muscle due to adrenergic vasoconstrictors, leukotrienes, in turn, have been responsible for marked increases in ACS events and
or serotonin. For reasons that are not clear, the prevalence of PVA has in premature mortality. The region in which these changes have been
decreased substantially during the past few decades, although it remains most prominent are central Asia, India, and Pakistan, as well as in the
more frequent in Japan than in North America or Western Europe. more developed regions of sub-Saharan Africa.
Clinical and Angiographic Manifestations Patients with However, while there are many similarities, there are major differences
between the rise of IHD which occurred in the high income countries
PART 6
PVA are generally younger and, with the exception of cigarette smok-
ing, have fewer coronary risk factors than do patients with NSTE-ACS. in mid-twentieth century, and that which is now taking place in low
Cardiac examination is usually unremarkable in the absence of ische- and middle income countries. When the former occurred, the coronary
mia. However, a minority of patients have a generalized vasospastic risk factors had not yet been clearly defined and treatments of ACS
disorder associated with migraine and/or Raynaud’s phenomenon. were primitive by current standards. It was the successful application
The clinical diagnosis of PVA is made by the detection of transient of prevention of IHD and therapy of ACS in high income countries
ST-segment elevation with rest pain, although many patients may also that was responsible for the above-mentioned striking improvements
exhibit episodes of silent ischemia. in life expectancy. The current challenge is to apply what was learned
Coronary angiography demonstrates transient coronary spasm as in high-income countries to the vast populations in the low and middle
the diagnostic hallmark of PVA. Atherosclerotic plaques in at least income countries that are now at high risk. This will require large edu-
one proximal coronary artery occur in about half of patients. Hyper- cational efforts directed at both the populations and their caregivers. An
ventilation or intracoronary acetylcholine has been used to provoke additional challenge will be to provide the trained specialized personnel,
focal coronary stenosis on angiography or to provoke rest angina with facilities, drugs, and devices to deal with these threats. The successful
ST-segment elevation to establish the diagnosis. implementation of measures to reduce threats in the developing world
is now principally a socio-politico-economic issue. One mitigating factor
TREATMENT is that many of the important drugs to prevent and treat these disorders,
such as statins, angiotensin converting enzyme inhibitors, diuretics, beta
Prinzmetal’s Variant Angina blockers, and calcium antagonists are off patent and are now inexpensive.
Nitrates and calcium channel blockers are the main therapeutic ■■FURTHER READING
agents. Aspirin may actually increase the severity of ischemic epi- Amsterdam EA et al: 2014 AHA/ACC Guideline for the Management of
sodes, possibly as a result of the sensitivity of coronary tone to mod- Patients with Non-ST-Elevation Acute Coronary Syndromes: A report
est changes in the synthesis of prostacyclin. Statin therapy has been of the American College of Cardiology/American Heart Association
shown to reduce the risk of major adverse events, although the pre- Task Force on Practice Guidelines. J Am Coll Cardiol 64:e139, 2014.
cise mechanism is not established. The response to beta blockers is Bohula EA et al: Atherothrombotic risk stratification and ezetimibe for
variable. Coronary revascularization may be helpful in patients who secondary prevention. J Am Coll Cardiol 69:911, 2017.
also have discrete, flow-limiting, proximal fixed obstructive lesions. Cannon CP et al: Ezetimibe added to statin therapy after acute coro-
Patients who have had ischemia-associated ventricular fibrillation nary syndromes. N Engl J Med 372:2387, 2015.
despite maximal medical therapy should receive an implantable de Luna AB et al: Prinzmetal angina: ECG changes and clinical consider-
cardioverter-defibrillator. ations: A consensus paper. Ann Noninvasive Electrocardiol 19:442, 2014.
Eisen A et al: Updates on acute coronary syndrome: A review. JAMA
Prognosis Many patients with PVA pass through an acute, active Cardiol 1:718, 2016.
phase, with frequent episodes of angina and cardiac events during Fuster V, Kovacic JC (eds): Acute Coronary Syndrome Compendium.
the first 6 months after presentation. Survival at 5 years is excellent Circ Res 114:1847, 2014.
(~90–95%), but as many as 20% of patients experience an MI. Patients Kolte D et al: Trends in Coronary Angiography, Revascularization,
with no or mild fixed coronary obstruction experience a low rate of car- and Outcomes of Cardiogenic Shock Complicating Non-ST-Elevation
diac death or MI compared to patients with associated severe obstruc- Myocardial Infarction. Am J Cardiol 117:1, 2016.
tive lesions, although about half of the patients without obstructive Lloyd-Jones DM et al: 2016 ACC Expert Consensus Decision Pathway
CAD still experience frequent angina at rest. Patients with PVA who on the Role of Non-Statin Therapies for LDL-Cholesterol Lowering
develop serious arrhythmias during spontaneous episodes of pain are at in the Management of Atherosclerotic Cardiovascular Disease Risk.
a higher risk for sudden cardiac death. In most patients who survive an J Am Coll Cardiol 68:92, 2016.
infarction or the initial 3- to 6-month period of frequent episodes, there Roffi M et al: 2015 ESC Guidelines for the management of acute coro-
is a tendency for symptoms and cardiac events to diminish over time. nary syndromes in patients presenting without persistent ST-segment
elevation: Task Force for the Management of Acute Coronary Syn-
■■GLOBAL CONSIDERATIONS dromes in Patients Presenting without Persistent ST-Segment Eleva-
Ischemic heart disease (IHD), and its most dangerous manifes- tion of the European Society of Cardiology. Eur Heart J 37:267, 2016.
tation, ACS, remains the most frequent cause of death and Steg PG et al: Effect of cangrelor on periprocedural outcomes in per-
disability worldwide. In the mid-twentieth century these con- cutaneous coronary interventions: A pooled analysis of patient-level
ditions were most common in high income countries. The elucidation data. Lancet 382:1981, 2013.
of risk factors leading to IHD and the development of therapies to
reduce the deleterious consequences of ACS were responsible for dra-
matic reductions in these events, and in cardiovascular and all cause
mortality. Although these achievements were most prominent in North
America, Western Europe, and Japan, they have not affected all popu-
lation groups equally. In Europe, there remains a northeast to south-
west gradient, with higher prevalence in northern Russia and the Baltic
269 ST-Segment Elevation
Myocardial Infarction
nations, and considerably lower prevalence in France, Italy, and Spain.
Simultaneous with these important advances in the high income Elliott M. Antman, Joseph Loscalzo
countries, the low and middle income countries have moved in the oppo-
site direction. The improvements in agriculture, nutrition, sanitation,
prevention and treatment of infections, management of maternal-early Acute myocardial infarction (AMI) is a most common diagnosis in
childhood disorders, as well as urbanization, and a reduction of physi- hospitalized patients in industrialized countries. In the United States,
cal labor have, in combination, led to marked increases in coronary risk ~660,000 patients experience a new AMI, and 305,000 experience a
factors—hypertension, cigarette smoking, obesity, diabetes mellitus, recurrent AMI each year. About half of AMI-related deaths occur before
and elevations of circulating low density lipoprotein cholesterol. These, the stricken individual reaches the hospital. Of note, the in-hospital

are those with a rich lipid core and a thin fibrous cap (Chap. 291e from 1873
Presentation Ischemic Discomfort
the 19th edition of Harrison’s). After an initial platelet monolayer forms
at the site of the disrupted plaque, various agonists (collagen, ADP,
Working Dx Acute coronary syndrome epinephrine, serotonin) promote platelet activation. After agonist stim-
ulation of platelets, thromboxane A2 (a potent local vasoconstrictor) is
CHAPTER 269 ST-Segment Elevation Myocardial Infarction

released, further platelet activation occurs, and potential resistance to
fibrinolysis develops.
In addition to the generation of thromboxane A2, activation of plate-
lets by agonists promotes a conformational change in the glycoprotein
IIb/IIIa receptor (Chap. 111). Once converted to its functional state,
ECG No ST elevation ST elevation this receptor develops a high affinity for soluble adhesive proteins (i.e.,
NSTEMI integrins) such as fibrinogen. Since fibrinogen is a multivalent mole-
cule, it can bind to two different platelets simultaneously, resulting in
platelet cross-linking and aggregation.
Biochem.
marker
The coagulation cascade is activated on exposure of tissue factor in
damaged endothelial cells at the site of the disrupted plaque. Factors VII
Myocardial infarction
Final Dx Unstable angina NQMI Qw MI
and X are activated, ultimately leading to the conversion of prothrombin
to thrombin, which then converts fibrinogen to fibrin (Chap. 112).
FIGURE 269-1 Acute coronary syndromes. Following disruption of a vulnerable Fluid-phase and clot-bound thrombin participate in an autoamplifica-
plaque, patients experience ischemic discomfort resulting from a reduction of tion reaction leading to further activation of the coagulation cascade.
flow through the affected epicardial coronary artery. The flow reduction may The culprit coronary artery eventually becomes occluded by a throm-
be caused by a completely occlusive thrombus (right) or subtotally occlusive bus containing platelet aggregates and fibrin strands (Fig. 269-2).
thrombus (left). Patients with ischemic discomfort may present with or without
ST-segment elevation. Of patients with ST-segment elevation, the majority (wide In rare cases, STEMI may be due to coronary artery occlusion caused
red arrow) ultimately develop a Q wave on the ECG (Qw MI), while a minority by coronary emboli, congenital abnormalities, coronary spasm, and a
(thin red arrow) do not develop Q wave and, in older literature, were said to have
sustained a non-Q-wave MI (NQMI). Patients who present without ST-segment
elevation are suffering from either unstable angina or a non-ST-segment elevation Vulnerable plaque Thrombogenic blood
MI (NSTEMI) (wide green arrows), a distinction that is ultimately made based ion
• inflammation • inflammation
on the presence or absence of a serum cardiac biomarker such as CK-MB or a • extension • comorbidities
cardiac troponin detected in the blood. The majority of patients presenting with • severity • environmental factors
NSTEMI do not develop a Q wave on the ECG; a minority develop a Qw MI (thin • location • genetic background
green arrow). Dx, diagnosis; ECG, electrocardiogram; MI, myocardial infarction.
(Adapted from CW Hamm et al: Lancet 358:1533, 2001, and MJ Davies: Heart
83:361, 2000; with permission from the BMJ Publishing Group.)
mortality rate after admission for AMI has declined from 10 to about
5% over the past decade. The 1-year mortality rate after AMI is about
15%. Mortality is approximately fourfold higher in elderly patients
(aged >75) as compared with younger patients.
When patients with prolonged ischemic discomfort at rest are first
seen, the working clinical diagnosis is that they are suffering from an
acute coronary syndrome (Fig. 269-1). The 12-lead electrocardiogram
(ECG) is a pivotal diagnostic and triage tool because it is at the center
of the decision pathway for management; it permits distinction of those Vulnerable myocardium
• inflammation
patients presenting with ST-segment elevation from those presenting
• ischemia duration/extent
without ST-segment elevation. Serum cardiac biomarkers are obtained • individual susceptibility
to distinguish unstable angina (UA) from non-ST-segment elevation
myocardial infarction (NSTEMI) and to assess the magnitude of an
ST-segment elevation myocardial infarction (STEMI). Epidemiologic Cardiomyocyte
studies indicate there is a shift in the pattern of AMI over the last swelling
15 years with more patients with NSTEMI than STEMI. This chapter
focuses on the evaluation and management of patients with STEMI, Interstitial
edema
while Chap. 268 discusses UA/NSTEMI.
Thrombus
PATHOPHYSIOLOGY: ROLE OF ACUTE debris
PLAQUE RUPTURE
STEMI usually occurs when coronary blood flow decreases abruptly Endothelial Leukocyte and platelet
after a thrombotic occlusion of a coronary artery previously affected dysfunction activation/interaction
by atherosclerosis. Slowly developing, high-grade coronary artery ste-
FIGURE 269-2 Critical determinants of myocardial infarction injury. The
noses do not typically precipitate STEMI because of the development overlapping of vulnerable plaque and thrombogenic blood are critical determinants
of a rich collateral network over time. Instead, STEMI occurs when a for myocardial infarction occurrence and extension. In addition, myocardial
coronary artery thrombus develops rapidly at a site of vascular injury. vulnerability, which is largely due to coronary microvascular dysfunction,
This injury is produced or facilitated by factors such as cigarette smok- contributes to extension and severity of ischemic injury. In the most severe
ing, hypertension, and lipid accumulation. In most cases, STEMI occurs form (known as no-reflow), structural and functional impairment sustain vascular
obstruction. Endothelial dysfunction triggers leukocyte and platelet activation/
when the surface of an atherosclerotic plaque becomes disrupted
interaction, whereas thrombotic debris may worsen the obstruction. Furthermore,
(exposing its contents to the blood) and conditions (local or systemic) cardiomyocyte swelling, interstitial edema, and tissue inflammation promote
favor thrombogenesis. A mural thrombus forms at the site of plaque extravascular compression. (Reproduced from F Montecucco et al: Eur Heart J
disruption, and the involved coronary artery becomes occluded. His- 37:1268, 2016. Published on behalf of the European Society of Cardiology. All
tologic studies indicate that the coronary plaques prone to disruption rights reserved. © The Author 2015.)

1874 wide variety of systemic—particularly inflammatory—diseases. The within the first hour of STEMI, about one-fourth of patients with
amount of myocardial damage caused by coronary occlusion depends anterior infarction have manifestations of sympathetic nervous system
on (1) the territory supplied by the affected vessel, (2) whether or hyperactivity (tachycardia and/or hypertension), and up to one-half
not the vessel becomes totally occluded, (3) the duration of coronary with inferior infarction show evidence of parasympathetic hyperactiv-
occlusion, (4) the quantity of blood supplied by collateral vessels to the ity (bradycardia and/or hypotension).
affected tissue, (5) the demand for oxygen of the myocardium whose The precordium is usually quiet, and the apical impulse may
PART 6
blood supply has been suddenly limited, (6) endogenous factors that be difficult to palpate. In patients with anterior wall infarction, an
can produce early spontaneous lysis of the occlusive thrombus, and (7) abnormal systolic pulsation caused by dyskinetic bulging of infarcted
the adequacy of myocardial perfusion in the infarct zone when flow is myocardium may develop in the periapical area within the first days
restored in the occluded epicardial coronary artery. of the illness and then may resolve. Other physical signs of ventricular
Patients at increased risk for developing STEMI include those with dysfunction include fourth and third heart sounds, decreased intensity
multiple coronary risk factors and those with UA (Chap. 268). Less of the first heart sound, and paradoxical splitting of the second heart
common underlying medical conditions predisposing patients to sound (Chap. 234). A transient midsystolic or late systolic apical sys-
STEMI include hypercoagulability, collagen vascular disease, cocaine tolic murmur due to dysfunction of the mitral valve apparatus may
abuse, and intracardiac thrombi or masses that can produce coronary be present. A pericardial friction rub may be heard in patients with
emboli. transmural STEMI at some time in the course of the illness, if they are
There have been major advances in the management of STEMI with examined frequently. The carotid pulse is often decreased in volume,
recognition that the “chain of survival” involves a highly integrated reflecting reduced stroke volume. Temperature elevations up to 38°C
system starting with prehospital care and extending to early hospital may be observed during the first week after STEMI. The arterial pres-
management so as to provide expeditious implementation of a reper- sure is variable; in most patients with transmural infarction, systolic
fusion strategy. pressure declines by ~10–15 mmHg from the preinfarction state.
CLINICAL PRESENTATION LABORATORY FINDINGS

In up to one-half of cases, a precipitating factor appears to be present STEMI progresses through the following temporal stages: (1) acute
before STEMI, such as vigorous physical exercise, emotional stress, or (first few hours–7 days), (2) healing (7–28 days), and (3) healed
a medical or surgical illness. Although STEMI may commence at any (≥29 days). When evaluating the results of diagnostic tests for STEMI,
time of the day or night, circadian variations have been reported such the temporal phase of the infarction must be considered. The labora-
that clusters are seen in the morning within a few hours of awakening. tory tests of value in confirming the diagnosis may be divided into four
Pain is the most common presenting complaint in patients with groups: (1) ECG, (2) serum cardiac biomarkers, (3) cardiac imaging,
STEMI. The pain is deep and visceral; adjectives commonly used to and (4) nonspecific indices of tissue necrosis and inflammation.
describe it are heavy, squeezing, and crushing; although, occasionally, it
is described as stabbing or burning (Chap. 11). It is similar in character ■■ELECTROCARDIOGRAM
to the discomfort of angina pectoris (Chap. 267) but commonly occurs The electrocardiographic manifestations of STEMI are described in
at rest, is usually more severe, and lasts longer. Typically, the pain Chap. 235. During the initial stage, total occlusion of an epicardial
involves the central portion of the chest and/or the epigastrium, and, coronary artery produces ST-segment elevation. Most patients initially
on occasion, it radiates to the arms. Less common sites of radiation presenting with ST-segment elevation ultimately evolve Q waves on
include the abdomen, back, lower jaw, and neck. The frequent location the ECG. However, Q waves in the leads overlying the infarct zone may
of the pain beneath the xiphoid and epigastrium and the patients’ vary in magnitude and even appear only transiently, depending on
denial that they may be suffering a heart attack are chiefly responsible the reperfusion status of the ischemic myocardium and restoration of
for the common mistaken impression of indigestion. The pain of STEMI transmembrane potentials over time. A small proportion of patients ini-
may radiate as high as the occipital area but not below the umbilicus. tially presenting with ST-segment elevation will not develop Q waves
It is often accompanied by weakness, sweating, nausea, vomiting, anx- when the obstructing thrombus is not totally occlusive, obstruction
iety, and a sense of impending doom. The pain may commence when is transient, or if a rich collateral network is present. Among patients
the patient is at rest, but when it begins during a period of exertion, it presenting with ischemic discomfort but without ST-segment eleva-
does not usually subside with cessation of activity, in contrast to angina tion, if a serum cardiac biomarker of necrosis (see below) is detected,
pectoris. the diagnosis of NSTEMI is ultimately made (Fig. 269-1). A minority
The pain of STEMI can simulate pain from acute pericarditis of patients who present initially without ST-segment elevation may
(Chap. 265), pulmonary embolism (Chap. 273), acute aortic dissection develop a Q-wave MI. Previously, it was believed that transmural
(Chap. 274), costochondritis, and gastrointestinal disorders. These myocardial infarction (MI) is present if the ECG demonstrates Q waves
conditions should therefore be considered in the differential diagnosis. or loss of R waves, and nontransmural MI may be present if the ECG
Radiation of discomfort to the trapezius is not seen in patients with shows only transient ST-segment and T-wave changes. However,
STEMI and may be a useful distinguishing feature that suggests peri- electrocardiographic-pathologic correlations are far from perfect and
carditis is the correct diagnosis. However, pain is not uniformly present terms such as Q-wave MI, non-Q-wave MI, transmural MI, and
in patients with STEMI. The proportion of painless STEMIs is greater in nontransmural MI have been replaced by STEMI and NSTEMI
patients with diabetes mellitus, and it increases with age. In the elderly, (Fig. 269-1). Contemporary studies using magnetic resonance imaging
STEMI may present as sudden-onset breathlessness, which may prog- (MRI) suggest that the development of a Q wave on the ECG is more
ress to pulmonary edema. Other less common presentations, with or dependent on the volume of infarcted tissue rather than the transmu-
without pain, include sudden loss of consciousness, a confusional state, rality of infarction.
a sensation of profound weakness, the appearance of an arrhythmia,
evidence of peripheral embolism, or merely an unexplained drop in ■■SERUM CARDIAC BIOMARKERS
arterial pressure. Certain proteins, referred to as serum cardiac biomarkers, are released
from necrotic heart muscle after STEMI. The rate of liberation of spe-
■■PHYSICAL FINDINGS cific proteins differs depending on their intracellular location, their
Most patients are anxious and restless, attempting unsuccessfully to molecular weight, and the local blood and lymphatic flow. Cardiac
relieve the pain by moving about in bed, altering their position, and biomarkers become detectable in the peripheral blood once the capac-
stretching. Pallor associated with perspiration and coolness of the ity of the cardiac lymphatics to clear the interstitium of the infarct zone
extremities occurs commonly. The combination of substernal chest is exceeded and spillover into the venous circulation occurs. The tem-
pain persisting for >30 min and diaphoresis strongly suggests STEMI. poral pattern of protein release is of diagnostic importance. The criteria
Although many patients have a normal pulse rate and blood pressure for AMI require a rise and/or fall in cardiac biomarker values with at

least one value above the 99th percentile of the upper reference limit 1875
for normal individuals.
Cardiac-specific troponin T (cTnT) and cardiac-specific troponin I (cTnI)
have amino-acid sequences different from those of the skeletal muscle
forms of these proteins. These differences permitted the development

of quantitative assays for cTnT and cTnI with highly specific mono-
clonal antibodies. cTnT and cTnI may increase after STEMI to levels
many times higher than the upper reference limit (the highest value
seen in 99% of a reference population not suffering from MI), the mea- Zone of necrosing
surement of cTnT or cTnI is of considerable diagnostic usefulness, and myocardium
they are now the preferred biochemical markers for MI (Fig. 269-3).
With improvements in the assays for the cardiac-specific troponins, it
is now possible to detect concentrations <1 ng/L in patients without
ischemic-type chest discomfort. The cardiac troponins are particularly Troponin free Cardiomyocyte
in cytoplasm
valuable when there is clinical suspicion of either skeletal muscle
injury or a small MI that may be below the detection limit for creatine
phosphokinase (CK) and its MB isoenzyme (CK-MB) measurements,
and they are, therefore, of particular value in distinguishing UA from
NSTEMI. In practical terms, the high-sensitivity troponin assays are of
less immediate value in patients with STEMI. Contemporary urgent
reperfusion strategies necessitate making a decision (based largely on
a combination of clinical and ECG findings) before the results of blood
tests have returned from the laboratory. Levels of cTnI and cTnT may
remain elevated for 7–10 days after STEMI. Myosin Actin Troponin complex
CK rises within 4–8 h and generally returns to normal by 48–72 h bound to actin filament
(Fig. 269-3). An important drawback of total CK measurement is its
lack of specificity for STEMI, as CK may be elevated with skeletal Lymphatic system
muscle disease or trauma, including intramuscular injection. The MB
isoenzyme of CK has the advantage over total CK that it is not present Venous system
in significant concentrations in extracardiac tissue and, therefore, is
considerably more specific. However, cardiac surgery, myocarditis, and
electrical cardioversion often result in elevated serum levels of the MB
isoenzyme. A ratio (relative index) of CK-MB mass to CK activity ≥2.5 Myoglobin and
CK isoforms
suggests but is not diagnostic of a myocardial rather than a skeletal
muscle source for the CK-MB elevation. 50
Multiples of the AMI cutoff limit
Many hospitals are using cTnT or cTnI rather than CK-MB as the
routine serum cardiac marker for diagnosis of STEMI, although any 20 Troponin
of these analytes remains clinically acceptable. It is not cost-effective to (large MI)
measure both a cardiac-specific troponin and CK-MB at all time points 10
in every patient.
While it has long been recognized that the total quantity of protein 5
released correlates with the size of the infarct, the peak protein con- CKMB
centration correlates only weakly with infarct size. Recanalization of 2
a coronary artery occlusion (either spontaneously or by mechanical Troponin
or pharmacologic means) in the early hours of STEMI causes earlier 1 (small MI)
peaking of biomarker measurements (Fig. 269-3) because of a rapid 10% CV/99th percentile
0
washout from the interstitium of the infarct zone, quickly overwhelm-
0 1 2 3 4 5 6 7 8 9
ing lymphatic clearance of the proteins.
The nonspecific reaction to myocardial injury is associated with poly- Days after onset of AMI
morphonuclear leukocytosis, which appears within a few hours after FIGURE 269-3 The zone of necrosing myocardium is shown at the top of the
the onset of pain and persists for 3–7 days; the white blood cell count figure, followed in the middle portion of the figure by a diagram of a cardiomyocyte
often reaches levels of 12,000–15,000/μL. The erythrocyte sedimenta- that is in the process of releasing biomarkers. The biomarkers that are released
tion rate rises more slowly than the white blood cell count, peaking dur- into the interstitium are first cleared by lymphatics followed subsequently by
ing the first week and sometimes remaining elevated for 1 or 2 weeks. spillover into the venous system. After disruption of the sarcolemmal membrane of
the cardiomyocyte, the cytoplasmic pool of biomarkers is released first (left-most
■■CARDIAC IMAGING arrow in bottom portion of figure). Markers such as myoglobin and CK isoforms
are rapidly released, and blood levels rise quickly above the cutoff limit; this is
Abnormalities of wall motion on two-dimensional echocardiography then followed by a more protracted release of biomarkers from the disintegrating
(Chap. 236) are almost universally present. Although acute STEMI myofilaments that may continue for several days. Cardiac troponin levels rise
cannot be distinguished from an old myocardial scar or from acute to about 20–50 times the upper reference limit (the 99th percentile of values
severe ischemia by echocardiography, the ease and safety of the pro- in a reference control group) in patients who have a “classic” acute myocardial
cedure make its use appealing as a screening tool in the Emergency infarction (MI) and sustain sufficient myocardial necrosis to result in abnormally
Department setting. When the ECG is not diagnostic of STEMI, early elevated levels of the MB fraction of creatine kinase (CK-MB). Clinicians can
now diagnose episodes of microinfarction by sensitive assays that detect cardiac
detection of the presence or absence of wall motion abnormalities by troponin elevations above the upper reference limit, even though CK-MB levels
echocardiography can aid in management decisions, such as whether may still be in the normal reference range (not shown). CV, coefficient of variation.
the patient should receive reperfusion therapy (e.g., fibrinolysis or a (Modified from EM Antman: Decision making with cardiac troponin tests. N Engl
percutaneous coronary intervention [PCI]). Echocardiographic estima- J Med 346:2079, 2002 and AS Jaffe, L Babiun, FS Apple: Biomarkers in acute
tion of left ventricular (LV) function is useful prognostically; detection cardiac disease: The present and the future. J Am Coll Cardiol 48:1, 2006.)
of reduced function serves as an indication for therapy with an inhib-
itor of the renin-angiotensin-aldosterone system. Echocardiography

1876 may also identify the presence of right ventricular (RV) infarction, ven- TABLE 269-1 Definition of Myocardial Infarction
tricular aneurysm, pericardial effusion, and LV thrombus. In addition,
Criteria for Acute Myocardial Infarction
Doppler echocardiography is useful in the detection and quantitation
of a ventricular septal defect and mitral regurgitation, two serious The term acute myocardial infarction (MI) should be used when there is
evidence of myocardial necrosis in a clinical setting consistent with acute
complications of STEMI. myocardial ischemia. Under these conditions, any one of the following criteria
Several radionuclide imaging techniques (Chap. 236) are available for meets the diagnosis for MI:
PART 6
evaluating patients with suspected STEMI. However, these imaging • Detection of a rise and/or fall of cardiac biomarker values (preferably
modalities are used less often than echocardiography because they are cardiac troponin [cTn]) with at least one value above the 99th percentile
more cumbersome and lack sensitivity and specificity in many clinical upper reference limit (URL) and with at least one of the following:
circumstances. Myocardial perfusion imaging with [201Tl] or [99mTc]- – Symptoms of ischemia
sestamibi, which are distributed in proportion to myocardial blood – New or presumed new significant ST-segment T-wave (ST-T) changes or
flow and concentrated by viable myocardium (Chap. 267), reveals a new left bundle branch block (LBBB)
defect (“cold spot”) in most patients during the first few hours after – Development of pathologic Q waves in the electrocardiogram (ECG)
development of a transmural infarct. Although perfusion scanning is – Imaging evidence of new loss of viable myocardium or new regional wall
extremely sensitive, it cannot distinguish acute infarcts from chronic motion abnormality
scars and, thus, is not specific for the diagnosis of acute MI. Radionu- – Identification of an intracoronary thrombus by angiography or autopsy
clide ventriculography, carried out with [99mTc]-labeled red blood cells, • Cardiac death with symptoms suggestive of myocardial ischemia and
frequently demonstrates wall motion disorders and reduction in the presumed new ischemic ECG changes of new LBBB, but death occurred
ventricular ejection fraction in patients with STEMI. While of value before cardiac biomarkers were obtained or before cardiac biomarker
in assessing the hemodynamic consequences of infarction and in aid- values would be increased.
ing in the diagnosis of RV infarction when the RV ejection fraction is • Percutaneous coronary intervention (PCI)–related MI is arbitrarily defined
depressed, this technique is nonspecific, as many cardiac abnormalities by elevation of cTn values (>5 × 99th percentile URL) in patients with
normal baseline values (≤99th percentile URL) or a rise of cTn values
other than MI alter the radionuclide ventriculogram. >20% if the baseline values are elevated and are stable or falling. In
MI can be detected accurately with high-resolution cardiac MRI addition, either (i) symptoms suggestive of myocardial ischemia, or (ii)
(Chap. 236) using a technique referred to as late enhancement. A new ischemic ECG changes, or (iii) angiographic findings consistent with a
standard imaging agent (gadolinium) is administered and images are procedural complication, or (iv) imaging demonstration of new loss of viable
obtained after a 10-min delay. Since little gadolinium enters normal myocardium or new regional wall motion abnormality are required.
myocardium, where there are tightly packed myocytes, but does per- • Stent thrombosis associated with MI when detected by coronary
colate into the expanded intercellular region of the infarct zone, there angiography or autopsy in the setting of myocardial ischemia and with a rise
and/or fall of cardiac biomarker values with at least one value above the
is a bright signal in areas of infarction that appears in stark contrast to 99th percentile URL.
the dark areas of normal myocardium.
• Coronary artery bypass grafting (CABG)–related MI is arbitrarily defined
An Expert Consensus Task Force for the Universal Definition of Myo- by elevation of cardiac biomarker values (>10 × 99th percentile URL)
cardial Infarction has provided a comprehensive set of criteria for the in patients with normal baseline cTn values (≤99th percentile URL). In
definition of MI that integrates the clinical and laboratory findings dis- addition, either (i) new pathologic Q waves or new LBBB, or (ii) angiographic
cussed earlier (Table 269-1) as well as a classification of MI into five types documented new graft or new native coronary artery occlusion, or (iii)
that reflect the clinical circumstances in which it may occur (Table 269-2). imaging evidence of new loss of viable myocardium or new regional wall
motion abnormality.
INITIAL MANAGEMENT Criteria for Prior Myocardial Infarction
Any one of the following criteria meets the diagnosis for prior MI:
■■PREHOSPITAL CARE • Pathologic Q waves with or without symptoms in the absence of
The prognosis in STEMI is largely related to the occurrence of two general nonischemic causes.
classes of complications: (1) electrical complications (arrhythmias) and • Imaging evidence of a region of loss of viable myocardium that is thinned
(2) mechanical complications (“pump failure”). Most out-of-hospital and fails to contract, in the absence of a nonischemic cause.
deaths from STEMI are due to the sudden development of ventricular • Pathologic findings of a prior MI.
fibrillation. The vast majority of deaths due to ventricular fibrillation Source: Data from K Thygesen: Eur Heart J 33:2551, 2012.
occur within the first 24 h of the onset of symptoms, and of these, over
half occur in the first hour. Therefore, the major elements of prehos-
pital care of patients with suspected STEMI include (1) recognition of of ECGs and management of STEMI, and online medical command and
symptoms by the patient and prompt seeking of medical attention; (2) control that can authorize the initiation of treatment in the field.
rapid deployment of an emergency medical team capable of perform-
ing resuscitative maneuvers, including defibrillation; (3) expeditious MANAGEMENT IN THE EMERGENCY
transportation of the patient to a hospital facility that is continuously DEPARTMENT
staffed by physicians and nurses skilled in managing arrhythmias and In the Emergency Department, the goals for the management of
providing advanced cardiac life support; and (4) expeditious imple- patients with suspected STEMI include control of cardiac discomfort,
mentation of reperfusion therapy. The greatest delay usually occurs not rapid identification of patients who are candidates for urgent reperfu-
during transportation to the hospital but, rather, between the onset of sion therapy, triage of lower-risk patients to the appropriate location
pain and the patient’s decision to call for help. This delay can best be in the hospital, and avoidance of inappropriate discharge of patients
reduced by health care professionals educating the public concerning with STEMI. Many aspects of the treatment of STEMI are initiated in
the significance of chest discomfort and the importance of seeking early the Emergency Department and then continued during the in-hospital
medical attention. Regular office visits with patients having a history of, phase of management (Fig. 269-4). The overarching goal is to minimize
or who are at risk for ischemic heart disease are important “teachable the time from first medical contact to initiation of reperfusion therapy.
moments” for clinicians to review the symptoms of STEMI and the This may involve transfer from a non-PCI hospital to one that is PCI
appropriate action plan. capable, with a goal of initiating PCI within 120 min of first medical
Increasingly, monitoring and treatment are carried out by trained contact (Fig. 269-4).
personnel in the ambulance, further shortening the time between the Aspirin is essential in the management of patients with suspected
onset of the infarction and appropriate treatment. General guidelines STEMI and is effective across the entire spectrum of acute coronary
for initiation of fibrinolysis in the prehospital setting include the ability syndromes (Fig. 269-1). Rapid inhibition of cyclooxygenase-1 in platelets
to transmit 12-lead ECGs to confirm the diagnosis, the presence of para- followed by a reduction of thromboxane A2 levels is achieved by buccal
medics in the ambulance, training of paramedics in the interpretation absorption of a chewed 160–325-mg tablet in the Emergency Department.

TABLE 269-2 Classification of Myocardial Infarction jugular venous pressure, clear lungs, and hypotension). Nitrates should 1877
not be administered to patients who have taken a phosphodiesterase-5
Type I: Spontaneous Myocardial Infarction
inhibitor for erectile dysfunction within the preceding 24 h, because it
Spontaneous myocardial infarction related to atherosclerotic plaque rupture, may potentiate the hypotensive effects of nitrates. An idiosyncratic reac-
ulceration, fissuring, erosion, or dissection with resulting intraluminal
tion to nitrates, consisting of sudden marked hypotension, sometimes

thrombus in one or more of the coronary arteries leading to decreased
myocardial blood flow or distal platelet emboli with ensuing myocyte necrosis. occurs but can usually be reversed promptly by the rapid administra-
The patient may have underlying severe coronary artery disease (CAD) but on tion of intravenous atropine.
occasion nonobstructive or no CAD. Morphine is a very effective analgesic for the pain associated with
Type 2: Myocardial Infarction Secondary to an Ischemic Imbalance STEMI. However, it may reduce sympathetically mediated arteriolar
In instances of myocardial injury with necrosis where a condition other than and venous constriction, and the resulting venous pooling may reduce
CAD contributes to an imbalance between myocardial oxygen supply and/ cardiac output and arterial pressure. These hemodynamic disturbances
or demand, e.g., coronary endothelial dysfunction, coronary artery spasm, usually respond promptly to elevation of the legs, but in some patients,
coronary embolism, tachy-brady-arrhythmias, anemia, respiratory failure, volume expansion with intravenous saline is required. The patient may
hypotension, and hypertension with or without left ventricular hypertrophy. experience diaphoresis and nausea, but these events usually pass and
Type 3: Myocardial Infarction Resulting in Death When Biomarker are replaced by a feeling of well-being associated with the relief of pain.
Values Are Unavailable Morphine also has a vagotonic effect and may cause bradycardia or
Cardiac death with symptoms suggestive of myocardial ischemia and advanced degrees of heart block, particularly in patients with inferior
presumed new ischemic electrocardiogram (ECG) changes or new left bundle infarction. These side effects usually respond to atropine (0.5 mg intra-
branch block (LBBB), but death occurring before blood samples could be venously). Morphine is routinely administered by repetitive (every
obtained or before cardiac biomarker could rise, or in rare cases, cardiac
5 min) intravenous injection of small doses (2–4 mg), rather than by the
biomarkers were not collected.
subcutaneous administration of a larger quantity, because absorption
Type 4a: Myocardial Infarction Related to Percutaneous Coronary may be unpredictable by the latter route.
Intervention (PCI)
Intravenous beta blockers are also useful in the control of the pain of
Myocardial infarction associated with PCI is arbitrarily defined by elevation of STEMI. These drugs control pain effectively in some patients, presum-
cardiac troponin (cTn) values >5 × 99th percentile upper reference limit (URL)
ably by diminishing myocardial O2 demand and hence ischemia. More
in patients with normal baseline values (≤99th percentile URL) or a rise of
cTn values >20% if the baseline values are elevated and are stable or falling. important, there is evidence that intravenous beta blockers reduce the
In addition, either (i) symptoms suggestive of myocardial ischemia, or (ii) risks of reinfarction and ventricular fibrillation (see “Beta-Adrenoceptor
new ischemic ECG changes or new LBBB, or (iii) angiographic loss of patency Blockers” below). A commonly employed regimen is metoprolol, 5 mg
of a major coronary artery or a side branch or persistent slow or no flow or every 2–5 min for a total of three doses, provided the patient has a heart
embolization, or (iv) imaging demonstration of new loss of viable myocardium rate >60 beats/min, systolic pressure >100 mmHg, a PR interval <0.24 s,
or new regional wall motion abnormality is required.
and rales that are no higher than 10 cm up from the diaphragm. Fifteen
Type 4b: Myocardial Infarction Related to Stent Thrombosis minutes after the last intravenous dose, an oral regimen is initiated of
Myocardial infarction associated with stent thrombosis is detected by coronary 50 mg every 6 h for 48 h, followed by 100 mg every 12 h.
angiography or autopsy in the setting of myocardial ischemia and with a rise Patient selection is important when considering beta blockers for
and/or fall of cardiac biomarker values with at least one value above the STEMI. Oral beta blocker therapy should be initiated in the first 24 h
99th percentile URL.
for patients who do not have any of the following: (1) signs of heart
Type 5: Myocardial Infarction Related to Coronary Artery Bypass failure, (2) evidence of a low-output state, (3) increased risk for cardio-
Grafting (CABG) genic shock, or (4) other relative contraindications to beta blockade (PR
Myocardial infarction associated with CABG is arbitrarily defined by elevation interval >0.24 s, second- or third-degree heart block, active asthma, or
of cardiac biomarker values >10 × 99th percentile URL in patients with reactive airway disease).
normal baseline cTn values (≤99th percentile URL). In addition, either (i) new
Unlike beta blockers, calcium antagonists are of little value in the
pathologic Q waves or new LBBB, or (ii) angiographic documented new graft or
new native coronary artery occlusion, or (iii) imaging evidence of new loss of acute setting, and there is evidence that short-acting dihydropyridines
viable myocardium or new regional wall motion abnormality. may be associated with an increased mortality risk.
Source: K Thygesen: Eur Heart J 33:2551, 2012.
MANAGEMENT STRATEGIES
The primary tool for screening patients and making triage decisions is
This measure should be followed by daily oral administration of aspi- the initial 12-lead ECG. When ST-segment elevation of at least 2 mm in
rin in a dose of 75–162 mg. two contiguous precordial leads and 1 mm in two adjacent limb leads
In patients whose arterial O2 saturation is normal, supplemental O2 is present, a patient should be considered a candidate for reperfusion
is of limited if any clinical benefit and therefore is not cost-effective. therapy (Figs. 269-1 and 269-4). The process of selecting patients for
However, when hypoxemia is present, O2 should be administered by fibrinolysis versus primary PCI (angioplasty or stenting; Chap. 270) is
nasal prongs or face mask (2–4 L/min) for the first 6–12 h after infarc- discussed below. In the absence of ST-segment elevation, fibrinolysis
tion; the patient should then be reassessed to determine if there is a is not helpful, and evidence exists suggesting that it may be harmful.
continued need for such treatment.
LIMITATION OF INFARCT SIZE
CONTROL OF DISCOMFORT The quantity of myocardium that becomes necrotic as a consequence of
Sublingual nitroglycerin can be given safely to most patients with STEMI. a coronary artery occlusion is determined by factors other than just the
Up to three doses of 0.4 mg should be administered at about 5-min site of occlusion. While the central zone of the infarct contains necrotic
intervals. In addition to diminishing or abolishing chest discomfort, tissue that is irretrievably lost, the fate of the surrounding ischemic
nitroglycerin may be capable of both decreasing myocardial oxygen myocardium (ischemic penumbra) may be improved by timely res-
demand (by lowering preload) and increasing myocardial oxygen sup- toration of coronary perfusion, reduction of myocardial O2 demands,
ply (by dilating infarct-related coronary vessels or collateral vessels). In prevention of the accumulation of noxious metabolites, and blunting
patients whose initially favorable response to sublingual nitroglycerin of the impact of mediators of reperfusion injury (e.g., calcium overload
is followed by the return of chest discomfort, particularly if accompa- and oxygen-derived free radicals). Up to one-third of patients with
nied by other evidence of ongoing ischemia such as further ST-segment STEMI may achieve spontaneous reperfusion of the infarct-related cor-
or T-wave shifts, the use of intravenous nitroglycerin should be consid- onary artery within 24 h and experience improved healing of infarcted
ered. Therapy with nitrates should be avoided in patients who present tissue. Reperfusion, either pharmacologically (by fibrinolysis) or by
with low systolic arterial pressure (<90 mmHg) or in whom there is PCI, accelerates the opening of infarct-related arteries in those patients
clinical suspicion of RV infarction (inferior infarction on ECG, elevated in whom spontaneous fibrinolysis ultimately would have occurred and

1878
STEMI patient who is a
candidate for reperfusion
Initially seen at a
non-PCI-capable
PART 6
Initially seen at a hospital*

PCI-capable DIDO time ≤30 min
hospital
Send to cath lab

for primary PCI
Transfer for Administer fibrinolytic
FMC-device time primary PCI agent within 30 min of
≤90 min FMC-device arrival when
(Class I, LOE: A) time as soon as anticipated FMC-
possible and device >120 min
≤120 min (Class I, LOE: B)
(Class I, LOE: B)
Diagnostic angiogram
Urgent transfer for Transfer for
PCI for patients angiography and
with evidence of revascularization
failed reperfusion within 3–24 h for
or reocclusion other patients as
Medical PCI CABG
(Class IIa, LOE: B) part of an
therapy only
invasive strategy†
(Class IIa, LOE: B)
*Patients with cardiogenic shock or severe heart failure initially seen at a non–PCI-capable hospital should be transferred for cardiac
catheterization and revascularization as soon as possible, irrespective of time delay from myocardial infarction (MI) onset (Class I, LOE: B).
†Angiography and revascularization should not be performed within the first 2–3 h after administration of fibrinolytic therapy.
FIGURE 269-4 Reperfusion therapy for patients with ST-segment elevation myocardial infarction (STEMI). The bold arrows and boxes are the preferred strategies.
Performance of percutaneous coronary intervention (PCI) is dictated by an anatomically appropriate culprit stenosis. CABG, coronary artery bypass graft; DIDO,
door-in–door-out; FMC, first medical contact; LOE, level of evidence; STEMI, ST-elevation myocardial infarction. (Adapted with permission from P O’Gara et al: Circulation
127:e362, 2013.)
also greatly increases the number of patients in whom restoration of 2–3 h when the clot is more mature and less easily lysed by fibrinolytic
flow in the infarct-related artery is accomplished. Timely restoration of drugs. However, PCI is expensive in terms of personnel and facilities,
flow in the epicardial infarct–related artery combined with improved and its applicability is limited by its availability, around the clock, in
perfusion of the downstream zone of infarcted myocardium results in only a minority of hospitals (Fig. 269-4).
a limitation of infarct size. Protection of the ischemic myocardium by
the maintenance of an optimal balance between myocardial O2 supply ■■FIBRINOLYSIS
and demand through pain control, treatment of congestive heart fail- If no contraindications are present (see below), fibrinolytic therapy
ure (CHF), and minimization of tachycardia and hypertension extends should ideally be initiated within 30 min of presentation (i.e., door-to-
the “window” of time for the salvage of myocardium by reperfusion needle time ≤30 min). The principal goal of fibrinolysis is prompt res-
strategies. toration of full coronary arterial patency. The fibrinolytic agents tissue
Glucocorticoids and nonsteroidal anti-inflammatory agents, with plasminogen activator (tPA), streptokinase, tenecteplase (TNK), and
the exception of aspirin, should be avoided in patients with STEMI. reteplase (rPA) have been approved by the U.S. Food and Drug Admin-
They can impair infarct healing and increase the risk of myocardial istration for intravenous use in patients with STEMI. These drugs all
rupture, and their use may result in a larger infarct scar. In addition, act by promoting the conversion of plasminogen to plasmin, which
they can increase coronary vascular resistance, thereby potentially subsequently lyses fibrin thrombi. Although considerable emphasis
reducing flow to ischemic myocardium. was first placed on a distinction between more fibrin-specific agents,
such as tPA, and non-fibrin-specific agents, such as streptokinase, it is
■■PRIMARY PERCUTANEOUS CORONARY now recognized that these differences are only relative, as some degree
INTERVENTION of systemic fibrinolysis occurs with the former agents. TNK and rPA
(See also Chap. 270) PCI, usually angioplasty and/or stenting without are referred to as bolus fibrinolytics since their administration does not
preceding fibrinolysis, referred to as primary PCI, is effective in restor- require a prolonged intravenous infusion.
ing perfusion in STEMI when carried out on an emergency basis in When assessed angiographically, flow in the culprit coronary artery
the first few hours of MI. It has the advantage of being applicable to is described by a simple qualitative scale called the Thrombolysis in
patients who have contraindications to fibrinolytic therapy (see below) Myocardial Infarction (TIMI) grading system: grade 0 indicates complete
but otherwise are considered appropriate candidates for reperfusion. occlusion of the infarct-related artery; grade 1 indicates some pene-
It appears to be more effective than fibrinolysis in opening occluded tration of the contrast material beyond the point of obstruction, but
coronary arteries and, when performed by experienced operators in dedicated without perfusion of the distal coronary bed; grade 2 indicates perfu-
medical centers, is associated with better short-term and long-term clin- sion of the entire infarct vessel into the distal bed, but with flow that is
ical outcomes. Compared with fibrinolysis, primary PCI is generally delayed compared with that of a normal artery; and grade 3 indicates
preferred when the diagnosis is in doubt, cardiogenic shock is present, full perfusion of the infarct vessel with normal flow. The latter is the
bleeding risk is increased, or symptoms have been present for at least goal of reperfusion therapy, because full perfusion of the infarct-related

coronary artery yields far better results in terms of limiting infarct size, Cardiac catheterization and coronary angiography should be car- 1879
maintenance of LV function, and reduction of both short- and long- ried out after fibrinolytic therapy if there is evidence of either (1)
term mortality rates. Additional methods of angiographic assessment failure of reperfusion (persistent chest pain and ST-segment elevation
of the efficacy of fibrinolysis include counting the number of frames >90 min), in which case a rescue PCI should be considered; or (2) coro-
on the cine film required for dye to flow from the origin of the infarct- nary artery reocclusion (re-elevation of ST segments and/or recurrent

related artery to a landmark in the distal vascular bed (TIMI frame count) chest pain) or the development of recurrent ischemia (such as recurrent
and determining the rate of entry and exit of contrast dye from the angina in the early hospital course or a positive exercise stress test
microvasculature in the myocardial infarct zone (TIMI myocardial per- before discharge), in which case an urgent PCI should be considered.
fusion grade). These methods have an even tighter correlation with out- Routine angiography and elective PCI even in asymptomatic patients
comes after STEMI than the more commonly employed TIMI flow grade. following administration of fibrinolytic therapy are used with less fre-
tPA and the other relatively fibrin-specific plasminogen activators, quency, given the numerous technologic advances that have occurred
rPA and TNK, are more effective than streptokinase at restoring full in the catheterization laboratory and the increasing number of skilled
perfusion—i.e., TIMI grade 3 coronary flow—and have a small edge in interventionalists. Coronary artery bypass surgery should be reserved
improving survival as well. The current recommended regimen of tPA for patients whose coronary anatomy is unsuited to PCI but in whom
consists of a 15-mg bolus followed by 50 mg intravenously over the first revascularization appears to be advisable because of extensive jeopar-
30 min, followed by 35 mg over the next 60 min. Streptokinase is admin- dized myocardium or recurrent ischemia.
istered as 1.5 million units (MU) intravenously over 1 h. rPA is adminis-
tered in a double-bolus regimen consisting of a 10-MU bolus given over HOSPITAL PHASE MANAGEMENT
2–3 min, followed by a second 10-MU bolus 30 min later. TNK is given
as a single weight-based intravenous bolus of 0.53 mg/kg over 10 s. In
■■CORONARY CARE UNITS
These units are routinely equipped with a system that permits con-
addition to the fibrinolytic agents discussed earlier, pharmacologic
tinuous monitoring of the cardiac rhythm of each patient and hemo-
reperfusion typically involves adjunctive antiplatelet and antithrom-
dynamic monitoring in selected patients. Defibrillators, respirators,
botic drugs, as discussed subsequently.
noninvasive transthoracic pacemakers, and facilities for introducing
Clear contraindications to the use of fibrinolytic agents include
pacing catheters and flow-directed balloon-tipped catheters are also
a history of cerebrovascular hemorrhage at any time, a nonhemor-
usually available. Equally important is the organization of a highly
rhagic stroke or other cerebrovascular event within the past year,
trained team of nurses who can recognize arrhythmias; adjust the
marked hypertension (a reliably determined systolic arterial pressure
dosage of antiarrhythmic, vasoactive, and anticoagulant drugs; and
>180 mmHg and/or a diastolic pressure >110 mmHg) at any time
perform cardiac resuscitation, including electroshock, when necessary.
during the acute presentation, suspicion of aortic dissection, and active
Patients should be admitted to a coronary care unit early in their
internal bleeding (excluding menses). While advanced age is associated
illness when it is expected that they will derive benefit from the
with an increase in hemorrhagic complications, the benefit of fibrino-
sophisticated and expensive care provided. The availability of electro-
lytic therapy in the elderly appears to justify its use if no other con-
cardiographic monitoring and trained personnel outside the coronary
traindications are present and the amount of myocardium in jeopardy care unit has made it possible to admit lower-risk patients (e.g., those
appears to be substantial. not hemodynamically compromised and without active arrhythmias)
Relative contraindications to fibrinolytic therapy, which require assess- to “intermediate care units.”
ment of the risk-to-benefit ratio, include current use of anti-coagulants The duration of stay in the coronary care unit is dictated by the
(international normalized ratio ≥2), a recent (<2 weeks) invasive or ongoing need for intensive care. If symptoms are controlled with oral
surgical procedure or prolonged (>10 min) cardiopulmonary resuscita- therapy, patients may be transferred out of the coronary care unit. Also,
tion, known bleeding diathesis, pregnancy, a hemorrhagic ophthalmic patients who have a confirmed STEMI but who are considered to be at
condition (e.g., hemorrhagic diabetic retinopathy), active peptic ulcer low risk (no prior infarction and no persistent chest discomfort, CHF,
disease, and a history of severe hypertension that is currently ade- hypotension, or cardiac arrhythmias) may be safely transferred out of
quately controlled. Because of the risk of an allergic reaction, patients the coronary care unit within 24 h.
should not receive streptokinase if that agent had been received within
the preceding 5 days to 2 years. Activity Factors that increase the work of the heart during the ini-
Allergic reactions to streptokinase occur in ~2% of patients who tial hours of infarction may increase the size of the infarct. Therefore,
receive it. While a minor degree of hypotension occurs in 4–10% of patients with STEMI should be kept at bed rest for the first 6–12 h.
patients given this agent, marked hypotension occurs, although rarely, However, in the absence of complications, patients should be encour-
in association with severe allergic reactions. aged, under supervision, to resume an upright posture by dangling
Hemorrhage is the most frequent and potentially the most serious their feet over the side of the bed and sitting in a chair within the first
complication. Because bleeding episodes that require transfusion are 24 h. This practice is psychologically beneficial and usually results in
more common when patients require invasive procedures, unnecessary a reduction in the pulmonary capillary wedge pressure. In the absence
venous or arterial interventions should be avoided in patients receiving of hypotension and other complications, by the second or third day,
fibrinolytic agents. Hemorrhagic stroke is the most serious compli- patients typically are ambulating in their room with increasing dura-
cation and occurs in ~0.5–0.9% of patients being treated with these tion and frequency, and they may shower or stand at the sink to bathe.
agents. This rate increases with advancing age, with patients >70 years By day 3 after infarction, patients should be increasing their ambula-
experiencing roughly twice the rate of intracranial hemorrhage as those tion progressively to a goal of 185 m (600 ft) at least three times a day.
<65 years. Large-scale trials have suggested that the rate of intracranial Diet Because of the risk of emesis and aspiration soon after STEMI,
hemorrhage with tPA or rPA is slightly higher than with streptokinase. patients should receive either nothing or only clear liquids by mouth
for the first 4–12 h. The typical coronary care unit diet should pro-
■■INTEGRATED REPERFUSION STRATEGY
vide ≤30% of total calories as fat and have a cholesterol content of
Evidence has emerged that suggests PCI plays an increasingly impor-
≤300 mg/d. Complex carbohydrates should make up 50–55% of total
tant role in the management of STEMI. Prior approaches that segre-
calories. Portions should not be unusually large, and the menu should
gated the pharmacologic and catheter-based approaches to reperfusion
be enriched with foods that are high in potassium, magnesium, and
have now been replaced with an integrated approach to triage and
fiber, but low in sodium. Diabetes mellitus and hypertriglyceridemia
transfer of STEMI patients to receive PCI (Fig. 269-4). To achieve the
are managed by restriction of concentrated sweets in the diet.
degree of integration required to care for a patient with STEMI, all
communities should create and maintain a regional system of STEMI Bowel Management Bed rest and the effect of the narcotics used
care that includes assessment and continuous quality improvement of for the relief of pain often lead to constipation. A bedside commode
emergency medical services and hospital-based activities. rather than a bedpan, a diet rich in bulk, and the routine use of a stool

1880 softener such as dioctyl sodium sulfosuccinate (200 mg/d) are recom- direct antithrombin bivalirudin. Advantages of LMWHs include high
mended. If the patient remains constipated despite these measures, a bioavailability permitting administration subcutaneously, reliable anti-
laxative can be prescribed. Contrary to prior belief, it is safe to perform coagulation without monitoring, and greater antiXa:IIa activity. Enoxa-
a gentle rectal examination on patients with STEMI. parin has been shown to reduce significantly the composite endpoints
of death/nonfatal reinfarction and death/nonfatal reinfarction/urgent
Sedation Many patients require sedation during hospitalization to revascularization compared with UFH in STEMI patients who receive
PART 6
withstand the period of enforced inactivity with tranquility. Diazepam

fibrinolysis. Treatment with enoxaparin is associated with higher rates
(5 mg), oxazepam (15–30 mg), or lorazepam (0.5–2 mg), given three to
of serious bleeding, but net clinical benefit—a composite endpoint
four times daily, is usually effective. An additional dose of any of the
that combines efficacy and safety—still favors enoxaparin over UFH.
above medications may be given at night to ensure adequate sleep.
Interpretation of the data on fondaparinux is difficult because of the
Attention to this problem is especially important during the first few
complex nature of the pivotal clinical trial evaluating it in STEMI

days in the coronary care unit, where the atmosphere of 24-h vigi-
(OASIS-6). Fondaparinux appears superior to placebo in STEMI
lance may interfere with the patient’s sleep. However, sedation is no
patients not receiving reperfusion therapy, but its relative efficacy and
substitute for reassuring, quiet surroundings. Many drugs used in the
safety compared with UFH is less certain. Owing to the risk of cathe-
coronary care unit, such as atropine, H2 blockers, and narcotics, can
ter thrombosis, fondaparinux should not be used alone at the time of
produce delirium, particularly in the elderly. This effect should not be
coronary angiography and PCI but should be combined with another
confused with agitation, and it is wise to conduct a thorough review
anticoagulant with antithrombin activity such as UFH or bivalirudin.
of the patient’s medications before arbitrarily prescribing additional
Contemporary trials of bivalirudin used an open-label design to evaluate
doses of anxiolytics.
its efficacy and safety compared with UFH plus a glycoprotein IIb/IIIa
inhibitor. Bivalirudin was associated with a lower rate of bleeding,
PHARMACOTHERAPY largely driven by reductions in vascular access site hematomas ≥5 cm
■■ANTITHROMBOTIC AGENTS or the administration of blood transfusions.
The use of antiplatelet and anticoagulant therapy during the initial Patients with an anterior location of the infarction, severe LV dys-
phase of STEMI is based on extensive laboratory and clinical evidence function, heart failure, a history of embolism, two-dimensional echoc-
that thrombosis plays an important role in the pathogenesis of this ardiographic evidence of mural thrombus, or atrial fibrillation are at
condition. The primary goal of treatment with antiplatelet and antico- increased risk of systemic or pulmonary thromboembolism. Such indi-
agulant agents is to maintain patency of the infarct-related artery, in viduals should receive full therapeutic levels of anticoagulant therapy
conjunction with reperfusion strategies. A secondary goal is to reduce (LMWH or UFH) while hospitalized, followed by at least 3 months of
the patient’s tendency to thrombosis and, thus, the likelihood of mural warfarin therapy.
thrombus formation or deep-venous thrombosis, either of which could
result in pulmonary embolization. The degree to which antiplatelet ■■BETA-ADRENOCEPTOR BLOCKERS
and anticoagulant therapy achieves these goals partly determines how The benefits of beta blockers in patients with STEMI can be divided into
effectively it reduces the risk of mortality from STEMI. those that occur immediately when the drug is given acutely and those
As noted previously (see “Management in the Emergency that accrue over the long term when the drug is given for secondary pre-
Department” earlier), aspirin is the standard antiplatelet agent for vention after an infarction. Acute intravenous beta blockade improves
patients with STEMI. The most compelling evidence for the benefits the myocardial O2 supply-demand relationship, decreases pain, reduces
of antiplatelet therapy (mainly with aspirin) in STEMI is found in the infarct size, and decreases the incidence of serious ventricular arrhyth-
comprehensive overview by the Antiplatelet Trialists’ Collaboration. mias. In patients who undergo fibrinolysis soon after the onset of chest
Data from nearly 20,000 patients with MI enrolled in 15 randomized pain, no incremental reduction in mortality rate is seen with beta block-
trials were pooled and revealed a relative reduction of 27% in the mor- ers, but recurrent ischemia and reinfarction are reduced.
tality rate, from 14.2% in control patients to 10.4% in patients receiving Thus, beta-blocker therapy after STEMI is useful for most patients
antiplatelet agents. (including those treated with an angiotensin-converting enzyme
Inhibitors of the P2Y12 ADP receptor prevent activation and aggre- [ACE] inhibitor) except those in whom it is specifically contraindicated
gation of platelets. The addition of the P2Y12 inhibitor clopidogrel to (patients with heart failure or severely compromised LV function, heart
background treatment with aspirin to STEMI patients reduces the block, orthostatic hypotension, or a history of asthma) and perhaps
risk of clinical events (death, reinfarction, stroke) and, in patients those whose excellent long-term prognosis (defined as an expected
receiving fibrinolytic therapy, has been shown to prevent reocclusion mortality rate of <1% per year, patients <55 years, no previous MI,
of a successfully reperfused infarct artery. New P2Y12 ADP receptor with normal ventricular function, no complex ventricular ectopy, and
antagonists, such as prasugrel and ticagrelor, are more effective than no angina) markedly diminishes any potential benefit.
clopidogrel in preventing ischemic complications in STEMI patients
undergoing PCI, but are associated with an increased risk of bleeding. ■■INHIBITION OF THE RENIN-ANGIOTENSIN-
Glycoprotein IIb/IIIa receptor inhibitors appear useful for preventing ALDOSTERONE SYSTEM
thrombotic complications in patients with STEMI undergoing PCI. ACE inhibitors reduce the mortality rate after STEMI, and the mortality
The standard anticoagulant agent used in clinical practice is unfrac- benefits are additive to those achieved with aspirin and beta blockers.
tionated heparin (UFH). The available data suggest that when UFH is The maximum benefit is seen in high-risk patients (those who are
added to a regimen of aspirin and a non-fibrin-specific thrombolytic elderly or who have an anterior infarction, a prior infarction, and/or
agent such as streptokinase, additional mortality benefit occurs (about globally depressed LV function), but evidence suggests that a short-
5 lives saved per 1000 patients treated). It appears that the immediate term benefit occurs when ACE inhibitors are prescribed unselectively
administration of intravenous UFH, in addition to a regimen of aspirin to all hemodynamically stable patients with STEMI (i.e., those with a
and relatively fibrin-specific fibrinolytic agents (tPA, rPA, or TNK), systolic pressure >100 mmHg). The mechanism involves a reduction in
helps to maintain patency of the infarct-related artery. This effect is ventricular remodeling after infarction (see “Ventricular Dysfunction”
achieved at the cost of a small increased risk of bleeding. The recom- later) with a subsequent reduction in the risk of CHF. The rate of recur-
mended dose of UFH is an initial bolus of 60 U/kg (maximum 4000 U) rent infarction may also be lower in patients treated chronically with
followed by an initial infusion of 12 U/kg per h (maximum 1000 U/h). ACE inhibitors after infarction.
The activated partial thromboplastin time during maintenance therapy Before hospital discharge, LV function should be assessed with an
should be 1.5–2 times the control value. imaging study. ACE inhibitors should be continued indefinitely in
Alternatives to UFH for anticoagulation of patients with STEMI are patients who have clinically evident CHF, in patients in whom an imag-
the low-molecular-weight heparin (LMWH) preparations, a synthetic ing study shows a reduction in global LV function or a large regional
version of the critical pentasaccharide sequence (fondaparinux), and the wall motion abnormality, or in those who are hypertensive.

Angiotensin receptor blockers (ARBs) should be administered pulmonary edema; and class IV, shock with systolic pressure <90 mmHg 1881
to STEMI patients who are intolerant of ACE inhibitors and who and evidence of peripheral vasoconstriction, peripheral cyanosis, men-
have either clinical or radiologic signs of heart failure. Long-term tal confusion, and oliguria. When this classification was established in
aldosterone blockade should be prescribed for STEMI patients with- 1967, the expected hospital mortality rate of patients in these classes
out significant renal dysfunction (creatinine ≥2.5 mg/dL in men and was as follows: class I, 0–5%; class II, 10–20%; class III, 35–45%; and

≥2.0 mg/dL in women) or hyperkalemia (potassium ≥5.0 mEq/L) who class IV, 85–95%. With advances in management, the mortality rate in
are already receiving therapeutic doses of an ACE inhibitor, have an each class has fallen, perhaps by as much as one-third to one-half.
LV ejection fraction ≤40%, and have either symptomatic heart failure Hemodynamic evidence of abnormal global LV function appears
or diabetes mellitus. A multidrug regimen for inhibiting the renin- when contraction is seriously impaired in 20–25% of the left ventricle.
angiotensin-aldosterone system has been shown to reduce both heart Infarction of ≥40% of the left ventricle usually results in cardiogenic
failure–related and sudden cardiac death–related cardiovascular mor- shock (Chap. 298). Positioning of a balloon flotation (Swan-Ganz) cath-
tality after STEMI, but has not been as thoroughly explored as ACE eter in the pulmonary artery permits monitoring of LV filling pressure;
inhibitors in STEMI patients. this technique is useful in patients who exhibit hypotension and/or
clinical evidence of CHF. Cardiac output can also be determined with
■■OTHER AGENTS a pulmonary artery catheter. With the addition of intraarterial pressure
Favorable effects on the ischemic process and ventricular remodeling monitoring, systemic vascular resistance can be calculated as a guide
(see below) previously led many physicians to routinely use intravenous to adjusting vasopressor and vasodilator therapy. Some patients with
nitroglycerin (5–10 μg/min initial dose and up to 200 μg/min as long STEMI have markedly elevated LV filling pressures (>22 mmHg)
as hemodynamic stability is maintained) for the first 24–48 h after the and normal cardiac indices (2.6–3.6 L/[min/m2]), while others have
onset of infarction. However, the benefits of routine use of intravenous relatively low LV filling pressures (<15 mmHg) and reduced cardiac
nitroglycerin are less in the contemporary era where beta-adrenoceptor indices. The former patients usually benefit from diuresis, while the
blockers and ACE inhibitors are routinely prescribed for patients with latter may respond to volume expansion.
STEMI.
Results of multiple trials of different calcium antagonists have failed ■■HYPOVOLEMIA
to establish a role for these agents in the treatment of most patients with This is an easily corrected condition that may contribute to the
STEMI. Therefore, the routine use of calcium antagonists cannot be hypotension and vascular collapse associated with STEMI in some
recommended. Strict control of blood glucose in diabetic patients with patients. It may be secondary to previous diuretic use, to reduced fluid
STEMI has been shown to reduce the mortality rate. Serum magnesium intake during the early stages of the illness, and/or to vomiting asso-
should be measured in all patients on admission, and any demon- ciated with pain or medications. Consequently, hypovolemia should
strated deficits should be corrected to minimize the risk of arrhythmias. be identified and corrected in patients with STEMI and hypotension
before more vigorous forms of therapy are begun. Central venous pres-
COMPLICATIONS AND THEIR MANAGEMENT sure reflects RV rather than LV filling pressure and is an inadequate
guide for adjustment of blood volume, because LV function is almost
■■VENTRICULAR DYSFUNCTION always affected much more adversely than RV function in patients
After STEMI, the left ventricle undergoes a series of changes in shape, with STEMI. The optimal LV filling or pulmonary artery wedge pres-
size, and thickness in both the infarcted and noninfarcted segments. sure may vary considerably among patients. Each patient’s ideal level
This process is referred to as ventricular remodeling and generally pre- (generally ~20 mmHg) is reached by cautious fluid administration dur-
cedes the development of clinically evident CHF in the months to years ing careful monitoring of oxygenation and cardiac output. Eventually,
after infarction. Soon after STEMI, the left ventricle begins to dilate.
the cardiac output plateaus, and further increases in LV filling pressure
Acutely, this results from expansion of the infarct, i.e., slippage of
only increase congestive symptoms and decrease systemic oxygenation
muscle bundles, disruption of normal myocardial cells, and tissue loss
without raising arterial pressure.
within the necrotic zone, resulting in disproportionate thinning and
elongation of the infarct zone. Later, lengthening of the noninfarcted
segments occurs as well. The overall chamber enlargement that occurs TREATMENT
is related to the size and location of the infarct, with greater dilation Congestive Heart Failure
following infarction of the anterior wall and apex of the left ventricle
and causing more marked hemodynamic impairment, more frequent The management of CHF in association with STEMI is similar to
heart failure, and a poorer prognosis. Progressive dilation and its clin- that of acute heart failure secondary to other forms of heart disease
ical consequences may be ameliorated by therapy with ACE inhibitors (avoidance of hypoxemia, diuresis, afterload reduction, inotropic
and other vasodilators (e.g., nitrates). In patients with an ejection frac- support) (Chap. 252), except that the benefits of digitalis admin-
tion <40%, regardless of whether or not heart failure is present, ACE istration to patients with STEMI are unimpressive. By contrast,
inhibitors or ARBs should be prescribed (see “Inhibition of the Renin- diuretic agents are extremely effective, as they diminish pulmonary
Angiotensin-Aldosterone System” earlier). congestion in the presence of systolic and/or diastolic heart failure.
LV filling pressure falls and orthopnea and dyspnea improve after
■■HEMODYNAMIC ASSESSMENT the intravenous administration of furosemide or other loop diuret-
Pump failure is now the primary cause of in-hospital death from ics. These drugs should be used with caution, however, as they can
STEMI. The extent of infarction correlates well with the degree of pump result in a massive diuresis with associated decreases in plasma
failure and with mortality, both early (within 10 days of infarction) and volume, cardiac output, systemic blood pressure, and, hence, coro-
later. The most common clinical signs are pulmonary rales and S3 and nary perfusion. Nitrates in various forms may be used to decrease
S4 gallop sounds. Pulmonary congestion is also frequently seen on the preload and congestive symptoms. Oral isosorbide dinitrate, topical
chest roentgenogram. Elevated LV filling pressure and elevated pulmo- nitroglycerin ointment, and intravenous nitroglycerin all have the
nary artery pressure are the characteristic hemodynamic findings, but advantage over a diuretic of lowering preload through venodilation
these findings may result from a reduction of ventricular compliance without decreasing the total plasma volume. In addition, nitrates
(diastolic failure) and/or a reduction of stroke volume with secondary may improve ventricular compliance if ischemia is present, as ische-
cardiac dilation (systolic failure) (Chap. 252). mia causes an elevation of LV filling pressure. Vasodilators must be
A classification originally proposed by Killip divides patients into used with caution to prevent serious hypotension. As noted earlier,
four groups: class I, no signs of pulmonary or venous congestion; ACE inhibitors are an ideal class of drugs for management of ven-
class II, moderate heart failure as evidenced by rales at the lung bases, tricular dysfunction after STEMI, especially for the long term. (See
S3 gallop, tachypnea, or signs of failure of the right side of the heart, “Inhibition of the Renin-Angiotensin-Aldosterone System” earlier.)
including venous and hepatic congestion; class III, severe heart failure,

1882 ■■CARDIOGENIC SHOCK possible noncardiac complications, lidocaine may predispose to an
Prompt reperfusion, efforts to reduce infarct size and treatment of excess risk of bradycardia and asystole. For these reasons, and with
ongoing ischemia and other complications of MI appear to have earlier treatment of active ischemia, more frequent use of beta-blocking
reduced the incidence of cardiogenic shock from 20 to about 7%. Only agents, and the nearly universal success of electrical cardioversion or
10% of patients with this condition present with it on admission, while defibrillation, routine prophylactic antiarrhythmic drug therapy is no
90% develop it during hospitalization. Typically, patients who develop longer recommended.
PART 6
cardiogenic shock have severe multivessel coronary artery disease Sustained ventricular tachycardia that is well tolerated hemodynami-
with evidence of “piecemeal” necrosis extending outward from the cally should be treated with an intravenous regimen of amiodarone (bolus
original infarct zone. The evaluation and management of cardiogenic of 150 mg over 10 min, followed by infusion of 1.0 mg/min for 6 h and
shock and severe power failure after STEMI are discussed in detail then 0.5 mg/min). A less desirable but alternative regimen is procain-
in Chap. 298. amide (bolus of 15 mg/kg over 20–30 min; infusion of 1–4 mg/min). If
ventricular tachycardia does not stop promptly, electroversion should
■■RIGHT VENTRICULAR INFARCTION be used (Chap. 241). An unsynchronized discharge of 200–300 J (mono-
Approximately one-third of patients with inferior infarction demon- phasic waveform; ~50% of these energies with biphasic waveforms)
strate at least a minor degree of RV necrosis. An occasional patient with is used immediately in patients with ventricular fibrillation or when
inferoposterior LV infarction also has extensive RV infarction, and rare ventricular tachycardia causes hemodynamic deterioration. Ventric-
patients present with infarction limited primarily to the RV. Clinically ular tachycardia or fibrillation that is refractory to electroshock may
significant RV infarction causes signs of severe RV failure (jugular be more responsive after the patient is treated with epinephrine (1 mg
venous distention, Kussmaul’s sign, hepatomegaly [Chap. 234]) with or intravenously or 10 mL of a 1:10,000 solution via the intracardiac route)
without hypotension. ST-segment elevations of right-sided precordial or amiodarone (a 75–150-mg bolus).
ECG leads, particularly lead V4R, are frequently present in the first 24 h Ventricular arrhythmias, including the unusual form of ventricular
in patients with RV infarction. Two-dimensional echocardiography is tachycardia known as torsades des pointes (Chaps. 247 and 249), may
helpful in determining the degree of RV dysfunction. Catheterization of occur in patients with STEMI as a consequence of other concurrent
the right side of the heart often reveals a distinctive hemodynamic pat- problems (such as hypoxia, hypokalemia, or other electrolyte distur-
tern resembling constrictive pericarditis (steep right atrial “y” descent bances) or of the toxic effects of an agent being administered to the
and an early diastolic dip and plateau in RV waveforms) (Chap. 265). patient (such as digoxin or quinidine). A search for such secondary
Therapy consists of volume expansion to maintain adequate RV pre- causes should always be undertaken.
load and efforts to improve LV performance with attendant reduction Although the in-hospital mortality rate is increased, the long-term
in pulmonary capillary wedge and pulmonary arterial pressures. survival is excellent in patients who survive to hospital discharge after
primary ventricular fibrillation; i.e., ventricular fibrillation that is a pri-
■■ARRHYTHMIAS mary response to acute ischemia that occurs during the first 48 h and
(See also Chaps. 239 and 241) The incidence of arrhythmias after is not associated with predisposing factors such as CHF, shock, bundle
STEMI is higher in patients seen early after the onset of symptoms. branch block, or ventricular aneurysm. This result is in sharp contrast
The mechanisms responsible for infarction-related arrhythmias include to the poor prognosis for patients who develop ventricular fibrillation
autonomic nervous system imbalance, electrolyte disturbances, ische- secondary to severe pump failure. For patients who develop ventricular
mia, and slowed conduction in zones of ischemic myocardium. An tachycardia or ventricular fibrillation late in their hospital course (i.e.,
arrhythmia can usually be managed successfully if trained personnel after the first 48 h), the mortality rate is increased both in-hospital
and appropriate equipment are available when it develops. Since and during long-term follow-up. Such patients should be considered
most deaths from arrhythmia occur during the first few hours after for electrophysiologic study and implantation of a cardioverter-
infarction, the effectiveness of treatment relates directly to the speed defibrillator (ICD) (Chap. 247). A more challenging issue is the pre-
with which patients come under medical observation. The prompt vention of sudden cardiac death from ventricular fibrillation late
management of arrhythmias constitutes a significant advance in the after STEMI in patients who have not exhibited sustained ventricular
treatment of STEMI. tachyarrhythmias during their index hospitalization. An algorithm for
Ventricular Premature Beats Infrequent, sporadic ventricular selection of patients who warrant prophylactic implantation of an ICD
premature depolarizations occur in almost all patients with STEMI and is shown in Fig. 269-5.
do not require therapy. Whereas in the past, frequent, multifocal, or Accelerated Idioventricular Rhythm Accelerated idioven-
early diastolic ventricular extrasystoles (so-called warning arrhythmias) tricular rhythm (AIVR, “slow ventricular tachycardia”), a ventricular
were routinely treated with antiarrhythmic drugs to reduce the risk of rhythm with a rate of 60–100 beats/min, often occurs transiently
development of ventricular tachycardia and ventricular fibrillation, during fibrinolytic therapy at the time of reperfusion. For the most
pharmacologic therapy is now reserved for patients with sustained part, AIVR, whether it occurs in association with fibrinolytic therapy
ventricular arrhythmias. Prophylactic antiarrhythmic therapy (either or spontaneously, is benign and does not presage the development of
intravenous lidocaine early or oral agents later) is contraindicated classic ventricular tachycardia. Most episodes of AIVR do not require
for ventricular premature beats in the absence of clinically important treatment if the patient is monitored carefully, as degeneration into a
ventricular tachyarrhythmias, because such therapy may actually more serious arrhythmia is rare.
increase the mortality rate. Beta-adrenoceptor blocking agents are effec-
tive in abolishing ventricular ectopic activity in patients with STEMI Supraventricular Arrhythmias Sinus tachycardia is the most
and in the prevention of ventricular fibrillation. As described earlier common supraventricular arrhythmia. If it occurs secondary to another
(see “Beta-Adrenoceptor Blockers”), they should be used routinely in cause (such as anemia, fever, heart failure, or a metabolic derange-
patients without contraindications. In addition, hypokalemia and hypo- ment), the primary problem should be treated first. However, if it
magnesemia are risk factors for ventricular fibrillation in patients with appears to be due to sympathetic overstimulation (e.g., as part of a
STEMI; to reduce the risk, the serum potassium concentration should be hyperdynamic state), then treatment with a beta blocker is indicated.
adjusted to ~4.5 mmol/L and magnesium to about 2.0 mmol/L. Other common arrhythmias in this group are atrial flutter and atrial
fibrillation, which are often secondary to LV failure. Digoxin is usu-
Ventricular Tachycardia and Fibrillation Within the first ally the treatment of choice for supraventricular arrhythmias if heart
24 h of STEMI, ventricular tachycardia and fibrillation can occur with- failure is present. If heart failure is absent, beta blockers, verapamil, or
out prior warning arrhythmias. The occurrence of ventricular fibril- diltiazem are suitable alternatives for controlling the ventricular rate,
lation can be reduced by prophylactic administration of intravenous as they may also help to control ischemia. If the abnormal rhythm per-
lidocaine. However, prophylactic use of lidocaine has not been shown sists for >2 h with a ventricular rate >120 beats/min, or if tachycardia
to reduce overall mortality from STEMI. In fact, in addition to causing induces heart failure, shock, or ischemia (as manifested by recurrent

1883
Sudden cardiac death
Learn more at
primary prevention protocols www. HRSonline.org

35% for Nonischemic cardiomyopathy
Ejection fraction ≤
40% for Ischemic cardiomyopathy
Any Post-MI or Ischemic Any

cardiomyopathy Post-MI
cardiomyopathy With revascularization Without revascularization cardiomyopathy
Not on optimal ICD waiting period >40 days Beyond ICD waiting period
(PCI or CAB)
medical therapy on Optimal Medical Therapy
ICD waiting period >3 months
Initiate or titrate medical therapy

Beta blocker — ACE/ARB — Aldosterone antagonist
Discharge home; Continue optimization of medical therapy

Consider consultation with heart rhythm specialist/consider wearable cardioverter defibrillator
Reassess EF @ 3 months Reassess EF @ 40 days
Nonischemic Consider further risk stratification/

Ischemic EF = 36–40% Consultation with heart rhythm
cardiomyopathy cardio- specialist*
EF ≤35% myopathy EF ≤35%
Refer for consultation with Heart Rhythm specialist
* Buxton AE, Lee KL, Fisher JD, Josephson ME, Prystowsky EN, Hafley G.A randomized study of the prevention of sudden death in patients with coronary artery disease.
Multicenter Unsustained Tachycardia Trial Investigators. N Engl J Med. December 16, 1999;341(25):1882–1890.
Recommended by SCA Prevention Protocols Working Group (Version 2; Revised; 9/10/2012; Review date: 9/10/2013) All rights reserved. Copyright ©2012 Heart Rhythm Society
FIGURE 269-5 Algorithm for assessment of need for implantation of a cardioverter-defibrillator. The appropriate management is selected based on measurement
of left ventricular ejection fraction, the timing following infarction, and whether revascularization has been performed. (Reproduced from data at www.hrsonline.org.)
pain or ECG changes), a synchronized electroshock (100–200 J mono- Pacing does appear to be beneficial in patients with inferoposterior
phasic waveform) should be used. infarction who have complete heart block associated with heart failure,
Accelerated junctional rhythms have diverse causes but may occur hypotension, marked bradycardia, or significant ventricular ectopic
in patients with inferoposterior infarction. Digitalis excess must be activity. A subgroup of these patients, those with RV infarction, often
ruled out. In some patients with severely compromised LV function, respond poorly to ventricular pacing because of the loss of the atrial
the loss of appropriately timed atrial systole results in a marked reduc- contribution to ventricular filling. In such patients, dual-chamber AV
tion of cardiac output. Right atrial or coronary sinus pacing is indicated sequential pacing may be required.
in such instances. External noninvasive pacing electrodes should be positioned
in a “demand” mode for patients with sinus bradycardia (rate
Sinus Bradycardia Treatment of sinus bradycardia is indicated
<50 beats/min) that is unresponsive to drug therapy, Mobitz II second-
if hemodynamic compromise results from the slow heart rate. Atro-
degree AV block, third-degree heart block, or bilateral bundle branch
pine is the most useful drug for increasing heart rate and should be
block (e.g., right bundle branch block plus left anterior fascicular
given intravenously in doses of 0.5 mg initially. If the rate remains
block). Retrospective studies suggest that permanent pacing may
<50–60 beats/min, additional doses of 0.2 mg, up to a total of 2.0 mg,
reduce the long-term risk of sudden death due to bradyarrhythmias
may be given. Persistent bradycardia (<40 beats/min) despite atropine
in the rare patient who develops combined persistent bifascicular and
may be treated with electrical pacing. Isoproterenol should be avoided.
transient third-degree heart block during the acute phase of MI.
Atrioventricular and Intraventricular Conduction Distur-
bances (See also Chap. 239) Both the in-hospital mortality rate ■■OTHER COMPLICATIONS
and the postdischarge mortality rate of patients who have complete Recurrent Chest Discomfort Because recurrent or persistent
atrioventricular (AV) block in association with anterior infarction are ischemia often heralds extension of the original infarct or reinfarction
markedly higher than those of patients who develop AV block with in a new myocardial zone and is associated with a near tripling of mor-
inferior infarction. This difference is related to the fact that heart block tality after STEMI, patients with these symptoms should be referred
in inferior infarction is commonly a result of increased vagal tone and/ for prompt coronary arteriography and mechanical revascularization.
or the release of adenosine and therefore is transient. In anterior wall Administration of a fibrinolytic agent is an alternative to early mechan-
infarction, however, heart block is usually related to ischemic malfunc- ical revascularization.
tion of the conduction system, which is commonly associated with
extensive myocardial necrosis. Pericarditis (See also Chap. 265) Pericardial friction rubs and/
Temporary electrical pacing provides an effective means of increas- or pericardial pain are frequently encountered in patients with STEMI
ing the heart rate of patients with bradycardia due to AV block. How- involving the epicardium. This complication can usually be managed
ever, acceleration of the heart rate may have only a limited impact on with aspirin (650 mg four times daily). It is important to diagnose the
prognosis in patients with anterior wall infarction and complete heart chest pain of pericarditis accurately, because failure to recognize it
block in whom the large size of the infarct is the major factor determin- may lead to the erroneous diagnosis of recurrent ischemic pain and/
ing outcome. It should be carried out if it improves hemodynamics. or infarct extension, with resulting inappropriate use of anticoagulants,

1884 nitrates, beta blockers, or coronary arteriography. When it occurs, com- patients, submaximal exercise stress testing may be carried out before
plaints of pain radiating to either trapezius muscle is helpful, because hospital discharge to detect residual ischemia and ventricular ectopy
such a pattern of discomfort is typical of pericarditis but rarely occurs and to provide the patient with a guideline for exercise in the early
with ischemic discomfort. Anticoagulants potentially could cause tam- recovery period. Alternatively, or in addition, a maximal (symptom-
ponade in the presence of acute pericarditis (as manifested by either limited) exercise stress test may be carried out 4–6 weeks after infarction.
pain or persistent rub) and therefore should not be used unless there is Evaluation of LV function is usually warranted as well. Recognition of
PART 6
a compelling indication. a depressed LV ejection fraction by echocardiography or radionuclide

ventriculography identifies patients who should receive medications
Thromboembolism Clinically apparent thromboembolism com- to inhibit the renin-angiotensin-aldosterone system. Patients in whom
plicates STEMI in ~10% of cases, but embolic lesions are found in 20%
angina is induced at relatively low workloads, those who have a large
of patients in necropsy series, suggesting that thromboembolism is
reversible defect on perfusion imaging or a depressed ejection frac-

often clinically silent. Thromboembolism is considered to be an impor-
tion, those with demonstrable ischemia, and those in whom exercise
tant contributing cause of death in 25% of patients with STEMI who die
provokes symptomatic ventricular arrhythmias should be considered
after admission to the hospital. Arterial emboli originate from LV mural
at high risk for recurrent MI or death from arrhythmia (Fig. 269-5).
thrombi, while most pulmonary emboli arise in the leg veins.
Cardiac catheterization with coronary angiography and/or invasive
Thromboembolism typically occurs in association with large
electrophysiologic evaluation is advised.
infarcts (especially anterior), CHF, and an LV thrombus detected by
Exercise tests also aid in formulating an individualized exercise pre-
echocardiography. The incidence of arterial embolism from a clot
scription, which can be much more vigorous in patients who tolerate
originating in the ventricle at the site of an infarction is small but real. Two-
exercise without any of the previously mentioned adverse signs. In
dimensional echocardiography reveals LV thrombi in about one-third
addition, predischarge stress testing may provide an important psy-
of patients with anterior wall infarction but in few patients with infe-
chological benefit, building the patient’s confidence by demonstrating
rior or posterior infarction. Arterial embolism often presents as a major
a reasonable exercise tolerance.
complication, such as hemiparesis when the cerebral circulation is
In many hospitals, a cardiac rehabilitation program with progres-
involved or hypertension if the renal circulation is compromised. When
sive exercise is initiated in the hospital and continued after discharge.
a thrombus has been clearly demonstrated by echocardiographic or
Ideally, such programs should include an educational component that
other techniques or when a large area of regional wall motion abnor-
informs patients about their disease and its risk factors.
mality is seen even in the absence of a detectable mural thrombus,
The usual duration of hospitalization for an uncomplicated STEMI
systemic anticoagulation should be undertaken (in the absence of
is about 3–5 days. The remainder of the convalescent phase may be
contraindications), as the incidence of embolic complications appears
accomplished at home. During the first 1–2 weeks, the patient should
to be markedly lowered by such therapy. The appropriate duration of
be encouraged to increase activity by walking about the house and out-
therapy is unknown, but 3–6 months is probably prudent.
doors in good weather. Normal sexual activity may be resumed during
Left Ventricular Aneurysm The term ventricular aneurysm is this period. After 2 weeks, the physician must regulate the patient’s
usually used to describe dyskinesis or local expansile paradoxical wall activity on the basis of exercise tolerance. Most patients will be able to
motion. Normally functioning myocardial fibers must shorten more return to work within 2–4 weeks.
if stroke volume and cardiac output are to be maintained in patients
with ventricular aneurysm; if they cannot, overall ventricular function SECONDARY PREVENTION
is impaired. True aneurysms are composed of scar tissue and neither Various secondary preventive measures are at least partly responsible
predispose to nor are associated with cardiac rupture. for the improvement in the long-term mortality and morbidity rates
The complications of LV aneurysm do not usually occur for weeks after STEMI. Long-term treatment with an antiplatelet agent (usually
to months after STEMI; they include CHF, arterial embolism, and aspirin) after STEMI is associated with a 25% reduction in the risk
ventricular arrhythmias. Apical aneurysms are the most common and of recurrent infarction, stroke, or cardiovascular mortality (36 fewer
the most easily detected by clinical examination. The physical finding events for every 1000 patients treated). An alternative antiplatelet
of greatest value is a double, diffuse, or displaced apical impulse. agent that may be used for secondary prevention in patients intolerant
Ventricular aneurysms are readily detected by two-dimensional echoc- of aspirin is clopidogrel (75 mg orally daily). ACE inhibitors or ARBs
ardiography, which may also reveal a mural thrombus in an aneurysm. and, in appropriate patients, aldosterone antagonists should be used
Rarely, myocardial rupture may be contained by a local area of indefinitely by patients with clinically evident heart failure, a moder-
pericardium, along with organizing thrombus and hematoma. Over ate decrease in global ejection fraction, or a large regional wall motion
time, this pseudoaneurysm enlarges, maintaining communication with abnormality to prevent late ventricular remodeling and recurrent
the LV cavity through a narrow neck. Because a pseudoaneurysm often ischemic events.
ruptures spontaneously, it should be surgically repaired if recognized. The chronic routine use of oral beta-adrenoceptor blockers for at
least 2 years after STEMI is supported by well-conducted, placebo-
POSTINFARCTION RISK STRATIFICATION controlled trials.
AND MANAGEMENT Evidence suggests that warfarin lowers the risk of late mortality
Many clinical and laboratory factors have been identified that are asso- and the incidence of reinfarction after STEMI. Most physicians pre-
ciated with an increase in cardiovascular risk after initial recovery from scribe aspirin routinely for all patients without contraindications
STEMI. Some of the most important factors include persistent ischemia and add warfarin for patients at increased risk of embolism (see
(spontaneous or provoked), depressed LV ejection fraction (<40%), “Thromboembolism” earlier). Several studies suggest that in patients
rales above the lung bases on physical examination or congestion on <75 years old a low dose of aspirin (75–81 mg/d) in combination with
chest radiograph, and symptomatic ventricular arrhythmias. Other warfarin administered to achieve an international normalized ratio
features associated with increased risk include a history of previous >2.0 is more effective than aspirin alone for preventing recurrent MI
MI, age >75, diabetes mellitus, prolonged sinus tachycardia, hypoten- and embolic cerebrovascular accident. However, there is an increased
sion, ST-segment changes at rest without angina (“silent ischemia”), an risk of bleeding and a high rate of discontinuation of warfarin that
abnormal signal-averaged ECG, nonpatency of the infarct-related cor- has limited clinical acceptance of combination antithrombotic therapy.
onary artery (if angiography is undertaken), and persistent advanced There is an increased risk of bleeding when warfarin is added to dual
heart block or a new intraventricular conduction abnormality on the antiplatelet therapy (see Chap. 267). However, patients who have had
ECG. Therapy must be individualized on the basis of the relative a stent implanted and have an indication for anticoagulation should
importance of the risk(s) present. receive dual antiplatelet therapies in combination with warfarin. Such
The goal of preventing reinfarction and death after recovery from patients should also receive a proton pump inhibitor to minimize the
STEMI has led to strategies to evaluate risk after infarction. In stable risk of gastrointestinal bleeding and should have regular monitoring

of their hemoglobin levels and stool hematest while on combination coronary intervention (PCI) is the most common revascularization 1885
antithrombotic therapy. procedure in the United States and is performed more than twice as
Finally, risk factors for atherosclerosis (Chap. 232) should be dis- often as coronary artery bypass surgery: nearly 900,000 patients a year.
cussed with the patient and, when possible, favorably modified. Interventional cardiology is a separate discipline in cardiology
that requires a dedicated 1-year interventional cardiology fellowship
CHAPTER 270 Percutaneous Coronary Interventions and Other Interventional Procedures

■■FURTHER READING following a 3-year general cardiology fellowship in order to obtain
Al-Khatib SM et al: Defibrillators: Selecting the right device for the a separate board certification. The discipline has also expanded to
right patient. Circulation 134:1390, 2016. include interventions for structural heart disease including treatment
Claeys MJ: Is primary percutaneous coronary intervention still the of congenital heart disease and valvular heart disease; it also includes
superior reperfusion strategy? JAMA Intern Med 175:216, 2015. interventions to treat peripheral vascular disease, including atheroscle-
Hollander JE et al: State-of-the-art evaluation of emergency depart- rotic and nonatherosclerotic lesions in the carotid, renal, aortic, and
ment patients presenting with potential acute coronary syndromes. peripheral arterial and venous circulations.
Circulation 134:547, 2016.
Kidambi A, Plein S: Risk stratification in acute myocardial infarction TECHNIQUE
with multiparametric cardiac magnetic resonance imaging: Getting to The initial procedure is performed in a similar manner as a diagnostic
the core of the matter. Eur Heart J 37:1060, 2016. cardiac catheterization (Chap. 237). Arterial access is obtained via the
Levine GN et al: 2015 ACC/AHA/SCAI focused update on primary femoral or radial artery. To prevent thrombotic complications during
percutaneous coronary intervention for patients with ST-elevation the procedure, patients who are anticipated to need an angioplasty
myocardial infarction: An update of the 2011 ACCF/AHA/SCAI are given aspirin (325 mg) and may be given a platelet P2Y12 inhibitor
guideline for percutaneous coronary intervention and the 2013 such as clopidogrel (loading dose of 600 mg), prasugrel (loading dose
ACCF/AHA guideline for the management of ST-elevation myo- of 60 mg), or ticagrelor (loading dose of 180 mg) before the procedure.
cardial infarction: A report of the American College of Cardiology/ Cangrelor, an IV P2Y12 inhibitor, is approved for use in patients who
American Heart Association Task Force on Clinical Practice Guide- have not received an oral agent prior to the procedure. During the
lines and the Society for Cardiovascular Angiography and Interven- procedure, anticoagulation is achieved by administration of unfrac-
tions. Circulation 133:1135, 2016. tionated heparin, enoxaparin (a low-molecular-weight heparin), or
Mannsverk J et al: Trends in modifiable risk factors are associated with bivalirudin (a direct thrombin inhibitor). In patients with ST-elevation
declining incidence of hospitalized and nonhospitalized acute coro- myocardial infarction, high-risk acute coronary syndrome, or a large
nary heart disease in a population. Circulation 133:7, 2016. thrombus in the coronary artery, an intravenous glycoprotein IIb/IIIa
Montecucco F et al: Pathophysiology of ST-segment elevation myo- inhibitor (abciximab, tirofiban, or eptifibatide) may also be given,
cardial infarction: Novel mechanisms and treatments. Eur Heart J though cangrelor may be as effective with less bleeding risk.
37:1268, 2016. Following placement of an introducing sheath into the artery, pre-
Mozaffarian D et al: Heart disease and stroke statistics—2016 update: formed guiding catheters are used to cannulate selectively the origins
A report from the American Heart Association. Circulation 133:e3, of the coronary arteries. Through the guiding catheter, a flexible,
2016. steerable guidewire is negotiated down the coronary artery lumen
Sugiyama T et al: Differential time trends of outcomes and costs of care using fluoroscopic guidance; it is then advanced through the stenosis
for acute myocardial infarction hospitalizations by ST elevation and and into the vessel beyond. This guidewire then serves as a “rail” over
type of intervention in the United States, 2001–2011. JAMA 4:e001445, which angioplasty balloons, stents, or other therapeutic devices can
2015. be advanced to enlarge the narrowed segment of coronary artery. The
artery is usually dilated with a balloon catheter followed by placement
of a stent. The catheters and introducing sheath are removed and the
artery manually held or in the case of radial access use of an inflatable
cuff. One of several femoral arterial closure devices can also be used to
achieve hemostasis. Because PCI is performed under local anesthesia
270 Percutaneous Coronary

Interventions and Other
and mild sedation, it requires only a short (1-day) hospitalization or
less.
Angioplasty works by stretching the artery and displacing the
plaque away from the lumen, enlarging the entire vessel (Figs. 270-1
Interventional Procedures and 270-2). The procedure rarely results in embolization of atheroscle-
rotic material. Owing to inelastic elements in the plaque, the stretching
David P. Faxon, Deepak L. Bhatt of the vessel by the balloon results in small localized dissections that
can protrude into the lumen and be a nidus for acute thrombus forma-
tion. If the dissections are severe, then they can obstruct the lumen or
Percutaneous transluminal coronary angioplasty (PTCA) was first induce a thrombotic occlusion of the artery (acute closure). Stents have
introduced by Andreas Gruentzig in 1977 as an alternative to coronary largely prevented this complication by holding the dissection flaps up
bypass surgery. The concept was initially demonstrated by Charles against the vessel wall (Fig. 270-1).
Dotter in 1964 in peripheral vessels. The development of a small inelas- Stents are currently used in >90% of coronary angioplasty proce-
tic balloon catheter by Gruentzig allowed expansion of the technique dures. Stents are wire meshes (usually made of stainless steel or other
into smaller peripheral and coronary vessels. Initial coronary experi- metals, such as cobalt chromium or nitinol) that are compressed over
ence was limited to single-vessel coronary disease and discrete proxi- a deflated angioplasty balloon. When the balloon is inflated, the stent
mal lesions due to the technical limitations of the equipment. Advances is enlarged to approximate the “normal” vessel lumen. The balloon is
in technology and greater operator experience allowed the procedure then deflated and removed, leaving the stent behind to provide a per-
to grow rapidly with expanded use in patients with more complex manent scaffold in the artery. Owing to the design of the struts, these
lesions and multivessel disease. The introduction of coronary stents in devices are flexible, allowing their passage through diseased and tor-
1994 was one of the major advances in the field. These devices reduced tuous coronary vessels. Stents are rigid enough to prevent elastic recoil
acute complications and reduced by half the significant problems of of the vessel and have dramatically improved the success and safety of
acute thrombosis and late restenosis (or recurrence of the stenosis). the procedure as a result.
Further reductions in restenosis were achieved by the introduction of Drug-eluting stents further enhanced the efficacy of PCI. An anti-
drug-eluting stents in 2003. These stents slowly release antiprolifera- proliferative agent is attached to the metal stent by use of a thin poly-
tive drugs directly into the plaque over a few months. Percutaneous mer coating. The antiproliferative drug elutes from the stent over a 1- to

1886
PART 6
A B C D
FIGURE 270-1 Schematic diagram of the primary mechanisms of balloon angioplasty and stenting. A. A balloon angioplasty catheter is positioned into the stenosis
over a guidewire under fluoroscopic guidance. B. The balloon is inflated, temporarily occluding the vessel. C. The lumen is enlarged primarily by stretching the vessel,
often resulting in small dissections in the neointima. D. A stent mounted on a deflated balloon is placed into the lesion and pressed against the vessel wall with balloon
inflation (not shown). The balloon is deflated and removed, leaving the stent permanently against the wall acting as a scaffold to hold the dissections against the wall
and prevent vessel recoil. (Adapted from EJ Topol: Textbook of Cardiovascular Medicine, 2nd ed. Philadelphia, Lippincott Williams & Wilkins, 2002.)
3-month period or longer after implantation. Drug-eluting stents have used to attach the drugs to the stents may be theoretically superior to
been shown to reduce clinical restenosis by 50%, so that in uncompli- permanent polymers in preventing late stent thrombosis. In addition,
cated lesions symptomatic restenosis occurs in 5–10% of patients. Not the everolimus-eluting biodegradable vascular scaffold (BVS) stent has
surprisingly, this led to the rapid acceptance of these devices; currently been shown to be reasonably safe with gradual degradation over sev-
80–90% of all stents implanted are drug-eluting. The first-generation eral years with improvement in vessel function. Additional bioresorb-
devices were coated with either sirolimus or paclitaxel. Second-generation able stents are under investigation. Drug-coated balloons are covered
drug-eluting stents use newer agents such as everolimus, biolimus, with an antiproliferative drug that can also reduce restenosis, and are
and zotarolimus. These second-generation drug-eluting stents appear used primarily to treat in-stent restenosis.
to be more effective with fewer complications, such as early or late Other interventional devices include atherectomy devices and
stent thrombosis, than the first-generation devices and, therefore, have thrombectomy catheters. These devices are designed to remove athero-
replaced the first-generation stents. Biodegradable polymers that are sclerotic plaque or thrombus and are used in conjunction with balloon
dilatation and stent placement. Rotational atherectomy is the most
commonly used adjunctive device and is modeled after a dentist’s drill,
with small round burrs of 1.25–2.5 mm at the tip of a flexible wire shaft.
The burr is passed over the guidewire up to the stenosis and drills
away atherosclerotic material. Because the atherosclerotic particles are
≤25 μm, they pass through the coronary microcirculation and rarely
cause problems. The device is particularly useful in heavily calcified
plaques that are resistant to balloon dilatation. Given the current
advances in stents, rotational atherectomy is infrequently used. Orbital
atherectomy is a newer approach to calcified lesions that also relies
on a spinning burr. Directional atherectomy catheters that slice off the
plaque and remove it are not used in the coronaries any longer but are
used in peripheral artery disease. In acute ST-elevation myocardial
infarction, specialized catheters without a balloon are used to aspirate
A thrombus in order to prevent embolization down the coronary vessel
and to improve blood flow before angioplasty and stent placement.
Current studies suggest that manual catheter thrombus aspiration
should not be used routinely, but in certain cases of a large thrombus
burden, can improve blood flow in primary PCI.
PCI of degenerated saphenous vein graft lesions has been associated
with a significant incidence of distal embolization of atherosclerotic
material, unlike PCI of native vessel disease. A number of distal pro-
tection devices have been shown to significantly reduce embolization
and myocardial infarction in this setting. Most devices work by using a
collapsible wire filter at the end of a guidewire that is expanded in the
distal vessel before PCI. If atherosclerotic debris is dislodged, the bas-
ket captures the material, and at the end of the PCI, the basket is pulled
into a delivery catheter and the debris safely removed from the patient.
B
FIGURE 270-2 Pathology of acute effects of balloon angioplasty with intimal
SUCCESS AND COMPLICATIONS
dissection and vessel stretching (A) and an example of neointimal hyperplasia
A successful procedure (angiographic success), defined as a reduction
and restenosis showing renarrowing of the vessel (B). (Panel A from M Ueda et al: of the stenosis to less than a 20% diameter narrowing, occurs in 95–99%
Eur Heart J 12:937, 1991; with permission. Panel B from CE Essed et al: Br Heart of patients. Lower success rates are seen in patients with tortuous,
J 49:393, 1983; with permission.) small, or calcified vessels or chronic total occlusions. Chronic total

occlusions have the lowest success rates and their recanalization is sig- (TLR or TVR) because many patients have mild restenosis that does 1887
nificantly better if the occlusion is recent (within 3 months) or there are not result in a recurrence of symptoms. The management of clinical
favorable anatomic features. Improvements in equipment and complex restenosis is usually to repeat the PCI with balloon dilatation and
antegrade and retrograde techniques have increased the success rates placement of another drug-eluting stent. Once a patient has had res-
of recanalization of chronic total occlusions to 70–80%. tenosis, the risk of a second restenosis is further increased. The risk

Serious complications are rare but include a mortality rate of factors for restenosis are diabetes, myocardial infarction, long lesions,
0.1–0.3% for elective cases, a large myocardial infarction in <3%, and small-diameter vessels, and suboptimal initial PCI result.
stroke in <0.1%. Patients who are elderly (>65 years), undergoing an
emergent or urgent procedure, have chronic kidney disease, present INDICATIONS
with an ST-segment elevation myocardial infarction (STEMI), or are The American College of Cardiology (ACC)/American Heart Associ-
in shock have significantly higher risk. Scoring systems can help to ation (AHA) guidelines extensively review the indications for PCI in
estimate the risk of the procedure. Myocardial infarction during PCI patients with stable angina, unstable angina, NSTEMI, and STEMI and
can occur for multiple reasons including an acute occluding thrombus, should be referred to for a comprehensive discussion of the indications.
severe coronary dissection, embolization of thrombus or atherosclerotic Briefly, the two principal indications for coronary revascularization in
material, or closure of a side branch vessel at the site of angioplasty patients with chronic stable angina (Chap. 267) are (1) to improve angina
or stent placement. Most myocardial infarctions are small and only symptoms in patients who remain symptomatic despite adequate med-
detected by a rise in the creatine phosphokinase (CPK) or troponin ical therapy and (2) to reduce mortality rates in patients with severe
level after the procedure. Only those with significant enzyme eleva- and extensive coronary disease. In patients with stable angina who are
tions (more than five times the upper limit of normal) are associated well controlled on medical therapy, studies such as the Clinical Out-
with a less favorable long-term outcome. Coronary stents have largely comes Utilizing Revascularization and Aggressive Drug Evaluation
prevented coronary dissections due to the scaffolding effect of the stent. (COURAGE) and Bypass Angioplasty Revascularization Investigation
All types of stents are prone to stent thrombosis (1–3%), either acute 2 Diabetes (BARI 2D) trials have shown that initial revascularization
(<24 h) or subacute (1–30 days), which can be ameliorated by greater does not lead to better outcomes (death or MI) and can be safely
attention to full initial stent deployment and the use of dual antiplate- delayed until symptoms worsen or evidence of severe ischemia on non-
let therapy (DAPT) (aspirin, plus a platelet P2Y12 receptor blocker invasive testing occurs. When revascularization is indicated, the choice
[clopidogrel, prasugrel, or ticagrelor]). Late (30 days–1 year) and very of PCI or CABG depends on a number of clinical and anatomic factors.
late stent thromboses (>1 year) occur very infrequently with stents but The Synergy between Percutaneous Coronary Intervention with Taxus
are slightly more common with first-generation drug-eluting stents, and Cardiac Surgery (SYNTAX) trial compared PCI with the paclitaxel
necessitating DAPT for up to 1 year or longer. Use of the second- drug-eluting stent to CABG in 1800 patients with three-vessel coronary
generation stents is associated with lower rates of late and very late disease or left main disease. The study found no difference in death or
stent thromboses, and shorter durations of DAPT (6 months) are recom- myocardial infarction at 1 year, but repeat revascularization was sig-
mended. Premature discontinuation of DAPT, particularly in the first nificantly higher in the stent-treated group (13.5 vs 5.9%), while stroke
month after implantation, is associated with a significantly increased was significantly higher in the surgical group (2.2 vs 0.6%). The pri-
risk for stent thrombosis (three- to ninefold greater). Stent thrombosis mary endpoint of death, myocardial infarction, stroke, or revasculari-
results in death in 10–20% and myocardial infarction in 30–70% of zation was significantly better with CABG, particularly in those with
patients. Elective surgery that requires discontinuation of antiplatelet the most extensive coronary artery disease such as three-vessel disease.
therapy after drug-eluting stent implantation should be postponed until The 5-year results confirm these findings. The Future Revascularization
after 3 months and preferably after 6 months, if at all possible. Evaluation in Patients With Diabetes Mellitus: Optimal Management
Restenosis, or renarrowing of the dilated coronary stenosis, is the of Multivessel Disease (FREEDOM) trial randomized 1900 patients
most common complication of angioplasty and occurs in 20–50% of with diabetes and multivessel disease and found a significantly lower
patients with balloon angioplasty alone, 10–30% of patients with bare primary endpoint of death, myocardial infarction, or stroke with CABG
metal stents, and 5–15% of patients with drug-eluting stents within than PCI. Recent trials comparing PCI with CABG have shown similar
the first year. The fact that stent place-
ment provides a larger acute luminal area
than balloon angioplasty alone reduces
the incidence of subsequent restenosis.
Drug-eluting stents further reduce resteno-
sis through a reduction in excessive neoin-
timal growth over the stent. If restenosis
does not occur, the long-term outcome is
excellent (Fig. 270-3). Clinical restenosis
is recognized by recurrence of angina or
symptoms within 12 months of the pro-
cedure. Less frequently, patients with res-
tenosis can present with non-ST-segment
elevation myocardial infarction (NSTEMI)
(10%) or STEMI (2%) as well. Very late
stent thrombosis and restenosis after 1 year
is more likely to be due to neoatheroscle-
rosis than intimal hyperplasia seen within
the first year. Clinical restenosis requires
confirmation of a significant stenosis at the
site of the prior PCI. Target lesion revascu-
larization (TLR) or target vessel revascular-
ization (TVR) is defined as angiographic
restenosis with repeat PCI or coronary
artery bypass grafting (CABG). By angi- FIGURE 270-3 Long-term results from one of the first patients to receive a sirolimus-eluting stent from early
ography, the incidence of restenosis is Sao Paulo experience. (From GW Stone, in D Baim [ed]: Cardiac Catheterization, Angiography and Intervention,
significantly higher than clinical restenosis 7th ed. Philadelphia, Lippincott Williams & Wilkins, 2006; with permission.)

1888 outcomes for those with less extensive disease, but a better outcome from thrombolysis, cannot be rapidly transferred to a hospital that can
when the coronary disease is severe and extensive. These studies sup- perform primary PCI, or in those who develop cardiogenic shock.
port CABG for those with the most severe left main and three-vessel
disease or those with diabetes. Lesser degrees of multivessel disease OTHER INTERVENTIONAL TECHNIQUES
in patients with or without diabetes have an equal outcome with PCI,
including left main disease with favorable angiographic characteristics. ■■STRUCTURAL HEART DISEASE
PART 6
The choice of PCI versus CABG is also related to the anticipated Interventional treatment for structural heart disease (adult congenital
procedural success and complications of PCI and the risks of CABG. heart disease and valvular heart disease) is a significant and growing
For PCI, the characteristics of the coronary anatomy are critically component of the field of interventional cardiology.
important. The location of the lesion in the vessel (proximal or distal), The most common adult congenital lesion to be treated with percu-
the degree of tortuosity, and the size of the vessel are considered. In taneous techniques is closure of atrial septal defects (Chap. 264). The
addition, the lesion characteristics, including the degree of the steno- procedure is done as in a diagnostic right heart catheterization with the
sis, the presence of calcium, lesion length, and presence of thrombus, passage of a catheter up the femoral vein into the right atrium. With
are assessed. The most common reason to decide not to do PCI is that echo and fluoroscopic guidance, the size and location of the defect can
the lesion(s) felt to be responsible for the patient’s symptoms are not be accurately defined, and closure is accomplished using one of several
treatable. This is most commonly due to the presence of a chronic total approved devices. All devices use a left atrial and right atrial wire mesh
occlusion (>3 months in duration) with unfavorable characteristics. A or covered disk that are pulled together to capture the atrial septum
lesion classification to characterize the likelihood of success or failure around the defect and seal it off. The Amplatzer Septal Occluder device
of PCI has been developed by the ACC/AHA. Lesions with the highest (AGA Medical, Minneapolis, Minnesota) is the most commonly used
success are called type A lesions (such as proximal non-calcified subto- in the United States. The success rate in selected patients is 85–95%,
tal lesions), and those with the lowest success or highest complication and the device complications are rare and include device embolization,
rate are type C lesions (such as chronic total occlusions). Intermediate infection, or erosion. Closure of patent foramen ovale (PFO) is done in
lesions are classified as type B1 or B2 depending on the number of a similar way. PFO closure may be considered in patients who have had
unfavorable characteristics. Approximately 25–30% of patients will not recurrent paradoxical stroke or transient ischemic attack (TIA) despite
be candidates for PCI due to unfavorable anatomy, whereas only 5% adequate medical therapy including anticoagulation or antiplatelet
of CABG patients will not be candidates for surgery due to coronary therapy. The CLOSURE I trial randomized 909 patients with crypto-
anatomy. The primary reason for being considered inoperable with genic stroke or TIA who had a PFO. Closure did not reduce the primary
CABG is the presence of severe comorbidities such as advanced age, endpoint of death within 30 days or death following a neurologic
frailty, severe chronic obstructive pulmonary disease (COPD), poor left cause during 2 years of follow-up or stroke/TIA within 2 years. Other
ventricular function, or lack of suitable surgical conduits or poor distal trials have confirmed these findings. However, the 10-year follow up
targets for bypass. from the Randomized Evaluation of Recurrent Stroke Comparing PFO
Another consideration in choosing a revascularization strategy is Closure to Established Current Standard of Care Treatment (RESPECT)
the degree of revascularization. In patients with multivessel disease, trial did suggest a benefit of closure in reducing the risk for recurrent
bypass grafts can usually be placed to all vessels >2 mm with sig- cryptogenic stroke. The use in the treatment of migraine is not sup-
nificant stenosis, whereas PCI may be able to treat only some of the ported by the current data.
lesions due to the presence of unfavorable anatomy. Assessment of the Similar devices can also be used to close patent ductus arteriosus
significance of intermediate lesions using fractional flow reserve (FFR) and ventricular septal defects. Other congenital diseases that can be
(Chap. 237) can assist in determining which lesions should be revascu- treated percutaneously include coarctation of the aorta, pulmonic
larized. The Fractional Flow Reserve versus Angiography for Multives- stenosis, peripheral pulmonary stenosis, and other abnormal commu-
sel Evaluation (FAME) trial showed a 30% reduction in adverse events nications between the cardiac chambers or vessels.
when revascularization by PCI was restricted to those lesions that were The treatment of valvular heart disease is the most rapidly growing
hemodynamically significant (FFR ≤0.80) rather than when guided by area in interventional cardiology. Until recently, the only available tech-
angiography alone. Thus, complete revascularization of all functionally niques were balloon valvuloplasty for the treatment of aortic, mitral,
significant lesions should be favored and considered when choosing or pulmonic stenosis (Chap. 256). Mitral valvuloplasty is the preferred
the optimal revascularization strategy. Given the multiple factors that treatment for symptomatic patients with rheumatic mitral stenosis
need to be considered in choosing the best revascularization for an who have favorable anatomy. The outcome in these patients is equal to
individual patient with multivessel disease, it is optimal to have a that of surgical commissurotomy. The success is highly related to the
discussion among the cardiac surgeon, interventional cardiologist, and echocardiographic appearance of the valve. The most favorable setting
the physicians caring for the patient (so-called Heart Team) to weigh is commissural fusion without calcification or subchordal fusion and
the choices properly. the absence of significant mitral regurgitation. Access is obtained from
Patients with acute coronary syndrome are at excess risk of short- the femoral vein using a transseptal technique in which a long metal
and long-term mortality. Randomized clinical trials have shown that catheter with a needle tip is advanced from the femoral vein through
PCI is superior to intensive medical therapy in reducing mortality the right atrium and atrial septum at the level of the foramen ovale
and myocardial infarction, with the benefit largely confined to those into the left atrium. A guidewire is advanced into the left ventricle,
patients who are high risk. High-risk patients are defined as those and a balloon-dilatation catheter is negotiated across the mitral valve
with any one of the following: refractory ischemia, recurrent angina, and inflated to a predetermined size to enlarge the valve. The most
positive cardiac-specific enzymes, new ST-segment depression, low commonly used dilatation catheter is the Inoue balloon. The technique
ejection fraction, severe arrhythmias, or a recent PCI or CABG. PCI is splits the commissural fusion and commonly results in a doubling
preferred over surgical therapy in most high-risk patients with acute of the mitral valve area. The success of the procedure in favorable
coronary syndromes unless they have severe multivessel disease or anatomy is 95% and severe complications are rare (1–2%). The most
the culprit lesion responsible for the unstable presentation cannot be common complications are tamponade due to puncture into the
adequately treated. In STEMI, thrombolysis or PCI (primary PCI) are pericardium during the transseptal puncture or the creation of severe
effective methods to restore coronary blood flow and salvage myo- mitral regurgitation due to damage to the valve leaflets.
cardium within the first 12 h after onset of chest pain. Because PCI is Severe mitral regurgitation can be treated percutaneously using
more effective in restoring flow than thrombolysis, it is preferred if the MitraClip (Abbott, Abbott Park, Illinois) device. The procedure
readily available within 90 min of presentation to the hospital. PCI is involves the passage of a catheter into the left atrium using the trans-
also performed following thrombolysis to facilitate adequate reperfu- septal technique. A special catheter with a metallic clip on the end is
sion or as a rescue procedure in those who do not achieve reperfusion passed through the mitral valve and retracted to catch and clip together

the mid portion of the anterior and posterior mitral valve leaflets. procedure may be preferred over the other. The success rate of periph- 1889
The clip creates a double opening in the mitral valve and thereby eral artery interventional procedures has been improving, including
reduces mitral regurgitation similar to the surgical Alfieri repair. In the treatment for long segments of occlusive disease historically treated by
Endovascular Valve Edge-to-Edge Repair Study (EVEREST II) trial, the peripheral bypass surgery (Fig. 270-5). The use of drug-coated balloons
device was less effective than surgical repair or replacement but was and drug-eluting stents has shown to reduce restenosis when compared

shown to be safe. Subsequent trials have shown it to be reasonably with balloon angioplasty alone. Peripheral intervention is increasingly
effective for patients who are not good candidates for surgical repair, part of the training of an interventional cardiologist, and most programs
particularly when the regurgitation is due to functional causes. now require an additional year of training after the interventional car-
Severe aortic stenosis can be treated with balloon valvuloplasty diology training year. The techniques and outcomes are described in
as well. In this setting, the valvuloplasty balloon catheter is placed detail in the chapter on peripheral vascular disease (Chap. 275).
retrograde across the aortic valve from the femoral artery and briefly
■■CIRCULATORY SUPPORT TECHNIQUES
inflated to stretch open the valve. The success is much less favorable,
The use of circulatory support techniques is indicated for the man-
with only 50% achieving an aortic valve area of >1 cm2 and a restenosis
agement of patients with shock or hemodynamic instability and occa-
rate of 25–50% after 6–12 months. This poor success rate has limited its
sionally is needed in order to safely perform PCI on hemodynamically
use to patients who are not surgical candidates or as a bridge to sur-
unstable patients. It also can be useful in helping to stabilize patients
gery or transcatheter aortic valve replacement (TAVR). In this setting,
before surgical interventions. The most commonly used device is the
the intermediate-term mortality rate of the procedure is high (10%).
percutaneous intraaortic balloon pump developed in the early 1960s. A
Repeat aortic valvuloplasty as a treatment for aortic valve restenosis 7- to 10-French, 25- to 50-mL balloon catheter is placed retrograde from
has been reported. the femoral artery into the descending aorta between the aortic arch
Percutaneous TAVR has been shown to be an effective treatment for and the abdominal aortic bifurcation. It is connected to a helium gas
intermediate, high-risk, and inoperable patients with aortic stenosis. inflation system that synchronizes the inflation to coincide with early
Currently, two valve models, the Edwards SAPIEN valve (Edwards diastole with deflation by mid-diastole. As a result, it increases early
Lifescience, Irvine, California) and the CoreValve ReValving system diastolic pressure, lowers systolic pressure, and lowers late diastolic
(Medtronic, Minneapolis, Minnesota) are available. In more than pressure through displacement of blood from the descending aorta
50,000 cases worldwide since 2002, follow-up shows no evidence of (counterpulsation). This results in an increase in coronary blood flow
restenosis or severe prosthetic valve dysfunction in the midterm, but and a decrease in afterload. It is contraindicated in patients with aortic
long-term outcomes of 5–10 years are not yet available. The CoreValve regurgitation, aortic dissection, or severe peripheral artery disease. The
is self-expanding, while the Edwards valve is balloon expanded. The major complications are vascular and thrombotic. Intravenous heparin
cannulas are large (14–22 French), and retrograde access via the femoral is given in order to reduce thrombotic complications.
artery is most commonly chosen, if possible. In patients with peripheral Another useful support device is the Impella (Abiomed, Danvers,
artery disease, access via the subclavian artery, aorta, or transapically Massachusetts). The Impella catheter is placed percutaneously from the
through a surgical incision can be used. Following balloon valvu- femoral artery into the left ventricle. The catheter has a small microaxial
loplasty, the valve is positioned across the valve and deployed with pump at its tip that can pump up to 2.5–5 L/min from the left ventricle
post-deployment balloon inflation to ensure full contact with the aortic to the aorta. The smaller devices can be placed percutaneously but the
annulus. The success rate is >90%, and the 30-day mortality rate is larger devices need surgical access. Other support devices include Tan-
2–15% based on preoperative risk. The Placement of Aortic Transcath- demHeart (CardiacAssist, Pittsburgh, Pennsylvania), which involves
eter Valve (PARTNER) randomized trial of the Edwards valve showed placement of a large 21-French catheter from the femoral vein through
a 55% reduction in 1-year mortality and major adverse events in the the right atrium into the left atrium using the transseptal technique
extreme-risk group randomized to TAVR compared with medical ther- and a catheter in the femoral artery. A centrifugal pump can deliver
apy. In separate randomized trials, moderate- and high-risk patients 5 L of blood per minute. It may be useful in patients in shock or with
had similar outcomes to surgical valve replacement at 1 year. As a STEMI or very-high-risk PCI. Patients can also be placed on peripheral
result, this valve is approved for both intermediate-risk, high-risk, and extracorporeal membrane oxygenation (ECMO) using large cannulas
extreme-risk patients with severe aortic stenosis. placed in the femoral artery and vein. This technique can be performed
Aortic and mitral bioprosthetic valve degeneration can be treated in the catheterization laboratory and is useful for support of patients
with repeat surgery or, in high-risk patients, with a valve-in-valve proce- with acute respiratory failure or cardiac failure.
dure where a percutaneous valve is placed inside
of the prior surgical valve. It has been shown to
be effective for aortic and mitral valves.
Pulmonic stenosis can also be effectively
treated with balloon valvuloplasty and per-
cutaneously replaced with the Melody valve
(Medtronic). Tricuspid valve interventions
remain experimental.
■■PERIPHERAL ARTERY
INTERVENTIONS
The use of percutaneous interventions to treat
symptomatic patients with arterial obstruction
in the carotid, renal, aortic, and peripheral ves-
sels is an effective alternative to vascular sur-
gery. Randomized clinical trial data support the
use of carotid stenting in patients at high risk
of complications from carotid endarterectomy
(Fig. 270-4). Recent trials suggest similar out-
comes with carotid stenting and carotid endar- A B
terectomy in patients at average risk, although FIGURE 270-4 A. An example of a high-risk patient who requires carotid revascularization, but who is not a
depending on the patient’s risk for peripro- candidate for carotid endarterectomy. B. Carotid artery stenting resulted in an excellent angiographic result.
cedural stroke or myocardial infarction, one (From M Belkin, DL Bhatt: Circulation 119:2302, 2009; with permission.)

1890
PART 6
A B C
D E
FIGURE 270-5 Peripheral interventional procedures have become highly effective at treating anatomic lesions previously amenable only to bypass surgery. A.
Complete occlusion of the left superficial femoral artery. B. Wire and catheter advanced into subintimal space. C. Intravascular ultrasound positioned in the subintimal
space to guide retrograde wire placement through the occluded vessel. D. Balloon dilation of the occlusion. E. Stent placement with excellent angiographic result. (From
A Al Mahameed, DL Bhatt: Cleve Clin J Med 73:S45, 2006; with permission. Copyright © 2006 Cleveland Clinic Foundation. All rights reserved.)
■■INTERVENTIONS FOR PULMONARY EMBOLISM decisions concerning which revascularization—PCI or CABG—is best
The treatment of deep vein thrombosis is intravenous anticoagulation, for an individual patient. Treatment of peripheral and cerebrovascular
with placement of an inferior vena cava filter if recurrent pulmonary disease can be effective with percutaneous techniques. Structural heart
emboli (PE) occur or anticoagulation is not possible. Postphlebitic disease is increasingly being treated with percutaneous options, with
syndrome is a serious condition due to chronic venous obstruction that a high likelihood that interventional approaches will compete with
can lead to chronic leg edema and venous ulcers. Preliminary studies open-heart surgery in a significant proportion of cases in years to come.
suggest that mechanical treatments may have a role in treatment, and
a large trial is ongoing. ■■FURTHER READING
PE should be treated with fibrinolytic agents if massive and in some Faxon DP, Williams DO: Interventional cardiology: Current status
cases if submassive. Surgical pulmonary embolectomy is an option for and future directions in coronary disease and valvular heart disease.
the treatment of massive PE with hemodynamic instability in patients Circulation 133:2697, 2016.
who have contraindications for systemic fibrinolysis or those in whom Levine GN et al: 2011 ACCF/AHA/SCAI Guideline for Percutaneous
it has failed. Catheter-based therapies for submassive and massive PEs Coronary Intervention: Executive Summary: A Report of the American
are still evolving, but studies have shown promise. The techniques College of Cardiology Foundation/American Heart Association Task
employed include the use of aspiration of the clot with a large catheter Force on Practice Guidelines and the Society for Cardiovascular Angi-
(10 French), intraclot infusion of a thrombolytic agent followed by ography and Interventions. Circulation 124:2574, 2011.
aspiration, ultrasound-assisted catheter-directed thrombolysis, and Moscucci M (ed): Grossman & Baim’s Cardiac Catheterization, Angiog-
use of rheolytic thrombectomy. Success for these techniques has been raphy, and Intervention 8th ed. Philadelphia, Lippincott Williams &
reported to be 80–90%, with major complications occurring in 2–4% of Wilkins, 2014.
patients. Vahl TP et al: Transcatheter aortic valve replacement 2016: A modern-
day “Through the looking-glass” adventure. J Am Coll Cardiol
■■INTERVENTIONS FOR REFRACTORY HYPERTENSION 67:1472, 2016.
The recent recognition of the importance of the renal sympathetic nerves
in modulating blood pressure has led to a technique to selectively
denervate renal sympathetic nerves in patients with refractory hyper-
tension. The procedure involves applying low-power radiofrequency
treatment via a catheter along the length of both renal arteries. In the
271 Hypertensive
randomized Symplicity HTN-2 trial, renal denervation significantly
reduced blood pressure compared with medical therapy. The Symplic- Vascular
ity device (Medtronic, Minnesota) is approved in Europe, though the
randomized and blinded U.S. Symplicity HTN-3 trial showed no effect. Disease
Further optimization of the technique is needed with evidence from
randomized trials of efficacy before approval in the United States. Theodore A. Kotchen
CONCLUSION
Interventional cardiology continues to expand its borders. Treatment Hypertension is one of the leading causes of the global burden of
for coronary artery disease, including complex anatomic subsets, con- disease. Elevated blood pressure affects more than one billion individ-
tinues to advance. Technological advances such as drug-eluting stents, uals and causes an estimated 9.4 million deaths per year. Hypertension
now already in their second generation are improving the results of doubles the risk of cardiovascular diseases, including coronary heart
PCI. PCI is the treatment of choice for patients with acute coronary disease (CHD), congestive heart failure (CHF), ischemic and hemor-
syndromes. For patients with stable coronary disease, PCI is effective rhagic stroke, renal failure, and peripheral arterial disease (PAD). It
in symptom alleviation. Use of a Heart Team is the best way to make often is associated with additional cardiovascular disease risk factors,

and the risk of cardiovascular disease increases with the total burden hypertension. Clinically, although replication has been a challenge, 1891
of risk factors. Although antihypertensive therapy reduces the risks of results of candidate gene studies and genome-wide association stud-
cardiovascular and renal disease, large segments of the hypertensive ies in large numbers of individuals have also identified a number of
population are either untreated or inadequately treated. hypertension-related genes, several of which are involved in pathways
that regulate arterial pressure, e.g., genes that encode components of
CHAPTER 271 Hypertensive Vascular Disease

EPIDEMIOLOGY the renin-angiotensin-aldosterone system, atrial natriuretic peptide, the
Blood pressure levels, the rate of age-related increases in blood pres- beta-2 adrenoreceptor, and alpha adducin (associated with increased
sure, and the prevalence of hypertension vary among countries and renal tubular reabsorption of sodium). Overall, identified genetic
among subpopulations within a country. Hypertension is present in all determinants account for ~1% of blood pressure variance, whereas
populations except for small numbers of individuals living in isolated based on family studies, heritability of hypertension is estimated to
societies. In industrialized societies, blood pressure increases steadily be in the range of 30–40%. One hypothesis to account for the “missing
during the first two decades of life. In children and adolescents, blood heritability” is that epigenetic modifications of DNA contribute to the
pressure is associated with growth and maturation. Blood pressure heritability of blood pressure. Epigenetic processes are changes in gene
“tracks” over time in children and between adolescence and young expression that occur without changes in DNA sequence. In contrast to
adulthood. In the United States, average systolic blood pressure is DNA sequence, the epigenome is relatively susceptible to modification
higher for men than for women during early adulthood, although by environmental exposures. Epigenetic dysregulation has emerged
among older individuals the age-related rate of rise is steeper for as a hallmark of several complex diseases, including hypertension.
women. Consequently, among individuals aged ≥60 years, systolic Several recent studies have described epigenetic modifications of
blood pressures of women are higher than those of men. Among adults, specific genes associated with hypertension. However, current results
diastolic blood pressure also increases progressively with age until of detailed genome-wide epigenetic modifications of DNA are limited
~55 years, after which it tends to decrease. The consequence is a wid- and conflicting.
ening of pulse pressure (the difference between systolic and diastolic Preliminary evidence suggests that there may also be genetic deter-
blood pressure) beyond age 60. minants of target organ damage and vascular disease attributed to
In the United States, ~78 million adults have hypertension. Hyper- hypertension. Family studies indicate significant heritability of left
tension prevalence is 33.5% in non-Hispanic blacks, 28.9% in non- ventricular mass, and there is considerable individual variation in the
Hispanic whites, and 20.7% in Mexican Americans. The likelihood responses of the heart to hypertension. Family studies and variations
of hypertension increases with age, and among individuals aged in candidate genes associated with renal damage suggest that genetic
≥60 years, the prevalence is 65.4%. Recent evidence suggests that the factors also may contribute to hypertensive nephropathy. Specific
prevalence of hypertension in the United States may be increasing, genetic variants have been linked to CHD and stroke. In the future, it is
possibly as a consequence of increasing obesity. The prevalence of possible that DNA and epigenetic analyses may predict individual risk
hypertension and stroke mortality rates is higher in the southeastern for hypertension and target organ damage and will identify responders
United States than in other regions. In African Americans, hyperten- to specific classes of antihypertensive agents.
sion appears earlier, is generally more severe, and results in higher
rates of morbidity and mortality from stroke, left ventricular hypertro- MECHANISMS OF HYPERTENSION
phy, CHF, and end-stage renal disease (ESRD) than in white Americans. To provide a framework for understanding the pathogenesis and
According to NHANES (National Health and Nutrition Examination treatment options for hypertensive disorders, it is useful to understand
Survey) data, in 2007–2010, 81.5% of those with hypertension were factors involved in the regulation of both normal and elevated arterial
aware they had it, 74.9% were being treated, but only 52.5% were pressure. Cardiac output and peripheral resistance are the two deter-
controlled. minants of arterial pressure (Fig. 271-1). Cardiac output is determined
Both environmental and genetic factors may contribute to regional by stroke volume and heart rate; stroke volume is related to myocardial
and racial variations in hypertension prevalence. Studies of societies contractility and to the size of the vascular compartment. Peripheral
undergoing “acculturation” and studies of migrants from a less to a resistance is determined by functional and anatomic changes in small
more urbanized setting indicate a profound environmental contribu- arteries (lumen diameter 100–400 μm) and arterioles.
tion to blood pressure. Obesity and weight gain are strong, indepen-
■■INTRAVASCULAR VOLUME
dent risk factors for hypertension. It has been estimated that 60% of
Sodium is predominantly an extracellular ion and is a primary deter-
hypertensives are >20% overweight. Among populations, hyperten-
minant of the extracellular fluid volume. When NaCl intake exceeds
sion prevalence is related to dietary NaCl intake, and the age-related
the capacity of the kidney to excrete sodium, vascular volume may
increase in blood pressure may be augmented by a high NaCl intake.
initially expand and cardiac output may increase. However, many vas-
Low dietary intakes of calcium and potassium also may contribute
cular beds have the capacity to autoregulate blood flow, and if constant
to the risk of hypertension. The urine sodium-to-potassium ratio (an
blood flow is to be maintained in the face of increased arterial pressure,
index of both sodium and potassium intakes) is a stronger correlate
resistance within that bed must increase, since
of blood pressure than is either sodium or potassium alone. Alcohol
consumption, psychosocial stress, and low levels of physical activity pressure across the vascular bed
also may contribute to hypertension. Blood Flow =
vascular resistance
■■GENETIC CONSIDERATIONS
The initial elevation of blood pressure in response to vascular
Although specific genetic variants have been identified in rare
volume expansion may be related to an increase of cardiac output;
Mendelian forms of hypertension (Table 271–5), these variants are
not applicable to the vast majority (>98%) of patients with hyper-
tension. For most individuals, it is likely that hypertension represents a Stroke volume
polygenic disorder in which a combination of genes acts in concert with Cardiac output
environmental exposures to make only a modest contribution to blood Heart rate
pressure. Furthermore, different subsets of genes may lead to different
phenotypes associated with hypertension, e.g., obesity, dyslipidemia, Arterial pressure
insulin resistance. Vascular structure
Adoption, twin, and family studies document a significant heri-
Peripheral resistance
table component to blood pressure levels and hypertension. Animal
models (including selectively bred rats and congenic rat strains) Vascular function
have identified a number of genetic loci and genes associated with FIGURE 271-1 Determinants of arterial pressure.

1892 however, over time, peripheral resistance increases and cardiac output observed in patients with pheochromocytoma, possibly due to the lack
reverts toward normal. Whether this hypothesized sequence of events of norepinephrine-induced vasoconstriction with assumption of the
occurs in the pathogenesis of hypertension is not clear. What is clear upright posture. Conversely, with chronic reduction of neurotransmit-
is that salt can activate a number of neural, endocrine/paracrine, and ter substances, adrenoreceptors may increase in number or be upreg-
vascular mechanisms, all of which have the potential to increase arte- ulated, resulting in increased responsiveness to the neurotransmitter.
rial pressure. The effect of sodium on blood pressure is related to the Chronic administration of agents that block adrenergic receptors may
PART 6
provision of sodium with chloride; non-chloride salts of sodium have result in upregulation, and abrupt withdrawal of those agents may pro-
little or no effect on blood pressure. As arterial pressure increases in duce a condition of temporary hypersensitivity to sympathetic stimuli.
response to a high NaCl intake, urinary sodium excretion increases For example, clonidine is an antihypertensive agent that is a centrally
and sodium balance is maintained at the expense of an increase in acting α2 agonist that inhibits sympathetic outflow. Rebound hyperten-
arterial pressure. The mechanism for this “pressure-natriuresis” phe- sion may occur with the abrupt cessation of clonidine therapy, probably
nomenon may involve a subtle increase in the glomerular filtration as a consequence of upregulation of α1 receptors.
rate, decreased absorbing capacity of the renal tubules, and possibly Several reflexes modulate blood pressure on a minute-to-minute
hormonal factors such as atrial natriuretic factor. In individuals with basis. One arterial baroreflex is mediated by stretch-sensitive sensory
an impaired capacity to excrete sodium, greater increases in arterial nerve endings in the carotid sinuses and the aortic arch. The rate of
pressure are required to achieve natriuresis and sodium balance. firing of these baroreceptors increases with arterial pressure, and the
NaCl-dependent hypertension may be a consequence of a decreased net effect is a decrease in sympathetic outflow, resulting in decreases
capacity of the kidney to excrete sodium, due either to intrinsic renal in arterial pressure and heart rate. This is a primary mechanism for
disease or to increased production of a salt-retaining hormone (min- rapid buffering of acute fluctuations of arterial pressure that may occur
eralocorticoid) resulting in increased renal tubular reabsorption of during postural changes, behavioral or physiologic stress, and changes
sodium. Renal tubular sodium reabsorption also may be augmented in blood volume. However, the activity of the baroreflex declines or
by increased neural activity to the kidney. In each of these situations, adapts to sustained increases in arterial pressure such that the barore-
a higher arterial pressure may be required to achieve sodium balance. ceptors are reset to higher pressures. Patients with autonomic neur-
Conversely, salt-wasting disorders are associated with low blood opathy and impaired baroreflex function may have extremely labile
pressure levels. ESRD is an extreme example of volume-dependent blood pressures with difficult-to-control episodic blood pressure spikes
hypertension. In ~80% of these patients, vascular volume and hyper- associated with tachycardia.
tension can be controlled with adequate dialysis; in the other 20%, In both normal-weight and obese individuals, hypertension often
the mechanism of hypertension is related to increased activity of the is associated with increased sympathetic outflow. Based on recordings
renin-angiotensin system and is likely to be responsive to pharmaco- of postganglionic muscle nerve activity (detected by a microelectrode
logic blockade of renin-angiotensin. inserted in a peroneal nerve in the leg), sympathetic outflow tends
to be higher in hypertensive than in normotensive individuals. Sym-
■■AUTONOMIC NERVOUS SYSTEM pathetic outflow is increased in obesity-related hypertension and in
Adrenergic reflexes modulate blood pressure over the short term, and hypertension associated with obstructive sleep apnea. Baroreceptor
adrenergic function, in concert with hormonal and volume-related activation via electrical stimulation of carotid sinus afferent nerves
factors, contributes to the long-term regulation of arterial pressure. lowers blood pressure in patients with “resistant” hypertension. Drugs
Norepinephrine, epinephrine, and dopamine all play important roles that block the sympathetic nervous system are potent antihypertensive
in tonic and phasic cardiovascular regulation. agents, indicating that the sympathetic nervous system plays a permis-
The activities of the adrenergic receptors are mediated by guanosine sive, although not necessarily a causative, role in the maintenance of
nucleotide-binding regulatory proteins (G proteins) and by intracellu- increased arterial pressure.
lar concentrations of downstream second messengers. In addition to Pheochromocytoma is the most blatant example of hypertension
receptor affinity and density, physiologic responsiveness to catecho- related to increased catecholamine production, in this instance by a
lamines may be altered by the efficiency of receptor-effector coupling tumor. Blood pressure can be reduced by surgical excision of the tumor
at a site “distal” to receptor binding. The receptor sites are relatively or by pharmacologic treatment with an α1 receptor antagonist or with
specific both for the transmitter substance and for the response that an inhibitor of tyrosine hydroxylase, the rate-limiting step in catecho-
occupancy of the receptor site elicits. Based on their physiology and lamine biosynthesis.
pharmacology, adrenergic receptors have been divided into two
principal types: α and β. These types have been differentiated further ■■RENIN-ANGIOTENSIN-ALDOSTERONE
into α1, α2, β1, and β2 receptors. Recent molecular cloning studies have The renin-angiotensin-aldosterone system contributes to the regulation
identified several additional subtypes. α Receptors are occupied and of arterial pressure primarily via the vasoconstrictor properties of angi-
activated more avidly by norepinephrine than by epinephrine, and the otensin II and the sodium-retaining properties of aldosterone. Renin is
reverse is true for β receptors. α1 Receptors are located on postsynaptic an aspartyl protease that is synthesized as an enzymatically inactive
cells in smooth muscle and elicit vasoconstriction. α2 Receptors are precursor, prorenin. Most renin in the circulation is synthesized in the
localized on presynaptic membranes of postganglionic nerve terminals renal afferent renal arteriole. Prorenin may be secreted directly into the
that synthesize norepinephrine. When activated by catecholamines, circulation or may be activated within secretory cells and released as
α2 receptors act as negative feedback controllers, inhibiting further active renin. Although human plasma contains two to five times more
norepinephrine release. In the kidney, activation of α1-adrenergic recep- prorenin than renin, there is no evidence that prorenin contributes to
tors increases renal tubular reabsorption of sodium. Different classes of the physiologic activity of this system. There are three primary stimuli
antihypertensive agents either inhibit α1 receptors or act as agonists of α2 for renin secretion: (1) decreased NaCl transport in the distal portion of
receptors and reduce systemic sympathetic outflow. Activation of myo- the thick ascending limb of the loop of Henle that abuts the correspond-
cardial β1 receptors stimulates the rate and strength of cardiac contraction ing afferent arteriole (macula densa), (2) decreased pressure or stretch
and consequently increases cardiac output. β1 Receptor activation also within the renal afferent arteriole (baroreceptor mechanism), and (3)
stimulates renin release from the kidney. Another class of antihyperten- sympathetic nervous system stimulation of renin-secreting cells via β1
sive agents acts by inhibiting β1 receptors. Activation of β2 receptors by adrenoreceptors. Conversely, renin secretion is inhibited by increased
epinephrine relaxes vascular smooth muscle and results in vasodilation. NaCl transport in the thick ascending limb of the loop of Henle, by
Circulating catecholamine concentrations may affect the number of increased stretch within the renal afferent arteriole, and by β1 receptor
adrenoreceptors in various tissues. Downregulation of receptors may blockade. In addition, angiotensin II directly inhibits renin secretion due
be a consequence of sustained high levels of catecholamines and pro- to angiotensin II type 1 receptors on juxtaglomerular cells, and renin
vides an explanation for decreasing responsiveness, or tachyphylaxis, secretion increases in response to pharmacologic blockade of either
to catecholamines. For example, orthostatic hypotension frequently is angiotensin-converting enzyme (ACE) or angiotensin II receptors.

Angiotensin II is the primary tropic factor regulating the synthesis 1893
Angiotensinogen
and secretion of aldosterone by the zona glomerulosa of the adrenal
cortex. Aldosterone synthesis is also dependent on potassium, and
Renin aldosterone secretion may be decreased in potassium-depleted indi-
viduals. Although acute elevations of adrenocorticotropic hormone

(ACTH) levels also increase aldosterone secretion, ACTH is not an
Angiotensin I important tropic factor for the chronic regulation of aldosterone.
Bradykinin
Aldosterone is a potent mineralocorticoid that increases sodium
reabsorption by amiloride-sensitive epithelial sodium channels (ENaC)
ACE-kininase II on the apical surface of the principal cells of the renal cortical collect-
ing duct (Chap. 303). Electric neutrality is maintained by exchanging
sodium for potassium and hydrogen ions. Consequently, increased
Inactive aldosterone secretion may result in hypokalemia and alkalosis. Beyond
Angiotensin II peptides
its renal effects, aldosterone can exert deleterious effects on the
cardiovascular system, including fibrosis, endothelial dysfunction,
inflammation, and oxidative stress, as well as an overall increase in
cardiovascular morbidity and mortality.
Cortisol also binds to the mineralocorticoid receptor but normally
functions as a less potent mineralocorticoid than aldosterone because
cortisol is converted to cortisone by the enzyme 11 β-hydroxysteroid
AT1 receptor AT2 receptor
dehydrogenase type 2. Cortisone has no affinity for the mineralocor-
ticoid receptor. Primary aldosteronism is a compelling example of
mineralocorticoid-mediated hypertension. In this disorder, adrenal
aldosterone synthesis and release are independent of renin-angiotensin,
and renin release is suppressed by the resulting volume expansion.
Aldosterone
Mineralocorticoid receptors are expressed in a number of tissues
in addition to the kidney, and mineralocorticoid receptor activation
FIGURE 271-2 Renin-angiotensin-aldosterone axis. ACE, angiotensin-converting
enzyme. induces structural and functional alterations in the heart, kidney, and
blood vessels, leading to myocardial fibrosis, nephrosclerosis, and vas-
Once released into the circulation, active renin cleaves a substrate, cular inflammation and remodeling, perhaps as a consequence of oxi-
angiotensinogen, to form an inactive decapeptide, angiotensin I dative stress. These effects are amplified by a high salt intake. In animal
(Fig. 271-2). A converting enzyme, located primarily but not exclu- models, high circulating aldosterone levels stimulate cardiac fibrosis
sively in the pulmonary circulation, converts angiotensin I to the active and left ventricular hypertrophy, and spironolactone (an aldosterone
octapeptide, angiotensin II, by releasing the C-terminal histidyl-leucine antagonist) prevents aldosterone-induced myocardial fibrosis. Patho-
dipeptide. The same converting enzyme cleaves a number of other pep- logic patterns of left ventricular geometry also have been associated
tides, including and thereby inactivating the vasodilator bradykinin. with elevations of plasma aldosterone concentration in hypertensive
Acting primarily through angiotensin II type 1 (AT1) receptors on cell patients. In patients with CHF, low-dose spironolactone reduces the
membranes, angiotensin II is a potent pressor substance, the primary risk of progressive heart failure and sudden death from cardiac causes
tropic factor for the secretion of aldosterone by the adrenal zona glo- by 30%. Due to a renal hemodynamic effect, in patients with primary
merulosa. Independent of its hemodynamic effects, angiotensin II may aldosteronism, high circulating levels of aldosterone also may cause
play a role in the pathogenesis of atherosclerosis through a direct cel- glomerular hyperfiltration and albuminuria.
lular action on the vessel wall. The angiotensin II type 2 (AT2) receptor Increased activity of the renin-angiotensin-aldosterone axis is not
has the opposite functional effects of the AT1 receptor. The AT2 receptor invariably associated with hypertension. In response to a low-NaCl
induces vasodilation, sodium excretion, and inhibition of cell growth diet or to volume contraction, arterial pressure and volume homeosta-
and matrix formation. Experimental evidence suggests that the AT2 sis may be maintained by increased activity of the renin-angiotensin-
receptor improves vascular remodeling by stimulating smooth muscle aldosterone axis. Secondary aldosteronism (i.e., increased aldosterone
cell apoptosis and contributes to the regulation of glomerular filtration secondary to increased renin-angiotensin), but not hypertension, also is
rate. AT1 receptor blockade induces an increase in AT2 receptor activity. observed in edematous states such as CHF and liver disease.
Renin-secreting tumors are clear examples of renin-dependent
hypertension. In the kidney, these tumors include benign hemangio- ■■VASCULAR MECHANISMS
pericytomas of the juxtaglomerular apparatus and, infrequently, renal Vascular radius and compliance of resistance arteries are important
carcinomas, including Wilms’ tumors. Renin-producing carcinomas determinants of arterial pressure. Resistance to flow varies inversely
also have been described in lung, liver, pancreas, colon, and adrenals. with the fourth power of the radius, and consequently, small decreases
Renovascular hypertension is another renin-mediated form of hyper- in lumen size significantly increase resistance. In hypertensive patients,
tension. Obstruction of the renal artery leads to decreased renal perfu- structural, mechanical, or functional changes may reduce the lumen
sion pressure, thereby stimulating renin secretion. Over time, possibly diameter of small arteries and arterioles. Remodeling refers to geomet-
as a consequence of secondary renal damage, this form of hypertension ric alterations in the vessel wall without a change in vessel volume.
may become less renin-dependent. Hypertrophic (increased cell size, and increased deposition of inter-
Angiotensinogen, renin, and angiotensin II are also synthesized cellular matrix) or eutrophic vascular remodeling results in decreased
locally in many tissues, including the brain, pituitary, aorta, arteries, lumen size and, hence, increased peripheral resistance. Apoptosis,
heart, adrenal glands, kidneys, adipocytes, leukocytes, ovaries, testes, low-grade inflammation, and vascular fibrosis also contribute to
uterus, spleen, and skin. Angiotensin II in tissues may be formed by remodeling. Lumen diameter also is related to elasticity of the vessel.
the enzymatic activity of renin or by other proteases, e.g., tonin, chy- Vessels with a high degree of elasticity can accommodate an increase
mase, and cathepsins. In addition to regulating local blood flow, tissue of volume with relatively little change in pressure, whereas in a semi-
angiotensin II is a mitogen that stimulates growth and contributes rigid vascular system, a small increment in volume induces a relatively
to modeling and repair. Excess tissue angiotensin II may contribute large increment of pressure.
to atherosclerosis, cardiac hypertrophy, and renal failure, and conse- An association between arterial stiffness and hypertension is
quently may be a target for pharmacologic therapy to prevent target well established. A stiffened vasculature is less able to buffer short-
organ damage. term alterations in flow. Although it has been assumed that arterial

1894 stiffness is a manifestation of hypertension, recent evidence suggests aortic stiffness are associated with activation of innate and adaptive
that vascular stiffness may also represent a cause of hypertension. Non- immunity. Many forms of hypertension in experimental animals are
invasive determination of pulse wave velocity between the carotid and associated with an inflammatory component requiring T lymphocytes.
femoral arteries is often interpreted as an index of arterial stiffness. Due Inflammation and exudative injury are closely coupled. Inflammation,
to arterial stiffness, central blood pressures (aortic, carotid) may not cor- vascular stretch, angiotensin II, and salt have all been shown to result
respond to brachial artery pressures. Ejection of blood into the aorta elic- in the generation of reactive oxygen species (ROS), which modify T cell
PART 6
its a pressure wave that is propagated at a given velocity. The forward function and further enhance inflammation. ROS also attenuate the
traveling wave generates a reflected wave that travels backward toward effects of endogenous small-molecule vasodilators. ROS within the
the ascending aorta. Although mean arterial pressure is determined by renal medulla is a key determinant of the set point of the renal pressure-
cardiac output and peripheral resistance, pulse pressure is related to natriuresis curve. Increasing evidence suggests that infiltration of T cells
the functional properties of large arteries and the amplitude and timing into the renal interstitium contributes to inflammation and oxidative
of the incident and reflected waves. Increased arterial stiffness results stress. Renal medullary oxidative stress disrupts pressure-natriuresis
in increased pulse wave velocity of both incident and reflected waves. and contributes to the development of hypertension in experimental
Due to the timing of these waves, the consequence is augmentation models. Clinically, markers of oxidative stress have been described in
of aortic systolic pressure and a reduction of aortic diastolic pressure, both hypertensive and pre-hypertensive patients.
i.e., an increase in pulse pressure. The aortic augmentation index, a
surrogate index of arterial stiffening, is calculated as the ratio of central PATHOLOGIC CONSEQUENCES OF
arterial pressure-to-pulse pressure. However, wave reflections are also HYPERTENSION
influenced by left ventricular structure and function. Central blood
pressure may be measured directly by placing a sensor in the aorta ■■HEART
or noninvasively by radial tonometry using commercially available Heart disease is the most common cause of death in hypertensive
devices. Central blood pressure and the aortic augmentation index are patients. Hypertensive heart disease is the result of structural and func-
strong, independent predictors of cardiovascular disease and all-cause tional adaptations leading to left ventricular hypertrophy, CHF, athero-
mortality. Central blood pressure also appears to be more strongly sclerotic coronary artery disease and microvascular disease, and cardiac
associated with pre-clinical organ damage than brachial blood pressure. arrhythmias, including atrial fibrillation. Individuals with left ventricu-
Ion transport by vascular smooth muscle cells may contribute to lar hypertrophy are at increased risk for CHD, stroke, CHF, and sudden
hypertension-associated abnormalities of vascular tone and vascu- death. Aggressive control of hypertension can regress or reverse left
lar growth, both of which are modulated by intracellular pH (pHi). ventricular hypertrophy and reduce the risk of cardiovascular disease.
Three ion transport mechanisms participate in the regulation of pHi: CHF may be related to systolic dysfunction, diastolic dysfunction, or
(1) Na+-H+ exchange, (2) Na+-dependent HCO3–-Cl– exchange, and a combination of the two. Abnormalities of diastolic function that range
(3) cation-independent HCO3–-Cl– exchange. Based on measurements from asymptomatic heart disease to overt heart failure are common
in cell types that are more accessible than vascular smooth muscle in hypertensive patients. Approximately one-third of patients with
(e.g., leukocytes, erythrocytes, platelets, skeletal muscle), activity CHF have normal systolic function but abnormal diastolic function.
of the Na+-H+ exchanger is increased in hypertension, and this may Diastolic dysfunction is an early consequence of hypertension-related
result in increased vascular tone by two mechanisms. First, increased heart disease and is exacerbated by left ventricular hypertrophy and
sodium entry may lead to increased vascular tone by activating ischemia. Cardiac catheterization provides the most accurate assess-
Na+-Ca2+ exchange and thereby increasing intracellular calcium. Sec- ment of diastolic function. Alternatively, diastolic function can be eval-
ond, increased pHi enhances calcium sensitivity of the contractile uated by several noninvasive methods, including echocardiography
apparatus, leading to an increase in contractility for a given intracel- and radionuclide angiography.
lular calcium concentration. Additionally, increased Na+-H+ exchange
may stimulate growth of vascular smooth muscle cells by enhancing ■■BRAIN
sensitivity to mitogens. Stroke is the second most frequent cause of death in the world; it
Vascular endothelial function also modulates vascular tone. The vas- accounts for 5 million deaths each year, with an additional 15 million
cular endothelium synthesizes and releases several vasoactive substances, persons having nonfatal strokes. Elevated blood pressure is the stron-
including nitric oxide, a potent vasodilator. Endothelium-dependent vaso- gest risk factor for stroke. Approximately 85% of strokes are due to
dilation is impaired in hypertensive patients. This impairment often is infarction, and the remainder are due to either intracerebral or sub-
assessed with high-resolution ultrasonography before and after the arachnoid hemorrhage. The incidence of stroke rises progressively with
hyperemic phase of reperfusion that follows 5 min of forearm ischemia. increasing blood pressure levels, particularly systolic blood pressure in
Alternatively, endothelium-dependent vasodilation may be assessed individuals aged >65 years. Treatment of hypertension decreases the
in response to an intra-arterially infused endothelium-dependent incidence of both ischemic and hemorrhagic strokes.
vasodilator, e.g., acetylcholine. Endothelin is a vasoconstrictor peptide Hypertension also is associated with impaired cognition in an aging
produced by the endothelium, and orally active endothelin antagonists population, and longitudinal studies support an association between
may lower blood pressure in patients with resistant hypertension. midlife hypertension and late-life cognitive decline. Hypertension is
Currently, it is not known if the hypertension-related vascular abnor- associated with beta amyloid deposition, a major pathologic factor in
malities of ion transport and endothelial function are primary alterations dementia. In addition to actual blood pressure level, arterial stiffness and
or secondary consequences of elevated arterial pressure. Limited evi- visit-to-visit blood pressure variability may be independently related
dence suggests that vascular compliance and endothelium-dependent to subclinical small vessel disease and subsequent cognitive decline.
vasodilation may be improved by aerobic exercise, weight loss, and Hypertension-related cognitive impairment and dementia may also be
antihypertensive agents. It remains to be determined whether these a consequence of a single infarct due to occlusion of a “strategic” larger
interventions affect arterial structure and stiffness via a blood pressure– vessel or multiple lacunar infarcts due to occlusive small vessel disease
independent mechanism and whether different classes of antihyperten- resulting in subcortical white matter ischemia. Several clinical trials
sive agents preferentially affect vascular structure and function. suggest that antihypertensive therapy has a beneficial effect on cog-
nitive function, although this remains an active area of investigation.
■■IMMUNE MECHANISMS, INFLAMMATION, AND Cerebral blood flow remains unchanged over a wide range of
OXIDATIVE STRESS arterial pressures (mean arterial pressure of 50–150 mmHg) through a
Inflammation and alterations of the immune response have been process termed autoregulation of blood flow. In patients with the clinical
implicated in the pathogenesis of vascular injury and hypertension syndrome of malignant hypertension, encephalopathy is related to fail-
for at least four decades. Patients with primary hypertension have ure of autoregulation of cerebral blood flow at the upper pressure limit,
increased circulating levels of autoantibodies. Both hypertension and resulting in vasodilation and hyperperfusion. Signs and symptoms of

hypertensive encephalopathy may include severe headache, nausea across levels of both systolic and diastolic blood pressure. The Multiple 1895
and vomiting (often of a projectile nature), focal neurologic signs, and Risk Factor Intervention Trial (MRFIT), which included >350,000 male
alterations in mental status. Untreated, hypertensive encephalopathy participants, demonstrated a continuous and graded influence of both
may progress to stupor, coma, seizures, and death within hours. It systolic and diastolic blood pressure on CHD mortality, extending
is important to distinguish hypertensive encephalopathy from other down to systolic blood pressures of 120 mmHg. Similarly, results of

neurologic syndromes that may be associated with hypertension, e.g., a meta-analysis involving almost 1 million participants indicate that
cerebral ischemia, hemorrhagic or thrombotic stroke, seizure disorder, ischemic heart disease mortality, stroke mortality, and mortality from
mass lesions, pseudotumor cerebri, delirium tremens, meningitis, acute other vascular causes are directly related to the height of the blood
intermittent porphyria, traumatic or chemical injury to the brain, and pressure, beginning at 115/75 mmHg, without evidence of a threshold.
uremic encephalopathy. Cardiovascular disease risk doubles for every 20-mmHg increase in
systolic and 10-mmHg increase in diastolic pressure. Among older
■■KIDNEY individuals, systolic blood pressure and pulse pressure are more
The kidney is both a target and a cause of hypertension. Primary renal powerful predictors of cardiovascular disease than is diastolic blood
disease is the most common etiology of secondary hypertension. Mech- pressure.
anisms of kidney-related hypertension include a diminished capacity Clinically, hypertension may be defined as that level of blood pres-
to excrete sodium, excessive renin secretion in relation to volume sta- sure at which the institution of therapy reduces blood pressure–related
tus, and sympathetic nervous system overactivity. Conversely, hyper- morbidity and mortality. Clinical criteria for defining hypertension
tension is a risk factor for renal injury and ESRD. The increased risk generally have been based on the average of two or more seated blood
associated with high blood pressure is graded, continuous, and present pressure readings during each of two or more outpatient visits. One
throughout the distribution of blood pressure above optimal pressure. classification recommends blood pressure criteria for defining normal
Renal risk appears to be more closely related to systolic than to diastolic blood pressure, prehypertension, hypertension (stages I and II), and
blood pressure, and black men are at greater risk than white men for isolated systolic hypertension, which is frequent among the elderly
developing ESRD at every level of blood pressure. (Table 271-1). In children and adolescents, hypertension generally
Atherosclerotic, hypertension-related vascular lesions in the kidney is defined as systolic and/or diastolic blood pressure consistently
primarily affect preglomerular arterioles, resulting in ischemic changes >95th percentile for age, sex, and height. Blood pressures between the
in the glomeruli and postglomerular structures. Glomerular injury also 90th and 95th percentiles are considered prehypertensive and are an
may be a consequence of direct damage to the glomerular capillaries indication for lifestyle interventions.
due to glomerular hyperperfusion. Studies of hypertension-related Home blood pressure and average 24-h ambulatory blood pressure
renal damage, primarily in experimental animals, suggest that loss of measurements are generally lower than clinic blood pressures. Because
autoregulation of renal blood flow at the afferent arteriole results in ambulatory blood pressure recordings yield multiple readings through-
transmission of elevated pressures to an unprotected glomerulus with out the day and night, they provide a more comprehensive assessment
ensuing hyperfiltration, hypertrophy, and eventual focal segmental of the vascular burden of hypertension than do a limited number of
glomerular sclerosis. With progressive renal injury there is a loss of office readings. Increasing evidence suggests that home blood pressures,
autoregulation of renal blood flow and glomerular filtration rate, result- including 24-h blood pressure recordings, more reliably predict target
ing in a lower blood pressure threshold for renal damage and a steeper organ damage than do office blood pressures. Blood pressure tends to
slope between blood pressure and renal damage. The result may be a be higher in the early morning hours, soon after waking, than at other
vicious cycle of renal damage and nephron loss leading to more severe times of day. Myocardial infarction and stroke are more common in the
hypertension, glomerular hyperfiltration, and further renal damage. early morning hours. Nighttime blood pressures are generally 10–20%
Glomerular pathology progresses to glomerulosclerosis, and eventually lower than daytime blood pressures, and an attenuated nighttime blood
the renal tubules may also become ischemic and gradually atrophic. pressure “dip” may be associated with increased cardiovascular disease
The renal lesion associated with malignant hypertension consists of risk. Recommended criteria for a diagnosis of hypertension, based on
fibrinoid necrosis of the afferent arterioles, sometimes extending into 24-h blood pressure monitoring, are average awake blood pressure
the glomerulus, and may result in focal necrosis of the glomerular tuft. ≥135/85 mmHg and asleep blood pressure ≥120/75 mmHg. These levels
Clinically, macroalbuminuria (a random urine albumin/creatinine approximate a clinic blood pressure of 140/90 mmHg.
ratio >300 mg/g) or microalbuminuria (a random urine albumin/ Approximately 15–20% of patients with stage 1 hypertension
creatinine ratio 30–300 mg/g) are early markers of renal injury. These based on office blood pressures have average ambulatory readings
are also risk factors for renal disease progression and cardiovascular <135/85 mmHg, termed “white coat hypertension.” Long-term out-
disease. comes of individuals with white coat hypertension are more similar to
normotensive individuals than to individuals with sustained hyper-
■■PERIPHERAL ARTERIES tension (elevation of both office and out-of-office blood pressures).
In addition to contributing to the pathogenesis of hypertension, blood To confirm hypertension, some authorities recommend ambulatory
vessels are a target organ for atherosclerotic disease secondary to long- blood pressure monitoring in all individuals with elevated clinic
standing elevated blood pressure. In hypertensive patients, vascular blood pressure, and postponing therapy with careful follow-up in
disease is a major contributor to stroke, heart disease, and renal fail- those individuals with normal out-of-office blood pressures who
ure. Further, hypertensive patients with arterial disease of the lower are at low cardiovascular risk. In contrast, the prognosis of “masked
extremities are at increased risk for future cardiovascular disease. hypertension” (normal office blood pressure and elevated out-of-office
Although patients with stenotic lesions of the lower extremities may be blood pressure) is nearly equivalent to that of sustained hypertension.
asymptomatic, intermittent claudication is the classic symptom of PAD.
The ankle-brachial index is a useful approach for evaluating PAD and
TABLE 271-1 Blood Pressure Classification
is defined as the ratio of noninvasively assessed ankle to brachial (arm)
systolic blood pressure. An ankle-brachial index <0.90 is considered BLOOD PRESSURE
CLASSIFICATION SYSTOLIC, mmHg DIASTOLIC, mmHg
diagnostic of PAD and is associated with >50% stenosis in at least one
major lower limb vessel. An ankle-brachial index <0.80 is associated Normal <120 and <80
with elevated blood pressure, particularly systolic blood pressure. Prehypertension 120–139 or 80–89
Stage 1 hypertension 140–159 or 90–99
DEFINING HYPERTENSION Stage 2 hypertension ≥160 or ≥100
From an epidemiologic perspective, there is no obvious level of blood Isolated systolic ≥140 and <90
pressure that defines hypertension. In adults, there is a continuous, hypertension
incremental risk of cardiovascular disease, stroke, and renal disease Source: Adapted from AV Chobanian et al: JAMA 289:2560, 2003.

1896 CLINICAL DISORDERS OF HYPERTENSION TABLE 271-3 Secondary Causes of Systolic and Diastolic
Depending on methods of patient ascertainment, ~80–95% of hyperten- Hypertension
sive patients are diagnosed as having primary, or “essential,” hyper- Renal Parenchymal diseases, renal cysts (including
tension. In the remaining 5–20% of hypertensive patients, a specific polycystic kidney disease), renal tumors (including
underlying disorder causing the elevation of blood pressure can be renin-secreting tumors), obstructive uropathy
identified (Tables 271-2 and 271-3). In individuals with “secondary” Renovascular Arteriosclerotic, fibromuscular dysplasia
PART 6
hypertension, a specific mechanism for the blood pressure elevation is Adrenal Primary aldosteronism, Cushing’s syndrome,
often more apparent. 17α-hydroxylase deficiency, 11β-hydroxylase
deficiency, 11-hydroxysteroid dehydrogenase
deficiency (licorice), pheochromocytoma
■■PRIMARY HYPERTENSION
Aortic coarctation
Primary hypertension tends to be familial and is likely to be the con-

sequence of an interaction between environmental and genetic factors. Obstructive sleep apnea
The prevalence of primary hypertension increases with age, and Preeclampsia/eclampsia
individuals with relatively high blood pressures at younger ages are Neurogenic Psychogenic, diencephalic syndrome, familial
at increased risk for the subsequent development of hypertension. It dysautonomia, polyneuritis (acute porphyria, lead
poisoning), acute increased intracranial pressure,
is likely that primary hypertension represents a spectrum of disorders acute spinal cord section
with different underlying pathophysiologies. In the majority of patients
Miscellaneous endocrine Hypothyroidism, hyperthyroidism, hypercalcemia,
with established hypertension, peripheral resistance is increased and acromegaly
cardiac output is normal or decreased; however, in younger patients Medications High-dose estrogens, adrenal steroids,
with mild or labile hypertension, cardiac output may be increased and decongestants, appetite suppressants,
peripheral resistance may be normal. cyclosporine, tricyclic antidepressants, monoamine
When plasma renin activity (PRA) is plotted against 24-h sodium oxidase inhibitors, erythropoietin, nonsteroidal
excretion, ~10–15% of hypertensive patients have high PRA and 25% anti-inflammatory agents, cocaine
have low PRA. High-renin patients may have a vasoconstrictor form of Mendelian forms of See Table 271-4
hypertension, whereas low-renin patients may have volume-dependent hypertension
hypertension. Inconsistent associations between plasma aldosterone
and blood pressure have been described in patients with primary Depending on the populations studied and the methodologies
hypertension. The association between aldosterone and blood pressure for defining insulin resistance, ~25–50% of nonobese, nondiabetic
is more striking in African Americans, and PRA tends to be low in hypertensive persons are insulin resistant. The constellation of insulin
hypertensive African Americans. This raises the possibility that subtle resistance, abdominal obesity, hypertension, and dyslipidemia has
increases in aldosterone may contribute to hypertension in at least been designated as the metabolic syndrome. As a group, first-degree rel-
some groups of patients who do not have overt primary aldostero- atives of patients with primary hypertension are also insulin resistant,
nism. Furthermore, spironolactone, an aldosterone antagonist, may be and hyperinsulinemia (a surrogate marker of insulin resistance) may
a particularly effective antihypertensive agent for some patients with predict the eventual development of hypertension and cardiovascular
primary hypertension, including some patients with “drug-resistant” disease. Although the metabolic syndrome may in part be heritable
hypertension. as a polygenic condition, the expression of the syndrome is modified
by environmental factors, such as degree of physical activity and diet.
■■OBESITY AND THE METABOLIC SYNDROME Insulin sensitivity increases and blood pressure decreases in response
(See also Chap. 401) There is a well-documented association between to weight loss. The recognition that cardiovascular disease risk factors
obesity (body mass index >30 kg/m2) and hypertension. Further, tend to cluster within individuals has important implications for the
cross-sectional studies indicate a direct linear correlation between body evaluation and treatment of hypertension. Evaluation of both hyper-
weight (or body mass index) and blood pressure. Centrally located tensive patients and individuals at risk for developing hypertension
body fat is a more important determinant of blood pressure elevation should include assessment of overall cardiovascular disease risk.
than is peripheral body fat. In longitudinal studies, a direct correlation Similarly, introduction of lifestyle modification strategies and drug
exists between change in weight and change in blood pressure over therapies should address overall risk and not focus exclusively on
time. Sixty percent of hypertensive adults are >20% overweight. It has hypertension.
been established that 60–70% of hypertension in adults may be directly
attributable to adiposity. ■■RENAL PARENCHYMAL DISEASES
Hypertension and dyslipidemia frequently occur together and in Virtually all disorders of the kidney may cause hypertension
association with resistance to insulin-stimulated glucose uptake. This (Table 271-3), and renal disease is the most common cause of secondary
clustering of risk factors is often, but not invariably, associated with hypertension. Hypertension is present in >80% of patients with chronic
obesity, particularly abdominal obesity. Insulin resistance also is asso- renal failure. In general, hypertension is more severe in glomerular
ciated with an unfavorable imbalance in the endothelial production of diseases than in interstitial diseases such as chronic pyelonephritis.
mediators that regulate platelet aggregation, coagulation, fibrinolysis, Conversely, hypertension may cause nephrosclerosis, and in some
and vessel tone. When these risk factors cluster, the risks for CHD, instances it may be difficult to determine whether hypertension or
stroke, diabetes, and cardiovascular disease mortality are increased renal disease was the initial disorder. Proteinuria >1000 mg/d and an
further. active urine sediment are indicative of primary renal disease. In either
instance, the goals are to control blood pressure and retard the rate of
progression of renal dysfunction.
TABLE 271-2 Systolic Hypertension with Wide Pulse Pressure
1. Decreased vascular compliance (arteriosclerosis) ■■RENOVASCULAR HYPERTENSION
2. Increased cardiac output Hypertension due to an occlusive lesion of a renal artery, renovascu-
a. Aortic regurgitation lar hypertension, is a potentially curable form of hypertension. Two
b. Thyrotoxicosis groups of patients are at risk for this disorder: older arteriosclerotic
c. Hyperkinetic heart syndrome patients who have a plaque obstructing the renal artery, frequently
d. Fever at its origin, and patients with fibromuscular dysplasia. Atheroscle-
e. Arteriovenous fistula rosis accounts for the large majority of patients with renovascular
f. Patent ductus arteriosus
hypertension. Although fibromuscular dysplasia may occur at any
age, it has a strong predilection for young white women. The lesions

of fibromuscular dysplasia are frequently bilateral and, in contrast to In the presence of bilateral renal artery stenosis or renal artery stenosis 1897
atherosclerotic renovascular disease, tend to affect more distal portions to a solitary kidney, progressive renal insufficiency may result from
of the renal artery. the use of these agents. Importantly, the renal insufficiency is generally
Renovascular hypertension should be considered in patients with reversible after discontinuation of the offending drug. Patients with
other evidence of atherosclerotic vascular disease. Severe or refractory fibromuscular disease have more favorable outcomes with vascular

hypertension, recent loss of hypertension control or recent onset of repair than do patients with atherosclerotic lesions, presumably owing
moderately severe hypertension, and unexplained deterioration of to their younger age, shorter duration of hypertension, and less sys-
renal function or deterioration of renal function associated with an temic disease.
ACE inhibitor should raise the possibility of renovascular hyperten-
sion. Approximately 50% of patients with renovascular hypertension ■■PRIMARY ALDOSTERONISM
have an abdominal or flank bruit, and the bruit is more likely to be Excess aldosterone production due to primary aldosteronism is a
hemodynamically significant if it lateralizes or extends throughout potentially curable form of hypertension. In patients with primary
systole into diastole. aldosteronism, increased aldosterone production is independent of the
If renal artery stenosis is suspected and if the clinical condition renin-angiotensin system, and the consequences are sodium retention,
warrants an intervention such as percutaneous transluminal renal hypertension, hypokalemia, and low PRA. The reported prevalence
angioplasty (PTRA), placement of a vascular endoprosthesis (stent), or of this disorder varies from <2 to ~15% of hypertensive individuals.
surgical renal revascularization, imaging studies should be the next step In part, this variation is related to the intensity of screening and the
in the evaluation. As a screening test, renal blood flow may be evaluated criteria for establishing the diagnosis.
with a radionuclide [131I]-orthoiodohippurate (OIH) scan, or glomeru- History and physical examination provide little information about
lar filtration rate may be evaluated with a [99mTc]-diethylenetriamine the diagnosis. The age at the time of diagnosis is generally the third
pentaacetic acid (DTPA) scan before and after a single dose of captopril through fifth decade. Hypertension is usually mild to moderate but
(or another ACE inhibitor). In patients with normal, or nearly normal, occasionally may be severe; primary aldosteronism should be con-
renal function, a normal captopril renogram essentially excludes sidered in all patients with refractory hypertension. Hypertension
functionally significant renal artery stenosis; however, its usefulness in these patients may be associated with glucose intolerance. Most
is limited in patients with renal insufficiency (creatinine clearance patients are asymptomatic; however, infrequently, polyuria, polydip-
<20 mL/min) or bilateral renal artery stenosis. Additional imaging sia, paresthesias, or muscle weakness may be present as a consequence
studies are indicated if the scan is positive. Doppler ultrasound of the of hypokalemic alkalosis. Although aldosterone is a salt-retaining hor-
renal arteries produces reliable estimates of renal blood flow velocity mone, patients with primary aldosteronism rarely have edema. Renal
and offers the opportunity to track a lesion over time. Positive studies dysfunction and cardiovascular disease are strikingly increased in
usually are confirmed at angiography, whereas false-negative results patients with primary aldosteronism compared to those with primary
occur frequently, particularly in obese patients. Gadolinium-contrast hypertension.
magnetic resonance angiography offers clear images of the proximal In a hypertensive patient with unprovoked hypokalemia (i.e., unre-
renal artery but may miss distal lesions. An advantage is the opportu- lated to diuretics, vomiting, or diarrhea), the prevalence of primary
nity to image the renal arteries with an agent that is not nephrotoxic. aldosteronism approaches 40–50%. In patients on diuretics, serum
Contrast arteriography remains the “gold standard” for evaluation and potassium <3.1 mmol/L (<3.1 meq/L) also raises the possibility of
identification of renal artery lesions. primary aldosteronism; however, serum potassium is an insensitive
Some degree of renal artery obstruction may be observed in almost and nonspecific screening test. Serum potassium is normal in ~25%
50% of patients with atherosclerotic disease, and there are several of patients subsequently found to have an aldosterone-producing
approaches for evaluating the functional significance of such a lesion to adenoma, and higher percentages of patients with other etiologies of
predict the effect of vascular repair on blood pressure control and renal primary aldosteronism are not hypokalemic.
function. Each approach has varying degrees of sensitivity and specific- The ratio of plasma aldosterone to PRA (PA/PRA) is a useful screen-
ity, and no single test is sufficiently reliable to determine a causal rela- ing test. These measurements preferably are obtained in ambulatory
tionship between a renal artery lesion and hypertension. Functionally patients in the morning. A ratio >30:1 in conjunction with a plasma
significant lesions generally occlude >70% of the lumen of the affected aldosterone concentration >555 pmol/L (>20 ng/dL) reportedly has a
renal artery. On angiography, the presence of collateral vessels to the sensitivity of 90% and a specificity of 91% for an aldosterone-producing
ischemic kidney suggests a functionally significant lesion. A lateraliz- adenoma. In a Mayo Clinic series, an aldosterone-producing adenoma
ing renal vein renin ratio (ratio >1.5 of affected side/contralateral side) subsequently was confirmed surgically in >90% of hypertensive
has a 90% predictive value for a lesion that would respond to vascular patients with a PA/PRA ratio ≥20 and a plasma aldosterone concen-
repair; however, the false-negative rate for blood pressure control is tration ≥415 pmol/L (≥15 ng/dL). There are, however, several caveats
50–60%. Measurement of the pressure gradient across a renal artery to interpreting the ratio. The cutoff for a “high” ratio is laboratory-
lesion does not reliably predict the response to vascular repair. and assay-dependent. Some anti-hypertensive agents may affect the
In the final analysis, a decision concerning vascular repair vs medical ratio (e.g., aldosterone antagonists, angiotensin receptor antagonists,
therapy and the type of repair procedure should be individualized. If and ACE inhibitors may increase renin; aldosterone antagonists
blood pressure is adequately controlled with medical therapy and renal may increase aldosterone). Current recommendations are to with-
function remains stable, there may be little impetus to pursue an evalu- draw aldosterone antagonists for at least 4–6 weeks before obtaining
ation for renal artery stenosis. Several recent randomized clinical trials these measurements. Because aldosterone biosynthesis is potassium-
have found that PTRA with stent placement in patients with arterioscle- dependent, hypokalemia should be corrected with oral potassium
rotic renal artery stenosis offers no advantages to medical therapy in supplements prior to screening. With these caveats, the ratio has been
reducing cardiovascular events and mortality or in preserving kidney reported to be useful as a screening test in measurements obtained
function. In addition, 5 of 7 trials found similar blood pressure control with patients taking their usual antihypertensive medications except
in the two groups of patients. These results suggest that laboratory for aldosterone antagonists, which should be discontinued six weeks
evaluation for renal artery stenosis and stent placement should be con- before testing. A high ratio in the absence of an elevated plasma
sidered only in those arteriosclerotic patients in whom medical therapy aldosterone level is considerably less specific for primary aldostero-
fails to control blood pressure or preserve renal function. Patients with nism since many patients with primary hypertension have low renin
long-standing hypertension, advanced renal insufficiency, or diabetes levels in this setting, particularly African Americans and elderly
mellitus are less likely to benefit from renal vascular repair. The most patients. In patients with renal insufficiency, the ratio may also be ele-
effective medical therapies include an ACE inhibitor or an angiotensin vated because of decreased aldosterone clearance. In patients with an
II receptor blocker; however, these agents decrease glomerular filtra- elevated PA/PRA ratio, the diagnosis of primary aldosteronism can be
tion rate in a stenotic kidney owing to efferent renal arteriolar dilation. confirmed by demonstrating failure to suppress plasma aldosterone to

1898 <277 pmol/L (<10 ng/dL) after IV infusion of 2 L of isotonic saline over by the zona fasciculata in patients with glucocorticoid-remediable
4 h; post-saline infusion plasma aldosterone values between 138 and hyperaldosteronism. The consequence is overproduction in the zona
277 pmol/L (5–10 ng/dL) are not determinant. Alternative confirma- fasciculata of both aldosterone and hybrid steroids (18-hydroxycortisol
tory tests include failure to suppress aldosterone (based on test-specific and 18-oxocortisol) due to oxidation of cortisol. The diagnosis may be
criteria) in response to an oral NaCl load, fludrocortisone, or captopril. established by urine excretion rates of these hybrid steroids that are
Several sporadic and familial adrenal abnormalities may culminate 20–30 times normal or by direct genetic testing. Therapeutically, sup-
PART 6
in the syndrome of primary aldosteronism, and appropriate therapy pression of ACTH with low-dose glucocorticoids corrects the hyperal-
depends on the specific etiology. The two most common causes of spo- dosteronism, hypertension, and hypokalemia. Aldosterone antagonists
radic primary aldosteronism are an aldosterone-producing adenoma are also therapeutic options. Patients with familial aldosteronism types II
and bilateral adrenal hyperplasia. Together, they account for >90% of and III are treated with aldosterone antagonists or adrenalectomy.
all patients with primary aldosteronism. The tumor is almost always

unilateral, and most often measures <3 cm in diameter. Most of the ■■CUSHING’S SYNDROME
remainder of these patients have bilateral adrenocortical hyperplasia (See also Chap. 379) Cushing’s syndrome is related to excess cortisol
(idiopathic hyperaldosteronism). Rarely, primary aldosteronism may be production due either to excess ACTH secretion (from a pituitary
caused by an adrenal carcinoma or an ectopic malignancy, e.g., ovarian tumor or an ectopic tumor) or to ACTH-independent adrenal pro-
arrhenoblastoma. Most aldosterone-producing carcinomas, in contrast duction of cortisol. Hypertension occurs in 75–80% of patients with
to adrenal adenomas and hyperplasia, produce excessive amounts of Cushing’s syndrome. The mechanism of hypertension may be related
other adrenal steroids in addition to aldosterone. Functional differences to stimulation of mineralocorticoid receptors by cortisol and increased
in hormone secretion may assist in the diagnosis of adenoma vs hypersecretion of other adrenal steroids. If clinically suspected based on
plasia. Aldosterone biosynthesis is more responsive to ACTH in patients phenotypic characteristics, in patients not taking exogenous glucocor-
with adenoma and more responsive to angiotensin in patients with ticoids, laboratory screening may be carried out with measurement of
hyperplasia. Consequently, patients with adenoma tend to have higher 24-h excretion rates of urine-free cortisol or an overnight dexametha-
plasma aldosterone in the early morning that decreases during the day, sone-suppression test. Late night salivary cortisol is also a sensitive and
reflecting the diurnal rhythm of ACTH, whereas plasma aldosterone convenient screening test. Further evaluation is required to confirm the
tends to increase with upright posture in patients with hyperplasia, diagnosis and identify the specific etiology of Cushing’s syndrome.
reflecting the normal postural response of the renin-angiotensin- Appropriate therapy depends on the etiology.
aldosterone axis. However, there is overlap in the ability of these measure-
ments to discriminate between adenoma and hyperplasia. Rare familial ■■PHEOCHROMOCYTOMA
forms of primary aldosteronism include glucocorticoid-remediable pri- (See also Chap. 380) Catecholamine-secreting tumors are located in
mary aldosteronism and familial aldosteronism types II and III. Genetic the adrenal medulla (pheochromocytoma) or in extra-adrenal paragan-
testing may assist in the diagnosis of these familial disorders. glion tissue (paraganglioma) and account for hypertension in ~0.05%
Adrenal computed tomography (CT) should be carried out in all of patients. If unrecognized, pheochromocytoma may result in lethal
patients diagnosed with primary aldosteronism. High-resolution CT cardiovascular consequences. Clinical manifestations, including hyper-
may identify tumors as small as 0.3 cm and is positive for an adrenal tension, are primarily related to increased circulating catecholamines,
tumor 90% of the time. If the CT is not diagnostic, an adenoma may although some of these tumors may secrete a number of other vasoactive
be detected by adrenal scintigraphy with 6 β-[I131] iodomethyl-19- substances. In a small percentage of patients, epinephrine is the pre-
norcholesterol after dexamethasone suppression (0.5 mg every 6 h for dominant catecholamine secreted by the tumor, and these patients may
7 days); however, this technique has decreased sensitivity for ade- present with hypotension rather than hypertension. The initial suspicion
nomas <1.5 cm. of the diagnosis is based on symptoms and/or the association of pheo-
When carried out by an experienced radiologist, bilateral adrenal chromocytoma with other disorders (Table 271-4). Approximately 20%
venous sampling for measurement of plasma aldosterone is the most of pheochromocytomas are familial with autosomal dominant inheri-
accurate means of differentiating unilateral from bilateral forms of pri- tance. Inherited pheochromocytomas may be associated with multiple
mary aldosteronism. The sensitivity and specificity of adrenal venous endocrine neoplasia (MEN) type 2A and type 2B, von Hippel-Lindau
sampling (95 and 100%, respectively) for detecting unilateral aldoster- disease, and neurofibromatosis (Table 271-4). Each of these syndromes
one hypersecretion are superior to those of adrenal CT; success rates are is related to specific, identifiable germ-line mutations. Additionally,
90–96%, and complication rates are <2.5%. One frequently used proto- mutations of succinate dehydrogenase genes are associated with
col involves sampling for aldosterone and cortisol levels in response paraganglioma syndromes, generally characterized by head and neck
to ACTH stimulation. An ipsilateral/contralateral aldosterone ratio paragangliomas. Laboratory testing consists of measuring catechola-
>4, with symmetric ACTH-stimulated cortisol levels, is indicative of mines in either urine or plasma, e.g., 24-h urine metanephrine excretion
unilateral aldosterone production. or fractionated plasma-free metanephrines. The urine measurement
Hypertension generally is responsive to surgery in patients with ade- is less sensitive but more specific. Genetic screening is available for
noma but not in patients with bilateral adrenal hyperplasia. Unilateral evaluating patients and relatives suspected of harboring a pheochro-
adrenalectomy, often done via a laparoscopic approach, is curative in mocytoma associated with a familial syndrome. Surgical excision is
40–70% of patients with an adenoma. Transient hypoaldosteronism may the definitive treatment of pheochromocytoma and results in cure in
occur up to 3 months postoperatively, resulting in hyperkalemia, which ~90% of patients.
should be treated with potassium-wasting diuretics and with fludrocor-
tisone, if needed. Patients with bilateral hyperplasia should be treated ■■MISCELLANEOUS CAUSES OF HYPERTENSION
medically. The drug regimen for these patients, as well as for patients Independent of obesity, hypertension occurs in >50% of individuals with
with an adenoma who are poor surgical candidates, should include obstructive sleep apnea. The severity of hypertension correlates with the
an aldosterone antagonist and, if necessary, other potassium-sparing severity of sleep apnea. Approximately 70% of patients with obstructive
diuretics. sleep apnea are obese. Hypertension related to obstructive sleep apnea
Glucocorticoid-remediable hyperaldosteronism is a rare, monogenic also should be considered in patients with drug-resistant hypertension
autosomal dominant disorder characterized by moderate to severe and patients with a history of snoring. The diagnosis can be confirmed
hypertension, often occurring at an early age. These patients may have by polysomnography. In obese patients, weight loss may alleviate or
a family history of hemorrhagic stroke at a young age. Hypokalemia is cure sleep apnea and related hypertension. Continuous positive airway
usually mild or absent. Normally, angiotensin II stimulates aldosterone pressure (CPAP) or bilevel positive airway pressure (BiPAP) adminis-
production by the adrenal zona glomerulosa, whereas ACTH stimu- tered during sleep is an effective therapy for obstructive sleep apnea.
lates cortisol production in the zona fasciculata. Owing to a chimeric With CPAP or BiPAP, patients with apparently drug-resistant hyperten-
gene on chromosome 8, ACTH also regulates aldosterone secretion sion may be more responsive to antihypertensive agents.

TABLE 271-4 Rare Mendelian Forms of Hypertension 1899
DISEASE PHENOTYPE GENETIC CAUSE

Glucocorticoid-remediable Autosomal dominant Chimeric 11β-hydroxylase/aldosterone gene on
hyperaldosteronism Absent or mild hypokalemia chromosome 8

17α-hydroxylase deficiency Autosomal recessive Random mutations of the CYP17 gene on
Males: pseudohermaphroditism chromosome 10
Females: primary amenorrhea, absent secondary sexual characteristics
11β-hydroxylase deficiency Autosomal recessive Mutations of the CYP11B1 gene on chromosome
Masculinization 8q21-q22
11β-hydroxysteroid dehydrogenase Autosomal recessive Mutations in the 11β-hydroxysteroid
deficiency (apparent Hypokalemia, low renin, low aldosterone dehydrogenase gene
mineralocorticoid excess
syndrome)
Liddle’s syndrome Autosomal dominant Mutation subunits of the epithelial sodium
Hypokalemia, low renin, low aldosterone channel SCNN1B and SCNN1C genes
Pseudohypoaldosteronism type II Autosomal dominant Linkage to chromosomes 1q31-q42 and
(Gordon’s syndrome) Hyperkalemia, normal glomerular filtration rate 17p11-q21
Hypertension exacerbated in Autosomal dominant Missense mutation with substitution of leucine for
pregnancy Severe hypertension in early pregnancy serine at codon 810 (MRL810)
Polycystic kidney disease Autosomal dominant Mutations in the PKD1 gene on chromosome 16
Large cystic kidneys, renal failure, liver cysts, cerebral aneurysms, and PKD2 gene on chromosome 4
valvular heart disease
Pheochromocytoma Autosomal dominant
(a) Multiple endocrine neoplasia, type 2A (a) Mutations in the RET protooncogene
Medullary thyroid carcinoma, hyperparathyroidism
(b) Multiple endocrine neoplasia, type 2B (b) Mutations in the RET protooncogene
Medullary thyroid carcinoma, mucosal neuromas, thickened corneal
nerves, alimentary ganglioneuromatoses, marfanoid habitus
(c) von Hippel-Lindau disease (c) Mutations in the VHL tumor-suppressor gene
Retinal angiomas, hemangioblastomas of the cerebellum and spinal
cord, renal cell carcinoma
(d) Neurofibromatosis type 1 (d) Mutations in the NF1 tumor-suppressor gene
Multiple neurofibromas, café-au-lait spots
Coarctation of the aorta is the most common congenital cardiovascular by genetic analysis. Several inherited defects in adrenal steroid
cause of hypertension (Chap. 264). The incidence is 1–8 per 1000 live biosynthesis and metabolism result in mineralocorticoid-induced
births. It is usually sporadic but occurs in 35% of children with Turner’s hypertension and hypokalemia. In patients with a 17α-hydroxylase
syndrome. Even when the anatomic lesion is surgically corrected in deficiency, synthesis of sex hormones and cortisol is decreased
infancy, up to 30% of patients develop subsequent hypertension and (Fig. 271-3). Consequently, these individuals do not mature sexually;
are at risk of accelerated coronary artery disease and cerebrovascular males may present with pseudohermaphroditism and females with pri-
events. Patients with less severe lesions may not be diagnosed until mary amenorrhea and absent secondary sexual characteristics. Because
young adulthood. Physical findings include diminished and delayed cortisol-induced negative feedback on pituitary ACTH production is
femoral pulses and a systolic pressure gradient between the right arm diminished, ACTH-stimulated adrenal steroid synthesis proximal to
and the legs and, depending on the location of the coarctation, between the enzymatic block is increased. Hypertension and hypokalemia are
the right and left arms. A blowing systolic murmur may be heard in consequences of increased synthesis of mineralocorticoids proximal
the posterior left interscapular areas. The diagnosis may be confirmed to the enzymatic block, particularly desoxycorticosterone. Increased
by chest x-ray and transesophageal echocardiography. Therapeutic steroid production and, hence, hypertension may be treated with low-
options include surgical repair and balloon angioplasty, with or with- dose glucocorticoids. An 11β-hydroxylase deficiency results in a salt-
out placement of an intravascular stent. Subsequently, many patients retaining adrenogenital syndrome that occurs in 1 in 100,000 live births.
do not have a normal life expectancy but may have persistent hyper- This enzymatic defect results in decreased cortisol synthesis, increased
tension, with death due to ischemic heart disease, cerebral hemorrhage, synthesis of mineralocorticoids (e.g., desoxycorticosterone), and shunt-
or aortic aneurysm. ing of steroid biosynthesis into the androgen pathway. In the severe
Several additional endocrine disorders, including thyroid diseases form, the syndrome may present early in life, including the newborn
and acromegaly, cause hypertension. Mild diastolic hypertension may period, with virilization and ambiguous genitalia in females and penile
be a consequence of hypothyroidism, whereas hyperthyroidism may enlargement in males, or in older children as precocious puberty and
result in systolic hypertension. Hypercalcemia of any etiology, the most short stature. Acne, hirsutism, and menstrual irregularities may be the
common being primary hyperparathyroidism, may result in hyperten- presenting features when the disorder is first recognized in adolescence
sion. Hypertension also may be related to a number of prescribed or or early adulthood. Hypertension is less common in the late-onset
over-the-counter medications. forms. Patients with an 11β-hydroxysteroid dehydrogenase deficiency
have an impaired capacity to metabolize cortisol to its inactive metabo-
MONOGENIC HYPERTENSION lite, cortisone, and hypertension is related to activation of mineralocor-
In addition to glucocorticoid-remediable primary aldosteronism, a ticoid receptors by cortisol. This defect may be inherited or acquired,
number of rare forms of monogenic hypertension have been identified due to licorice-containing glycyrrhizin acid. The same substance is
(Table 271–4). These disorders may be recognized by their characteristic present in the paste of several brands of chewing tobacco. The defect
phenotypes, and in many instances the diagnosis may be confirmed in Liddle’s syndrome (Chaps. 49 and 379) results from constitutive

1900
Cholesterol
(17α hydroxylase)
PART 6
Pregnenolone 17 OH Pregnenolone DHEA

Progesterone 17 OH Progesterone Androstenedione Testosterone
(21 hydroxylase)
Deoxycorticosterone Deoxycortisol
(11β hydroxylase)
Corticosterone Cortisol
(11β hydroxysteroid dehydrogenase)
Aldosterone Cortisone
Mineralocorticoid Glucocorticoid Androgen

FIGURE 271-3 Adrenal enzymatic defects. DHEA, dehydroepiandrosterone.
activation of amiloride-sensitive ENaC on the distal renal tubule, TREATMENT

resulting in excess sodium reabsorption; the syndrome is ameliorated
by amiloride. Hypertension exacerbated in pregnancy (Chap. 466) may Hypertension
be due to activation of the mineralocorticoid receptor by progesterone.
LIFESTYLE INTERVENTIONS
Implementation of lifestyles that favorably affect blood pressure has
APPROACH TO THE PATIENT implications for both the prevention and the treatment of hyperten-
Hypertension sion. Health-promoting lifestyle modifications are recommended for
individuals with prehypertension and as an adjunct to drug therapy
HISTORY AND PHYSICAL
The initial assessment of a hypertensive patient should include a
complete history and physical examination to confirm a diagnosis TABLE 271-5 Relevant History and Physical
of hypertension, screen for other cardiovascular disease risk factors, History
screen for secondary causes of hypertension, identify cardiovascular Duration of hypertension
consequences of hypertension and other comorbidities, assess blood Previous therapies: responses and side effects
pressure–related lifestyles, and determine the potential for interven- Family history of hypertension and cardiovascular disease
tion. Most patients with hypertension have no specific symptoms Dietary and psychosocial history
referable to their blood pressure elevation. Table 271-5 lists salient Other risk factors: weight change, dyslipidemia, smoking, diabetes, physical
features of the history and physical examination of the hypertensive inactivity
patient. Evidence of secondary hypertension: history of renal disease; change in
Reliable measurements of blood pressure depend on attention appearance; muscle weakness; spells of sweating, palpitations, tremor;
to the details of the technique and conditions of the measurement. erratic sleep, snoring, daytime somnolence; symptoms of hypo- or
Proper training of observers, positioning of the patient, and selection hyperthyroidism; use of agents that may increase blood pressure
of cuff size are essential. Owing to recent regulations preventing the Evidence of target organ damage: history of TIA, stroke, transient blindness;
use of mercury because of concerns about its potential toxicity, most angina, myocardial infarction, congestive heart failure; sexual function
office measurements are made with aneroid sphygmomanometers Other comorbidities
or with oscillometric devices. These instruments should be cali- Physical
brated periodically, and their accuracy confirmed. Body habitus
LABORATORY TESTING Blood pressure in both arms
Table 271-6 lists recommended laboratory tests in the initial evalu- Supine and standing blood pressures
ation of hypertensive patients. Repeat measurements of renal func- Funduscopic examination of retina
tion, serum electrolytes, fasting glucose, and lipids may be obtained Quality of femoral and pedal pulses
after the introduction of a new antihypertensive agent and then Vascular and abdominal bruits
annually or more frequently if clinically indicated. More extensive Cardiac rate and rhythm
laboratory testing is appropriate for patients with apparent drug- Signs of congestive heart failure
resistant hypertension or when the clinical evaluation suggests a
Signs of secondary hypertension
secondary form of hypertension.
Abbreviation: TIA, transient ischemic attack.

TABLE 271-6 Basic Laboratory Tests for Initial Evaluation reduction of blood pressure. In patients with advanced renal disease, 1901
dietary protein restriction may have a modest effect in mitigating
SYSTEM TEST
renal damage by reducing the intrarenal transmission of systemic
Renal Microscopic urinalysis, albumin excretion, serum
BUN and/or creatinine
arterial pressure.
The DASH (Dietary Approaches to Stop Hypertension) trial con-

Endocrine Serum sodium, potassium, calcium, TSH
vincingly demonstrated that over an 8-week period a diet high in
Metabolic Fasting blood glucose, total cholesterol, HDL and
fruits, vegetables, and low-fat dairy products lowers blood pressure
LDL (often computed) cholesterol, triglycerides
in individuals with high-normal blood pressures or mild hyperten-
Other Hematocrit, electrocardiogram
sion. Reduction of daily NaCl intake to <6 g (100 meq) augmented
Abbreviations: BUN, blood urea nitrogen; HDL, high-density lipoprotein; LDL, low- the effect of this diet on blood pressure. Fruits and vegetables are
density lipoprotein; TSH, thyroid-stimulating hormone.
enriched sources of potassium, magnesium, and fiber, and dairy
products are an important source of calcium.
in hypertensive individuals. These interventions should address
PHARMACOLOGIC THERAPY
overall cardiovascular disease risk. Although the impact of lifestyle
interventions on blood pressure is more pronounced in persons Lowering systolic blood pressure by 10–12 mmHg and diastolic
with hypertension, in short-term trials, weight loss and reduction blood pressure by 5–6 mmHg confers relative risk reductions of
of dietary NaCl have been shown to prevent the development of 35–40% for stroke and 12–16% for CHD within 5 years of the ini-
hypertension. In hypertensive individuals, even if these interven- tiation of treatment. The risk of heart failure is reduced by >50%;
tions do not produce a sufficient reduction in blood pressure to although the benefit of blood pressure lowering on progression
avoid drug therapy, the number of medications or doses required of renal failure is less apparent, hypertension control is the single
for blood pressure control may be reduced. Dietary modifications most effective intervention for slowing the rate of progression of
that effectively lower blood pressure are weight loss, reduced NaCl hypertension-related kidney disease.
intake, increased potassium intake, moderation of alcohol consump- There is considerable variation in individual responses to dif-
tion, and an overall healthy dietary pattern (Table 271-7). ferent classes of antihypertensive agents, and the magnitude of
Prevention and treatment of obesity are important for reducing response to any single agent may be limited by activation of
blood pressure and cardiovascular disease risk. In short-term trials, counter-regulatory mechanisms. Most available agents reduce sys-
even modest weight loss can lead to a reduction of blood pres- tolic blood pressure by 7–13 mmHg and diastolic blood pressure
sure and an increase in insulin sensitivity. Average blood pressure by 4–8 mmHg when corrected for placebo effect. More often than
reductions of 6.3/3.1 mmHg have been observed with a reduction not, combinations of agents, with complementary antihypertensive
in mean body weight of 9.2 kg. Regular physical activity facilitates mechanisms, are required to achieve goal blood pressure reduc-
weight loss, decreases blood pressure, and reduces the overall risk of tions. Selection of antihypertensive agents and combinations of
cardiovascular disease. Blood pressure may be lowered by 30 min of agents should be individualized, taking into account age, severity
moderately intense physical activity, such as brisk walking, 6–7 days of hypertension, other cardiovascular disease risk factors, comorbid
a week, or by more intense, less frequent workouts. conditions, and practical considerations related to cost, side effects,
There is individual variability in the sensitivity of blood pressure and frequency of dosing (Table 271-8).
to NaCl, and this variability may have a genetic basis. Several genetic Diuretics Low-dose thiazide diuretics may be used alone or in
loci have been associated with NaCl sensitivity. Based on results of combination with other antihypertensive drugs. Thiazides inhibit
meta-analyses, lowering of blood pressure by limiting daily NaCl the Na+/Cl– pump in the distal convoluted tubule and hence
intake to 4.4–7.4 g (75–125 meq) results in blood pressure reductions increase sodium excretion. In the long term, they also may act as
of 3.7–4.9/0.9–2.9 mmHg in hypertensive individuals and lesser vasodilators. Thiazides are safe, efficacious, inexpensive, and reduce
reductions in normotensive individuals. Results of randomized clinical events. They provide additive blood pressure–lowering
clinical trials on the impact of sodium reduction on the incidence of effects when combined with beta blockers, angiotensin-converting
cardiovascular events are conflicting; however, for obvious practical enzyme inhibitors (ACEIs), or angiotensin receptor blockers (ARBs).
reasons, such studies are challenging and often are not sufficiently In contrast, addition of a diuretic to a calcium channel blocker is
powered to detect differences in cardiovascular endpoints. Although less effective. Usual doses of hydrochlorothiazide range from 6.25 to
reduced salt intakes are generally recommended for both the pre- 50 mg/d. Owing to an increased incidence of metabolic side effects
vention and treatment of hypertension, overly rigorous salt restric- (hypokalemia, insulin resistance, increased cholesterol), higher
tion may have adverse cardiovascular outcomes in diabetic patients doses generally are not recommended. Chlorthalidone is a diuretic
and in patients with CHF aggressively treated with diuretics. Potas- structurally similar to hydrochlorothiazide, and like hydrochloro-
sium and calcium supplementation have inconsistent, modest anti- thiazide, it blocks sodium-chloride cotransport in the early distal
hypertensive effects, and, independent of blood pressure, potassium tubule. However, chlorthalidone has a longer half-life (40–60 h
supplementation may be associated with reduced stroke mortality. vs 9–15 h) and an antihypertensive potency ~1.5–2.0 times that of
Consuming three or more alcoholic drinks per day (a standard hydrochlorothiazide. Potassium loss is also greater with chlorthali-
drink contains ~14 g ethanol) is associated with higher blood pres- done. Two potassium-sparing diuretics, amiloride and triamterene,
sures, and a reduction of alcohol consumption is associated with a act by inhibiting ENaC in the distal nephron. These agents are weak
antihypertensive agents but may be used in combination with a
thiazide to protect against hypokalemia. The main pharmacologic
TABLE 271-7 Lifestyle Modifications to Manage Hypertension target for loop diuretics is the Na+-K+-2Cl– cotransporter in the thick
Weight reduction Attain and maintain BMI <25 kg/m2 ascending limb of the loop of Henle. Loop diuretics generally are
Dietary salt reduction <6 g NaCl/d reserved for hypertensive patients with reduced glomerular filtra-
Adapt DASH-type dietary Diet rich in fruits, vegetables, and low-fat dairy tion rates (reflected in serum creatinine >220 μmol/L [>2.5 mg/dL]),
plan products with reduced content of saturated and CHF, or sodium retention and edema for some other reason, such as
total fat treatment with a potent vasodilator, e.g., minoxidil.
Moderation of alcohol For those who drink alcohol, consume ≤2
consumption drinks/d in men and ≤1 drink/d in women Blockers of the Renin–Angiotensin System ACEIs decrease the
Physical activity Regular aerobic activity, e.g., brisk walking for production of angiotensin II, increase bradykinin levels, and reduce
30 min/d sympathetic nervous system activity. ARBs provide selective block-
Abbreviations: BMI, body mass index; DASH, Dietary Approaches to Stop ade of AT1 receptors, and the effect of angiotensin II on unblocked
Hypertension (trial). AT2 receptors may augment their hypotensive effect. Both classes

1902 TABLE 271-8 Examples of Oral Drugs Used in Treatment of Hypertension
USUAL TOTAL DAILY
DOSEa (DOSING
DRUG CLASS EXAMPLES FREQUENCY/DAY) OTHER INDICATIONS CONTRAINDICATIONS/CAUTIONS
Diuretics
PART 6
Thiazides Hydrochlorothiazide 6.25–50 mg (1–2) Diabetes, dyslipidemia,

Chlorthalidone 25–50 mg (1) hyperuricemia, gout, hypokalemia
Loop diuretics Furosemide 40–80 mg (2–3) CHF due to systolic dysfunction, renal Diabetes, dyslipidemia,
Ethacrynic acid 50–100 mg (2–3) failure hyperuricemia, gout, hypokalemia
Aldosterone antagonists Spironolactone 25–100 mg (1–2) CHF due to systolic dysfunction, primary Renal failure, hyperkalemia
Eplerenone 50–100 mg (1–2) aldosteronism

K+ retaining Amiloride 5–10 mg (1–2) Renal failure, hyperkalemia
Triamterene 50–100 mg (1–2)
Beta blockers Asthma, COPD, 2nd- or 3rd-degree
Cardioselective Atenolol 25–100 mg (1) Angina, CHF due to systolic dysfunction, heart block, sick-sinus syndrome
post-MI, sinus tachycardia, ventricular
tachyarrhythmias
Metoprolol 25–100 mg (1–2)
Nonselective Propranolol 40–160 mg (2)
Propranolol LA 60–180 (1)
Combined alpha/beta Labetalol 200–800 mg (2)
Carvedilol 12.5–50 mg (2)
Alpha antagonists
Selective Prazosin 2–20 mg (2–3) Prostatism
Doxazosin 1–16 mg (1)
Terazosin 1–10 mg (1–2)
Nonselective Phenoxybenzamine 20–120 mg (2–3) Pheochromocytoma
Sympatholytics
Central Clonidine 0.1–0.6 mg (2)
Clonidine patch 0.1–0.3 mg (1/week)
Methyldopa 250–1000 mg (2)
Reserpine 0.05–0.25 mg (1)
Guanfacine 0.5–2 mg (1)
ACE inhibitors Captopril 25–200 mg (2) Post-MI, coronary syndromes, CHF with Acute renal failure, bilateral
Lisinopril 10–40 mg (1) low ejection fraction, nephropathy renal artery stenosis, pregnancy,
hyperkalemia
Ramipril 2.5–20 mg (1–2)
Angiotensin II antagonists Losartan 25–100 mg (1–2) CHF with low ejection fraction, Renal failure, bilateral renal artery
Valsartan 80–320 mg (1) nephropathy, ACE inhibitor cough stenosis, pregnancy, hyperkalemia
Candesartan 2–32 mg (1–2)
Renin inhibitors Aliskiren 150–300 mg (1) Diabetic nephropathy Pregnancy
Calcium antagonists
Dihydropyridines Nifedipine (long-acting) 30–60 mg (1)
Nondihydropyridines Verapamil (long-acting) 120–360 mg (1–2) Post-MI, supraventricular tachycardias, 2nd- or 3rd-degree heart block
Diltiazem (long-acting) 180–420 mg (1) angina
Direct vasodilators Hydralazine 25–100 mg (2) Severe coronary artery disease
Minoxidil 2.5–80 mg (1–2)
At the initiation of therapy, lower doses may be preferable for elderly patients and for select combinations of antihypertensive agents.
a
Abbreviations: ACE, angiotensin-converting enzyme; CHF, congestive heart failure; COPD, chronic obstructive pulmonary disease; MI, myocardial infarction.
of agents are effective antihypertensive agents that may be used Side effects of ACEIs and ARBs include functional renal insuf-
as monotherapy or in combination with diuretics, calcium antago- ficiency due to efferent renal arteriolar dilation in a kidney with a
nists, and alpha blocking agents. ACEIs and ARBs improve insulin stenotic lesion of the renal artery. Additional predisposing conditions
action and ameliorate the adverse effects of diuretics on glucose to renal insufficiency induced by these agents include dehydration,
metabolism. Although the overall impact on the incidence of dia- CHF, and use of nonsteroidal anti-inflammatory drugs. Dry cough
betes is modest, compared with amlodipine (a calcium antagonist), occurs in ~15% of patients, and angioedema occurs in <1% of patients
valsartan (an ARB) has been shown to reduce the risk of developing taking ACEIs. Angioedema occurs most commonly in individuals
diabetes in high-risk hypertensive patients. ACEI/ARB combina- of Asian origin and more commonly in African Americans than in
tions are less effective in lowering blood pressure than is the case whites. Hyperkalemia due to hypoaldosteronism is an occasional
when either class of these agents is used in combination with other side effect of both ACEIs and ARBs.
classes of agents. In patients with vascular disease or a high risk An alternative approach to blocking the renin-angiotensin system
of diabetes, combination ACEI/ARB therapy has been associated has recently been introduced into clinical practice for the treatment
with more adverse events (e.g., cardiovascular death, myocardial of hypertension: direct renin inhibitors. Blockade of the renin-
infarction, stroke, and hospitalization for heart failure) without angiotensin system is more complete with renin inhibitors than with
increases in benefit. ACEIs or ARBs. Aliskiren is the first of a class of oral, nonpeptide

1903
competitive inhibitors of the enzymatic activity of renin. Mono- nerve terminal norepinephrine. Although they are potentially effec-
therapy with aliskiren seems to be as effective as an ACEI or ARB tive antihypertensive agents, their usefulness is limited by ortho-
for lowering blood pressure, but not more effective. Further blood static hypotension, sexual dysfunction, and numerous drug-drug
reductions may be achieved when aliskiren is used in combination interactions. Rebound hypertension is another concern with abrupt

with a thiazide diuretic or a calcium antagonist. Currently, aliskiren cessation of drugs with a short half-life.
is not considered a first-line antihypertensive agent. Calcium Channel Blockers Calcium antagonists reduce vascular
Aldosterone Antagonists Spironolactone is a nonselective aldoster- resistance through L-channel blockade, which reduces intracellu-
one antagonist that may be used alone or in combination with lar calcium and blunts vasoconstriction. This is a heterogeneous
a thiazide diuretic. It may be a particularly effective agent in group of agents that includes drugs in the following three classes:
patients with low-renin primary hypertension, resistant hyperten- phenylalkylamines (verapamil), benzothiazepines (diltiazem), and
sion, and primary aldosteronism. In patients with CHF, low-dose 1,4-dihydropyridines (nifedipine-like). Used alone and in combina-
spironolactone reduces mortality and hospitalizations for heart tion with other agents (ACEIs, beta blockers, α1-adrenergic block-
failure when given in addition to conventional therapy with ACEIs, ers), calcium antagonists effectively lower blood pressure; however,
digoxin, and loop diuretics. Because spironolactone binds to pro- it is unclear if adding a diuretic to a calcium blocker results in a fur-
gesterone and androgen receptors, side effects may include gyneco- ther lowering of blood pressure. Side effects of flushing, headache,
mastia, impotence, and menstrual abnormalities. These side effects and edema with dihydropyridine use are related to their potencies
are circumvented by a newer agent, eplerenone, which is a selective as arteriolar dilators; edema is due to an increase in transcapillary
aldosterone antagonist. pressure gradients, not to net salt and water retention.
Beta Blockers β-Adrenergic receptor blockers lower blood pres- Direct Vasodilators Direct vasodilators decrease peripheral
sure by decreasing cardiac output owing to a reduction of heart rate resistance and concomitantly activate mechanisms that defend
and contractility. Other proposed mechanisms by which beta block- arterial pressure, notably the sympathetic nervous system, the renin-
ers lower blood pressure include a central nervous system effect and angiotensin-aldosterone system, and sodium retention. Usually,
inhibition of renin release. Beta blockers are particularly effective they are not considered first-line agents but are most effective when
in hypertensive patients with tachycardia, and their hypotensive added to a combination that includes a diuretic and a beta blocker.
potency is enhanced by co-administration with a diuretic. In lower Hydralazine is a potent direct vasodilator that has antioxidant
doses, some beta blockers selectively inhibit cardiac β1 receptors and nitric oxide–enhancing actions, and minoxidil is a particularly
and have less influence on β2 receptors on bronchial and vascular potent agent and is used most frequently in patients with renal
smooth muscle cells; however, there seems to be no difference in insufficiency who are refractory to all other drugs. Hydralazine may
the antihypertensive potencies of cardioselective and nonselective induce a lupus-like syndrome, and side effects of minoxidil include
beta blockers. Some beta blockers have intrinsic sympathomimetic hypertrichosis and pericardial effusion. Intravenous nitroprusside
activity, although it is uncertain whether this constitutes an overall can be used to treat malignant hypertension and life-threatening left
advantage or disadvantage in cardiac therapy. Beta blockers with- ventricular heart failure associated with elevated arterial pressure.
out intrinsic sympathomimetic activity decrease the rate of sud-
COMPARISONS OF ANTIHYPERTENSIVES
den death, overall mortality, and recurrent myocardial infarction.
In patients with CHF, beta blockers have been shown to reduce Based on pooling results from clinical trials, meta-analyses of the
the risks of hospitalization and mortality. Overall, beta blockers efficacy of different classes of antihypertensive agents suggest essen-
may be less protective against cardiovascular and cerebrovascular tially equivalent blood pressure–lowering effects of the following
endpoints, and some beta blockers may have less effect on central six major classes of antihypertensive agents when used as mono-
aortic pressure than other classes of antihypertensive agents. How- therapy: thiazide diuretics, beta blockers, ACEIs, ARBs, calcium
ever, beta blockers remain appropriate therapy for hypertensive antagonists, and α1 blockers. On average, standard doses of most
patients with concomitant heart disease and related comorbidities. antihypertensive agents reduce blood pressure by 8–10/4–7 mmHg;
Carvedilol and labetalol block both β receptors and peripheral however, there may be subgroup differences in responsiveness.
α-adrenergic receptors. The potential advantages of combined β- Younger patients may be more responsive to beta blockers and
and α-adrenergic blockade in treating hypertension remain to be ACEIs, whereas patients aged >50 years may be more responsive
determined. Nebivolol represents another class of cardioselective to diuretics and calcium antagonists. There is a limited relationship
beta blockers that has additional vasodilator actions related to between plasma renin and blood pressure response. Patients with
enhancement of nitric oxide activity. Whether this confers greater high-renin hypertension may be more responsive to ACEIs and
clinical effectiveness remains to be determined. ARBs than to other classes of agents, whereas patients with low-
renin hypertension are more responsive to diuretics and calcium
`-Adrenergic Blockers Postsynaptic, selective α-adrenoreceptor antagonists. Hypertensive African Americans tend to have low renin
antagonists lower blood pressure by decreasing peripheral vascular and may require higher doses of ACEIs and ARBs than whites for
resistance. They are effective antihypertensive agents used either optimal blood pressure control, although this difference is abolished
as monotherapy or in combination with other agents. However, when these agents are combined with a diuretic. Beta blockers
in clinical trials of hypertensive patients, alpha blockade has not also appear to be less effective than thiazide diuretics in African
been shown to reduce cardiovascular morbidity and mortality or to Americans than in non-African Americans. Early pharmacogenetic
provide as much protection against CHF as other classes of antihy- studies, utilizing a candidate gene approach, genome-wide scans, or
pertensive agents. These agents are also effective in treating lower integrated metabolomic and genetic profiles, have shown associa-
urinary tract symptoms in men with prostatic hypertrophy. Non- tions of gene polymorphisms with blood pressure responsiveness to
selective α-adrenoreceptor antagonists bind to postsynaptic and specific antihypertensive drugs. However, the reported effects have
presynaptic receptors and are used primarily for the management generally been too small to affect clinical decisions, and associated
of patients with pheochromocytoma. polymorphisms remain to be confirmed. Currently, in practical
Sympatholytic Agents Centrally acting α2 sympathetic agonists terms, the presence of comorbidities often influences the selection of
decrease peripheral resistance by inhibiting sympathetic outflow. antihypertensive agents.
They may be particularly useful in patients with autonomic neurop- A meta-analysis of >30 randomized trials of blood pressure–
athy who have wide variations in blood pressure due to barorecep- lowering therapy indicates that for a given reduction in blood pres-
tor denervation. Drawbacks include somnolence, dry mouth, and sure, the major drug classes seem to produce similar overall net
rebound hypertension on withdrawal. Peripheral sympatholytics effects on total cardiovascular events. In both nondiabetic and dia-
decrease peripheral resistance and venous constriction by depleting betic hypertensive patients, most trials have failed to show significant

1904 differences in cardiovascular outcomes with different drug regimens decreasing renin release. Sustained activation of the baroreflex most
as long as equivalent decreases in blood pressure were achieved. For likely lowers blood pressure by other mechanisms as well; however,
example, the Antihypertensive and Lipid-Lowering Treatment to Pre- clinical experience with this intervention is limited. Enthusiasm for
vent Heart Attack Trial (ALLHAT) demonstrated that the occurrence renal denervation has been questioned by the results of Simplicity
of CHD and nonfatal myocardial infarction, as well as overall mortal- 3, a randomized, prospective clinical trial, comparing bilateral renal
ity, was virtually identical in hypertensive patients treated with either denervation with a sham procedure in 535 patients with resistant
PART 6
an ACEI (lisinopril), a diuretic (chlorthalidone), or a calcium antago- hypertension. At the end of six months there was no benefit of
nist (amlodipine). However, there is some evidence that beta blockers renal artery denervation on both office and ambulatory systolic
are inferior to other classes of agents for prevention of cardiovascular blood pressures, the trial’s primary endpoints. It remains to be seen
events, stroke, renal failure, and all-cause mortality, whereas calcium whether these interventions will be adopted into clinical practice.
channel blockers may be inferior and diuretics but superior to other

classes of agents for the prevention of heart failure. BLOOD PRESSURE GOALS OF ANTIHYPERTENSIVE THERAPY
However, in specific patient groups, ACEIs may have particular Based on clinical trial data, the maximum protection against
advantages, beyond that of blood pressure control, in reducing combined cardiovascular endpoints is achieved with pressures
cardiovascular and renal outcomes. ACEIs and ARBs decrease intra- <135–140 mmHg for systolic blood pressure and <80–85 mmHg
glomerular pressure and proteinuria and may retard the rate of for diastolic blood pressure; however, treatment has not reduced
progression of renal insufficiency, not totally accounted for by their cardiovascular disease risk to the level in non-hypertensive individ-
hypotensive effects, in both diabetic and nondiabetic renal diseases. uals. According to a recent meta-analysis, the magnitude of the pro-
In patients with type 2 diabetes, treatment with an ACEI, an ARB, portional reduction of cardiovascular events is broadly consistent
or aliskiren decreases proteinuria and delays the progression of regardless of baseline co-morbidity, although the absolute benefit
renal disease. In experimental models of hypertension and diabetes, of blood pressure reduction is greater among individuals with the
renal protection with aliskiren is comparable to that with ACEIs and highest risk for cardiovascular events.
ARBs. However, in patients with type 2 diabetes, addition of ali- The degree of benefit derived from antihypertensive agents is
skiren to an ACEI provides no additional protection against cardio- related to the magnitude of the blood pressure reduction. Guide-
vascular or renal disease and may be associated with more adverse lines establishing blood pressure targets for hypertension control
outcomes. Among African Americans with hypertension-related continue to evolve. An intensive blood pressure lowering strategy
renal disease, ACEIs appear to be more effective than beta blockers is superior to a less intensive strategy for prevention of stroke
or dihydropyridine calcium channel blockers in slowing, although and myocardial infarction. For example, the SPRINT trial studied
not preventing, the decline of glomerular filtration rate. The reno- 9361 subjects aged >50 years at increased risk for cardiovascular
protective effect of these renin-angiotensin blockers, compared with evens. Intensive blood pressure control (systolic blood pressure
other antihypertensive drugs, is less obvious at lower blood pres- <120 mmHg) reduced the risk of cardiovascular events and mortality
sures. In most patients with hypertension and heart failure due to by 25% compared with less intensive control (systolic blood pressure
systolic and/or diastolic dysfunction, the use of diuretics, ACEIs or 135–139 mmHg). More intense control may also be associated with a
ARBs, and beta blockers is recommended to improve survival. Inde- higher incidence of adverse events (e.g., syncope, electrolyte abnor-
pendent of blood pressure, in both hypertensive and normotensive malities, deterioration of renal function), and recent studies suggest
individuals, ACEIs attenuate the development of left ventricular that the benefits of intensive blood-pressure lowering outweigh the
hypertrophy, improve symptomatology and risk of death from risks. Nevertheless, the absolute impact of more intensive control is
CHF, and reduce morbidity and mortality rates in post-myocardial relatively small. In the final analysis, patients need to be carefully
infarction patients. Similar benefits in cardiovascular morbidity monitored, and clinical decision making should be individualized.
and mortality rates in patients with CHF have been observed with In diabetic patients, effective blood pressure control reduces
the use of ARBs. ACEIs provide better coronary protection than do the risk of cardiovascular events and death as well as the risk for
calcium channel blockers, whereas calcium channel blockers pro- microvascular disease (nephropathy, retinopathy). Various guide-
vide more stroke protection than do either ACEIs or beta blockers. lines have been recommended for hypertension control in patients
Results of a large, double-blind, prospective clinical trial (Avoiding with type 2 diabetes (<140/90, <140/85, <130/80). One widely
Cardiovascular Events through Combination Therapy in Patients cited Action to Control Cardiovascular Risk in Diabetes clinical
Living with Systolic Hypertension [ACCOMPLISH Trial]) indi- trial (ACCORD) failed to find superiority of intensive blood pres-
cated that combination treatment with an ACEI (benazepril) plus sure lowering (<120 mmHg) over standard blood pressure control
a calcium antagonist (amlodipine) was superior to treatment with (<140 mmHg) in reducing the risk of the study’s primary outcome (a
the ACEI plus a diuretic (hydrochlorothiazide) in reducing the risk composite endpoint of myocardial infarction, stroke, and cardiovas-
of cardiovascular events and death among high-risk patients with cular death) in diabetic patients. However, that trial did demonstrate
hypertension. However, the combination of an ACEI and a diuretic a significant reduction of stroke and left ventricular hypertrophy
has recently been shown to produce major reductions in morbidity with more intensive therapy.
and mortality in the very elderly. In patients with chronic renal insufficiency, a small, non-progressive
After a stroke, combination therapy with an ACEI and a diuretic, increase in the serum creatinine concentration may occur with inten-
but not with an ARB, has been reported to reduce the rate of recur- sive blood pressure lowering. This generally reflects a hemodynamic
rent stroke. Some of these apparent differences may reflect differ- response, not structural renal injury, indicating that intraglomerular
ences in trial design and/or patient groups. pressure has been reduced. Blood pressure control should not be
There has been a recent resurgence of interest in two non- allowed to deteriorate in order to prevent the modest creatinine
pharmacologic, antihypertensive therapies that interrupt sympa- rise. Among older patients with isolated systolic hypertension,
thetic outflow: (1) device-based carotid baroreflex activation by further lowering of diastolic blood pressure does not result in harm.
electrical stimulation of the carotid sinus; and (2) endovascular However, relatively little information is available concerning the
radiofrequency ablation of the renal sympathetic nerves. Both have risk-versus-benefit ratio of intensive antihypertensive therapy in
been suggested as potential options for resistant hypertension. individuals >80 years of age, and in this population, gradual blood
Whereas renal denervation is a minimally invasive procedure, pressure reduction to a less aggressive target level of control may be
carotid baroreceptor stimulation is a surgical procedure, usually per- appropriate (e.g., 130–150 mmHg).
formed under general anesthesia that currently involves implanting To achieve recommended blood pressure goals, the majority of
electrodes on both the right and left carotid arteries. Both inter- individuals with hypertension will require treatment with more
ventions inhibit sympathetic drive and decrease blood pressure than one drug. Three or more drugs frequently are needed in
by increasing the capacity of the kidney to excrete sodium and by patients with diabetes and renal insufficiency. For most agents,

reduction of blood pressure at half-standard doses is only ~20% less TABLE 271-10 Usual Intravenous Doses of Antihypertensive Agents 1905
than at standard doses. Appropriate combinations of agents at these Used in Hypertensive Emergenciesa
lower doses may have additive or almost additive effects on blood ANTIHYPERTENSIVE
pressure with a lower incidence of side effects. AGENT INTRAVENOUS DOSE
The term resistant hypertension refers to patients with blood pres-

Nitroprusside Initial 0.3 (μg/kg)/min; usual 2–4 (μg/kg)/min;
sures persistently >140/90 mmHg despite taking three or more maximum 10 (μg/kg)/min for 10 min
antihypertensive agents, including a diuretic. Resistant or difficult-to- Nicardipine Initial 5 mg/h; titrate by 2.5 mg/h at 5–15 min
control hypertension is more common in patients aged >60 years intervals; max 15 mg/h
than in younger patients. Resistant hypertension may be related to Labetalol 2 mg/min up to 300 mg or 20 mg over 2 min, then
“pseudoresistance” (high office blood pressures and lower home 40–80 mg at 10-min intervals up to 300 mg total
blood pressures), nonadherence to therapy, identifiable causes of Enalaprilat Usual 0.625–1.25 mg over 5 min every 6–8 h;
hypertension (including obesity and excessive alcohol intake), and maximum 5 mg/dose
the use of any of a number of nonprescription and prescription Esmolol Initial 80–500 μg/kg over 1 min, then 50–
drugs (Table 271-3). Rarely, in older patients, pseudohypertension 300 (μg/kg)/min
may be related to the inability to measure blood pressure accurately Phentolamine 5–15 mg bolus
in severely sclerotic arteries. This condition is suggested if the radial Nitroglycerin Initial 5 μg/min, then titrate by 5 μg/min at 3–5-min
pulse remains palpable despite occlusion of the brachial artery by the intervals; if no response is seen at 20 μg/min,
cuff (Osler maneuver). The actual blood pressure can be determined incremental increases of 10–20 μg/min may be used
by direct intra-arterial measurement. Evaluation of patients with Hydralazine 10–50 mg at 30-min intervals
resistant hypertension might include home blood pressure monitor- a
Constant blood pressure monitoring is required. Start with the lowest dose.
ing to determine if office blood pressures are representative of the Subsequent doses and intervals of administration should be adjusted according
usual blood pressure. A more extensive evaluation for a secondary to the blood pressure response and duration of action of the specific agent.
form of hypertension should be undertaken if no other explanation
for hypertension resistance becomes apparent. anemia, and encephalopathy. Historic inquiry should include ques-
tions about the use of monoamine oxidase inhibitors and recre-
HYPERTENSIVE EMERGENCIES
ational drugs (e.g., cocaine, amphetamines).
Probably due to the widespread availability of antihypertensive Although blood pressure should be lowered rapidly in patients
therapy, in the United States there has been a decline in the num- with hypertensive encephalopathy, there are inherent risks of overly
bers of patients presenting with “crisis levels” of blood pressure. aggressive therapy. In hypertensive individuals, the upper and
Most patients who present with severe hypertension are chronically lower limits of autoregulation of cerebral blood flow are shifted
hypertensive, and in the absence of acute end organ damage, precip- to higher levels of arterial pressure, and rapid lowering of blood
itous lowering of blood pressure may result in significant morbidity pressure to below the lower limit of autoregulation may precipi-
and should be avoided. The key to successful management of severe tate cerebral ischemia or infarction as a consequence of decreased
hypertension is to differentiate hypertensive crises from hyperten- cerebral blood flow. Renal and coronary blood flows also may
sive urgencies. The degree of target organ damage, rather than the decrease with overly aggressive acute therapy. The initial goal of
level of blood pressure alone, determines the rapidity with which therapy is to reduce mean arterial blood pressure by no more than
blood pressure should be lowered. Tables 271-9 and 271-10 list a 25% within minutes to 2 h or to a blood pressure in the range of
number of hypertension-related emergencies and recommended 160/100–110 mmHg. This may be accomplished with IV nitroprus-
therapies. side, a short-acting vasodilator with a rapid onset of action that
Malignant hypertension is a syndrome associated with an abrupt allows for minute-to-minute control of blood pressure. Parenteral
increase of blood pressure in a patient with underlying hyperten- labetalol and nicardipine are also effective agents for the treatment
sion or related to the sudden onset of hypertension in a previously of hypertensive encephalopathy.
normotensive individual. The absolute level of blood pressure is In patients with malignant hypertension without encephalopa-
not as important as its rate of rise. Pathologically, the syndrome is thy or another catastrophic event, it is preferable to reduce blood
associated with diffuse necrotizing vasculitis, arteriolar thrombi, pressure over hours or longer rather than minutes. This goal may
and fibrin deposition in arteriolar walls. Fibrinoid necrosis has been effectively be achieved initially with frequent dosing of short-acting
observed in arterioles of kidney, brain, retina, and other organs. oral agents such as captopril, clonidine, and labetalol.
Clinically, the syndrome is recognized by progressive retinopathy Acute, transient blood pressure elevations that last days to weeks
(arteriolar spasm, hemorrhages, exudates, and papilledema), deteri- frequently occur after thrombotic and hemorrhagic strokes. Autoreg-
orating renal function with proteinuria, microangiopathic hemolytic ulation of cerebral blood flow is impaired in ischemic cerebral tissue,
and higher arterial pressures may be required to maintain cerebral
blood flow. Although specific blood pressure targets have not been
TABLE 271-9 Preferred Parenteral Drugs for Selected Hypertensive defined for patients with acute cerebrovascular events, aggressive
Emergencies reductions of blood pressure are to be avoided. With the increasing
Hypertensive encephalopathy Nitroprusside, nicardipine, labetalol availability of improved methods for measuring cerebral blood
Malignant hypertension (when IV Labetalol, nicardipine, nitroprusside, flow (using CT technology), studies are in progress to evaluate the
therapy is indicated) enalaprilat effects of different classes of antihypertensive agents on both blood
Stroke Nicardipine, labetalol, nitroprusside pressure and cerebral blood flow after an acute stroke. Currently, in
Myocardial infarction/unstable Nitroglycerin, nicardipine, labetalol, the absence of other indications for acute therapy, for patients with
angina esmolol cerebral infarction who are not candidates for thrombolytic therapy,
Acute left ventricular failure Nitroglycerin, enalaprilat, loop one recommended guideline is to institute antihypertensive therapy
diuretics only for patients with a systolic blood pressure >220 mmHg or a dia-
Aortic dissection Nitroprusside, esmolol, labetalol stolic blood pressure >130 mmHg. If thrombolytic therapy is to be
Adrenergic crisis Phentolamine, nitroprusside used, the recommended goal blood pressure is <185 mmHg systolic
Postoperative hypertension Nitroglycerin, nitroprusside, labetalol, pressure and <110 mmHg diastolic pressure. In patients with hem-
nicardipine orrhagic stroke, there is no consistent evidence that acute reduc-
Preeclampsia/eclampsia of pregnancy Hydralazine, labetalol, nicardipine tions of systolic blood pressure to a more aggressive target than
Source: Adapted from DG Vidt, in S Oparil, MA Weber (eds): Hypertension, 2nd ed. 140–179 mmHg improves functional outcome. The management
Philadelphia, Elsevier Saunders, 2005. of hypertension after subarachnoid hemorrhage is controversial.

1906 Cautious reduction of blood pressure is indicated if mean arterial and/or compromise of proximal perfusion pressures with large-vessel
pressure is >130 mmHg. disease (Fig. 272-1).
In addition to pheochromocytoma, an adrenergic crisis due to
catecholamine excess may be related to cocaine or amphetamine MACROVASCULAR DISEASE
overdose, clonidine withdrawal, acute spinal cord injuries, and an Large-vessel renal artery occlusive disease can result from extrinsic
interaction of tyramine-containing compounds with monoamine compression of the vessel, intimal dissection, fibromuscular dysplasia
PART 6
oxidase inhibitors. These patients may be treated with phentolamine (FMD), or, most commonly, atherosclerotic disease. Any disorder that
or nitroprusside. reduces perfusion pressure to the kidney can activate mechanisms that
Treatment of hypertension in patients with acute aortic dissec- tend to restore renal pressures at the expense of developing systemic
tion is discussed in Chap. 274, and treatment of hypertension in hypertension. Because restoration of perfusion pressures can reverse
pregnancy is discussed in Chap. 466. these pathways, renal artery stenosis is considered a specifically treat-
able “secondary” cause of hypertension.
■■FURTHER READING Renal artery stenosis is common and often has only minor hemody-
Ettehad D et al: Blood pressure lowering for prevention of cardio- namic effects. FMD is reported in 3–5% of normal subjects presenting
vascular disease and death: A systematic review and meta-analysis. as potential kidney donors without hypertension. It may present clin-
Lancet 387:957, 2016. ically with hypertension in younger individuals (between age 15 and
Feinberg AP, Fallin MD: Epigenetics at the crossroads of genes and 50), most often women. FMD does not often threaten kidney function,
the environment. JAMA 314:1129, 2015. but sometimes produces total occlusion and can be associated with
Go AS et al: An effective approach to high blood pressure control: A renal artery aneurysms. Atherosclerotic renal artery stenosis (ARAS)
science advisory from the American Heart Association, the American is common in the general population (6.8% of a community-based
College of Cardiology, and the Centers for Disease Control and Pre- sample above age 65). The prevalence increases with age and for
vention. Hypertension 63:878, 2014. patients with other vascular conditions such as coronary artery disease
Guo F et al: Trend in prevalence, awareness, management, and control (18–23%) and/or peripheral aortic or lower extremity disease (>30%).
of hypertension among United States adults, 1999 to 2010. J Am Coll If untreated, ARAS progresses in nearly 50% of cases over a 5-year
Cardiol 60:599, 2012. period, sometimes to total occlusion. Intensive treatment of arterial
Harrison DG et al: Inflammation, immunity and hypertension. blood pressure and statin therapy appear to slow these rates and
Hypertension 57:132, 2011. improve clinical outcomes.
Hughes TM, Sink TM: Hypertension and its role in cognitive function: Critical levels of stenosis lead to a reduction in perfusion pressure
Current evidence and challenges for the future. Am J Hypertension that activates the renin-angiotensin system, reduces sodium excretion,
29:149, 2016. and activates sympathetic adrenergic pathways. These events lead to
Oh YS et al: National Heart, Lung, and Blood Institute Working Group systemic hypertension characterized by angiotensin dependence in the
Report on Salt in Human Health and Sickness: Building on the early stages, widely varying pressures, loss of circadian blood pres-
current scientific evidence. Hypertension 68:281, 2016. sure (BP) rhythms, and accelerated target organ injury, including left
Raman G et al: Comparative effectiveness of management strategies ventricular hypertrophy and renal fibrosis. Renovascular hypertension
for renal artery stenosis: An updated systematic review. Ann Intern can be treated with agents that block the renin-angiotensin system and
Med 165:635, 2016. other drugs that modify these pressor pathways. It can also be treated
Sprint Research Group: A randomized trial of intensive versus with restoration of renal blood flow by either endovascular or surgical
standard blood pressure control. N Engl J Med 373:2103, 2015. revascularization. Most patients require continued antihypertensive
drug therapy because revascularization alone rarely lowers BP to
normal.
ARAS and systemic hypertension tend to affect both the post-stenotic
and contralateral kidneys, reducing overall glomerular filtration rate
(GFR) in ARAS. When kidney function is threatened by large-vessel
272 Renovascular Disease

disease primarily, it has been labeled ischemic nephropathy. Moder-
ately reduced blood flow that develops gradually is associated with
reduced GFR and limited oxygen consumption with preserved tissue
Stephen C. Textor oxygenation. Hence, kidney function often remains stable during med-
ical therapy, sometimes for years. With more advanced disease, reduc-
tions in cortical perfusion and frank tissue hypoxia develop. Unlike
The renal vasculature is unusually complex with rich arteriolar flow FMD, ARAS develops in patients with other risk factors for atheroscle-
to the cortex in excess of metabolic requirements, consistent with its rosis and is commonly superimposed upon preexisting small-vessel
primary function as a filtering organ. After delivering blood to cortical disease in the kidney resulting from hypertension, aging, and diabetes.
glomeruli, the postglomerular circulation supplies deeper medullary Nearly 85% of patients considered for renal revascularization have
segments that support energy-dependent solute transport at multiple stage 3–5 chronic kidney disease (CKD) with GFR <60 mL/min per
levels of the renal tubule. These postglomerular vessels carry less 1.73 m2. The presence of ARAS is a strong predictor of morbidity- and
blood, and high oxygen consumption leaves the deeper medullary mortality-related cardiovascular events, independent of whether renal
regions at the margin of hypoxemia. Vascular disorders that commonly revascularization is undertaken.
threaten the blood supply of the kidney include large-vessel atheroscle- Diagnostic approaches to renal artery stenosis depend partly on the
rosis, fibromuscular diseases, and embolic disorders. Microvascular specific clinical questions to be addressed. Noninvasive characterization
injury, including inflammatory and primary hematologic disorders, of the renal vasculature may be achieved by several techniques, sum-
is described in Chap. 311. marized in Table 272-1. Although activation of the renin-angiotensin
The glomerular capillary endothelium shares susceptibility to oxi- system is a key step in developing renovascular hypertension, it
dative stress, pressure injury, and inflammation with other vascular is transient. Levels of renin activity are therefore subject to timing,
territories. Rates of urinary albumin excretion (UAE) are predictive of the effects of drugs, and sodium intake, and do not reliably predict
systemic atherosclerotic disease events. Increased UAE may develop the response to vascular therapy. Renal artery velocities by Doppler
years before cardiovascular events. UAE and the risk of cardiovascular ultrasound >200 cm/s generally predict hemodynamically important
events are both reduced with pharmacologic therapy such as statins. lesions (>60% vessel lumen occlusion), although some treatment trials
Experimental studies demonstrate functional changes and rarefaction require velocity >300 cm/s to avoid false positives. The renal resistive
of renal microvessels under conditions of accelerated atherosclerosis index has predictive value regarding the viability of the kidney.

1907
Medulla
CHAPTER 272 Renovascular Disease

Cortex
Normal MV proliferation MV rarefaction

(early atherosclerosis) (chronic renal ischemia)
FIGURE 272-1 Examples of micro-CT images from vessels defined by radiopaque casts injected into the renal vasculature. These illustrate the complex, dense
cortical capillary network supplying the kidney cortex that can either proliferate or succumb to rarefaction under the influence of atherosclerosis and/or occlusive
disease. Changes in blood supply are followed by tubulointerstitial fibrosis and loss of kidney function. MV, microvascular. (From LO Lerman, AR Chade: Curr Opin
Nephrol Hyper 18:160, 2009, with permission.)
It remains operator- and institution-dependent, however. Captopril- medical therapy with follow-up for disease progression is equally
enhanced renography has a strong negative predictive value when effective. Multiple prospective randomized controlled trials have
entirely normal. Magnetic resonance angiography (MRA) is now less failed to identify compelling benefits for interventional procedures
often used, as gadolinium contrast has been associated with neph- regarding short-term results of BP and renal function. Studies of
rogenic systemic fibrosis. Contrast-enhanced computed tomography cardiovascular outcomes including stroke, congestive heart failure,
(CT) with vascular reconstruction provides excellent vascular images myocardial infarction, and end-stage renal failure, suggest a small
and functional assessment, but carries a small risk of contrast toxicity. mortality benefit for revascularized subjects without proteinuria.
Medical therapy should include blockade of the renin-angiotensin
system, attainment of goal BPs, cessation of tobacco, statins, and
TREATMENT aspirin. Follow-up requires surveillance for progressive occlusion
Renal Artery Stenosis manifest by worsening renal function and/or loss of BP control.
Renal revascularization is now often reserved for patients failing
While restoring renal blood flow and perfusion seems intuitively medical therapy or developing additional complications.
beneficial for high-grade occlusive lesions, revascularization proce- Techniques of renal revascularization are improving. With expe-
dures also pose hazards and expense. Patients with FMD are com- rienced operators, major complications occur in 5–9% of cases,
monly younger females with otherwise normal vessels and a long life including renal artery dissection, capsular perforation, hemorrhage,
expectancy. These patients often respond well to percutaneous renal and occasional atheroembolic disease. Although not common, athe-
artery angioplasty. If BP can be controlled to goal levels and kidney roembolic disease can be catastrophic and accelerate both hyperten-
function remains stable in patients with ARAS, it may be argued that sion and kidney failure, precisely the events that revascularization
TABLE 272-1 Summary of Imaging Modalities for Evaluating the Kidney Vasculature
Perfusion Studies to Assess Differential Renal Blood Flow
Captopril renography with Captopril-mediated fall in filtration Normal study excludes renovascular Multiple limitations in patients with
technetium 99mTc mertiatide pressure amplifies differences in hypertension advanced atherosclerosis or creatinine
(99mTc MAG3) renal perfusion >2.0 mg/dL (177 μmol/L)
Vascular Studies to Evaluate the Renal Arteries
Duplex ultrasonography Shows the renal arteries and Inexpensive; widely available, Heavily dependent on operator’s experience;
measures flow velocity as a suitable for follow-up studies less useful than invasive angiography for the
means of assessing the severity of diagnosis of fibromuscular dysplasia and
stenosis abnormalities in accessory renal arteries
Computed tomographic Shows the renal arteries and Provides excellent images; stents Expensive, moderate volume of contrast
angiography perirenal aorta do not cause artifacts required
Magnetic resonance Shows the renal arteries and Not nephrotoxic, but concerns for Expensive; gadolinium excluded in renal
angiography perirenal aorta gadolinium toxicity exclude use in failure, unable to visualize stented vessels
GFR <30 mL/min/1.73 m2; provides
excellent images
Intraarterial angiography Shows location and severity of Considered “gold standard” for Expensive, associated hazard of
vascular lesion diagnosis of large-vessel disease, atheroemboli, contrast toxicity, procedure-
usually performed simultaneous related complications, e.g., dissection
with planned intervention
Abbreviation: GFR, glomerular filtration rate.

1908 TABLE 272-2 Clinical Factors That Determine the Role of sedimentation rate, and hypocomplementemia (15%). Establishing this
Revascularization in Addition to Medical Therapy for Renal Artery diagnosis can be difficult and is often by exclusion. Definitive diagnosis
Stenosis depends on kidney biopsy demonstrating microvessel occlusion with
Factors Favoring Medical Therapy and Revascularization for Renal cholesterol crystals that leave a “cleft” in the vessel. Biopsies obtained
Artery Stenosis from patients undergoing surgical revascularization of the kidney
• Progressive decline in GFR during treatment of systemic hypertension indicate that silent cholesterol emboli are frequently present before any
PART 6
• Failure to achieve adequate blood pressure control with optimal medical further manipulation is performed.
therapy (medical failure) No effective therapy is available for atheroembolic disease once it
• Rapid or recurrent decline in the GFR in association with a reduction in has developed. Withdrawal of anticoagulation is recommended. Late
systemic pressure recovery of kidney function after supportive measures sometimes
• Decline in the GFR during therapy with ACE inhibitors or ARBs occurs, and statin therapy may improve outcome. The role of embolic
• Recurrent congestive heart failure in a patient in whom the adequacy of left protection devices in the renal circulation is unclear, but a few prospec-
ventricular function does not explain a cause tive trials have failed to demonstrate major benefits. These devices are
Factors Favoring Medical Therapy and Surveillance of Renal Artery limited to distal protection during the endovascular procedure and
Disease offer no protection from embolic debris developing after removal.
• Controlled blood pressure with stable renal function (e.g., stable renal
insufficiency) THROMBOEMBOLIC RENAL DISEASE
• Stable renal artery stenosis without progression on surveillance studies
Thrombotic occlusion of renal vessels or branch arteries can lead to
(e.g., serial duplex ultrasound) declining renal function and hypertension. It is difficult to diagnose
• Very advanced age and/or limited life expectancy and is often overlooked, especially in elderly patients. Thrombosis
• Extensive comorbidity that make revascularization too risky
can develop as a result of local vessel abnormalities, such as local
dissection, trauma, or inflammatory vasculitis. Local microdissections
• High risk for or previous experience with atheroembolic disease
sometimes lead to patchy, transient areas of infarctions labeled “seg-
• Other concomitant renal parenchymal diseases that cause progressive
mental arteriolar mediolysis.” Although hypercoagulability conditions
renal dysfunction (e.g., interstitial nephritis, diabetic nephropathy)
sometimes present as renal artery thrombosis, this is rare. It can also
Abbreviations: ACE, angiotensin-converting enzyme; ARBs, angiotensin receptor derive from distant embolic events, e.g., the left atrium in patients
blockers; GFR, glomerular filtration rate.
with atrial fibrillation or from fat emboli originating from traumatized
tissue, most commonly large bone fractures. Cardiac sources include
is intended to prevent. Although renal blood flow usually can be
vegetations from subacute bacterial endocarditis. Systemic emboli to
restored by endovascular stenting, recovery of renal function is
the kidneys may also arise from the venous circulation if right-to-left
limited to about 25% of cases, with no change in 50% and some
shunting occurs, e.g., through a patent foramen ovale.
deterioration evident in others. Patients with rapid loss of kidney
Clinical manifestations vary depending on the rapidity of onset and
function, sometimes associated with antihypertensive drug therapy,
extent of occlusion. Acute arterial thrombosis may produce flank pain,
or with vascular disease affecting the entire functioning kidney
fever, leukocytosis, nausea, and vomiting. If kidney infarction results,
mass are more likely to recover function after restoring blood flow.
enzymes such as lactate dehydrogenase (LDH) rise to extreme levels. If
When hypertension is refractory to effective therapy, revasculariza-
both kidneys are affected, renal function will decline precipitously with
tion offers real benefits. Table 272-2 summarizes currently accepted
a drop in urine output. If a single kidney is involved, renal functional
guidelines for considering renal revascularization.
changes may be minor. Hypertension related to sudden release of renin
from ischemic tissue can develop rapidly, as long as some viable tissue
ATHEROEMBOLIC RENAL DISEASE in the “peri-infarct” border zone remains. If the infarct zone demarcates
Emboli to the kidneys arise most frequently as a result of cholesterol precisely, the rise in BP and renin activity may resolve. Diagnosis of
crystals breaking free of atherosclerotic vascular plaque and lodg- renal infarction may be established by vascular imaging with MRI, CT
ing in downstream microvessels. Most clinical atheroembolic events angiography, or arteriography (Fig. 272-2).
follow angiographic procedures, often of the coronary vessels. It has
been argued that nearly all vascular interventional procedures lead to ■■MANAGEMENT OF ARTERIAL THROMBOSIS OF THE
plaque fracture and release of microemboli, but clinical manifestations KIDNEY
develop only in a fraction of these. The incidence of clinical atheroem- Options for interventions of newly detected arterial occlusion include
boli has been increasing with more vascular procedures and longer life surgical reconstruction, anticoagulation, thrombolytic therapy,
spans. Atheroembolic renal disease is suspected in >3% of elderly sub- endovascular procedures, and supportive care, particularly antihyper-
jects with end-stage renal disease (ESRD) and is likely underdiagnosed. tensive drug therapy. Application of these methods depends on the
It is more frequent in males with a history of diabetes, hypertension, patient’s overall condition, the precipitating factors (e.g., local trauma
and ischemic cardiac disease. Atheroemboli in the kidney are strongly or systemic illness), the magnitude of renal tissue and function at risk,
associated with aortic aneurysmal disease and renal artery stenosis. and the likelihood of recurrent events in the future. For unilateral dis-
Most clinical cases can be linked to precipitating events, such as angi- ease, for example, arterial dissection with thrombosis, supportive care
ography, vascular surgery, anticoagulation with heparin, thrombolytic with anticoagulation may suffice. Acute, bilateral occlusion is poten-
therapy, or trauma. Clinical manifestations of this syndrome commonly tially catastrophic, producing anuric renal failure. Depending on the
develop between 1 and 14 days after an inciting event and may con- precipitating event, surgical or thrombolytic therapies can sometimes
tinue to develop for weeks thereafter. Systemic embolic disease mani- restore kidney viability.
festations, such as fever, abdominal pain, and weight loss, are present
in less than half of patients, although cutaneous manifestations includ-
MICROVASCULAR INJURY ASSOCIATED WITH
ing livedo reticularis and localized toe gangrene may be more common. HYPERTENSION
Worsening hypertension and deteriorating kidney function are com- ■■ARTERIOLONEPHROSCLEROSIS
mon, sometimes reaching a malignant phase. Progressive renal failure
can occur and require dialytic support. These cases often develop after “Malignant” Hypertension Although BP rises with age, it has
a stuttering onset over many weeks and have an ominous prognosis. long been recognized that some individuals develop rapidly progressive
Mortality rate after 1 year reaches 38%, and although some may even- BP elevations with target organ injury including retinal hemorrhages,
tually recover sufficiently to no longer require dialysis, many do not. encephalopathy, and declining kidney function. Placebo arms during
Beyond the clinical manifestations above, laboratory findings the controlled trials of hypertension therapy identified progression
include rising creatinine, transient eosinophilia (60–80%), elevated to severe levels in 20% of subjects over 5 years. If untreated, patients

1909
CHAPTER 272 Renovascular Disease

A B
FIGURE 272-2 A. CT angiogram illustrating loss of circulation to the upper pole of the right kidney in a patient with fibromuscular disease and a renal artery aneurysm.
Activation of the renin-angiotensin system produced rapidly developing hypertension. B. Angiogram illustrating high-grade renal artery stenosis affecting the left kidney.
This lesion is often part of widespread atherosclerosis and sometimes is an extension of aortic plaque. This lesion develops in older individuals with preexisting
atherosclerotic risk factors.
with target organ injury including papilledema and declining kidney “Hypertensive Nephrosclerosis” Based on experience with
function suffered mortality rates in excess of 50% over 6–12 months, malignant hypertension and epidemiologic evidence linking BP
hence the designation “malignant.” Postmortem studies of such with long-term risks of kidney failure, it has long been assumed
patients identified vascular lesions, designated “fibrinoid necrosis,” that lesser degrees of hypertension induce less severe, but prevalent,
with breakdown of the vessel wall, deposition of eosinophilic material changes in kidney vessels and loss of kidney function. As a result, a
including fibrin, and a perivascular cellular infiltrate. A separate lesion large portion of patients reaching ESRD without a specific etiologic
was identified in the larger interlobular arteries in many patients diagnosis are assigned the designation “hypertensive nephrosclero-
with hyperplastic proliferation of the vascular wall cellular elements, sis.” Pathologic examination commonly identifies afferent arteriolar
deposition of collagen, and separation of layers, designated the thickening with deposition of homogeneous eosinophilic material
“onionskin” lesion. For many of these patients, fibrinoid necrosis led (hyaline arteriolosclerosis) associated with narrowing of vascular
to obliteration of glomeruli and loss of tubular structures. Progressive lumina. Clinical manifestations include retinal vessel changes associ-
kidney failure ensued and, without dialysis support, led to early ated with hypertension (arteriolar narrowing, arteriovenous crossing
mortality in untreated malignant-phase hypertension. These vascular changes), left ventricular hypertrophy, and elevated BP. The role of
changes could develop with pressure-related injury from a variety these vascular changes in kidney function is unclear. Postmortem
of hypertensive pathways, including but not limited to activation of and biopsy samples from normotensive kidney donors demonstrate
the renin-angiotensin system and severe vasospasm associated with similar vessel changes associated with aging, dyslipidemia, and glu-
catecholamine release. Occasionally, endothelial injury is sufficient to cose intolerance. Although BP reduction does slow progression of
induce microangiopathic hemolysis, as discussed below. proteinuric kidney diseases and is warranted to reduce the excessive
Antihypertensive therapy is the mainstay of therapy for malignant cardiovascular risks associated with CKD, antihypertensive therapy
hypertension. With effective BP reduction, manifestations of vascular does not alter the course of kidney dysfunction identified specifically
injury, including microangiopathic hemolysis and renal dysfunction, as hypertensive nephrosclerosis.
can improve over time. Whereas prior reports before the era of drug
therapy suggested that 1-year mortality rates exceeded 90%, current ■■FURTHER READING
survival over 5 years exceeds 50%. de Mast Q, Beutler JJ: The prevalence of atherosclerotic renal artery
Malignant hypertension is less common in Western countries, stenosis in risk groups: A systemic literature review. J Hypertens
although it persists in parts of the world where medical care and 27:1333, 2009.
antihypertensive drug therapy are less available. It most commonly Freedman BI, Cohen AH: Hypertension-attributed nephropathy:
develops in patients with treated hypertension who neglect to take What’s in a name? Nat Rev Nephrol 12:27, 2016.
medications or who may use vasospastic drugs, such as cocaine. Renal Herrmann SM et al: Management of atherosclerotic renovascular dis-
abnormalities typically include rising serum creatinine and occasion- ease after Cardiovascular Outcomes in Renal Atherosclerotic Lesions
ally hematuria and proteinuria. Biochemical findings may include (CORAL). Nephrol Dial Transplant 30:366, 2015.
evidence of hemolysis (anemia, schistocytes, and reticulocytosis) and Modi KS, Rao VK: Atheroembolic renal disease. J Am Soc Nephrol
changes associated with kidney failure. African-American males are 12:1781 2001.
more likely to develop rapidly progressive hypertension and kidney Parikh SA et al: SCAI expert consensus statement for renal artery
failure than are whites in the United States. Genetic polymorphisms stenting appropriate use. Catheter Cardiovasc Interv 84:1163, 2014.
for APOL1 that are common in the African-American population Persu A et al: European consensus on the diagnosis and management
predispose to subtle focal sclerosing glomerular disease, with severe of fibromuscular dysplasia. J Hypertens 32:1367, 2014.
hypertension developing at younger ages secondary to renal disease Textor SC et al: Percutaneous revascularization for ischemic nephrop-
in this instance. athy: The past, present and future. Kidney Int 83:28, 2013.

1910 These prothrombotic networks contain histones that stimulate platelet
273 Deep Venous Thrombosis

and Pulmonary
aggregation and promote platelet-dependent thrombin generation.
Venous thrombi form and flourish in an environment of stasis, low
oxygen tension, and upregulation of proinflammatory genes.
Thromboembolism Prothrombotic States The two most common autosomal domi-
PART 6
nant genetic mutations are factor V Leiden, which causes resistance to

Samuel Z. Goldhaber the endogenous anticoagulant, activated protein C (which inactivates
clotting factors V and VIII), and the prothrombin gene mutation, which
increases the plasma prothrombin concentration (Chaps. 61 and 113).
■■EPIDEMIOLOGY Antithrombin, protein C, and protein S are naturally occurring coagula-
Venous thromboembolism (VTE) encompasses deep venous thrombo- tion inhibitors. Deficiencies of these inhibitors are associated with VTE
sis (DVT) and pulmonary embolism (PE) and causes cardiovascular but are rare. Antiphospholipid antibody syndrome is the most common
death and disability as well as psychological illness and emotional acquired cause of thrombophilia and is associated with venous or
distress. In the United States, the Surgeon General estimates that there arterial thrombosis. Other common predisposing factors include can-
are 100,000 to 180,000 deaths annually from PE and has declared that cer, obesity, cigarette smoking, systemic arterial hypertension, chronic
PE is the most common preventable cause of death among hospitalized obstructive pulmonary disease, chronic kidney disease, blood transfu-
patients. In a Canadian study, almost half of PE patients at 1 year had sion, long-haul air travel, air pollution, estrogen-containing contracep-
exercise limitation, decreased walking distance, or dyspnea, which tives, pregnancy, postmenopausal hormone replacement, surgery, and
lowered their quality of life. Survivors may suffer the complications of trauma. Inflammation predisposes to thrombosis, and conditions such
chronic thromboembolic pulmonary hypertension or postthrombotic as psoriasis and inflammatory bowel disease have become recognized
syndrome. Chronic thromboembolic pulmonary hypertension causes risk factors of VTE. Sedentary lifestyle is an increasingly prevalent
breathlessness, especially with exertion. Postthrombotic syndrome etiology of fatal PE. A Japanese study found that each 2 h per day
(also known as chronic venous insufficiency) damages the venous valves increment of television watching is associated with a 40% increased
of the leg and worsens the quality of life by causing ankle or calf likelihood of fatal PE.
swelling and leg aching, especially after prolonged standing. In its
most severe form, postthrombotic syndrome causes skin ulceration Embolization When deep venous thrombi (Fig. 273-2) detach from
(Fig. 273-1). their site of formation, they embolize to the vena cava, right atrium,
and right ventricle, and lodge in the pulmonary arterial circulation,
■■PATHOPHYSIOLOGY thereby causing acute PE. Paradoxically, these thrombi occasionally
embolize to the arterial circulation through a patent foramen ovale or
Inflammation and Platelet Activation Virchow’s triad of atrial septal defect. Many patients with PE have no evidence of DVT
venous stasis, hypercoagulability, and endothelial injury leads to
because the clot has already embolized to the lungs.
recruitment of activated platelets, which release microparticles. These
microparticles contain proinflammatory mediators that bind neu- Physiology The most common gas exchange abnormalities are
trophils, stimulating them to release their nuclear material and form arterial hypoxemia and an increased alveolar-arterial O2 tension gra-
web-like extracellular networks called neutrophil extracellular traps. dient, which represents the inefficiency of O2 transfer across the lungs.
Anatomic dead space increases because breathed gas does not enter gas
exchange units of the lung. Physiologic dead space increases because
ventilation to gas exchange units exceeds venous blood flow through
the pulmonary capillaries.
Other pathophysiologic abnormalities include:
1. Increased pulmonary vascular resistance due to vascular obstruc-
tion or platelet secretion of vasoconstricting neurohumoral agents
such as serotonin. Release of vasoactive mediators can produce
ventilation-perfusion mismatching at sites remote from the embolus,
thereby accounting for discordance between a small PE and a large
alveolar-arterial O2 gradient.
FIGURE 273-1 Skin ulceration in the lateral malleolus from postthrombotic

syndrome of the leg. FIGURE 273-2 Deep venous thrombosis at autopsy.

2. Impaired gas exchange due to increased alveolar dead space from TABLE 273-1 Clinical Decision Rules 1911
vascular obstruction, hypoxemia from alveolar hypoventilation rel- Low Clinical Likelihood of Deep Venous Thrombosis (DVT) If Point
ative to perfusion in the nonobstructed lung, right-to-left shunting, Score Is Zero or Less; Moderate Likelihood If Score Is 1 to 2; High
or impaired carbon monoxide transfer due to loss of gas exchange Likelihood If Score Is 3 or Greater
surface.
CHAPTER 273 Deep Venous Thrombosis and Pulmonary Thromboembolism

CLINICAL VARIABLE DVT SCORE
3. Alveolar hyperventilation due to reflex stimulation of irritant receptors.
Active cancer 1
4. Increased airway resistance due to constriction of airways distal to the
Paralysis, paresis, or recent cast 1
bronchi.
5. Decreased pulmonary compliance due to lung edema, lung hemor- Bedridden for >3 days; major surgery <12 weeks 1
rhage, or loss of surfactant. Tenderness along distribution of deep veins 1
Entire leg swelling 1
Pulmonary Hypertension, Right Ventricular (RV) Unilateral calf swelling >3 cm 1
Dysfunction, and RV Microinfarction Pulmonary artery Pitting edema 1
obstruction and neurohumoral mediators cause a rise in pulmonary Collateral superficial nonvaricose veins 1
artery pressure and in pulmonary vascular resistance. When RV Alternative diagnosis at least as likely as DVT –2
wall tension rises, RV dilation and dysfunction ensue, with release
High Clinical Likelihood of Pulmonary Embolism (PE) if Point Score
of the cardiac biomarker, brain natriuretic peptide, due to abnormal
Exceeds 4
RV stretch. The interventricular septum bulges into and compresses
an intrinsically normal left ventricle (LV). Diastolic LV dysfunction CLINICAL VARIABLE PE SCORE
reduces LV distensibility and impairs LV filling. Increased RV wall Signs and symptoms of DVT 3.0
tension also compresses the right coronary artery, limits myocardial Alternative diagnosis less likely than PE 3.0
oxygen supply, and precipitates right coronary artery ischemia and RV Heart rate >100/min 1.5
microinfarction, with release of cardiac biomarkers such as troponin. Immobilization >3 days; surgery within 4 weeks 1.5
Underfilling of the LV may lead to a fall in LV cardiac output and sys- Prior PE or DVT 1.5
temic arterial pressure, with consequent circulatory collapse and death. Hemoptysis 1.0
Cancer 1.0
■■CLASSIFICATION OF PULMONARY EMBOLISM AND
DEEP VENOUS THROMBOSIS
Pulmonary Embolism Massive PE accounts for 5–10% of cases, Wells Point Score criteria help estimate the clinical likelihood of DVT
and is characterized by extensive thrombosis affecting at least half and PE (Table 273-1). Patients with a low-to-moderate likelihood of
of the pulmonary vasculature. Dyspnea, syncope, hypotension, and DVT or PE should undergo initial diagnostic evaluation with d-dimer
cyanosis are hallmarks of massive PE. Patients with massive PE may testing alone (see “Blood Tests”) without obligatory imaging tests
present in cardiogenic shock and can die from multisystem organ fail- (Fig. 273-3). However, patients with a high clinical likelihood of VTE
ure. Submassive PE accounts for 20–25% of patients, and is character- should skip d-dimer testing and undergo imaging as the next step in
ized by RV dysfunction despite normal systemic arterial pressure. The the diagnostic algorithm.
combination of right heart failure and release of cardiac biomarkers
indicates a high risk of clinical deterioration. Low-risk PE constitutes Clinical Pearls Not all leg pain is due to DVT, and not all dyspnea
about 65–75% of cases. These patients have an excellent prognosis. is due to PE (Table 273-2). Sudden, severe calf discomfort suggests a
ruptured Baker’s cyst. Fever and chills usually herald cellulitis rather
Deep Venous Thrombosis Lower extremity DVT usually begins than DVT. Physical findings, if present, may consist only of mild palpa-
in the calf and propagates proximally to the popliteal vein, femoral tion discomfort in the lower calf. However, massive DVT often presents
vein, and iliac veins. Leg DVT is about 10 times more common than with marked thigh swelling, tenderness, and erythema. Recurrent
upper extremity DVT, which is often precipitated by placement left thigh edema especially in young women raises the possibility of
of pacemakers, internal cardiac defibrillators, or indwelling central May-Thurner Syndrome, with right proximal iliac artery compression
venous catheters. The likelihood of upper extremity DVT increases
as the catheter diameter and number of lumens increase. Superficial
venous thrombosis usually presents with erythema, tenderness, and a ALGORITHM FOR DIAGNOSTIC IMAGING
“palpable cord.” Patients are at risk for extension of the thrombosis to Suspect DVT or PE
the deep-venous system.
■■DIAGNOSIS Assess clinical likelihood
Clinical Evaluation PE is known as “the Great Masquerader.”

Diagnosis is difficult because symptoms and signs are nonspecific.
DVT PE
The most common symptom is unexplained breathlessness. When
occult PE occurs concomitantly with overt congestive heart failure or
pneumonia, clinical improvement often fails to ensue despite standard
medical treatment of the concomitant illness. This scenario presents a Low Not low Not high High
clinical clue to the possible coexistence of PE.
Hospitalization for syncope was associated with a 17% rate of newly D-dimer D-dimer
diagnosed PE in an Italian multicenter study of 560 patients. Among
those patients who had no alternative explanation for syncope, 25%
had PE. Even when there was an alternative explanation for syncope,
Normal High Normal High
13% had PE. When clinical suspicion was high according to the Wells
Score or when the plasma d-dimer level was elevated, 42% had PE. PE
in these patients was anatomically extensive, and 42% had thrombus in No DVT Imaging test needed No PE Imaging test needed
the main pulmonary artery.
With DVT, the most common symptom is a cramp or “charley FIGURE 273-3 How to decide whether diagnostic imaging is needed. For
horse” in the lower calf that persists and intensifies over several days. assessment of clinical likelihood, see Table 273-1.

1912 TABLE 273-2 Differential Diagnosis secure when thrombus is directly visualized. It appears homogeneous
and has low echogenicity (Fig. 273-4). The vein itself often appears
Deep Venous Thrombosis (DVT)
mildly dilated, and collateral channels may be absent.
Ruptured Baker’s cyst Venous flow dynamics can be examined with Doppler imaging.
Muscle strain/injury Normally, manual calf compression causes augmentation of the Doppler
Cellulitis flow pattern. Loss of normal respiratory variation is caused by an
PART 6
Acute postthrombotic syndrome/venous insufficiency obstructing DVT or by any obstructive process within the pelvis. For
Pulmonary Embolism (PE) patients with a technically poor or nondiagnostic venous ultrasound,
Pneumonia, asthma, chronic obstructive pulmonary disease one should consider alternative imaging modalities for DVT, such as
Congestive heart failure computed tomography (CT) and magnetic resonance imaging.
Pericarditis CHEST ROENTGENOGRAPHY A normal or nearly normal chest x-ray

Pleurisy: “viral syndrome,” costochondritis, musculoskeletal discomfort often occurs in PE. Well-established abnormalities include focal
Rib fracture, pneumothorax oligemia (Westermark’s sign), a peripheral wedged-shaped density
Acute coronary syndrome usually located at the pleural base (Hampton’s hump), and an enlarged
right descending pulmonary artery (Palla’s sign).
Anxiety
CHEST CT CT of the chest with intravenous contrast is the principal
imaging test for the diagnosis of PE (Fig. 273-5). “Thin-cut chest CT
images” can provide exquisite detail, with ≤1 mm of resolution during
of the left proximal iliac vein. However, if a leg is diffusely edema-
a short breath hold. Sixth-order branches can be visualized with res-
tous, DVT is unlikely. More probable is an acute exacerbation of
olution superior to that of conventional invasive contrast pulmonary
venous insufficiency due to postthrombotic syndrome. Upper extrem-
angiography. The CT scan also provides an excellent four-chamber
ity venous thrombosis may present with asymmetry in the supraclavi-
view of the heart. RV enlargement on chest CT indicates an increased
cular fossa or in the circumference of the upper arms.
likelihood of death within the next 30 days compared with PE patients
Pulmonary infarction usually indicates a small PE. This condition is
who have normal RV size. When imaging is extended distally below
exquisitely painful because the thrombus lodges peripherally, near the
the chest to the knee, pelvic and proximal leg DVT also can be diag-
innervation of pleural nerves. Nonthrombotic PE etiologies include fat
nosed by CT scanning. In patients without PE, the lung parenchymal
embolism after pelvic or long bone fracture, tumor embolism, bone
images may establish alternative diagnoses not apparent on chest x-ray
marrow, and air embolism. Cement embolism and bony fragment
that explain the presenting symptoms and signs, such as pneumonia,
embolism can occur after total hip or knee replacement. Intravenous
emphysema, pulmonary fibrosis, pulmonary mass, and aortic pathol-
drug users may inject themselves with a wide array of substances that
ogy. Sometimes, asymptomatic early-stage lung cancer is diagnosed
can embolize, such as hair, talc, and cotton. Amniotic fluid embolism
incidentally. Major efforts are underway to reduce radiation and con-
occurs when fetal membranes leak or tear at the placental margin.
trast material requirements for chest CT. “Triple rule-out CT” utilizes
Nonimaging Diagnostic Modalities • BLOOD TESTS The ECG-synchronized acquisition, adjusts contrast material timing, and
quantitative plasma d-dimer enzyme-linked immunosorbent assay (ELISA) opacifies both the thoracic aorta and pulmonary artery circulation to
rises in the presence of DVT or PE because of the breakdown of fibrin exclude the three major causes of acute chest pain: PE, acute aortic
by plasmin. Elevation of d-dimer indicates endogenous although often syndrome, and acute coronary syndrome.
clinically ineffective thrombolysis. The sensitivity of the d-dimer is LUNG SCANNING Lung scanning has become a second-line diagnostic
>80% for DVT (including isolated calf DVT) and >95% for PE. The test for PE, used mostly for patients who cannot tolerate intravenous
d-dimer is less sensitive for DVT than for PE because the DVT thrombus contrast. Small particulate aggregates of albumin labeled with a
size is smaller. A normal d-dimer is a useful “rule out” test. However, gamma-emitting radionuclide are injected intravenously and are
the d-dimer assay is not specific. Levels increase in patients with myo- trapped in the pulmonary capillary bed. The perfusion scan defect
cardial infarction, pneumonia, sepsis, cancer, and the postoperative indicates absent or decreased blood flow, possibly due to PE. Ventila-
state and those in the second or third trimester of pregnancy. Therefore, tion scans, obtained with a radiolabeled inhaled gas such as xenon or
d-dimer rarely has a useful role among hospitalized patients, because krypton, improve the specificity of the perfusion scan. Abnormal ven-
levels are frequently elevated due to systemic illness. tilation scans indicate abnormal nonventilated lung, thereby providing
ELEVATED CARDIAC BIOMARKERS Serum troponin and possible explanations for perfusion defects other than acute PE, such as
plasma heart-type fatty acid–binding protein levels
increase because of RV microinfarction. Myocardial stretch
causes release of brain natriuretic peptide or NT-pro-brain No Compression Compression
natriuretic peptide.
ELECTROCARDIOGRAM The most frequently cited abnor-
mality, in addition to sinus tachycardia, is the S1Q3T3 sign:
an S wave in lead I, a Q wave in lead III, and an inverted
CFA CFA
T wave in lead III (Chap. 235). This finding is relatively
specific but insensitive. RV strain and ischemia cause the
most common abnormality, T-wave inversion in leads V1
to V4.
Noninvasive Imaging Modalities • VENOUS CFV CFV
ULTRASONOGRAPHY Ultrasonography of the deep-venous
system relies on loss of vein compressibility as the pri-
mary diagnostic criterion for DVT. When a normal vein
is imaged in cross-section, it readily collapses with gentle
manual pressure on the ultrasound transducer. This cre-
ates the illusion of a “wink.” With acute DVT, the vein
loses its compressibility because of passive distention by FIGURE 273-4 Venous ultrasound, with and without compression of the leg veins. CFA, common
acute thrombus. The diagnosis of acute DVT is even more femoral artery; CFV, common femoral vein; GSV, great saphenous vein; LT, left.

1913
ALGORITHM FOR DVT AND PE DIAGNOSIS
DVT imaging test

Venous ultrasound
Diagnostic Nondiagnostic
Stop MR CT Phlebography
PE Imaging Test
Chest CT
FIGURE 273-5 Large bilateral proximal PE on a coronal chest CT image in

a 54-year-old man with lung cancer and brain metastases. He had developed Diagnostic Nondiagnostic, unavailable, or unsafe
sudden onset of chest heaviness and shortness of breath while at home. There
are filling defects in the main and segmental pulmonary arteries bilaterally (white
arrows). Only the left upper lobe segmental artery is free of thrombus. Stop Lung scan
asthma and chronic obstructive pulmonary disease. A high-probability

scan for PE is defined as two or more segmental perfusion defects in Diagnostic Nondiagnostic
the presence of normal ventilation.
The diagnosis of PE is very unlikely in patients with normal and
Stop Venous ultrasound
nearly normal scans and, in contrast, is about 90% certain in patients
with high-probability scans. Unfortunately, most patients have nondi-
agnostic scans, and fewer than one-half of patients with angiographi-
cally confirmed PE have a high probability scan. As many as 40% of Positive Negative
patients with high clinical suspicion for PE but “low-probability” scans
do, in fact, have PE at angiography.
Treat for PE Transesophageal ECHO or MR or
MAGNETIC RESONANCE (MR) (CONTRAST-ENHANCED) IMAGING When invasive pulmonary angiography
ultrasound is equivocal, MR venography with gadolinium contrast is
an excellent imaging modality to diagnose DVT. MR pulmonary angi- FIGURE 273-6 Imaging tests to diagnose DVT and PE. ECHO, echocardiography.
ography may detect large proximal PE, but is not reliable for smaller
segmental and subsegmental PE.
ECHOCARDIOGRAPHY Echocardiography is not a reliable diagnostic Integrated Diagnostic Approach An integrated diagnostic
imaging tool for acute PE because most patients with PE have normal approach (Fig. 273-3) streamlines the workup of suspected DVT and
echocardiograms. However, echocardiography is a very useful diagnostic PE (Fig. 273-6).
tool for detecting conditions that may mimic PE, such as acute myocardial
infarction, pericardial tamponade, and aortic dissection. Transthoracic
echocardiography rarely images thrombus directly. The best-known TREATMENT
indirect sign of PE on transthoracic echocardiography is McConnell’s Deep Venous Thrombosis
sign: hypokinesis of the RV free wall with normal or hyperkinetic motion
of the RV apex. One should consider transesophageal echocardiography PRIMARY THERAPY
when CT scanning facilities are not available or when a patient has renal Primary therapy consists of clot dissolution with pharmacomechanical
failure or severe contrast allergy that precludes administration of contrast therapy that usually includes low-dose catheter-directed thromboly-
despite premedication with high-dose steroids. This imaging modality sis. This approach is reserved for patients with extensive femoral,
can identify saddle, right main, or left main PE. iliofemoral, or upper extremity DVT. The open vein hypothesis pos-
Invasive Diagnostic Modalities • PULMONARY ANGIOGRAPHY tulates that patients who receive primary therapy will sustain less
Chest CT with contrast (see above) has virtually replaced invasive pul- long-term damage to venous valves, with consequent lower rates
monary angiography as a diagnostic test. Invasive catheter-based diag- of postthrombotic syndrome. A National Heart, Lung, and Blood
nostic testing is reserved for patients with technically unsatisfactory Institute–sponsored randomized controlled trial called ATTRACT
chest CTs and for those in whom an interventional procedure such as (NCT00790335) is testing this hypothesis by randomizing femo-
catheter-directed thrombolysis is planned. A definitive diagnosis of PE ral and iliofemoral DVT patients to conventional anticoagulation
requires visualization of an intraluminal filling defect in more than one versus pharmacomechanical catheter-directed thrombolysis, and
projection. Secondary signs of PE include abrupt occlusion (“cut-off”) assessing the frequency of postthrombotic syndrome 2 years after
of vessels, segmental oligemia or avascularity, and a prolonged arterial randomization.
phase with slow filling, and tortuous, tapering peripheral vessels. SECONDARY PREVENTION
CONTRAST PHLEBOGRAPHY Venous ultrasonography has virtually Anticoagulation or placement of an inferior vena caval (IVC) filter
replaced contrast phlebography as the principal diagnostic test for constitutes secondary prevention of VTE. In 2016, the FDA approved
suspected DVT. a new retrievable IVC filter that is inserted at the bedside with

1914 ultrasound visualization of the femoral or internal jugular vein TABLE 273-3 Anticoagulation of Venous Thromboembolism (VTE)
(Angel® Filter) but without the need for any fluoroscopic or other
Non-Warfarin Anticoagulation
radiological imaging.
For patients with swelling of the legs when acute DVT is diag- Unfractionated heparin, bolus and continuous infusion, to achieve activated
partial thromboplastin time (aPTT) 2–3 times the upper limit of the laboratory
nosed, below-knee graduated compression stockings may be pre- normal, or
scribed, usually 30–40 mmHg, to lessen patient discomfort. They
PART 6
Enoxaparin 1 mg/kg twice daily with normal renal function, or

should be replaced every 3 months because they lose their elasticity.
Dalteparin 200 U/kg once daily or 100 U/kg twice daily, with normal renal
However, prescription of vascular compression stockings in asymp- function, or
tomatic newly diagnosed acute DVT patients does not prevent the
Tinzaparin 175 U/kg once daily with normal renal function, or
development of postthrombotic syndrome.
Fondaparinux weight-based once daily; adjust for impaired renal function
Direct thrombin inhibitors: argatroban or bivalirudin (with suspected or proven

heparin-induced thrombocytopenia)
TREATMENT
Rivaroxaban 15 mg twice daily for 3 weeks, followed by 20 mg once daily with
Pulmonary Embolism the dinner meal thereafter
Apixaban 10 mg twice daily for 1 week, followed by 5 mg twice daily thereafter
RISK STRATIFICATION Dabigatran 5 days of unfractionated heparin, low-molecular-weight heparin
Hemodynamic instability, RV dysfunction on echocardiography, RV (LMWH), or fondaparinux followed by dabigatran 150 mg twice daily
enlargement on chest CT, or elevation of the troponin level due to Edoxaban 5 days of unfractionated heparin, LMWH, or fondaparinux followed
RV microinfarction portend a high risk of an adverse clinical out- by edoxaban 60 mg once daily with normal renal function, weight >60 kg, in
come despite anticoagulation. When RV function remains normal in the absence of potent P-glycoprotein inhibitors
a hemodynamically stable patient, a good clinical outcome is highly Warfarin Anticoagulation
likely with anticoagulation alone (Fig. 273-7). Requires 5–10 days of administration to achieve effectiveness as
monotherapy
ANTICOAGULATION
(Unfractionated heparin, LMWH, and fondaparinux are the usual immediately
Effective anticoagulation is the foundation for successful treatment of effective “bridging agents” used when initiating warfarin)
DVT and PE. There are three major strategies: (1) the classical but wan- Usual start dose is 5 mg
ing strategy of parenteral anticoagulation with unfractionated heparin Titrate to international normalized ratio (INR), target 2.0–3.0
(UFH), low-molecular-weight heparin (LMWH), or fondaparinux
Continue parenteral anticoagulation for a minimum of 5 days and until two
“bridged” to warfarin, (2) parenteral therapy switched after 5 days sequential INR values, at least 1 day apart, achieve the target INR range
to a novel oral anticoagulant such as dabigatran (a direct thrombin
inhibitor) or edoxaban (an anti-Xa agent), or (3) oral anticoagulation
monotherapy with rivaroxaban or apixaban (both are anti-Xa agents) Low-Molecular-Weight Heparins These fragments of UFH exhibit
with a 3-week or 1-week loading dose, respectively, followed by a less binding to plasma proteins and endothelial cells and con-
maintenance dose without parenteral anticoagulation. For patients sequently have greater bioavailability, a more predictable dose
with VTE in the setting of suspected or proven heparin-induced response, and a longer half-life than does UFH. No monitoring or
thrombocytopenia, one can choose between two parenteral direct dose adjustment is needed unless the patient is markedly obese or
thrombin inhibitors: argatroban and bivalirudin (Table 273-3). has chronic kidney disease.
Unfractionated Heparin UFH anticoagulates by binding to and
accelerating the activity of antithrombin, thus preventing additional Fondaparinux Fondaparinux, an anti-Xa pentasaccharide, is
thrombus formation. UFH is dosed to achieve a target activated administered as a weight-based once-daily subcutaneous injec-
partial thromboplastin time (aPTT) of 60–80 s. The most popular tion in a prefilled syringe. No laboratory monitoring is required.
nomogram uses an initial bolus of 80 U/kg, followed by an initial Fondaparinux is synthesized in a laboratory and, unlike LMWH
infusion rate of 18 U/kg per h in patients with normal liver func- or UFH, is not derived from animal products. It does not cause
tion. The major advantage of UFH is its short half-life, which is heparin-induced thrombocytopenia. The dose must be adjusted
especially useful in patients in whom hour-to-hour control of the downward for patients with renal dysfunction.
intensity of anticoagulation is desired. Heparin also has pleiotropic
effects that may decrease systemic and local inflammation. Warfarin This vitamin K antagonist prevents carboxylation acti-
vation of coagulation factors II, VII, IX, and X. The full effect of
warfarin requires at least 5 days, even if the prothrombin time,
used for monitoring, becomes elevated more rapidly. If warfarin is
ALGORITHM FOR PE MANAGEMENT initiated as monotherapy during an acute thrombotic illness, a par-
Risk stratify
adoxical exacerbation of hypercoagulability increases the likelihood
of thrombosis. Overlapping UFH, LMWH, fondaparinux, or parent-
eral direct thrombin inhibitors with warfarin for at least 5 days will
Normotension Normotension nullify the early procoagulant effect of warfarin.
Hypotension
plus normal RV plus RV hypokinesis
Warfarin dosing In an average-size adult, warfarin is often initiated
in a dose of 5 mg. The prothrombin time is standardized by calcu-
Secondary Individualize Primary lating the international normalized ratio (INR), which assesses the
prevention therapy therapy anticoagulant effect of warfarin (Chap. 61). The target INR is usually
2.5, with a range of 2.0–3.0.
The warfarin dose is usually titrated empirically to achieve the
Anticoagulation
Anticoagulation
Embolectomy:
target INR. Proper dosing is difficult because hundreds of drug-drug
IVC filter plus and drug-food interactions affect warfarin metabolism. Increasing age
alone catheter/surgical
thrombolysis and systemic illness reduce the required warfarin dose. Pharmacoge-
nomics may provide more precise initial dosing of warfarin. CYP2C9
FIGURE 273-7 Acute management of pulmonary thromboembolism. RV, right variant alleles impair the hydroxylation of S-warfarin, thereby lower-
ventricular; IVC, inferior vena cava. ing the dose requirement. Variants in the gene encoding the vitamin K

epoxide reductase complex 1 (VKORC1) can predict whether patients not appear to increase the risk of recurrent VTE. However, patients 1915
require low, moderate, or high warfarin doses. However, genetic test- with antiphospholipid antibody syndrome may warrant indefinite-
ing is not used clinically to dose patients with warfarin. duration anticoagulation, even if the initial VTE was provoked by
Centralized anticoagulation clinics have improved the efficacy trauma or surgery.
and safety of warfarin dosing. Patients can self-monitor their INR

with a home point-of-care fingerstick machine and can occasionally INFERIOR VENA CAVA FILTERS
be taught to self-dose their warfarin. The two principal indications for insertion of an IVC filter are
Warfarin can cause major hemorrhage, including intracranial (1) active bleeding that precludes anticoagulation and (2) recurrent
hemorrhage, even when the INR remains within the desired ther- venous thrombosis despite intensive anticoagulation. Prevention of
apeutic range. Warfarin can cause “off target” side effects such as recurrent PE in patients with right heart failure who are not candidates
alopecia or arterial vascular calcification. Some patients complain for fibrinolysis and prophylaxis of extremely high-risk patients are
that warfarin makes them feel cold or fatigued. “softer” indications for filter placement. The filter itself may fail by per-
mitting the passage of small- to medium-size clots. Large thrombi may
Novel Oral Anticoagulants Novel oral anticoagulants (NOACs) embolize to the pulmonary arteries via collateral veins that develop.
are administered in a fixed dose, establish effective anticoagulation Paradoxically, by providing a nidus for clot formation, filters
within hours of ingestion, require no laboratory coagulation mon- increase the DVT rate, even though they usually prevent PE. There-
itoring, and have few of the drug-drug or drug-food interactions. fore, a common complication is recurrent DVT or caval thrombosis
Betrixaban, a direct factor Xa inhibitor, was approved by the FDA with marked leg swelling. Retrievable filters can now be placed for
in 2017 for VTE prophylaxis in acutely ill medical patients during patients with an anticipated temporary bleeding disorder or for
hospitalization and continuing for a total duration of 5 to 6 weeks. patients at temporary high risk of PE, such as individuals under-
Rivaroxaban and apixaban, direct factor Xa inhibitors, are approved going bariatric surgery who have a prior history of perioperative
as monotherapy for acute and extended treatment of DVT and PE. The filters can be retrieved for months after insertion, unless
PE, without a parenteral “bridging” anticoagulant. Dabigatran, a thrombus forms and is trapped within the filter. The retrievable filter
direct thrombin inhibitor, and edoxaban, a factor Xa inhibitor, are becomes permanent if it remains in place or if, for technical reasons
approved for treatment of VTE after an initial 5-day course of par- such as rapid endothelialization, it cannot be removed.
enteral anticoagulation.
Complications of Anticoagulants The most serious adverse effect MANAGEMENT OF MASSIVE PE
of anticoagulation is hemorrhage. For life-threatening or intracra- For patients with massive PE and hypotension, replete volume with
nial hemorrhage due to heparin or LMWH, protamine sulfate can 500 mL of normal saline. Additional fluid should be infused with
be administered. There is no specific reversal agent for bleeding extreme caution because excessive fluid administration exacerbates
caused by fondaparinux or factor Xa inhibitors. However, the RV wall stress, causes more profound RV ischemia, and worsens
dabigatran antibody, idarucizumab, is an effective and rapidly act- LV compliance and filling by causing further interventricular sep-
ing antidote for dabigatran that is now licensed for use. Andexanet tal shift toward the LV. Dopamine and dobutamine are first-line
is a universal anti-Xa antidote for betrixaban, rivaroxaban, apix- inotropic agents for treatment of PE-related shock. Maintain a low
aban, and edoxaban that is undergoing review by the FDA. threshold for initiating these pressors. Often, a “trial-and-error”
Major bleeding from warfarin is best managed with prothrombin approach works best; other agents that may be effective include
complex concentrate. With less serious bleeding, fresh-frozen plasma norepinephrine, vasopressin, or phenylephrine.
or intravenous vitamin K can be used. Oral vitamin K is effective for FIBRINOLYSIS
managing minor bleeding or an excessively high INR in the absence Successful fibrinolytic therapy rapidly reverses right heart fail-
of bleeding. ure and may result in a lower rate of death and recurrent PE by
Duration of Anticoagulation For DVT isolated to an upper extrem- (1) dissolving much of the anatomically obstructing pulmonary arte-
ity or calf that has been provoked by surgery, trauma, estrogen, or rial thrombus, (2) preventing the continued release of serotonin and
an indwelling central venous catheter or pacemaker, 3 months of other neurohumoral factors that exacerbate pulmonary hyperten-
anticoagulation usually suffice. For an initial episode of provoked sion, and (3) lysing much of the source of the thrombus in the pelvic
proximal leg DVT or PE, 3–6 months of anticoagulation used to be or deep leg veins, thereby decreasing the likelihood of recurrent PE.
the classic teaching. However, the EINSTEIN CHOICE study found The preferred systemically administered fibrinolytic regimen is
that patients with provoked VTE derived as great a risk reduction in 100 mg of recombinant tissue plasminogen activator (tPA) pre-
recurrent VTE with extended duration anticoagulation as patients scribed as a continuous peripheral intravenous infusion over 2 h.
with unprovoked VTE. For patients with cancer and VTE, prescribe The sooner thrombolysis is administered, the more effective it is.
LMWH as monotherapy without warfarin and continue anticoagu- However, this approach can be used for at least 14 days after the PE
lation indefinitely unless the patient is rendered cancer-free. has occurred. A popular off-label dosing regimen is 50 mg of TPA
Among patients with idiopathic, unprovoked VTE, the recur- administered over 2 h. This lower dose is widely perceived to be
rence rate is high after cessation of anticoagulation. VTE that occurs associated with fewer bleeding complications.
during long-haul air travel is considered unprovoked. Unprovoked Contraindications to fibrinolysis include intracranial disease,
VTE may be caused by an exacerbation of an underlying inflamma- recent surgery, and trauma. The overall major bleeding rate is about
tory state and can be conceptualized as a chronic illness, with latent 10%, including a 2–3% risk of intracranial hemorrhage. Careful
periods between flares of recurrent episodes. American College of screening of patients for contraindications to fibrinolytic therapy
Chest Physicians (ACCP) guidelines recommend considering anti- (Chap. 269) is the best way to minimize bleeding risk.
coagulation for an indefinite duration with a target INR between 2 The only Food and Drug Administration–approved indication
and 3 for patients with idiopathic VTE and a low bleeding risk. An for PE fibrinolysis is massive PE. For patients with submassive PE,
alternative approach after the first 6 months of anticoagulation is to who have preserved systolic blood pressure but moderate or severe
reduce the intensity of anticoagulation and to lower the target INR RV dysfunction, use of fibrinolysis remains controversial. Results of
range to between 1.5 and 2. Another approach for patients at lower a 1006-patient European multicentered randomized trial of submas-
risk of recurrence, especially if there is an important reason to avoid sive PE, using the thrombolytic agent tenecteplase versus heparin
long-term anticoagulation, is to consider low-dose aspirin after com- alone, showed that death or hemodynamic collapse within 7 days of
pleting the initial period of standard anticoagulation. randomization was reduced by 56% in the tenecteplase group. How-
Counterintuitively, the presence of genetic mutations such as ever, hemorrhagic stroke occurred in 2% of tenecteplase patients
heterozygous factor V Leiden and prothrombin gene mutation does versus 0.2% in patients who only received heparin.

1916 PHARMACOMECHANICAL CATHETER-DIRECTED THERAPY TABLE 273-4 Prevention of Venous Thromboembolism Among
Many patients have relative contraindications to full-dose throm- Hospitalized Patients
bolysis. Pharmacomechanical catheter-directed therapy usually CONDITION PROPHYLAXIS STRATEGY
combines physical fragmentation or pulverization of thrombus High-risk Unfractionated heparin 5000 units SC bid or tid
with catheter-directed low-dose thrombolysis. Mechanical tech- nonorthopedic Enoxaparin 40 mg daily
niques include catheter maceration and intentional embolization surgery
PART 6
Dalteparin 2500 or 5000 units daily

of clot more distally, suction thrombectomy, rheolytic hydrolysis, Cancer surgery, Enoxaparin 40 mg daily, consider 1 month of
and low-energy ultrasound-facilitated thrombolysis. The dose of including gynecologic prophylaxis
alteplase can be markedly reduced, usually to a range of 20–25 mg, cancer surgery
instead of the peripheral intravenous systemic dose of 100 mg. In Major orthopedic Warfarin (target INR 2.0–3.0)
2014, the FDA approved ultrasound-facilitated catheter-directed surgery Enoxaparin 40 mg daily

thrombolysis for acute massive and submassive PE. Using a total Enoxaparin 30 mg bid
tPA dose of 24 mg, this approach decreased RV dilation, reduced Dalteparin 2500 or 5000 units daily
pulmonary hypertension, decreased anatomic thrombus burden, Fondaparinux 2.5 mg daily
and minimized intracranial hemorrhage. Lower doses and durations Rivaroxaban 10 mg daily, beginning 6-10 hours
of TPA are currently being studied. postoperatively
Aspirin 81–325 mg daily
PULMONARY EMBOLECTOMY
Dabigatran 110 mg first day, then 220 mg daily
The risk of major hemorrhage with systemically administered
Apixaban 2.5 mg bid, beginning 12–24 h
fibrinolysis has prompted a renaissance of interest in surgical embolec- postoperatively
tomy, an operation that had almost become extinct. More rapid refer- Intermittent pneumatic compression (with or without
ral before the onset of irreversible multisystem organ failure and pharmacologic prophylaxis)
improved surgical technique have resulted in a high survival rate. Medically ill Unfractionated heparin 5000 units bid or tid
PULMONARY THROMBOENDARTERECTOMY patients, during Enoxaparin 40 mg daily
hospitalization
Chronic thromboembolic pulmonary hypertension develops in Dalteparin 2500 or 5000 units daily
2–4% of acute PE patients. Therefore, PE patients who have initial Fondaparinux 2.5 mg daily
pulmonary hypertension (usually diagnosed with Doppler echoc- Medically ill patients, Betrixaban 80 mg daily for 35–42 days
ardiography) should be followed up at about 6 weeks with a repeat during and after
hospitalization
echocardiogram to determine whether pulmonary arterial pressure
has normalized. Patients impaired by dyspnea due to chronic Anticoagulation Intermittent pneumatic compression devices (but
contraindicated whether graduated compression stockings are effective
thromboembolic pulmonary hypertension should be considered in medical patients remains uncertain)
for pulmonary thromboendarterectomy, which, when successful,
can markedly reduce, and sometimes even cure, pulmonary hyper-
tension (Chap. 277). The operation requires median sternotomy,
■■FURTHER READING
cardiopulmonary bypass, deep hypothermia, and periods of hypo-
Becattini C, Giancarlo A: Treatment of venous thromboembolism
thermic circulatory arrest. The mortality rate at experienced centers
with new anticoagulant agents. J Am Coll Cardiol 67:1941, 2016.
is ~5%. Inoperable patients should be managed with pulmonary
Braekkan SK et al: Venous thromboembolism and subsequent work-
vasodilator therapy and balloon angioplasty of pulmonary arterial
related disability. J Thromb Haemost 14:1977, 2016.
webs.
Cohen AT et al: Extended thromboprophylaxis with betrixaban in
EMOTIONAL SUPPORT acutely ill medical patients. N Engl J Med 375:534, 2016.
Patients with VTE may feel overwhelmed when they learn that Gibson CM et al: Extended-duration betrixaban reduces the risk of
they are suffering from PE or DVT. Some have never previously stroke versus standard-dose enoxaparin among hospitalized medi-
encountered serious cardiovascular illness. They fear they will not cally ill patients: An APEX trial substudy (acute medically ill venous
be able to adapt to the new limitations imposed by anticoagula- thromboembolism prevention with extended duration betrixaban).
tion. They worry about the health of their families and the genetic Circulation 135:648, 2017.
implications of their illness. Those who are advised to discontinue Kahn SR et al: Functional and exercise limitations after a first episode
anticoagulation may feel especially vulnerable about the potential of pulmonary embolism: Results of the ELOPE prospective cohort
for suffering recurrent VTE. At Brigham and Women’s Hospi- study. Chest 151:1058, 2017.
tal, a physician-nurse–facilitated PE support group was initiated Kearon C et al: Antithrombotic therapy for VTE disease: CHEST
to address these concerns and has met monthly for >25 years. guideline and expert panel report. CHEST 149:315, 2016.
The nonprofit organization, North American Thrombosis Forum Konstantinides SV et al: Management of pulmonary embolism. J Am
(www.NATFonline.org), has initiated other online support groups Coll Cardiol 67:975, 2015.
which garner worldwide participation. Piazza G et al: A prospective, single-arm, multicenter trial of
ultrasound-facilitated, catheter-directed, low-dose fibrinolysis for
acute massive and submassive pulmonary embolism. The SEATTLE
■■PREVENTION OF VTE II study. J Am Coll Cardiol Cardiovasc Interv 8:1382, 2015.
Prevention of DVT and PE (Table 273-4) is of paramount importance Poterucha TJ et al: More than an anticoagulant: Do heparins have
because VTE is difficult to detect and poses a profound medical and direct anti-inflammatory effects? Thromb Haemost 117:437, 2017.
economic burden. Low-dose UFH or LMWH is the most common Prandoni P et al: Prevalence of pulmonary embolism among patients
form of in-hospital prophylaxis. Computerized reminder systems can hospitalized for syncope. N Engl J Med 375:1524, 2016.
increase the use of preventive measures and, at Brigham and Women’s Raskob GE et al: The MARINER trial of rivaroxaban after hospital
Hospital, have reduced the symptomatic VTE rate by >40%. Audits of discharge for medical patients at high risk of VTE. Thromb Haemost
hospitals to ensure that prophylaxis protocols are being used will also 115:1240, 2016.
increase utilization of preventive measures. Duration of prophylaxis is Shirakawa T et al: Watching television and risk of mortality from
an important consideration. Extended-duration prophylaxis with the pulmonary embolism among Japanese men and women. Circulation
novel anti-Xa agent, betrixaban, appears to be both effective and safe in 134:355, 2016.
medically ill patients during hospitalization, after hospital discharge, Weitz JI et al: Rivaroxaban or aspirin for extended treatment of venous
and is undergoing FDA review. thromboembolism. N Engl J Med 376:1211, 2017.

elastin and collagen. The causes of aortic aneurysms may be broadly 1917
274 Diseases of the Aorta

Mark A. Creager, Joseph Loscalzo
categorized as degenerative disorders, genetic or developmental dis-
eases, vasculitis, infections, and trauma (Table 274-1). Inflammation,
oxidative stress, proteolysis, and biomechanical wall stress contribute
to the degenerative processes that characterize most aneurysms of the
CHAPTER 274 Diseases of the Aorta

abdominal and descending thoracic aorta. These are mediated by B cell
and T cell lymphocytes, macrophages, inflammatory cytokines, and
The aorta is the conduit through which blood ejected from the left
matrix metalloproteinases that degrade elastin and collagen and alter
ventricle is delivered to the systemic arterial bed. In adults, its diam-
the tensile strength and ability of the aorta to accommodate pulsatile
eter is ~3 cm at the origin and in the ascending portion, 2.5 cm in the
stretch. The associated histopathology demonstrates destruction of
descending portion in the thorax, and 1.8–2 cm in the abdomen. The
elastin and collagen, decreased vascular smooth muscle, in-growth of
aortic wall consists of a thin intima composed of endothelium, suben-
new blood vessels, and inflammation. Factors associated with degener-
dothelial connective tissue, and an internal elastic lamina; a thick tunica
ative aortic aneurysms include aging, cigarette smoking, hypercholes-
media composed of smooth muscle cells and extracellular matrix; and
terolemia, hypertension, and male sex.
an adventitia composed primarily of connective tissue enclosing the
The most common pathologic condition associated with degen-
vasa vasorum and nervi vascularis. In addition to the conduit function
erative aortic aneurysms is atherosclerosis. Many patients with aortic
of the aorta, its viscoelastic and compliant properties serve a buffering
aneurysms have coexisting risk factors for atherosclerosis, as well as
function. The aorta is distended during systole to allow a portion of
atherosclerosis in other blood vessels.
the stroke volume and elastic energy to be stored, and it recoils during
diastole so that blood continues to flow to the periphery. Owing to its
continuous exposure to high pulsatile pressure and shear stress, the TABLE 274-1 Diseases of the Aorta: Etiology and Associated Factors
aorta is particularly prone to injury and disease resulting from mechan- Aortic aneurysm
ical trauma. The aorta is also more prone to rupture than is any other Degenerative
vessel, especially with the development of aneurysmal dilation, since Aging
its wall tension, as governed by Laplace’s law (i.e., proportional to the Cigarette smoking
product of pressure and radius), will be increased.
Hypercholesterolemia
CONGENITAL ANOMALIES OF THE AORTA Hypertension
Congenital anomalies of the aorta usually involve the aortic arch and Atherosclerosis
its branches. Symptoms such as dysphagia, stridor, and cough may Genetic or developmental
occur if an anomaly causes a ring around or otherwise compresses the Marfan’s syndrome
esophagus or trachea. Anomalies associated with symptoms include Loeys-Dietz syndrome
double aortic arch, origin of the right subclavian artery distal to the Ehlers-Danlos syndrome type IV
left subclavian artery, and right-sided aortic arch with an aberrant left Turner’s syndrome
subclavian artery. A Kommerell’s diverticulum is an anatomic remnant Familial
of a right aortic arch. Most congenital anomalies of the aorta do not Bicuspid aortic valve
cause symptoms and are detected during catheter-based procedures.
Chronic aortic dissection
The diagnosis of suspected congenital anomalies of the aorta typically
Aortitis (see below)
is confirmed by computed tomographic (CT) or magnetic resonance
(MR) angiography. Surgery is used to treat symptomatic anomalies. Infective (see below)
Coarctation of the aorta (Chap. 264) typically occurs near the inser- Trauma
tion of the ligamentum arteriosum, adjacent to the left subclavian Acute aortic syndromes (aortic dissection, acute intramural hematoma,
artery. It may be associated with a bicuspid aortic valve, aortic arch penetrating atherosclerotic ulcer)
hypoplasia, other congenital heart defects, and intracranial aneu- Degenerative disorders (see above)
rysms. A pulse delay or pressure differential between the upper and Genetic/developmental disorders (see above)
lower extremities should raise suspicion of aortic coarctation. Imaging Hypertension
modalities, including echocardiography, CT and MR angiography are Aortitis (see below)
used to confirm the diagnosis. If untreated, hypertension develops in Pregnancy
the arteries proximal to the coarctation. Treatment of hemodynamically Trauma
significant aortic coarctation includes endovascular stent implantation Aortic occlusion
if feasible or surgical repair.
Atherosclerosis
AORTIC ANEURYSM Thromboembolism
An aneurysm is defined as a pathologic dilation of a segment of a blood Aortitis
vessel. A true aneurysm involves all three layers of the vessel wall and is Vasculitis
distinguished from a pseudoaneurysm, in which the intimal and medial Takayasu’s arteritis
layers are disrupted and the dilated segment of the aorta is lined by Giant cell arteritis
adventitia only and, at times, by perivascular clot. Aneurysms also may Rheumatic
be classified according to their gross appearance. A fusiform aneurysm Rheumatoid aortitis
affects the entire circumference of a segment of the vessel, resulting HLA-B27–associated spondyloarthropathies
in a diffusely dilated artery. In contrast, a saccular aneurysm involves Behçet’s syndrome
only a portion of the circumference, resulting in an outpouching of the
Cogan’s syndrome
vessel wall. Aortic aneurysms also are classified according to location,
IgG4-related systemic disease
i.e., abdominal versus thoracic. Aneurysms of the descending thoracic
aorta are usually contiguous with infradiaphragmatic aneurysms and Idiopathic aortitis
are referred to as thoracoabdominal aortic aneurysms. Infective
Syphilis
■■ETIOLOGY Tuberculosis
Aortic aneurysms result from conditions that cause degradation or Mycotic (Salmonella, staphylococcal, streptococcal, fungal)
abnormal production of the structural components of the aortic wall:

1918 Medial degeneration, previously designated cystic medial necrosis, is
the histopathologic term used to describe the degeneration of collagen
and elastic fibers in the tunica media of the aorta as well as the loss of
medial cells that are replaced by multiple clefts of mucoid material,
such as proteoglycans. Medial degeneration characteristically affects
the proximal aorta, results in circumferential weakness and dilation,
PART 6
and leads to the development of fusiform aneurysms involving the

ascending aorta and the sinuses of Valsalva. This pathologic condition
occurs in patients with Marfan’s syndrome, Loeys-Dietz syndrome,
Ehlers-Danlos syndrome type IV (Chap. 406), hypertension, congenital
bicuspid aortic valves, Turner’s syndrome, and familial thoracic aortic

aneurysm syndromes; sometimes it appears as an isolated condition in
patients without any other apparent disease.
Familial clusterings of aortic aneurysms occur in 20% of patients,
suggesting a hereditary basis for the disease. Mutations of the gene
that encodes fibrillin-1 are present in patients with Marfan’s syndrome.
Fibrillin-1 is an important component of extracellular microfibrils,
which support the architecture of elastic fibers and other connective
tissue. Deficiency of fibrillin-1 in the extracellular matrix leads to
excessive signaling by transforming growth factor β (TGF-β). Loeys-
Dietz syndrome is caused by mutations in the genes that encode TGF-β
receptors 1 (TGFBR1) and 2 (TGFBR2). Increased signaling by TGF-β
and mutations of TGFBR1, TGFBR2, TGFBR3, as well as TGFB2 and
TGFB3, may cause thoracic aortic aneurysms. Mutations of SMAD3,
which encodes a downstream signaling protein involved with TGF FIGURE 274-1 A chest x-ray of a patient with a thoracic aortic aneurysm.
binding to its receptors, have been described in a syndrome of thoracic
aortic aneurysm; craniofacial, skeletal, and cutaneous anomalies; and
osteoarthritis. Mutations of the genes encoding the smooth muscle– whereas atherosclerosis is the condition most frequently associated
specific alpha-actin (ACTA2), smooth muscle cell–specific myosin with aneurysms of the descending thoracic aorta. The average growth
heavy chain 11 (MHC11), and myosin light chain kinase (MYLK) and rate of thoracic aneurysms is 0.1–0.2 cm per year. Thoracic aortic aneu-
mutations of TGFBR2 and SMAD3 have been reported in some patients rysms associated with Marfan’s syndrome or aortic dissection may
with nonsyndromic familial thoracic aortic aneurysms. Mutations of expand at a greater rate. The risk of rupture is related to the size of the
type III procollagen have been implicated in Ehlers-Danlos type IV aneurysm and the presence of symptoms, ranging approximately from
syndrome. 2–3% per year for thoracic aortic aneurysms <4.0 cm in diameter to 7%
The infectious causes of aortic aneurysms include syphilis, tuber- per year for those >6 cm in diameter. Most thoracic aortic aneurysms
culosis, and other bacterial infections. Syphilis (Chap. 177) is a rela- are asymptomatic; however, compression or erosion of adjacent tissue
tively uncommon cause of aortic aneurysm. Syphilitic periaortitis and by aneurysms may cause symptoms such as chest pain, shortness of
mesoaortitis damage elastic fibers, resulting in thickening and weak- breath, cough, hoarseness, and dysphagia. Aneurysmal dilation of the
ening of the aortic wall. Approximately 90% of syphilitic aneurysms ascending aorta may cause congestive heart failure as a consequence of
are located in the ascending aorta or aortic arch. Tuberculous aneurysms aortic regurgitation, and compression of the superior vena cava may
(Chap. 173) typically affect the thoracic aorta and result from direct produce congestion of the head, neck, and upper extremities.
extension of infection from hilar lymph nodes or contiguous abscesses A chest x-ray may be the first test that suggests the diagnosis of a
as well as from bacterial seeding. Loss of aortic wall elasticity results thoracic aortic aneurysm (Fig. 274-1). Findings include widening of the
from granulomatous destruction of the medial layer. A mycotic aneurysm mediastinal shadow and displacement or compression of the trachea or
is a rare condition that develops as a result of staphylococcal, strepto- left main stem bronchus. Echocardiography, particularly transesopha-
coccal, Salmonella, or other bacterial or fungal infections of the aorta, geal echocardiography, can be used to assess the proximal ascending
usually at an atherosclerotic plaque. These aneurysms are usually aorta and descending thoracic aorta. Contrast-enhanced CT, magnetic
saccular. Blood cultures are often positive and reveal the nature of the resonance imaging (MRI), and conventional invasive aortography are
infective agent. sensitive and specific tests for assessment of aneurysms of the thoracic
Vasculitides associated with aortic aneurysm include Takayasu’s aorta and involvement of branch vessels (Fig. 274-2). In asymptomatic
arteritis and giant cell arteritis, which may cause aneurysms of the aor- patients whose aneurysms are too small to justify surgery, noninvasive
tic arch and descending thoracic aorta. Spondyloarthropathies such as testing with either contrast-enhanced CT or MRI should be performed
ankylosing spondylitis, rheumatoid arthritis, psoriatic arthritis, relapsing at least every 6–12 months to monitor expansion.
polychondritis, and reactive arthritis (formerly known as Reiter’s syn-
drome) are associated with dilation of the ascending aorta. Aortic aneu-
rysms occur in patients with Behçet’s syndrome (Chap. 357), Cogan’s TREATMENT
syndrome, and IgG4-related systemic disease. Aortic aneurysms also Thoracic Aortic Aneurysms
result from idiopathic aortitis. Traumatic aneurysms may occur after
penetrating or nonpenetrating chest trauma and most commonly β-Adrenergic blockers currently are recommended for patients with
affect the descending thoracic aorta just beyond the site of insertion of thoracic aortic aneurysms, particularly those with Marfan’s syn-
the ligamentum arteriosum. Chronic aortic dissections are associated drome, who have evidence of aortic root dilatation to reduce the
with weakening of the aortic wall that may lead to the development of rate of further expansion. Additional medical therapy should be
aneurysmal dilatation. given as necessary to control hypertension. Angiotensin receptor
antagonists may reduce the rate of aortic dilation in patients with
■■THORACIC AORTIC ANEURYSMS Marfan’s syndrome by blocking TGF-β signaling. Clinical outcome
The clinical manifestations and natural history of thoracic aortic trials have found that the rate of aortic root enlargement in patients
aneurysms depend on their location. Medial degeneration is the most with Marfan’s syndrome was similar with atenolol and losartan.
common pathology associated with ascending aortic aneurysms, Operative repair with placement of a prosthetic graft is indicated

Abdominal radiography may demonstrate the calcified outline of 1919
the aneurysm; however, about 25% of aneurysms are not calcified and
cannot be visualized by x-ray imaging. An abdominal ultrasound can
delineate the transverse and longitudinal dimensions of an abdominal
aortic aneurysm and may detect mural thrombus. Abdominal ultra-

sound is useful for serial documentation of aneurysm size and can be
used to screen patients at risk for developing an aortic aneurysm. In
one large study, ultrasound screening of men aged 65–74 years was
associated with a risk reduction in aneurysm-related death of 42%.
For this reason, screening by ultrasonography is recommended for
men aged 65–75 years who have ever smoked. In addition, siblings or
offspring of persons with abdominal aortic aneurysms, as well as indi-
viduals with thoracic aortic or peripheral arterial aneurysms, should
be considered for screening for abdominal aortic aneurysms. CT with
contrast and MRI are accurate noninvasive tests to determine the loca-
tion and size of abdominal aortic aneurysms and to plan endovascular
or open surgical repair (Fig. 274-3). Contrast aortography may be used
for the evaluation of patients with aneurysms, but the procedure car-
ries a small risk of complications such as bleeding, allergic reactions,
and atheroembolism. Since the presence of mural thrombi may reduce
the luminal size, aortography may underestimate the diameter of an
aneurysm.
FIGURE 274-2 A magnetic resonance angiogram demonstrating a fusiform
aneurysm of the ascending thoracic aorta. (Courtesy of Dr. Michael Steigner, TREATMENT
Brigham and Women’s Hospital, Boston, MA, with permission.)
Abdominal Aortic Aneurysms
in patients with symptomatic ascending thoracic aortic aneurysms Statins are indicated to reduce the risk of cardiovascular events
and for most asymptomatic aneurysms, including those associated related to atherosclerosis. Medical therapies, such as β-adrenergic
with bicuspid aortic valves, when the aortic root or ascending aortic blockers and renin-angiotensin inhibitors, have not proven effective
diameter is ≥5.5 cm, or when the growth rate is >0.5 cm per year. in reducing the rate of aneurysm growth. Operative repair of the
Replacement of the ascending aorta >4.5 cm is reasonable in patients aneurysm with insertion of a prosthetic graft or endovascular place-
with bicuspid aortic valves undergoing aortic valve replacement ment of an aortic stent graft (Fig. 274-3) is indicated for abdominal
because of severe aortic stenosis or aortic regurgitation. In patients aortic aneurysms of any size that are expanding rapidly or are
with Marfan’s syndrome, ascending thoracic aortic aneurysms of associated with symptoms. For asymptomatic aneurysms, abdom-
4–5 cm should be considered for surgery. Operative repair is indi- inal aortic aneurysm repair is indicated if the diameter is ≥5.5 cm.
cated for patients with degenerative descending thoracic aortic In randomized trials of patients with abdominal aortic aneurysms
aneurysms when the diameter is >6 cm, and endovascular repair <5.5 cm, there was no difference in the long-term (5- to 8-year) mor-
should be considered if feasible when the diameter is >5.5 cm. tality rate between those followed with ultrasound surveillance and
Repair is also recommended when the diameter of a descending those undergoing elective surgical repair. Thus, serial noninvasive
thoracic aortic aneurysm has increased >1 cm per year. follow-up of smaller aneurysms (<5.5 cm) is an alternative to imme-
diate repair. The decision to perform an open surgical operation or
endovascular repair is based in part on the vascular anatomy and
■■ABDOMINAL AORTIC ANEURYSMS
comorbid conditions. Endovascular repair of abdominal aortic aneu-
Abdominal aortic aneurysms occur more frequently in males than in
rysms has a lower short-term morbidity rate, but a comparable long-
females, and the incidence increases with age. Cigarette smoking is
term mortality rate with open surgical reconstruction. Long-term
a potent modifiable risk factor. Abdominal aortic aneurysms ≥4.0 cm
surveillance with CT or MR aortography is indicated after endovas-
may affect 1–2% men aged >50 years. At least 90% of all abdominal aor-
cular repair to detect leaks and possible aneurysm expansion.
tic aneurysms >4.0 cm are related to atherosclerotic disease, and most
In surgical candidates, careful preoperative cardiac and general
of these aneurysms are below the level of the renal arteries. Prognosis
medical evaluations (followed by appropriate therapy for compli-
is related to both the size of the aneurysm and the severity of coexist-
cating conditions) are essential. Preexisting coronary artery disease,
ing coronary artery and cerebrovascular disease. The risk of rupture
congestive heart failure, pulmonary disease, diabetes mellitus, and
increases with the size of the aneurysm: the 5-year risk for aneurysms
advanced age add to the risk of surgery. With careful preoperative
<5 cm is 1–2%, whereas it is 20–40% for aneurysms >5 cm in diameter.
cardiac evaluation and postoperative care, the operative mortality
The formation of mural thrombi within aneurysms may predispose to
rate approximates 1–2%. After acute rupture, the mortality rate
peripheral embolization.
of emergent operation is 45–50%. Endovascular repair with stent
An abdominal aortic aneurysm commonly produces no symptoms.
placement is an alternative approach to treat ruptured aneurysms
It usually is detected on routine examination as a palpable, pulsatile,
and may be associated with a lower mortality rate.
expansile, and nontender mass, or it is an incidental finding observed
on an abdominal imaging study performed for other reasons. As
abdominal aortic aneurysms expand, however, they may become ACUTE AORTIC SYNDROMES
painful. Some patients complain of strong pulsations in the abdomen; The four major acute aortic syndromes are aortic rupture (discussed
others experience pain in the chest, lower back, or scrotum. Aneurys- earlier), aortic dissection, intramural hematoma, and penetrating
mal pain is usually a harbinger of rupture and represents a medical atherosclerotic ulcer. Aortic dissection is caused by a circumferential
emergency. More often, acute rupture occurs without any prior warn- or, less frequently, transverse tear of the intima. It often occurs along
ing, and this complication is always life-threatening. Rarely, there is the right lateral wall of the ascending aorta where the hydraulic shear
leakage of the aneurysm with severe pain and tenderness. Acute pain stress is high. Another common site is the descending thoracic aorta
and hypotension occur with rupture of the aneurysm, which requires just below the ligamentum arteriosum. The initiating event is either
an emergency operation. a primary intimal tear with secondary dissection into the media or

1920
PART 6
FIGURE 274-3 A computed tomographic angiogram depicting a fusiform abdominal aortic aneurysm before (left) and after (right) treatment with a bifurcated stent
graft. (Courtesy of Drs. Elizabeth George and Frank Rybicki, Brigham and Women’s Hospital, Boston, MA, with permission.)
a medial hemorrhage that dissects into and disrupts the intima. The or Loeys-Dietz syndrome, and similarly may affect patients with
pulsatile aortic flow then dissects along the elastic lamellar plates of Ehlers-Danlos syndrome. The incidence also is increased in patients
the aorta and creates a false lumen. The dissection usually propagates with inflammatory aortitis (i.e., Takayasu’s arteritis, giant cell arteritis),
distally down the descending aorta and into its major branches, but congenital aortic valve anomalies (e.g., bicuspid valve), coarctation of
it may propagate proximally. Distal propagation may be limited by
atherosclerotic plaque. In some cases, a secondary distal intimal dis- Type A
ruption occurs, resulting in the reentry of blood from the false to the
true lumen.
There are at least two important pathologic and radiologic variants
of aortic dissection: intramural hematoma without an intimal flap
and penetrating atherosclerotic ulcer. Acute intramural hematoma is
thought to result from rupture of the vasa vasorum with hemorrhage
into the wall of the aorta. Most of these hematomas occur in the
descending thoracic aorta. Acute intramural hematomas may progress
to dissection and rupture. Penetrating atherosclerotic ulcers are caused
by erosion of a plaque into the aortic media, are usually localized, and
are not associated with extensive propagation. They are found primar-
ily in the middle and distal portions of the descending thoracic aorta
and are associated with extensive atherosclerotic disease. The ulcer can
Type B
erode beyond the internal elastic lamina, leading to medial hematoma,
and may progress to false aneurysm formation or rupture.
Several classification schemes have been developed for thoracic
aortic dissections. DeBakey and colleagues initially classified aortic
dissections as type I, in which an intimal tear occurs in the ascending
aorta but involves the descending aorta as well; type II, in which the
dissection is limited to the ascending aorta; and type III, in which the
intimal tear is located in the descending aorta with distal propagation
of the dissection (Fig. 274-4). Another classification (Stanford) is that
of type A, in which the dissection involves the ascending aorta (prox-
imal dissection), and type B, in which it is limited to the arch and/or
descending aorta (distal dissection). From a management standpoint,
classification of aortic dissections and intramural hematomas into type FIGURE 274-4 Classification of aortic dissections. Stanford classification: Type A
A or B is more practical and useful, since DeBakey types I and II are dissections (top) involve the ascending aorta independent of site of tear and distal
managed in a similar manner. extension; type B dissections (bottom) involve transverse and/or descending
aorta without involvement of the ascending aorta. DeBakey classification: Type I
The factors that predispose to aortic dissection include those asso-
dissection involves ascending to descending aorta (top left); type II dissection is
ciated with medial degeneration and others that increase aortic wall limited to ascending or transverse aorta, without descending aorta (top center +
stress (Table 274-1). Systemic hypertension is a coexisting condition top right); type III dissection involves descending aorta only (bottom left). (From
in 70% of patients. Aortic dissection is the major cause of morbid- DC Miller, in RM Doroghazi, EE Slater [eds]: Aortic Dissection. New York, McGraw-Hill,
ity and mortality in patients with Marfan’s syndrome (Chap. 406) 1983, with permission.)

the aorta, and a history of aortic trauma. In addition, the risk of dissec- 1921
TREATMENT
tion is increased in otherwise normal women during the third trimester
of pregnancy. Aortic dissection also may occur as a consequence of Aortic Dissection
weight lifting, cocaine use, or deceleration injury.
Medical therapy should be initiated as soon as the diagnosis is

■■CLINICAL MANIFESTATIONS considered. The patient should be admitted to an intensive care
The peak incidence of aortic dissection is in the sixth and seventh unit for hemodynamic monitoring. Unless hypotension is present,
decades. Men are more affected than women by a ratio of 2:1. The therapy should be aimed at reducing cardiac contractility and sys-
presentations of aortic dissection and its variants are the consequences temic arterial pressure, and thus shear stress. For acute dissection,
of intimal tear, dissecting hematoma, occlusion of involved arteries, unless contraindicated, β-adrenergic blockers should be adminis-
and compression of adjacent tissues. Acute aortic dissection presents tered parenterally, using intravenous propranolol, metoprolol, or the
with the sudden onset of pain (Chap. 11), which often is described as short-acting esmolol to achieve a heart rate of ~60 beats/min. This
very severe and tearing and is associated with diaphoresis. The pain should be accompanied by sodium nitroprusside infusion to lower
may be localized to the front or back of the chest, often the interscap- systolic blood pressure to ≤120 mmHg. Labetalol (Chap. 271), a drug
ular region, and typically migrates with propagation of the dissection. with both β- and α-adrenergic blocking properties, also may be used
Other symptoms include syncope, dyspnea, and weakness. Physical as a parenteral agent in acute therapy for dissection.
findings may include hypertension or hypotension, loss of pulses, The calcium channel antagonists verapamil and diltiazem may be
aortic regurgitation, pulmonary edema, and neurologic findings due used intravenously if nitroprusside or β-adrenergic blockers cannot
to carotid artery obstruction (hemiplegia, hemianesthesia) or spinal be employed. The addition of a parenteral angiotensin-converting
cord ischemia (paraplegia). Bowel ischemia, hematuria, and myocar- enzyme (ACE) inhibitor such as enalaprilat to a β-adrenergic blocker
dial ischemia have all been observed. These clinical manifestations also may be considered. Isolated use of a direct vasodilator such as
reflect complications resulting from the dissection occluding the hydralazine is contraindicated because these agents can increase
major arteries. Furthermore, clinical manifestations may result from hydraulic shear and may propagate the dissection.
the compression of adjacent structures (e.g., superior cervical ganglia, Emergent or urgent surgical correction is the preferred treatment
superior vena cava, bronchus, esophagus) by the expanding dissection for acute ascending aortic dissections and intramural hematomas
causing aneurysmal dilation, and include Horner’s syndrome, superior (type A). Surgery involves excision of the intimal flap, obliteration
vena cava syndrome, hoarseness, dysphagia, and airway compromise. of the false lumen, and placement of an interposition graft. Aortic
Hemopericardium and cardiac tamponade may complicate a type valve repair or a composite valve-graft conduit is used if the aortic
A lesion with retrograde dissection. Acute aortic regurgitation is an valve is disrupted. The overall in-hospital mortality rate after sur-
important and common (>50%) complication of proximal dissection. gical treatment of patients with aortic dissection is reported to be
It is the outcome of either a circumferential tear that widens the aortic 15–25%. The major causes of perioperative mortality and morbidity
root or a disruption of the annulus by a dissecting hematoma that include myocardial infarction, paraplegia, renal failure, tampon-
tears a leaflet(s) or displaces it, inferior to the line of closure. Signs of ade, hemorrhage, and sepsis. Thoracic endovascular aortic repair
aortic regurgitation include bounding pulses, a wide pulse pressure, with an endoluminal stent graft is indicated for complicated type B
a diastolic murmur often radiating along the right sternal border, and dissections, including those characterized by propagation, com-
evidence of congestive heart failure. The clinical manifestations depend promise of major aortic branches, impending rupture, or continued
on the severity of the regurgitation. pain. Other transcatheter techniques, such as fenestration of the
In dissections involving the ascending aorta, the chest x-ray often intimal flaps and stenting of narrowed branch vessels to increase
reveals a widened superior mediastinum. A pleural effusion (usually flow to compromised organs, are used in selected patients. Surgical
left-sided) also may be present. This effusion is typically serosanguine- correction is indicated for complicated type B dissections, partic-
ous and not indicative of rupture unless accompanied by hypotension ularly if endovascular repair is not feasible. Hybrid procedures
and falling hematocrit. In dissections of the descending thoracic aorta, consisting of both surgery and endovascular repair may be used
a widened mediastinum may be observed on chest x-ray. In addition, when the dissection involves both the aortic arch and the descend-
the descending aorta may appear to be wider than the ascending ing thoracic aorta. For uncomplicated and stable distal dissections
portion. An electrocardiogram that shows no evidence of myocardial and intramural hematomas (type B), medical therapy is the pre-
ischemia is helpful in distinguishing aortic dissection from myocardial ferred treatment. The in-hospital mortality rate of medically treated
infarction. Rarely, the dissection involves the right or, less commonly, patients with type B dissection is ~10%. Long-term therapy for patients
left coronary ostium and causes acute myocardial infarction. with aortic dissection and intramural hematomas (with or without
The diagnosis of aortic dissection can be established by noninvasive surgery) consists of control of hypertension and reduction of cardiac
techniques such as echocardiography, CT, and MRI. Aortography is contractility with the use of β-adrenergic blockers plus other anti-
used less commonly because of the accuracy of these noninvasive tech- hypertensive agents, such as ACE inhibitors or calcium antagonists.
niques. Transthoracic echocardiography can be performed simply and Patients with chronic type B dissection and intramural hematomas
rapidly and has an overall sensitivity of 60–85% for aortic dissection. should be followed on an outpatient basis every 6–12 months with
For diagnosing proximal ascending aortic dissections, its sensitivity contrast-enhanced CT or MRI to detect propagation or expansion.
exceeds 80%; it is less useful for detecting dissection of the arch and Patients with Marfan’s syndrome are at high risk for postdissection
descending thoracic aorta. Transesophageal echocardiography requires complications. The long-term prognosis for patients with treated
greater skill and patient cooperation, but is very accurate in identifying dissections is generally good with careful follow-up; the 10-year
dissections of the ascending and descending thoracic aorta but not the survival rate is ~60%.
arch, achieving 98% sensitivity and ~90% specificity. Echocardiogra-
phy also provides important information regarding the presence and ■■CHRONIC ATHEROSCLEROTIC OCCLUSIVE DISEASE
severity of aortic regurgitation and pericardial effusion. CT and MRI Atherosclerosis may affect the thoracic and abdominal aorta. Occlu-
are both highly accurate in identifying the intimal flap and the extent sive aortic disease caused by atherosclerosis usually is confined to the
of the dissection and involvement of major arteries; each has a sensi- distal abdominal aorta below the renal arteries. Frequently the disease
tivity and specificity >90%. They are useful in recognizing intramural extends to the iliac arteries (Chap. 275). Claudication characteristically
hemorrhage and penetrating ulcers. The relative utility of transesoph- involves the buttocks, thighs, and calves and may be associated with
ageal echocardiography, CT, and MRI depends on the availability and impotence in males (Leriche’s syndrome). The severity of the symp-
expertise in individual institutions as well as on the hemodynamic toms depends on the adequacy of collaterals. With sufficient collateral
stability of the patient, with CT and MRI obviously less suitable for blood flow, a complete occlusion of the abdominal aorta may occur
unstable patients. without the development of ischemic symptoms. The physical findings

1922 include the absence of femoral and other distal pulses bilaterally and polymyalgia rheumatica. Obstruction of medium-size arteries (e.g.,
the detection of an audible bruit over the abdomen (usually at or below temporal and ophthalmic arteries) and major branches of the aorta
the umbilicus) and the common femoral arteries. Atrophic skin, loss and the development of aortitis and aortic regurgitation are important
of hair, and coolness of the lower extremities usually are observed. In complications of the disease. High-dose glucocorticoid therapy should
advanced ischemia, rubor on dependency and pallor on elevation can be administered early and then gradually tapered. Immunosuppressive
be seen. therapy with methotrexate may allow reduction in steroid dosage and
PART 6
The diagnosis usually is established by physical examination and reduce the risk of relapse. Biologically targeted therapies are under
noninvasive testing, including leg pressure measurements, Doppler investigation.
velocity analysis, pulse volume recordings, and duplex ultrasonogra-
phy. The anatomy may be defined by MRI, CT, or conventional aortog- ■■RHEUMATIC AORTITIS
raphy, typically performed when one is considering revascularization. Rheumatoid arthritis (Chap. 351), ankylosing spondylitis (Chap. 355),
Catheter-based endovascular or operative treatment is indicated in psoriatic arthritis (Chap. 355), reactive arthritis (formerly known as
patients with lifestyle-limiting or debilitating symptoms of claudica- Reiter’s syndrome) (Chap. 355), relapsing polychondritis, and inflam-
tion and patients with critical limb ischemia. matory bowel disorders may all be associated with aortitis involving
the ascending aorta. The inflammatory lesions usually involve the
■■ACUTE AORTIC OCCLUSION ascending aorta and may extend to the sinuses of Valsalva, the mitral
Acute occlusion in the distal abdominal aorta constitutes a medical valve leaflets, and adjacent myocardium. The clinical manifestations
emergency because it threatens the viability of the lower extremities; it are aneurysm, aortic regurgitation, and involvement of the cardiac
usually results from an occlusive (saddle) embolus that almost always conduction system.
originates from the heart. Rarely, acute occlusion may occur as the
result of in situ thrombosis in a preexisting severely narrowed segment ■■IDIOPATHIC AORTITIS
of the aorta. Idiopathic abdominal aortitis is characterized by adventitial and
The clinical picture is one of acute ischemia of the lower extremities. periaortic inflammation with thickening of the aortic wall. It is associ-
Severe rest pain, coolness, and pallor of the lower extremities and ated with abdominal aortic aneurysms and idiopathic retroperitoneal
the absence of distal pulses bilaterally are the usual manifestations. fibrosis. Affected individuals may present with vague constitutional
Diagnosis should be established rapidly by MRI, CT, or aortography. symptoms, fever, and abdominal pain. Retroperitoneal fibrosis can
Emergency thrombectomy or revascularization is indicated. cause ureteral obstruction and hydronephrosis. Glucocorticoids and
immunosuppressive agents may reduce the inflammation.
AORTITIS
Aortitis, a term referring to inflammatory disease of the aorta, may ■■INFECTIVE AORTITIS
be caused by large vessel vasculitides such as Takayasu’s arteritis and Infective aortitis may result from direct invasion of the aortic wall by
giant cell arteritis, rheumatic and HLA-B27–associated spondyloar- bacterial pathogens such as Staphylococcus, Streptococcus, and Salmonella
thropathies, Behçet’s syndrome, antineutrophil cytoplasmic antibody or by fungi. These bacteria cause aortitis by infecting the aorta at sites
(ANCA)–associated vasculitides, Cogan’s syndrome, Erdheim-Chester of atherosclerotic plaque. Bacterial proteases lead to degradation of col-
disease, IgG4-related systemic disease, and infections such as syphilis, lagen, and the ensuing destruction of the aortic wall leads to the forma-
tuberculosis, and Salmonella, or may be associated with retroperitoneal tion of a saccular aneurysm referred to as a mycotic aneurysm. Mycotic
fibrosis. Aortitis may result in aneurysmal dilation and aortic regur- aneurysms have a predilection for the suprarenal abdominal aorta. The
gitation, occlusion of the aorta and its branch vessels, or acute aortic pathologic characteristics of the aortic wall include acute and chronic
syndromes. inflammation, abscesses, hemorrhage, and necrosis. Mycotic aneu-
rysms typically affect the elderly and occur in men three times more
■■TAKAYASU’S ARTERITIS frequently than in women. Patients may present with fever, sepsis,
(See also Chap. 356) This inflammatory disease often affects the and chest, back, or abdominal pain; there may have been a preceding
ascending aorta and aortic arch, causing obstruction of the aorta and diarrheal illness. Blood cultures are positive in the majority of patients.
its major arteries. Takayasu’s arteritis is also termed pulseless disease Both CT and MRI are useful to diagnose mycotic aneurysms. Treatment
because of the frequent occlusion of the large arteries originating from includes antibiotic therapy and surgical removal of the affected part
the aorta. It also may involve the descending thoracic and abdominal of the aorta and revascularization of the lower extremities with grafts
aorta and occlude large branches such as the renal arteries. Aortic aneu- placed in uninfected tissue.
rysms also may occur. The pathology is a panarteritis characterized by Syphilitic aortitis is a late manifestation of luetic infection (Chap. 177)
mononuclear cells and occasionally giant cells, with marked intimal that usually affects the proximal ascending aorta, particularly the aortic
hyperplasia, medial and adventitial thickening, and, in the chronic root, resulting in aortic dilation and aneurysm formation. Syphilitic
form, fibrotic occlusion. The disease is most prevalent in young females aortitis occasionally may involve the aortic arch or the descending
of Asian descent but does occur in women of other geographic and aorta. The aneurysms may be saccular or fusiform and are usually
ethnic origins and also in young men. During the acute stage, fever, asymptomatic, but compression of and erosion into adjacent structures
malaise, weight loss, and other systemic symptoms may be evident. may result in symptoms; rupture also may occur.
Elevations of the erythrocyte sedimentation rate and C-reactive protein The initial lesion is an obliterative endarteritis of the vasa vasorum,
are common. The chronic stages of the disease, which is intermittently especially in the adventitia. This is an inflammatory response to the
active, present with symptoms related to large artery occlusion, such as invasion of the adventitia by the spirochetes. Destruction of the aortic
upper extremity claudication, cerebral ischemia, and syncope. The pro- media occurs as the spirochetes spread into this layer, usually via the
cess is progressive, and there is no definitive therapy. Glucocorticoids lymphatics accompanying the vasa vasorum. Destruction of collagen
and immunosuppressive agents are effective in some patients during and elastic tissues leads to dilation of the aorta, scar formation, and
the acute phase. Biologically targeted agents are under investigation. calcification. These changes account for the characteristic radiographic
Surgical bypass or endovascular intervention of a critically stenotic appearance of linear calcification of the ascending aorta.
artery may be necessary. The disease typically presents as an incidental chest radiographic
finding 15–30 years after initial infection. Symptoms may result from
■■GIANT CELL ARTERITIS aortic regurgitation, narrowing of coronary ostia due to syphilitic aor-
(See also Chap. 356) This vasculitis occurs in older individuals and titis, compression of adjacent structures (e.g., esophagus), or rupture.
affects women more often than men. Primarily large and medium-size Diagnosis is established by a positive serologic test, i.e., rapid plasmin
arteries are affected. The pathology is that of focal granulomatous reagin (RPR) or fluorescent treponemal antibody. Treatment includes
lesions involving the entire arterial wall; it frequently is associated with penicillin and surgical excision and repair.

■■FURTHER READING common symptom is intermittent claudication, which is defined as a 1923
Buck DB et al: Endovascular treatment of abdominal aortic aneurysms. pain, ache, cramp, numbness, or a sense of fatigue in the muscles; it
Nat Rev Cardiol 11:112, 2014. occurs during exercise and is relieved by rest. The site of claudication is
Erbel R et al: 2014 ESC Guidelines on the diagnosis and treatment of distal to the location of the occlusive lesion. For example, buttock, hip,
aortic diseases: Document covering acute and chronic aortic diseases thigh, and calf discomfort occurs in patients with aortoiliac disease,
CHAPTER 275 Arterial Diseases of the Extremities

of the thoracic and abdominal aorta of the adult. The Task Force for whereas calf claudication develops in patients with femoral-popliteal
the Diagnosis and Treatment of Aortic Diseases of the European disease. Symptoms are far more common in the lower than in the upper
Society of Cardiology (ESC). Eur Heart J 35:2873, 2014. extremities because of the higher incidence of obstructive lesions in
Gornik HL, Creager MA: Aortitis. Circulation 117:3039, 2008. the former region. In patients with severe arterial occlusive disease in
Guirguis-Blake JM et al: Ultrasonography screening for abdominal whom resting blood flow cannot accommodate basal nutritional needs
aortic aneurysms: A systematic evidence review for the US Preventive of the tissues, critical limb ischemia may develop. Patients complain
Services Task Force. Ann Intern Med 160:321, 2014. of rest pain or a feeling of cold or numbness in the foot and toes. Fre-
Hiratzka LF et al: 2010 ACCF/AHA/AATS/ACR/ASA/SCA/SCAI/ quently, these symptoms occur at night when the legs are horizontal
SIR/STS/SVM guidelines for the diagnosis and management of and improve when the legs are in a dependent position. With severe
patients with Thoracic Aortic Disease: A report of the American ischemia, rest pain may be persistent.
College of Cardiology Foundation/American Heart Association Task Important physical findings of PAD include decreased or absent
Force on Practice Guidelines, American Association for Thoracic Sur- pulses distal to the obstruction, the presence of bruits over the nar-
gery, American College of Radiology, American Stroke Association, rowed artery, and muscle atrophy. With more severe disease, hair loss,
Society of Cardiovascular Anesthesiologists, Society for Cardiovascu- thickened nails, smooth and shiny skin, reduced skin temperature, and
lar Angiography and Interventions, Society of Interventional Radiol- pallor or cyanosis are common physical signs. In patients with critical
ogy, Society of Thoracic Surgeons, and Society for Vascular Medicine. limb ischemia, ulcers or gangrene may occur. Elevation of the legs and
Circulation 121:e266, 2010. repeated flexing of the calf muscles produce pallor of the soles of the
Isselbacher EM et al: Hereditary influence in thoracic aortic aneurysm feet, whereas rubor, secondary to reactive hyperemia, may develop
and dissection. Circulation 133:2516, 2016. when the legs are dependent. The time required for rubor to develop
Kent KC: Clinical practice. Abdominal aortic aneurysms. N Engl J Med or for the veins in the foot to fill when the patient’s legs are transferred
371:2101, 2014. from an elevated to a dependent position is related to the severity of
Nienaber CA, Clough RE: Management of acute aortic dissection. the ischemia and the presence of collateral vessels. Patients with severe
Lancet 385:800, 2015. ischemia may develop peripheral edema because they keep their legs
in a dependent position much of the time. Ischemic neuropathy can
result in numbness and hyporeflexia.
Noninvasive Testing The history and physical examination are
often sufficient to establish the diagnosis of PAD. An objective assess-
ment of the presence and severity of disease is obtained by noninvasive
275 Arterial Diseases of the techniques. Arterial pressure can be recorded noninvasively in the legs
by placement of sphygmomanometric cuffs at the ankles and the use of
Extremities a Doppler device to auscultate or record blood flow from the dorsalis
pedis and posterior tibial arteries. Normally, systolic blood pressure
Mark A. Creager, Joseph Loscalzo in the legs and arms is similar. Indeed, ankle pressure may be slightly
higher than arm pressure due to pulse-wave amplification. In the pres-
ence of hemodynamically significant stenoses, the systolic blood pres-
■■PERIPHERAL ARTERY DISEASE sure in the leg is decreased. Thus, the ratio of the ankle and brachial
Peripheral artery disease (PAD) is defined as a clinical disorder in artery pressures (termed the ankle:brachial index, or ABI) is 1.00–1.40 in
which there is a stenosis or occlusion in the aorta or the arteries of the normal individuals. ABI values of 0.91–0.99 are considered “border-
limbs. Atherosclerosis is the leading cause of PAD in patients >40 years line,” and those <0.90 are abnormal and diagnostic of PAD. ABIs >1.40
old. Other causes include thrombosis, embolism, vasculitis, fibromus- indicate noncompressible arteries secondary to vascular calcification.
cular dysplasia, entrapment, cystic adventitial disease, and trauma. Other noninvasive tests include segmental pressure measurements,
The highest prevalence of atherosclerotic PAD occurs in the sixth and segmental pulse volume recordings, duplex ultrasonography (which
seventh decades of life. As in patients with atherosclerosis of the coro- combines B-mode imaging and Doppler flow velocity waveform
nary and cerebral vasculature, there is an increased risk of developing analysis), transcutaneous oximetry, and stress testing (usually using a
PAD in cigarette smokers and in persons with diabetes mellitus, hyper- treadmill). Placement of pneumatic cuffs enables assessment of systolic
pressure along the legs. The presence of pressure gradients between
cholesterolemia, hypertension, or renal insufficiency.
sequential cuffs provides evidence of the presence and location of
Pathology (See also Chap. 291e from HPIM 19e) Segmental hemodynamically significant stenoses. In addition, the amplitude of
lesions that cause stenosis or occlusion are usually localized to large the pulse volume contour becomes blunted in the presence of signifi-
and medium-size vessels. The pathology of the lesions includes ath- cant PAD. Duplex ultrasonography is used to image and detect stenotic
erosclerotic plaques with calcium deposition, thinning of the media, lesions in native arteries and bypass grafts.
patchy destruction of muscle and elastic fibers, fragmentation of the Treadmill testing allows the physician to assess functional limita-
internal elastic lamina, and thrombi composed of platelets and fibrin. tions objectively. Decline of the ABI immediately after exercise provides
The primary sites of involvement are the abdominal aorta and iliac further support for the diagnosis of PAD in patients with equivocal
arteries (30% of symptomatic patients), the femoral and popliteal symptoms and findings on examination.
arteries (80–90% of patients), and the more distal vessels, including Magnetic resonance angiography (MRA), computed tomographic
the tibial and peroneal arteries (40–50% of patients). Atherosclerotic angiography (CTA), and conventional catheter-based angiography
lesions occur preferentially at arterial branch points, which are sites of should not be used for routine diagnostic testing, but are performed
increased turbulence, altered shear stress, and intimal injury. Involve- before potential revascularization (Fig. 275-1). Each test is useful in
ment of the distal vasculature is most common in elderly individuals defining the anatomy to assist planning for endovascular and surgical
and patients with diabetes mellitus. revascularization procedures.
Clinical Evaluation Fewer than 50% of patients with PAD are Prognosis The natural history of patients with PAD is influ-
symptomatic, although many have a slow or impaired gait. The most enced primarily by the extent of coexisting coronary artery and

1924
PART 6
FIGURE 275-1 Magnetic resonance angiography of a patient with intermittent claudication, showing stenoses of the distal abdominal aorta and right common iliac
artery (A) and stenoses of the right and left superficial femoral arteries (B). (Courtesy of Dr. Edwin Gravereaux, with permission.)
cerebrovascular disease. Approximately one-third to one-half of including aspirin and the ADP antagonist, clopidogrel, reduce the
patients with symptomatic PAD have evidence of coronary artery risk of adverse cardiovascular events in patients with atherosclerosis
disease (CAD) based on clinical presentation and electrocardiogram, and are recommended for patients with symptomatic PAD, includ-
and over one-half have significant CAD by coronary angiography. ing those with intermittent claudication or critical limb ischemia or
Patients with PAD have a 15–25% 5-year mortality rate and a two- to prior lower extremity revascularization. Outcomes with ticragrelor
sixfold increased risk of death from coronary heart disease. Mortality are similar to those with clopidogrel. The benefit of dual antiplatelet
rates are highest in those with the most severe PAD. Measurement therapy with both aspirin and clopidogrel compared with aspirin
of ABI is useful for detecting PAD and identifying persons at risk alone in reducing cardiovascular morbidity and mortality rates in
for future atherothrombotic events. The likelihood of symptomatic patients with PAD is uncertain. When added to other antiplatelet
progression of PAD is lower than the chance of succumbing to CAD. therapy, vorapaxar, a protease activated receptor-1 antagonist that
Approximately 75–80% of nondiabetic patients who present with mild inhibits thrombin-mediated platelet activation, decreases the risk
to moderate claudication remain symptomatically stable. Deterioration of adverse cardiovascular events in patients with atherosclerosis,
is likely to occur in the remainder, with ~1–2% of the group ultimately including PAD. It also reduces the risk of acute limb ischemia
developing critical limb ischemia each year. Approximately 25–30% of and peripheral revascularization; however, it is associated with an
patients with critical limb ischemia undergo amputation within 1 year. increased rate of moderate bleeding. The anticoagulant warfarin
The prognosis is worse in patients who continue to smoke cigarettes or is as effective as antiplatelet therapy in preventing adverse cardio-
have diabetes mellitus. vascular events but causes more major bleeding; therefore, it is not
indicated to improve outcomes in patients with chronic PAD. The
combination of a low dose of the oral factor Xa inhibitor, rivarox-
TREATMENT aban, and aspirin improves cardiovascular outcomes in patients
Peripheral Artery Disease with established atherosclerosis, including PAD, but is associated
with increased risk of bleeding.
Patients with PAD should receive therapies to reduce the risk of Therapies for intermittent claudication and critical limb ische-
associated cardiovascular events, such as myocardial infarction mia include supportive measures, medications, exercise training,
and death, and to improve limb symptoms, prevent progression endovascular interventions, and surgery. Supportive measures
to critical limb ischemia, and preserve limb viability. Risk fac- include meticulous care of the feet, which should be kept clean
tor modification and antiplatelet therapy should be initiated to and protected against excessive drying with moisturizing creams.
improve cardiovascular outcomes. The importance of discontinuing Well-fitting and protective shoes are advised to reduce trauma.
cigarette smoking cannot be overemphasized. The physician must Elastic support hose should be avoided, as it reduces blood flow
assume a major role in this lifestyle modification. Counseling and to the skin. In patients with critical limb ischemia, shock blocks
adjunctive drug therapy with the nicotine patch, bupropion, or under the head of the bed together with a canopy over the feet may
varenicline increase smoking cessation rates and reduce recidivism. improve perfusion pressure and ameliorate some of the rest pain.
It is important to control blood pressure in hypertensive patients. Patients with claudication should be encouraged to exercise
Angiotensin-converting enzyme inhibitors and angiotensin receptor regularly and at progressively more strenuous levels. Supervised
blockers may reduce the risk of cardiovascular events in patients exercise training programs for 30- to 45-min sessions, three to five
with symptomatic PAD. β-Adrenergic blockers do not worsen clau- times per week for at least 12 weeks, prolong walking distance. The
dication and may be used to treat hypertension, especially in beneficial effect of supervised exercise training on walking perfor-
patients with coexistent CAD. Treatment of hypercholesterolemia mance in patients with claudication often is similar to or greater
with statins is advocated to reduce the risk of myocardial infarction, than that realized after a revascularization procedure. Structured
stroke, and death. The 2013 ACC/AHA Guideline on the Treatment home and community-based exercise programs are also effective.
of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk Pharmacologic treatment of PAD has not been as successful as the
in Adults recommends high intensity statin treatment in patients medical treatment of CAD (Chap. 267). In particular, vasodilators as
with atherosclerotic disorders, including PAD. Platelet inhibitors, a class have not proved to be beneficial. During exercise, peripheral

vasodilation occurs distal to sites of significant arterial stenoses. As endarterectomy. The most frequently used procedure is the aor- 1925
a result, perfusion pressure falls, often to levels lower than that gen- tobifemoral bypass using knitted Dacron grafts. Immediate graft
erated in the interstitial tissue by the exercising muscle. Drugs such patency approaches 99%, and 5- and 10-year graft patency rates in
as α-adrenergic blocking agents, calcium channel antagonists, and survivors are >90% and 80%, respectively. Operative complications
other vasodilators have not been shown to be effective in patients include myocardial infarction and stroke, infection of the graft,

with PAD. peripheral embolization, and sexual dysfunction from interruption
Cilostazol, a phosphodiesterase inhibitor with vasodilator and of autonomic nerves in the pelvis. The operative mortality rate
antiplatelet properties, increases claudication distance by 40–60% ranges from 1 to 3%, mostly due to ischemic heart disease.
and improves measures of quality of life. The mechanism of action Operative therapy for femoral-popliteal artery disease includes
accounting for its beneficial effects is not known. Pentoxifylline, a in situ and reverse autogenous saphenous vein bypass grafts, place-
substituted xanthine derivative, increases blood flow to the micro- ment of polytetrafluoroethylene (PTFE) or other synthetic grafts, and
circulation and enhances tissue oxygenation. Although several thromboendarterectomy. The operative mortality rate ranges from 1
placebo-controlled studies have found that pentoxifylline modestly to 3%. The long-term patency rate depends on the type of graft used,
increases the duration of exercise, its efficacy has not been confirmed the location of the distal anastomosis, and the patency of runoff
in other clinical trials. Statins appeared effective for treatment of vessels beyond the anastomosis. Patency rates of femoral-popliteal
intermittent claudication in initial clinical trials, but more studies are saphenous vein bypass grafts approach 90% at 1 year and 70–80%
needed to confirm the efficacy of this class of drugs. at 5 years. Five-year patency rates of infrapopliteal saphenous vein
There is no definitive medical therapy for critical limb ischemia. bypass grafts are 60–70%. In contrast, 5-year patency rates of infrap-
Vasodilator prostaglandins are not effective in relieving symp- opliteal PTFE grafts are <30%.
toms or preventing limb loss. Enthusiasm for therapy with angio- Preoperative cardiac risk assessment may identify individuals
genic growth factors abated when clinical trials of intramuscular who are especially likely to experience an adverse cardiac event
gene transfer of DNA encoding vascular endothelial growth factor, during the perioperative period. Patients with angina, prior myo-
fibroblast growth factor, hepatocyte growth factor, or hypoxia- cardial infarction, heart failure, diabetes, or renal insufficiency are
inducible factor 1α failed to demonstrate improvement in symptoms among those at increased risk. Stress testing with treadmill exercise
or outcomes in patients with intermittent claudication or critical (if feasible), radionuclide myocardial perfusion imaging, or echoc-
limb ischemia. Most clinical trials of bone marrow–derived vascular ardiography permits further stratification of risk in these patients,
progenitor cells to promote angiogenesis and preserve limb viability particularly those with poor or unknown functional capacity
in patients with critical limb ischemia have failed to demonstrate (Chap. 270). Patients with abnormal test results require close super-
benefit, though a meta-analysis of these trials suggested a modest vision and adjunctive management with anti-ischemic medications.
reduction in the risk of amputation. This remains an active area of Coronary angiography and coronary artery revascularization com-
preclinical and clinical investigation. pared with optimal medical therapy do not improve outcomes in
most patients undergoing peripheral vascular surgery, but car-
REVASCULARIZATION diac catheterization should be considered in patients with unstable
Revascularization procedures, including catheter-based and surgi- angina and angina refractory to medical therapy as well as those
cal interventions, are usually indicated for patients with disabling, suspected of having left main or three-vessel CAD.
progressive, or severe symptoms of intermittent claudication despite
medical therapy in order to improve walking distance and func- ■■FIBROMUSCULAR DYSPLASIA
tional capacity. These are also indicated in patients with critical Fibromuscular dysplasia is a hyperplastic disorder that affects
limb ischemia to relieve pain and prevent limb loss. MRA, CTA, or medium-size and small arteries. It occurs predominantly in females
conventional angiography should be performed to assess vascular and usually involves the renal and carotid arteries but can affect
anatomy in patients who are being considered for revasculariza- extremity vessels such as the iliac and subclavian arteries. The histo-
tion. Endovascular interventions include percutaneous transluminal logic classification includes intimal fibroplasia (also classified as focal),
balloon angioplasty (PTA) (including drug coated balloons), stent medial dysplasia (multifocal), and adventitial hyperplasia. Medial
placement (including drug eluting stents), stent grafts, and atherec- dysplasia is subdivided into medial fibroplasia, perimedial fibropla-
tomy (Chap. 270). When endovascular intervention is performed in sia, and medial hyperplasia. Medial fibroplasia is the most common
conjunction with a supervised exercise program, walking distance type and is characterized by alternating areas of thinned media and
improves more than with exercise training alone. fibromuscular ridges. The internal elastic lamina usually is preserved.
PTA and stenting of the iliac artery are associated with higher The iliac arteries are the limb arteries most likely to be affected by
success rates than are PTA and stenting of the femoral and popliteal fibromuscular dysplasia. It is identified angiographically by a “string
arteries. Approximately 90–95% of iliac PTAs are initially successful, of beads” appearance caused by thickened fibromuscular ridges con-
and the 3-year patency rate is >75%. Patency rates may be higher tiguous with thin, less-involved portions of the arterial wall, which
if a stent is placed in the iliac artery. The initial success rate for is typical of medial fibroplasia, or less commonly, as a focal tubular
femoral-popliteal PTA and stenting approximate 90% with 60% stenosis, and which is more typical of intimal fibroplasia. When limb
3-year patency rates. Outcomes following stenting of longer femoral- vessels are involved, clinical manifestations are similar to those for
popliteal lesions (>5–10 cm) generally are better than after PTA. Sev- atherosclerosis, including claudication and rest pain. PTA and surgical
eral clinical trials have found lower restenosis rates with drug-coated reconstruction have been beneficial in patients with debilitating symp-
balloons than with PTA, and with drug eluting stents compared with toms or threatened limbs.
bare metal stents. Patency rates are influenced by the severity and
length of pretreatment stenoses; the prognosis of occlusive lesions ■■THROMBOANGIITIS OBLITERANS
is worse than that of nonocclusive stenotic lesions. Endovascular Thromboangiitis obliterans (Buerger’s disease) is an inflammatory
interventions of the infrapoplital, tibial, and peroneal arteries, often occlusive vascular disorder involving small and medium-size arteries
in conjunction with treatment of more proximal lesions, can be used and veins in the distal upper and lower extremities. Cerebral, visceral,
to treat critical limb ischemia and prevent limb loss. and coronary vessels may be affected rarely. This disorder develops
Several operative procedures are available for treating patients most frequently in men <40 years of age. The prevalence is higher in
with aortoiliac and femoral-popliteal artery disease. The preferred Asians and individuals of Eastern European descent. Although the
operative procedure depends on the location and extent of the cause of thromboangiitis obliterans is not known, there is a definite
obstruction(s) and the general medical condition of the patient. relationship to cigarette smoking in patients with this disorder.
Operative procedures for aortoiliac disease include aortobifemoral In the initial stages of thromboangiitis obliterans, polymorpho-
bypass, axillofemoral bypass, femoro-femoral bypass, and aortoiliac nuclear leukocytes infiltrate the walls of the small and medium-size

1926 arteries and veins. The internal elastic lamina is preserved, and a 1 h. Paralysis may occur with severe and persistent ischemia. Physical
cellular, inflammatory thrombus develops in the vascular lumen. As findings include loss of pulses distal to the occlusion, cyanosis or pal-
the disease progresses, mononuclear cells, fibroblasts, and giant cells lor, mottling, decreased skin temperature, muscle stiffening, loss of sen-
replace the neutrophils. Later stages are characterized by perivascular sation, weakness, and/or absent deep tendon reflexes. If acute arterial
fibrosis, organized thrombus, and recanalization. occlusion occurs in the presence of an adequate collateral circulation,
The clinical features of thromboangiitis obliterans often include a as is often the case in acute graft occlusion, the symptoms and findings
PART 6
triad of claudication of the affected extremity, Raynaud’s phenome- may be less severe. In this situation, the patient complains about an
non, and migratory superficial vein thrombophlebitis. Claudication abrupt decrease in the distance walked before claudication occurs or
usually is confined to the calves and feet or the forearms and hands of modest pain and paresthesia. Pallor and coolness are evident, but
because this disorder primarily affects distal vessels. In the presence of sensory and motor functions generally are preserved. The clinical
severe digital ischemia, trophic nail changes, painful ulcerations, and evaluation includes Doppler assessment of peripheral blood flow. The
gangrene may develop at the tips of the fingers or toes. The physical diagnosis of acute limb ischemia is usually apparent from the clinical
examination shows normal brachial and popliteal pulses but reduced presentation. In most circumstances, MRA, CTA, or catheter-based
or absent radial, ulnar, and/or tibial pulses. MRA, CTA, and conven- arteriography is used to confirm the diagnosis and demonstrate the
tional arteriography are helpful in making the diagnosis. Smooth, location and extent of arterial occlusion.
tapering segmental lesions in the distal vessels are characteristic, as are
collateral vessels at sites of vascular occlusion. Proximal atherosclerotic
disease is usually absent. The diagnosis can be confirmed by excisional TREATMENT
biopsy and pathologic examination of an involved vessel. Acute Limb Ischemia
There is no specific treatment except abstention from tobacco. The
prognosis is worse in individuals who continue to smoke, but results Once the diagnosis is made, the patient should be anticoagulated
are discouraging even in those who stop smoking. Arterial bypass of with intravenous heparin to prevent propagation of the clot and
the larger vessels may be used in selected instances, as well as local recurrent embolism. In cases of severe ischemia of recent onset, par-
debridement, depending on the symptoms and severity of ischemia. ticularly when limb viability is jeopardized, immediate intervention
Antibiotics may be useful; anticoagulants and glucocorticoids are not to ensure reperfusion is indicated. Catheter-directed thrombolysis/
helpful. If these measures fail, amputation may be required. thrombectomy, surgical thromboembolectomy, and arterial bypass
procedures are used to restore blood flow to the ischemic extremity
■■VASCULITIS promptly, particularly when a large proximal vessel is occluded.
Other vasculitides may affect the arteries that supply the upper and Intraarterial thrombolytic therapy with recombinant tissue plas-
lower extremities. Takayasu’s arteritis and giant cell (temporal) arteri- minogen activator, reteplase, or tenecteplase is most effective when
tis are discussed in Chap. 356. acute arterial occlusion is recent (<2 weeks) and caused by a throm-
bus in an atherosclerotic vessel, arterial bypass graft, or occluded
■■ACUTE LIMB ISCHEMIA stent. Thrombolytic therapy is also indicated when the patient’s
Acute limb ischemia occurs when arterial occlusion results in the sud- overall condition contraindicates surgical intervention or when
den cessation of blood flow to an extremity. The severity of ischemia smaller distal vessels are occluded, thus preventing surgical access.
and the viability of the extremity depend on the location and extent of Meticulous observation for hemorrhagic complications is required
the occlusion and the presence and subsequent development of collat- during intraarterial thrombolytic therapy. Another endovascu-
eral blood vessels. Principal causes of acute arterial occlusion include lar approach to thrombus removal is percutaneous mechanical
embolism, thrombus in situ, arterial dissection, and trauma. thrombectomy using devices that employ hydrodynamic forces
The most common sources of arterial emboli are the heart, aorta, and or rotating baskets to fragment and remove the clot. These treat-
large arteries. Cardiac disorders that cause thromboembolism include ments may be used alone but usually are used in conjunction with
atrial fibrillation; acute myocardial infarction; ventricular aneurysm; pharmacologic thrombolysis. Surgical revascularization is preferred
cardiomyopathy; infectious and marantic endocarditis; thrombi asso- when restoration of blood flow must occur within 24 h to prevent
ciated with prosthetic heart valves; and atrial myxoma. Emboli to the limb loss or when symptoms of occlusion have been present for
distal vessels may also originate from proximal sites of atherosclerosis >2 weeks. Amputation is performed when the limb is not viable,
and aneurysms of the aorta and large vessels. Less frequently, an arte-
as characterized by loss of sensation, paralysis, and the absence of
rial occlusion results paradoxically from a venous thrombus that has
Doppler-detected blood flow in both arteries and veins.
entered the systemic circulation via a patent foramen ovale or another
Long-term anticoagulation is indicated when acute limb ischemia
septal defect. Arterial emboli tend to lodge at vessel bifurcations
is caused by cardiac thromboembolism. Emboli resulting from infec-
because the vessel caliber decreases at those sites; in the lower extrem-
tive endocarditis, the presence of prosthetic heart valves, or atrial
ities, emboli lodge most frequently in the femoral artery, followed by
myxoma often require surgical intervention to remove the cause.
the iliac artery, aorta, and popliteal and tibioperoneal arteries.
Acute arterial thrombosis in situ occurs most frequently in athero-
sclerotic vessels at the site of an atherosclerotic plaque or aneurysm and ■■ATHEROEMBOLISM
in arterial bypass grafts. Trauma to an artery may disrupt continuity Atheroembolism is another cause of limb ischemia. In this condition,
of blood flow and cause acute limb ischemia via formation of an acute multiple small deposits of fibrin, platelets, and cholesterol debris
arterial thrombus or by disruption of an artery’s integrity and extrava- embolize from proximal atherosclerotic lesions or aneurysmal sites.
sation of blood. Arterial occlusion may complicate arterial punctures Large protruding aortic atheromas are a source of emboli that may
and placement of catheters; it also may result from arterial dissection lead to limb ischemia, as well as stroke and renal insufficiency. Athero-
if the intimal flap obstructs the artery. Less common causes include embolism may occur after intraarterial procedures. Since atheroemboli
thoracic outlet compression syndrome, which causes subclavian artery to limbs tend to lodge in the small vessels of the muscle and skin
occlusion, and entrapment of the popliteal artery by abnormal place- and may not occlude the large vessels, distal pulses usually remain
ment of the medial head of the gastrocnemius muscle. Polycythemia palpable. Patients complain of acute pain and tenderness at the site of
and hypercoagulable disorders (Chaps. 99 and 112) are also associated embolization. Digital vascular occlusion may result in ischemia and
with acute arterial thrombosis. the “blue toe” syndrome; digital necrosis and gangrene may develop
(Fig. 275-2). Localized areas of tenderness, pallor, and livedo reticularis
■■CLINICAL FEATURES (see below) occur at sites of emboli. Skin or muscle biopsy may demon-
The symptoms of an acute arterial occlusion depend on the location, strate cholesterol crystals.
duration, and severity of the obstruction. Often severe pain, paresthe- Ischemia resulting from atheroemboli is notoriously difficult to
sia, numbness, and coldness develop in the involved extremity within treat. Local foot care and occasionally amputation may be needed to

1927
demonstrate thoracic outlet compression of the subclavian artery.
Neurophysiologic tests such as the electromyogram, nerve conduc-
tion studies, and somatosensory evoked potentials may be abnormal
if the brachial plexus is involved, but the diagnosis of neurogenic

thoracic outlet syndrome is not necessarily excluded if these tests are
normal owing to their low sensitivity.
Most patients can be managed conservatively. They should be
advised to avoid the positions that cause symptoms. Many patients
benefit from shoulder girdle exercises. Surgical procedures such as
removal of the first rib and resection of the scalenus anticus muscle
are necessary occasionally for relief of symptoms or treatment of
ischemia.
■■POPLITEAL ARTERY ENTRAPMENT

Popliteal artery entrapment typically affects young athletic men and
women when the gastrocnemius or popliteus muscle compresses
the popliteal artery and causes intermittent claudication. Thrombo-
sis, embolism, or popliteal artery aneurysm may occur. The pulse
FIGURE 275-2 Atheroembolism causing cyanotic discoloration and impending examination may be normal unless provocative maneuvers such as
necrosis of the toes (“blue toe” syndrome). ankle dorsiflexion and plantar flexion are performed. The diagnosis
is confirmed by duplex ultrasound, CTA, MRA, or conventional angi-
treat necrotic areas. Analgesics are indicated for pain relief. Usually ography. Treatment involves surgical release of the popliteal artery or
neither surgical revascularization procedures nor thrombolytic therapy vascular reconstruction.
is helpful because of the multiplicity, composition, and distal location ■■POPLITEAL ARTERY ANEURYSM
of the emboli. Therapy with antiplatelet drugs and statins improves Popliteal artery aneurysms are the most common peripheral artery
cardiovascular outcome in patients with atherosclerosis, but it is not aneurysms. Approximately 50% are bilateral. Patients with popliteal
established whether either class of drugs prevents recurrent athero- artery aneurysms often have aneurysms of other arteries, especially
embolism. Similarly, it is not known whether anticoagulant therapy is the aorta. The most common clinical presentation is limb ischemia
effective. Surgical intervention to remove or bypass the atherosclerotic secondary to thrombosis or embolism. Rupture occurs less frequently.
vessel or aneurysm that causes the recurrent atheroemboli may be Other complications include compression of the adjacent popliteal vein
necessary. or peroneal nerve. Popliteal artery aneurysm can be detected by palpa-
tion and confirmed by duplex ultrasonography. Repair is indicated for
■■THORACIC OUTLET COMPRESSION SYNDROME
symptomatic aneurysms or when the diameter exceeds 2–3 cm, owing
This is a symptom complex resulting from compression of the neu-
to the risk of thrombosis, embolism, or rupture.
rovascular bundle (artery, vein, or nerves) at the thoracic outlet as it
courses through the neck and shoulder. Cervical ribs, abnormalities of ■■ARTERIOVENOUS FISTULA
the scalenus anticus muscle, proximity of the clavicle to the first rib, Abnormal communications between an artery and a vein, bypassing
or abnormal insertion of the pectoralis minor muscle may compress the capillary bed, may be congenital or acquired. Congenital arte-
the subclavian artery, subclavian vein, and brachial plexus as these riovenous fistulas are a result of persistent embryonic vessels that
structures pass from the thorax to the arm. Depending on the structures fail to differentiate into arteries and veins; they may be associated
affected, thoracic outlet compression syndrome is divided into arterial, with birthmarks, can be located in almost any organ of the body, and
venous, and neurogenic forms. Patients with neurogenic thoracic out- frequently occur in the extremities. Acquired arteriovenous fistulas
let compression may develop shoulder and arm pain, weakness, and either are created to provide vascular access for hemodialysis or occur
paresthesias. Patients with arterial compression may experience clau- as a result of a penetrating injury such as a gunshot or knife wound
dication, Raynaud’s phenomenon, and even ischemic tissue loss and or as complications of arterial catheterization or surgical dissection.
gangrene. Venous compression may cause thrombosis of the subclavian An uncommon cause of arteriovenous fistula is rupture of an arterial
and axillary veins; this is often associated with effort and is referred to aneurysm into a vein.
as Paget-Schroetter syndrome. The clinical features depend on the location and size of the fistula.
Frequently, a pulsatile mass is palpable, and a thrill and a bruit lasting
APPROACH TO THE PATIENT throughout systole and diastole are present over the fistula. With long-
standing fistulas, clinical manifestations of chronic venous insufficiency,
Thoracic Outlet Compression Syndrome including peripheral edema; large, tortuous varicose veins; and stasis
Examination of a patient with arterial thoracic outlet compression pigmentation become apparent because of the high venous pressure.
syndrome is often normal unless provocative maneuvers are per- Evidence of ischemia may occur in the distal portion of the extremity.
formed. Occasionally, distal pulses are decreased or absent and Skin temperature is higher over the arteriovenous fistula. Large arteri-
digital cyanosis and ischemia may be evident. ovenous fistulas may result in an increased cardiac output with conse-
Several maneuvers that support the diagnosis of arterial thoracic quent cardiomegaly and high-output heart failure (Chap. 252).
outlet compression syndrome may be used to precipitate symp- The diagnosis is often evident from the physical examination. Com-
toms, cause a subclavian artery bruit, and diminish arm pulses. pression of a large arteriovenous fistula may cause reflex slowing of the
These maneuvers include the abduction and external rotation test, heart rate (Nicoladoni-Branham sign). Duplex ultrasonography may
in which the affected arm is abducted by 90° and the shoulder is detect an arteriovenous fistula, especially one that affects the femoral
externally rotated; the scalene maneuver (extension of the neck and artery and vein at the site of catheter access. CTA and conventional
rotation of the head to the side of the symptoms); the costoclavicular angiography can confirm the diagnosis and are useful in demonstrat-
maneuver (posterior rotation of shoulders); and the hyperabduction ing the site and size of the arteriovenous fistula.
maneuver (raising the arm 180°). A chest x-ray will indicate the pres- Management of arteriovenous fistulas may involve surgery, radio-
ence of cervical ribs. Duplex ultrasonography, MRA, and contrast therapy, or embolization. Congenital arteriovenous fistulas are often
angiography can be performed during provocative maneuvers to difficult to treat because the communications may be numerous and
extensive, and new communications frequently develop after ligation

1928 of the most obvious ones. Many of these lesions are best treated con-
TABLE 275-1 Classification of Raynaud’s Phenomenon
servatively using elastic support hose to reduce the consequences of Primary or idiopathic Raynaud’s phenomenon
venous hypertension. Occasionally, embolization with autologous
Secondary Raynaud’s phenomenon
material, such as fat or muscle, or with hemostatic agents, such as gela-
Collagen vascular diseases: scleroderma, systemic lupus erythematosus,
tin sponges or silicon spheres, is used to obliterate the fistula. Acquired rheumatoid arthritis, dermatomyositis, polymyositis, mixed connective tissue
arteriovenous fistulas are usually amenable to surgical treatment that
PART 6
disease, Sjögren’s syndrome

involves division or excision of the fistula. Occasionally, autogenous Arterial occlusive diseases: atherosclerosis of the extremities, thromboangiitis
or synthetic grafting is necessary to reestablish continuity of the artery obliterans, acute arterial occlusion, thoracic outlet syndrome
and vein. Pulmonary hypertension
Neurologic disorders: intervertebral disk disease, syringomyelia, spinal cord
■■RAYNAUD’S PHENOMENON
tumors, stroke, poliomyelitis, carpal tunnel syndrome, complex regional pain

Raynaud’s phenomenon is characterized by episodic digital ischemia, syndrome
manifested clinically by the sequential development of digital blanching, Blood dyscrasias: cold agglutinins, cryoglobulinemia, cryofibrinogenemia,
cyanosis, and rubor of the fingers or toes after cold exposure and sub- myeloproliferative disorders, lymphoplasmacytic lymphoma
sequent rewarming. Emotional stress may also precipitate Raynaud’s Trauma: vibration injury, hammer hand syndrome, electric shock, cold injury,
phenomenon. The color changes are usually well demarcated and are typing, piano playing
confined to the fingers or toes. Typically, one or more digits will appear Drugs and toxins: ergot derivatives, methysergide, β-adrenergic receptor
white when the patient is exposed to a cold environment or touches a blockers, bleomycin, vinblastine, cisplatin, gemcitabine, vinyl chloride
cold object (Fig. 275-3A). The blanching, or pallor, represents the ische-
mic phase of the phenomenon and results from vasospasm of digital
arteries. During the ischemic phase, capillaries and venules dilate, and Raynaud’s phenomenon is broadly separated into two categories:
cyanosis results from the deoxygenated blood that is present in these idiopathic, termed primary Raynaud’s phenomenon, and secondary
vessels. A sensation of cold or numbness or paresthesia of the digits Raynaud’s phenomenon, which is associated with other disease states
often accompanies the phases of pallor and cyanosis. or known causes of vasospasm (Table 275-1).
With rewarming, the digital vasospasm resolves, and blood flow
into the dilated arterioles and capillaries increases dramatically. Primary Raynaud’s Phenomenon This appellation is applied
This “reactive hyperemia” imparts a bright red color to the digits. In when the secondary causes of Raynaud’s phenomenon have been
addition to rubor and warmth, patients often experience a throbbing, excluded. Over 50% of patients with Raynaud’s phenomenon have the
painful sensation during the hyperemic phase. Although the triphasic primary form. Women are affected about five times more often than
color response is typical of Raynaud’s phenomenon, some patients may men, and the age of presentation is usually between 20 and 40 years.
develop only pallor and cyanosis; others may experience only cyanosis. The fingers are involved more frequently than the toes. Initial episodes
A B C
D E F
FIGURE 275-3 Vascular diseases associated with temperature: A. Raynaud’s phenomenon; B. acrocyanosis; C. livedo reticularis; D. pernio; E. erythromelalgia; and
F. frostbite.

may involve only one or two fingertips, but subsequent attacks may receptor antagonists, and the chemotherapeutic agents bleomycin, 1929
involve the entire finger and may include all the fingers. The toes are vinblastine, cisplatin, and gemcitabine.
affected in 40% of patients. Although vasospasm of the toes usually
occurs in patients with symptoms in the fingers, it may happen alone. TREATMENT
Rarely, the earlobes, the tip of the nose, tongue, nipple, or penis are

involved. Raynaud’s phenomenon occurs frequently in patients who Raynaud’s Phenomenon
also have migraine headaches or variant angina. These associations
Most patients with Raynaud’s phenomenon experience only mild
suggest that there may be a common predisposing cause for the
and infrequent episodes. These patients need reassurance and
vasospasm.
should be instructed to dress warmly and avoid unnecessary cold
Results of physical examination are often entirely normal; the radial,
exposure. In addition to gloves and mittens, patients should pro-
ulnar, and pedal pulses are normal. The fingers and toes may be cool
tect the trunk, head, and feet with warm clothing to prevent cold-
between attacks and may perspire excessively. Nailfold capillaroscopy
induced reflex vasoconstriction. Tobacco use is contraindicated.
reveals normal superficial capillaries, which appear as regularly spaced Drug treatment should be reserved for severe cases. Dihydro-
hairpin loops. Thickening and tightening of the digital subcutaneous pyridine calcium channel antagonists such as nifedipine, isradipine,
tissue (sclerodactyly) develop in 10% of patients. Angiography of the felodipine, and amlodipine decrease the frequency and severity
digits for diagnostic purposes is not indicated. of Raynaud’s phenomenon. Diltiazem may be considered but is
In general, patients with primary Raynaud’s disease have milder less effective. The postsynaptic α1-adrenergic antagonist prazosin
clinical manifestations. Fewer than 1% of these patients lose a part of a has been used with favorable responses; doxazosin and terazosin
digit. After the diagnosis is made, the disease improves spontaneously may also be effective. Phosphodiesterase type 5 inhibitors such
in ~15% of patients and progresses in about 30%. as sildenafil, tadalafil, and vardenafil may improve symptoms in
Secondary Causes of Raynaud’s Phenomenon Raynaud’s patients with secondary Raynaud’s phenomenon, as occurs with
phenomenon occurs in 80–90% of patients with systemic sclerosis systemic sclerosis. There is limited evidence that topical nitroglyc-
(scleroderma) and is the presenting symptom in 30% (Chap. 353). It erin preparations are effective. Digital sympathectomy is helpful in
may be the only symptom of scleroderma for many years. Abnor- some patients who are unresponsive to medical therapy. Injection
malities of the digital vessels may contribute to the development of of botulinum toxin into the perivascular tissue of the wrist or palm
Raynaud’s phenomenon in this disorder. Ischemic fingertip ulcers may improved ischemic manifestations of severe Raynaud’s phenome-
develop and progress to gangrene and autoamputation. About 20% non in case series, but controlled clinical trials are lacking.
of patients with systemic lupus erythematosus (SLE) have Raynaud’s
phenomenon (Chap. 349). Occasionally, persistent digital ischemia ■■ACROCYANOSIS
develops and may result in ulcers or gangrene. In most severe cases, In this condition, there is arterial vasoconstriction and secondary dila-
the small vessels are occluded by a proliferative endarteritis. Ray- tion of the capillaries and venules with resulting persistent cyanosis of
naud’s phenomenon occurs in about 30% of patients with dermatomy- the hands and, less frequently, the feet. Cyanosis may be intensified by
ositis or polymyositis (Chap. 358). It frequently develops in patients exposure to a cold environment. Acrocyanosis may be categorized as
with rheumatoid arthritis and may be related to the intimal prolifera- primary or secondary to an underlying condition. In primary acrocyano-
tion that occurs in the digital arteries. sis, women are affected much more frequently than men, and the age of
Atherosclerosis of the extremities is a common cause of Raynaud’s onset is usually <30 years. Generally, patients are asymptomatic but seek
phenomenon in men aged >50 years. Thromboangiitis obliterans is an medical attention because of the discoloration. The prognosis is favor-
uncommon cause of Raynaud’s phenomenon but should be considered able, and pain, ulcers, and gangrene do not occur. Examination reveals
in young men, particularly those who are cigarette smokers. The devel- normal pulses, peripheral cyanosis, and moist palms (Fig. 275-3B).
opment of cold-induced pallor in these disorders may be confined to Trophic skin changes and ulcerations do not occur. The disorder can
one or two digits of the involved extremity. Occasionally, Raynaud’s be distinguished from Raynaud’s phenomenon because it is persistent
phenomenon may follow acute occlusion of large and medium-sized and not episodic, the discoloration extends proximally from the digits,
arteries by a thrombus or embolus. Embolization of atheroembolic and blanching does not occur. Ischemia secondary to arterial occlusive
debris may cause digital ischemia. The latter situation often involves disease can usually be excluded by the presence of normal pulses. Cen-
one or two digits and should not be confused with Raynaud’s phe- tral cyanosis and decreased arterial oxygen saturation are not present.
nomenon. In patients with thoracic outlet compression syndrome, Patients should be reassured and advised to dress warmly and avoid
Raynaud’s phenomenon may result from diminished intravascular cold exposure. Pharmacologic intervention is not indicated.
pressure, stimulation of sympathetic fibers in the brachial plexus, or a Secondary acrocyanosis may result from hypoxemia, vasopressor
combination of both. Raynaud’s phenomenon occurs in patients with medications, connective tissue diseases, atheroembolism, antiphospho-
primary pulmonary hypertension (Chap. 277); this is more than coin- lipid antibodies, cold agglutinins, or cryoglobulins and is associated
cidental and may reflect a neurohumoral abnormality that affects both with anorexia nervosa and postural orthostatic tachycardia syndrome.
the pulmonary and digital circulations. Treatment should be directed at the underlying disorder.
A variety of blood dyscrasias may be associated with Raynaud’s
phenomenon. Cold-induced precipitation of plasma proteins, hyper- ■■LIVEDO RETICULARIS
viscosity, and aggregation of red cells and platelets may occur in In this condition, localized areas of the extremities develop a mottled or
patients with cold agglutinins, cryoglobulinemia, or cryofibrinogen- rete (netlike) appearance of reddish to blue discoloration (Fig. 275-3C).
emia. Hyperviscosity syndromes that accompany myeloprolifera- The mottled appearance may be more prominent after cold exposure.
tive disorders and lymphoplasmacytic lymphoma (Waldenström’s There are primary and secondary forms of livedo reticularis. The pri-
macroglobulinemia) should also be considered in the initial evaluation mary, or idiopathic, form of this disorder may be benign or associated
of patients with Raynaud’s phenomenon. with ulcerations. The benign form occurs more frequently in women
Raynaud’s phenomenon occurs often in patients whose vocations than in men, and the most common age of onset is the third decade.
require the use of vibrating hand tools, such as chain saws or jack- Patients with the benign form are usually asymptomatic and seek
hammers. The frequency of Raynaud’s phenomenon also seems to be attention for cosmetic reasons. These patients should be reassured and
increased in pianists and keyboard operators. Electric shock injury to advised to avoid cold environments. No drug treatment is indicated.
the hands or frostbite may lead to the later development of Raynaud’s Primary livedo reticularis with ulceration is also called atrophie blanche
phenomenon. en plaque. The ulcers are painful and may take months to heal. Second-
Several drugs have been causally implicated in Raynaud’s phenom- ary livedo reticularis can occur with atheroembolism (see above), SLE
enon. They include ergot preparations, methysergide, β-adrenergic and other vasculitides, antiphospholipid antibodies, hyperviscosity,

1930 cryoglobulinemia, and Sneddon’s syndrome (ischemic stroke and Kullo IJ, Rooke TW: Peripheral artery disease. N Engl J Med 374:861,
livedo reticularis). Rarely, skin ulcerations develop. 2016.
Olin JW et al: Fibromuscular dysplasia: State of the science and critical
■■PERNIO (CHILBLAINS) unanswered questions: A Scientific Statement from the American
Pernio is a vasculitic disorder associated with exposure to cold; acute Heart Association. Circulation 129:1048, 2014.
forms have been described. Raised erythematous lesions develop on Thukkani AK, Kinlay S: Endovascular intervention for peripheral
PART 6
the lower part of the legs and feet in cold weather (Fig. 275-3D). They artery disease. Circ Res 116:1599, 2015.
are associated with pruritus and a burning sensation, and they may Vartanian SM, Conte MS: Surgical intervention for peripheral arte-
blister and ulcerate. Pathologic examination demonstrates angiitis rial disease. Circ Res 116:1614, 2015.
characterized by intimal proliferation and perivascular infiltration of Wigley FM, Flavahan NA: Raynaud’s Phenomenon. N Engl J Med
mononuclear and polymorphonuclear leukocytes. Giant cells may be
375:556, 2016.
present in the subcutaneous tissue. Patients should avoid exposure
to cold, and ulcers should be kept clean and protected with sterile
dressings. Sympatholytic drugs and dihydropyridine calcium channel
antagonists may be effective in some patients.
■■ERYTHROMELALGIA
276 and
This disorder is characterized by burning pain and erythema of the
extremities (Fig. 275-3E). The feet are involved more frequently than Chronic Venous Disease
the hands, and males are affected more frequently than females. Ery-
thromelalgia may occur at any age but is most common in middle age. Lymphedema
It may be primary (also termed erythermalgia) or secondary. Mutations
Mark A. Creager, Joseph Loscalzo
in the SCN9A gene, which encodes the Nav1.7 voltage-gated sodium
channel expressed in sensory and sympathetic nerves, has been
described in inherited forms of erythromelalgia. The most common
causes of secondary erythromelalgia are myeloproliferative disorders ■■CHRONIC VENOUS DISEASE
such as polycythemia vera and essential thrombocytosis. Less common Chronic venous diseases range from telangiectasias and reticular
causes include drugs, such as calcium channel blockers, bromocriptine, veins, to varicose veins, to chronic venous insufficiency with edema,
and pergolide; neuropathies; connective tissue diseases such as SLE; skin changes, and ulceration. This section of the chapter will focus
and paraneoplastic syndromes. Patients complain of burning in the on identification and treatment of varicose veins and chronic venous
extremities that is precipitated by exposure to a warm environment insufficiency, since these problems are encountered frequently by the
and aggravated by a dependent position. The symptoms are relieved internist. The estimated prevalence of varicose veins in the United
by exposing the affected area to cool air or water or by elevation. Ery- States is ~15% in men and 30% in women. Chronic venous insufficiency
thromelalgia can be distinguished from ischemia secondary to periph- with edema affects ~7.5% of men and 5% of women, and the prevalence
eral arterial disorders because the peripheral pulses are present. There increases with age ranging from 2% among those <50 years of age
is no specific treatment; aspirin may produce relief in patients with to 10% of those 70 years of age. Approximately 20% of patients with
erythromelalgia secondary to myeloproliferative disease. Treatment chronic venous insufficiency develop venous ulcers.
of associated disorders in secondary erythromelalgia may be helpful.
■■VENOUS ANATOMY
■■FROSTBITE Veins in the extremities can be broadly classified as either superficial
In this condition, tissue damage results from severe environmental or deep. The superficial veins are located between the skin and deep
cold exposure or from direct contact with a very cold object. Tissue fascia. In the legs, these include the great and small saphenous veins
injury results from both freezing and vasoconstriction. Frostbite usu- and their tributaries. The great saphenous vein is the longest vein in the
ally affects the distal aspects of the extremities or exposed parts of body. It originates on the medial side of the foot and ascends anterior
the face, such as the ears, nose, chin, and cheeks. Superficial frostbite to the medial malleolus and then along the medial side of the calf and
involves the skin and subcutaneous tissue. Patients experience pain or thigh, and drains into the common femoral vein. The small saphenous
paresthesia, and the skin appears white and waxy. After rewarming, vein originates on the dorsolateral aspect of the foot, ascends posterior
there is cyanosis and erythema, wheal-and-flare formation, edema, and to the lateral malleolus and along the posterolateral aspect of the calf,
superficial blisters. Deep frostbite involves muscle, nerves, and deeper and drains into the popliteal vein. The deep veins of the leg accom-
blood vessels. It may result in edema of the hand or foot, vesicles and pany the major arteries. There are usually paired peroneal, anterior
bullae, tissue necrosis, and gangrene (Fig. 275-3F). tibial, and posterior tibial veins in the calf, which converge to form the
Initial treatment is rewarming, performed in an environment popliteal vein. Soleal tributary veins drain into the posterior tibial or
where reexposure to freezing conditions will not occur. Rewarming peroneal veins, and gastrocnemius tributary veins drain into the pop-
is accomplished by immersion of the affected part in a water bath at liteal vein. The popliteal vein ascends in the thigh as the femoral vein.
temperatures of 40°–44°C (104°–111°F). Massage, application of ice The confluence of the femoral vein and deep femoral vein form the
water, and extreme heat are contraindicated. The injured area should common femoral vein, which ascends in the pelvis as the external iliac
be cleansed with soap or antiseptic, and sterile dressings should be and then common iliac vein, which converges with the contralateral
applied. Analgesics are often required during rewarming. Antibiotics common iliac vein at the inferior vena cava. Perforating veins connect
are used if there is evidence of infection. The efficacy of sympathetic the superficial and deep systems in the legs at multiple locations, nor-
blocking drugs is not established. After recovery, the affected extremity mally allowing blood to flow from the superficial to deep veins. In the
may exhibit increased sensitivity to cold. arms, the superficial veins include the basilic, cephalic, and median
■■FURTHER READING cubital veins and their tributaries. The basilic and cephalic veins course
Bonaca MP, Creager MA: Pharmacological treatment and current along the medial and lateral aspects of the arm, respectively, and these
management of peripheral artery disease. Circ Res 116:1579, 2015. are connected via the median cubital vein in the antecubital fossa.
Creager MA et al: Acute limb ischemia. N Engl J Med 366:2198, 2012. The deep veins of the arms accompany the major arteries and include
Gerhard-Herman MD et al: 2016 AHA/ACC guideline on the man- the radial, ulnar, brachial, axillary, and subclavian veins. The subcla-
agement of patients with lower extremity peripheral artery disease: vian vein converges with the internal jugular vein to form the bra-
A report of the American College of Cardiology/American Heart chiocephalic vein, which joins the contralateral brachiocephalic vein to
Association Task Force on Clinical Practice Guidelines. Circulation form the superior vena cava. Bicuspid valves are present throughout
135:e726, 2017. the venous system to direct the flow of venous blood centrally.

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1850 pericardial effusions.

in the average age of the world’s population. With urbanization in

are both increasing rapidly, so that in analyses of the global burden of

267 Ischemic Heart Disease

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CHAPTER 267 Ischemic Heart Disease

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Repetitive/progressive manifestations of ischemia

Regional wall motion

Decreased segmental perfusion

Altered metabolism/abnormal ST segment

Decreased subendocardial perfusion

Endothelial and microvascular dysfunction

Near term Prolonged

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CHAPTER 267 Ischemic Heart Disease

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CHAPTER 267 Ischemic Heart Disease

Evaluation of the patient with known or suspected IHD

Possible indications for stress testing of patient:

Can patient exercise adequately?

Are confounding features

Perform treadmill An imaging study

Nuclear Cardiac Cardiac

ECG ECHO MIBI CMR PET

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FIGURE 267-3 (Continued)

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CHAPTER 267 Ischemic Heart Disease

HEALTHY, DEPENDENT ON AGE, ACTIVITY

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CHAPTER 267 Ischemic Heart Disease

TABLE 267-3 Energy Requirements for Some Common Activities

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generally very poor, and a conscientious physician must not under-

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CHAPTER 267 Ischemic Heart Disease

Harrisons_20e_Part6_p1649-p1942.indd 1861 6/1/18 12:54 PM

reflex tachycardia, methemoglobinemia adrenergic blockers, calcium-channel

impotence, masked signs of decompensated heart failure,

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CHAPTER 267 Ischemic Heart Disease

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be detected by using radionuclide scans of myocardial perfusion and

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CHAPTER 267 Ischemic Heart Disease

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Low likelihood High likelihood

4. Diagnosis Non-cardiac UA Other NSTEMI STEMI

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Plaque erosion Calcified nodule

Symptoms suggestive of ACS

Noncardiac diagnosis Chronic stable angina Possible ACS Definite ACS

Treatment as indicated See Chap. 267 No ST-segment ST-segment

Observe 12 h or more Nondiagnostic ECG ST- and/or T-

Stress study to provoke ischemia See Chap. 269

Negative Positive Admit to hospital