Effects of T3 Administration on Ex Vivo Rat Hearts Subjected to Normothermic Perfusion: Therapeutic Implications in Donor Heart Preservation and Repair

Abstract

The present study investigated the effects of triiodothyronine (T3) administration in ex vivo model of rat heart normothermic perfusion. T3 is cardioprotective and has the potential to repair the injured myocardium. Isolated hearts were subjected to normothermic perfusion (NP) with Krebs-Henseleit for 4 h with vehicle (NP) or 60 nM T3 in the perfusate (NP + T3). Left ventricular end diastolic pressure (LVEDP), left ventricular developed pressure (LVDP), perfusion pressure (PP) and percentage of change of these parameters from the baseline values were measured. Activation of stress induced kinase signaling was assessed in tissue samples. Baseline parameters were similar between groups. LVEDP was increased from the baseline by 13% (70) for NP + T3 vs. 139% (160) for NP group, p = 0.048. LVDP was reduced by 18.2% (5) for NP + T3 vs. 25.3% (19) for NP group, p = 0.01. PP was increased by 41% (19) for NP + T3 vs.91% (56) for NP group, p = 0.024. T3 increased activation of pro-survival Akt by 1.85 fold (p = 0.047) and AMPK by 2.25 fold (p = 0.01) and reduced activation of pro-apoptotic p38 MAPK by 3fold (p = 0.04) and p54 JNK by 4.0 fold (p = 0.04). Administration of T3 in normothermic perfusion had favorable effects on cardiac function and perfusion pressure and switched death to pro-survival kinase signaling.

Donor Heart Preservation: Current Knowledge and the New Era of Machine Perfusion

“…T3 seems to affect microvasculature, debilitating tissue hypoxia microvascular dysfunction following normothermic perfusion. We found that T3 administration after 4 h of normothermic perfusion resulted in a significantly lower coronary perfusion pressure as compared to untreated hearts, indicating the reduced resistance of coronary vessels [69]. Similar observations have been reported in experimental settings of microvascular dysfunction in ischemia-reperfusion injury.…”

“…Mourouzis et al showed that the administration of T3 during normothermic perfusion with non-blood crystalloid buffer was shown to have favorable effects on cardiac function and perfusion pressure, and switched death to pro-survival kinase signaling. Especially, the improvement of coronary perfusion pressure with the addition of T3 in the perfusate indicates a favorable effect on microvascular function during ex vivo normothermic perfusion [68,69]. Experimental evidence suggests that T3 exerts its cardioprotective actions likely by suppressing pro-apoptotic signaling, such as p38 MAPK and JNKs, and increasing the activation of cardioprotective molecules like PI3 K/Akt and AMPK.…”