Empagliflozin Supplementation in Cardioplegic Solution Improves Donor Heart Preservation by Maintaining Mitochondrial Homeostasis
Abstract
BACKGROUND: Prolonged cold ischemia and subsequent reperfusion are major causes of primary graft dysfunction in heart transplantation. Empagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, has shown cardioprotective effects in ischemia-reperfusion injury, but its role in donor heart preservation and the underlying mechanisms remain unexplored.
METHODS: We evaluated the effects of empagliflozin supplementation in University of Wisconsin (UW) preservation solution using both in vitro and in vivo models. HL-1 cardiomyocytes were subjected to cold hypoxia/reoxygenation injury to simulate donor preservation conditions. A murine heterotopic heart transplantation model with 24-hour cold storage was used to assess graft function, myocardial injury, fibrosis, and immune response. Mechanistic studies were conducted using AMPK and Drp1 inhibitors to investigate mitochondrial signaling pathways.
RESULTS: Empagliflozin (500 nM) significantly improved cardiomyocyte viability, reduced apoptosis, and preserved mitochondrial membrane potential under cold hypoxia/reoxygenation stress. In vivo, empagliflozin-supplemented UW solution improved early graft contractility, attenuated myocardial injury, reduced serum injury markers, and alleviated histological damage and immune cell infiltration. Long-term follow-up revealed mitigation of chronic rejection, with reduced fibrosis, vasculopathy, and immune activation. Mechanistically, empagliflozin activated AMPK, inhibited Drp1…
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