Mardi Gomberg-Maitland, MD, Department of Medicine, New York Hospital-Cornell Medical Center, New York, William H. Frishman, MD, Department of Medicine, New York Medical College, Valhalla, N.Y.

Am Heart J 135(2):187-196, 1998. © 1998 Mosby-Year Book, Inc

Abstract

Thyroid hormone directly affects the heart and peripheral vascular system. The hormone can increase myocardial inotropy and heart rate and dilate peripheral arteries to increase cardiac output. An excessive deficiency of thyroid hormone can cause cardiovascular disease and aggravate many preexisting conditions. In severe systemic illness and after major surgical procedures changes in thyroid function can occur, leading to the "euthyroid sick syndrome." Patients will have normal or decreased levels of T₄, decreased free and total T₃, and usually normal levels of thyroid stimulating hormone. This syndrome may be an adaptive response to systemic illness that usually will revert to normal without hormone supplementation as the illness subsides. Recently, however, many investigators have explored the benefits of thyroid hormone supplementation in those diseases associated with euthyroid sick syndrome. Thyroid hormone's effects on the cardiovascular system make it an attractive therapy for those patients with impaired hemodynamics and low T₃. Thyroid hormone has also been considered a treatment for patients with congestive heart failure, for patients undergoing cardiopulmonary bypass and heart transplantation, and for patients with hyperlipidemia. At present there is no evidence suggesting a favorable treatment outcome using thyroid hormone supplementation for any systemic condition except in those patients with documented hypothyroidism.

Introduction

For many years, a relationship has been recognized between thyroid hormone, the heart, and the peripheral vascular system. In 1786, Parry^[1] first described the clinical features of a patient with thyrotoxicosis that included palpitations, irregular pulse, and dyspnea. Forty-nine years later, Graves^[2] provided descriptions of diffuse toxic goiter. The profound cardiac manifestations of thyrotoxicosis led early observers to wrongly conclude that the disease originated within the heart.^[3] Eventually, researchers acknowledged that an overactive thyroid gland was the direct cause of the disease.^[3-5] In 1918, Zondek^[6] first described a patient with the features of the "myxedema" heart: dilated cardiac silhouette, low electrocardiographic voltage, and slow heart action. This patient's symptoms can be explained by a pericardial effusion, a common entity in hypothyroid patients. Despite the early associations between thyroid disease and the cardiovascular system, including the use of thyroid ablative therapy for treating angina pectoris, it is only recently that thyroid hormone has been considered a potential therapeutic agent in cardiovascular disease. To understand thyroid hormone's potential uses, this chapter will first review its physiologic action in normal and disease states then examine therapeutic uses of thyroid hormone in cardiovascular disease.

Synthesis of thyroxine (T₄) and triiodothyronine (T₃) occurs within the thyroid gland. T₄, the primary secretory product, is relatively inactive. Eighty-five percent of T₃, the biologically active compound, is derived from peripheral conversion of T₄ by the 5'-monodeiodinase enzyme.^[7] The actions of thyroid hormone occur mostly through T₃ binding with nuclear receptors that regulate expression of thyroid hormone responsive genes.^[8-10] Because T₃ is bound to this receptor with a higher affinity than T₄, this analog has a higher biologic activity.^[11] There are two T₃ receptor genes, and ß,^[12] with at least two messenger RNA splice products for each gene: _l and ₂,^[10] and ß_l and ß₂.^[12] T₃ is not bound by 2.^[10] T₃ also has some extranuclear actions that occur independently of nuclear T₃ receptor binding or increases in protein synthesis.^[13] Extranuclear effects result in rapid stimulation of amino acid, sugar,^[14] and calcium transport.^[15]

Changes in cardiac function are mediated by T₃ regulation of cardiac-specific genes.^[13] T₃ administration in animals enhances myocardial contractility by stimulating synthesis of the fast myosin heavy chain and inhibiting the expression of the slow ß isoform.^[13,16] T₃ in animals also causes increased sarcoplasmic reticulum (SR) Ca²⁺ adenosine triphosphatase (ATPase) and decreased expression of the Ca²⁺ ATPase regulatory protein phospholamban.^[17] T₃ also modulates the expression of heart sodium-potassium ATPase,^[18,19] malic enzyme,^[20] atrial natriuretic factor,^[21] calcium channels,^[22] and the ß-adrenergic receptors.^[23] Walker et al.^[24] demonstrated that T₃ enhanced contractility by potentiating ß-adrenergic receptor stimulation. Intracelluar cyclic adenosine monophosphate (cAMP) levels increased, leading to increased myocyte Ca²⁺ levels and increased L-type Ca²⁺ channel density.^[24]

Human heart ventricles contain predominantly myosin heavy chain ß,^[9] and therefore do not have a myosin shift after T₃ administration.^[25] The enhanced contractility in human beings is predominantly the result of an elevated expression of SR Ca²⁺ ATPase.^[13] Despite the predominance of the ß isoform in human beings, some investigators have demonstrated increased isoform after T₃ administration.^[26] Landenson et al.^[26] described a man with hypothyroidism and heart failure who increased his myosin heavy chain mRNA 11-fold during treatment. Overall, thyroid hormone increases ATP utilization, with more heat and less contractile energy production.^[27] This inefficiency may explain heart failure after prolonged hyperthyroidism.

Contractile performance is also mediated by hemodynamic factors. Left ventricular (LV) function changes with alterations in afterload, preload, and heart rate.^[28] A change in myosin heavy chain ß to is observed in euthyroid rats under cardiac loading conditions.^[29] Therefore, a combination of T₃ regulation on both cardiac-specific genes and on hemodynamic variables may produce increased cardiac contractility.

Peripheral Hemodynamic Changes

One of the earliest responses to thyroid hormone administration is a decrease in peripheral vascular resistance^[30] (Table I). Some investigators have proposed that thyroid hormone administration increases metabolic activity and oxygen consumption, thereby releasing local vasodilators.^[31] These factors, in turn, produce the lowered systemic vascular resistance. A low systemic vascular resistance then decreases diastolic blood pressure, which in turn increases cardiac output (Fig. 1).^[32] This increased cardiac output supports an increased basal metabolic rate^[30] and increased oxygen consumption by enhancing the oxygen delivery to the periphery.^[33] T₃ administration also increases total blood volume. This produces a rise in right atrial pressure, an increased preload, and thus an elevated cardiac output.^[32,34,35]

Figure 1. A model by which thyroid hormone-mediated changes in tissue oxygen consumption and thermogenesis can lead to alterations in cardiovascular hemodynamics. (Reprinted with permission from Laragh JH, Brenner BM, Kaplan NM, editors. Endocrine mechanisms in hypertension. Vol. 2. New York: Raven Press; 1989.)

The low peripheral vascular resistance may also be the result of direct action of thyroid hormone on arteriolar smooth muscle tone. T₃ may alter the sodium and potassium flux in smooth muscle cells, leading to a decrease in smooth muscle contractility and vascular tone.^[36,37] After T₃ administration, normal animals increase cardiac output and stroke volume with decreased peripheral vascular resistance.^[38] Treatment of postischemic, reperfused animal hearts with T₃ enhanced LV performance in both normo-thermic^[39] and hypothermic^[40] models. However, T₃ had no effect on the intrinsic contractility of noninjured animal hearts.^[39,40]

Hypothyroid patients hemodynamically manifest low cardiac output, decreased stroke volume, decreased intravascular volume, increased vascular resistance, increased circulation time, and a prolonged diastolic relaxation time.^[31,41,42] Hyperthyroid patients exhibit the opposite hemodynamic picture.^[31,42,43] In fact, T₃ administration to hypothyroid patients reduces the elevated peripheral vascular resistance.^[34] The effects of T₃ on the coronary vasculature are presently undetermined, although a recent study in postischemic dogs found a decrease in coronary vascular resistance after T₃ administration.^[39]

Interaction with the Sympathoadrenal System

Hyperthyroid patients have clinical symptoms similar to patients in a hyperadrenergic state, whereas hypothyroid symptoms suggest a state of decreasing sympathetic tone.^[44] Many investigators speculate that thyroid hormone interacts with catecholamines such that hyperthyroid patients have an increased sensitivity to catecholamine action^[45] and hypothyroid patients have a decreased sensitivity to catecholamine action.^[44] Catecholamine levels are decreased or normal in hyperthyroidism and are increased in hypothyroidism, in agreement with an altered sensitivity.^[46] Thyroid hormone administration can increase ß-adrenergic receptor expression and, consequently, ß-adrenergic sensitivity. Hormone administration also enhances expression of the stimulatory subunit of the guanosine triphosphate (GTP)-binding protein (Gs).^[47-50] However, in human beings, an enhanced sympathetic response with thyroid hormone has been difficult to prove. One study found no change in ß-receptor sensitivity with hormone administration.^[51] In experimental models, thyroid administration in both isolated myocytes^[52] and whole-heart preparations^[53] demonstrated effects independent of ß-adrenergic receptor stimulation. In contrast, other investigators have found increased LV shortening in hyperthyroid patients with ß-adrenergic stimulation.^[54]

Ventricular Function

Hyperthyroid patients have hypertrophic hearts. Experimental models of hyperthyroidism in animals have reproduced this finding. Within 1 week of T₄ administration, animal hearts exhibit a 135% increase in LV size versus controls.^[55,56] Because thyroid hormone increases cardiac protein synthesis,^[57] this had been the postulated cause of cardiac hypertrophy in hyperthyroid patients.^[56] To test this hypothesis, Klein^[58] administered propranolol with T₄ to animals. The addition of propranolol prevented both the increased heart rate and hypertrophic response. Klein and Hong^[55] demonstrated that cardiac hypertrophy was not observed in a heterotopically transplanted rat heart without a hemodynamic load. Thyroid hormone had no direct effect on amino acid incorporation and therefore no measurable effect on myocardial contractile protein synthesis. They concluded that cardiac work mediated cardiac hypertrophy.

Hyperthyroid Heart Disease

Cardiac symptoms are commonly observed among hyperthyroid patients. These patients commonly present with an arrhythmia. Patients may have atrial premature contractions, paroxysmal atrial tachycardia, atrial flutter, atrial fibrillation,^[59] Wolff-Parkinson-White syndrome, prolonged PR intervals, ST segment elevations, and shortened QT intervals.^[32] Complications of atrial fibrillation,^[60] the most common arrhythmia, include arterial thromboembolism and congestive heart failure (CHF).^[59] Mitral valve prolapse syndromes are more common in women with Graves' disease.^[61] Complications, however, are rare.^[62] Also, hyperthyroid patients can present with angina symptoms in the absence of coronary artery disease.^[63]

Many hyperthyroid patients are hypertensive, but at present no extensive study of blood pressure changes in hyperthyroidism has been completed.^[64] An increased frequency of systolic hypertension is observed in thyrotoxic patients over the age of 65 years.^[65] The hypertension is likely the result of the inability of the vasculature to accommodate the increased cardiac output and stroke volume.^[64] This mechanism also explains the infrequent presence of diastolic hypertension.^[66]

Forfar et al.^[67] proposed that hyperthyroid disease is associated with a reversible cardiomyopathy. They studied the effects of exercise and ß-adrenoceptor blockade on LV function in both the hyperthyroid and euthyroid states. Hyperthyroid patients had elevated LV ejection fractions (EF) at rest but experienced significant declines in LVEFs with exercise. In contrast, euthyroid patients demonstrated a rise in LVEFs with exercise. Pretreatment with propranolol caused similar reductions in resting LVEFs in both hyperthyroid and euthyroid states. Propranolol had no effect on the diminished LVEF during exercise in hyperthyroid states, but significantly lessened the LVEF rise in euthyroid states during exercise. They concluded that the abnormal LV function during exercise suggested a reversible functional cardiomyopathy. The cardiomyopathy appeared to be the direct result of excess thyroid hormones, independent of ß-adrenoceptor activation. However, thyrotoxic patients can have symptoms of high output cardiac failure due to causes other than dilated cardiomyopathy. Patients with supranormal EFs, complaining of dyspnea on exertion in the absence of cardiac failure, may have respiratory muscle weakness.^[32] Patients may have symptoms of high output cardiac failure due to their expanded blood volume and total body sodium with LV dysfunction.^[68]

Hypothyroid Heart Disease

With longstanding hypothyroidism, patients may develop various cardiac manifestations. Patients can present with dyspnea on exertion, fatigue, and edema that may be the result of either pericardial effusion or CHF. Pericardial effusion is often misdiagnosed as CHF.^[59] Hypothyroid patients are usually bradycardic,^[59] and they can also present with pleural effusion.^[30] Patients also have an increased incidence of hypercholesterolemia^[69] and hypertriglyceridemia.^[32,70,71] Patients have an increased low-density lipoprotein (LDL), very-low-density lipoprotein (VLDL), high-density lipoprotein (HDL),^[70] apolipoprotein B-71 (Apo B^[71]), and lipoprotein(a) (Lp[a]).^[72] When these patients are provided thyroid hormone replacement, their plasma cholesterol decreases.^[73] It has been demonstrated that patients with hypothyroidism have an intrinsic defect of receptor-mediated LDL catabolism, which is reversible with hormone replacement.^[74,75] Both symptomatic and subclinical hypothyroidism may be risk factors for premature coronary artery disease (Table II).^[76-80] Surprisingly, hypothyroid patients have a low incidence of myocardial infarction and angina.^[32] This may result from the decreased metabolic demands placed on the heart^[32] and decreased platelet adhesiveness.^[81]

Although hypothyroid patients have a low incidence of myocardial infarction and angina, they do have an increased prevalence of hypertension.^[31] In a review of 12 previously published studies, the overall prevalence of hypertension was 21%.^[64] Hypertension of hypothyroidism appears to be caused by a low-renin state, developed as a result of increased peripheral vascular resistance.^[32] Some investigators have also observed an elevation in both total body and intracellular sodium.^[65] If thyroid hormone acts directly on the vasculature,^[82] the lack of thyroid hormone can lead to smooth muscle contraction within vessels of the peripheral circulation. This elevated vascular resistance would result in an elevated blood pressure.^[64]

Euthyroid Sick Syndrome

The changes in thyroid function that occur in virtually all illnesses and after surgical procedures are referred to as the euthyroid sick syndrome. Patients have normal or decreased free and total T₄, decreased free and total T₃ and, usually, normal thyroid stimulating hormone (TSH).^[83] Four proposed mechanisms may explain the pathogenesis of this syndrome. First, is the decreased extrathyroidal conversion of T₄ to T₃ resulting from decreased delivery of T₄ to the intracellular deiodinases or a decrease in the deiodinase activity.^[84] Second is a decrease in thyrotropin secretion leading to a fall in thyroidal secretion of T₄ and T₃. The process is potentiated by a fall in T₄ serum concentration, thus producing less substrate for T₃ conversion.^[84] Third, the production of thyroxine binding globulin, transthyretin, and albumin or their affinity for thyroid hormones may decline.^[84] Impaired deiodination results in a decline of total T₄ and T₃ levels and a rise in reverse triiodothyronine (rT₃). Fourth, tissue uptake of T₄ and T₃ may be decreased, as well as nuclear and postreceptor hormone actions.^[84] The medical community has assumed that the decrease in T₃ and T₄ with elevated rT₃ has no pathophysiologic consequences.^[84,85] Many believe that the syndrome is an adaptive metabolic response to conserve energy in disease states.^[84] However, recent experimental data with T₃ administration has questioned this assumption.

Congestive Heart Failure

Thyroid hormone metabolism is frequently abnormal in patients with CHF. Some patients with CHF have been described with the euthyroid sick syndrome.^[86] Hypothroxinemia is a predictor of high mortality in severely ill intensive care unit patients.^[87] Given the poor prognosis associated with low thyroid hormone levels, various researchers wondered if supplementation with T₃ could improve clinical outcomes. Patients with CHF have low cardiac outputs and high systemic vascular resistance. Thyroid hormone administration in depleted patients reverses these abnormalities (Table III). Thus the question asked was whether thyroid hormone could ameliorate CHF.

Animal studies preceded studies in humans. Rats with CHF given L-thyroxine demonstrated improved LV performance without alterations in heart rate.^[88] Short-term administration with both low and high doses of L-thyroxine produced similar results. In addition, neither dose altered the cardiac myosin isoenzyme distribution. Rabbits with postmyocardial infarction CHF who were treated with 3,5-diiodothyropropionic acid (DITPA), a thyroid hormone analog, demonstrated improved LV performance with reduced end diastolic pressure.^[89] Rabbits also had no significant change in heart rate or in myosin isoenzyme distribution. Mahaffey et al.^[89] believed that DITPA could reverse abnormal calcium handling, but that the most likely explanation for the improved performance was the upregulation of thyroid hormone-responsive genes such as the SR Ca+2ATPase.^[89]

Hamilton et al.^[86] studied 84 patients with advanced heart failure (average ejection fraction [EF] 18% +/- 5%). Patients had low T₃ levels, or increased rT₃, with normal free thyroxine (fT₄), and investigators determined that a low fT₃/rT₃ index was a negative prognostic factor. The index was associated with lower EFs, higher filling pressures, lower serum sodium, and poor nutritional status but not to duration or cause of heart failure. When data were evaluated by multivariate Cox regression analysis with known predictors of poor outcome, such as ejection fraction, serum sodium, and hemodynamic variables, the T₃/reverse T₃ level was the only independent predictor of prognosis. Patients with a low ratio had poor 6-week survival, and a predicted 1 year actuarial survival of 37% compared with a 100% predicted survival with a normal ratio. The index was also the strongest predictor of mortality.^[86]

The authors postulated that the altered thyroid hormone metabolism may predict clinical outcome by indicating disease severity. The low conversion to T₃ may be an adaptive mechanism to decreased catabolism.^[86] Recently, Hamilton et al.^[90] studied 23 patients with Class III or Class IV CHF and low output cardiac failure who were given 6 hours of intravenous T₃ treatment.^[90] Cardiac output increased and was thought to be caused by vascular smooth muscle cell relaxation, leading to peripheral vasodilation.^[91] Patients had no change in heart rate and basal metabolic rate, and no patients experienced angina or ventricular ectopy. Cardiac output increased by >1.0 L/mm in 50% of patients with no significant change in LVEF or filling pressures.^[90,91] They concluded that the patients with CHF tolerated the T₃ therapy well, and that the hemodynamic effects produced require further study.

L-thyroxine may prove to be a useful therapy in idiopathic dilated cardiomyopathy (IDC). Exercise tolerance was studied in a randomized, placebo-controlled trial of 20 patients with IDC treated with 100 µg/day of L-thyroxine for 1 week.^[92] Patients had Class II or Class III CHF with EF <40%. Patients given L-thyroxine had improved cardiac output and a drop in systemic vascular resistance, independent of adrenergic influences. The improved exercise performance on the cardiopulmonary exercise stress test was explained by a higher oxygen consumption at peak exercise due to improved oxygen uptake by skeletal muscles,^[93] increased musculature perfusion,33 or improved muscle metabolism by local action of L-thyroxine occurring during training.^[33]

Patients with hyperthyroidism can also develop a DC with both high-output and low-output cardiac failure. A prolonged tachycardia and high output state caused by thyrotoxicosis is thought to eventually produce dilation of the left ventricle. A consequent progressive decline in systolic function leads to a low cardiac output failure. Reduction of excess hormone levels may reverse this failure. Umpierrez et al.^[94] studied 7 patients with hyperthyroidism, DC, and low-output cardiac failure and treated them with propylthiouracil or methimazole.^[94] Five of 7 patients had echocardiographic resolution of DC and normalization of LV function. Thus treatment of hyperthyroidism can reverse related cardiac disease.

Moruzzi et al.^[95] studied 20 patients with IDC in a 3 month double-blind, placebo-controlled trial to investigate the positive and negative effects of thyroxine use. L-thyroxine (100 µg/kg orally) was administered versus placebo, and echocardiographic parameters, cardiopulmonary exercise test, and hemodynamic parameters were obtained before and after treatment. L-thyroxine therapy increased left ventricular ejection fraction, cardiac output, and left ventricular diastolic dimension and decreased systemic vascular resistance. Functional capacity and peak exercise cardiac output improved. The beneficial effects were sustained with the longer therapy regimen.

Although present interest is in treatment of CHF patients with euthyroid sick syndrome and IDC, clinicians should not forget about the importance of treatment in the thyrotoxic patient with heart failure.

Cardiopulmonary Bypass Surgery

Thyroid hormone supplementation has been used to improve hemodynamics after cardiopulmonary bypass surgery (CPBS) (Table IV). Postoperative patients often have a low cardiac output and an elevated systemic vascular resistance, similar to that observed in hypothyroid patients. Additionally, approximately 50% to 75% of patients have a euthyroid sick state for 1 to 4 days after surgery.^[96] If T₃ is a potent vasodilator and inotrope, these patients could benefit from T₃ treatment. Some believe that surgically associated hypothermia, hemodilution, caloric deprivation, and activation of inflammatory mediators^[97] decrease T₃ levels.^[98] Pigs given 6 µg of T₃ during CPBS showed a beneficial inotropic effect and had improved overall survival.^[99]

Hsu et al.^[100] studied the effects of T₃ replacement in pigs after myocardial injury with hemodynamic compromise. T₃ (0.2 µg/kg) or saline solution was administered immediately, 30, 60, 90, and 120 minutes after reperfusion. T₃ increased ventricular systolic function and cardiac index without affecting myocardial oxygen consumption or infarct size. The authors concluded that T₃ supplementation to pigs in "euthyroid sick syndrome" after cardiac surgery was beneficial. T₃ administration after bypass surgery in sheep also improved cardiac performance without negatively affecting oxygen utilization.^[101]

Novitzky et al.^[102] performed two randomized, placebo-controlled trials of T₃ therapy in patients undergoing cardiac revascularization surgery. Study 1 evaluated patients with EF <30% and Study 2 evaluated patients with EF >40%. Patients with intraoperative and postoperative T₃ therapy in Study 1 required fewer adjunctive inotropic agents and diuretics. Patients with intraoperative and postoperative T₃ therapy in Study 2 had improved stroke volume and cardiac output, with reduced systemic and pulmonary vascular resistances. The authors concluded that T₃ administration appeared to be beneficial to all patients undergoing open heart surgery, but patients with better preoperative cardiovascular status derived greater benefit.

Present research, however, indicates that although T₃ does exert beneficial inotropic and hemodynamic effects in bypass patients, administration is not recommended. Teiger et al.^[103] studied 20 CBPS patients given intravenous T₃ or placebo in a prospective, double-blind, placebo-controlled trial. The doses of T₃ (expressed in µg/kg of body weight) were 0.20, 0.15, 0.10, 0.05, and 0.05. Hormone was administered at the time of aortic cross-clamp removal and 4, 8, 12, and 24 hours thereafter. Total thyroid levels declined, however, after correction for hemodilution; they failed to demonstrate a decline in the active thyroid hormones. No significant difference was found in postoperative hemodynamics between the two groups. Also, T₃ therapy did not increase the degree of myocardial ß-adrenergic responsiveness. The studies by both Teiger et al.^[103] and Novitsky et al.^[102] were small scale, nonrandomized studies, and thus provoked further investigation.

Two recently published studies support the results of Teiger et al.^[103] Klemperer et al.,^[98] in a large-scale, prospective, placebo-controlled, double-blind trial of high-risk CPBS patients, administered large doses of T₃ (intravenous 0.8 µg/kg followed by 0.113 µg/kg/hr x 6 hr) at the time of cross-clamp removal and continuously thereafter. Thirty minutes after the start of CPBS, before T₃ administration, mean serum T₃ levels decreased by approximately 40%. After T₃ infusion, T₃ levels increased twofold in treated patients, with a consequent increase in cardiac output and decline in systemic vascular resistance. Despite supranormal levels of T₃ at surgery, levels normalized by the first postoperative day. The study demonstrated improved cardiovascular performance in the early postoperative period but found no change in inotropic requirements. They concluded that T₃ should not be used as a substitute for recommended drug therapy during and after CPBS. Utiger,^[84] in an accompanying editorial, agreed with the authors' recommendation, stating that physicians must realize that patients may have many abnormalities that can affect T₃ and or T₄ levels. However, because replacement doses of hormone in seriously ill patients with low serum thyroxine levels^[85] do not hasten recovery or improve survival, replacement is not practical. Low levels of thyroid hormones are probably part of a host's defense mechanism.^[86]

Bennett-Guerrero et al.^[104] also conducted a prospective, randomized, double-blind, placebo-controlled trial using the same dose of T₃ as Klemperer et al.^[98] In contrast to the study by Klemperer et al,^[98] this group found no significant change in hemodynamic factors. Use of T₃, despite its minor improvements on myocardial performance, was not recommended for routine use in CPBS patients. Neither study measured thyroid-stimulating hormone, which may have proved important.^[105] Therefore, replacement therapy with large doses of T₃ in CPBS patients is currently not advised.

Cardiac Transplantation

The administration of T₃ to brain-dead organ donors has proved successful in maintaining organ viability (low free and total T₃ occurs after brain death in experimental animals^[106] and humans beings^[107]). Hemodynamic stability, reduced inotropic agent requirement, and metabolic derangement normalization have been documented in potential organ donors after T₃ therapy.^[107,108] Brain death causes loss of both anterior and posterior pituitary function, thus producing low levels of cortisol, antidiuretic hormone, and active thyroid stimulating hormone.^[108] Jeevanandam et al.^[108] infused T₃ 0.6 µg/kg at 139.17 +/- 32.00 minutes before harvest in 24 heart donors.

Hemodynamics were recorded 4 hours after transplantation. T₃ infusion decreased filling pressures while maintaining hemodynamics, allowed diuresis, and decreased inotropic support. One week after transplant, echocardiography of all patients demonstrated ejection fractions >50%. T₃ administration is not yet standard practice. A large-scale, double-blind, placebo-controlled study is needed to assess T₃ therapy before organ transplantation. This therapy could increase the number of potential donor organs.

Hyperlipidemia

The hormone thyroxine has been used as a hyper-cholesterolemic agent in euthyroid patients. The stereoisomer dextrothyroxine (d-thyroxine) initially was chosen for clinical use because it was said to have more selective effects on metabolism than levoxythyroxine. d-Thyroxine lowers the concentration of LDL-cholesterol by 10% to 20%, but has little effect on plasma triglycerides or on the concentration of HDL cholesterol.^[109] However, in usual therapeutic doses of 4 to 6 mg/dl, d-thyroxine can cause cardiac arrhythmias and hypermetabolic effects in euthyroid patients.^[110] In the Coronary Drug Project, when d-thyroxine was compared with placebo, it caused a higher incidence of adverse cardiovascular effects (including increased mortality rate) in male survivors of acute myocardial infarction.^[111] Thus d-thyroxine treatment was discontinued in the study.

Arem and Patsch^[112] assessed the effects of levothyroxine replacement on lipids, lipoproteins, and apolipoproteins in patients with subclinical hypothyroidism. After patients in the euthyroid state received 4 months of therapy, they had a decrease in LDL-cholesterol and apoprotein B levels. Both the ratios of total cholesterol/HDL-cholesterol and LDL-cholesterol/HDL-cholesterol declined.

It can be concluded from the above that thyroxine replacement can favorably alter the lipid and lipoprotein levels of patients with overt and borderline hypothyroidism. Therefore, screening for these conditions is mandatory when assessing patients with a lipid abnormality. However, the routine use of thyroxine treatment to lower LDL-cholesterol and raise HDL-cholesterol cannot be recommended in euthyroid patients. The potential for cardiac toxicity outweighs the beneficial effect.

Conclusion

Thyroid hormone therapy may provide promise in cardiovascular disease therapy. Replacement therapy in patients with cardiovascular disease having both a euthyroid sick state and hemodynamic abnormalities may be useful. However, it is not known whether the euthyroid sick state is a beneficial adaptation in these patients. Further investigations are needed before routine replacement therapy can be recommended for treatment of patients with CHF or for patients needing organ transplant surgery.

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