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

• Published in: Journal of the American Heart Association Vol. 14; no. 11; p. e040214
• Main Authors: Martínez‐Falguera, Daina, Aranyó, Júlia, Ferrer‐Curriu, Gemma, Teis, Albert, Revuelta‐Lopez, Elena, Diaz‐Güemes, Idoia, Monguió‐Tortajada, Marta, Fadeuilhe, Edgar, Rodríguez‐Leor, Oriol, Poblador, Francesc, Montejo, Borja, Roura, Santiago, Villuendas, Roger, Sarrias, Axel, Bazan, Victor, Jorge, Esther, Delgado, Victoria, Jimenez‐Trinidad, Francisco Rafael, Rigol, Montserrat, Martinez‐Micaelo, Neus, Amigó, Núria, Bayes‐Genis, Antoni, Bisbal, Felipe, Gálvez‐Montón, Carolina
• Format: Journal Article
• Language: English
• Published: England John Wiley and Sons Inc 03.06.2025; Wiley
• Subjects: Aminobutyrates - administration & dosage; Aminobutyrates - pharmacology; Animals; Benzhydryl Compounds - administration & dosage; Benzhydryl Compounds - pharmacology; Biphenyl Compounds - pharmacology; Disease Models, Animal; Drug Combinations; Drug Therapy, Combination; empagliflozin; fibrosis; Glucosides - administration & dosage; Glucosides - pharmacology; inflammation; Male; myocardial infarction; Myocardial Infarction - complications; Myocardial Infarction - drug therapy; Myocardial Infarction - metabolism; Myocardial Infarction - physiopathology; Myocardium - metabolism; Myocardium - pathology; Original Research; Oxidative Stress - drug effects; sacubitril/valsartan; Sodium-Glucose Transporter 2 Inhibitors - pharmacology; Swine; Tachycardia, Ventricular - etiology; Tachycardia, Ventricular - physiopathology; Tachycardia, Ventricular - prevention & control; Time Factors; Valsartan - pharmacology; ventricular arrhythmia; Ventricular Function, Left - drug effects; Ventricular Remodeling - drug effects; empagliflozin; ventricular arrhythmia; fibrosis; inflammation; myocardial infarction; sacubitril/valsartan
• ISSN: 2047-9980; 2047-9980
• DOI: 10.1161/JAHA.124.040214

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