Metformin's effects beyond ischemia: Evaluating cardioprotection in nonischemic myocardium in a large animal model of coronary and metabolic disease

Abstract

Objective: This study evaluated the effects of metformin (MET) on nonischemic myocardium in a large animal model of coronary artery disease and metabolic syndrome (MS). Although prior work has shown MET improves perfusion and function in ischemic tissue, this study assessed whether its cardioprotective effects extend to nonischemic regions.

Methods: Yorkshire swine (n = 12) were fed a high-fat diet to induce MS and then underwent ameroid constrictor placement around the left circumflex artery to simulate coronary artery disease. Animals received either oral MET (1000 mg/day) or placebo for 7 weeks. Regional myocardial perfusion was assessed via microsphere injections at rest and during pacing. Nonischemic myocardial tissue was identified using gold microsphere distribution and analyzed using immunoblotting, immunofluorescence, and hemodynamic assessment. Statistical significance was evaluated using Student t test or the Mann Whitney U test.

Results: Despite no significant changes in perfusion, MET-treated animals demonstrated significantly reduced apoptotic markers (caspase 9, cleaved caspase 9, apoptosis-inducing factor, and Bcl2-associated agonist of cell death (BAD); P < .05) and increased phosphorylated BAD/BAD ratios. Prosurvival signaling was enhanced with elevated phosphorylated protein kinase B (AKT)/AKT, phosphorykated mammalian target of rapamycin (mTOR)/mTOR, and phosphorylated AMP-activated protein kinase (AMPK)/AMPK ratios (P < .05). Tansferase dUTP nick end labeling staining confirmed decreased apoptosis histologically. Functionally, MET improved cardiac output, stroke volume, and maximum derivative of volume in the myocardium (P < .05), correlating with reductions in apoptotic signaling.

Conclusions: MET was associated with significantly reduced apoptosis and promoted prosurvival signaling in nonischemic myocardium without altering perfusion. These findings suggest that MET's cardioprotective effects are not limited to ischemic tissue, highlighting its potential role as a systemic therapy for coronary artery disease and metabolic syndrome, including as an adjunct in cardiac surgery.

Keywords: coronary artery disease; metabolic syndrome; metformin; nonischemic myocardium.