Introduction: Ischemic post-conditioning (iPoCo) by repetitive coronary re-occlusion at immediate reperfusion reduces myocardial infarct size. The mechanical manipulation of the culprit lesion, however, carries the risk of coronary microembolization. Use of exogenous tri-iodothyronine (T3) could serve as an alternative conditioning strategy. We studied T3’s impact on infarct size and its potential recruitment of classical cardioprotective pathways.

Methods and Results: Isolated buffer-perfused rat hearts were subjected to 30 min/ 120 min global zero-flow ischemia/reperfusion. During reperfusion, iPoCo (2x 30 s/ 30 s global zero-flow ischemia/reperfusion) -as reference- or T3 infusion (100, 200, 300, 500 µg/L) was initiated. Infarct size was demarcated by TTC staining and calculated as percent of ventricular mass. Infarct size was reduced with iPoCo to 16±7% vs. 36±4% without iPoCo. T3 (100, 200, 300, 500 µg/L) reduced infarct size with a maximum effect at 300 µg/L (27±5%; 23±18%; 14±2% 18±6%). In a further set of experiments, the Akt inhibitor wortmannin and/or theERK1/2 inhibitor U0126or the STAT3 inhibitor stattic (1 µmol/L each), respectively, were added to the reperfusion buffer. Wortmannin, U0126 and their combination -but not stattic - abrogated the cardioprotection by 300 µg/L T3 (Figure A). Adult ventricular cardiomyocytes were isolated from rat hearts and exposed to 30 min/ 5 min hypoxia/reoxygenation without/with 300 µg/L T3. T3 preserved cardiomyocyte viability, calculated as percent viable of total cells after hypoxia/reoxygenation (Figure B). Again, wortmannin, U0126 and their combination -but not stattic- abrogated protection (Figure B). Mitochondria were isolated at early reperfusion from buffer-perfused rat hearts without/with 300 µg/L T3 at reperfusion or iPoCo, respectively. With T3 at reperfusion mitochondrial function was improved, i.e.: increased respiration (+43%), adenosine triphosphate production (+74%), calcium retention capacity (+52%) and decreased reactive oxygen species formation (-28%). Changes were comparable to that induced by iPoCo (+51%; +55%; +48; -32%, respectively).

Conclusion: T3 at reperfusion is cardioprotective at the cardiomyocyte level, involves Akt and ERK, and targets mitochondria.