M EC H A N I S M S O F D I S E AS E

Mechanisms of Disease Thyroid hormone increases blood volume.6 As a

F R A N K L I N H . E P S T E I N , M . D. , Editor
T HYROID H ORMONE AND THE
C ARDIOVASCULAR S YSTEM
IRWIN KLEIN, M.D., AND
result of the decrease in systemic vascular resistance,
the effective arterial filling volume falls, causing an in-
crease in renin release and activation of the angioten-
sin–aldosterone axis.16 This, in turn, stimulates renal
sodium reabsorption, leading to an increase in plasma
volume. Thyroid hormone also stimulates erythropoi-
etin secretion. The combined effect of these two ac-
tions is an increase in blood volume and preload,
KAIE OJAMAA, PH.D.
which further increases cardiac output (Fig. 1).
CELLULAR MECHANISMS OF THYROID

T
HYROID hormone has many effects on the HORMONE ACTION
heart and vascular system.1 Many of the clinical
To understand the alterations in cardiac function
manifestations of hyperthyroidism are due to
that accompany thyroid disease, it is necessary to re-
the ability of thyroid hormone to alter cardiovascular
view the mechanisms by which thyroid hormone acts
hemodynamics.2 The hemodynamic effects of hypo-
on cardiac myocytes and vascular smooth-muscle
thyroidism are opposite to those of hyperthyroidism,
cells.2,3,14 Triiodothyronine is the biologically relevant
although the clinical manifestations are less obvious.
thyroid hormone molecule in cardiac myocytes, as in
This review will integrate what is known about the
other cells, and there is evidence that the cell mem-
mechanisms of thyroid hormone action on the heart2-5
brane contains specific transport proteins for triiodo-
with recent observations from both experimental and
thyronine17 (Fig. 2). Conversion of thyroxine to triio-
clinical studies of hyperthyroidism and hypothyroid-
dothyronine does not occur to any measurable degree
ism. We will also address the potential role of thyroid
in cardiac myocytes.17 Once in the myocyte, triiodo-
hormone treatment in patients with acute or chronic
thyronine enters the nucleus and binds to nuclear re-
cardiac disease.
ceptors that then bind to thyroid hormone response
EFFECTS OF THYROID HORMONE elements in target genes (Fig. 2). The triiodothyro-
ON MYOCARDIAL CONTRACTILITY nine nuclear receptors bind to DNA as monomers or
AND HEMODYNAMICS homodimers, or as heterodimers composed of a tri-
iodothyronine nuclear receptor and another receptor
The effects of triiodothyronine, the active cellular
from the steroid hormone receptor family.18 Occupan-
form of thyroid hormone, on cardiovascular physiol-
cy of receptors by triiodothyronine in combination
ogy are shown in Figure 1, and the effects of hyper-
with recruited coactivators leads to optimal transcrip-
thyroidism and hypothyroidism on various hemody-
tional activation. In the absence of triiodothyronine,
namic measures are listed in Table 1. It is clear from
the receptors repress genes that are positively regulat-
many invasive and noninvasive measurements in pa-
ed by thyroid hormone.19
tients with thyroid disease that cardiac functions such
Triiodothyronine-responsive genes that encode both
as heart rate, cardiac output, and systemic vascular re-
structural and regulatory proteins in the heart are list-
sistance are closely linked to thyroid status. In addition
ed in Table 2. The two myosin heavy chains (a and b)
to the well-recognized action of thyroid hormone to
are myofibrillar proteins that make up the thick fila-
increase peripheral oxygen consumption and substrate
ment of the contractile apparatus of cardiac myocytes.
requirements, which causes a secondary increase in
In animals, transcription of the a-myosin heavy chain
cardiac contractility, the hormone also increases cardi-
is activated by triiodothyronine, whereas transcription
ac contractility directly.2-4 Triiodothyronine decreases
of the b-myosin heavy chain is repressed.19,20 In hu-
systemic vascular resistance by dilating the resistance
mans, the b-myosin heavy chain predominates,21,22 and
arterioles of the peripheral circulation.13 The vasodi-
although cardiac contractile function is markedly al-
lation is due to a direct effect of triiodothyronine on
tered in patients with thyroid disease, the changes in
vascular smooth-muscle cells that promotes relax-
expression of myosin heavy-chain isoforms are prob-
ation.14 The clinical correlate of this finding is that a
ably of insufficient magnitude to account for the func-
high dose of triiodothyronine decreases systemic vas-
tional changes.22,23
cular resistance and increases cardiac output within
Production of the sarcoplasmic reticulum proteins,
hours after coronary-artery bypass grafting.15
calcium-activated ATPase (Ca2+-ATPase) and phos-
pholamban, is regulated by triiodothyronine acting
From the Division of Endocrinology, Department of Medicine, North
through changes in gene transcription.3,24 Release of
Shore University Hospital, Manhasset, N.Y., and the Departments of Med- calcium and its reuptake into the sarcoplasmic retic-
icine and Cell Biology, New York University School of Medicine, New York. ulum are critical determinants of systolic contractile
Address reprint requests to Dr. Klein at the Division of Endocrinology,
North Shore University Hospital, 300 Community Dr., Manhasset, NY function and diastolic relaxation3,8,24 (Fig. 2). Active
11030, or at iklein@nshs.edu. transport of calcium into the lumen of the sarcoplas-

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 The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne

Increased Decreased
tissue systemic vascular
thermogenesis resistance
Decreased
effective arterial
filling volume

Increased
Triiodothyronine renal sodium
reabsorption

Increased blood
volume
Increased Increased cardiac
cardiac output 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 (thermo-
genesis), vascular resistance, blood volume, cardiac contractility, and heart rate. Adapted from Klein and Levey,6 with the permis-
sion of the publisher.

changes in contractility and explains the increased

TABLE 1. CHANGES IN CARDIOVASCULAR FUNCTION diastolic function in patients with hyperthyroidism.8
ASSOCIATED WITH THYROID DISEASE.*
The increased heart rate, widened pulse pressure,
and increased cardiac output of patients with hyper-
VALUES VALUES thyroidism resemble a state of increased adrenergic ac-
NORMAL INHYPER- HYPO-
IN
MEASURE RANGE THYROIDISM THYROIDISM
tivity,27 despite normal or low serum concentrations of
catecholamines.4 Studies of the various components of
Systemic vascular resistance 1500–1700 700–1200 2100–2700
(dyn·sec·cm¡5)
the adrenergic-receptor complex in plasma membranes
Heart rate (beats/min) 72–84 88–130 60–80 have shown that b-adrenergic receptors, guanine-
Ejection fraction (%) 50–60 >60 «60 nucleotide regulatory proteins, and adenylyl cyclase
Cardiac output (liters/min) 4.0–6.0 >7.0 <4.5 types V and VI are all altered by changes in thyroid
Isovolumic relaxation time (msec) 60–80 25–40 >80 status (Table 2).28,29 The net effect of these changes
Blood volume (% of normal value) 100 105.5 84.5 is that the sensitivity of the heart to adrenergic stim-
ulation is normal in hyperthyroidism.27,28 Several
*The values for patients with hyperthyroidism and those with hypothy-
roidism are taken from Klein and Levey,6 Graettinger et al.,7 Mintz et al.,8 plasma-membrane ion transporters, such as Na+/K+–
Biondi et al.,9 Wieshammer et al.,10 Forfar et al.,11 Feldman et al.,12 Park et ATPase, Na+/Ca2+ exchanger, and voltage-gated po-
al.,13 Ojamaa et al.,14 and Klemperer et al.15
tassium channels, including Kv1.5, Kv4.2, and Kv4.3,
are also regulated at both the transcriptional and post-
transcriptional levels by thyroid hormone (Table 2),30,31
thus coordinating the electrochemical and mechanical
mic reticulum by Ca2+-ATPase is regulated by phos- responses of the myocardium.
pholamban, whose activity, in turn, is modified by In addition to modulating the rate of transcription
its level of phosphorylation.24 Thus, changes in the of multiple genes, thyroid hormone has extranuclear
relative amounts of these proteins and the state of actions in cardiac myocytes32 (Fig. 2). In the short
phosphorylation of phospholamban may account for term, triiodothyronine changes the performance char-
altered diastolic function in both heart failure and acteristics of various sodium, potassium, and calcium
thyroid disease.24,25 In transgenic mice lacking phos- channels in the heart, and changes in intracellular lev-
pholamban, cardiac contractility was found to be in- els of calcium and potassium can increase inotropy and
creased and thyroid hormone treatment had no addi- chronotropy.33 Thus, both transcriptional and non-
tional inotropic effect.26 This result confirms the role transcriptional effects of thyroid hormone may act in
of phospholamban in thyroid hormone–mediated concert to modulate the function of the myocardium

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 M EC H A N I S M S O F D I S E AS E

Ca2+ Triiodothyronine

Sarcoplasmic Cell
reticulum membrane

Ca2+ Phospholamban
Nucleus

Ca2+ Ca2+-
Ca2+ ATPase Thyroid
hormone
response
element
Triiodothyronine
Actin Myosin nuclear
mRNA
receptor

Cyclic AMP
Ca2+

Protein
synthesis

Guanine-nucleotide–
binding protein

K+

Na+
Ca2+

K+ Adenylyl
cyclase b-Adrenergic
Na+ Na+/K+– receptor
ATPase Voltage-
Na+/Ca2+ gated K+
exchanger channel

Triiodothyronine

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-nucleotide–binding proteins, Na+/Ca2+ exchanger, Na+/K+–ATPase, and voltage-gated potassium chan-
nels. 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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 The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne
TABLE 2. REGULATION OF GENES CODING FOR CARDIAC PROTEINS
BY THYROID HORMONE.
POSITIVE REGULATION NEGATIVE REGULATION
a-Myosin heavy chain b-Myosin heavy chain
Sarcoplasmic reticulum Ca2+-ATPase Phospholamban
b1-Adrenergic receptors Adenylyl cyclase types V and VI
Guanine-nucleotide–regulatory Triiodothyronine nuclear receptor
proteins a1
Na+/K+–ATPase Na+/Ca2+ exchanger
Voltage-gated potassium channels
(Kv1.5, Kv4.2, Kv4.3)
and the vascular system under physiologic and patho-
logic conditions.5
HYPERTHYROIDISM
Excess thyroid hormone causes palpitations, with
some degree of exercise impairment and a widened
pulse pressure, independently of the cause of the hy-
perthyroidism.7-9,34 The changes in heart rate result
from both an increase in sympathetic tone and a de-
crease in parasympathetic tone.4,34,35 Tachycardia, with
heart rates greater than 90 beats per minute, is com-
mon 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, rest-
ing 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 de-
crease in systemic vascular resistance, an increase in
resting heart rate, increases in left ventricular contrac-
tility 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 re-
sistance to the increase in systemic blood flow in pa-
tients with hyperthyroidism is evidenced by the results
of studies in which the administration of arterial vas-
oconstrictors, atropine and phenylephrine, decreased
peripheral blood flow and cardiac output by 34 per-
cent in patients with hyperthyroidism but had no ef-
fect 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 de-
scribed previously.24,25 The rate of increase in intra-
ventricular 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-
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tral valve during diastole, are increased.8 Administra-
tion of a b-adrenergic–receptor 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 car-
diac muscle.3,20,25
Atrial Fibrillation
Sinus tachycardia is the most common rhythm dis-
turbance 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 or-
ganic 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 uncom-
mon in the absence of additional symptoms and signs
of hyperthyroidism.42 However, as many as 13 per-
cent 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 ret-
rospective 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 embo-
lization. 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 (Naka-
zawa HK: personal communication). In younger pa-
tients with hyperthyroidism and atrial fibrillation who
do not have other heart disease, hypertension, or in-
dependent risk factors for embolization, the risk of
anticoagulant therapy probably outweighs the bene-
fits.41 Conversely, in older patients who are known or
suspected to have heart disease, or in those with chron-
ic atrial fibrillation, anticoagulant therapy should be
initiated.
Treatment of hyperthyroidism is frequently associ-
ated 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 re-
version 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 pa-
tient’s condition has been made euthyroid.
 M EC H A N I S M S O F D I S E AS E
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 devel-
oped 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 concentra-
tions.39 These results have raised the question of
whether patients with definitely low serum thyrotro-
pin concentrations should be treated to forestall atrial
fibrillation. The treatment could consist of radioiodine
or an antithyroid drug or, alternatively, a b-adrener-
gic–receptor antagonist.46 The last is known to slow
the heart rate, and in a small number of patients with
subclinical hyperthyroidism caused by thyroxine ther-
apy, it prevented atrial fibrillation.9 This observation
may be especially relevant to patients with thyroid can-
cer, 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 con-
tractile 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 hyperthyroid-
ism, cardiac output is high, and the subnormal re-
sponse 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, long-
standing hyperthyroidism have poor cardiac contrac-
tility, 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-relat-
ed heart failure.21,34,45
In older patients with heart disease, the increased
workload that results from hyperthyroidism may fur-
ther impair cardiac function.4 The presence of ischemic
or hypertensive heart disease may compromise the abil-
ity of the myocardium to respond to the metabolic
demands of hyperthyroidism.2,7,36,45 Prompt recogni-
tion 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 treat-
ment of hyperthyroidism.47
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Initial treatment of patients with the entire spectrum
of cardiac-related symptoms and signs of hyperthy-
roidism, from sinus tachycardia and exertional dyspnea
to heart failure, should include a b-adrenergic–recep-
tor antagonist, such as propranolol, or a selective b1-
adrenergic–receptor 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 hor-
mone will persist.8,9,11 The rapid onset of action of pro-
pranolol 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 ob-
structive lung disease and asthma are contraindications
to the use of a b-adrenergic–receptor antagonist, heart
failure is not.34 Definitive therapy can then be accom-
plished safely with iodine-131 alone or in combination
with an antithyroid drug.46
Subclinical Hyperthyroidism
Alterations in cardiac hemodynamics have been re-
ported in some, but not all, studies of patients with
subclinical hyperthyroidism.9,48,49 The alterations in-
clude an increase in heart rate and left ventricular mass
that improves in response to treatment with a b-adre-
nergic–receptor antagonist, whereas the positive ino-
tropic response persists.9
As noted above, patients with subclinical hyperthy-
roidism are at increased risk for atrial fibrillation.9,39
These findings support the long-standing observation
that elderly patients with few symptoms of hyperthy-
roidism may present with either cardiac-rhythm dis-
turbances 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 exacerba-
tion of underlying ischemic heart disease.4,34,36,45
HYPOTHYROIDISM
The hemodynamic changes typical of hypothyroid-
ism 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 atten-
uated 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 pa-
tients with severe, long-standing hypothyroidism.22,23
The low cardiac output is caused by bradycardia, a de-
crease in ventricular filling, and a decrease in cardiac
contractility.10,50 Systemic vascular resistance may in-
crease by as much as 50 percent,14,23 and diastolic re-
laxation and filling are slowed.10 However, heart failure
is rare, because the cardiac output is usually sufficient
 The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne
to meet the lowered demand for peripheral oxygen de-
livery.22 Positron-emission tomographic studies of ox-
ygen consumption in patients with hypothyroidism
have revealed that myocardial work efficiency is low-
er 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 ven-
tricular ectopy is rare in patients with hyperthyroid-
ism, the opposite is true of hypothyroidism.4,23 Hy-
pothyroidism prolongs the cardiac action potential
and the QT interval.31 This, in turn, predisposes the
patient to ventricular irritability and, in rare cases, ac-
quired torsade de pointes.52 These changes may arise
at least in part from the regulatory effect of triiodo-
thyronine 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 is-
chemic 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 pa-
tients with hypothyroidism who were evaluated for
clinical evidence of ischemic heart disease after the ini-
tiation of thyroid hormone therapy, new or worsening
angina or acute myocardial infarction was rare, and
more patients had improvement in anginal symp-
toms.53 These findings reinforce the important and
potentially beneficial effects of thyroid hormone in im-
proving the efficiency of myocardial oxygen consump-
tion51 and simultaneously lowering systemic vascular
resistance.13,14
As many as 7 to 10 percent of older women have
subclinical hypothyroidism (characterized by high se-
rum 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 subclin-
ical hypothyroidism are treated with thyroxine, they
improve clinically and systolic and diastolic contrac-
tility increases.56,57
Hypothyroidism may result in accelerated athero-
sclerosis and coronary artery disease, presumably be-
cause of the associated hypercholesterolemia and hy-
pertension.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 like-
ly to have a history of myocardial infarction and had a
higher frequency of calcification of the aorta.58 Wheth-
er patients with subclinical hypothyroidism should be
treated is still the subject of disagreement, but from a
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cardiac perspective, treatment offers benefit with min-
imal risk.51,53,56,57
AMIODARONE AND THYROID FUNCTION
Amiodarone is an iodine-rich antiarrhythmic drug
with proven benefit in the treatment of patients with
ventricular and atrial arrhythmias. It inhibits the con-
version 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 treat-
ed with amiodarone, serum triiodothyronine concen-
trations fall by 20 to 25 percent and remain low.59
Serum thyroxine and thyrotropin concentrations in-
crease, sometimes to above the normal range, but then
decline slightly. In 5 to 25 percent of patients, amio-
darone causes hypothyroidism.60 Most patients in this
group have some preexisting thyroid disease, such as
chronic autoimmune thyroiditis, that prevents nor-
mal 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 meas-
urements of serum thyrotropin should be performed
at two-month intervals during the first year of treat-
ment with amiodarone, and less often thereafter.60,62
It has been suggested that the antiarrhythmic ac-
tions of amiodarone are due to a decrease in the ac-
tion 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 thyrox-
ine; it is not necessary to discontinue amiodarone,
and thyroxine therapy should not reduce the antiar-
rhythmic efficacy of amiodarone.4 Because of the lip-
ophilic nature of the drug, total body iodine stores and
urinary iodine excretion do not return to normal lev-
els until six to nine months after amiodarone is discon-
tinued.59
There are two forms of amiodarone-induced hy-
perthyroidism, designated type 1 and type 2. Type 1
hyperthyroidism is caused by iodine excess and typ-
ically 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 interleu-
kin-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
 M EC H A N I S M S O F D I S E AS E
type 2 hyperthyroidism have little or no thyroid en-
largement 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-adrenergic–receptor antagonist may be
helpful, especially in patients with tachyarrhythmias or
exercise intolerance resulting from muscle weakness.46
Whether surgical thyroidectomy to treat amiodarone-
induced 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
CHANGES IN THYROID FUNCTION
THAT ACCOMPANY HEART DISEASE
Thyroid hormone metabolism is altered in many
patients with acute or chronic cardiac disease, as it is
in patients with other nonthyroidal illnesses. For ex-
ample, in patients with uncomplicated acute myocar-
dial infarction, serum triiodothyronine concentrations
fall by about 20 percent, and serum free triiodothy-
ronine concentrations fall by about 40 percent, with
a nadir on day 4 after the infarction.63
Patients with heart failure also have low serum tri-
iodothyronine concentrations, and the decrease is pro-
portional 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 hypothy-
roidism and were taking thyroxine, and 31 percent had
low serum triiodothyronine concentrations but nor-
mal serum thyroxine and thyrotropin concentrations
(Ascheim D: personal communication). Whether the
changes in thyroid hormone metabolism contribute
to the impairment of cardiovascular function in pa-
tients 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 µg of tri-
iodothyronine resulted in an increase in cardiac out-
put 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 thy-
roxine daily for 12 weeks improved exercise perform-
ance, increased the cardiac index, and decreased sys-
temic vascular resistance.67
The decrease in the serum triiodothyronine concen-
tration that occurs in patients with nonthyroidal ill-
nesses 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-
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Copyright © 2001 Massachusetts Medical Society. All rights reserved.
rum concentrations of triiodothyronine were induced
by caloric restriction.69 Diminished cardiac contractil-
ity and altered gene expression similar to those seen in
experimental hypothyroidism developed in the ani-
mals.31 Replacement doses of triiodothyronine in-
creased 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
illnesses.64-66
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 sug-
gested 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 sur-
gery 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
µg per kilogram of body weight over a period of
6 hours (average total dose, 110 µg), starting imme-
diately after surgery, had a higher cardiac output and
lower systemic resistance during the first 24 hours af-
ter 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 tri-
iodothyronine (24 percent vs. 46 percent),73 although
postoperative mortality was not altered.15,73 These re-
sults were confirmed in a similar study of 170 pa-
tients.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 ef-
fects in any of the studies.15,71-75
In children undergoing bypass surgery for the cor-
rection of complex congenital heart disease, serum tri-
iodothyronine concentrations fall by more than 60
percent and remain low for up to eight days after sur-
gery.76,77 The decrease was more prolonged in children
who had more complex surgical procedures.78 Phar-
macologic evaluation of 28 children given triiodothy-
ronine postoperatively indicated that the clearance of
the hormone from the circulation was more rapid than
predicted from studies of normal adults.79 Recent ran-
domized studies in infants undergoing cardiopulmo-
nary 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
 The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne
CONCLUSIONS
Thyroid hormone has both direct and indirect ac-
tions on the cardiovascular system. Patients with thy-
roid disease, especially those with hyperthyroidism, of-
ten 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 thy-
roid 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 non-
thyroidal illnesses, have changes in thyroid hormone
metabolism that may alter cardiac function. Although
some data suggest that the administration of triiodo-
thyronine may benefit some patients with cardiovas-
cular disease, further studies are required to establish
specific treatment recommendations.
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