Irwin L. Klein
The changes in cardiovascular function that occur in patients with hypothyroidism are opposite those of thyrotoxicosis (see Chapter 31) (1). Symptoms and signs related to cardiovascular dysfunction are much less prominent in patients with hypothyroidism than in those with thyrotoxicosis. This chapter reviews the pathophysiologic basis for the cardiac findings of hypothyroidism and the potential of hypothyroidism as a risk factor for accelerated atherosclerosis.
The hemodynamic changes associated with hypothyroidism are listed in Table 53.1. Compared with normal subjects, patients with hypothyroidism have an increase of 50% to 60% in peripheral vascular resistance; this increase is accompanied by a 30% to 50% decrease in resting cardiac output (2,3). The net effect of the decrease in blood flow and the decrease in tissue oxygen consumption that occurs in hypothyroidism is that arteriovenous oxygen extraction across major organs is similar in patients with hypothyroidism and normal subjects (2). Studies of the molecular mechanism underlying the increase in systemic vascular resistance suggest that thyroid hormone, specifically triiodothyronine (T3), may have a direct vasodilator action on vascular smooth muscle cells (4,5). In addition endothelium-derived vascular relaxation, which involves nitric oxide release and action, is impaired in both mild and overt hypothyroidism (6,7). Thus, in the absence of T3, vascular smooth muscle tone and systemic vascular resistance may increase. This increase can in part be reversed by acute T3 administration (8).
TABLE 53.1. CARDIOVASCULAR HEMODYNAMICS IN HYPOTHYROIDISM
Systemic vascular resistance
50%–60% above normal
30%–50% below normal
↓ or normal
Noarrowed pulse pressure
20% prevalence of disatolic hypertension
↓ or normal
↓ or normal
Systolic and diastolic function both impaired
Pericardial effusion may suggest cardiomegaly
All measurements of left ventricular contractility and performance are lower in patients with both acute and chronic hypothyroidism (9,10,11,12). Cardiac output (index) is decreased as a result of decreases in both stroke volume and, to a lesser extent, heart rate (1,12). The duration of both the preejection period and the isovolumic contraction time is prolonged compared with normal subjects, and these times decrease in response to thyroid hormone therapy (9,12). In addition, and perhaps more important, the rate of ventricular relaxation during diastole is slower, and diastolic filling and compliance are impaired (3,6). The rate of diastolic filling may decrease from normal values of 400 mL per second to less than 300 mL per second. The mechanisms underlying the impaired ventricular performance in patients with hypothyroidism are multifactorial and appear to result from changes in the expression of important myocyte-specific regulatory proteins and in pre- and afterload (1,12,13,14). As noted in Chapter 31, the expression of many cardiac genes is modulated by thyroid hormone, and in experimental animals, lowering serum concentrations of thyroxine (T4) and T3 alters the expression of the distribution of the heavy chain isoforms of myosin and of the calcium regulatory proteins (15,16,17). Myocyte nuclei contain T3 receptors that bind to specific DNA sequences of several genes, and thus many of the cardiac actions of T3 occur at the level of gene transcription. Decreases in the expression of the genes for the sarcoplasmic reticulum calcium adenosine triphosphatase (ATPase), Na+,K+-ATPase, β-adrenergic receptors, and voltage-gated potassium channels (Kv) all may play a role in the altered cardiac physiology in patients with hypothyroidism (see Chapter 8 and Chapter 31) (1,13,17).
The rate of tension development during cardiac systole is determined in part by the rate at which myosin catalyzes the hydrolysis of ATP. There are two isoforms of myosin ATPase, α and β, in cardiac myocytes. The predominant form in human ventricular tissue is β-myosin (18,19). In one hypothyroid patient with severe left ventricular dysfunction, the content of α-myosin in ventricular muscle increased slightly during treatment with T4, but β-myosin predominated at both times (17). The patient's left ventricular contractile function improved during treatment, most probably a result of improved calcium handling (cycling) in cardiac muscle cells (20). The activities of several enzymes involved in regulating calcium fluxes in the heart are controlled by thyroid hormone. These include the calcium-activated ATPase of the sarcoplasmic reticulum and phospholamban (21,22). In addition, in hypothyroidism, the increase in systemic vascular resistance (afterload) and decrease in blood volume and venous return (preload) impair cardiovascular hemodynamics (1,11,12).
As a result of the increase in systemic vascular resistance and decrease in cardiac output, mean blood pressure is largely unaltered in hypothyroidism (1,2). There may be an increase in diastolic pressure and a decrease in systolic pressure, so the pulse pressure is low. Hypothyroid patients may have diastolic hypertension that declines, sometimes to normal, during treatment with thyroid hormone as systemic vascular resistance decreases (23,24).
Plasma volume is decreased in patients with hypothyroidism (11), an unexpected finding because some patients have pitting edema suggestive of fluid overload. Capillary permeability is increased, and therefore the albumin and water content in the interstitial space is increased. Fluid may accumulate not only in gravity-dependent regions, but also in the pericardial pleural and other spaces (25). Patients with hypothyroidism also have nonpitting edema (myxedema), caused by the accumulation of hydrophilic glycosaminoglycans in the interstitial space (see Chapter 52).
The response of hypothyroid patients to exercise supports the hypothesis that peripheral circulatory changes mediate many of the changes in cardiac performance. Exercise lowers systemic vascular resistance in patients with hypothyroidism, causing an increase in cardiac index, heart rate, and stroke volume to 85% to 90% of the responses in normal subjects (26). These observations indicate that the reduced left ventricular function in hypothyroid patients at rest is at least partially the result of a decrease in hemodynamic loading.
Most patients with hypothyroidism have few symptoms directly referable to the cardiovascular system (27). Although fatigue, lack of energy, exertional dyspnea, and exercise intolerance have been attributed to impaired cardiac performance, they are more likely to be related to psychological or skeletal muscle dysfunction (28). Whether or not congestive heart failure with orthopnea and paroxysmal nocturnal dyspnea occurs solely as a result of hypothyroidism is discussed later.
Patients with hypothyroidism can have angina-like pain (26), and many have hypercholesterolemia (see Chapter 60). Various metabolic changes and cardiac risk factors predisposing to atherosclerosis are present in patients even with mild hypothyroidism (Table 53.2) (29). An occasional patient with normal coronary arteries has angina that resolves with thyroid hormone therapy (26).
TABLE 53.2. CARDIOVASCULAR RISK ASSOCIATED WITH HYPOTHYROIDISM AND EFFECT OF THYROID HORMONE THERAPY
Response to Thyroid Hormone therapy
Left ventricular diastolic dysfunction
Impaired endothelium-mediated vasodilatation
High serum homocysteine concentration
+, modest improvement; ++, marked improvement.
The abnormalities that may be found on physical examination of the cardiovascular system in patients with hypothyroidism include bradycardia, narrow pulse pressure, low-amplitude pulse, diminished apical impulse, and distant heart sounds (1,2,3,10) (Table 53.1). The bradycardia may result from a loss of the chronotropic action of thyroid hormone directly on the sinoatrial pacemaker cells (1); heart rate analysis reveals changes in both sympathetic and parasympathetic tone (30). The abnormal heart sounds may be caused by decreased left ventricular contractility or a pericardial effusion (9,10,25,31). From 20% to 40% of patients with hypothyroidism have a diastolic blood pressure greater than 90 mm Hg (11,23,32,33). Patients not only complain of cold intolerance but also may have cold feet and hands because of decreased skin blood flow.
Patients with hypothyroidism may have edema of the extremities or presacral region, mostly caused by increased extravasation of albumin and water. Myxedema, the characteristic nonpitting edema of the face, hands, and feet, occurs only in patients with severe, long-standing untreated hypothyroidism, and is rarely seen now (see Chapter 52).
Pericardial effusions occur in a variable frequency in patients with hypothyroidism (3,25). The effusions are usually small and escape detection, but occasional patients with severe, long-standing hypothyroidism have large effusions (25,34). However, even large effusions rarely affect cardiac function (35,36). The protein content of the fluid tends to be high, most likely because of an increase in albumin transudation. The fluid usually has a high cholesterol concentration and may be viscous. The pericardial effusions disappear gradually during treatment with T4 (25). Rare patients with severe, long-standing hypothyroidism have effusions in other spaces, including the peritoneal cavity, pleural cavities, and joints (36).
Hemoglobin and hematocrit values may be slightly low (see Chapter 57) (36). The partial thromboplastin time and other measures of coagulation may be prolonged in overt hypothyroidism (37). Serum total and low-density lipoprotein cholesterol, lipoprotein(a), and apolipoprotein B concentrations are often high, and some patients have high serum triglyceride concentrations (see Chapter 60). There is a progressive increase in serum total cholesterol concentrations across the entire spectrum of hypothyroidism (38).
Serum creatine kinase concentrations are high in as many as 30% of patients (28,36). Most of the increase is in the MM fraction, indicating that its source is skeletal rather than cardiac muscle (39). Serum myoglobin concentrations and urinary myoglobin excretion also may be high. These findings indicate that the permeability of muscle cell membranes is increased. The half-life of creatine kinase in serum is prolonged, which contributes to the high serum concentration (28). The serum concentrations of other muscle-related enzymes, such as aldolase, may also be high (see Chapter 63).
Hypothyroidism classically has been associated with bradycardia, but the degree of slowing of the heart rate is often modest (30,40). The function of the atrial pacemaker is normal and atrial ectopy is rare, but premature ventricular beats and occasionally ventricular tachycardia can occur (3). This is in contrast to thyrotoxicosis, in which atrial tachyarrhythmias are common and ventricular arrhythmias are rare. The syndrome of torsade de pointes with a long QT interval and ventricular tachycardia can occur with hypothyroidism and resolve with T4 treatment alone (41). The duration of the action potential may be prolonged, perhaps reflecting a decrease in voltage-gated potassium channels.
Low-voltage and nonspecific ST wave changes are other electrocardiographic abnormalities found in some patients with hypothyroidism (3,34,36). Although occasionally suggestive of myocardial ischemia (29), these changes are more likely to disappear during T4 treatment than with antiangina drug treatment (26). The low voltage may be a result of pericardial effusion, altered myocyte ion conduction, or cardiac atrophy (25,34).
All measures of left ventricular contractility and cardiac workload, as determined by echocardiography, are decreased in patients with hypothyroidism (10,12,14,42,43,44). These include systolic time intervals and measures of diastolic performance, such as isovolumic filling and compliance. Whereas cardiac contractility and work are impaired at rest, they increase during exercise (26), confirming the importance of loading conditions and heart rate as determinants of cardiac output (12). Even mild degrees of hypothyroidism of short duration are associated with predictable prolongation in the isovolumic relaxation time (14,44); thus, diastolic relaxation appears to be a sensitive and specific measurement of the cardiovascular response to thyroid hormone (3). The latter in turn most likely reflects the decrease in cardiac myocyte calcium cycling (45). Positron emission tomography and magnetic resonance imaging of the heart in patients with hypothyroidism demonstrate the expected decreases in oxidative metabolism and cardiac contractility and work. With the accompanying increase in systemic vascular resistance and afterload, the net effect is to render the heart energy inefficient (46).
Asymmetric hypertrophy of the intraventricular septum has been reported in patients with hypothyroidism, but evidence that it is caused by thyroid hormone deficiency is lacking (47). It is not likely to be responsible for the abnormalities in left ventricular function that occur in hypothyroidism, because these abnormalities often occur in the absence of any changes in cardiac morphology.
From 20% to 40% of patients with hypothyroidism have hypertension; diastolic pressure is increased more than systolic pressure (11). The increase in diastolic pressure is due primarily to the increase in systemic vascular resistance. As noted above, T3 may act as a direct vasodilator, and therefore vascular tone may increase in its absence (4,5,11,24). The blood pressure in these patients is less sensitive to variations in salt intake, as reflected by changes in blood pressure in response to sodium restriction, as compared with other hypertensive patients (3,11,33).
In large series of hypertensive patients, varying degrees of hypothyroidism were a contributing factor in about 3% to 5% (see Chapter 55) (23). This is a low-renin form of hypertension that may occur early in the course of the hypothyroidism (32,33). Among hypothyroid patients with hypertension, some have normal or near-normal blood pressure after treatment with T4 alone (11,23,32).
The presence of impaired left ventricular contractility, diastolic hypertension, increased systemic vascular resistance, and peripheral edema suggests that hypothyroidism can cause heart failure (2,17,48). However, documentation of hypothyroidism as the sole cause of congestive heart failure is rare (1,3,49,50). Arteriovenous oxygen extraction is normal in hypothyroid patients, whereas it is increased in patients with organic heart disease and heart failure (2). Patients with hypothyroidism have an increase in cardiac output and a decrease in systemic vascular resistance in response to exercise, unlike patients with heart failure (2,10). Also, in contrast to patients with heart failure, patients with hypothyroidism are able to excrete a sodium load (51) and do not develop signs of pulmonary fluid overload characteristic of intrinsic heart disease. As noted above, limitations of exercise capacity are more likely the result of skeletal muscle fatigue and weakness and from pulmonary-related causes than from cardiac insufficiency (See Chapters 54 and 63). Although histologic changes in the heart of patients dying of profound hypothyroidism include myocyte swelling and mucinous edema (52), the most characteristic findings are the functional abnormalities related to impaired diastolic relaxation (1,3,14).
All the changes in cardiovascular function in patients with hypothyroidism improve in response to treatment with T4 or T3 (see Chapter 67) (31,49). In most patients the symptoms are chronic, and hemodynamic performance is not impaired sufficiently to require urgent therapy (3,8,9,53). Young patients can be given full replacement doses of T4, for example, 100 to 150 µg daily. Older patients initially should be given lower doses, for example, 50 µg daily, and older patients with coronary artery disease even lower doses, for example, 25 µg daily. In patients with severe hypothyroidism treated with high doses of T3, cardiovascular performance improves within 48 to 96 hours (49). T4 treatment reverses not only the abnormalities in cardiac contractility and systemic vascular resistance, often including blood pressure, but also the high serum lipid concentrations and other biochemical abnormalities in weeks or months (11,23,25,28).
SPECIAL CLINICAL SITUATIONS
Hypothyroidism, Thyroid Hormone Therapy, and Coronary Artery Disease
Patients with hypothyroidism might be expected to have an increased risk for coronary artery disease, since they may have hypertension and they often have hypercholesterolemia (11,34,38,40). In a case control autopsy study, coronary artery disease was more prevalent in hypothyroid patients with coexistent hypertension, but not in normotensive hypothyroid patients, compared with euthyroid patients (54). In a cross-sectional study of 280 nursing home patients there was an increase in the frequency of hypercholesterolemia and coronary artery disease in patients with hypothyroidism, as compared with patients with normal thyroid function (53,54a). Similarly, an increase in abdominal aortic calcification and incident myocardial infarction was noted in a study of women 55 years of age or older with subclinical hypothyroidism in Amsterdam (see Chapters 77 and 78) (55).
Hypothyroidism may predispose to the development of atherosclerosis and coronary artery disease by several mechanisms (11,29,56) (Table 53.2). Hypercholesterolemia [and high serum lipoprotein(a) concentrations] and increased systemic vascular resistance with diastolic hypertension are well-recognized cardiovascular risk factors. In addition, hypothyroidism is associated with slightly high serum homocysteine concentrations (perhaps secondary to decreased folic acid absorption) and impaired endothelium-mediated vasodilatation (6,7). Although patients with overt hypothyroidism have abnormal platelet function and impaired hemostasis, subclinical hypothyroidism is associated with increased platelet aggregation and impaired fibrinolysis, changes that could be proatherogenic (57). In one study, the serum concentrations of C-reactive protein, an acute inflammatory marker associated with risk for cardiovascular disease, were slightly higher in patients with both overt and subclinical hypothyroidism than normal subjects; the concentrations did not decrease during T4therapy in the patients with subclinical hypothyroidism (the only group studied) (58).
In patients with coronary artery disease who develop hypothyroidism, the decreases in cardiac work and oxygen demand were previously thought to promote better tolerance of decreases in myocardial blood flow. These considerations led some clinicians either to not treat or to give only a low dose of T4 to patients with known or suspected coronary artery disease (26). [Hypothyroid dogs tolerate myocardial ischemia less well than do euthyroid dogs, and myocardial damage is more extensive and ventricular arrhythmias are more common after experimentally induced myocardial infarction than in euthyroid animals (59)]. However, given the deleterious effects of hypothyroidism on cardiac function and the debilitating effects of hypothyroidism per se, it is not reasonable to withhold or limit T4 replacement for a theoretic benefit on myocardial ischemia (1,3).
With regard to angina pectoris, the effects of thyroid hormone treatment are mostly beneficial. In the largest study of this issue, 1,503 hypothyroid patients received thyroid hormone therapy and subsequently were evaluated for angina pectoris and myocardial infarction (60). Of the 55 patients with known symptomatic coronary artery disease, 38% improved with treatment, 46% had no change, and only 16% had more symptoms. Thirty-five patients had chest pain after thyroid hormone therapy was begun, but in two thirds of them the pain began more than 1 year after initiation of treatment. Considering the demographics of the overall study group, several hundred patients were probably at risk for coronary artery disease; thus, the overall incidence of symptoms attributable to coronary artery disease after initiation of thyroid hormone therapy was low. Thyroid hormone therapy should not be withheld on the grounds that angina pectoris might occur.
Occasional hypothyroid patients have sufficiently extensive coronary artery disease to justify coronary artery bypass surgery before or soon after T4 therapy is begun (3,61). The operation can be performed safely and without excessive morbidity in these patients (61,62), as can coronary angioplasty or stenting (63). Postoperatively, full-dose T4 therapy is most likely to prevent progression of coronary artery disease (64).
Thyroid Hormone Therapy in Heart Disease and After Cardiac Surgery
Thyroid hormone metabolism, specifically the extrathyroidal conversion of T4 to T3, is altered in patients with both chronic and acute cardiac disease, as in many other illnesses (see section on Nonthyroidal Illness in Chapter 11). A study of 573 patients with all types of cardiac disease identified a low serum free T3 concentration as a predictor of death; during a mean follow-up period of 11 months, 14% of the patients with a low serum free T3 concentration at base line died, as compared with 3% of the patients with normal serum free T3 concentrations (65). In a study of patients with congestive heart failure, serum total and free T3 concentrations were inversely related to the degree of heart failure, as assessed by New York Heart Association scoring criteria (66). Short-term treatment of heart failure patients with intravenous T3 increases cardiac output and reduces systemic vascular resistance, and has no adverse effects (67,68). Whether the illness- or surgery-related decrease in serum T3 concentrations results in thyroid deficiency in the heart or other organs is debated. In one study in animals, induction of nonthyroidal illness resulted in changes in gene expression in cardiac muscle and changes in cardiac function similar to those that occur in hypothyroidism, and administration of low doses of T3 reversed the changes (69). All these findings, and the reports that T3 administration after experimental myocardial infarction in animals improved cardiovascular hemodynamics, suggest that low serum T3 concentrations may have deleterious effects on cardiac function (70).
Serum T3 concentrations decrease acutely after cardiopulmonary surgery in both children and adults; the decrease is greater and more prolonged in children, especially those with complicated congenital heart defects (8,24,71,72,73). This decline, and the marked effect of thyroid hormone on cardiac contractility, provided the rationale for administering T3 as a potential positive inotropic agent and a novel vasodilator in these patients. Children with serum T3concentrations less than 40 ng/dL (0.6 nM) who were given T3 intravenously for 48 to 96 hours after surgery had improved cardiovascular hemodynamics and renal perfusion, with a reduced need for inotropic support (71,72). Among patients with coronary artery disease undergoing elective coronary artery bypass grafting, intravenous administration of high doses of T3 immediately after surgery was associated with an increase in cardiac output and a decrease in systemic vascular resistance during the first 24 hours after surgery, as compared with placebo (24). In addition, the frequency of postoperative atrial fibrillation was reduced by 50%; postoperative mortality in the two groups was similar (74).
Patients with subclinical hypothyroidism have changes in cardiovascular function and risk factors for cardiovascular disease that are similar to but smaller in magnitude to those of patients with overt hypothyroidism described above (see Chapter 78) (12,14). In a study of these patients, the rate of isovolumic relaxation, diastolic flow, and systemic vascular resistance improved during thyroid hormone therapy (14). Long-term benefits of T4 therapy in these patients have not been documented (75). Nonetheless, the improvement in cardiac dynamics and the at least partial reversal of some of the risk factors (e.g., serum cholesterol) that occur during T4 therapy suggest that these patients should have long-term cardiovascular benefits from therapy.
1. Klein I, Ojamaa K. Thyroid hormone and the cardiovascular system. N Engl J Med 2001;344:501.
2. Graettinger JS, Muenster JJ, Checchia CS, et al. A correlation of clinical and hemodynamic studies in patients with hypothyroidism. J Clin Invest 1957;37:502.
3. Klein I. Endocrine disorders and cardiovascular disease. In: Braunwald E, Zipes DP, Libby P, eds Heart disease, 7th ed. New York: WB Saunders, 2004 (in press).
4. Ojamaa K, Balkman C, Klein I. Acute effects of triiodothyronine on arterial smooth muscle cells. Ann Thorac Surg 1993; 56(suppl):61.
5. Park KW, Dai HB, Ojamaa K, et al. The direct vasomotor effect of thyroid hormones on rat skeletal muscle resistance arteries. Anesth Analg 1997;85:734.
6. Lekakis J, Papamichael C, Alevizaki M, et al. Flow mediated endothelium dependent vasodilatation is impaired in subjects with hypothyroidism. Thyroid 1997;7:411.
7. Taddei S, Caraccio N, Virdis A, et al. Impaired endothelial-dependent vasodilatation in subclinical hypothyroidism. J Clin Endocrinol Metab 2003;88:3731.
8. Klemperer JD, Ojamaa K, Klein I. Thyroid hormone therapy in cardiovascular disease. Prog Cardiovasc Dis 1996;38:329.
9. Crowley WF Jr, Ridgway EC, Bough EW, et al. Non-invasive evaluation of cardiac function in hypothyroidism. N Engl J Med 1977;296:1.
10. Wieshammer S, Keck F, Waitzinger J, et al. Acute hypothyroidism slows the rate of left ventricular diastolic relaxation. Can J Physiol Pharmacol 1988;67:1007.
11. Danzi S, Klein I. Thyroid hormone and blood pressure regulation. In: Curr Hypertension Rep 2003;5:513.
12. Biondi B, Palmieri EA, Lombardi L, et al. Effects of thyroid hormone on cardiac function. J Clin Endocrinol Metab 2002;87: 968.
13. Bluhm WF, Meyer M, Sayen MR, et al. Over-expression of SERCA improves cardiac contractile function in hypothyroid mice. Cardiovasc Res 1999;43:382.
14. Biondi B, Palmieri EA, Lombardi L, et al. Effects of subclinical thyroid dysfunction on the heart. Ann Intern Med 2002;137:904.
15. Ojamaa K, Klein I. In vivo regulation of recombinant cardiac myosin heavy chain gene expression by thyroid hormone. Endocrinology 1993;132:1002.
16. Danzi S, Klein I. Thyroid hormone-regulated cardiac gene expression and cardiovascular disease. Thyroid 2002;12:467.
17. Ladenson PW, Sherman SI, Baughman KL, et al. Reversible alterations in myocardial gene expression in a young man with dilated cardiomyopathy and hypothyroidism. Proc Natl Acad Sci U S A 1992;89:5251.
18. Reiser PJ, Portman MA, Ning X, et al. Human cardiac myosin heavy chain isoforms in fetal and failing adult atria and ventricles. Am J Physiol 2001;280:H1814.
19. Magner JA, Clark W, Allenby P. Congestive heart failure and sudden death in a young woman with thyrotoxicosis. West J Med 1990;8:553.
20. Khoury SF, Hoit BD, Dave V, et al. Effect of thyroid hormone on left ventricular performance and regulation of contractile and calcium cycling proteins in the baboon. Circ Res 1996;79:727.
21. Carr AN, Kranias EG. Thyroid hormone regulation of calcium cycling proteins. Thyroid 2002;12:453.
22. Ojamaa K, Klein I. Thyroid hormone regulation of phospholamban phosphorylation in the rat heart. Endocrinology 2000; 141:2139.
23. Streeten DHP, Anderson GH Jr, Howland T, et al. Effects of thyroid function on blood pressure: recognition of hypothyroid hypertension. Hypertension 1988;11:78.
24. Klemperer JD, Klein I, Gomez M, et al. Thyroid hormone treatment after coronary-artery bypass surgery. N Engl J Med 1995; 333:1522.
25. Kabadi UM, Kumar SP. Pericardial effusion in primary hypothyroidism. Am Heart J 1990;120:159.
26. Myerowitz P, Kamienski R, Swanson D, et al. Diagnosis and management of the hypothyroid patient with chest pain. J Thorac Cardiovasc Surg 1983;86:57.
27. Zulewski H, Muller B, Eter P. Estimation of tissue hypothyroidism by a new clinical score: Evaluation of patients with various grades of hypothyroidism and controls. J Clin Endocrinol Metab 1997;82:771.
28. Klein I, Mantell P, Parker M, et al. Resolution of abnormal muscle enzymes in hypothyroidism. Am J Med Sci 1980;279:159.
29. Biondi B, Klein I. Hypothyroidism as a risk factor for cardiovascular disease. Endocrine 2004;24:1.
30. Inukai T, Takanashi K, Kobayashi H, et al. Power spectral analysis of heart rate in hyperthyroidism and hypothyroidism. Horm Metab Res 1998;30:531.
31. Bough EW, Crowley WF, Ridgway E, et al. Myocardial function in hypothyroidism. Arch Intern Med 1978;138:1476.
32. Dernellis J, Panaretou M. Effects of thyroid replacement therapy on arterial blood pressure in patients with hypertension and hypothyroidism. Am Heart J 2002;143:718.
33. Marcisz C, Jonderko G, Kucharz EJ. Influence of short-time application of a low sodium diet on blood pressure in patients with hyperthyroidism or hypothyroidism during therapy. Am J Hypertens 2001;14:995.
34. Zimmerman J, Yahalom J, Bron H. Clinical spectrum of pericardial effusion as the presenting feature of hypothyroidism. Am Heart J 1984;106:770.
35. Oliver C, Martin F. Low QRS voltage in cardiac tamponade: a study of 70 cases. Int J Cardiol 2002;83:93.
36. Klein I, Levey GS. Unusual manifestations of hypothyroidism. Arch Intern Med 1984;144:123.
37. Attivissimo LA, Lichtman SM, Klein I. Acquired von Willebrand's syndrome causing a hemorrhagic diathesis in a patient with hypothyroidism. Thyroid 1995;5:399.
38. Canaris GJ, Manowitz NR, Ridgway EC. The Colorado thyroid disease prevalence study. Arch Intern Med 2000;160:526.
39. Madariaga MG. Polymyositis-like syndrome in hypothyroidism. Thyroid 2002;12:381.
40. Staub JJ, Althaus BU, Engler H, et al. Spectrum of subclinical and overt hypothyroidism: effect on thyrotropin, prolactin and thyroid reserve and metabolic impact on peripheral target tissues. Am J Med 1992;92:631.
41. Fredlund B, Olsson SB. Long QT interval and ventricular tachycardia of “torsade de pointe” type in hypothyroidism. Acta Med Scand 1983;213:231.
42. Virtanen VK, Saha HH, Groundstroem KW, et al. Thyroid hormone substitution therapy rapidly enhances left ventricular diastolic function in hypothyroid patients. Cardiology 2001;96:59.
43. Tielens E, Pillay M, Storm C, et al. Changes in cardiac function at rest before and after treatment of hypothyroidism. Am J Cardiol 2000, 85:376.
44. Brenta G, Mutti LA, Schnitman M, et al. Assessment of left ventricular diastolic function by radionuclide ventriculography at rest and exercise in subclinical hypothyroidism and its response to l-thyroxine therapy. Am J Cardiol 2003;91:1327.
45. Dillmann WH. Cellular action in primary thyroid hormone on the heart. Thyroid 2002;12:447.
46. Bengel FM, Nekolla SG, Ibrahim T, et al. Effect of thyroid hormones on cardiac function, geometry, and oxidative metabolism assessed non-invasively by positron emission tomography and magnetic resonance imaging. J Clin Endocrinol Metab 2000;85:1822.
47. Bernstein R, Muller C, Midtbo K, et al. Coronary dysfunction in severe hypothyroidism. In: Braverman LE, Eber O, Langsteger W, eds. Heart and thyroid. Vienna: Blackwell, 1994:154.
48. Lowes BD, Minobe W, Abraham WT, et al. Changes in gene expression in the intact human heart: downregulation of α-myosin heavy chain in hypertrophied, failing ventricular myocardium. J Clin Invest 1997;100:2315.
49. Ladenson PW, Goldenheim PD, Ridgway EC. Rapid pituitary and peripheral tissue responses to intravenous l-triiodothyronine in hypothyroidism. J Clin Endocrinol Metab 1983;56:1252.
50. Tielens ET, Pillay M, Storm C, et al. Cardiac function at rest in hypothyroidism evaluated by equilibrium radionuclide angiography. Clin Endocrinol (Oxf) 1999;50:497.
51. DeRubertis FR Jr, Michelis MF, Bloom ME, et al. Impaired water excretion in myxedema. Am J Med 1971;51:41.
52. LaDue JS. Myxedema heart: a pathological and therapeutic study. Ann Intern Med 1943;18:332.
53. Klein I, Danzi S. Evaluation of the therapeutic efficacy of different levothyroxine preparations in the treatment of human thyroid disease. Thyroid 2003;13:1127.
54. Steinberg AD. Myxedema and coronary artery disease: a comparative autopsy study. Ann Intern Med 1968;68:338.
54a. Mya MM, Aronow WS. Subclinical hyperthyroidism is associated with coronary artery disease in older persons. J Gerontol A Biol Sci Med Sci 2002;57:M658.
55. Hak AE, Pols HA, Visser TJ, et al. Subclinical hypothyroidism is an independent risk factor for atherosclerosis and myocardial infarction in elderly women: the Rotterdam Study. Ann Intern Med 2000;132:270.
56. Cappola AR, Ladenson PW. Hypothyroidism and atherosclerosis. J Clin Endocrinol Metab 2003;88:2438.
57. Chadarevian R, Bruckert E, Leenhardt L, et al. Components of the fibrinolytic system are differently altered in moderate and severe hypothyroidism. J Clin Endocrinol Metab 2001;86:732.
58. Christ-Crain M, Meier C, Guglielmetti M, et al. Elevated C-reactive protein and homocysteine values: cardiovascular risk factors in hypothyroidism? A cross-sectional and a double-blind, placebo-controlled trial. Atherosclerosis 2003;166:379.
59. Karlsberg RA, Friscia DA, Aronow WS, et al. Deleterious influence of hypothyroidism on evolving myocardial infarction in conscious dogs. J Clin Invest 1981;67:1024.
60. Keating FR Jr, Parkin TW, Selby JB, et al. Treatment of heart disease associated with myxedema. Prog Cardiovasc Dis 1961;3: 364.
61. Drucker DJ, Burrow GD. Cardiovascular surgery in the hypothyroid patient. Arch Intern Med 1985;145:1585.
62. Ladenson PW, Levin AA, Ridgway EC, et al. Complications of surgery in hypothyroid patients. Am J Med 1984;77:261.
63. Sherman SI, Ladenson PW. Percutaneous transluminal coronary angioplasty in hypothyroidism. Am J Med 1991;90:367.
64. Pek M, O'Neill BJ. Effect of thyroid hormone therapy on angiographic coronary artery disease progression. Can J Cardiol 1997; 13:273.
65. Iervasi G, Pingitore A, Landi P, et al. Low T3 syndrome: a strong prognostic predictor of death in patients with heart disease. Circulation 2003;107:708.
66. Asheim DD, Hyrniewicz K. Thyroid hormone metabolism in patients with congestive heart failure: the low triiodothyronine state. Thyroid 2002 12(6):511.
67. Hamilton MA, Stevenson LW. Thyroid hormone abnormalities in heart failure: possibilities for therapy. Thyroid 1996;6:527.
68. Hamilton MA, Stevenson LW, Fonarow GC, et al. Safety and hemodynamic effects of intravenous triiodothyronine in advanced congestive heart failure. Am J Cardiol 1998;81:443.
69. Katzeff HL, Powell SR, Ojamaa K. Alterations in cardiac contractility and gene expression during low-T3 syndrome: prevention with T3. Am J Physiol 1997;273:E951.
70. Ojamaa K, Kenessey A, Shenoy R, et al. Thyroid hormone metabolism and cardiac gene expression after acute myocardial infarction in the rat. Am J Physiol 2000;279:E1319.
71. Chowdhury D, Parnell V, Ojamaa K, et al. Usefulness of triiodothyronine (T3) treatment after surgery for complex congenital heart disease in infants and children. Am J Cardiol 1999;84: 1107.
72. Portman MA, Fearneyhough C, Ning X-H, et al. Triiodothyronine repletion in infants during cardiopulmonary bypass for congenital heart disease. J Thorac Cardiovasc Surg 2000;120: 604.
73. Mainwaring RD, Lamberti JJ, Carter TL Jr, et al. Reduction in triiodothyronine levels following modified Fontan procedure. J Card Surg 1994;9:322.
74. Klemperer JD, Klein IL, Ojamaa K, et al. Triiodothyronine therapy lowers the incidence of atrial fibrillation after cardiac operations. Ann Thorac Surg 1996;61:1323.
75. Surks MI, Ortiz E, Daniels GH, et al. Subclinical thyroid disease: scientific review and guidelines for diagnosis and management. JAMA 2004;291:228.