International Journal of

Clinical Cardiology & Research

Review Article

Micro Vascular and Macro Vascular Disease in

Systemic Hypertension: The Role of Cardiac Imaging
and Nitric Oxide Synthase Gene Polymorphism -
Galal E Nagib Elkilany1*, Abeer Saeed Ghobashi2, Jan Fedacko3, Mai
Salama4, Jaipaul Singh5, Sherif Baath Allah6, Mohammed Elmahal7,
Adel H Allam8, Ahmad Adham Raafat9 and Hani Aiash10
1,4
Professor and Consultant of Cardiology (SCU), Tanta University, Egypt
2
Professor of Radio-Diagnosis, Tanta University, Egypt
3
Kosice Medical University, Slovakia
5
School of Forensic and Applied Sciences, University of Central Lancashire, Preston, UK
6
RAK Medical and Masafi Hospital; Health Science University, UAE
7
London University and Masafi Hospital, UAE
8
Professor of Cardiology, AL-Azhar University, Egypt
9
Alexandria University, Alexandria, Egypt
10
SUNY Upstate Medical University, Syracuse, NY, USA

*Address for Correspondence: Galal Eldin Nagib Elkilany, Professor of Cardiology-SCU and Consultant
of Cardiology at Tanta University, ARE, 132 Holly Drive, LaPlace, LA , 70068 , USA, Professor and
Consultant of Cardiology - SCU and at Tanta University , ARE , Kings College Hospital London , Dubai
, UAE and Emirates International Hospital , Sharjah, UAE, Tel: 973-981-7875; ORCID ID: https://orcid.
org/0000-0001-8327-7862; E-mail:

Submitted: 21 January 2020; Approved: 11 February 2020; Published: 13 February 2020

Cite this article: Nagib Elkilany GE, Ghobashi AS, Fedacko J, Salama M, Singh J, et al. Micro
Vascular and Macro Vascular Disease in Systemic Hypertension: The Role of Cardiac Imaging and
Nitric Oxide Synthase Gene Polymorphism. Int J Clin Cardiol Res. 2020;4(1): 001-008.

Copyright: © 2020 Nagib Elkilany GE, et al. This is an open access article distributed under
the Creative Commons Attribution License, which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly cited.

ISSN: 2639-3786
 International Journal of Clinical Cardiology & Research

ABSTRACT
Systemic Hypertension (HTN) accounts for the largest amount of attributable Cardiovascular (CV) mortality worldwide. There are
several factors responsible for the development of HTN and its CV complications. Multicenter trials revealed that risk factors responsible
for Micro Vascular Disease (MVD) are similar for those attributable to Coronary Artery Disease (CAD) which include tobacco use,
unhealthy cholesterol levels, HTN, obesity and overweight, physical inactivity, unhealthy diet, diabetes, insulin resistance, increasing age
and genetic predisposition. In addition, the defective release of Nitric Oxide (NO) could be a putative candidate for HTN and MVD. This
study reviewed the risk stratification of hypertensive population employing cardiac imaging modalities which are of crucial importance
in diagnosis. It further emphasized the proper used of cardiac imaging to determine patients at increased CV risk and identify the
management strategy. It is now known that NO has an important effect on blood pressure, and the basal release of endothelial Nitric Oxide
(eNOS) in HTN may be reduced. Although there are different forms of eNOS gene allele, there is no solid data revealing the potential role
of the polymorphism of the eNOS in patients with HTN and coronary vascular diseases. In the present article, the prevalence of eNOS
G298 allele in hypertensive patients with micro vascular angina will be demonstrated.
This review provides an update on appropriate and justified use of non-invasive imaging tests in hypertensive patients and its
important role in proper diagnosis of MVD and CAD. Second, eNOS gene allele and its relation to essential hypertension and angina
pectoris are also highlighted.
Keywords: Systemic hypertension; Cardiac imaging; Coronary artery disease; Micro vascular disease; Nitric oxide synthase gene
allele

INTRODUCTION variety of other potential physiologic mechanisms to play a causal role

in the pathogenesis of hypertension. There are changes in the arterial
Hereditary factors contributed directly to the occurrence wall in patients with hyperinsulinemia, and characteristic decreases
of hypertension, as evidenced by family studies showing that in elasticity of the arterial wall have been noted in hypertensive
premature onset of hypertension among first degree relatives patients with insulin resistance. Hyperglycemia, hyperinsulinemia,
yielded a remarkable high risk of 3.8 times to develop this disorder and hypertriglyceridemia appear to jointly contribute to increased
[1]. However, it remains unclear how many genes or which genetic arterial stiffness. There are, however, ethnic and racial disparities
determinants might constitute such hereditary background. The in the association of insulin, insulin sensitivity, and blood pressure,
gene encoding endothelial Nitric Oxide Synthase (eNOS) is regarded as this relation is not strongly observed in the black population in
as one of the potentially logical candidate for hypertension, since
the United States and elsewhere. This may reflect complex relations
its enhanced production or enzyme bioavailability can lead to the
among obesity, diabetes, and hypertension, which are more common
constitutive release of nitric oxide in endothelial cells, which exerts
in patients with African ancestry [6].
vaso protective effects in Blood Pressure (BP) regulation [2].
Pathogenesis mechanisms
The clinical cluster of typical anginal chest pain, a positive
response to stress testing and angiographically normal coronary The mechanisms underlying angina pectoris in essential arterial
arteries is relatively common in patients with systemic hypertension. Hypertension Patients (HTN) without obstructive Coronary
Functional and structural mechanisms affecting the coronary Artery Disease (CAD) are still largely unknown. Several functional
microcirculation are often responsible for micro vascular angina in pathophysiological abnormalities have been reported in these patients
patients with hypertension. and have been postulated to represent the pathogenic basis for angina
in these patients, including endothelial dysfunction, increased
Capillary rarefaction and left ventricular hypertrophy are common
sympathetic tone, micro vascular spasm, estrogen deficiency,
structural abnormalities responsible for micro vascular dysfunction
psychological disorders, and increased pain sensitivity. Furthermore,
in hypertension. The higher prevalence of micro vascular angina in
women than in men, and its relation to menopausal status have led hypertensive patients have a higher likelihood of presenting with
to the suggestion that estrogen deficiency may play a pathogenic role features of the metabolic syndrome, e.g., hypertension, dyslipidemia,
in the subgroup of peri- and post-menopausal women with angina obesity and insulin resistance, compared with the general population
and hypertension [3,4]. Similar considerations also apply to arterial (30% versus 8%, respectively) [6,7]. This occurs more frequently in
hypertension, the incidence of which increases greatly in women postmenopausal women. Insulin resistance, therefore, may represent
after the menopause. The link between estrogen deficiency and the an important mechanism for vascular dysfunction in this setting [8].
development of micro vascular angina and hypertension is complex Structural abnormalities are also important, i.e., capillary rarefaction
and includes abnormal endothelial function, altered autonomic [9] as well as medial hypertrophy and/or fibrosis of arteriolar vessels.
nervous system responses and the activation of the Renin Angiotensin Myocardial ischemia triggered by functional and/or anatomical
Aldosterone System (RAAS) [4]. abnormalities in the coronary microcirculation has been documented
in many studies using radionuclide Myocardial Perfusion Imaging
Patients with HTN and micro vascular angina [4,5] often show (MPI) techniques as well as stress induced alterations of cardiac high
slow flow and tortuous coronary arteries, suggestive of small vessel energy phosphate, as assessed by magnetic resonance spectrometry
“obstruction”. Moreover, there is a complex relation among insulin [10,11].
sensitivity, hypertension, and endothelial function. Although there
are few prospective data on the relation between insulin levels and In summary, both coronary micro vascular spasm and/or a
the development of hypertension, there is some evidence that insulin reduced micro vascular vasodilator capacity have been demonstrated
resistance precedes the onset of established hypertension in high risk to cause myocardial ischemia and anginal symptoms in patients with
patients. Because insulin is a vasodilator, it would need to activate a hypertension and micro vascular angina.

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 International Journal of Clinical Cardiology & Research

The pivotal role of endothelial Nitric Oxide Gene (eNOS) reduced coronary flow response to acetylcholine or atrial pacing
Allele and by inappropriate endothelial vasoconstrictor activity, mainly
mediated by Endothelin-1 (ET-1) production [10]. Both coronary
Although there are many genes responsible for the development
and peripheral micro- vascular dysfunction have been demonstrated
of HTN and different polymorphisms of eNOS gene, we observed
in hypertensive patients with chest pain, normal appearing coronary
an important polymorphism of eNOS gene since 2004. In this study,
angiograms, and no left ventricular hypertrophy by echocardiography.
Myocardial Perfusion Imaging (MPI) and coronary angiography was
Angina may occur in patients with arterial hypertension in the
performed for 60 consecutive hypertensive patients complaining of
absence of epicardial coronary artery disease due to an abnormally
chest pain, whom are admitted at our critical care department at
elevated resistance of the coronary microvasculature [4,13].
Tanta University Hospital11. We revealed that 15 patients had chest
pain with true ischemia and reversible myocardial perfusion defects Microvascular function and structure are generally considered to
(multiple and mild) but normal epicardial coronary arteries (micro be the consequence of high blood pressure levels, there is evidence
vascular angina), while 15 patients had significant CAD, and 20 that micro vascular changes, i.e., capillary rarefaction, and endothelial
hypertensive patients showed normal perfusion scan and coronary dysfunction may anticipate the clinical onset of arterial hypertension.
angiography. In conclusion; this study revealed that, the prevalence This is supported by the finding of decreased capillary density in
of the NOS G298 allele was higher in the hypertensive group with borderline hypertensive subjects and even in the normotensive
microvascular angina (documented by MPI) than it was among the offspring of hypertensive parents as well as the presence of endothelial
control participants (p < 0.005). In addition, we found that eNOS dysfunction in the normotensive offspring of hypertensive patients
allele was significantly higher in the hypertensive group than in [13].
the control participants, but there was no significant difference in
Hypertension and coronary artery disease (Macro
homozygote mutants among hypertensive participants, x-syndrome
Vascular Disease)
and patients with CAD [11] (figure 1).
High blood pressure is a major modifiable risk factor for all clinical
Similarly, a recent meta-analyze of three eNOS widely evaluated
manifestations of Coronary Artery Disease (CAD). In people without
polymorphisms was demonstrated and they include G894T
known cardiovascular disease, the lowest systolic (down to 90-114
(rs1799983) in exon 7, 4b/a in intron 4, and T2786C (rs2070744)
mmHg) and the lowest diastolic (down to 60-74 mmHg) pressures
in promoter region, in association with hypertension from both
are associated with the lowest risk for developing CAD. Although
English and Chinese publications, while addressing between
diastolic blood pressure is the strongest predictor of CAD in younger
study heterogeneity and publication bias [12]. The investigators
and middle aged people, this relationship becomes inverted and pulse
of this meta-analysis, ascertained the role of eNOS G894T and
pressure shows the strongest direct relationship with CAD in people
4b/a polymorphisms on hypertension in Asians, and T2786C
above 60 years of age [14].
polymorphism in white population [12].
Pathophysiological mechanisms of blood pressure as a risk factor
Micro vascular disease in systemic hypertension
for CAD are complex and include the influence of blood pressure as a
Patients with systemic hypertension often experience chest pain physical force on the development of the atherosclerotic plaque, and
despite the absence of obstructive coronary artery disease, which is the relationship between pulsatile hemodynamics/arterial stiffness
caused by coronary micro vascular dysfunction. Structural coronary and coronary perfusion. Treatment of arterial hypertension has been
micro vascular abnormalities such as capillary rarefaction and proven to prevent coronary events in patients without clinical CAD.
functional mechanisms such as endothelial dysfunction are common Recent studies suggest that a lower systolic blood pressure may be
causes for the development of angina pectoris in hypertensive appropriate, whereas caution is advised with diastolic blood pressure
individuals [13]. below 60 mmHg [14].
The presence of endothelial dysfunction in patients with The risk of CAD events in hypertensive patients further increase
hypertension and microvascular angina has been suggested by a in the presence of dyslipidemia. High cholesterol level, the major
modifiable risk factor for heart disease, has both an environmental
as well as a genetic component (mutations in the LDL receptor,
80 76.7
ApoB, PCSK9, and ApoE genes) [15]. Familial Hypercholesterolemia
80 73.3
68 (FH) is characterized by isolated elevation of plasma low density
60 55 lipoprotein cholesterol and is associated with high risk of premature
cardiovascular disease. Premature CAD in the presence of
40 hypercholesterolemia might be due to an unhealthy lifestyle alone or
%

due to genetic factors in combination with an unhealthy lifestyle [15].

20 10
Atherosclerosis in the eras of ancient Egypt
0
Definite or probable atherosclerosis was present in mummies
who lived during virtually every era of ancient Egypt, which
published recently in JACC as the “Horus study” [16], a time span
Figure 1: Diagrams showing the frequency of mutation among studied groups:
of 2,000 years. The investigators performed whole body, Multi Slice
Nitric oxide synthase gene G298 allele: Is it a marker of microvascular angina Computed Tomography Scanning (MSCT) on 52 ancient Egyptian
in hypertensive population? Abbreviations: Co (control), Hy (Hypertension), mummies from the Middle Kingdom to the Greco Roman period
X-(X-Syndrome / microvascular disease), CAD (Coronary Artery Disease), to identify cardiovascular structures and arterial calcifications. The
IHD (Ischemic Heart Disease) and Tot (Total) (Taken from reference 11). estimated age at the time of death was measured from the computed

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 International Journal of Clinical Cardiology & Research

tomography skeletal evaluation. Adel Alam, et al. [16] reported change of HTN. Probably, repetitive ischemic insults due to macro-
forty-four of 52 mummies had identifiable Cardiovascular (CV) vascular and micro-vascular abnormalities and interstitial fibrosis
structures, and 20 of these had either definite atherosclerosis (defined cause an early intrinsic depression of subendocardial longitudinal
as calcification within the wall of an identifiable artery, n = 12) or fiber contractility in these patients, especially in those who have
probable atherosclerosis (defined as calcifications along the expected hypertrophic hearts. For this reason, longitudinal myocardial
course of an artery). Calcifications were found in the aorta as well as performance is impaired at an early stage in patients with HTN. In
the coronary, carotid, iliac, femoral, and peripheral leg arteries. The addition, in the first stage of the disease the sparing of circumferential
20 mummies with definite or probable atherosclerosis were older at fibers results in Ejection Fraction (EF) remaining within the normal
time of death (mean age 45.1 +/- 9.2 years) than the mummies with range [17] (Figure 3).
CV tissue but no atherosclerosis (mean age 34.5 +/- 11.8 years, p =
Thus, GLS provides additional information in the evaluation
0.002). Two mummies had evidence of severe arterial atherosclerosis
of LVH and myocardial ischemia in HTN, and regional changes in
with calcifications in virtually every arterial bed. Definite coronary
atherosclerosis was present in 2 mummies, including a princess who
lived between 1550 and 1580 BCE. This finding represents the earliest
documentation of coronary atherosclerosis in a human [16] (Figure
2).
Interestingly, the investigators of Horus study [16] demonstrated
an evidence of atherosclerosis in almost all the dynastic eras of ancient

(A) (B)

Figure 3: A. Systolic strain measured in apical LAX view showing depressed

peak systolic strain and evidence of Post Systolic Shortening (PSS) at mid
and basal segments of posterior lateral LV wall in Acute Coronary Syndrome
(ACS) patient, CAG should evidence of subtotal circumflex coronary artery.
B. Global longitudinal systolic strain STE of HTN patients with normal EF,
Figure 2: Atherosclerosis in Ancient Egyptian Mummies from the ‘Horus although his GLS was depressed (-14%).
Study. Multi-slice CT coronary angiography showed extensive calcification
of right coronary artery and left anterior descending coronary artery, aorta
and iliac arteries in young Egyptian king who died at his 3rd decade of life. longitudinal strain seem to identify specific myocardial deformation
Taken from reference [16] and permission was granted from Dr. Adel Allam, patterns for some forms of myocardial hypertrophy [18]. It is clear
corresponding author of the ‘Horus Study’. nowadays that myocardial fiber mechanical dysfunction precedes
histopathological changes such as fibrosis and hypertrophy in
Egypt. The prevalence of modern day risk factors for atherosclerosis essential hypertension which can be detected in the preclinical stage
in ancient Egypt is challenging to estimate. Tobacco was unavailable, of the disease, through a reduced tissue Doppler derived systolic and
and without modern transportation, an active lifestyle was likely, diastolic velocities and depressed GLS either before or even without
but the incidence of hypertension and diabetes mellitus is unknown. the development of LVH [17-19].
Although the diet of a particular ancient Egyptian with or without Stress imaging studies in HTN patients with suspected
atherosclerosis is difficult to ascertain, hieroglyphic inscriptions CAD
on Egyptian temple walls indicate that beef, sheep, goats, wildfowl,
bread, and cake were regularly consumed suggested that the ancient Myocardial Perfusion Imaging (MPI); Single Photon Emission
Egyptian diet may have been atherogenic (high in saturated fat), Computed Tomography (SPECT); Stress Echocardiography (SE);
particularly among the clergy who consumed the ritual feasts left by Cardiac Magnetic Resonance Imaging (CMR).
families mourning their deceased relatives. Myocardial ischemia ESC guidelines, recommend the search for
Cardiac imaging in systemic hypertension complaining myocardial ischemia in hypertensive patients with suspected history
of chest pain of CAD. Diagnosis of myocardial ischemia in hypertensive patients
is particularly challenging because HTN substantially lowers the
Identification of myocardial ischemia among hypertensive specificity of exercise ECG and perfusion scintigraphy [19,20]. When
population is recommended to reclassify patients who are at risk. exercise ECG is either uninterpretable or ambiguous, an imaging
Non-invasive CV imaging is progressively being used and continues test of inducible ischemia by functional study such as perfusion
to provide new technological opportunities to CAD (Macro vascular) scintigraphy [21], SE [22], or stress CMR [23], is warranted. Among
and micro vascular dysfunction evaluation at early stage. the imaging tests, stress echo has been shown to have higher specificity
Echocardiography and deformation imaging resting but reduced sensitivity compared with SPECT imaging [24]. In
study fact, stress induced wall motion abnormalities are highly specific
for detecting epicardial coronary artery stenosis angiographic ally,
Diabetes and hypertension are two major risk factors which are whereas myocardial perfusion abnormalities are frequently detected
often associated with the impairment of Global Longitudinal Systolic in hypertensive patients with normal coronary arteries and coronary
Strain (GLS), GLS are also common findings in patients with Heart micro vascular disease angiographically (Figure 4,5). Use of dual echo
Failure with Preserved Ejection Fraction (HFpEF) and it is now well imaging of regional wall motion and Coronary Flow Reserve (CFR)
known that Left Ventricular Hypertrophy (LVH) is the key structural (normal values > 2) on left anterior descending artery to distinguish

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 International Journal of Clinical Cardiology & Research

epicardial coronary stenosis from isolated coronary microcirculatory reclassify patient’s risk.
dysfunction (reduced CFR without wall motion abnormalities) has
Although echocardiography and allied techniques (MSCT, CMR,
been proposed. Stress CMR is a valuable option to assess myocardial
MPI) are the second line study in the evaluation of hypertensive
ischemia in HTN patients and should be considered when stress
patients, it gives many clues suggesting poor prognosis associated with
echocardiography is expected to be sub optimal due to poor window
hypertension, including LVH, decreased LV systolic function, impaired
[25]. Figure 5 shows SPECT Myocardial Perfusion Imaging, STE and
LV diastolic function, and increased left atrial size and impaired systolic
CMR.
function. Along with conventional echocardiographic methods, tissue
Doppler imaging, three dimensional echocardiography, SE and GLS
speckle tracking echocardiography are emerging echocardiographic
modalities in the evaluation of hypertensive patients in the current
echocardiographic laboratories. Understanding conventional and
newer echocardiographic parameters is important in the diagnosis
and assessment of cardio vascular risk in hypertensive patients.
Recommendations of echocardiography in the current
hypertension guidelines
(A) (B)
In the 2013, ESH/ESC Guidelines for the management of arterial
hypertension, echocardiography is the second line study based on
Figure 4: A. Stress echocardiography in HTN patient with severe LVH in
medical history, physical examination, and findings from routine
parasternal, apical 4 chamber, apical 2 chambers and apical 3 chambers
views.
laboratory tests [28]. The guidelines recommended performing
B. Myocardial Contrast Echocardiography (MCE) of a patient presented at echocardiographic examination in patients who are suspected
our chest pain unit with acute chest pain without cardiac enzyme biomarkers with having Left Ventricular Hypertrophy (LVH), Left Atrial (LA)
elevation. dilatation, or Concomitant Heart Diseases (CAD).
Advances in echocardiography and CMR techniques over the
last decade have provided new insights into the morphological
and pathophysiological changes associated with Hypertensive
Heart Disease (HHD). Comprehensive assessment of systolic and
diastolic function provides prognostically relevant data. CMR is a
particularly attractive imaging technique, provides the most accurate
and reproducible measures of LV function and mass, and enables
myocardial fibrosis assessment which could identify patients at
(A) (B)
risk of serious cardiac arrhythmias and sudden arrhythmic death.
In addition, CMR is the most reliable means of distinguishing
Figure 5: Diagrams showing longitudinal strain by 3D speckle-tracking
hypertension related LVH from other causes and can also be used to
echocardiography in a patient with acute myocardial infarction on the day PCI
of an occluded LAD followed by late enhancement CRM. Images in (A) show screen for secondary causes of systemic hypertension [29].
endomyocardial scar matching STE and MPI in (B).
Cardiac impact of hypertension therapy LVH regression
LVH represents an important end organ consequence of
MSCT coronary angiography
hypertension. Population based studies using echocardiography
Coronary artery calcium is recognized as an independent have demonstrated hypertrophy to be closely linked with adverse
predictor of CV events and mortality, whereas absence of coronary events [30], including stroke, renal impairment, left ventricular
calcium is associated with a very high negative predictive value [26]. dysfunction, atrial and ventricular arrhythmias, and sudden cardiac
Yet the role for risk stratification of uncomplicated HTN is not well arrhythmia or premature death [31]. The eventual development of
defined. In fact, the inclusion of coronary calcium into prediction complications from LVH represents long term effects that are too
models mainly improves risk stratification of hypertensive patients final to guide clinical therapy, and too slow as a research outcome.
at intermediate risk (SCORE risk between 5 and 10%), whereas little Therefore, LVH has been proposed as a surrogate marker of outcome.
value has been demonstrated in patients at low risk [27].On the other LVH has been shown to be reversed or prevented by a variety of
hand, the limited availability, costs, and radiation exposure (±1 mSv) haemodynamic, non haemodynamic and pharmacological factors
represent substantial limitations to wide spread implementation of [32]. While reductions in the ventricular mass have been associated
coronary calcium evaluation in clinical practice. with improved outcome across populations, in studies which identify
Clinical implications of cardiac imaging on health care regression of hypertrophy on an individual basis, large populations
and “HTN patients” management are required to overcome the variability of these measurements. Thus,
while the association between LVH regression and improved outcome
The correct diagnosis of hypertension and precise assessment of has now been recognized in a number of studies [33]. This role of
cardiovascular risk are essential to give proper treatment in patients echocardiography in accurate detection of LVH and its regression
with hypertension. Risk stratification in HTN patients is of crucial is great and definitely may be improved by the enhancement and
importance to properly manage patients at increasing risk and prevent clinical use of 3DE, which has been validated against CMR [34].
adverse events. A symptomatic involvement of different organs in
HTN patients represents an independent determinant of CV risk and Moreover, LVH occurs in 36-41% of hypertensive subjects [35],
the identification of target organ damage is recommended to further but hypertension is not the only cause of this problem. Hypertrophy

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may be influenced by obesity, diabetes, the metabolic syndrome, with those treated with the beta blocker atenolol (17.7 g/m2 ) [40].
and renal impairment, among other etiologies. Progression of the Finally, despite a 20% incidence of LVH regression with placebo,
condition may lead to ischemia, both due to concurrent CAD as well diuretic therapy with chlorthalidone and hydrochlorthiazide,
as failure of vascular proliferation to match myocardial proliferation, respectively, demonstrated greater LVH regression over alternative
vascular compression, and the effect of raised LV pressure on agents in both the TOMHS (Treatment of Mild Hypertension Study)
subendocardial flow (relative ischemia) or even MVD. Hence, the and Department of Veterans Affairs Cooperative Study Group on
role of non-invasive cardiac imaging is crucial in order to identify the Antihypertensive Agents [41,42].
etiology of myocardial ischemia in such patient’s population.
In summary, echocardiography may be helpful in several scenarios.
Investigation of chest pain symptoms Patients with hypertensive heart disease who become symptomatic
require follow-up echocardiography to evaluate systolic and diastolic
Chest pain in patients with hypertension may signify concurrent
function. Dissociation between blood pressure measurements and LV
CAD or may simply reflect sub endocardial ischemia due to LV
hypertrophy is an indication for further testing. On the other hand,
hypertrophy and increased afterload. The diagnosis of CAD has
stress echocardiography or MPI showed be performed for evaluation
particular challenges in this setting, because ‘false positive’ results may
of the nature of chest pain in hypertensive patients with LVH.
occur when sub endocardial ischemia causes abnormal stress ECG or
myocardial perfusion scan in the absence of flow limiting epicardial Genetic testing in HTN patients
coronary disease [36]. A normal stress electrocardiogram, performed
Studies involving adoptive families and twins have demonstrated
to a high workload, has a high negative predictive value, but an
the genetic basis of hypertension and shown that genetic factors
abnormal or ambiguous test warrants further evaluation. There is
account for about 40% of the variance in blood pressure among
some evidence in favor of preferential use of stress echocardiography
individuals. Arterial hypertension is genetically complex: Multiple
for this purpose, because stress induced wall motion abnormalities
genes influence the blood pressure phenotype through allelic effects
are highly specific for CAD, while perfusion defects (MPI) in
from single genes and gene interactions. Moreover, environmental
hypertensive patients may arise from abnormal myocardial flow
factors also modify the blood pressure phenotype. This complexity
reserve not due to epicardial coronary disease [37].
explains why the identification of the underlying genes has not
Role of echocardiography in decision to initiate treatment been as successful in hypertension as in other diseases (such as type
1 and type 2 diabetes mellitus). The identification of the genetic
Effects of antihypertensive agents on Left Ventricular Mass determinants of hypertension has been most successful in endocrine
(LVM) and other echocardiographic surrogate endpoints (e.g. LA forms of hypertension, which have well defined phenotypes that
size and diastolic function) have been extensively studied. Several permit a precise patient stratification into homogeneous cohorts [43].
large studies sponsored by the National Institutes of Health and the
US Veterans Administration Cooperative Studies program have Research has shown that genetic factors contribute significantly
evaluated the effects of antihypertensive mono therapy. In general, to the susceptibility of developing hypertension [44-47]. A study
it appears likely that there are differences between the efficacy of of Caucasian and African American children revealed the T235
antihypertensive drugs and their effects on LVH. LVH regression allele on the angiotensinogen gene to be more common in African
does not adversely affect cardiac function and may be associated with American children compared to Caucasian. This is meaningful such
improvements in diastolic function. However, although the finding that the T235 allele is positively correlated with increased serum
of increased LVM on echocardiography could potentially guide angiotensinogen levels and hypertension in African American boys
selection of initial or intensity of therapy in hypertensive patients, and girls, when compared to Caucasian children (p < 0.01) [48].
JNC 7 recommendations do not risk stratify patients for treatment on Other groups addressing African Americans have found that Single
the basis of target organ damage. Current guidelines recommend the Nucleotide Polymorphisms (SNPs) on SLC4A5, a sodium bicarbonate
use of combination treatment to get blood pressure to goal, thus blood transporter gene found on chromosome 2, were also significantly
pressure remains the primary target of therapy. A part of the problem associated with hypertension [49,50].
with getting a more central role for echocardiography to guide A promising area for the application of genetic testing to
therapy is that despite the adverse prognosis associated with LVH in personalized medicine is the prediction of responses and adverse
hypertension, there are inconsistent data from numerous studies that reactions to antihypertensive drugs.
have evaluated the comparative efficacy of specific antihypertensive
agents in LVH regression, as well as survival benefits associated CONCLUSION
with LVH regression. In a meta-analysis of trials of antihypertensive Patients with systemic hypertension often experience chest pain
therapy, angiotensin converting enzyme inhibitors were the most despite the absence of obstructive coronary artery disease, which
effective agents, leading to a 13.3% reduction in LVM compared is caused by coronary micro vascular dysfunction. eNOS gene
with 9.3% for calcium channel blockers, 6.8% for diuretics, and 5.5% polymorphism is proved to be an important etiology in micro vascular
for beta blockers [38]. However, in a comparison of Enalapril and angina (x-syndrome) among hypertensive patients. In addition, the
long acting nifedipine in patients with essential hypertension, the eNOS mutant gene showed a significant increase in isolated HPN
PRESERVE (Prospective Randomized Enalapril Study Evaluating and in patients with CAD as well. The major cardiovascular risk
Regression of Ventricular Enlargement) trial, systolic and diastolic factors responsible for small vessel disease (micro-vascular) are
pressures, as well as LVM were reduced to a similar degree with both similar for those attributable to CAD (macro-vascular) in systemic
agents [39]. On the other hand, the LIFE (Losartan Intervention For hypertension. Repetitive ischemic insults in HTN patients due to
Endpoint Reduction in Hypertension) trial echocardiographic sub macro-vascular and micro-vascular abnormalities and interstitial
study demonstrated superior LVM reduction (21.7 g/m2 ) in patients fibrosis can cause an early intrinsic depression of sub endocardial
treated with the angiotensin receptor blocker losartan compared longitudinal fiber contractility and this can be detected clearly non-

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invasively by GLS speckle tracking echocardiography. Similarly, familial hypercholesterolemia. Nature Clin Pract Cardiovasr Med. 2007; 4:
microvascular dysfunction can be demonstrated with great certainty 214-225. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/17380167

by MPI. Currently, non-invasive cardiac imaging is being increasingly 16. Adel H Allam, Randall C Thompson, L Samuel Wann, Michael I Miyamoto,
used, and innovative imaging techniques are on the way that might Abd el Halim Nur el Din, Gomaa Abd el Maksoud, et al. Atherosclerosis in
further refine risk stratification of hypertensive patients and provide ancient Egyptian mummies the horus study. Cardiovasc Imaging: JACC.
opportunities to better target therapeutic strategies. 2011; 4: 315-27. https://bit.ly/2w2N0Dq

17. Todaro MC, Khandheria BK, Longobardo L, Zito C, Cusma Piccione M, Di

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