Empagliflozin Improves Cardiac Functional Recovery after Prolonged Cold Storage of Donor Hearts in an Isolated Working Rat Heart Model

Purpose Many donor hearts are unsuitable for transplantation after prolonged cold storage or donation after circulatory death. Improved donor heart recovery is observed after supplementation of preservation solutions with sodium-hydrogen exchange inhibitors (NHEI) cariporide/zoniporide (Gao et al, 2010, BJP; Cropper et al, 2003, JHLT). NHEI are not clinically used due to neurotoxicity observed in cariporide clinical trials however the search for suitable NHEI alternatives continues. One promising alternative is the sodium-glucose cotransporter 2 inhibitor Empagliflozin (Empa) - the first anti-diabetic drug to yield positive cardiovascular outcomes. Studies have shown Empa mimics NHEI and slows pH recovery in cardiomyocytes following an acidic load. This study tests the cardioprotective efficacy of Empa-supplementation in cardiac preservation solution during prolonged cold storage of donor hearts. Methods Wistar rat (320-420g; n=5-7) hearts were perfused ex-vivo and baseline hemodynamic measurements acquired. Hearts were arrested and stored in Celsior±0.3-10µM Empa, or zoniporide (1µM) (6h, 4°C) then reperfused (37°C, Langendorff 15min, working 30min). Post-reperfusion aortic flow (AF) and cardiac output (CO) were expressed as a percentage of baseline measurements. Coronary effluent (pre-storage, 15, 30, and 45 min reperfusion) was assessed for lactate dehydrogenase (LDH) release. Results Donor hearts supplemented with Empa during cold storage showed a dose-dependent improvement in cardiac functional recovery. Compared to unsupplemented control hearts, 10µM Empa-supplemented hearts showed significantly improved AF (54±11% vs 10±7%, p=0.006) and CO (55±12 vs 16±8, p=0.03) recovery. Hearts supplemented with 1µM zoniporide also showed significantly improved AF (63±7%, p=0.002 vs control) and CO (65±9%, p=0.01) recovery. A trend for reduced LDH efflux was observed in hearts supplemented with 1-10µM Empa or zoniporide compared to control hearts. Conclusion Supplementation of cardiac preservation solution with 10µM Empa yields significantly improved functional recovery after prolonged cold storage, with similar cardioprotective efficacy to the NHEI zoniporide. Given the approved clinical use of Empa, this study highlights its potential as a suitable alternative for NHEI in donor heart preservation.