Werner & Ingbar's The Thyroid: A Fundamental & Clinical Text, 9th Edition

31.The Cardiovascular System in Thyrotoxicosis

Irwin L. Klein

Sara Danzi

Almost two centuries ago, Caleb Parry reported on the association between thyrotoxicosis and the cardiovascular system (1), and it is now clear that some of the most profound and characteristic symptoms and signs of thyrotoxicosis are those relating to the cardiovascular system (2). Understanding these effects has increased our understanding of the actions of thyroid hormone (3,4). This chapter reviews the molecular, cellular, and organ responses to thyrotoxicosis as it affects the cardiovascular system.

CARDIOVASCULAR HEMODYNAMICS

The changes in cardiovascular hemodynamics that occur in patients with thyrotoxicosis are summarized in Table 31.1 (5,6). There are predictable decreases in systemic vascular resistance and diastolic blood pressure, and increases in cardiac output, systolic blood pressure, heart rate, left ventricular ejection fraction, cardiac contractility and mass, and blood volume (6) (Fig. 31.1).

FIGURE 31.1. Actions of thyroid hormone on the heart and vascular system. (From Klein I. Thyroid hormone and the cardiovascular system. Am J Med 1990;88:631, with permission.)

TABLE 31.1. CARDIOVASCULAR HEMODYNAMICS IN THYROTOXICOSIS


 Change

Comments


Systemic vascular resistance

50%–70% lower

Cardiac output

200%–300% increase

Blood pressure

 

 

   Systolic

Especially in elderly patients

   Diastolic

Widened pulse pressure

Heart rate

Most often sinus tachycardia; 2%–15% of patients have atrial fibrillation

Cardiac contractility

Increase in both systolic and diastolic function

Cardiac mass

Hypertrophy from increased cardiac work

Blood volume

Increased serum erythropoietin and sodium reabsorption


One of the earliest cardiovascular responses to thyroid hormone administration is a decrease in systemic vascular resistance (7), which may decrease by as much as 50% to 70%. The result is an increase in blood flow to the skin, muscles, kidneys, viscera, and heart (5). The decrease in vascular resistance is specific for the systemic circulation. It may be caused by a direct vascular action of thyroid hormone (7,8,9), or it may be due to stimulation of vascular endothelial cells to release vasoactive substances such as nitric oxide (9,10). In patients with thyrotoxicosis, β-adrenergic blockade blunts the thyroid hormone–mediated decrease in systemic vascular resistance and the accompanying increase in cardiac output, and administration of vasoconstrictor drugs increases systemic vascular resistance and simultaneously decreases cardiac output (11).

Cardiac contractility is increased in virtually all patients with thyrotoxicosis (2,12,13). Measures of systolic function, such as the rate of increase in ventricular pressure or velocity of contraction, are uniformly increased (12). Measures of diastolic function, including the rate of diastolic relaxation and compliance, also are increased (13).

Cardiac contraction results from the interdigitation of the two major contractile proteins, actin and myosin, requires myosin-catalyzed hydrolysis of adenosine triphosphate (ATP) and has an absolute requirement for calcium (4). One determinant of systolic contractility is the maximum velocity of muscle fiber shortening, which correlates with the inherent ATPase activity of the myosin molecule. There are two isoforms of cardiac myosin, α-myosin and β-myosin; the ATPase activity of the heavy chains of α-myosin is greater than that of the heavy chains of β-myosin. Each heavy chain is encoded by a different gene; the expression of the gene for the heavy chain of α-myosin is stimulated by triiodothyronine (T3) in rodents through an increase in gene transcription and posttranscriptional actions (14,15,16,17,18). There are substantial species differences in the expression of cardiac myosin and the response to T3. In humans, cardiac muscle obtained at autopsy contains predominantly β-myosin (3), as did the cardiac muscle of a patient with thyrotoxicosis who died suddenly (19). Although thyroxine (T4) therapy increased the content of mRNA for the heavy chain of α-myosin in a patient with severe hypothyroidism (20), it is unlikely that thyroid hormone is a major determinant of myosin isoforms or that substantial alterations in myosin gene expression occur in humans with thyroid disease (3,21).

Calcium release from and reuptake into the sarcoplasmic reticulum of cardiac muscle regulates the rate of ventricular contraction and relaxation. The gene for the cardiac-specific calcium ATPase (SERCA2) that regulates the sequestration of calcium in the sarcoplasmic reticulum during diastole is regulated by thyroid hormone (4,22). In addition, the expression of the protein phospholamban, which is a negative regulator of calcium uptake by the sarcoplasmic reticulum, is inhibited by T3 (22). Taken together, these observations could account for the increase in calcium uptake in the sarcoplasmic reticulum and explain the increased rate of development of systolic tension and diastolic relaxation in the heart of patients with thyrotoxicosis (13,22).

Increases in resting heart rate are characteristic of thyrotoxicosis (Table 31.2); more than 90% of patients have resting tachycardia, and many have heart rates of 120 beats per minute or higher (21,23,24). In addition to the increase in cardiac contractility, there also is an increase in cardiac preload and a decrease in afterload, which combine to cause marked increases in cardiac output both at rest and with exercise (25) (Fig. 31.1). Careful analysis of heart rate regulation in patients with thyrotoxicosis revealed an increase in sympathetic tone and a decrease in parasympathetic tone, the change from normal being greater in the former (26). In addition, thyroid hormone may directly stimulate the sinus node pacemaker (21).

TABLE 31.2. PROMINENT SYMPTOMS AND SIGNS OF CARDIOVASCULAR DYSFUNCTION IN PATIENTS WITH THYROTOXICOSIS


Palpitations

Exercise intolerance

Dyspnea on exertion

Angina pectoris

Orthopnea

Tachycardia

Atrial fibrillation

Hyperdynamic precordium

Widened pulse pressure

Cardiac flow murmurs

Pedal edema

Third heart sound (S3)


Serum erythropoietin concentrations are increased in patients with thyrotoxicosis, presumably in response to the need to increase peripheral oxygen delivery. Renal sodium reabsorption is increased as a result of activation of the renin–angiotensin–aldosterone system and increases in renal perfusion and renal Na+,K+-ATPase activity. These changes may explain the increases in total blood volume, plasma volume, and erythrocyte mass reported in patients with thyrotoxicosis (3,6).

CARDIOVASCULAR PATHOPHYSIOLOGY

Cardiac Effects

T3 regulates the transcription and translation of multiple cardiac genes, and it (and perhaps also T4) may have extranuclear actions on cardiac muscle as well (4,15,27) (Table 31.3). T3 regulates gene transcription by binding to specific nuclear receptors, and the complexes bind to specific DNA sequences [thyroid hormone–response elements (TREs)] located on target genes in cardiac myocytes (28,29) (Fig. 31.2). The two isoforms of the T3 nuclear receptors (α1, and β) that bind T3, and the α2 form, that does not bind T3 have been identified in left ventricular muscle and in isolated cultured cardiac myocytes (see Chapter 8) (16). T3 has direct effects on the rate of gene transcription in isolated cardiac myocytes (14,15). These effects occur within 30 minutes and result in an increase in myocyte RNA content and protein synthesis (4,14). T3 also increases the rate of translation and stability of messenger RNA (mRNA) in these cells (15,18).

FIGURE 31.2. Cellular mechanisms of action of triiodothyronine (T3) on cardiac myocytes. T3 binds to T3 nuclear receptors, and the T3 receptor complexes then bind to thyroid hormone response elements of specific myocyte genes, including the genes for α-myosin heavy chains, Ca2+-ATPase, phospholamban, sarcoplasmic reticulum, β-adrenergic receptors, adenylyl cyclase, guanine-nucleotide-binding proteins, Na+/Ca2+ exchangers, Na+/K+-ATPase, and voltage-gated potassium channels. T3 also has nonnuclear actions on ion channels in the cell membrane. (Reproduced from Klein I, Ojamaa K. Thyroid hormone and the cardiovascular system. N Engl J Med 2001;344:501, with permission.)

TABLE 31.3. EFFECTS OF TRIIODOTHYRONINE ON CARDIAC GENE EXPRESSION


Gene

Effect

Comment


Myosin heavy chain content

 Effect mainly in small animals

   α

Fast myosin

   β

Slow myosin

Sarcoplasmic Ca-ATPase reticulum

May determine ventricular diastolic function through calcium regulation

Phospholamban

Acts in concert with sarcoplasmic reticulum Ca-ATPase

Na+, K+-ATPase

Tissue- and isoform-specific regulation of transmembrane ion flux

Atrial natriuretic hormone

Reduces renal salt and water reabsorption, and lowers blood pressure

β-adrenergic receptor

Tissue-specific, may in part explain the change in adrenergic tone characteristic of thyrotoxicosis through changes in adenylyl cyclase activity

Adenylyl cyclase catalytic subunit

Isoform-specific regulation

Gs proteina

 Gi proteinb

 Potassium channel (Kv1.5)

Rapidly responsive, voltage-gated potassium channel


a The guanine nucleotide-binding protein that mediates stimulation of adenylyl cyclase activity.

b The guanine nucleotide-binding protein that mediates inhibition of adenylyl cyclase activity.

The different isoforms of the T3 nuclear receptors present in cardiac myocytes may mediate the different genomic actions of T3 in both the atria and ventricles (16). Indeed, some of the functional and chamber-specific effects of thyroid hormone on the heart may be mediated by a specific receptor isoform. Studies of mice with deletions or mutations of the receptors suggest that the α1 form of the receptor mediates T3 stimulation of heart rate (30), and that the β form is less important in so far as the actions of T3 in the heart are concerned (31).

Evidence for indirect effects of thyroid hormone on the heart mediated by changes in cardiovascular hemodynamics comes from studies of the cardiac hypertrophic (growth) response to thyrotoxicosis. In humans and animals, chronic thyrotoxicosis causes variable degrees of cardiac hypertrophy (3,23). If this hypertrophy was caused by a direct effect of thyroid hormone on cardiac protein synthesis, it should not be affected by β-adrenergic blockade. However, both propranolol and bisoprolol block or reverse thyroid hormone–induced cardiac hypertrophy (32). These results suggest that increased cardiac work is the major mediator of the cardiac growth response in thyrotoxicosis. Further confirmation comes from experiments with heterotopically transplanted hearts in which the heart was exposed to high serum thyroid hormone concentrations without an accompanying increase in cardiac work (18,33). Under these circumstances, cardiac hypertrophy did not occur, but cardiac gene expression and heart rate increased (18).

In addition to its genomic actions, T3 has nongenomic or nonnuclear actions on the heart. These actions, because of their rapid time course and lack of associated changes in mRNA or protein synthesis, imply that T3 acts at the plasma membrane, sarcoplasmic reticulum, or mitochondria (27,34). In the plasma membrane of cardiac myocytes, T3, in a concentration of 10 mol/L, increases Na+ ion currents by opening Na+ ion channels. Additional plasma membrane actions that may be directly regulated by T3 include shortening the duration of action potentials by an effect on voltage-dependent potassium channels and increasing calcium transport in the sarcoplasmic reticulum, nucleotide translocase activity, magnesium flux, and oxidative phosphorylation in mitochondria (27). These nongenomic actions of T3 may explain, at least in part, the increases in cardiac contractility and cardiac output and decreases in systemic vascular resistance that occur within a few hours in patients given high doses of T3 intravenously after cardiopulmonary bypass surgery (7).

Peripheral Circulatory Effects

In patients with thyrotoxicosis, systemic vascular resistance is reduced from normal values (~1,700 dynes/sec/cm3) to values as low as 500 to 700 dynes/sec/cm3 (5,6). In animals given T3, the decrease is rapid, occurring before changes in heart rate or cardiac contractility. The decrease in resistance is especially prominent in skeletal muscle, and it also occurs in other organs, including skin and viscera (5,8,11). As systemic vascular resistance declines, so does blood pressure, which in turn causes a reflex increase in heart rate, stroke volume, and cardiac output (Fig. 31.1). The reflex nature of these latter changes is supported by the observation that prevention of the decline in systemic vascular resistance with the β-adrenergic agonist propranolol mitigates or prevents some of the inotropic and chronotropic responses to T3 (11).

As noted above, T3 reduces peripheral vascular resistance through two separate mechanisms (8,35). One is due to a direct action of T3 on arterial smooth muscle tone, as indicated by the ability of T3 to cause relaxation of cultured vascular smooth muscle cells (8). Second, T3 stimulates the synthesis, secretion, or action of vasodilators by endothelial cells (11). In rats, synthesis of nitric oxide from L-arginine by nitric oxide synthase in endothelium is stimulated by thyroid hormone (35), and in patients with thyrotoxicosis, increased nitric oxide production contributes to the decreased vascular resistance and increased vascular reactivity (36). In addition, the vascular response to acetylcholine, another endothelium-dependent vasodilator, is increased in patients with thyrotoxicosis. In contrast, the vascular response to nitroprusside, an endothelium-independent vasodilator, is not increased, indicating that the endothelium is a specific target for thyroid hormone in mediating peripheral vascular effects (36).

Thyroid hormone increases the synthesis and secretion of renin and angiotensinogen, the formation of angiotensin II, and the secretion of aldosterone (6,33). This activation of the renin–angiotensin–aldosterone system contributes to the increases in renal sodium absorption and blood volume that occur in thyrotoxicosis.

Thyrotoxicosis can cause hypertension (33,37). This is primarily systolic hypertension, with decreased or normal diastolic pressure and an increase in pulse pressure. The increase in systolic pressure is in part due to decreased arterial compliance, which in turn appears to be the result of the tachycardia that is so common in patients with thyrotoxicosis (25). The prevalence of this finding is estimated at 25% in patients between 30 and 65 years of age (6,37).

CLINICAL MANIFESTATIONS

The cardiovascular symptoms and signs of thyrotoxicosis are some of the most characteristic and disabling manifestations of the disorder (2,38) (Table 31.2). Many of these symptoms and signs mimic those that occur in states of increased β-adrenergic activity, such as pheochromocytoma (39). The overlap of symptoms and signs of thyrotoxicosis and those of hyperadrenergic states suggested that catecholamine metabolism might be altered in thyrotoxicosis (4,39), but in fact plasma norepinephrine and epinephrine concentrations are normal or low, and urinary excretion of catecholamine metabolites (including normetanephrine, metanephrine, and vanillylmandelic acid) is normal (see Chapter 38) (40).

Nearly all patients have tachycardia, and most have palpitations. The latter symptom refers to a sensation of forceful beating of the heart (2,23,38), and it may be caused by sinus tachycardia or atrial arrhythmias (3,26,41), increased cardiac contractility, or both. Patients often note that their heart rate increases excessively during exercise and declines slowly after exercise (38). The heart rate is rapid both during the day and during sleep, and the normal diurnal variation in heart rate is blunted (2,4,26). This change may be due to decreased parasympathetic tone, which is also suggested by the loss of normal heart rate variability as measured by changes in the R-R interval on the electrocardiogram (26).

Other common cardiovascular symptoms include exercise intolerance and dyspnea on exertion (13). These symptoms are probably caused by a less-than-normal increase in cardiac output (25) and respiratory muscle weakness (2,42). Treatment of patients with thyrotoxicosis with β-adrenergic antagonist drugs results in improvement in both muscle strength and exercise performance (38,40,42).

In elderly patients, the cardiac manifestations of thyrotoxicosis may be limited to resting tachycardia (23,41), and other symptoms may be absent, possibly due to a relative paucity of adrenergic activity (38,39,43). With the onset of atrial fibrillation (44,45), the extent of cardiovascular manifestations increases, and rate-related heart failure may occur (2,3).

Rarely, young patients with thyrotoxicosis may have chest pain similar in almost all respects to angina pectoris (2,3,46). The mechanism is either relative myocardial ischemia resulting from a mismatch between cardiac oxygen supply and demand (47), or coronary artery spasm (46). Anginal pain that begins after the onset of thyrotoxicosis usually disappears after antithyroid treatment is begun. In older patients, the increased myocardial oxygen demand due to thyrotoxicosis may unmask previously unsuspected coronary artery disease (2,21,47).

The clinical importance of these cardiovascular effects of thyrotoxicosis is evident from recent studies that confirmed the suspicion that the mortality of patients with thyrotoxicosis is increased, primarily as a result of cardiovascular disease (48,49). In particular, atrial fibrillation is a poor prognostic feature, especially in older patients, as is the combination of thyrotoxicosis and valvular or hypertensive heart disease (see Chapter 77).

Physical Examination

Tachycardia is perhaps the most common of all abnormal findings on physical examination of patients with thyrotoxicosis. Not only is the measured heart rate fast, but often the pulse in the larger arteries is bounding due to widened pulse pressure with high systolic and low diastolic blood pressures (5,6) (Table 31.2). Mean blood pressure is usually normal or slightly low. Older patients may have an exaggerated increase in systolic blood pressure because of the loss of elasticity of the larger (capacitance) arteries (25); their mean blood pressure may also be high (6,43).

Findings on physical examination suggesting an increase in cardiac contractility and cardiac output include a rapid increase in the carotid upstroke, a sharp and easily audible first heart sound, a hyperdynamic precordium, and a prominent apical impulse. Auscultation may reveal a systolic murmur caused by rapid flow of blood through the aortic outflow tract. Systolic murmurs due to regurgitant flow across the mitral valve may arise from left ventricular dilatation or mitral valve prolapse. A systolic “scratch” is occasionally heard in the pulmonic area (second left intercostal space), corresponding to contact between the pleural and pericardial surfaces during cardiac contraction. This murmur may also be due to an increase in pulmonary artery pressure (6,33,50). These clinical findings are confirmed by noninvasive cardiac diagnostic studies in patients with thyrotoxicosis, including radionuclide angiography to measure left ventricular ejection fraction and Doppler echocardiography to assess cardiac systolic and diastolic performance (13,47).

The occurrence of pedal edema or pleural effusions signifies the presence of fluid overload. Rarely, as noted below, symptoms and signs of true congestive heart failure, including a decrease in left ventricular contractility, the presence of a third heart sound (S3), and paroxysmal nocturnal dyspnea, may be present (2,3,19,21).

Cardiac Rhythm Disturbances

Sinus tachycardia at rest, during sleep, and during exercise is the most consistent rhythm disturbance in patients with thyrotoxicosis (24,25,26,51). The reported prevalence rates for supraventricular arrhythmias (supraventricular tachycardia or atrial fibrillation) in patients with thyrotoxicosis vary greatly (Table 31.2). Some studies report a very low prevalence (< 1% to 2%) of these arrhythmias, perhaps reflecting early diagnosis; in other studies from 5% to 15% of patients had atrial fibrillation (2,44,45). Although most patients with thyrotoxicosis who have atrial fibrillation are elderly, it can occur in younger patients (52). The ventricular rate in atrial fibrillation is often rapid, as a result of an increased rate of conduction of electrical impulse through the atrioventricular node. Most patients with atrial fibrillation have the arrhythmia for a relatively short time (< 4 to 8 weeks) before the diagnosis of thyrotoxicosis is made. In the absence of evidence for chronicity, spontaneous reversion to sinus rhythm within 8 to 12 weeks after the initiation of antithyroid treatment is the rule (44). Reversion to sinus rhythm during or after treatment of the thyrotoxicosis is less common in elderly patients with chronic atrial fibrillation or patients who have underlying coronary or other heart disease, and in these patients electrical cardioversion may be needed to restore sinus rhythm (44). Patients restored to sinus rhythm by electrical cardioversion or drug therapy are more likely to remain in sinus rhythm if treated with disopyramide (53,54).

The development of atrial fibrillation poses the potential for systemic embolization, including stroke. However, the risk for embolism is low, and its occurrence is limited largely to older patients with coexisting heart disease (55). The value of anticoagulation is controversial; it is discussed in more detail below.

Atrial flutter and other supraventricular tachyarrhythmias (including paroxysmal atrial tachycardia) occur but are uncommon in patients with thyrotoxicosis. Ventricular premature contractions and ventricular fibrillation are extremely rare (21,40,56,57), and their occurrence suggests the presence of hypokalaemic periodic paralysis (see Chapter 41) (58).

Electrocardiographic changes include not only disturbances in rhythm but also nonspecific ST segment and T-wave abnormalities. The P-R interval is often short, secondary to the increased rate of conduction through the atrioventricular node. Some patients have electrocardiographic signs of left ventricular hypertrophy, which disappear during antithyroid therapy or β-adrenergic blockade (59). Patients with angina-like symptoms may have ST-segment elevations, suggesting myocardial ischemia (46).

Congestive Heart Failure

Some patients with thyrotoxicosis have heart failure. Most are elderly, and therefore likely to have underlying heart disease, or they have atrial fibrillation (41). In the absence of atrial fibrillation, heart failure is rare (3,21). Hypertension, valvular heart disease, or coronary artery disease predisposes patients to cardiac contractile dysfunction when the workload and oxygen consumption increase, as characteristically occurs in thyrotoxicosis (3,25,47). Nonetheless, heart failure—or at least fluid overload—can occur in patients, even young patients, with thyrotoxicosis with no known heart disease and in the absence of atrial fibrillation. This finding has led to the suggestion that thyrotoxicosis can cause cardiomyopathy. More likely, plasma volume and cardiac preload are increased at the same time that cardiac contractility is increased, giving rise to circulatory congestion (3,25).

Excluding patients with atrial fibrillation and rapid ventricular rates, a comparison of patients with thyrotoxicosis who did or did not have heart failure revealed two important differences. Patients with heart failure had higher levels of systemic vascular resistance and a disproportionate increase in systemic vascular resistance with exercise (5). Heart failure in patients with thyrotoxicosis who do not have underlying heart disease usually is considered to be “high output” (21). That a high cardiac output per se could lead to cardiac failure is controversial, and high-output heart failure may not be heart failure but rather circulatory congestion caused by fluid retention (5,6). Support for this possibility comes from the finding of increased blood volume with increased venous filling pressures and peripheral edema (21) and the prompt clinical response to diuretic treatment (33).

In patients with thyrotoxicosis, cardiac output does not increase to the same extent as it does in normal subjects in response to exercise, stress (infection), surgery, or pregnancy (3,21,25). As a result, atrial filling pressures increase, leading to pulmonary and peripheral edema (a situation inevitably worsened by atrial fibrillation because it impairs atrial and ventricular filling) (47). This limitation in cardiac output is a result of a less than expected increase in left ventricular contractility during exercise (60), which improves after antithyroid treatment, suggesting the presence of a reversible thyrotoxic cardiomyopathy. An alternative explanation is that resting systemic vascular resistance is already maximally lowered and therefore cannot decline further with exercise (5,6). In the absence of such a decline, left ventricular afterload and contractility may not increase, and therefore cardiac output would not increase. These observations further reinforce the importance of changes in systemic vascular resistance, blood volume, and loading conditions as determinants of cardiovascular function in thyrotoxicosis (3,25).

Perhaps the most compelling explanation of impaired left ventricular function (decreased ejection fraction, decreased diastolic compliance, and an S3 on physical examination) in patients with thyrotoxicosis is the observation that persistent tachyarrhythmias per se decrease left ventricular contractile function, causing rate-related heart failure (33,61). Sustained tachycardia in general decreases ventricular systolic and diastolic function, which resolves when the heart rate slows (62), and there is no reason to doubt that sustained sinus tachycardia (or atrial fibrillation) in patients with thyrotoxicosis has the same effect (2,24,63). Additional support for the importance of this mechanism of cardiac dysfunction in patients with thyrotoxicosis is the rapid improvement in ventricular function that occurs when the heart rate is slowed by administration of a β-adrenergic antagonist drug (40). The finding that heart failure improves with antithyroid treatment obscures the fact that it is the heart rate that is simultaneously controlled and may have been the primary cause for the heart failure (21,41,61).

Subclinical Thyrotoxicosis

Subclinical thyrotoxicosis is defined as a low serum thyrotropin (TSH) concentration and normal serum free T4 and T3 concentrations. Many of these patients have no symptoms or signs of thyrotoxicosis, but some have resting tachycardia or transient episodes of atrial fibrillation that are unrecognized (23), and they may be at risk for the cardiovascular manifestations associated with overt thyrotoxicosis (see Chapter 79) (33,64,65). For example, among older people, the 10-year risk for atrial fibrillation in those with serum TSH concentrations of less than or equal to 1 mU/L was three times higher than in those with normal serum TSH concentrations (45). In a similar study, a low serum TSH concentration in patients 61 years of age and older was associated with increased all-cause and cardiovascular mortality (see Chapter 77) (65). Furthermore, young and middle-aged patients with subclinical thyrotoxicosis have some cardiac dysfunction, in that they have higher average heart rates, increased left ventricular mass, increased systolic contractility, and impaired diastolic function, as compared with age-matched normal subjects (62). These changes improve in response to antithyroid therapy, strongly suggesting that the changes are caused by the small increases in serum T4 and T3 concentrations within the normal reference range that define subclinical thyrotoxicosis (66,67,68).

TREATMENT

Patients with thyrotoxicosis should be treated to reverse the hemodynamic changes that accompany thyrotoxicosis without impairing the ability of the heart to meet the needs of peripheral tissues for oxygen and substrates (2,3,47) (Table 31.4). Ultimately this requires antithyroid treatment of some type (67). However, the available treatments do not rapidly reduce thyroid hormone secretion, and therefore treatments that can rapidly reduce the actions of thyroid hormone often are indicated in patients with thyrotoxicosis who have cardiovascular dysfunction (40,69).

TABLE 31.4. TREATMENTS FOR CARDIOVASCULAR MANIFESTATIONS OF THYROTOXICOSIS


Acute treatment of tachycardia or exercise-related symptoms

   β-adrenergic antagonist drugs

   Calcium channel–blocking drugs (when β-blockade is contraindicated)

Acute treatment of heart failure

   β-adrenergic antagonist drugs: indicated for rate-related heart failure and control of ventricular response in atrial fibrillation

   Diuretic drugs

   Digoxin: greater than usual loading and maintenance dosage may be needed

   Anticoagulation: consider for patient with chronic atrial fibrillation

Chronic treatment of hyperthyroidism

   Radioiodine

   Antithyroid drug therapy


Because of the importance of reduction in heart rate, initial therapy of patients with thyrotoxicosis with or without underlying heart disease is best accomplished by administration of a β-adrenergic receptor antagonist drug (40). Propranolol, a nonselective β-adrenergic antagonist drug, has been used most often for this purpose; usually, it is given in divided doses of 80 to 240 mg per day (13,42). Selective β-adrenergic antagonist drugs like atenolol or metoprolol are equally effective. Propranolol in low doses (1 to 2 mg) can be given by slow intravenous infusion in more acutely ill patients, provided that they are monitored continuously. The goal is to slow the heart rate, which should decrease not only palpitations but also any signs of cardiac decompensation, maintain blood pressure, and improve some of the noncardiac symptoms of thyrotoxicosis (38,42). Although heart failure was previously considered a contraindication to administration of β-adrenergic antagonist drugs, it is not in patients with thyrotoxicosis because of the benefit of heart rate control in reversing left ventricular dysfunction. The β-adrenergic antagonist drug should be continued, in decreasing doses, until the patient is euthyroid (40,67).

Calcium-channel blockers, when administered orally, also slow the heart rate in patients with thyrotoxicosis (24). Acute administration of these drugs, however, may have the undesired effect of further lowering systemic vascular resistance, leading to hemodynamic instability, which in turn requires treatment by volume expansion. When β-adrenergic antagonist drugs are contraindicated, a calcium-channel blocker can be given to control atrial fibrillation or other supraventricular arrhythmias, but it should be given cautiously to avoid hypotension or negative inotropic actions (3,21).

Patients with symptoms and signs of heart failure, including peripheral (or pulmonary) edema, should be treated with furosemide. Diuresis is as effective as it is with other forms of congestive heart failure. Volume contraction, however, should be avoided because it can impair cardiac filling and lower cardiac output. In addition to diuresis with furosemide, digoxin can be beneficial in both controlling the symptoms and signs of heart failure and slowing the ventricular rate in patients with atrial fibrillation. The clearance of digoxin is increased, and cardiac sensitivity to digoxin may be decreased, in patients with thyrotoxicosis, and therefore higher than average doses may be needed (33).

Treatment of thyrotoxicosis is discussed in detail in Chapter 45. Among the available treatments, radioiodine seems particularly appropriate for patients with many cardiovascular manifestations of thyrotoxicosis. Among 356 patients with cardiovascular manifestations of thyrotoxicosis, including atrial fibrillation, angina pectoris, or heart failure, more than 90% had improvement in their symptoms and signs after treatment with radioactive iodine (41). In one study, mortality from cardiovascular disease was increased in patients treated with radioiodine, as compared with the population at large, but the increase was probably due to the presence of severe thyrotoxicosis rather than to the radioiodine therapy (48).

The role of anticoagulation in patients with thyrotoxicosis who have atrial fibrillation is controversial. A retrospective study supporting the use of anticoagulation involved a relatively small number of patients (70), and was not confirmed by other, larger retrospective studies (44,55). It appears that age, rather than the presence of atrial fibrillation, is the major risk factor for systemic embolization in these patients (56,71). Although anticoagulation clearly lowers the incidence of embolization in patients with atrial fibrillation in general (72), it has risks. Furthermore, in many patients with thyrotoxicosis who have new-onset atrial fibrillation, the rhythm reverts to sinus rhythm soon after antithyroid treatment is initiated (44). Therefore, anticoagulation is not universally indicated; low-dose aspirin is a reasonable alternative. Anticoagulation should be considered, however, in patients with thyrotoxicosis who have underlying cardiac disease or in whom the atrial fibrillation persists, subject to the age and other guidelines applicable to any patient with atrial fibrillation (72). Patients with thyrotoxicosis tend to be more sensitive to warfarin than those who are euthyroid (see Chapter 35).

SELECTED CLINICAL SITUATIONS

Treatment with Amiodarone

Amiodarone is an iodine-rich antiarrhythmic drug that is effective in patients with ventricular and atrial tachyarrhythmias. It may induce both hypothyroidism and thyrotoxicosis (see section Effect of Excess Iodide in Chapter 11) (73), and therefore thyroid function should be assessed regularly in patients receiving amiodarone, and for at least 6 months after it is stopped, because it is excreted very slowly. The prevalence of amiodarone–induced thyrotoxicosis is as high as 10% (73,74). There are two types of amiodarone–induced thyrotoxicosis. Type 1 occurs primarily in patients who have preexisting thyroid disease, mostly mulinodular goiter, and is thought to be due to iodine excess, and type 2 is a form of thyroiditis (73,74). Patients with type 1 amiodarone–induced thyrotoxicosis have usually been treated with an antithyroid drug, and sometimes also potassium perchlorate (to block thyroid uptake of iodine) or surgery, and those with type 2 amiodarone–induced thyrotoxicosis with a glucocorticoid (73,74,75,76). In fact, in many patients the thyrotoxicosis cannot be neatly categorized as type 1 or 2, and initial therapy should probably consist of an antithyroid drug and a glucocorticoid (33,73,74,75). Cessation of amiodarone has little immediate effect, even if acceptable from the perspective of the patient's cardiac disorder, because the drug is stored in adipose tissue and excreted very slowly (months) (74).

Pregnancy

The cardiovascular changes of pregnancy, which are similar to those of thyrotoxicosis, result from the need to deliver oxygen and substrates to the enlarging placenta, which is perfused through a low-resistance vascular bed, and the developing fetus (77). In pregnant women with thyrotoxicosis the hemodynamic effects of the two conditions are additive. In these women, appropriate antithyroid treatment usually prevents any untoward burden on the heart (40,67,77). Peripheral edema, marked tachycardia, or symptoms of cardiac decompensation should be treated in the same way in pregnant women with thyrotoxicosis as in other patients. β-adrenergic antagonist drugs should be given cautiously because they may cause fetal growth retardation when given in early pregnancy and prolong labor and delivery when given nearer to or at term (40,77).

Right Heart Failure and Pulmonary Hypertension

Right heart failure often accompanies left heart failure, but predominantly right-sided heart failure with preserved left ventricular function is rare in patients with thyrotoxicosis (78). However, pulmonary hypertension may not be rare in patients with thyrotoxicosis; in one study the prevalence was 41% (50), indicating that excess thyroid hormone does not lower pulmonary vascular resistance, in contrast to its effects on systemic vascular resistance.

Primary pulmonary hypertension is a rare, often fatal disease of unknown etiology that primarily affects young women. Among these patients, the frequency of Graves' disease (and chronic autoimmune thyroiditis) is increased (79).

REFERENCES

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