Treatment of subclinical hypothyroidism reverses ischemia and prevents myocyte loss and progressive LV dysfunction in hamsters with dilated cardiomyopathy

Abstract

. Treatment of subclinical hypothyroidism reverses ischemia and prevents myocyte loss and progressive LV dysfunction in hamsters with dilated cardiomyopathy. Am J Physiol Heart Circ Physiol 289: H2409 -H2415, 2005. First published July 15, 2005; doi:10.1152/ajpheart.00483.2005.-Growing evidence suggests that thyroid dysfunction may contribute to progression of cardiac disease to heart failure. We investigated the effects of a therapeutic dose of thyroid hormones (TH) on cardiomyopathic (CM) hamsters from 4 to 6 mo of age. CM hamsters had subclinical hypothyroidism (normal thyroxine, elevated TSH). Left ventricular (LV) function was determined by echocardiography and hemodynamics. Whole tissue pathology and isolated myocyte size and number were assessed. TH treatment prevented the decline in heart rate and rate of LV pressure increase and improved LV ejection fraction. The percentage of fibrosis/necrosis in untreated 4-mo-old CM (4CM; 15.5 Ϯ 2.2%) and 6-mo-old CM (6CM; 21.5 Ϯ 2.4%) hamsters was pronounced and was reversed in treated CM (TCM; 11.9 Ϯ 0.9%) hamsters. Total ventricular myocyte number was the same between 4-and 6-mo-old controls but was reduced by 30% in 4CM and 43% in 6CM hamsters. TH treatment completely prevented further loss of myocytes in TCM hamsters. Compared with agematched controls, resting and maximum coronary blood flow was impaired in 4CM and 6CM hamsters. Blood flow was completely normalized by TH treatment. We conclude that TH treatment of CM hamsters with subclinical hypothyroidism normalized impaired coronary blood flow, which prevented the decline in LV function and loss of myocytes. thyroid hormones; remodeling; fibrosis; blood flow THE EFFECTS OF THYROID HORMONES (TH) on the cardiovascular system have been well studied. It is clear that both hypothyroidism and hyperthyroidism can lead to deleterious changes in cardiovascular function. Decreased TH levels have been reported in a variety of nonthyroidal illnesses (18), including congestive heart failure (12) and myocardial infarction (6). The decrease in TH levels also appears to be related to the severity of heart failure (12). This is not a minor point, because low 3,5,3'-triiodothyronine (T 3 ) concentrations are a strong, independent predictive marker of poor prognosis in cardiac patients and might represent a determining factor directly implicated in the evolution and prognosis of these conditions (14). Growing evidence also suggests that subclinical thyroid dysfunction might play an important role in heart failure (10, 21). This is highly relevant from a clinical standpoint because this patient group does not typically receive TH treatment.Development of heart failure is accompanied by a variety of neuroendocrine changes. Cardiac failure was shown to be associated with both a decline in circulating TH levels (11,17) and altered cardiac TH signaling, as evidenced by changes in myocardial expression of TH nuclear receptor isoforms (15,16). The observation that short-term TH administration improves cardiac performance, both in anim...

MECHANISMS IN ENDOCRINOLOGY: Heart failure and thyroid dysfunction

“…The administration of replacement doses of L-T 4 reduces myocyte apoptosis and is able to improve cardiovascular performance and ventricular remodelling in experimental hypothyroidism (7,18,89,96). This is in line with the results of some randomized and placebo-controlled studies that demonstrated (74,75,79,97,98).…”

“…The conversion of T 4 to T 3 is impaired and a low serum T 3 syndrome may develop in cardiac dysfunction (7,89,90,91,92). This condition is a strong predictor of mortality in patients with severe heart disease (7,89,90,91,92).…”

“…Randomized controlled studies are necessary to evaluate the efficacy of L-T 4 administration in preventing the risk of HF and its negative prognosis in patients with overt and SHypo. Some studies suggest that replacement doses of T 3 may improve cardiovascular remodelling and function in patients with HF and low T 3 syndrome (7,89). Further studies are necessary to assess the potential therapeutic use of THs and their analogues in treating or preventing HF (103,104).…”

Thyroid Hormone Stimulates Protein Synthesis in the Cardiomyocyte by Activating the Akt-mTOR and p70S6K Pathways

“…The observation that thyroid hormone treatment of patients and experimental animal models of heart failure can improve cardiac function has been attributed in part to its regulation of cardiac genes (1)(2)(3)(4)(5). It has also been well documented that thyroid hormones stimulate physiologic cardiac hypertrophy (6); however, the intracellular mechanisms underlying this response remain poorly defined.…”

“…Recent published studies supporting the cytosolic localization and non-transcriptional activities of thyroid hormone receptors may underlie thyroid hormone-induced physiological growth (9 -11). Evidence of protein-protein interactions between cytosolic thyroid hormone receptors and the p85␣ regulatory subunit of phosphatidylinositol 3-kinase (PI3K), 2 and activation of PI3K activity by T3 treatment have been reported (12,13). Activation of the PI3K␣-Akt-mTOR pathway by IGF-1 and transgenic animal models expressing molecular components of this pathway have implicated the PI3K-Akt signaling pathway in determining heart size and physiologic cardiac growth (14 -18).…”