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Mechanisms of Disease
F R A N K L I N H . E P S T E I N , M. D. , Editor





HYROID hormone has many effects on the

heart and vascular system.1 Many of the clinical
manifestations of hyperthyroidism are due to
the ability of thyroid hormone to alter cardiovascular
hemodynamics.2 The hemodynamic effects of hypothyroidism are opposite to those of hyperthyroidism,
although the clinical manifestations are less obvious.
This review will integrate what is known about the
mechanisms of thyroid hormone action on the heart2-5
with recent observations from both experimental and
clinical studies of hyperthyroidism and hypothyroidism. We will also address the potential role of thyroid
hormone treatment in patients with acute or chronic
cardiac disease.

The effects of triiodothyronine, the active cellular

form of thyroid hormone, on cardiovascular physiology are shown in Figure 1, and the effects of hyperthyroidism and hypothyroidism on various hemodynamic measures are listed in Table 1. It is clear from
many invasive and noninvasive measurements in patients with thyroid disease that cardiac functions such
as heart rate, cardiac output, and systemic vascular resistance are closely linked to thyroid status. In addition
to the well-recognized action of thyroid hormone to
increase peripheral oxygen consumption and substrate
requirements, which causes a secondary increase in
cardiac contractility, the hormone also increases cardiac contractility directly.2-4 Triiodothyronine decreases
systemic vascular resistance by dilating the resistance
arterioles of the peripheral circulation.13 The vasodilation is due to a direct effect of triiodothyronine on
vascular smooth-muscle cells that promotes relaxation.14 The clinical correlate of this finding is that a
high dose of triiodothyronine decreases systemic vascular resistance and increases cardiac output within
hours after coronary-artery bypass grafting.15
From the Division of Endocrinology, Department of Medicine, North
Shore University Hospital, Manhasset, N.Y., and the Departments of Medicine and Cell Biology, New York University School of Medicine, New York.
Address reprint requests to Dr. Klein at the Division of Endocrinology,
North Shore University Hospital, 300 Community Dr., Manhasset, NY
11030, or at

Thyroid hormone increases blood volume.6 As a

result of the decrease in systemic vascular resistance,
the effective arterial filling volume falls, causing an increase in renin release and activation of the angiotensinaldosterone axis.16 This, in turn, stimulates renal
sodium reabsorption, leading to an increase in plasma
volume. Thyroid hormone also stimulates erythropoietin secretion. The combined effect of these two actions is an increase in blood volume and preload,
which further increases cardiac output (Fig. 1).

To understand the alterations in cardiac function

that accompany thyroid disease, it is necessary to review the mechanisms by which thyroid hormone acts
on cardiac myocytes and vascular smooth-muscle
cells.2,3,14 Triiodothyronine is the biologically relevant
thyroid hormone molecule in cardiac myocytes, as in
other cells, and there is evidence that the cell membrane contains specific transport proteins for triiodothyronine17 (Fig. 2). Conversion of thyroxine to triiodothyronine does not occur to any measurable degree
in cardiac myocytes.17 Once in the myocyte, triiodothyronine enters the nucleus and binds to nuclear receptors that then bind to thyroid hormone response
elements in target genes (Fig. 2). The triiodothyronine nuclear receptors bind to DNA as monomers or
homodimers, or as heterodimers composed of a triiodothyronine nuclear receptor and another receptor
from the steroid hormone receptor family.18 Occupancy of receptors by triiodothyronine in combination
with recruited coactivators leads to optimal transcriptional activation. In the absence of triiodothyronine,
the receptors repress genes that are positively regulated by thyroid hormone.19
Triiodothyronine-responsive genes that encode both
structural and regulatory proteins in the heart are listed in Table 2. The two myosin heavy chains (a and b)
are myofibrillar proteins that make up the thick filament of the contractile apparatus of cardiac myocytes.
In animals, transcription of the a-myosin heavy chain
is activated by triiodothyronine, whereas transcription
of the b-myosin heavy chain is repressed.19,20 In humans, the b-myosin heavy chain predominates,21,22 and
although cardiac contractile function is markedly altered in patients with thyroid disease, the changes in
expression of myosin heavy-chain isoforms are probably of insufficient magnitude to account for the functional changes.22,23
Production of the sarcoplasmic reticulum proteins,
calcium-activated ATPase (Ca2+-ATPase) and phospholamban, is regulated by triiodothyronine acting
through changes in gene transcription.3,24 Release of
calcium and its reuptake into the sarcoplasmic reticulum are critical determinants of systolic contractile
function and diastolic relaxation3,8,24 (Fig. 2). Active
transport of calcium into the lumen of the sarcoplas-

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systemic vascular


effective arterial
filling volume
renal sodium


Increased blood

cardiac output

Increased cardiac
inotropy and chronotropy

Figure 1. Effects of Thyroid Hormone on Cardiovascular Hemodynamics.

The diagram shows the way in which triiodothyronine increases cardiac output by affecting tissue oxygen consumption (thermogenesis), vascular resistance, blood volume, cardiac contractility, and heart rate. Adapted from Klein and Levey,6 with the permission of the publisher.











Systemic vascular resistance

15001700 7001200 21002700
Heart rate (beats/min)
Ejection fraction (%)
Cardiac output (liters/min)
Isovolumic relaxation time (msec)
Blood volume (% of normal value)
*The values for patients with hyperthyroidism and those with hypothyroidism are taken from Klein and Levey,6 Graettinger et al.,7 Mintz et al.,8
Biondi et al.,9 Wieshammer et al.,10 Forfar et al.,11 Feldman et al.,12 Park et
al.,13 Ojamaa et al.,14 and Klemperer et al.15

mic reticulum by Ca2+-ATPase is regulated by phospholamban, whose activity, in turn, is modified by

its level of phosphorylation.24 Thus, changes in the
relative amounts of these proteins and the state of
phosphorylation of phospholamban may account for
altered diastolic function in both heart failure and
thyroid disease.24,25 In transgenic mice lacking phospholamban, cardiac contractility was found to be increased and thyroid hormone treatment had no additional inotropic effect.26 This result confirms the role
of phospholamban in thyroid hormonemediated

changes in contractility and explains the increased

diastolic function in patients with hyperthyroidism.8
The increased heart rate, widened pulse pressure,
and increased cardiac output of patients with hyperthyroidism resemble a state of increased adrenergic activity,27 despite normal or low serum concentrations of
catecholamines.4 Studies of the various components of
the adrenergic-receptor complex in plasma membranes
have shown that b-adrenergic receptors, guaninenucleotide regulatory proteins, and adenylyl cyclase
types V and VI are all altered by changes in thyroid
status (Table 2).28,29 The net effect of these changes
is that the sensitivity of the heart to adrenergic stimulation is normal in hyperthyroidism.27,28 Several
plasma-membrane ion transporters, such as Na+/K+
ATPase, Na+/Ca2+ exchanger, and voltage-gated potassium channels, including Kv1.5, Kv4.2, and Kv4.3,
are also regulated at both the transcriptional and posttranscriptional levels by thyroid hormone (Table 2),30,31
thus coordinating the electrochemical and mechanical
responses of the myocardium.
In addition to modulating the rate of transcription
of multiple genes, thyroid hormone has extranuclear
actions in cardiac myocytes32 (Fig. 2). In the short
term, triiodothyronine changes the performance characteristics of various sodium, potassium, and calcium
channels in the heart, and changes in intracellular levels of calcium and potassium can increase inotropy and
chronotropy.33 Thus, both transcriptional and nontranscriptional effects of thyroid hormone may act in
concert to modulate the function of the myocardium

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Cyclic AMP


binding protein




Voltagegated K+


Figure 2. Sites of Action of Triiodothyronine on Cardiac Myocytes.
Triiodothyronine enters the cell, possibly by a specific transport mechanism, and binds to nuclear triiodothyronine receptors. The
complex then binds to thyroid hormone response elements of the genes for several cell constituents and regulates transcription of
these genes, including those for Ca2+-ATPase and phospholamban in the sarcoplasmic reticulum, myosin, b -adrenergic receptors,
adenylyl cyclase, guanine-nucleotidebinding proteins, Na+/Ca2+ exchanger, Na+/K+ATPase, and voltage-gated potassium channels. Nonnuclear triiodothyronine actions on ion channels for sodium (Na+), potassium (K+), and calcium (Ca2+) ions are indicated
at the cell membrane. Dashed arrows indicate pathways with multiple steps, and mRNA denotes messenger RNA.

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a-Myosin heavy chain

Sarcoplasmic reticulum Ca2+-ATPase
b1-Adrenergic receptors
Voltage-gated potassium channels
(Kv1.5, Kv4.2, Kv4.3)

b-Myosin heavy chain

Adenylyl cyclase types V and VI
Triiodothyronine nuclear receptor
Na+/Ca2+ exchanger

and the vascular system under physiologic and pathologic conditions.5


Excess thyroid hormone causes palpitations, with

some degree of exercise impairment and a widened
pulse pressure, independently of the cause of the hyperthyroidism.7-9,34 The changes in heart rate result
from both an increase in sympathetic tone and a decrease in parasympathetic tone.4,34,35 Tachycardia, with
heart rates greater than 90 beats per minute, is common at rest and during sleep; in addition, the normal
increase in heart rate during exercise is exaggerated.35
In a study of 880 patients of widely varying ages, resting tachycardia was second only to goiter as the most
common sign of hyperthyroidism.36
In patients with hyperthyroidism, cardiac output is
50 to 300 percent higher than in normal subjects.
The increase is due to the combined effects of a decrease in systemic vascular resistance, an increase in
resting heart rate, increases in left ventricular contractility and ejection fraction, and an increase in blood
volume (Fig. 1 and Table 1).7,12,23,34 The importance
of the contribution of decreased systemic vascular resistance to the increase in systemic blood flow in patients with hyperthyroidism is evidenced by the results
of studies in which the administration of arterial vasoconstrictors, atropine and phenylephrine, decreased
peripheral blood flow and cardiac output by 34 percent in patients with hyperthyroidism but had no effect in normal subjects.37,38
Patients with hyperthyroidism have increased left
ventricular systolic and diastolic contractile function,
a finding consistent with changes in the expression
of contractile and calcium-regulatory proteins, as described previously.24,25 The rate of increase in intraventricular pressure during systole, the left ventricular
ejection fraction, and the rate of blood flow across
the aortic valve are all increased.12 Similarly, the rates
of chamber relaxation (isovolumic relaxation) and left
ventricular filling, measured as the flow across the mi-

tral valve during diastole, are increased.8 Administration of a b-adrenergicreceptor antagonist to patients
with hyperthyroidism slows the heart rate but does
not alter systolic or diastolic contractile performance,8,9
confirming that thyroid hormone acts directly on cardiac muscle.3,20,25
Atrial Fibrillation

Sinus tachycardia is the most common rhythm disturbance in patients with hyperthyroidism (Table 1).
However, its clinical importance is overshadowed by
the challenges posed by atrial fibrillation, which occurs
in 5 to 15 percent of patients with hyperthyroidism
and which may be the presenting problem.34,39-41 The
higher prevalence rates are derived from studies of
older patients with known or suspected underlying organic heart disease.36,40 A large study found that less
than 1 percent of cases of new-onset atrial fibrillation
were caused by overt hyperthyroidism.42 Therefore,
although serum thyrotropin should be measured in
all patients with new-onset atrial fibrillation in order
to rule out thyroid disease, this association is uncommon in the absence of additional symptoms and signs
of hyperthyroidism.42 However, as many as 13 percent of patients with unexplained atrial fibrillation
have biochemical evidence of hyperthyroidism.40
Whether patients with hyperthyroidism who have
atrial fibrillation should receive anticoagulant therapy
is controversial. In each patient, the risk of bleeding
during anticoagulant treatment must be weighed
against the risk of systemic embolization.41 In a retrospective study of 610 patients with hyperthyroidism,
age rather than the presence of atrial fibrillation
was the main risk factor for embolization.43 In another
study, of 11,354 patients with hyperthyroidism, 288
had atrial fibrillation, of whom 6 had systemic embolization. Of these six patients, five were more than 50
years of age and had atrial fibrillation for more than six
months, and four had congestive heart failure (Nakazawa HK: personal communication). In younger patients with hyperthyroidism and atrial fibrillation who
do not have other heart disease, hypertension, or independent risk factors for embolization, the risk of
anticoagulant therapy probably outweighs the benefits.41 Conversely, in older patients who are known or
suspected to have heart disease, or in those with chronic atrial fibrillation, anticoagulant therapy should be
Treatment of hyperthyroidism is frequently associated with reversion to sinus rhythm; in one study, this
occurred in 62 percent of 163 patients within 8 to 10
weeks after they returned to a euthyroid state.44 In
older patients with or without underlying heart disease
or atrial fibrillation of longer duration, the rate of reversion to sinus rhythm is lower.34,36,44,45 In the absence
of spontaneous reversion, electrical or pharmacologic
cardioversion should be attempted only after the patients condition has been made euthyroid.

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Subclinical hyperthyroidism (characterized by low

serum thyrotropin concentrations and normal serum
thyroid hormone concentrations) in people 60 years
of age or older was associated with nearly a tripling
of the likelihood of atrial fibrillation during a 10-year
follow-up period; specifically, atrial fibrillation developed during follow-up in 21 percent of subjects with
definitely low serum thyrotropin concentrations (0.1
mU per liter), as compared with 12 percent of those
with slightly low concentrations (0.2 to 0.4 mU per
liter) and 8 percent of those with normal concentrations.39 These results have raised the question of
whether patients with definitely low serum thyrotropin concentrations should be treated to forestall atrial
fibrillation. The treatment could consist of radioiodine
or an antithyroid drug or, alternatively, a b-adrenergicreceptor antagonist.46 The last is known to slow
the heart rate, and in a small number of patients with
subclinical hyperthyroidism caused by thyroxine therapy, it prevented atrial fibrillation.9 This observation
may be especially relevant to patients with thyroid cancer, in whom thyroxine therapy is used purposely to
suppress thyrotropin secretion.
Heart Failure

Patients with hyperthyroidism may occasionally have

exertional dyspnea or other symptoms and signs of
heart failure.2,4 In view of the increased cardiac contractile function of patients with hyperthyroidism,8,34
the development of heart failure is unexpected and
raises the question of hyperthyroid cardiomyopathy.11
As noted above, in most patients with hyperthyroidism, cardiac output is high, and the subnormal response to exercise11 may be the result of an inability
to increase heart rate maximally or to lower vascular
resistance further, as normally occurs with exercise.7,8,34
The term high-output failure is not appropriate,
however, because the ability of the heart to maintain
increased cardiac output at rest and with exercise is
preserved.4,12,34 Occasional patients with severe, longstanding hyperthyroidism have poor cardiac contractility, low cardiac output, and symptoms and signs
of heart failure, including a third heart sound and
pulmonary congestion. This complex of findings most
commonly occurs with persistent sinus tachycardia or
atrial fibrillation and is the result of so-called rate-related heart failure.21,34,45
In older patients with heart disease, the increased
workload that results from hyperthyroidism may further impair cardiac function.4 The presence of ischemic
or hypertensive heart disease may compromise the ability of the myocardium to respond to the metabolic
demands of hyperthyroidism.2,7,36,45 Prompt recognition and effective management of cardiac as well as
other organ-system manifestations in patients over
50 years of age are important, because cardiovascular
complications are the chief cause of death after treatment of hyperthyroidism.47

Initial treatment of patients with the entire spectrum

of cardiac-related symptoms and signs of hyperthyroidism, from sinus tachycardia and exertional dyspnea
to heart failure, should include a b-adrenergicreceptor antagonist, such as propranolol, or a selective b1adrenergicreceptor antagonist, such as atenolol.8,46
The goal of therapy is to lower the heart rate to nearly
normal.8,27 This will cause the tachycardia-mediated
component of ventricular dysfunction to improve,
whereas the direct inotropic effects of thyroid hormone will persist.8,9,11 The rapid onset of action of propranolol and the resulting improvement in the cardiac,
neuromuscular, and psychological manifestations of
hyperthyroidism indicate that it should be given to
most patients with overt symptoms.46 Although obstructive lung disease and asthma are contraindications
to the use of a b-adrenergicreceptor antagonist, heart
failure is not.34 Definitive therapy can then be accomplished safely with iodine-131 alone or in combination
with an antithyroid drug.46
Subclinical Hyperthyroidism

Alterations in cardiac hemodynamics have been reported in some, but not all, studies of patients with
subclinical hyperthyroidism.9,48,49 The alterations include an increase in heart rate and left ventricular mass
that improves in response to treatment with a b-adrenergicreceptor antagonist, whereas the positive inotropic response persists.9
As noted above, patients with subclinical hyperthyroidism are at increased risk for atrial fibrillation.9,39
These findings support the long-standing observation
that elderly patients with few symptoms of hyperthyroidism may present with either cardiac-rhythm disturbances or unexplained tachycardia.2,4,24,36,45 Serum
thyrotropin should be measured in all elderly patients
with systolic hypertension, a widened pulse pressure,
recent-onset angina, atrial fibrillation, or an exacerbation of underlying ischemic heart disease.4,34,36,45

The hemodynamic changes typical of hypothyroidism are opposite to those of hyperthyroidism, but they
are accompanied by fewer symptoms and signs (Table
1).23 The most common signs are bradycardia, mild
hypertension, a narrowed pulse pressure, and attenuated activity on the precordial examination. Other
characteristic but nonspecific findings are high serum
concentrations of cholesterol and creatine kinase (the
skeletal-muscle MM isoform).2,23 Pericardial effusions
and nonpitting edema (myxedema) can occur in patients with severe, long-standing hypothyroidism.22,23
The low cardiac output is caused by bradycardia, a decrease in ventricular filling, and a decrease in cardiac
contractility.10,50 Systemic vascular resistance may increase by as much as 50 percent,14,23 and diastolic relaxation and filling are slowed.10 However, heart failure
is rare, because the cardiac output is usually sufficient

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to meet the lowered demand for peripheral oxygen delivery.22 Positron-emission tomographic studies of oxygen consumption in patients with hypothyroidism
have revealed that myocardial work efficiency is lower than in normal subjects.51 From 10 to 25 percent of
patients have diastolic hypertension, which, combined
with the increase in vascular resistance, raises cardiac
afterload and cardiac work.23,51
Although atrial arrhythmias are common and ventricular ectopy is rare in patients with hyperthyroidism, the opposite is true of hypothyroidism.4,23 Hypothyroidism prolongs the cardiac action potential
and the QT interval.31 This, in turn, predisposes the
patient to ventricular irritability and, in rare cases, acquired torsade de pointes.52 These changes may arise
at least in part from the regulatory effect of triiodothyronine on the expression of various ion channels
in the heart (Table 2).31
Thyroxine therapy reverses all the cardiovascular
changes associated with hypothyroidism.2,10,22,50 Young
patients with no evidence of organic heart disease can
be given a replacement dose of thyroxine at the outset.
Older patients, or those with known or suspected ischemic heart disease, should initially be given about
25 percent of the anticipated replacement dose, and
the dose should then be increased in stepwise fashion
at six-to-eight-week intervals.50 In a large study of patients with hypothyroidism who were evaluated for
clinical evidence of ischemic heart disease after the initiation of thyroid hormone therapy, new or worsening
angina or acute myocardial infarction was rare, and
more patients had improvement in anginal symptoms.53 These findings reinforce the important and
potentially beneficial effects of thyroid hormone in improving the efficiency of myocardial oxygen consumption51 and simultaneously lowering systemic vascular
As many as 7 to 10 percent of older women have
subclinical hypothyroidism (characterized by high serum thyrotropin concentrations and normal serum
thyroid hormone concentrations).54 This condition
causes changes in cardiovascular function similar to,
but less marked than, those that occur in patients with
overt hypothyroidism.55,56 When patients with subclinical hypothyroidism are treated with thyroxine, they
improve clinically and systolic and diastolic contractility increases.56,57
Hypothyroidism may result in accelerated atherosclerosis and coronary artery disease, presumably because of the associated hypercholesterolemia and hypertension.23,51,53 Direct evidence of such an effect of
overt hypothyroidism is lacking. However, in a study
of 1149 postmenopausal women in the Netherlands,
those with subclinical hypothyroidism were more likely to have a history of myocardial infarction and had a
higher frequency of calcification of the aorta.58 Whether patients with subclinical hypothyroidism should be
treated is still the subject of disagreement, but from a

cardiac perspective, treatment offers benefit with minimal risk.51,53,56,57


Amiodarone is an iodine-rich antiarrhythmic drug

with proven benefit in the treatment of patients with
ventricular and atrial arrhythmias. It inhibits the conversion of thyroxine to triiodothyronine in most, if not
all, tissues.59,60 Because of its high iodine content, it can
also inhibit thyroid hormone synthesis and secretion.
In patients with normal thyroid function who are treated with amiodarone, serum triiodothyronine concentrations fall by 20 to 25 percent and remain low.59
Serum thyroxine and thyrotropin concentrations increase, sometimes to above the normal range, but then
decline slightly. In 5 to 25 percent of patients, amiodarone causes hypothyroidism.60 Most patients in this
group have some preexisting thyroid disease, such as
chronic autoimmune thyroiditis, that prevents normal recovery from the antithyroid action of iodine.
Amiodarone causes hyperthyroidism in another 2 to
10 percent of patients, with a lower incidence reported
in the United States than elsewhere.59-61 Serial measurements of serum thyrotropin should be performed
at two-month intervals during the first year of treatment with amiodarone, and less often thereafter.60,62
It has been suggested that the antiarrhythmic actions of amiodarone are due to a decrease in the action of triiodothyronine on the heart. However, other
drugs, such as iopanoic acid, that inhibit extrathyroidal
conversion of thyroxine to triiodothyronine do not
have antiarrhythmic actions, and the antiarrhythmic
efficacy of amiodarone does not depend on changes in
serum thyroid hormone concentrations.4,59 Therefore,
a patient in whom hypothyroidism develops during
treatment with amiodarone, like any other patient
with hypothyroidism, should be treated with thyroxine; it is not necessary to discontinue amiodarone,
and thyroxine therapy should not reduce the antiarrhythmic efficacy of amiodarone.4 Because of the lipophilic nature of the drug, total body iodine stores and
urinary iodine excretion do not return to normal levels until six to nine months after amiodarone is discontinued.59
There are two forms of amiodarone-induced hyperthyroidism, designated type 1 and type 2. Type 1
hyperthyroidism is caused by iodine excess and typically occurs in patients with nodular goiters who live
in regions in which iodine intake is somewhat low.
Type 2 hyperthyroidism is caused by an inflammatory
process that causes the release of preformed thyroxine
and triiodothyronine from the thyroid gland, possibly
in response to the inflammatory cytokine interleukin-6.61 Patients with type 1 hyperthyroidism may have
normal or even high 24-hour values for the uptake of
radioiodine by the thyroid gland, and therefore they
can be treated with radioiodine. Alternatively, they can
be treated with an antithyroid drug.46 Patients with

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type 2 hyperthyroidism have little or no thyroid enlargement and low values for uptake of radioiodine
by the thyroid. The most effective therapy for these
patients is prednisone at doses of 30 to 40 mg daily.61
There is usually improvement in several weeks, after
which the dose can gradually be reduced. Treatment
with an antithyroid drug alone is usually ineffective.
However, a b-adrenergicreceptor antagonist may be
helpful, especially in patients with tachyarrhythmias or
exercise intolerance resulting from muscle weakness.46
Whether surgical thyroidectomy to treat amiodaroneinduced hyperthyroidism is feasible depends on the
risk to the patient associated with anesthesia. Such
treatment will lower the serum levels of thyroxine and
triiodothyronine very predictably.46

Thyroid hormone metabolism is altered in many

patients with acute or chronic cardiac disease, as it is
in patients with other nonthyroidal illnesses. For example, in patients with uncomplicated acute myocardial infarction, serum triiodothyronine concentrations
fall by about 20 percent, and serum free triiodothyronine concentrations fall by about 40 percent, with
a nadir on day 4 after the infarction.63
Patients with heart failure also have low serum triiodothyronine concentrations, and the decrease is proportional to the degree of heart failure, as assessed by
the New York Heart Association (NYHA) functional
classification.64 In a prospective study of 112 patients
with NYHA class II to IV heart failure, 6 percent had
subclinical hypothyroidism, 9 percent had hypothyroidism and were taking thyroxine, and 31 percent had
low serum triiodothyronine concentrations but normal serum thyroxine and thyrotropin concentrations
(Ascheim D: personal communication). Whether the
changes in thyroid hormone metabolism contribute
to the impairment of cardiovascular function in patients with heart failure is not known.65 Two studies
have addressed this issue. In 23 patients with advanced
heart failure, a single intravenous dose of 58 g of triiodothyronine resulted in an increase in cardiac output and a decrease in systemic vascular resistance two
hours after administration, without any evidence of
myocardial ischemia, rhythm disturbances, or other
untoward effects.66 In a study of 20 patients with
chronic heart failure, treatment with 0.1 mg of thyroxine daily for 12 weeks improved exercise performance, increased the cardiac index, and decreased systemic vascular resistance.67
The decrease in the serum triiodothyronine concentration that occurs in patients with nonthyroidal illnesses could alter cardiac function and the expression
of cardiac genes (i.e., the cardiac phenotype).5,15,68 To
address this issue, left ventricular systolic and diastolic
function was evaluated in animals in which low se-

rum concentrations of triiodothyronine were induced

by caloric restriction.69 Diminished cardiac contractility and altered gene expression similar to those seen in
experimental hypothyroidism developed in the animals.31 Replacement doses of triiodothyronine increased left ventricular function and normalized the
expression of triiodothyronine-responsive genes, thus
providing evidence of the potential therapeutic value
of triiodothyronine replacement for the improvement
of cardiac contractility in patients with nonthyroidal
In patients undergoing cardiopulmonary bypass,
serum total and free triiodothyronine concentrations
decrease transiently in the immediate postoperative
period.15,70 A reduction in surgical mortality was suggested by an open-label study of 68 patients who were
treated with intravenous triiodothyronine at the time
of removal of the aortic cross-clamp,71 and by another
study in which 111 consecutive patients at high risk
who were undergoing coronary-artery bypass grafting
were given triiodothyronine immediately before surgery and for four to eight hours postoperatively.72 In
a prospective, randomized study of 142 patients, those
given triiodothyronine intravenously at a dose of 1.4
g per kilogram of body weight over a period of
6 hours (average total dose, 110 g), starting immediately after surgery, had a higher cardiac output and
lower systemic resistance during the first 24 hours after surgery than those given placebo.15 In this study,
the frequency of atrial fibrillation during the first four
days after surgery was lower in the patients given triiodothyronine (24 percent vs. 46 percent),73 although
postoperative mortality was not altered.15,73 These results were confirmed in a similar study of 170 patients.74 However, in a third study of 211 patients, in
which triiodothyronine or dopamine was compared
with placebo, there were no differences in outcome.75
Administration of triiodothyronine had no adverse effects in any of the studies.15,71-75
In children undergoing bypass surgery for the correction of complex congenital heart disease, serum triiodothyronine concentrations fall by more than 60
percent and remain low for up to eight days after surgery.76,77 The decrease was more prolonged in children
who had more complex surgical procedures.78 Pharmacologic evaluation of 28 children given triiodothyronine postoperatively indicated that the clearance of
the hormone from the circulation was more rapid than
predicted from studies of normal adults.79 Recent randomized studies in infants undergoing cardiopulmonary bypass showed that triiodothyronine repletion
could be accomplished safely80 and with a resulting
improvement in postoperative cardiac function.81 In
children with congenital heart disease who were given
triiodothyronine to restore serum concentrations to
normal after surgery, cardiac output increased by more
than 20 percent and vascular resistance decreased by
25 percent, as compared with untreated children.82

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Thyroid hormone has both direct and indirect actions on the cardiovascular system. Patients with thyroid disease, especially those with hyperthyroidism, often have symptoms and signs indicating changes in
cardiovascular hemodynamics. Indeed, symptoms and
signs referable to the cardiovascular system may be the
only manifestations of thyroid dysfunction, and thyroid function should therefore be assessed by the
measurement of serum thyrotropin concentrations in
all patients with cardiovascular disease. Patients with
cardiovascular disease, like patients with other nonthyroidal illnesses, have changes in thyroid hormone
metabolism that may alter cardiac function. Although
some data suggest that the administration of triiodothyronine may benefit some patients with cardiovascular disease, further studies are required to establish
specific treatment recommendations.
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3. Dillmann WH. Biochemical basis of thyroid hormone action in the
heart. Am J Med 1990;88:626-30.
4. Polikar R , Burger AG, Scherrer U, Nicod P. The thyroid and the heart.
Circulation 1993;87:1435-41.
5. Klemperer J, Ojamaa K, Klein I. Thyroid hormone therapy in cardiovascular disease. Prog Cardiovasc Dis 1996;38:329-36.
6. Klein I, Levey GS. The cardiovascular system in thyrotoxicosis. In:
Braverman LE, Utiger RD, eds. Werner & Ingbars the thyroid: a fundamental and clinical text. 8th ed. Philadelphia: Lippincott Williams &
Wilkins, 2000:596-604.
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