Metformin Preconditioning Augments Cardiac Perfusion and Performance in a Large Animal Model of Chronic Coronary Artery Disease

• Published in: Annals of surgery Vol. 280; no. 4; pp. 547 - 556
• Main Authors: Stone, Christopher, Sabe, Sharif, Harris, Dwight D, Broadwin, Mark, Kant, Rajeev, Kanuparthy, Meghamsh, Abid, M Ruhul, Sellke, Frank W
• Format: Journal Article
• Language: English
• Published: United States 01-10-2024
• ISSN: 0003-4932; 1528-1140; 1528-1140
• DOI: 10.1097/SLA.0000000000006437

To test the efficacy of metformin during the induction of coronary ischemia on myocardial performance in a large animal model of coronary artery disease (CAD) and metabolic syndrome (MS), with or without concomitant extracellular vesicular (EV) therapy.
Although surgical and endovascular revascularization are durably efficacious for many patients with CAD, up to one-third are poor candidates for standard therapies. For these patients, many of whom have comorbid MS, adjunctive strategies are needed. EV therapy has shown promise in this context, but its efficacy is attenuated by MS. We investigated whether metformin pretreatment could ameliorate therapeutic decrements associated with MS.
Yorkshire swine (n=29) were provided a high-fat diet to induce MS, whereupon an ameroid constrictor was placed to induce CAD. Animals were initiated on 1000 mg PO metformin or placebo; all then underwent repeat thoracotomy for intramyocardial injection of EVs or saline. Swine were maintained for five weeks before acquisition of functional and perfusion data immediately prior to terminal myocardial harvest. Immunoblotting and immunofluorescence were performed on the most ischemic tissue from all groups.
Regardless of EV administration, animals that received metformin exhibited significantly improved ejection fraction, cardiac index, and contractility at rest and during rapid myocardial pacing; improved perfusion to the most ischemic myocardial region at rest and during pacing; and markedly reduced apoptosis.
Metformin administration reduced apoptotic cell death, improved perfusion, and augmented both intrinsic and load-dependent myocardial performance in a highly translatable large animal model of chronic myocardial ischemia and metabolic syndrome.