INTRODUCTION — Thyroid hormone has important effects on cardiac muscle, the peripheral circulation, and the sympathetic nervous system that alter cardiovascular hemodynamics in a predictable way in patients with hyperthyroidism. The main changes are :
●Increases in heart rate, cardiac contractility, systolic and mean pulmonary artery pressure, cardiac output, diastolic relaxation, and myocardial oxygen consumption
●Reductions in systemic vascular resistance and diastolic pressure
The major cardiovascular manifestations of hyperthyroidism will be reviewed here. Other symptoms associated with this disorder are discussed separately. (See "Overview of the clinical manifestations of hyperthyroidism in adults".)
PATHOPHYSIOLOGY — The cellular actions of thyroid hormone are mediated by the binding of triiodothyronine (T3) to nuclear receptors. It is T3 and not thyroxine (T4) that is transported into the cardiac myocyte. The subsequent binding of the T3-receptor complexes to DNA regulates the expression of genes, specifically those regulating calcium cycling in the cardiac myocyte [1,2]. T3 may also have non-nuclear actions through mechanisms not yet fully understood .
Adrenergic effects — Some actions of T3 on the heart produce clinical findings similar to those of beta-adrenergic stimulation . The interaction between T3 and the adrenergic nervous system is best exemplified by the ability of essentially all beta blockers to alleviate many of the symptoms of hyperthyroidism (see "Beta blockers in the treatment of hyperthyroidism"). This may involve increased beta-adrenergic receptor density, increased expression of the stimulatory guanine nucleotide-binding protein (G protein), and downregulation of the cardiac-specific isoform of the adenylyl cyclase catalytic subunit [5-7]. Whether humans with hyperthyroidism have increased sensitivity to catecholamines is uncertain, but it seems clear that T3 effects on the heart can occur independently of beta-adrenergic receptor stimulation .
Chronotropic and inotropic stimulation — Hyperthyroidism predictably increases heart rate and cardiac contractility [6,8]. Virtually all measures of cardiac function (including left ventricular ejection fraction [LVEF], the rate of ventricular pressure development, diastolic relaxation, and cardiac output) are increased . As a result, cardiac output increases by as much as 250 percent and pulse pressure widens (figure 1). These functional changes are most likely the result of an increase in expression of myocardial sarcoplasmic reticulum calcium-dependent adenosine triphosphatase, a decrease in the expression of its inhibitor, phospholamban, and a decline in systemic vascular resistance .
●Tachycardia, at rest, during sleep, and exaggerated during exercise.
●Palpitations, due to both tachycardia and more forceful cardiac contractility.
●Hyperdynamic precordium, indicative of the increase in cardiac contractility and cardiac workload.
●Systolic hypertension with widened pulse pressure .
●Exertional dyspnea, which is more due to respiratory and skeletal muscle weakness than cardiac dysfunction.
●Angina-like chest pain, with electrocardiogram (ECG) changes suggesting myocardial ischemia, which can occur especially in women; this appears to be the result of coronary vasospasm  and responds to treatment with orally administered calcium channel blockers and rendering the patients euthyroid.
●Increase in left ventricular (LV) mass index and LV hypertrophy [12,13].
●Increased ventricular irritability, especially in amiodarone-treated patients with a prior history of ventricular ectopy (often in the setting of implanted cardiac defibrillators) .
Hyperthyroidism is also associated with an increased risk of atrial fibrillation, heart failure, pulmonary hypertension, and angina, as described in the following sections.
Atrial fibrillation — Hyperthyroid patients with normal hearts have more premature supraventricular depolarizations, premature atrial complex (PAC; also referred to a premature atrial beat, premature supraventricular complex, or premature supraventricular beat), more nonsustained supraventricular tachycardias, increased heart rate, and reduced heart rate variability . The latter is primarily the result of decreased parasympathetic tone. These electrical triggers may contribute to paroxysmal atrial tachycardia, atrial fibrillation, and atrial flutter. Among these arrhythmias, atrial fibrillation is the most common, occurring in 5 to 15 percent of patients, especially patients ≥60 years of age [6,18,19]. In a population-based study of 40,628 patients with clinical hyperthyroidism, 8.3 percent had atrial fibrillation or flutter . Factors associated with increased risk included male sex, increasing age, coronary heart disease, heart failure, and valvular heart disease . The association with increasing age presumably reflects the age-related reduction in the threshold for developing atrial fibrillation.
Complications of atrial fibrillation in patients with hyperthyroidism include heart failure and thromboembolism, although it remains controversial whether atrial fibrillation in hyperthyroidism is associated with a higher thromboembolic risk than atrial fibrillation in other settings [1,6,19] (see "Atrial fibrillation in adults: Selection of candidates for anticoagulation"). Patients with overt thyrotoxicosis, especially females of East Asian descent (eg, Japanese, Chinese, and Korean), may present with focal neurologic findings, falsely suggesting central nervous system embolic events when indeed it is the result of central arterial vasospasm (moyamoya disease) [4,20,21]. (See 'Stroke' below.)
Approximately 55 to 75 percent of patients with atrial fibrillation due to hyperthyroidism and no other underlying cardiac valvular disease will return to sinus rhythm within three to six months after treatment of the thyrotoxic state . In patients with persistent atrial fibrillation, the question of additional forms of therapy needs to be addressed. (See "Management of atrial fibrillation: Rhythm control versus rate control".)
The other atrial arrhythmias associated with hyperthyroidism are most likely to be detected by monitoring, because they do not often cause symptoms. The risk of ventricular arrhythmias in the non-ischemic (normal) heart is not increased .
Heart failure — Heart failure is most commonly seen as a result of longstanding, often untreated disease with coexistent atrial fibrillation. In one study, only 6 percent of hyperthyroid patients had heart failure, average age was 66 years; 94 percent had coexistent atrial fibrillation and 47 percent had LV systolic dysfunction . In others, it is a complication of prolonged marked sinus tachycardia. The signs and symptoms of heart failure almost always resolve when the ventricular rate is slowed, normal sinus rhythm is restored, and the patients are rendered euthyroid [4,5,22].
In one study, half had LV systolic dysfunction with LV ejection fraction <50 percent, and 85 percent had resolution of LV dysfunction after attaining euthyroidism .
Heart failure in the absence of underlying cardiac disease or arrhythmia is thought to reflect a rate-related cardiomyopathy, which disappears when the hyperthyroidism is treated. There is no clear histopathologic correlate of this cardiomyopathy, and treatment is primarily directed at rate control with beta-adrenergic blockade . Pulmonary hypertension can also produce signs of isolated right heart failure with a rise in central venous pressure, neck vein distension, and hepatic congestion [4,23]. (See 'Pulmonary hypertension' below and "Arrhythmia-induced cardiomyopathy".)
Hyperthyroidism is associated with an increase in N-terminal pro-B natriuretic peptide (NT-proBNP) in hyperthyroid patients without cardiac insufficiency . NT-proBNP was positively correlated with LV end-diastolic diameter and interventricular septal thickness, and negatively correlated with LV ejection fraction . Mild iatrogenic hyperthyroidism is also associated with an increase in NT-proBNP, without a measurable increase in systolic blood pressure or pulse pressure . This may reflect the increased atrial size which results from increased renal sodium reabsorption, plasma volume, or pulmonary hypertension .
Tricuspid and/or mitral regurgitation have also been described in patients with hyperthyroidism of all causes [26-28].
Pulmonary hypertension — Pulmonary hypertension has been reported with increasing frequency in patients with overt hyperthyroidism. Pulmonary artery pressures average twice normal values (10 mmHg) and may be as high as 30 to 50 mmHg. These changes reverse with treatment of the hyperthyroidism and may reflect the increase in cardiac output without the concomitant decline in pulmonary vascular resistance observed in the systemic circulation [26-28]. (See "Treatment and prognosis of pulmonary arterial hypertension in adults (group 1)".)
Angina pectoris — Patients with angina may have chest pain more often when they become hyperthyroid, presumably because of the increase in cardiac oxygen consumption, due either to a direct effect of triiodothyronine (T3) on cardiac muscle or to an increase in peripheral oxygen demand. In the young patient with normal coronary anatomy, this may be due to coronary vasospasm (Prinzmetal angina).
Other patients first develop angina when they become hyperthyroid. In a hospital-based study of 1049 patients who were admitted emergently, 6 percent had high serum T3 concentrations at the time of admission; these patients had a 2.6-fold higher risk of having angina pectoris or a myocardial infarction at that time, as compared with those patients with normal serum T3 concentrations .
Stroke — Ischemic cerebrovascular disease is a rare complication of hyperthyroidism. In addition, neurologic findings similar to that seen in moyamoya disease have been described in several patients with Graves' disease (especially those of East Asian descent [eg, Japanese, Chinese, Korean]) and may simulate the clinical findings of embolic disease. It is important to distinguish these two entities since the treatment is different. (See "Neurologic manifestations of hyperthyroidism and Graves' disease".)
SUBCLINICAL HYPERTHYROIDISM — Patients with subclinical hyperthyroidism (normal serum thyroid hormone and low serum thyroid-stimulating hormone [TSH] concentrations) have more subtle cardiac findings. These include increases in heart rate and cardiac contractility and modest degrees of cardiac hypertrophy and, at least in older adults, an increase in risk of atrial fibrillation as compared with euthyroid subjects (figure 2). Subclinical hyperthyroidism is reviewed in detail elsewhere. (See "Subclinical hyperthyroidism in nonpregnant adults", section on 'Cardiovascular effects'.)
TREATMENT — The cardiovascular manifestations of hyperthyroidism are best corrected by treating the hyperthyroidism, whether with radioiodine or an antithyroid drug. (See "Graves' hyperthyroidism in nonpregnant adults: Overview of treatment" and "Treatment of toxic adenoma and toxic multinodular goiter" and "Radioiodine in the treatment of hyperthyroidism" and "Thionamides in the treatment of Graves' disease".)
Beta blockers, such as propranolol or atenolol, are also useful in relieving palpitations and in slowing the heart rate in patients with sinus tachycardia  (see "Beta blockers in the treatment of hyperthyroidism"). It is important to recognize that while calcium channel blockers of all types are commonly used in the acute treatment of atrial fibrillation, the intravenous use of these agents pose a potential risk in patients with underlying thyrotoxicosis. The vasodilatory and negative inotropic properties of these drugs can lead to hypotension and cardiovascular collapse [31,32].
Additional measures may be needed in patients with atrial fibrillation, marked palpitations, or severe tachycardia [1,5,33]. The management of atrial fibrillation is reviewed in detail elsewhere. (See "Atrial fibrillation in adults: Selection of candidates for anticoagulation".)
Among patients with overt heart failure, standard therapy should be given if the patient is older, known or suspected to have preexisting heart disease or hypertension, or the heart failure does not improve when the heart rate is slowed (see "Primary pharmacologic therapy for heart failure with reduced ejection fraction", section on 'Beta blocker'). In certain circumstances, especially with severe hyperthyroidism or thyroid storm, intensive cardiovascular monitoring and treatment of other comorbid conditions (infection, trauma, acute psychiatric illness) is required [4,6]. (See "Thyroid storm".)
●Cardiovascular hemodynamics – Thyroid hormone has important effects on cardiac muscle, the peripheral circulation, and the sympathetic nervous system. Some actions of triiodothyronine (T3) on the heart produce clinical findings similar to those of beta-adrenergic stimulation. Hyperthyroidism predictably increases heart rate and cardiac contractility. Virtually all measures of cardiac function (including left ventricular ejection fraction [LVEF], the rate of ventricular pressure development, diastolic relaxation, and cardiac output) are increased (table 1). (See 'Chronotropic and inotropic stimulation' above.)
●Cardiac clinical manifestations – Hyperthyroidism is also associated with an increased risk of atrial fibrillation, heart failure, pulmonary hypertension, and angina-like symptoms. (See 'Clinical manifestations' above.)
●Treatment of cardiovascular manifestations – The cardiovascular manifestations of hyperthyroidism are best corrected by treating the hyperthyroidism, whether with radioiodine or an antithyroid drug. Beta blockers, such as propranolol or atenolol, are also useful in relieving palpitations and in slowing the heart rate in patients with sinus tachycardia. (See 'Treatment' above and "Radioiodine in the treatment of hyperthyroidism" and "Thionamides in the treatment of Graves' disease" and "Beta blockers in the treatment of hyperthyroidism".)
Additional measures may be needed in patients with atrial fibrillation, marked palpitations, severe tachycardia, or heart failure. In certain circumstances, especially with severe hyperthyroidism or thyroid storm, intensive cardiovascular monitoring and treatment of other comorbid conditions (infection, trauma, acute psychiatric illness) is required. (See "Thyroid storm" and "Primary pharmacologic therapy for heart failure with reduced ejection fraction", section on 'Beta blocker' and "Atrial fibrillation in adults: Selection of candidates for anticoagulation".)
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