Thyroid hormone treatment to mend a broken heart.

Beginning in development and extending to adult physiology, a close relationship exists between the thyroid gland and the heart (1). Both thyroid and cardiac anlage migrate together during ontogeny. This intimacy continues into adult life when changes in thyroid function produce the classic cardiovascular and hemodynamic findings of hyper- and hypothyroidism (2). The important physiological link is affirmed by the predictable changes in cardiovascular function that occur across the entire range of thyroid disease states. Hyperthyroidism produces increased heart rate and cardiac contractility and lowers systemic vascular resistance resulting in a marked increase in cardiac output (2,3). In contrast, hypothyroidism results in impaired left ventricular (LV) contractile and relaxation functions, increased systemic vascular resistance, and low cardiac output, similar to that seen with congestive heart failure (1,4,5). There are numerous parallels between hypothyroidism and heart failure, including decreased serum thyroid hormone, especially T3 levels (6). The significance of this is reinforced by studies of biopsied LV myocardium showing alterations in expression of thyroid hormone-responsive genes that are similar in hypothyroidism and heart failure. These changes include the genes encoding the proteins that regulate calcium cycling, β1-adrenergic receptors, and the myosin heavy chain contractile proteins (4). Although the prevalence of thyroid gland dysfunction and primary hypothyroidism is not significantly different in patients with heart failure, well-known alterations in thyroid hormone metabolism give rise to low serum T3 levels in heart failure and a variety of other cardiac disease states (6,7,8). In both children and adults undergoing cardiac surgery with cardiopulmonary bypass and in patients after uncomplicated acute myocardial infarction, there is a predictable fall in serum T3 (9,10,11). Controversy persists about the significance of these changes in serum thyroid hormone levels (12). It has been suggested that a low T3 level after an acute myocardial infarction or in the course of chronic cardiac disease is somehow adaptive, reducing metabolic demands during these nonthyroidal illnesses. At the same time, multiple reports have demonstrated potential benefit of T3 replacement in patients undergoing cardiac surgery, with acute myocarditis and, in the current issue of JCEM, with heart failure (8,9,10,13). Iervasi et al. (7) and the cardiothoracic research group in Pisa have previously shown that low serum T3 levels are the single most significant predictor of cardiovascular and all-cause mortality in adults with heart disease. Although the basis for this observation is not entirely clear, preclinical studies have suggested that a variety of cardiac pathological processes, including acute myocardial infarction, lead to impaired LV function and a concomitant fall in serum T3 (14). In those studies, T3 replacement improved LV function and restored myocyte gene expression to euthyroid levels, similar to that seen in the treatment of hypothyroidism (5). In this context, the current JCEM report of the beneficial effects of T3 replacement in human heart failure is especially interesting and serves as proof of the concept that altered thyroid hormone metabolism plays a pathogenic role in progression of cardiac disease states (13). The authors prospectively studied 20 heart failure patients with low T3 levels and randomized 10 to treatment with T3 by infusion for 72 h. This treatment restored serum T3 levels to normal and produced a significant increase in stroke volume and LV end diastolic volume when compared with pretreatment levels. The beneficial effects were also objectively confirmed with a decrease in the neurohumoral profile, including a fall in plasma norepinephrine, aldosterone, and N-terminal prohormone B-type natriuretic peptide. The last of these is an especially sensitive measure of heart failure, and this degree of improvement after a relatively short treatment time is quite remarkable. In contrast to what might have been predicted, and allaying concerns about untoward effects of T3 in this setting, T3 treatment actually resulted in a decrease in heart rate (13). The authors question whether the fall in serum T3 is a result of or, alternatively, contributes to progression of heart failure. Previous work would suggest that both hypotheses are correct. As seen in Fig. 1​1,, a variety of cardiovascular disease states including hypertension, ischemic heart disease, and cardiomyopathies, as well as aging and diabetes, can impair systolic and diastolic LV function leading to heart failure (15). Concomitant with this, and perhaps mediated by one of a number of proinflammatory cytokines (16), there is a fall in serum T3 directly proportional in magnitude to the severity of the heart failure (6). Taken together, these processes promote pathological remodeling of the LV, which in the setting of neurohormonal activation exacerbates cardiac dysfunction. Thus, the finding that low serum T3 levels portend increased cardiac risk is explained mechanistically and represents the basis for T3 therapy to restore serum levels to normal. In this scenario, and as shown by others, T4 is less effective due to the impaired metabolism to T3 (16,17). Figure 1 Rationale for the use of T3 in the treatment of the failing heart. Current treatment of heart failure often requires multiple medications, including β-adrenergic blocking drugs, angiotensin converting enzyme inhibitors, aldosterone antagonists, digitalis, and diuretics. Despite maximum medical therapy, mortality remains high, and novel treatment strategies are actively sought (18). One field of investigation is that of gene therapy in which a variety of viral vectors encoding specific cardiac regulatory and structural proteins are directed to the impaired myocyte. Because calcium uptake and release by the sarcoplasmic reticulum is frequently impaired in heart failure, the ability to increase sarcoplasmic reticulum calcium-activated ATPase or to lower its inhibitory regulator phospholamban are attractive targets for genetic manipulation (19). Studies of the cellular mechanisms of thyroid hormone action on the cardiac myocyte have demonstrated that, similar to the hypothyroid myocardium, treatment of the failing heart with T3 produces a salutary change in the cardiac phenotype (14). In the current report, the authors observe a T3-mediated increase in end diastolic volume, a hemodynamic consequence of enhanced diastolic compliance and diastolic filling (1). As long as this is not accompanied by an increase in end diastolic pressure, these changes would represent a positive lusitropic effect. Other thyroid hormone-responsive genes that may play a role in the improved cardiac contractile function include β1-adrenergic receptor, stimulatory guanine nucleotide binding proteins (Gs), α-myosin heavy chain, sodium-calcium exchanger, and perhaps the voltage-gated potassium channels (Kv) (2). Because the majority of patients who die of heart failure do so as the result of a ventricular arrhythmia, a positive effect on Kv expression leading to a shortening of the QT interval on the electrocardiogram is therapeutically desirable (18). Nongenomic effects of T3 on ion channels and cytosolic signaling pathways and to lower systemic vascular resistance have also been documented. Perhaps most important is the observation in this report, and many previous studies, that T3 treatment does not produce untoward effects when administered in either physiological or short-term pharmacological doses to patients with concomitant cardiac disease (4,5,8,9,10,11,13,14,20). There have been no reported episodes of supraventricular arrhythmias, increases in heart rate, or worsening of cardiac ischemia in any of the reported series to date. In contrast to what might have been predicted, T3 treatment of high-risk patients undergoing coronary artery bypass graft surgery led to a significantly lower incidence of postoperative atrial fibrillation (20). To restore serum T3 levels to normal, the current study and most previous investigations have employed short-term iv therapy. Although potentially useful in acute studies, this is not feasible for long-term therapy. Unfortunately, when administered by standard oral dose formulation, the 7- to 8-h half-life of T3 leads to peak serum levels that are frequently above the upper limits of the physiological range as early as 2 h after administration (21). The heart appears to be sensitive to changes in serum T3 levels in both primary hypothyroidism and nonthyroidal illnesses (1,22). Thus, any long-term studies undertaken to establish both safety and efficacy of T3 treatment for heart failure would optimally employ a formulation of T3 not currently available. The clinical reality that such patients will already be treated with β-adrenergic blocker provides a combination of treatments with therapeutic synergy (4). The potential usefulness of T3 in this setting may encourage investigation into its use as therapy in other chronic disease and wasting states and in more acute clinical situations where low serum T3 levels have been observed (12).