Initiating Empagliflozin and Sacubitril/Valsartan Early After Acute Myocardial Infarction: Mechanistic Study

Background: Empagliflozin and sacubitril/valsartan are established in heart failure treatment, but their effects after myocardial infarction (MI) are less clear. This study evaluated early empagliflozin initiation, with or without sacubitril/valsartan, on post-MI inflammation, oxidative stress, metabolism, fibrosis, cardiac function, and ventricular tachycardia (VT) risk in a pig model.

Methods: A total of 24 of 30 pigs survived the MI procedure and were subsequently randomized to receive beta-blocker treatment alone (control-MI), beta-blocker+empagliflozin, or beta-blocker+empagliflozin+sacubitril/valsartan. Immune response, metabolic profile, and cardiac function were monitored. At 30 days after MI, programmed electrical stimulation and high-density mapping were performed and VT inducibility was assessed. Tissue samples were collected for cardiac inflammation, oxidative stress, and metabolic analyses.

Results: Empagliflozin reduced circulating leukocytes at 2 and 15 days after MI (P=0.010 and P=0.050, respectively) and decreased C-C chemokine receptor 2+ monocytes at 15 days (P=0.049). Nitric oxide bioavailability increased in remote myocardium (P=0.059), along with cardioprotective liver lipids and collagen III in the myocardial scar (P=0.023). No effect on cardiac function or VT inducibility was observed at 30 days. With empagliflozin+sacubitril/valsartan, scar collagen I decreased (P=0.082), left ventricular compliance improved (P=0.029), electrophysiological remodeling improved (reduced border-zone corridors [P=0.006] and deceleration zones [P=0.008]), and VT inducibility decreased (P=0.025).

Conclusions: In this pig model of nonreperfused MI treated with beta-blocker, early initiation of empagliflozin reduced inflammation, improved nitric oxide bioavailability, increased protective liver lipids, and modified scar composition without affecting cardiac function or VT risk. With empagliflozin+sacubitril/valsartan treatment, scar collagen I and VT inducibility declined and left ventricular remodeling was enhanced.