Differential effects of short‐term thyroid hormone analog DITPA on postischemic cardiac contractile function of wild‐type (WT) and endothelial nitric oxide synthase knockout (eNOS‐KO) mice

Abstract

Circulating and cardiac thyroid hormone (TH) levels are reduced in advanced heart disease and after acute myocardial ischemia/reperfusion (I/R). Hypertrophied hearts are more prone to ischemic stress than non-hypertrophied hearts, whereas, hyperthyroid hearts are protected against ischemic stress. eNOS-KO mice are hypertensive with hypertrophied heart and suffer exaggerated postischemic cardiac dysfunction compared to WT mice. DITPA (3,5-diiodothyropropionic acid), a TH analog, has been advocated for treating heart failure, however, it is unknown whether DITPA treatment could improve postischemic myocardial function in hypertrophied eNOS-KO hearts. In vitro I/R studies were performed in Langendorff hearts from WT and eNOS-KO mice after 7-days treatment with DITPA (3.75 mg/kg/day, SC), and the results were compared with untreated control mice. With 45-min reperfusion after 30-min ischemia, DITPA-treated eNOS-KO hearts had significantly improved recovery of coronary flow (110% vs. 80% of baseline, P<0.01), LV developed pressure (50% vs. 25% of baseline, P<0.01), LV end diastolic pressure (60 vs. 90 mmHg, P<0.05) than the control eNOS-KO hearts. Conversely, the beneficial effects of DITPA were less or absent in WT hearts and associated with severe arrhythmias. These findings suggest that TH therapy can improve postischemic myocardial function in hypertrophic hearts with chronic eNOS-deficiency.