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Recognition and management of cardiovascular disease related to thyroid dysfunction
Recognition and Management of Cardiovascular Disease Related to Thyroid Dysfunction PAULW. LADENSON,M.D.,Baltimore, Maryland
Hypothyroidism and hyperthyroidism are both associated with clinically significant cardiovascular derangements. In hypothyroidism, these include pericardial effusion, heart failure, and the complex interrelationship between hypothyroidism and ischemic heart disease. Cardiovascular disorders associated with hyperthyroidism include atrial tachyarrhythmias, mitral valve dysfunction, and heart failure. Although these usually occur in individuals with intrinsic heart disease, thyroid dysfunction alone rarely causes serious but reversible cardiovasc,dAr dysfunction. Patients with commonly encountered cardiac disorders, e.g., idiopathic cardiomyopathy and atrial fibrillation, should be screened for potentially contributing subclinical thyroid diseases. In patients with heart failure and hypothyroidism, initial mAnAgement should focus on diagnosis and optimal management of any primary cardiac disease, whereas in hyperthyroidism, aggressive measures to control excess thyroid hormone action should generally have the highest priority.
From the Division of Endocrinology and Metabolism, The Johns Hopkins University School of Medicine, Baltimore, Maryland. This study was presented in part at the 64th Annual Meeting of the American Thyroid Association, San Francisco, California. Requests for reprints should be addressed to Paul W. Ladenson, M.D., Division of Endocrinology and Metabolism, The Johns Hopkins Hospital, Blalock 904, Baltimore, Maryland 21205.
638
June 1990 The American Journal of Medicine Volume 88
hyroid hormones affect the cardiovascular system T directly by altering cardiac contractile force and frequency, and indirectly by modulating tissue metabolism, extracellular fluid volume and distribution, and catecholamine effects. Therefore, both deficiency and excess of thyroid hormone can be associated with clinically important cardiovascular derangements, particularly in individuals with intrinsic heart disease. In hypothyroidism, these include the common and potentially confusing presence of pericardial effusion, the less frequent problem of heart failure, and the complex interrelationship between hypothyroidism and ischemic heart disease. Cardiovascular disorders associated with hyperthyroidism include atrial tachyarrhythmias, mitral valve dysfunction, and heart failure. HYPOTHYROIDISM
The features of the "myxedema heart" were first described in 1918 by Zondek [1], who described the characteristic dilated cardiac silhouette, low electrocardiographic voltage, and slow indolent heart action, all of which were reversed by thyroid hormone therapy. We now recognize that these abnormalities were partially attributable to pericardial effusion, the most common cardiovascular complication of hypothyroidism, reported to be present in at least 30% of untreated patients [2]. These effusions typically have a high protein concentration and are, like other serous effusions in hypothyroidism, due to increased capillary permeability [3]. Their slow accumulation probably accounts for the relative rarity of hemodynamic compromise, even with large effusions [4]. Indeed, the principal clinical problem caused by pericardial effusion in the myxedematous patient, who may complain of fatigue, dyspnea, and edema, is potential misdiagnosis of congestive heart failure. Following institution of thyroid hormone replacement therapy, pericardial effusions typically resolve over 2 to 12 months without sequelae [5]. Heart failure in patients with hypothyroidism generally represents exacerbation of intrinsic cardiac disease by the superimposed hemodynamic effects of thyroid hormone deficiency: bradycardia, diminished myocardial contractility, and markedly increased peripheral cardiovascular resistance [6]. Rarely, hypothyroidism alone may cause a reversible cardiomyopathy that is severe enough to cause heart failure. No clinical or radiologic features reliably distinguish hypothyroid heart failure from other dilated cardiomyopathies, except for the general clinical features of myxedema, which may be subtle. Therefore, hypothyroidism should be excluded in all individuals without a clear etiology of heart disease. Failure to recognize underlying thyroid hormone deficiency permits progression of cardiovascular dysfunction and subjects the patient to risk of intoxication with digitalis glyco-
THYROID-RELATED HEART DISEASE / LADENSON
sides, which are cleared less rapidly in hypothyroidism [7]. Management of heart failure in hypothyroid patients requires prompt diagnosis and treatment of the intrinsic heart disorder that almost invariably coexists, and reversal of hypothyroidism. Early identification of primary cardiac disease is essential since some disorders may actually be exacerbated by thyroid hormone replacement, e.g., ischemic heart disease and aortic stenosis. For the hypothyroid patient with heart failure, thyroid hormone represents a physiologic and potent positive inotropic agent. Numerous noninvasive [8] and invasive [9] studies have demonstrated reversibility of the decreased myocardial contractility associated with hypothyroidism. Although L-triiodothyronine (T3) is more potent with a more rapid onset of action [10], L-thyroxine (T4) also significantly enhances myocardial performance within 1 week [11]. Furthermore, the longer T4 half-life makes it a more physiologic and practical preparation for long-term replacement therapy. Digitalis glycosides also increase myocardial tension development in hypothyroidism [12] and may be a useful adjunctive therapy, particularly when clinical and radiologic features predicting digitalis responsiveness are present [13]. The coexistence of hypothyroidism and atherosclerotic coronary artery disease not infrequently poses a challenging dilemma for the clinician. The pathogenesis of atherosclerosis may be accelerated by the diastolic hypertension [14] and elevated serum low-density lipoprotein cholesterol concentration [15] that are characteristic of hypothyroidism. Whether hypothyroidism per se and serologic evidence of autoimmune thyroiditis are associated with additional independent risks of atherosclerosis remains controversial [16]. Regardless, successful management of established risk factors for progression of coronary artery disease requires recognition and treatment of hypothyroidism. In hypothyroid patients with established atherosclerotic coronary artery disease, it is difficult to predict accurately the impact of thyroid hormone replacement therapy on myocardial oxygen demand (Figure 1). The positive chronotropic and inotropic effects of thyroid hormone augment myocardial oxygen consumption, which can worsen ischemia in patients with flow-limiting coronary arterial obstructions. On the other hand, increased myocardial contractility may reduce ventricular end-diastolic volume and wall tension (preload) in dilated hearts, and will predictably decrease peripheral vascular resistance (afterload). The variability predicted by these theoretic considerations has been confirmed in clinical management of hypothyroid patients with ischemic heart disease. Among hypothyroid patients with pre-existing angina pectoris and treated with thyroid hormone, Keating et al [17] reported improvement or no change in more than 80%. In this series consisting primarily of older adults, less than 1% of treated hypothyroid patients had new onset of angina. Furthermore, the reported 1year cardiovascular mortality for all treated hypothyroid patients with coincident ischemic heart disease, 3%, compares favorably with the 9% to 15% mortality reported among other patients with atherosclerotic heart disease in that era [18]. This study and other uncontrolled clinical trials have led to formulation of widely accepted empiric recommendations for hormone replacement therapy
8
¢¢
>, )<
o m o o
:S
Heart Rate
Contractility Preload (dP/dt) (wall tension)
Afterload (PVR)
Figure 1. Predicted effects of thyroid hormone therapy on determinants of myocardial oxygen consumption in hypothyroidism, d P / d t = change in pressure/time; PVR = peripheral vascular resistance.
in hypothyroid patients with known or suspected ischemic heart disease. L-thyroxine is the drug of choice and should be initiated in a low dosage, usually 25 #g/ day, with 12.5 to 25 #g increases in daily doses at 4- to 6-week intervals until the serum thyrotropin (TSH) level is restored to the normal range. If clinical or electrocardiographic evidence of worsening myocardial ischemia complicates the course of gradual hormone replacement, the L-thyroxine dose should be reduced. ~-Adrenergic blocking agents can be added if thyroid hormone therapy exacerbates ischemic heart disease, or can even be instituted prophylactically, unless their use is contraindicated by heart failure or bronchospasm. Although long-term suboptimal L-thyroxine replacement is occasionally necessary, the failure to ameliorate risk factors for progressive atherosclerosis, i.e., hyperbetalipoproteinemia or diastolic hypertension, makes this a relatively unattractive option. For patients in whom myocardial ischemia cannot be controlled during progressive L-thyroxine replacement or in whom invasive therapy is indicated by other conventional cardiologic criteria, coronary artery bypass graft surgery or angioplasty should be considered. Three retrospective controlled studies have demonstrated the relative safety of cardiac surgery in carefully monitored hypothyroid subjects [19-21]. Higher incidences of perioperative heart failure, gastrointestinal and neuropsychiatric complications, and infection without a febrile response were observed in hypothyroid surgical patients [21], hut these did not significantly alter their mortality or duration of hospitalization. Careful monitoring for and avoidance of these potential problems as well as respiratory failure, hyponatremia, impaired drug metabolism, and aortic friability are essential. Although a course of preoperative L-thyroxine may lessen risk of some complications, the danger of preoperative myocardial infarction and cardiac arrhythmia in patients with unstable myocardial ischemia generally outweighs these concerns. HYPERTHYROIDISM
Parry [22] first observed a patient with severe thyrotoxicosis in 1786, 49 years before Graves and 54 years before yon Basedow published descriptions of diffuse toxic goiter. In retrospect, this patient's palpitations, irregular pulse, dyspnea, and hemoptysis suggest the June 1990 The American Journal of Medicine Volume 88
639
THYROID-RELATED HEART DISEASE / LADENSON
presence of both an atrial tachyarrhythmia and heart failure, the principal cardiovascular complications of thyrotoxicosis. Atrial premature contractions, paroxysmal atrial tachycardia, and atrial fibrillation and flutter may all occur in patients with hyperthyroidism. Atrial fibrillation is the most common clinically significant tachyarrhythmia, reported to occur in 10% to 22% of hyperthyroid patients [23,24]. The prevalence of thyrotoxic atrial fibrillation increases with age and is more common in men [25], probably reflecting their increased prevalence of intrinsic heart disease. Atrial fibrillation can complicate even subclinical hyperthyroidism in the elderly, who may not manifest other classical clinical features of hyperthyroidism. Forfar et al [26] detected subtle hyperthyroidism in 12.5% of elderly patients with atrial fibrillation that had previously been considered idiopathic. Based on these observations, it is prudent to screen all patients with atrial fibrillation for hyperthyroidism with a high-sensitivity serum TSH radioimmunoassay. Complications of thyrotoxic atrial fibrillation include arterial thromboembolism and congestive heart failure. The reported 10% to 40% incidence of embolic complications [27-29] justifies anticoagulant therapy, particularly in patients with an abnormal mitral valve or dilated atrium. Atrial fibrillation is often a major contributor to the pathogenesis of heart failure in hyperthyroidism. Ventricular diastolic filling may be compromised by the loss of coordinated atrial contraction and by shortening of the diastolic interval when there is a rapid ventricular response. In addition to aggressive treatment of hyperthyroidism (see last paragraph), management of patients with thyrotoxic atrial fibrillation includes anticoagulation, control of the ventricular response rate, and appropriately timed cardioversion. Because hyperthyroidism is associated with accelerated catabolism of vitamin Kdependent clotting factors, the coumarin dose requirement may be lower in hyperthyroid patients [30]. Whether the ventricular response is controlled with digitalis glycosides,/%adrenergic antagonists, or calcium channel blockers, the target ventricular rate, approximately 120 beats/minute, should be higher than that usually sought in euthyroid patients. Until hyperthyroidism is effectively treated, attempts to lower ventricular rate further are likely to result in drug toxicity. The increased metabolic clearance of digitalis glycosides in hyperthyroidism may, however, necessitate a higher maintenance dosage [7]. Unless contraindicated by impaired myocardial contractility or bronchospasm,/~-adrenergic antagonists have been shown to be relatively more effective in controlling ventriculax rate than calcium channel blockers, which are more likely to provoke hypotension [31]. Cardioversion should generally be deferred until euthyroidism is restored, since reversion to atrial fibrillation is very likely in persistently thyrotoxic patients. Nakazawa et al [32] observed that patients with spontaneous cardioversion had cardioversion within 3 months after becoming euthyroid. Patients with persistent atrial fibrillation after this interval should then undergo pharmacologic or electrical cardioversion. Intervention is also more likely to be required if atrial fibrillation has been present for more than 13 months. Mitral valve dysfunction in hyperthyroid patients has been reported in two contexts. Mitral valve pro640
June 1990 The American Journal of Medicine Volume88
lapse syndrome occurs more commonly in women with both Graves' disease [33] and autoimmune thyroiditis [34] than in women without thyroid disease. As in other individuals with this valvular anomaly, clinically significant mitral regurgitation, arrhythmia, or thromboembolism is rare [35]. A distinct and reversible form of hemodynamically significant mitral regurgitation in association with ventricular dilatation has been reported in hyperthyroidism, particularly in children [36]. The pathogenesis of heart failure in individuals with hyperthyroidism is incompletely understood and controversial. The vast majority of these patients have intrinsic heart disease that has been decompensated by peripheral vasodilatation, by rate- and rhythm-related impairments of ventricular diastolic filling, and occasionally by mitral regurgitation. However, the postulate that thyrotoxicosis alone may cause heart failure [37] is supported by numerous reports of patients who have no identifiable underlying heart disease and in whom normal cardiac function is restored with reversal of hyperthyroidism. Although hyperthyroid patients may have en elevated resting ejection fraction by radionuclide ventriculography, Forfar et al [38] demonstrated progressive impairment of myocardial contractility with exertion. To argue that hyperthyroidism causes "high-output" heart failure simply begs the question; the fundamental cause of this reversible cardiomyopathy has not been established. Histopathologic evidence of myocarditis is an inconstant finding [39]. Other postulated mechanisms, e.g., nutritional deficits or relative myocardial ischemia, have not yet been experimentally proven. The primary consideration in management of heart failure in the hyperthyroid patient is aggressive treatment of hyperthyroidism itself. Synthesis of thyroid hormones should be inhibited with an antithyroid drug. Although methimazole's longer duration of action makes it a more effective agent in mildly to moderately hyperthyroid ambulatory patients [40], propylthiouracil (PTU) is generally preferable in severe thyrotoxicosis complicated by heart failure. PTU not only inhibits intrathyroidal organification of iodide and coupling of iodinated tyrosines, but also partially blocks extrathyroidal conversion of T4 to T3 [41], an even more potent iodothyronine. To decrease release of pre-existing intraglandular thyroid hormone stores, oral or intravenous iodide (potassium iodide or sodium iodide, respectively) should be added once antithyroid medication has been started. Alternatively, an iodinecontaining radiocontrast agent, e.g., sodium ipodate, that interferes with both hormone release and extrathyroidal T4-to-T3 conversion [42], can be employed. ~-Adrenergic antagonists offer prompt control of sympathomimetic manifestations of hyperthyroidism and, as previously discussed, may be valuable in controlling associated tachyarrhythmias. In patients with heart failure, oral or intravenous propranolol should only be employed under vigilant observation, ideally with invasive hemodynamic monitoring. Because of the already dilated vascular bed in hyperthyroid patients, diuretics should only be employed with great care and vasodilators are generally contraindicated. Except for their potential value in controlling ventricular rate in patients with atrial fibrillation, the digitalis glycosides should not be expected to enhance myocardial contractility in hyperthyroidism [12].
THYROID-RELATED HEART DISEASE / LADENSON
REFERENCES 1. Zondek H: Das myxodemherz. Munch Med Wochenschr 1918; 65:1180-1183. 2. Kerber RE, Sherman B: Echocardiographicevaluation of pericardial effusion in myxedema. Circulation 1975; 52: 823-827. 3. Parring HH, Hansen JM, Nielson SL, Rossing N, Munck O, Lassen NA: Mechanisms of edema formation in myxedema: increased protein extravasation and relatively slow lymphatic drainage. N Engl J Med 1979; 301: 460-465. 4. Manolis AS, Varriale P, Ostrowski RM: Hypothyroid cardiac tamponade. Arch Intern Med 1987; 147: 1167-1169. 5. Khaleeli AA, Memon N: Factors affecting resolution of pericardial effusions in primary hypothyroidism: a clinical, biochemical, and echocardiographic study. Postgrad Med J 1982; 58: 473-476. 6. Graettinger JS, Muenster JJ, Selverstone LA, Campbell JA: A correlation of clinical and hemodynamic studies in patients with hyperthyroidism with and without congestive heart failure. J Clin Invest 1959; 19: 1316-1327. 7. Doherty JE, Perkins WH: Digoxin metabolism in hypo- and hyperthyroidism. Ann Intern Med 1966; 64: 489-507. 8. Amidi M, Leon DF, DeGroot WJ, Kroetz FW, Leonard JJ: Effect of the thyroid state on myocardial contractility and ventricular ejection rate in man. Circulation 1968; 38: 229-239. 9. Graettinger JS, MuensterJJ, Checchia CS, Grissom RL, CampbellJA: A correlation of clinical and hemodynamic studies in patients with hypothyroidism. J Clin Invest 1958; 19: 502-510. 10. Ladenson PW, Goldenheim PD, Ridgway EC: Rapid pituitary and peripheral tissue responsesto intravenous L-triiodothyronine in hypothyroidism. J Clin Endocrinol Metab 1983; 56: 1252-1259. 11, Ladenson PW, Ridgway EC: Early peripheral responses to intravenous L-thyroxine in primary hypothyroidism. Am J Med 1982; 73: 467-474. 12. Buccino RA, Spann JF Jr, Pool PE, Sonnenblick EH, Braunwald E: Influenceof thyroid state on the intrinsic contractile properties and energy stores of the myocardium. J Clin Invest 1967; 46: 1669-1681. 13. Lee DC, Johnson RA, Bingham JB, et al: Heart failure in outpatients: a randomized trial of digoxin versus placebo. N Engl J Med 1982; 306: 699-705. 14. Bing RF, Briggs SJ, Burden AC, Russell GI, SwalesJD, Thurston H: Reversible hypertension and hypothyroidism. Clin Endocrinol 1980; 13: 339-342. 15. Abrams JJ, Grundy SM: Cholesterol metabolism in hypothyroidism and hyperthyroidism in man. J Lipid Res 1981; 22: 323-338. 16. Becker C: Hypothyroidism and atherosclerotic heart disease: pathogenesis, medical management, and the role of coronary artery bypass surgery. Endocr Rev 1985; 6: 432-440. 17. Keating FRJr, Parkin rw, Selby JB, Dickinson LS: Treatment of heart disease associated with myxedema. Prog Cardiovasc Dis 1960; 3: 364-381. 18, Block WJ, Crumpacker EL, Dry TJ, Gage RP: Prognosis of angina pectoris: observation in 6,882 cases. JAMA 1952; 150: 259-264. 19. Paine TD, Rogers WJ, Baxley WA, Russell RO: Coronary arterial surgery in patients with incapacitating angina pectoris and myxedema. Am J Cardiol 1977; 40: 226-231. 20. Hay ID: Thyroxine therapy in hypothyroid patients undergoing coronary revascularization: a retrospective analysis. Ann Intern Med 1981; 95: 456-462.
21. Ladenson PW, Levin AA, RidgwayEC, DanielsGH: Complications of surgery in hypothyroid patients. Am J Med 1984; 77: 261-266. 22. Parry CH: In: Collections from the unpublished works of the late Caleb Hillier Parry, vol 1. London: Underwood, 1825; 478. 23. SandierG, Wilson GM: The nature and prognosis of heart diseasein thyrotoxicosis. Q J Med 1959; 28: 347-369. 24. Agner T, AbundalT, Thorsteinzson B, Agner E: A re-evaluationof atrial fibrillation in thyrotoxicosis. Dan Med Bull 1984; 31: 157-159. 25. Forfar JC, Caldwell GC: Hyperthyroid heart disease. Clin Endocrinol Metab 1985; 14: 491-508. 26. Forfar JC, Miller HC, Toft AD: Occult thyrotoxicosis: a correctable cause of 'idiopathic' atrial fibrillation. Am J Cardiol 1979; 44: 9-12. 27. Yuen RWM, Gutteridge DH, Thompson PL, Robinson JS: Embolism in thyrotoxic atrial fibrillation. Med J Aust 1979; 1: 630-631. 28. Staffurth JS, Gibberd JS, Ng Tang Fui S: Arterial embolism in thyrotoxicosis with atrial fibrillation. Br Med J 1977; 3: 688-690. 29. Bar-sela S, Ehrenfeld M, Eliakim M: Arterial embolism in thyrotoxicosis with atrial fibrillation. Arch Intern Med 1981; 141: 1191-1192. 30. Mclntosh TJ, Brunk SF, Koll N: Increasedsensitivity to warfarin in thyrotoxicosis (abstr). J Clin Invest 1970; 49: 63a. 31. CIozelJP, Danchin N, Genton P, ThomasJL, Cherrier F: Effectsof propranolol and verapamil on heart rate and blood pressurein hypothyroidism. Clin Pharmacol Ther 1984; 36: 64-69. 32. NakazawaHK, Sakurai K, HamadaN, Momotani N, Ito K: Managementof atrial fibrillation in the post-thyrotoxic state. Am J Med 1982; 72: 903-906. 33. Channick BJ, Adlin EV, Marks AD, eta/: Hyperthyroidism and mitral-valve prolapse. N Engl J Med 1981; 305: 497-500. 34. Marks AD, Channick BJ, Adlin EV, Kesler RK, Braitman L, Denenberg BS: Chronic thyroiditis and mitral valve prolapse. Ann Intern Med 1985; 102: 479-483. 35. DevereuxRB, Kramer-FoxR, Kligfield P: Mitral valve prolapse: causes, clinical manifestations, and management. Ann Intern Med 1989; 111: 305-317. 36. ReynoldsJL, Woody HB: Thyrotoxic mitral regurgitation. Am J Dis Child 1971; 122: 544-548. 37. Likoff WB, Levine SA: Thyrotoxicosis as the sole cause of heart failure. Am J Med Sci 1943; 206: 425-434. 38. Forfar JC, Muir AL, Sawers SA, Tort AD: Abnormal left ventricular function in hyperthyroidism: evidencefor a possible reversiblecardiomyopathy. N EnglJ Med 1982; 307: 1165-1170. 39. Sachs RN, Vignot M, Modigliani E, et a# Absencede lesionshistologiques ultrastructurales du myocarde dans I'insuffisance cardiaque de I'hyperthyroidie. Ann Med Interne (Paris) 1986; 137: 375-378. 40. Okamura K, Ikenoue H, Shiroozu A, Sato K, Yoshinari M: Reevaluationof the effects of methylmercaptoimidazole and propylthiouracil in patients with Graves hyperthyroidism. J Clin Endocrinol Metab 1987; 65: 719-723. 41. Chopra IJ: A study of extrathyroidal conversion of thyroxine (T4) to 3,3',5triiodothyronine (T3) in vitro. Endocrinology 1977; 101: 453-463. 42. Robuschi G, Manfredi A, Salvi M, et al: Effect of sodium ipodate and iodide on free T4 and free T3 concentrations in patients with Graves' disease. J Endocrinol Invest 1986; 9: 287-291.
June 1990
The American Journal of Medicine
Volume 88
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Hypothyroidism and hyperthyroidism are both associated with clinically significant cardiovascular derangements. In hypothyroidism, these include pericardial effusion, heart failure, and the complex interrelationship between hypothyroidism and ischemic heart disease. Cardiovascular disorders associated with hyperthyroidism include atrial tachyarrhythmias, mitral valve dysfunction, and heart failure. Although these usually occur in individuals with intrinsic heart disease, thyroid dysfunction alone rarely causes serious but reversible cardiovasc,dAr dysfunction. Patients with commonly encountered cardiac disorders, e.g., idiopathic cardiomyopathy and atrial fibrillation, should be screened for potentially contributing subclinical thyroid diseases. In patients with heart failure and hypothyroidism, initial mAnAgement should focus on diagnosis and optimal management of any primary cardiac disease, whereas in hyperthyroidism, aggressive measures to control excess thyroid hormone action should generally have the highest priority.
From the Division of Endocrinology and Metabolism, The Johns Hopkins University School of Medicine, Baltimore, Maryland. This study was presented in part at the 64th Annual Meeting of the American Thyroid Association, San Francisco, California. Requests for reprints should be addressed to Paul W. Ladenson, M.D., Division of Endocrinology and Metabolism, The Johns Hopkins Hospital, Blalock 904, Baltimore, Maryland 21205.
638
June 1990 The American Journal of Medicine Volume 88
hyroid hormones affect the cardiovascular system T directly by altering cardiac contractile force and frequency, and indirectly by modulating tissue metabolism, extracellular fluid volume and distribution, and catecholamine effects. Therefore, both deficiency and excess of thyroid hormone can be associated with clinically important cardiovascular derangements, particularly in individuals with intrinsic heart disease. In hypothyroidism, these include the common and potentially confusing presence of pericardial effusion, the less frequent problem of heart failure, and the complex interrelationship between hypothyroidism and ischemic heart disease. Cardiovascular disorders associated with hyperthyroidism include atrial tachyarrhythmias, mitral valve dysfunction, and heart failure. HYPOTHYROIDISM
The features of the "myxedema heart" were first described in 1918 by Zondek [1], who described the characteristic dilated cardiac silhouette, low electrocardiographic voltage, and slow indolent heart action, all of which were reversed by thyroid hormone therapy. We now recognize that these abnormalities were partially attributable to pericardial effusion, the most common cardiovascular complication of hypothyroidism, reported to be present in at least 30% of untreated patients [2]. These effusions typically have a high protein concentration and are, like other serous effusions in hypothyroidism, due to increased capillary permeability [3]. Their slow accumulation probably accounts for the relative rarity of hemodynamic compromise, even with large effusions [4]. Indeed, the principal clinical problem caused by pericardial effusion in the myxedematous patient, who may complain of fatigue, dyspnea, and edema, is potential misdiagnosis of congestive heart failure. Following institution of thyroid hormone replacement therapy, pericardial effusions typically resolve over 2 to 12 months without sequelae [5]. Heart failure in patients with hypothyroidism generally represents exacerbation of intrinsic cardiac disease by the superimposed hemodynamic effects of thyroid hormone deficiency: bradycardia, diminished myocardial contractility, and markedly increased peripheral cardiovascular resistance [6]. Rarely, hypothyroidism alone may cause a reversible cardiomyopathy that is severe enough to cause heart failure. No clinical or radiologic features reliably distinguish hypothyroid heart failure from other dilated cardiomyopathies, except for the general clinical features of myxedema, which may be subtle. Therefore, hypothyroidism should be excluded in all individuals without a clear etiology of heart disease. Failure to recognize underlying thyroid hormone deficiency permits progression of cardiovascular dysfunction and subjects the patient to risk of intoxication with digitalis glyco-
THYROID-RELATED HEART DISEASE / LADENSON
sides, which are cleared less rapidly in hypothyroidism [7]. Management of heart failure in hypothyroid patients requires prompt diagnosis and treatment of the intrinsic heart disorder that almost invariably coexists, and reversal of hypothyroidism. Early identification of primary cardiac disease is essential since some disorders may actually be exacerbated by thyroid hormone replacement, e.g., ischemic heart disease and aortic stenosis. For the hypothyroid patient with heart failure, thyroid hormone represents a physiologic and potent positive inotropic agent. Numerous noninvasive [8] and invasive [9] studies have demonstrated reversibility of the decreased myocardial contractility associated with hypothyroidism. Although L-triiodothyronine (T3) is more potent with a more rapid onset of action [10], L-thyroxine (T4) also significantly enhances myocardial performance within 1 week [11]. Furthermore, the longer T4 half-life makes it a more physiologic and practical preparation for long-term replacement therapy. Digitalis glycosides also increase myocardial tension development in hypothyroidism [12] and may be a useful adjunctive therapy, particularly when clinical and radiologic features predicting digitalis responsiveness are present [13]. The coexistence of hypothyroidism and atherosclerotic coronary artery disease not infrequently poses a challenging dilemma for the clinician. The pathogenesis of atherosclerosis may be accelerated by the diastolic hypertension [14] and elevated serum low-density lipoprotein cholesterol concentration [15] that are characteristic of hypothyroidism. Whether hypothyroidism per se and serologic evidence of autoimmune thyroiditis are associated with additional independent risks of atherosclerosis remains controversial [16]. Regardless, successful management of established risk factors for progression of coronary artery disease requires recognition and treatment of hypothyroidism. In hypothyroid patients with established atherosclerotic coronary artery disease, it is difficult to predict accurately the impact of thyroid hormone replacement therapy on myocardial oxygen demand (Figure 1). The positive chronotropic and inotropic effects of thyroid hormone augment myocardial oxygen consumption, which can worsen ischemia in patients with flow-limiting coronary arterial obstructions. On the other hand, increased myocardial contractility may reduce ventricular end-diastolic volume and wall tension (preload) in dilated hearts, and will predictably decrease peripheral vascular resistance (afterload). The variability predicted by these theoretic considerations has been confirmed in clinical management of hypothyroid patients with ischemic heart disease. Among hypothyroid patients with pre-existing angina pectoris and treated with thyroid hormone, Keating et al [17] reported improvement or no change in more than 80%. In this series consisting primarily of older adults, less than 1% of treated hypothyroid patients had new onset of angina. Furthermore, the reported 1year cardiovascular mortality for all treated hypothyroid patients with coincident ischemic heart disease, 3%, compares favorably with the 9% to 15% mortality reported among other patients with atherosclerotic heart disease in that era [18]. This study and other uncontrolled clinical trials have led to formulation of widely accepted empiric recommendations for hormone replacement therapy
8
¢¢
>, )<
o m o o
:S
Heart Rate
Contractility Preload (dP/dt) (wall tension)
Afterload (PVR)
Figure 1. Predicted effects of thyroid hormone therapy on determinants of myocardial oxygen consumption in hypothyroidism, d P / d t = change in pressure/time; PVR = peripheral vascular resistance.
in hypothyroid patients with known or suspected ischemic heart disease. L-thyroxine is the drug of choice and should be initiated in a low dosage, usually 25 #g/ day, with 12.5 to 25 #g increases in daily doses at 4- to 6-week intervals until the serum thyrotropin (TSH) level is restored to the normal range. If clinical or electrocardiographic evidence of worsening myocardial ischemia complicates the course of gradual hormone replacement, the L-thyroxine dose should be reduced. ~-Adrenergic blocking agents can be added if thyroid hormone therapy exacerbates ischemic heart disease, or can even be instituted prophylactically, unless their use is contraindicated by heart failure or bronchospasm. Although long-term suboptimal L-thyroxine replacement is occasionally necessary, the failure to ameliorate risk factors for progressive atherosclerosis, i.e., hyperbetalipoproteinemia or diastolic hypertension, makes this a relatively unattractive option. For patients in whom myocardial ischemia cannot be controlled during progressive L-thyroxine replacement or in whom invasive therapy is indicated by other conventional cardiologic criteria, coronary artery bypass graft surgery or angioplasty should be considered. Three retrospective controlled studies have demonstrated the relative safety of cardiac surgery in carefully monitored hypothyroid subjects [19-21]. Higher incidences of perioperative heart failure, gastrointestinal and neuropsychiatric complications, and infection without a febrile response were observed in hypothyroid surgical patients [21], hut these did not significantly alter their mortality or duration of hospitalization. Careful monitoring for and avoidance of these potential problems as well as respiratory failure, hyponatremia, impaired drug metabolism, and aortic friability are essential. Although a course of preoperative L-thyroxine may lessen risk of some complications, the danger of preoperative myocardial infarction and cardiac arrhythmia in patients with unstable myocardial ischemia generally outweighs these concerns. HYPERTHYROIDISM
Parry [22] first observed a patient with severe thyrotoxicosis in 1786, 49 years before Graves and 54 years before yon Basedow published descriptions of diffuse toxic goiter. In retrospect, this patient's palpitations, irregular pulse, dyspnea, and hemoptysis suggest the June 1990 The American Journal of Medicine Volume 88
639
THYROID-RELATED HEART DISEASE / LADENSON
presence of both an atrial tachyarrhythmia and heart failure, the principal cardiovascular complications of thyrotoxicosis. Atrial premature contractions, paroxysmal atrial tachycardia, and atrial fibrillation and flutter may all occur in patients with hyperthyroidism. Atrial fibrillation is the most common clinically significant tachyarrhythmia, reported to occur in 10% to 22% of hyperthyroid patients [23,24]. The prevalence of thyrotoxic atrial fibrillation increases with age and is more common in men [25], probably reflecting their increased prevalence of intrinsic heart disease. Atrial fibrillation can complicate even subclinical hyperthyroidism in the elderly, who may not manifest other classical clinical features of hyperthyroidism. Forfar et al [26] detected subtle hyperthyroidism in 12.5% of elderly patients with atrial fibrillation that had previously been considered idiopathic. Based on these observations, it is prudent to screen all patients with atrial fibrillation for hyperthyroidism with a high-sensitivity serum TSH radioimmunoassay. Complications of thyrotoxic atrial fibrillation include arterial thromboembolism and congestive heart failure. The reported 10% to 40% incidence of embolic complications [27-29] justifies anticoagulant therapy, particularly in patients with an abnormal mitral valve or dilated atrium. Atrial fibrillation is often a major contributor to the pathogenesis of heart failure in hyperthyroidism. Ventricular diastolic filling may be compromised by the loss of coordinated atrial contraction and by shortening of the diastolic interval when there is a rapid ventricular response. In addition to aggressive treatment of hyperthyroidism (see last paragraph), management of patients with thyrotoxic atrial fibrillation includes anticoagulation, control of the ventricular response rate, and appropriately timed cardioversion. Because hyperthyroidism is associated with accelerated catabolism of vitamin Kdependent clotting factors, the coumarin dose requirement may be lower in hyperthyroid patients [30]. Whether the ventricular response is controlled with digitalis glycosides,/%adrenergic antagonists, or calcium channel blockers, the target ventricular rate, approximately 120 beats/minute, should be higher than that usually sought in euthyroid patients. Until hyperthyroidism is effectively treated, attempts to lower ventricular rate further are likely to result in drug toxicity. The increased metabolic clearance of digitalis glycosides in hyperthyroidism may, however, necessitate a higher maintenance dosage [7]. Unless contraindicated by impaired myocardial contractility or bronchospasm,/~-adrenergic antagonists have been shown to be relatively more effective in controlling ventriculax rate than calcium channel blockers, which are more likely to provoke hypotension [31]. Cardioversion should generally be deferred until euthyroidism is restored, since reversion to atrial fibrillation is very likely in persistently thyrotoxic patients. Nakazawa et al [32] observed that patients with spontaneous cardioversion had cardioversion within 3 months after becoming euthyroid. Patients with persistent atrial fibrillation after this interval should then undergo pharmacologic or electrical cardioversion. Intervention is also more likely to be required if atrial fibrillation has been present for more than 13 months. Mitral valve dysfunction in hyperthyroid patients has been reported in two contexts. Mitral valve pro640
June 1990 The American Journal of Medicine Volume88
lapse syndrome occurs more commonly in women with both Graves' disease [33] and autoimmune thyroiditis [34] than in women without thyroid disease. As in other individuals with this valvular anomaly, clinically significant mitral regurgitation, arrhythmia, or thromboembolism is rare [35]. A distinct and reversible form of hemodynamically significant mitral regurgitation in association with ventricular dilatation has been reported in hyperthyroidism, particularly in children [36]. The pathogenesis of heart failure in individuals with hyperthyroidism is incompletely understood and controversial. The vast majority of these patients have intrinsic heart disease that has been decompensated by peripheral vasodilatation, by rate- and rhythm-related impairments of ventricular diastolic filling, and occasionally by mitral regurgitation. However, the postulate that thyrotoxicosis alone may cause heart failure [37] is supported by numerous reports of patients who have no identifiable underlying heart disease and in whom normal cardiac function is restored with reversal of hyperthyroidism. Although hyperthyroid patients may have en elevated resting ejection fraction by radionuclide ventriculography, Forfar et al [38] demonstrated progressive impairment of myocardial contractility with exertion. To argue that hyperthyroidism causes "high-output" heart failure simply begs the question; the fundamental cause of this reversible cardiomyopathy has not been established. Histopathologic evidence of myocarditis is an inconstant finding [39]. Other postulated mechanisms, e.g., nutritional deficits or relative myocardial ischemia, have not yet been experimentally proven. The primary consideration in management of heart failure in the hyperthyroid patient is aggressive treatment of hyperthyroidism itself. Synthesis of thyroid hormones should be inhibited with an antithyroid drug. Although methimazole's longer duration of action makes it a more effective agent in mildly to moderately hyperthyroid ambulatory patients [40], propylthiouracil (PTU) is generally preferable in severe thyrotoxicosis complicated by heart failure. PTU not only inhibits intrathyroidal organification of iodide and coupling of iodinated tyrosines, but also partially blocks extrathyroidal conversion of T4 to T3 [41], an even more potent iodothyronine. To decrease release of pre-existing intraglandular thyroid hormone stores, oral or intravenous iodide (potassium iodide or sodium iodide, respectively) should be added once antithyroid medication has been started. Alternatively, an iodinecontaining radiocontrast agent, e.g., sodium ipodate, that interferes with both hormone release and extrathyroidal T4-to-T3 conversion [42], can be employed. ~-Adrenergic antagonists offer prompt control of sympathomimetic manifestations of hyperthyroidism and, as previously discussed, may be valuable in controlling associated tachyarrhythmias. In patients with heart failure, oral or intravenous propranolol should only be employed under vigilant observation, ideally with invasive hemodynamic monitoring. Because of the already dilated vascular bed in hyperthyroid patients, diuretics should only be employed with great care and vasodilators are generally contraindicated. Except for their potential value in controlling ventricular rate in patients with atrial fibrillation, the digitalis glycosides should not be expected to enhance myocardial contractility in hyperthyroidism [12].
THYROID-RELATED HEART DISEASE / LADENSON
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21. Ladenson PW, Levin AA, RidgwayEC, DanielsGH: Complications of surgery in hypothyroid patients. Am J Med 1984; 77: 261-266. 22. Parry CH: In: Collections from the unpublished works of the late Caleb Hillier Parry, vol 1. London: Underwood, 1825; 478. 23. SandierG, Wilson GM: The nature and prognosis of heart diseasein thyrotoxicosis. Q J Med 1959; 28: 347-369. 24. Agner T, AbundalT, Thorsteinzson B, Agner E: A re-evaluationof atrial fibrillation in thyrotoxicosis. Dan Med Bull 1984; 31: 157-159. 25. Forfar JC, Caldwell GC: Hyperthyroid heart disease. Clin Endocrinol Metab 1985; 14: 491-508. 26. Forfar JC, Miller HC, Toft AD: Occult thyrotoxicosis: a correctable cause of 'idiopathic' atrial fibrillation. Am J Cardiol 1979; 44: 9-12. 27. Yuen RWM, Gutteridge DH, Thompson PL, Robinson JS: Embolism in thyrotoxic atrial fibrillation. Med J Aust 1979; 1: 630-631. 28. Staffurth JS, Gibberd JS, Ng Tang Fui S: Arterial embolism in thyrotoxicosis with atrial fibrillation. Br Med J 1977; 3: 688-690. 29. Bar-sela S, Ehrenfeld M, Eliakim M: Arterial embolism in thyrotoxicosis with atrial fibrillation. Arch Intern Med 1981; 141: 1191-1192. 30. Mclntosh TJ, Brunk SF, Koll N: Increasedsensitivity to warfarin in thyrotoxicosis (abstr). J Clin Invest 1970; 49: 63a. 31. CIozelJP, Danchin N, Genton P, ThomasJL, Cherrier F: Effectsof propranolol and verapamil on heart rate and blood pressurein hypothyroidism. Clin Pharmacol Ther 1984; 36: 64-69. 32. NakazawaHK, Sakurai K, HamadaN, Momotani N, Ito K: Managementof atrial fibrillation in the post-thyrotoxic state. Am J Med 1982; 72: 903-906. 33. Channick BJ, Adlin EV, Marks AD, eta/: Hyperthyroidism and mitral-valve prolapse. N Engl J Med 1981; 305: 497-500. 34. Marks AD, Channick BJ, Adlin EV, Kesler RK, Braitman L, Denenberg BS: Chronic thyroiditis and mitral valve prolapse. Ann Intern Med 1985; 102: 479-483. 35. DevereuxRB, Kramer-FoxR, Kligfield P: Mitral valve prolapse: causes, clinical manifestations, and management. Ann Intern Med 1989; 111: 305-317. 36. ReynoldsJL, Woody HB: Thyrotoxic mitral regurgitation. Am J Dis Child 1971; 122: 544-548. 37. Likoff WB, Levine SA: Thyrotoxicosis as the sole cause of heart failure. Am J Med Sci 1943; 206: 425-434. 38. Forfar JC, Muir AL, Sawers SA, Tort AD: Abnormal left ventricular function in hyperthyroidism: evidencefor a possible reversiblecardiomyopathy. N EnglJ Med 1982; 307: 1165-1170. 39. Sachs RN, Vignot M, Modigliani E, et a# Absencede lesionshistologiques ultrastructurales du myocarde dans I'insuffisance cardiaque de I'hyperthyroidie. Ann Med Interne (Paris) 1986; 137: 375-378. 40. Okamura K, Ikenoue H, Shiroozu A, Sato K, Yoshinari M: Reevaluationof the effects of methylmercaptoimidazole and propylthiouracil in patients with Graves hyperthyroidism. J Clin Endocrinol Metab 1987; 65: 719-723. 41. Chopra IJ: A study of extrathyroidal conversion of thyroxine (T4) to 3,3',5triiodothyronine (T3) in vitro. Endocrinology 1977; 101: 453-463. 42. Robuschi G, Manfredi A, Salvi M, et al: Effect of sodium ipodate and iodide on free T4 and free T3 concentrations in patients with Graves' disease. J Endocrinol Invest 1986; 9: 287-291.
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