Thyroid Hormones and CVD

JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY VOL. 71, NO.
16, 2018
ª 2018 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
PUBLISHED BY ELSEVIER
THE PRESENT AND FUTURE
STATE-OF-THE-ART REVIEWS
Thyroid Hormones and

Cardiovascular Function and Diseases
Salman Razvi, MD,a,b Avais Jabbar, MD,a,c Alessandro Pingitore, MD,d Sara Danzi, PHD,e Bernadette Biondi, MD,f
Irwin Klein, MD,g Robin Peeters, MD,h Azfar Zaman, MD,c,i Giorgio Iervasi, MDd
ABSTRACT
Thyroid hormone (TH) receptors are present in the myocardium and vascular tissue, and minor alterations in TH
concentration can affect cardiovascular (CV) physiology. The potential mechanisms that link CV disease with thyroid
dysfunction are endothelial dysfunction, changes in blood pressure, myocardial systolic and diastolic dysfunction,
and dyslipidemia. In addition, cardiac disease itself may lead to alterations in TH concentrations (notably, low
triiodothyronine syndrome) that are associated with higher morbidity and mortality. Experimental data and small
clinical trials have suggested a beneficial role of TH in ameliorating CV disease. The aim of this review is to provide
clinicians dealing with CV conditions with an overview of the current knowledge of TH perturbations in CV disease.
(J Am Coll Cardiol 2018;71:1781–96) © 2018 by the American College of Cardiology Foundation.
D espite major advances in their prevention

and treatment, cardiovascular (CV) dis-
eases remain the single largest cause of
death globally (1). Recurrent ischemia resulting in
Illustration). Patients who are overtly hypo- or hy-
perthyroid show CV and hematologic manifestations
that are well-documented, and both can, if left un-
treated, accelerate the onset of symptomatic CV dis-
adverse CV events following optimal treatment for ease. However, the clinical significance of mild
an acute coronary syndrome occurs in approximately thyroid dysfunction (subclinical thyroid disease) is
10% of subjects in randomized controlled trials (RCTs) uncertain. Minor changes in TH concentration may
(2), and this number nearly doubles in real-world reg- have an adverse impact on the CV system, and sub-
istries (3). The inexorable progress of CV disease, clinical thyroid dysfunction has been associated with
despite optimal guideline-based primary and second- a 20% to 80% increase in vascular morbidity and
ary prevention, suggests a multifactorial etiology and mortality risk (4–6). Observational studies report
the need to assess other precipitants that may exacer- increased adverse CV biomarkers and myocardial
bate existing CV disease. strain in patients with subclinical thyroid disease,
Thyroid hormone (TH) receptors (TRs) are present but, in the absence of mechanistic studies and large
in myocardium and vascular endothelial tissues, RCTs, no cause and effect has been proven. Never-
thereby allowing changes in circulating TH concen- theless, thyroid disease, both overt and subclinical, is
tration to modulate end-organ activity (Central a global burden and associated with increased CV
From the aInstitute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom; bGateshead Health NHS
Listen to this manuscript’s Foundation Trust, Gateshead, United Kingdom; cFreeman Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust,
audio summary by Newcastle upon Tyne, United Kingdom; dClinical Physiology Institute, Consiglio Nazionale dele Ricerche (CNR), Pisa, Italy;
JACC Editor-in-Chief e
Queensborough Community College, The City University of New York, Bayside, New York; fDepartment of Clinical Medicine and
Dr. Valentin Fuster. Surgery, University of Naples Federico II, Naples, Italy; gSchool of Medicine, New York University, New York, New York; hDe-
partment of Internal Medicine, Academic Center for Thyroid Diseases, Erasmus Medical Centre, Rotterdam, the Netherlands; and
the iInstitute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom. Dr. Razvi has received speaker
fees from Merck KGaA and EXCEMED. All other authors have reported that they have no relationships relevant to the contents of
this paper to disclose.
Manuscript received October 22, 2017; revised manuscript received January 26, 2018, accepted February 13, 2018.
ISSN 0735-1097/$36.00 https://doi.org/10.1016/j.jacc.2018.02.045

1782 Razvi et al. JACC VOL. 71, NO. 16, 2018
Thyroid Hormones and the Cardiovascular System APRIL 24, 2018:1781–96
ABBREVIATIONS disease. The wide availability and afford- The contractile apparatus of the cardiac myocyte
AND ACRONYMS ability of treatments for correcting TH contains the myosin heavy chains (MHCs), a and b
dysfunction has led to increased interest in ( a -MHC and b-MHC). a -MHC, the fast myosin, and
AF = atrial fibrillation
exploring the role of TH in CV disease. This b -MHC, the slow myosin, are positively and nega-
AIT = amiodarone-induced
review summarizes the role of TH in CV tively regulated by T3, respectively. Cardiac
thyrotoxicosis
function and diseases. contractility is further regulated by several impor-
AMI = acute myocardial
infarction tant cardiac proteins, including the sarcoplasmic
MOLECULAR AND CELLULAR reticulum calcium adenosine triphosphatase
CV = cardiovascular
MECHANISMS OF TH ACTION (SERCA2) and its inhibiting counterpart phospho-
CHD = coronary heart disease
lamban (PLB). SERCA2 functions to pump calcium
D (1–3) = deiodinase
PHYSIOLOGY OF THYROID FUNCTION. ions (Ca 2þ) back into the sarcoplasmic reticulum in
enzymes (1–3)
Thyroid function is regulated by the the relaxation phase of myofilament contraction.
HF = heart failure
hypothalamic-pituitary-thyroid axis via a SERCA2 is positively regulated by T 3, whereas PLB
LDL = low density lipoprotein
classic endocrine feedback loop mechanism. is negatively regulated. Together, they are respon-
MHC = myosin heavy chain
Thyrotropin-releasing hormone (TRH) is sible for the kinetics of calcium ion influx into (and
PLB = phospholamban secreted at the level of the hypothalamus and subsequent efflux from) the sarcoplasmic reticulum.
rT3 = reverse T3 stimulates the anterior pituitary to produce Efficient calcium sequestration and release is
SCH = subclinical thyroid-stimulating hormone (TSH), which, essential for energetically optimal cardiac myocyte
hypothyroidism
in turn, drives the thyroid gland to release TH. relaxation and contraction. This lusitropic effect of
SERCA = sarcoplasmic TH levels regulate TRH and TSH production
reticulum adenosine
TH is a characteristic of T 3 regulation of myocyte
triphosphatase
and release (7). TSH has a log-linear relation- contractility (9). Decreased calcium cycling in the
ship with thyroxine (T 4 ) levels; therefore, cardiac myocyte has been reported in the impaired
SHyper = subclinical
hyperthyroidism even mild changes in TH concentrations lead diastolic function of hypothyroidism, with aging in
SVR = systemic vascular to large changes in TSH. Thus, serum TSH is a humans, and in experimental models of HF. Other
resistance robust marker of systemic TH status. The 2 important cardiac genes regulated by TH include
T3 = triiodothyronine main iodinated THs are T 4 and triiodothyro- those encoding the TR proteins themselves, the
T4 = thyroxine nine (T 3). Both have biological effects; how- voltage-gated potassium ion (Kþ) channels (Kv1.5
TH = thyroid hormones ever, T 3 is considered the active and more and Kv4.2), and the sodium/calcium ion (Na þ/Ca2þ)
TR = thyroid hormone receptor
potent hormone. The normal negative feed- exchanger (NCX1).
back regulation of thyroid function is dis- In addition to the genomic effects of T3 described
TRH = thyrotropin releasing
hormone rupted by illness, including conditions such previously, TH (both T 4 and T 3) exert nongenomic
TSH = thyrotropin as acute myocardial infarction (AMI) or heart effects on the cardiac myocyte and, as discussed later,
failure (HF), and is characterized by a reduc- on the vasculature. Nongenomic effects are usually
tion in serum TH without a concomitant rise in circu- receptor-independent and largely occur at the plasma
lating TSH levels (termed nonthyroidal illness and membrane, regulating ion transporter activity (10).
further discussed later). With the recognition that TSH Nongenomic mechanisms are identified by their rapid
is extremely sensitive to subtle changes in circulating rate of action. Several ion channels that are transcrip-
TH concentrations, and with the advent of high- tionally regulated by TH are also post-translationally
sensitivity TSH assays, clinicians are able to detect regulated by nongenomic mechanisms. These com-
subtle changes in thyroid function, leading to the bined mechanisms at the level of the atrial myocyte are
concept of subclinical thyroid disease. responsible, in part, for the ability of T3 to increase
TH ACTION ON CARDIAC MYOCYTES. Genomic ef- the heart rate. The other pathway mediating
fects of TH are mediated by TH nuclear receptors the chronotropic effect of thyrotoxicosis relates to
located in the intracellular compartment. The protein the decrease in vagal tone and enhanced adrenergic
receptors bind T 3 with greater (>10) affinity than T 4 tone characteristic of hyperthyroidism (11).
(8). In mammals, these receptor proteins exist in 2 Unlike steroid hormones, T3 is not lipid-soluble
isoforms, a and b (TR a and TR b ), and bind to TH and must be transported into the cytoplasm of TH-
response elements in the promoter regions of TH- responsive cells. Several families of TH transporters
responsive genes. TR a and TRb activate expression have been identified, including the Na þ-taurocholate
of positively regulated genes in the presence of T 3 cotransporting polypeptides, the Na þ-independent
and repress expression in its absence. The TR a 1 iso- organic anion transporting polypeptides, the hetero-
form has been shown to play an important role in the dimeric L-type amino acid transporters, and, perhaps
regulation of cardiac genes (Figure 1). A list of cardiac most importantly, the monocarboxylate transporters
genes regulated by TH can be found in Table 1. (MCTs) 8 and 10, which are highly specific for
JACC VOL. 71, NO. 16, 2018 Razvi et al. 1783
APRIL 24, 2018:1781–96 Thyroid Hormones and the Cardiovascular System
C ENTR AL I LL U STRA T I O N The Interactions Between Thyroid Hormones and the Cardiovascular System
Razvi, S. et al. J Am Coll Cardiol. 2018;71(16):1781–96.
Thyroid hormones (TH) have a complex relationship with the cardiovascular system through multiple mechanisms. The main effects of thyroid hormones are observed
on the heart (by influencing rate, rhythm, myocardial contraction, and risk of coronary artery disease), the vascular tree (through regulating blood pressure via smooth
muscle tone and endothelial function), and by direct effects on cardiovascular risk factors (via lipid metabolism and modulation of inflammatory pathways).
iodothyronines. MCT8 and 10 are expressed in the TH ACTION ON THE VASCULATURE. TH effects on
rodent heart, but it is unclear whether they have a the vasculature include genomic and nongenomic
role in the human heart. In humans, MCT8 mutations mechanisms that occur at both the vascular smooth
are the cause of Allan-Herndon-Dudley syndrome, an muscle and endothelial cell levels. Nongenomic, in-
X-linked syndrome with specific thyroid and neuro- direct effects of TH include ion channel activation
logical defects, and heart rate abnormalities, thus (Na þ, Kþ, Ca2þ) and regulation of specific signal trans-
suggesting a role for MCT8 in TH transport in human duction pathways. Activation of phosphatidylinositol
cardiac tissues. MCT10 has a greater affinity for T 3 3-kinase and serine/threonine protein kinase path-
than T 4, and an even greater capacity to transport T 3 ways cause the production of endothelial nitric oxide,
than MCT8 (12). The cardiac myocyte TH-responsive leading to a reduction in systemic vascular resistance
genes are expressed as a function of serum T 3, and through its effects on vascular smooth muscle cells
not T 4 , implying that T 4 is neither transported across (6,13). Several studies have shown that TH regulates
the myocyte sarcolemma nor deiodinated into T 3. endothelial nitric oxide production and vascular tone,
Therefore, optimal myocyte gene expression remains and that patients with hypothyroidism (both overt and
dependent on serum T 3 levels, and if they fall, despite subclinical) exhibit impaired endothelial function,
the fact that TSH and T 4 levels may be normal, the which improves with TH replacement therapy (14–16).
heart will express a hypothyroid phenotype. In addition, T 3 can produce a vasodilatory effect within
F I G U R E 1 Cellular Pathways and Mechanisms of Action of T 3 on the Cardiac Myocyte
T3 has both genomic and nongenomic effects on the cardiac myocyte. Genomic effects are mediated by the transport of plasma T3 into the cardiac myocyte and direct
binding to the TR, which, in turn, regulates transcription of specific cardiac genes. Positively regulated genes are transcribed and negatively regulated genes are
repressed in the presence of T3. Nongenomic mechanisms include direct modulation of membrane ion channels. Modified from Klein et al. (71). AC ¼ adenylyl cyclase; b-
AR ¼ b-adrenergic receptor; Ca2þ ¼ calcium ions; Ca2þ ATPase ¼ sarcoplasmic reticulum calcium adenosine triphosphatase; cAMP ¼ cyclic adenosine monophosphate;
GS ¼ stimulatory G (guanine nucleotide binding) protein; Kþ ¼ potassium ions; Kv ¼ voltage-gated potassium ion channel; mRNA ¼ messenger ribonucleic acid; Na-K
ATPase ¼ sodium-potassium adenosine triphosphatase; Naþ ¼ sodium ions; NCX ¼ sodium calcium exchanger; PLB ¼ phospholamban; T3 ¼ triiodothyronine;
TR ¼ thyroid hormone receptor; TRE ¼ thyroid hormone response element.
T A B L E 1 T 3 -Regulated Cardiac Genes

hours after administration to patients undergoing
Positively Regulated Negatively Regulated
coronary artery bypass grafting (17). Similar effects are
a-MHC b-MHC
observed when patients with chronic HF are treated
Voltage-gated Kþ channels Naþ/Ca2þ exchanger (NCX1)
(Kv1.5, Kv4.2) with intravenous T 3 (18). Thus, T 3 has the unique
SERCA2 Phospholamban pharmacological properties of an inodilator acting
Naþ/Kþ ATPase Adenylyl cyclase types V, VI primarily on diastolic dysfunction.
b1-adrenergic receptor Thyroid hormone receptor a1 The pulmonary vasculature is not as responsive to
Adenine nucleotide Thyroid hormone transporters (MCT8, 10)
the vasodilatory effects TH as is the systemic vascu-
translocase (ANT1)
lature (19). Pulmonary artery hypertension that re-
ATPase ¼ adenosine triphosphatase; Ca2þ ¼ calcium; Kþ ¼ potassium; solves after return to the euthyroid state has been
Naþ ¼ sodium; MHC ¼ myosin heavy chain; SERCA ¼ sarcoplasmic reticulum
adenosine triphosphatase; T3 ¼ triiodothyronine.
reported in patients with thyrotoxicosis mainly due
to a fall in cardiac output.
F I G U R E 2 The Role of Thyroid Hormones in the Pathophysiology of Heart Failure
Increased Myocardial
workload dysfunction*
Bone marrow
dysfunction*
Reduced cardiac
output*
Increased
sympathetic
Increased activity*
vein return RAA activation*
Vasoconstriction *
Reduced renal blood
flow
Reduced GFR
Increased renal
sodium retention*
Low thyroid function reduces cardiac function and induces morphological, molecular, and structural changes of the myocardium. Low thyroid
function also increases peripheral vascular resistance, plasma noradrenaline concentrations, and plasma renin activity, and reduces eryth-
ropoietin. *Critical points where low thyroid state (function) may contribute to the progression and worsening of heart failure.
GFR ¼ glomerular filtration rate; HF ¼ heart failure; RAA ¼ renin-angiotensin-aldosterone axis; TH ¼ thyroid hormones.
TH AND CARDIOPROTECTION. Cardioprotection is miR-34a) levels are elevated in the early phase of
an emerging target of therapeutic intervention in AMI and are positively correlated with LV diastolic
AMI to minimize irreversible ischemic damage and dimension (24). Moreover, T 3 mitochondrial protec-
favor functional recovery of the ischemic-damaged tion is also exerted through other pathways,
myocardium (20). THs have a role in car- including mitochondrial adenosine triphosphate–
dioprotection due to activation of cytoprotective dependent potassium pathway, peroxisome
mechanisms, stimulation of cell growth, neo- proliferator-activated receptor gamma coactivator
angiogenesis, and metabolic adaptation. The net 1-alpha, and the mitochondrial transcription factor A
result, as documented by histological and functional (25). These are key intracellular signals controlling
parameters, is a reduction in myocardial damage and mitochondrial activity and biogenesis, and their
positive reverse left ventricular (LV) remodeling, overexpression limits post-ischemic LV remodeling
resulting in a delay, or even absence, of evolution and impairment of cardiac performance. Further-
toward post-ischemic irreversible HF. Recent exper- more, T 3 treatment preserves the expression of
imental studies using the ischemia/reperfusion rat hypoxia-inducible factor 1-alpha, whose protective
model showed multiple protective effects of TH, effect against reperfusion injury is mediated by
particularly on mitochondria. TH is a regulator of the inhibiting the mitochondrial opening of the perme-
tumor suppressor p53, which is activated during ability transition pore (26).
AMI, enhancing the mitochondrial apoptosis In the context of HF, THs have a cardioprotective
pathway (21). p53 expression, in turn, is blunted by role through multifaceted direct or indirect actions at
microRNA 30a (miR-30a), which is down-regulated the level of the myocytes, the interstitium, and the
in the post-ischemic setting. This favors p53 accu- vasculature (Figure 2) (6). THs have an antiapoptotic
mulation, and therefore enhances mitochondrial effect on myocytes via activation of the phosphati-
dysfunction and bcl-2–like protein 4 activation, dylinositol 3-kinase/serine/threonine protein kinase
resulting in extended myocardial cell loss (22). T 3 and protein kinase C signaling cascades, the expres-
treatment counteracts the decrease in miR-30a sion, phosphorylation, and translocation of heat
levels, thus limiting the activation of p53 and the shock proteins 70 and 27, and the suppression of p38
cascade leading to mitochondrial injury and cell mitogen-activated protein kinase signaling (27). In
death in the AMI border zone (23). This finding is addition, TH treatment reduces interstitial fibrosis in
relevant because, in patients with post-ischemic HF, animal models of ischemic and nonischemic HF, and
p53-responsive microRNA (miR-192, miR-194, and this effect can be partially related to the influence of
(16,41). Thus, an association, if present, is likely to be

T A B L E 2 Effect of Thyroid Dysfunction on CV Disease Risk Factors
weak, with SCH contributing to a small increase in
Overt Hyperthyroidism Overt Hypothyroidism serum LDL-C, ranging between 3 and 15 mg/dl (0.1 to
and Subclinical and Subclinical
Hyperthyroidism Hypothyroidism 0.4 mmol/l) (42). This could, in theory, contribute to
Lipid Mild reduction Increased total cholesterol the high risk of CV disease observed in this popula-
parameters and LDL cholesterol tion (Table 2).
Hypertension Systolic hypertension Diastolic hypertension
Wide pulse pressure TH, VASCULATURE, AND BLOOD PRESSURE.
Endothelial Excessive endothelial NO production Impaired endothelial Hyperthyroidism causes a hyperdynamic circulation,
dysfunction and exaggerated vascular reactivity dependent vasodilation
Increased arterial stiffness and Increased arterial stiffness
characterized by increased cardiac contractility and
carotid intima-media thickness in heart rate, increased preload, and decreased systemic
longstanding untreated disease
vascular resistance (SVR), resulting in significantly
Thrombogenicity Increased fibrinogen and vWF in Unclear
overt disease increased cardiac output. Although hyperthyroidism
Cardiac function Increased risk of atrial arrhythmias LV systolic and diastolic can increase systolic blood pressure, the net effect is
Increased atrial size, LV mass, and dysfunction at rest
dependent on the balance between increased cardiac
impaired diastolic function in and during exercise
longstanding untreated disease output and decreased SVR (43,44). The relationship
between subclinical hyperthyroidism (SHyper) and
CV ¼ cardiovascular; LDL ¼ low-density lipoprotein; LV ¼ left ventricular; NO ¼ nitric oxide; vWF ¼ von Wil-
lebrand factor.
blood pressure is less clear, with most published
studies showing no association (45–47). Furthermore,
some studies have shown SHyper patients to have
increased carotid intima-media thickness and carotid
TH on the activity of metalloproteinases and their
artery plaques (48,49), although this was not
inhibitors (28). Furthermore, the antifibrotic effect of
confirmed in a recent large, population-based study
TH is also linked to the T 3-induced inhibition of pro-
(50).
fibrotic pathways, (29), and is supported by the as-
Overt and SCH are associated with diastolic hyper-
sociation of low serum T 3 levels with the presence of
tension, impaired vascular function, and increased ca-
cardiac fibrosis in patients with idiopathic dilated
rotid intima hyperplasia (45,47). Endothelial-dependent
cardiomyopathy (30).
vasodilation is lower in overtly hypothyroid and SCH
patients (51), and improves with levothyroxine treat-
THYROID DISEASE AND CV RISK FACTORS
ment (15,16), as does pulse wave velocity, a surrogate
measure of arterial stiffness (52,53).
TH AND HYPERLIPIDEMIA. Hyperthyroidism reduces
Several factors could likely contribute to arterial
cholesterol levels, which are reversed when euthyr-
stiffness and endothelial dysfunction in SCH and
oidism is achieved. Hypothyroidism is associated
hypothyroidism, including hyperlipidemia and a
with a small but significant increase in lipid parame-
proinflammatory state (54–56). Thus, in the Rotter-
ters (31), in particular, an elevation of low-density
dam Study, aortic calcification and the prevalence of
lipoproteins (LDLs) (32). Hypothyroidism is associ-
myocardial infarction was higher in patients with SCH
ated with increased oxidation of LDL, which pro-
who were positive for thyroid autoantibodies than in
motes atherogenesis and reverses with treatment
those with SCH alone (57). Both hyperlipidemia and
(33,34). Lipoprotein(a), a more potent marker of
thyroid antibodies are thought to reduce expression
atherogenesis, also increases in overt hypothyroidism
of endothelial nitric oxide synthase, thereby impair-
and decreases with TH replacement (35,36).
ing vasodilation (15). In addition, increased arterial
The effect of subclinical hypothyroidism (SCH) on
stiffness and a low renin state are contributory factors
hyperlipidemia is less clear (37–39). Hyperlipidemia
leading to blood pressure and vascular dysregulation
in hypothyroidism is due to a decrease in LDL re-
due to the lack of the normal vasodilatory effects of T 3
ceptors, resulting in reduced cholesterol clearance
(4,43) (Table 2).
from the liver and decreased activity of cholesterol
7a -hydroxylase, which is activated by TH, in breaking TH AND THROMBOGENESIS. Overt and SHyper have
down cholesterol (32). A Cochrane review of 6 RCTs been associated with increased markers of thrombo-
concluded that levothyroxine treatment of SCH had genesis (fibrinogen and factor X levels) (58,59). Hy-
no overall effect in reducing total cholesterol, but perthyroid patients may also have higher von
suggested a trend toward reducing LDL cholesterol Willebrand antigen levels compared with euthyroid
(LDL-C) levels >155 mg/dl in a subgroup analysis (40). patients, leading to enhanced platelet plug forma-
Two subsequent trials suggested that the reduction of tion, which decreases after treatment (60). The rele-
LDL-C was approximately 0.3 mmol/l (11.6 mg/dl) vance of these findings is uncertain, although a
review of published case reports in hyperthyroidism

F I G U R E 3 Thrombus Area Ex Vivo in Representative Patients With Non–ST-Segment
suggests a tendency toward increased overall Elevation Myocardial Infarction by Thyroid Status
thrombosis (61). The increased cerebral thrombosis
and cerebrovascular events in overt hyperthyroidism SCH Euthyroid
warrant further scrutiny to investigate if such events
are due to increased thrombosis, related to alterations thr
hrom
ombu
b s
bu thrrom
ombu
bus
bus
in the vascular tree (increased carotid intima-media
thickness), or due to a higher risk of atrial fibrilla-
tion (AF) (49).
Studies investigating coagulation in overt hypo-
thyroidism have yielded conflicting results, with
2 studies showing hypercoagulability (62,63) and
1 study showing increased fibrinolysis (64). Interest-
ingly, a study comparing moderate and severely hy- (Left) Patient with subclinical hypothyroidism (SCH). (Right) Euthyroid patient. Reprinted
pothyroid patients with euthyroid controls found that with permission from Viswanathan et al. (69).
patients with moderate hypothyroidism had

decreased fibrinolytic activity and were more sus-
function and enhancing LV relaxation (diastolic flow
ceptible to clot formation, whereas patients with se-
velocities and isovolumic relaxation time) (72).
vere hypothyroidism had increased fibrinolysis and
However, despite the high cardiac output state, hy-
lower tissue plasminogen activator antigen (65). In
perthyroid patients have impaired cardiopulmonary
SCH, factor VII activity and the factor VII activity–to–
function during effort, reflecting their reduced CV
factor VII antigen ratio were significantly increased in
and respiratory reserve during exercise (70).
women with SCH compared with controls (66).
Untreated hyperthyroidism is associated with
Another study showed decreased antithrombin III
increased CV morbidity and mortality (73). Overt hy-
activity and increased levels of fibrinogen, factor VII,
perthyroidism has been associated with 16%
and plasminogen activator inhibitor antigen in SCH
increased risk of major CV events, mainly due to
patients to explain a potential hypercoagulable state
higher incidence of HF events (74). Severe hyper-
(67). This is further supported by a study that found
thyroidism may induce so-called high-output HF,
lower global fibrinolytic activity, such as tissue plas-
even in patients without underlying heart disease.
minogen activator, in SCH patients than in euthyroid
controls (68). The effects of TH on platelet function
are unclear (60). A study using the Badimon chamber, F I G U R E 4 Mechanistic Effects of Duration of Hyperthyroidism on the Evolution of
Heart Failure
a surrogate ex vivo model of plaque rupture in a
moderately stenosed coronary artery, showed
Short-Term Long-Term Untreated
increased thrombus in patients with SCH 7 to 10 days Hyperthyroidism Hyperthyroidism
post–non-ST-segment elevation myocardial infarc-
Blood Improved Cardiac
tion compared with euthyroid patients, despite dual Volume Diastolic Relaxation Workload
antiplatelet therapy (69) (Figure 3). This heightened and LVM
thrombogenic state may, in part, explain the higher

Impaired
CV risk seen in patients with SCH. In summary, both LVEDV Relaxation
TH deficiency and excess can alter the coagulation
pathway, although the precise clinical relevance of
SVR Atrial Size
this finding is unclear (Table 2).
Stroke Heart Arterial

CARDIOVASCULAR CONSEQUENCES OF
Volume Rate Stiffness
OVERT HYPERTHYROIDISM AND SHyper
Risk of
Hyperthyroidism is a clinical condition characterized AF, HF,
Cardiac
CHD, STROKE
by TH excess, commonly due to Graves’ disease, toxic Output
adenoma, and toxic multinodular goiter (70). TH
excess increases cardiac output by affecting stroke
AF ¼ atrial fibrillation; CHD ¼ coronary heart disease; HF ¼ heart failure; LVEDV ¼ left
volume and heart rate (6,71). Echocardiographic data ventricular end-diastolic volume; LVM ¼ left ventricular mass; SVR ¼ systemic vascular
indicate that short-term hyperthyroidism induces resistance.
positive CV changes by improving LV systolic
This congestive circulation results from the increases population, is diagnosed when the serum TSH level is
in blood volume and heart rate, and the associated persistently subnormal with concomitant free TH
pulmonary arterial hypertension (Figure 4). Clinical levels at the upper limits of their respective reference
features of this condition are pleural effusion, hepatic intervals (4). It can be further classified as grade 1
congestion, and fluid retention, which can improve (low, but detectable serum TSH levels [e.g., TSH 0.1 to
with diuretic agents and beta-blockers (75). 0.39 mU/l]) or grade 2 (suppressed serum TSH
Hyperthyroidism is linked to increased supraven- levels < 0.1 mU/l) (4). Similar to overt hyperthyroid-
tricular ectopic activity (76). The onset of AF may ism, patients with SHyper may have an increased risk
increase CV morbidity and mortality, resulting from of AF, HF, and CV disease. The Thyroid Studies
severe HF and stroke (75). T 3 increases systolic de- Collaboration, an international consortium, assessed
polarization and diastolic repolarization, and de- individual participant data from prospective cohort
creases the action potential duration, the refractory studies to estimate the risk of HF and coronary heart
period of the atrial myocardium, and the atrial/ven- disease (CHD) during median follow-ups of 10.4 and 7
tricular nodal refractory period. The reduced intera- years, respectively (84,85). In age- and sex-adjusted
trial action potential duration facilitates the analyses, these risks were significantly higher in
occurrence of AF by enhancing the spreading of participants with grade 2 SHyper (hazard ratio [HR]:
ectopic activity from the left atrium (76). Experi- 1.94; 95% confidence interval [CI]: 1.01 to 3.72 for HF;
mental studies have shown that TH excess can pro- HR: 1.21; 95% CI: 0.99 to 1.46 for CHD events; and HR:
voke the occurrence of paroxysmal AF by increasing 1.29; 95% CI: 1.02 to 1.62 for CHD mortality) than in
triggered activity in pulmonary veins (76). Approxi- those with grade 1 SHyper. Moreover, grade 2 SHyper
mately 13% of patients with new-onset AF have was associated with a higher risk of developing AF
biochemical evidence of hyperthyroidism, whereas (HR: 2.54; 95% CI: 1.08 to 5.99) than grade 1 SHyper
AF is noted in 10% to 15% of patients with hyper- (HR: 1.63; 95% CI: 1.10 to 2.41) (85). The attributable
thyroidism (compared with 0.5% of the general pop- risk for AF was 41.5% in these patients, and it was not
ulation). The main risk factors for the development of altered by the presence of existing CV disease or other
AF in hyperthyroid patients are increasing age, CV risk factors (85). Interestingly, the risk of AF,
ischemic heart disease, congestive HF, or heart valve sudden cardiac death, and reduced life expectancy
disease (77). The risk of ischemic stroke is enhanced have been noted to be related to higher free T4 levels,
by 44% in adults with hyperthyroidism compared even within the euthyroid range, in 1 prospective
with euthyroid controls (78). Advanced age and the study of middle-aged and older people from Rotter-
presence of associated CV risk factors (history of HF, dam (86). Conflicting results have been reported on
hypertension, or diabetes mellitus, previous throm- the association between SHyper and stroke. A meta-
boembolism, left atrial enlargement, and LV analysis of 6 studies did not find any evidence sup-
dysfunction) can further elevate the embolic risk (70). porting an increased risk of stroke in participants
Despite the evidence of the increased rate of stroke, with SHyper (87). Similarly, a Danish population
no trials have been performed to assess the risk- study did not find any link between the risk of stroke
benefit ratio of the efficacy of anticoagulation treat- and overt, mild, and severe hyperthyroidism after
ment in patients with AF and hyperthyroidism. stratifying the analysis according to TSH levels (74).
Patients with severe hyperthyroidism may have cor- Management of SHyper should include control of
onary vasospasm leading to chest pain at rest or thyroid function and prevention of CV complications.
myocardial ischemia (6,70,71,79). Mild and usually International guidelines strongly recommend treat-
asymptomatic pulmonary arterial hypertension has ment of grade 2 SHyper (TSH < 0.1 mIU/l) in patients
been reported, especially in autoimmune hyperthy- older than 65 years of age and in younger patients with
roidism, with an incidence ranging from 36% to 65% comorbidities (81,82). They also recommend treat-
in echocardiographic studies (80). ment of grade 1 SHyper in patients older than 65 years
Prompt recognition and effective treatment of of age in the presence of CV risk factors or complica-
hyperthyroidism is crucial to improve the prognosis tions, although this recommendation is weak because
of hyperthyroid patients (81–83). Antithyroid drugs of low-quality evidence (81,82). Treatment of grade 1
and beta-blockers represent the first-line therapy to SHyper is not recommended in young adults.
control CV involvement of overt hyperthyroidism by
restoring euthyroidism and controlling the heart CV CONSEQUENCES OF OVERT AND SCH
rate (82).
SHyper, affecting up to 1% of the iodine-replete Overt hypothyroidism is diagnosed when serum TSH
and up to 10% of the iodine-deficient adult is elevated and circulating THs are low and is
ventricular filling and relaxation (90,91). SCH can also

T A B L E 3 Causes of Hypothyroidism, Including
Subclinical Hypothyroidism
impair relaxation of vascular smooth muscle cells,
inducing increases in systemic vascular resistance and
Autoimmune disease Hashimoto’s autoimmune thyroiditis,
TSH receptor–blocking antibodies arterial stiffness, as well as changes in endothelial
Structural Thyroid damage due to thyroidectomy or function by reduction of nitric oxide availability,
radiation (radioactive iodine therapy or
external radiotherapy of head and neck)
without apparent clinical significance (92). Population
Release of Post-thyroiditis state studies support these findings, with the Whickham
preformed TH Survey cohort revealing higher systolic and diastolic
Pituitary disease Secondary hypothyroidism due to TSH
blood pressures and total cholesterol concentrations in
deficiency
Drugs Antithyroid drugs, lithium, amiodarone, SCH individuals than in euthyroid controls (93), and the
tyrosine kinase inhibitors, interferon EPIC-Norfolk (European Prospective Investigation of
therapy, radiographic contrast
agents, sulfonamides Cancer, Norfolk) study reporting a worse CV risk factor
Thyroid infiltration Amyloidosis, hemochromatosis, profile (94).
acquired immunodeficiency There is conflicting evidence from population
syndrome, sarcoidosis,
Riedel’s thyroiditis studies about the association of SCH with CV disease
Other Inadequate TH replacement or and mortality. A number of observational studies of
noncompliance for overt
community-dwelling individuals have shown an
hypothyroidism, industrial
and environmental agents. increased risk for CV disease (56,95–97). In addition,
SCH after admission for an acute cardiac problem has
TH ¼ thyroid hormone; TSH ¼ thyrotropin.
been associated with an up to 3.6-fold increase in car-
diac mortality and a 2.3-fold increase in overall death
prevalent in 0.2% to 2% of nonpregnant adults (31,37). (98). However, this relationship has not been
The causes of hypothyroidism are described in confirmed in all studies (94,99,100). This discrepancy
Table 3. Overt hypothyroidism has several cardiac in results between the various cohorts is likely due to
manifestations, including a reduction in cardiac differences in the underlying populations studied and
output, a decrease in heart rate, and an increase in the study design. One of the major factors that in-
peripheral vascular resistance and diastolic dysfunc- fluences CV risk in SCH populations is age, and several
tion (71). There are also significant changes in modi- observations have concluded that older individuals
fiable atherosclerotic risk factors, including with SCH may have a lower risk of CV disease than
hypercholesterolemia, diastolic hypertension, younger ones (101). Furthermore, a retrospective
increased carotid intimal-media thickness, and observational study showed that treatment of SCH
reduced endothelial nitric oxide, which accompany with levothyroxine was associated with fewer
overt hypothyroidism. All these clinical features are ischemic heart disease events in younger individuals,
reversible with TH replacement (88). but this was not evident in older people (102). In
SCH is diagnosed when serum THs are within their addition, several studies of older patients have shown
reference range in the presence of raised serum TSH SCH to have either a protective or no impact on CV
concentrations. SCH can be classified as grade 1 (TSH disease risk (103–105). A patient-level meta-analysis of
>4.0 or 4.5, but <10 mU/l) or grade 2 (TSH >10 mU/l). several prospective cohort studies, providing 542,494
In fact, most (at least 80%) patients with hypothy- person-years of follow-up, showed that SCH is associ-
roidism have SCH (31). However, there is a lack of ated with a higher risk of CV events and mortality in
consensus on what constitutes the “normal” upper people with higher serum TSH levels, particularly in
limit of TSH leading to controversy on definition, those with TSH levels >10 mU/l, irrespective of age (21).
prevalence and clinical significance of SCH (89). The Despite the known CV risks associated with SCH,
stated prevalence of SCH in published reports ranges high-quality evidence for treatment is lacking, mainly
from 4% to 10% of the adult population, being more as current data is derived from observational studies
common in women and older individuals (31,37). This or small interventional trials with cardiac risk factor
wide range reflects that a variety of factors can in- changes as outcomes. Trials of levothyroxine in SCH
fluence serum TSH levels such as age, sex, body mass using surrogate markers have shown improvement in
index, race, smoking habits, iodine intake, time of LV function, vascular endothelial function, athero-
sampling, concomitant medical conditions and genic lipid particles, or cardiac mitochondrial func-
treatments, plus the cutoff concentrations of serum tion (4,91,105–108).
TSH used to define the condition. RCTs are needed to evaluate the clinical benefits
The most frequent cardiac abnormality observed in and safety of treatment of SCH in reducing CV risk.
SCH is diastolic dysfunction due to impaired Meanwhile, international guidelines suggest that
treatment should only be considered in those with was first shown in a rat model of right ventricular
more severe disease (serum TSH >10 mU/l), symp- (RV) hypertrophy and failure, where D3 activity
toms of hypothyroidism, or younger than 70 years increased in the chronically overloaded RV, with no
of age, particularly if they also have other CV risk change of activity in the LVs of the same hearts (116).
factors (109). D3 activity in the RV of rats with HF was significantly
higher than that in the RV of rats with hypertrophy
INTERPLAY BETWEEN NONTHYROIDAL alone. Follow-up studies in a post-AMI model in mice
ILLNESS AND CV DISEASE showed a strong and stable induction of D3 activity in
the remodeling ventricle from 1 week to at least
A few hours after the onset of acute illness, marked 8 weeks after AMI (118), and studies in rats have
changes in serum TH levels occur. This is referred to shown that the acute decrease in serum T 4 and T 3
as nonthyroidal illness (NTI). A decrease in T 3 and after AMI is mediated by the induction of D3 activity
increase in reverse T3 (rT 3) are the most characteristic in the heart (115). The induction of D3 is localized in
and persistent abnormalities of NTI. In severely ill cardiomyocytes only and is associated with a
patients, T 4 levels drop as well. Both low T 4 and T 3 substantial decrease in tissue T 3 concentrations and
levels, as well as high rT3 levels are associated with a T 3 -dependent gene expression (118). This change in
worse prognosis. TSH levels may rise briefly after the T 3 -dependent gene expression was independent of
onset of disease, but despite the drop in serum T 3 the circulating T 3 concentration in mice, showing that
(and in severe illness also T 4) levels, circulating TSH pathological ventricular remodeling after AMI leads
usually remains within the low to normal range. to high and stable induction of D3 activity in car-
Decreased activation and increased inactivation of TH diomyocytes, resulting in a subsequent local hypo-
are the major causes of these changes in the acute thyroid condition. Whether this local hypothyroidism
phase of NTI, whereas an altered feedback setting at inside the myocardium in patients with HF is bene-
the hypothalamus-pituitary level is more important ficial or harmful is unclear.
in the chronic phase of severe illness. As low levels of Similar to critical illness in general, lower circu-
TH are associated with a decreased metabolic rate, lating levels of T 3 in patients with AMI are associated
the changes in TH homeostasis during the acute with a more severe clinical condition and with poorer
phase of NTI have been interpreted as an attempt to clinical outcome (119,120), particularly in patients with
save energy expenditure, which does not require any LV dysfunction, large AMI, and intense proin-
intervention. However, this remains controversial, flammatory and stress responses (121,122). This is not
has been a debate for many years, and may be only the case in the acute setting, but also in the longer
different in the acute and chronic phases of illness term after recovery from AMI. Low T3 and high rT 3
(110,111). levels at the time of AMI are an independent predictor
Similar changes occur in patients with CV disease of both short-term and long-term mortality (120), and
(CVD). NTI occurs in 15% to 20% of patients with AMI lower T3 levels after AMI are an independent predictor
(112,113). A rapid but transient decrease in serum TH of late recovery of LV function after 6 months (123).
concentrations occurs immediately after AMI (114), Also, in patients with chronic HF, NTI has been asso-
with maximal changes between 24 h and 36 h after ciated with a worse prognosis (96,124,125). However,
the onset of pain. These changes are due to increased considering the strong effects of disease in general on
inactivation of TH by the inactivating enzyme deio- thyroid function, it is impossible to distinguish be-
dinase 3 (D3) and decreased activation by D1 and D2 tween cause and consequence in these clinical obser-
activity (115,116) (Figure 5). Although a reduction in vational studies. Interestingly, ameliorating oxidative
oxygen consumption by lowering TH levels during stress with antioxidants prevents the acute reduction
acute ischemia could be considered beneficial, the net of serum T3 levels in patients with AMI, although it is
effect of lower TH levels in the heart may still be unknown if this has any effect on cardiac function or
detrimental because of its important role in post- outcomes (126).
ischemic LV remodeling, maintaining CV function
and mitochondrial integrity (6). As in patients with TH IN AMI AND ISCHEMIA
other chronic illnesses, NTI is also very common in REPERFUSION INJURY
patients with HF, with a prevalence of approximately
20% to 30% (117). Although these changes may, in Low T 3 syndrome (an isolated reduction of serum T 3
part, be due to the illness in general, animal studies levels with normal T4 and TSH concentrations) after
provide convincing evidence for additional, specific AMI is observed in up to 1 in 5 patients (114), whereas
down-regulation of local TH action in CV disease. This SCH is observed in almost 12% (127). T 3 down-
regulation is consistent with experimental data

F I G U R E 5 Thyroid Function Changes in Critical Nonthyroidal Illness
showing that changes in circulating TH parameters
after AMI are a result of increased D3 activity and
reduced D1 and D2 activity (115). Convincing data
A Hypothalamus TRH
show that TH metabolism abnormalities occurring TSH
-
TRH
+
during early stage of AMI are associated with Pituitary TSH
TSH
increased incidence of cardiac events. The degree of +
TH down-regulation is associated with higher Thyroid T4

impairment of cardiac function and higher inflam- D1, D2 D3
matory response (114,121). T3 rT3

The increase in rT 3, the inactive TH metabolite, is a D3 D1, D2
predictor of both short- and long-term mortality in- T2
dependent of other traditional parameters (120).
B
Similarly, in 501 patients with AMI (of whom 34% had
low T 3 syndrome), the rate of major cardiac events at T2 D3
follow-up was higher in those with low free triiodo-
TH receptor
thyronine (FT 3) levels than in those with preserved T3 T3 T3
FT 3 circulating levels, and, importantly, FT 3 was the

D2 TRE
most important predictor of subsequent cardiac
events (119). In another study of 457 AMI patients, T4 T4
thyroid dysfunction including SCH, SHyper, and low Protein
D3 mRNA
T 3 syndrome was associated with higher incidence of capillary

rT3
major cardiac events (112). Furthermore, in patients cardiomyocyte
with AMI and early reperfusion therapy, T3 circu-

lating levels correlated with LV ejection fraction both (A) The hormonal changes that occur in the hypothalamic–pituitary–thyroid (HPT) axis
at the early, in-hospital phase and at the 6-month during critical illness. (B) Changes in thyroid hormone entry and metabolism at the
follow-up visit. Interestingly, T3 at 6 months was an level of the cardiomyocyte. Direction of arrows ([ Y) indicate increase (upward) or
independent predictor of LV ejection fraction changes decrease (downward), respectively, whereas equal to ([) sign means no change.
D (1–3) ¼ deiodinase enzymes 1–3; rT3 ¼ reverse triiodothyronine; TRH ¼ thyrotropin
between the early and follow-up periods (123). How-
releasing hormone; TSH ¼ thyrotropin; T4 ¼ thyroxine; T2 ¼ diiodothyronine; other
ever, pathophysiological and therapeutic relevance of abbreviations as in Figures 1 and 2.
the thyroid dysregulation after AMI are far from
elucidated. No interventional studies of TH replace-
ment in AMI patients have been published to date, of HF patients, respectively (129). Serum T 3 levels may
therefore making a causal relationship between thy- be an independent predictor of LV dysfunction and
roid dysfunction and outcomes difficult to ascertain. New York Heart Association functional class (130).
Overall, the experimental and observational find- Furthermore, in addition to conventional risk factors,
ings mentioned previously are in contrast to the TH metabolism alterations have been associated with a
common interpretation that TH down-regulation af- worse prognosis in patients with both ischemic and
ter AMI is an adaptive, favorable process that helps in nonischemic LV dysfunction in both acute decom-
reducing catabolism and energy expenditure (128), pensated and chronic stable HF (131–133). In particular,
and suggests the potential critical role of the thyroid patients with reduced LV ejection fraction and low T 3
system in cardioprotection in AMI. Future research to have higher mortality than patients with similar LV
better understand the interaction between acute TH ejection fractions, but normal T 3 (134). This result was
changes and cardiac ischemia, particularly ischemia- also confirmed in a large multicenter cohort of patients
reperfusion injury, and whether normalizing thyroid with ischemic and nonischemic HF with severe LV
function parameters may have a role, is required. dysfunction (LV ejection fraction #35%), in which
abnormal TH function was associated with signifi-
TH IN HF cantly increased risk for death (135).
There are a few clinical studies that used disparate
In the clinical setting, the most frequent alteration of methodologies to study the effects of TH replacement
TH metabolism is the low T 3 syndrome that occurs in therapy in HF patients. However, the overall results
15% to 30% of patients with HF, with the incidence showed an improvement in CV performance, induced
changing in relation to the clinical severity of the dis- by both direct and indirect actions. Moreover, there
ease. SCH and SHyper, in contrast, occur in 6% and 3% was also evidence of neuroendocrine system
MODULATION OF TH LEVELS BY DRUGS AND

F I G U R E 6 Structural Resemblance of Amiodarone to Thyroid Hormones T 4 and T 3
ITS IMPACT ON CV SYSTEM
Amiodarone
I AMIODARONE. Amiodarone is a potent class III anti-
O C2H5 arrhythmic drug that also possesses beta-blocking
C O CH2 CH2N properties. It is an iodinated derivative of benzofuran
C2H5
and is structurally similar to TH (Figure 6). Amiodarone
C4H9 I
O contains iodine, and a 200-mg tablet contains 500
Thyroxine
times more iodine than the average daily requirement
I I (138). Both hyper- and hypothyroidism can occur with
NH2
amiodarone therapy. Amiodarone-induced thyroid
HO O CH2 CH COOH dysfunction occurs because of both its iodine content
and its direct toxic effects on thyroid parenchyma.
I I
However, the majority of patients commenced on
Triiodothyronine amiodarone (nearly 90%) remain euthyroid, at least in
I I the short to medium term. The prevalence of
NH2
amiodarone-induced hypothyroidism is between 5%
HO O CH2 CH COOH
and 22%, depending on iodine status, being more
I common in iodine-sufficient regions and in those with
existing thyroid autoimmunity, and thus is more
There is a structural similarity between amiodarone and thyroid hormones, with each frequently observed in women. The management of
molecule of the drug containing 2 iodine atoms, whereas T4 has 4 and T3 has 3 iodine amiodarone-induced hypothyroidism is similar to that
atoms. This structural likeness contributes, in part, to the effects of the drug on thyroid for all other forms of the condition: levothyroxine
hormones and function.
replacement. If amiodarone therapy is discontinued,
then levothyroxine treatment can be stopped after 2 to
4 months in individuals without pre-existing thyroid
inactivation, resulting from the significant reduction autoimmunity. Patients with underlying autoimmune
in vasoconstrictor/sodium-retaining noradrenaline, thyroid disease may remain hypothyroid, and thus
aldosterone, and N-terminal pro-B-type natriuretic require lifelong levothyroxine treatment, even after
peptide plasma levels (18). These positive results amiodarone cessation. However, amiodarone-induced
contrast with those of another study, which showed thyrotoxicosis (AIT) is seen in 2% to 12% of those
that oral T 3 treatment is not beneficial in patients with treated with the drug and is more frequently observed
HF and moderate LV dysfunction (mean ejection frac- in iodine-deficient areas. AIT is classified into 2
tion of 43%) (136). Therefore, these discordant results different categories based on the presence of under-
suggest that T 3 therapy may benefit only a subgroup of lying thyroid disease. Type 1 AIT occurs in those with
patients, and that the dose and modality of adminis- pre-existing multinodular goiter or latent Graves’
tration may influence its effectiveness. None of the disease and is due to increased synthesis and release of
interventional studies of TH in patients with HF TH. Type 2 AIT, conversely, is observed in those
revealed any major or minor side effects, and it was without any thyroid abnormalities and is due to
well-tolerated. In contrast, a trial of destructive thyroiditis, leading to the release of pre-
3,5-diidrothyropropionic acid (DITPA), a TH analog, formed TH into the circulation. It is, however, common
was stopped prematurely due to the occurrence of to have patients with a combination of both types of
thyrotoxic side effects and a trend toward increased AIT coexisting. AIT can be a difficult condition to
mortality, suggesting excess DITPA administration diagnose and treat. Management of AIT includes
(137). These results underscore an important endpoint cessation of amiodarone, if possible (although its long
of TH treatment, which is to restore and maintain half-life means that the effects could last for months
levels of circulating TH and TSH to within their after cessation), with further treatment depending on
respective reference ranges. Large multicenter trials the underlying etiology. Type 1 AIT is usually treated
documenting a definite role of TH treatment in HF are with high doses of antithyroid drugs, whereas type 2
lacking. Considering that HF affects millions of in- AIT is treated with corticosteroids.
dividuals in the United States, and that TH therapy in a PROPRANOLOL. Propranolol decreases circulating
selected group may be safe and effective, TH could serum T 3 levels in a dose-dependent manner due to
offer a clinically useful and cost-effective treatment if inhibition of the deiodinase enzymes (139). This ef-
confirmed in large-scale trials. fect is observed in hyperthyroid, euthyroid, and
levothyroxine-treated hypothyroid patients. Serum CONCLUSIONS

free T 4 and TSH levels remain unchanged. In a clinical
context, propranolol is favored over other beta- The CV system is a major target of TH action, and
blockers in the management of hyperthyroidism due even subtle changes in thyroid function can lead to
to its nonselective b-blocking activity (to reduce cardiac dysfunction. A number of experimental
systemic symptoms such as tremor and anxiety), studies and observational clinical data in both
membrane-stabilizing action, and reduction in serum hypo- and hyperthyroidism suggest that modulation
T 3 levels (20% to 30%, depending on the dose). of TH may be beneficial in reducing CV disease.
IODINE-CONTAINING CONTRAST DYES USED IN However, high-quality evidence is required before
ANGIOGRAPHY. As observed with amiodarone, this can be translated into clinical practice. Simi-
excess amounts of iodine in any form can result in larly, there is increasing evidence that changes in
thyroid dysfunction, particularly in susceptible in- TH levels in otherwise euthyroid patients with CV
dividuals. Iodinated contrast media, as used in coro- disease (such as AMI or HF) may be a marker of
nary angiograms, contain at least 2,000 times more poor prognosis, and clinical trials are required to
iodine (depending on the amount of contrast used) see if TH therapy may be efficacious and safe.
than the recommended daily allowance in the United Clinical trials of TH therapy in AMI patients are
States (140). This supraphysiological dose of iodine underway and could provide evidence for or
exposure has no major effects on thyroid function in against their use in routine clinical care (142,143).
most euthyroid individuals but may cause thyroid These therapies, if proven, could provide cost-
dysfunction (both hyper- and hypothyroidism) in effective and widely available treatments to mil-
susceptible groups. Data on the prevalence of thyroid lions of patients worldwide.
dysfunction after coronary angiogram contrast expo-
sure is sparse, and no guidelines exist. However, ADDRESS FOR CORRESPONDENCE: Dr. Salman
case-control studies suggest that iodinated contrast Razvi, Institute of Genetic Medicine, Newcastle Uni-
media exposure at least doubles the risk of subse- versity, International Centre for Life, Central
quent overt hyperthyroidism and triples the risk of Parkway, Newcastle upon Tyne NE1 3BZ, United
overt hypothyroidism (141). Kingdom. E-mail: [email protected].
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Thyroid Hormones and CVD

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JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY VOL. 71, NO.

ª 2018 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION

THE PRESENT AND FUTURE

Thyroid Hormones and

D espite major advances in their prevention

ISSN 0735-1097/$36.00 https://doi.org/10.1016/j.jacc.2018.02.045

Thyroid Hormones and the Cardiovascular System APRIL 24, 2018:1781–96

Razvi, S. et al. J Am Coll Cardiol. 2018;71(16):1781–96.

Thyroid Hormones and the Cardiovascular System APRIL 24, 2018:1781–96

F I G U R E 1 Cellular Pathways and Mechanisms of Action of T 3 on the Cardiac Myocyte

T A B L E 1 T 3 -Regulated Cardiac Genes

F I G U R E 2 The Role of Thyroid Hormones in the Pathophysiology of Heart Failure

Thyroid Hormones and the Cardiovascular System APRIL 24, 2018:1781–96

(16,41). Thus, an association, if present, is likely to be

review of published case reports in hyperthyroidism

patients with moderate hypothyroidism had

thrombogenic state may, in part, explain the higher

Stroke Heart Arterial

Thyroid Hormones and the Cardiovascular System APRIL 24, 2018:1781–96

ventricular ﬁlling and relaxation (90,91). SCH can also

Thyroid Hormones and the Cardiovascular System APRIL 24, 2018:1781–96

regulation is consistent with experimental data

TH down-regulation is associated with higher Thyroid T4

matory response (114,121). T3 rT3

FT 3 circulating levels, and, importantly, FT 3 was the

T 3 syndrome was associated with higher incidence of capillary

with AMI and early reperfusion therapy, T3 circu-

Thyroid Hormones and the Cardiovascular System APRIL 24, 2018:1781–96

MODULATION OF TH LEVELS BY DRUGS AND

levothyroxine-treated hypothyroid patients. Serum CONCLUSIONS

Thyroid Hormones and the Cardiovascular System APRIL 24, 2018:1781–96

Thyroid Hormones and the Cardiovascular System APRIL 24, 2018:1781–96

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