Metformin's Effects Beyond Ischemia: Evaluating Cardioprotection in Non-Ischemic Myocardium in a Large Animal Model of Coronary and Metabolic Disease.

Objective: This study evaluated the effects of metformin (MET) on non-ischemic myocardium in a large animal model of coronary artery disease (CAD) and metabolic syndrome (MS). While prior work has shown MET improves perfusion and function in ischemic tissue, this study assessed whether its cardioprotective effects extend to non-ischemic 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 CAD. 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. Non-ischemic myocardial tissue was identified using gold microsphere distribution and analyzed using immunoblotting, immunofluorescence, and hemodynamic assessment. Statistical significance was evaluated using Student's 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, AIF, BAD; p < 0.05) and increased pBAD/BAD ratios. Pro-survival signaling was enhanced with elevated pAKT/AKT, pmTOR/mTOR, and pAMPK/AMPK ratios (p < 0.05). TUNEL staining confirmed decreased apoptosis histologically. Functionally, MET improved cardiac output, stroke volume, and dV/dt Max in the myocardium (p < 0.05), correlating with reductions in apoptotic signaling.

Conclusions: MET was associated with significantly reduced apoptosis and promoted pro-survival signaling in non-ischemic 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 CAD and MS, including as an adjunct in cardiac surgery.