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Dapagliflozin enhances hemodynamic and metabolic recovery following cardioplegic arrest in the isolated working mouse heart

Year: 2025

Type: article

Abstract: This experimental study investigates the potential of sodium-glucose cotransporter 2 inhibitor (SGLT2i) dapagliflozin to enhance cardiac hemodynamic and metabolism function following ischemia/reperfusion (I/R) after cold cardioplegic arrest. Hearts of adult male C57BL/6 J mice were excised and mounted on an isolated working heart system. Cold ischemia (100 min) was induced using St. Thomas’ #2 cardioplegia, applied every 20 min, followed by 30 min of reperfusion. Continuous monitoring of cardiac parameters was performed. The experimental groups were the following (1) cold cardioplegic arrest as control (n = 12), (2) dapagliflozin applied to perfusion buffer 30 min prior to ischemia (n = 16), (3) arrested hearts receiving dapagliflozin as an adjunct to cardioplegia (n = 13), and (4) no-arrested, no-treated hearts (n = 6). Post-protocol, biopsies of hearts were frozen for subsequent metabolic and RT-qPCR analysis. Additionally, cell culture experiments on HUVECS and cardiac myoblasts were performed. Cold I/R markedly reduced systolic and diastolic function. Notably, dapagliflozin administered before ischemia significantly improved left ventricular recovery by enhancing contractility, aortic flow, and left ventricle diastolic function, whereas adding dapagliflozin only to the cardioplegic solution did not yield similar effects. High-energy phosphate (HEP) measurements revealed a statistically significant increase of myocardial energy charge in hearts treated with dapagliflozin via cardioplegia. These functional and metabolic findings were supported by improved cell viability and higher HEP content in HUVECS and cardiac myoblasts, when pre-treated with SGLT2i. Our findings underscore the potential of SGLT2i to improve hemodynamic recovery following cardioplegic arrest, supporting further exploration of dapagliflozin as novel myocardial protective regimen in cardiac surgery. Pre-ischemic dapagliflozin improves post-ischemic function in the isolated murine working heart. Adult C57BL/6 J mouse hearts were mounted on a working heart apparatus, perfused with Krebs–Henseleit buffer and treated with dapagliflozin (10 µM) for 30 min prior to cold cardioplegic arrest. Hearts then underwent 100 min of cold ischemia (St. Thomas’ #2 solution every 20 min) followed by 30 min of normothermic reperfusion. Dapagliflozin applied only to the cardioplegic solution did not confer the same benefit (not shown). • Pre-ischemic dapagliflozin improved LV function after cold cardioplegia. • Dapagliflozin in cardioplegia alone did not enhance functional recovery. • Pre-treatment preserved energy charge and viability in vitro under oxidative stress. • Pre-treatment preserved fatty-acid oxidation enzymes during reperfusion. • Supports SGLT2i as a perioperative myocardial protection strategy.

Source: Biomedicine & Pharmacotherapy

DOI: 10.1016/j.biopha.2025.118771