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Thyroid Hormone Dan Cardiovascular Nejm
Thyroid Hormone Dan Cardiovascular Nejm
Thyroid Hormone Dan Cardiovascular Nejm
Mechanisms of Disease
F R A N K L I N H . E P S T E I N , M. D. , Editor
AND
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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
Decreased
systemic vascular
resistance
Increased
tissue
thermogenesis
Decreased
effective arterial
filling volume
Increased
renal sodium
reabsorption
Triiodothyronine
Increased blood
volume
Increased
cardiac output
Increased cardiac
inotropy and chronotropy
MEASURE
NORMAL
RANGE
VALUES
HYPER-
IN
THYROIDISM
VALUES
HYPO-
IN
THYROIDISM
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Triiodothyronine
Ca2+
Cell
membrane
Sarcoplasmic
reticulum
Ca2+
Ca2+
Ca2+
Phospholamban
Ca2+ATPase
Thyroid
hormone
response
element
Myosin
Actin
Nucleus
Triiodothyronine
nuclear
receptor
mRNA
Cyclic AMP
Ca2+
Protein
synthesis
Guanine-nucleotide
binding protein
K+
Na+
Ca2+
Adenylyl
cyclase
K+
Na+
Na+/Ca2+
exchanger
Na+/K+
ATPase
Voltagegated K+
channel
b-Adrenergic
receptor
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-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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The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne
NEGATIVE REGULATION
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
initiated.
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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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
HYPOTHYROIDISM
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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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 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
resistance.13,14
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
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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
CHANGES IN THYROID FUNCTION
THAT ACCOMPANY HEART DISEASE
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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
CONCLUSIONS
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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