Thyroid hormone administration early after infarction attenuates cardiac remodeling and significantly improves myocardial performance.

Hyperthyroid hearts are shown to display a phenotype of cardioprotection against ischemic stress, but the underlying signaling mechanisms remain largely unknown. The present study investigated the possible relation of HSP70 to the thyroid hormone induced cardioprotection. HSP70 is a redox-regulated molecular chaperone, and enhances cell survival under stress. Thyroxin (25 microg/100 g body weight) was administered to Wistar male rats for four days (THYR-4d) and two weeks (THYR-14d), respectively, while untreated animals served as controls (CON-4d, CON-14d). Isolated hearts from control and thyroxin treated rats were subjected to 20 min zero-flow ischemia followed by 45 min of reperfusion (I/R). The amount of HSP70 in the myocardium for THYR-14d was 1.85 times the levels of CON-14d (p < 0.05). The levels of HSP70 expression were no different between THYR-4d and CON-4d, p > 0.05. This was only accompanied by an increase in MDA levels (used as an index of oxidative stress) in THYR-14d compared to untreated hearts. These changes corresponded to a differential response of the heart to I/R; post-ischemic recovery of function was significantly increased in THYR-14d compared to CON-14d, and was no different between the THYR-4d and CON-4d hearts. In conclusion, long-term thyroxin administration results in increased tolerance of the myocardium to I/R and enhances the expression of HSP70 which may, at least in part, account for this response.

Objective: Previous experimental studies have provided evidence showing that changes in thyroid hormone signaling correspond to alterations in myocardial function in animal models of heart failure. The present study further explores whether thyroid hormone alterations are correlated with the functional status of the myocardium in patients with heart failure. Methods: In this study, 37 patients with mean ejection fraction (EF%) of 26.2 (8.2) were included. Myocardial performance was assessed by echocardiography and cardiopulmonary exercise testing. Total tri-iodothyronine (T 3 ), thyroxine, and TSH levels were measured in plasma. Results: Total T 3 was strongly correlated with VO 2max (rZ0.78, PZ2!10 K8). Furthermore, multivariate analysis revealed that total T 3 was an independent predictor of VO 2max (PZ0.000 005). A weaker but significant correlation was also found between total T 3 and EF% (rZ0.56, PZ0.0004), systolic (rZ0.43, PZ0.009) and diastolic (rZ0.46, PZ0.004) blood pressure. Conclusions: changes in thyroid hormone were closely correlated to myocardial functional status in patients with heart failure. These data probably indicate a possible role of thyroid hormone in the pathophysiology of heart failure and confirm previous experimental reports.European Journal of Endocrinology 157 515-520

The present study investigated whether changes in thyroid hormone (TH) signalling can occur after acute myocardial infarction (AMI) with possible physiological consequences on myocardial performance. TH may regulate several genes encoding important structural and regulatory proteins particularly through the TRa1 receptor which is predominant in the myocardium. AMI was induced in rats by ligating the left coronary artery while sham-operated animals served as controls. This resulted in impaired cardiac function in AMI animals after 2 and 13 weeks accompanied by a shift in myosin isoforms expression towards a fetal phenotype in the non-infarcted area. Cardiac hypertrophy was evident in AMI hearts after 13 weeks but not at 2 weeks. This response was associated with a differential pattern of TH changes at 2 and 13 weeks; T 3 and T 4 levels in plasma were not changed at 2 weeks but T 3 was significantly lower and T 4 remained unchanged at 13 weeks. A twofold increase in TRa1 expression was observed after 13 weeks in the non-infarcted area, P!0.05 versus sham operated, while TRa1 expression remained unchanged at 2 weeks. A 2.2-fold decrease in TRb1 expression was found in the non-infarcted area at 13 weeks, P!0.05, while no change in TRb1 expression was seen at 2 weeks. Parallel studies with neonatal cardiomyocytes showed that phenylephrine (PE) administration resulted in 4.5-fold increase in the expression of TRa1 and 1.6-fold decrease in TRb1 expression versus untreated, P!0.05. In conclusion, cardiac dysfunction which occurs at late stages after AMI is associated with increased expression of TRa1 receptor and lower circulating tri-iodothyronine levels. Thus, apo-TRa1 receptor state may prevail contributing to cardiac fetal phenotype. Furthermore, down-regulation of TRb1 also contributes to fetal phenotypic changes. a1-adrenergic signalling is, at least in part, involved in this response. 156 415-424 European Journal of Endocrinology

It has been previously shown that regulators of physiological growth such as thyroid hormone (TH) can favorably remodel the post ischaemic myocardium. Here, we further explored whether this effect can be preserved in the presence of co-morbidities such as diabetes which accelerates cardiac remodeling and increases mortality after myocardial infarction. Acute myocardial infarction (AMI) was induced by left coronary ligation in rats with type I diabetes (DM) induced by streptozotocin administration (STZ; 35 mg/kg; i.p.) while sham-operated animals served as controls (SHAM). AMI resulted in distinct changes in cardiac function and geometry; EF% was significantly decreased in DM-AMI [37.9 ± 2.0 vs. 74.5 ± 2.1 in DM-SHAM]. Systolic and diastolic chamber dimensions were increased without concomitant increase in wall thickness and thus, wall tension index [WTI, the ratio of (Left Ventricular Internal Diameter at diastole)/2*(Posterior Wall thickness)], an index of wall stress, was found to be significantly increased in DM-AMI; 2.27 ± 0.08 versus 1.70 ± 0.05. 2D-Strain echocardiographic analysis showed reduced systolic radial strain in all segments, indicating increased loss of cardiac myocytes in the infarct related area and less compensatory hypertrophy in the viable segments. This response was accompanied by a marked decrease in the expression of TRα1 and TRβ1 receptors in the diabetic myocardium without changes in circulating T3 and T4. Accordingly, the expression of TH target genes related to cardiac contractility was altered; β-MHC and PKCα were significantly increased. TH (L-T4 and L-T3) administration prevented these changes and resulted in increased EF%, normal wall stress and increased systolic radial strain in all myocardial segments. Acute myocardial infarction in diabetic rats results in TH receptor down-regulation with important physiological consequences. TH treatment prevents this response and improves cardiac hemodynamics.