Thyroid hormone receptor α1 (TRα1) is shown to be critical for the maturation of 
cardiomyocytes and for the cellular response to stress. TRα1 is altered during 
post ischemic cardiac remodeling but the physiological significance of this 
response is not fully understood. Thus, the present study explored the potential 
consequences of selective pharmacological inhibition of TRα1 on the mechanical 
performance of the post-infarcted heart. Acute myocardial infarction was induced 
in mice (AMI), while sham operated animals served as controls (SHAM). A group of 
mice was treated with debutyl-dronedarone (DBD), a selective TRα1 inhibitor 
(AMI-DBD). AMI resulted in low T3 levels in plasma and in down-regulation of 
TRα1 and TRβ1 expression. Left ventricular ejection fraction (LVEF%) was 
significantly reduced in AMI [33 (SEM 2.1) vs 79(2.5) in SHAM, p < 0.05] and was 
further declined in AMI-DBD [22(1.1) vs 33(2.1), respectively, p < 0.05]. 
Cardiac mass was increased in AMI but not in AMI-DBD hearts, resulting in 
significant increase in wall tension index. This increase in wall stress was 
accompanied by marked activation of p38 MAPK, a kinase that is sensitive to 
mechanical stretch and exerts negative inotropic effect. Furthermore, AMI 
resulted in β-myosin heavy chain overexpression and reduction in the ratio of 
SR(Ca)ATPase to phospholamban (PLB). The latter further declined in AMI-DBD 
mainly due to increased expression of PLB. AMI induces downregulation of thyroid 
hormone signaling and pharmacological inhibition of TRα1 further depresses 
post-ischemic cardiac function. p38 MAPK and PLB may, at least in part, be 
involved in this response.