Abstract 14312: Inhibition of the Electron Transport Chain and Inflammasome Pathway Preserve Function in Donor Hearts After Circulatory Death

Abstract

Introduction: Hearts by donation after circulatory death (DCD) have the potential to increase the number of transplantable hearts. However, the DCD process promotes ischemia and reperfusion injury (IRI). Mitochondrial damage and NLRP3 inflammasome activation contribute to the DCD heart damage. Blockade of electron transport chain (ETC) with the reversible inhibitor amobarbital (AMO) or the NLRP3 inhibitor 16773340 (NLRP3-I) can mitigate IRI. Hypothesis: AMO and/or NLRP3-I given to the DCD hearts at the moment of heterotopic heart transplantation afford lasting protection to the DCD hearts. Methods: We induced the DCD process in anesthetized rats that were intubated and ventilated by paralyzing the animal with vecuronium bromide and removing the ventilatory support. Treatment groups were AMO (1 mM), NLRP3-I, AMO+NLRP3-I, and vehicle (N=8-10/group). The DCD hearts were procured after 25 min of in-body ischemia then flushed with ice-cold cardioplegia solution supplemented or not with the AMO. NLRP3-I was administered orally (100 mg/kg) to the recipient before HTx and once a day. Control beating-heart donors (CBD) were procured without ischemia by giving the cardioplegia. The donor hearts underwent heterotopic transplantation in the abdomen of recipients. After 14 days, the function of the DCD heart was measured using an intraventricular balloon. Results: The developed pressure (DP), the peak -dP/dt, and the rate pressure product (RPP) of DCD hearts were significantly reduced compared to the CBD controls (63±7% vs 99±8%; -851±113 vs -1221±123; 20,729±2,268 vs 11,874±1,987, respectively; all p<0.05). AMO, NLRP3-I, and AMO+NLRP3-I preserved the DCD heart function (all parameters, p<0.03). Double treatment AMO+NLRP3-I trended toward a better improvement without reaching statistical significance over single treatments. Conclusions: Inhibition of ETC with AMO alone or combined with NLRP3 inhibition preserved the function of DCD hearts.