Cardiac remodeling of viable myocardium occurs after acute myocardial infarction (AMI) and further contributes to cardiac dysfunction. The present study explored whether thyroid hormone (TH) administered shortly after AMI in rats can attenuate cardiac remodeling and improve cardiac function. TH regulates important structural and regulatory proteins in the myocardium including myosin isoform expression and calcium cycling proteins. AMI was induced in Wistar male rats by ligating left coronary artery (AMI, n=10), while sham-operated rats were used as controls (SHAM, n=10). Animals with acute myocardial infarction were also treated with 0.05% thyroid powder in food (AMI-THYR, n=10). Within 2 weeks, cardiac function was impaired as assessed by echocardiography and under isometric conditions in Langendorff preparations. Ejection fraction (EF%) was 71.5 (SEM, 2.7) in SHAM versus 30.0 (2.0) in AMI, P<0.05. +dp/dt was 3886 (566) in SHAM versus 2266 (206) in AMI hearts, P<0.05 and -dp/dt was 1860 (46) in SHAM versus 1633 (120) in AMI hearts, P=ns. Such changes were associated with alterations in myosin isoform expression in the non-infarcted area; AMI hearts expressed 34% alpha-MHC and 66% beta-MHC versus 52% alpha-MHC and 48% beta-MHC in SHAM, P<0.05, while the expression of SERCA and phospholamban (PLB) remained unchanged. Furthermore, a mismatch of left ventricular size and cardiac mass (2*Posterior Wall thickness/LVIDd was decreased) was observed. After TH treatment, AMI-THYR hearts expressed 71% alpha-MHC and 29% beta-MHC, P<0.05 versus SHAM and AMI and the ratio of SERCA/PLB was increased by 2.0-fold, P<0.05 versus SHAM and AMI. These changes corresponded to a marked improvement in cardiac function; EF% was raised to 45.8 (1.7), P<0.05 versus AMI while +dp/dt and -dp/dt were 3800 (435) and 2600 (200), respectively, in AMI-THYR hearts, P<0.05 versus AMI. The ratio of 2*Posterior Wall thickness/LVIDd was normalized. Thyroid hormone administration early after infarction attenuates cardiac remodeling and significantly improves myocardial performance.

We have previously shown that long-term thyroxine administration can protect the heart against ischemia. In the present study, we investigated whether thyroxine-induced cardioprotection can mimic the pattern of protection that is afforded by a well-established cardioprotective means such as ischemic preconditioning. In a Langendorff-perfused rat heart preparation, after an initial stabilization, normal and thyroxine-treated hearts were subjected to 20 minutes of zero-flow global ischemia followed by 45 minutes of reperfusion. In thyroxine-treated hearts, phospho-p38 mitogen-activated protein kinase (MAPK) was found to be less at the end of the ischemic period, whereas ischemic contracture was accelerated and postischemic recovery was increased in comparison to normal hearts. In addition, normal hearts were subjected to a four-cycle preconditioning protocol before ischemia. Phospho-p38 MAPK was found to be less at the end of the ischemic period in preconditioned hearts, whereas ischemic contracture was accelerated and postischemic functional recovery was increased in those hearts in comparison to nonpreconditioned hearts. An increase in basal expression and phosphorylation of PKCδ was also found to occur after long-term thyroxine administration. We conclude that long-term thyroxine administration can protect the heart from ischemic injury through a pattern of protection that closely resembles that of ischemic preconditioning.

Thyroid hormone (TH) signaling is altered in response to various stresses including myocardial ischemia. The present study investigated potential implication of TH signaling in the pathophysiology of postischemic remodeling. Acute myocardial infarction was induced in rats by coronary artery ligation (AMI). After 34 weeks, 6 animals were on congestive heart failure (CHF) as indicated by measurements in lung and right ventricular weight. 7 animals were in compensated state (Non-CHF) and 8 sham-operated animals (SHAM) served as controls. Progression to congestive heart failure was characterized by marked decrease in EF% and all other functional echocardiographic parameters. Furthermore, beta-MHC expression was significantly increased in CHF. A distinct pattern of thyroid hormone receptor (TR) expression was observed in the course of postischemic remodeling; TR alpha 1 was upregulated and TR beta 1 was downregulated in Non-CHF, and TR alpha 1 expression was markedly decreased during the transition from Non-CHF to CHF resulting in tissue hypothyroidism. Circulating T3 and T4 remained unchanged. This response was associated with marked decrease in mTOR activation. A potential link between mTOR and TR alpha 1 expression was shown in a neonatal cardiomyocytes model of PE (phenylephrine)-induced pathological growth. Phenylephrine increased the expression of TR alpha 1 in nucleus and this response was abrogated in the case of mTOR inhibition by rapamycin. In conclusion, progression to congestive heart failure after myocardial infarction is associated with suppressed expression of TR alpha 1 and results in tissue hypothyroidism. This process may, at least in part, be mTOR dependent.

The present study investigated the response of the hypothyroid heart to ischaemia-reperfusion. Hypothyroidism was induced in Wistar rats by oral administration of propylthiouracil (0.05%) for 3 weeks (HYPO rats), while normal animals (NORM) served as controls. Isolated hearts from NORM and HYPO animals were perfused in Langendorff mode and subjected to zero-flow global ischaemia followed by reperfusion (I/R). Post-ischaemic recovery of left ventricular developed pressure was expressed as % of the initial value (LVDP%). Basal expression of protein kinase C epsilon (PKCepsilon) and PKCdelta and phosphorylation of p46 and p54 c-jun NH(2)-terminal kinases (JNKs) in response to I/R were assessed by Western blotting. LVDP% was found to be significantly higher in HYPO hearts than in NORM. At baseline, PKCepsilon expression was 1.4-fold more in HYPO than in NORM hearts, P<0.05, while PKCdelta was not changed. Furthermore, basal phospho-p54 and -p46 JNK levels were 2.2- and 2.6-fold more in HYPO than in NORM hearts, P<0.05. In response to I/R, in NORM hearts, phospho-p54 and -p46 JNK levels were 5.5- and 6.0-fold more as compared with the baseline values, P<0.05, while they were not significantly altered in HYPO hearts. HYPO hearts seem to display a phenotype of cardioprotection against ischaemia-reperfusion and this is associated with basal PKCepsilon overexpression and attenuated JNK activation after I/R.