Graves’ Disease and the Manifestations of Thyrotoxicosis
DeGroot LJ.
ncbi.nlm.nih.gov/books/NBK2...
First and foremost of the symptoms deriving from the circulatory system are palpitations and tachycardia. The heart may beat with extreme violence, which may be distressing to the patient, particularly at night or on exercise. The pulse on palpation is rapid and bounding. The systolic blood pressure is frequently elevated. The diastolic blood pressure is characteristically decreased, and the pulse pressure is elevated, being usually between 50 and 80 mm Hg.
Left ventricular hypertrophy may be suggested on physical examination. A bounding precordium is so typically found that its absence is a point against the diagnosis of hyperthyroidism. However, in the majority of instances, roentgenograms show the heart to be normal in transverse diameter. A systolic murmur is usually heard over the precordium. One reason for this murmur is the development of mitral valve prolapse during thyrotoxicosis. [328]This can be detected by angiography, or more easily by echography. It is postulated that papillary muscle dysfunction due to inadequate ATP supplies may be responsible for the lesion. Prolapse is usually not clinically evident but rarely is a cause of symptomatic mitral valve insufficiency. The prolapse can revert to normal with therapy [328].
Interpretation of physical signs, especially systolic murmur and gallop rhythm, in the heart is difficult and uncertain in the presence of thyrotoxicosis. In evaluating heart status in thyrotoxicosis, one should concentrate chiefly on the presence or absence of signs of failure rather than on physical signs in the heart itself. If no signs of failure are present, the best procedure regarding abnormal cardiac findings is to ascertain whether they persist after thyrotoxicosis has been abolished.
A grating pulmonic systolic sound ("Lerman Scratch"), which has some of the characteristics of a pericardial friction rub, is occasionally heard over the sternum in the second left interspace. It is heard best at the end of full expiration. Its intensity subsides as thyrotoxicosis improves. The diagnosis of pericarditis may be suggested on the basis of this sound. The fact that it is superficial and tends to disappear on inspiration suggests a pleuropericardial origin. It may be related to the dilated pulmonary conus often seen on x-ray films in thyrotoxic patients. The sign has no prognostic significance.
Extrasystoles are frequent, and paroxysmal atrial tachycardia and atrial fibrillation, paroxysmal or continuous, occur in 6 - 12% of patients. Even subclinical hyperthyroidism is associated with a fivefold greater chance of developing atrial fibrillation, and it is effectively the same as the situation with overt hyperthyroidism (329). Precordial pain that seems distinct from angina pectoris occurs occasionally. Cardiac enlargement and congestive heart failure may occur with or without prior heart disease [331, 332]. (Figure 10-9). The electrocardiographic manifestations are confined to tachycardia, increased voltage, and sometimes a prolongation of the PR interval [332], unless there is a dysrhythmia or an accompanying but unrelated disorder of the heart.
Patients with coronary atherosclerosis often develop angina during thyrotoxicosis. Occasionally angina develops de novo in young women with arteriography-proven normal coronary arteries. This condition has been ascribed to an imbalance between increased cardiac work and blood supply, so that a functionally deficient blood supply occurs even with a patent vessel [333]. Severe coronary vasospasm has been observed during angiography in patients with GD (334). Myocardial damage occurs in toxic patients with CHF (335) and myocardial infarction can occur in toxic patients with normal coronary vessels [336].
In thyrotoxicosis the heart rate, stroke volume, and cardiac output are increased. Circulation time is decreased. There is dilatation of superficial capillaries. Coronary blood flow and myocardial oxygen consumption in each stroke are increased [337]. Circulating plasma volume is increased. AV oxygen differences are variable but tend to be normal. Cardiac output in response to exercise is excessive in relation to oxygen consumed.
The relation of cardiac systolic time intervals to thyroid function has provided a valuable in vivo bioassay of hormone action. The pre-ejection period is shortened in thyrotoxicosis, and the left ventricular ejection time remains relatively normal. The interval from initiation of the QRS complex to arrival of the arterial pulse in the brachial artery is reduced [338]. Cardiac diastolic function as evaluated by echocardiography remains normal in the majority of patients [339].
Congestive heart failure and atrial fibrillation, when due to or associated with thyrotoxicosis, are relatively resistant to the action of digoxin. Accelerated metabolism of digoxin, plus the cardiac inefficiency and irritability produced by thyrotoxicosis, may be at least two of the factors producing this resistance. Although the response to the drug will be blunted, a beneficial effect will occur if a proper level of digoxin is attained.
Atrial fibrillation should be treated by anticoagulation if it is persistent, since it is associated with serious embolism in 10% of cases. The usual contraindications of old age, HBP, bleeding tendency, recent CVA, etc. apply, and the dose of Coumadin needed is lower than normal in thyrotoxic patients. AF tends to revert spontaneously to normal when hyperthyroidism is cured, but this may not occur before six months, or not at all, if AF was of long standing. Therapeutic cardio- version is recommended if AF persists six months beyond achievement of euthyroidism. Long term follow-up studies have revealed increased mortality from cardiovascular and cerebral vascular disease in patients with a past history of overt hyperthyroidism treated with radioiodine, and in patients with subclinical hyperthyroidism. Possibly development of atrial fibrillation and other supraventricular dysrhythmias may account for increased vascular mortality (340). Treatment of thyrotoxic heart disease has been reviewed recently [341]. A review of the impact of hyperthyroidism on cardiac function in older patients is available [342].
It has been suggested that the changes in the cardiovascular system are secondary to increased demand for metabolites and to increased heat production. Dilatation of superficial capillaries for the dissipation of heat does cause increased blood flow and cardiac output. However, a direct action of thyroid hormone on the heart is also increased, since the sinus node has higher intrinsic activity, the isolated thyrotoxic heart beats faster than normal, and isolated papillary muscle from a thyrotoxic heart has a shortened contraction time [343-345]. The heart shares in the general increase in respiratory quotient found in skeletal muscle. Adenosine transport into myocardial cells and its phosphorylation are increased [345]. Excess thyroid hormone increases cardiac Na+-K+ activated membrane ATPase, and sarcoplasmic reticulum Ca++-activated ATPase, both of which contribute to the heightened contractility of cardiac muscle. In addition excess thyroid hormone, at least in experimental animals, causes, by a direct effect on DNA transcription rates, an increased synthesis of alpha-myosin heavy chain with high ATPase activity, and decrease of beta myosin heavy chain synthesis. This alteration in alpha/beta ratio is associated with increased contractility [346]. In addition to the gene-mediated effects of thyroid hormone on the heart, triiodothyronine has direct effects that cause lower systemic vascular resistance and a higher cardiac output (347)
Whether an autoimmune process is involved in low output cardiac dysfunction in patients with Graves’ disease was investigated by myocardial biopsy of eleven patients in a study by Fatourechi and Edwards. Two of the group had lymphocytic infiltrates suggestive of an autoimmune process, whereas the others did not, indicating that this process may occur but would be an unusual cause of cardiac dysfunction [348].
Table 6Cardiac Manifestation of Graves' Disease
• Tachycardia
• LVH and strain on EKG
• Premature atrial and ventricular contractions
• Atrial fibrillation
• Congestive heart failure
• Angina with (or without) coronary artery disease
• Myocardial infarction
• Systemic embolization
• Death from cardiovascular collapse
• Resistance to some drug effects (digoxin, coumadin)
• Residual cardiomegaly
The cardiovascular changes may be due in part to increased sensitivity to circulating epinephrine. Thyroid hormone administration may increase, or not alter, the catecholamine content of the heart. Guanethidine partially restores cardiac dynamics to normal, perhaps by releasing catecholamine from the heart and thus reducing the cardiac stimulation caused by this agent. Guanethidine and beta-adrenergic blockers slow the tachycardia of thyrotoxicosis. Concomitant with this slowing is an increase in stroke volume, and there may be either a decrease [223] or little change in cardiac output [350]. T4 can increase the heart rate directly in a manner not mediated by catecholamines [351], and presumably this direct chromatotropic effect adds to coincident sympathetic effects on the heart. Thyrotoxicosis causes increased beta-adrenergic receptors in the heart and increased responsiveness to isoproterenol [352, 353]. Alpha-adrenergic and cholinergic receptors are reduced. In animal studies, adenyl cyclase may be activated by T3, but reduced cardiac levels of ATP limit the response through protein kinase activation. The net effect is beta-adrenergic sensitization and cholinergic desensitization. Thyrotoxicosis also increases beta-adrenergic receptors on a variety of tissues [355]. An increased number of -adrenergic receptors could cause hyper-responsiveness to adrenergic agonists, and could mediate the heightened plasma cAMP levels noted in thyrotoxic patients in the basal state (in some studies) and after assumption of an upright posture or administration of glucagon and epinephrine [356, 356]. Propranolol treatment normalizes the cAMP responses to these drugs and, of course, inhibits the action of beta-adrenergic agonists on the heart. Possibly these actions of propranolol explain its ability to reduce somewhat the consumption of oxygen in thyrotoxicosis.
The impact of the interrelation of excess thyroid hormone and the sympathetic nervous system in humans is not finally settled [357]. There is clear evidence for increased beta- adrenergic receptors in the heart and elsewhere in thyrotoxicosis, as inferred from animal studies. Responses of the thyrotoxic human to adrenergic agonists are probably not excessive in relation to responses in normal subjects, although this question is much debated. Beta-adrenergic blockade clearly reduces some pathophysiologic responses, including the increased nitrogen and oxygen consumption, toward but not to normal. Metabolism of the heart and other organs is stimulated directly by thyroid hormone, and sympathetic effects are additive. It remains possible that the sympathetic responses are in fact exaggerated; it is also clear that sympathetic responses do not "mediate" thyroid hormone action. Left ventricular reserve is impaired in thyrotoxicosis, and beta adrenergic blockage can lead to increased pulmonary artery pressure in some circumstances and further impair cardiac function (358). This suggests caution in administering beta-blockers to patients with severe hyperthyroidism and any evidence of circulatory dysfunction. We have seen administration of propranolol to patients with severe hyperthyroidism on rare instances to cause cardiovacular collapse and shock.
While this discussion has concentrated on the cardiovascular effects of thyrotoxicosis, it is worth remembering that long-term mild excess of thyroid hormone causes impaired cardiac reserve and exercise capacity [358]. Subclinical thyrotoxicosis can alter cardiac function, with increased heart rate, increased left ventricular mass index, increased cardiac contractility, diastolic dysfunction, and induction of ectopic atrial beats or arrhythmias (359). Some of these changes are reversible when euthyroidism is restored.
Smit et al studied 25 patients with a history of differentiated thyroid carcinoma with more than 10 yr of TSH suppressive therapy with L-T4. Medication was titrated in a single-blinded fashion to establish continuation of TSH suppression (low-TSH group) or euthyroidism (euthyroid group). At baseline, diastolic function was impaired in all lopr-TSH patients as indicated by abnormal values for the peak flow of the early filling phase (E, 55.3 +/- 9.5 mm/sec), the ratio of E and the peak flow of the atrial filling phase (E/A ratio, 0.87 +/- 0.13), the early diastolic velocity obtained by tissue Doppler (E', 5.7 +/- 1.3 cm/sec), and the peak atrial filling velocity obtained by tissue Doppler (A', 6.8 +/- 1.4 cm/sec), prolonged E deceleration time (234 +/- 34 msec), and isovolumetric relaxation time (121 +/- 15 msec). After 6 months, significant improvements were observed in the euthyroid group in the E/A ratio (+41%; P < 0.001), E deceleration time (-18%; P = 0.006), isovolumetric relaxation time (-25%; P < 0.001), E' (+31%; P < 0.001), and the E'/A' ratio (+40%; P < 0.001). Prolonged subclinical hyperthyroidism is accompanied by diastolic dysfunction that is at least partly reversible after restoration of euthyroidism. Because isolated diastolic dysfunction may be associated with increased mortality, this finding is of clinical significance (359).
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