Abstract 12911: Metformin Preserves ATP Concentration, Attenuates Action Potential Shortening, and Prevents Ventricular Fibrillation During Low-flow Ischemia in Normal Hearts
Introduction: Metformin (MET) is the most common drug used to treat type 2 diabetes, in part because it is believed to reduce cardiovascular mortality. However, it is unknown whether MET provides protection from ischemic ventricular fibrillation (VF) in the normal heart. In a region of ischemic myocardium, reduced energy charge causes ATP-sensitive potassium channels to open, shortening the action potential (AP). The resulting dispersion of AP duration and refractoriness may predispose to VF. We determined effects of MET on myocardial ATP concentration, AP, and VF during regional ischemia in metabolically normal pigs.
Methods: Normal domestic pigs were treated with a clinically relevant dose of MET (30 mg/kg/d, n=25) for 2-3 weeks and compared with untreated controls (CTL, n=23). Under anesthesized, open-chest conditions, phospho-AMP activated protein kinase (pAMPK, Thr172) was measured in myocardial biopsies taken before ischemia (n=8 each group). Low-flow ischemia was induced by 50% LAD flow reduction. [ATP] was measured in myocardial biopsies at 15 min ischemia (MET n=8, CTL n=7). Monophasic AP was recorded at baseline and at 15 min ischemia. Survival free of VF was observed during 90 min of ischemia and 45 min reperfusion.
Results: pAMPK was 85% greater in MET than in CTL (p<0.001), establishing a myocardial effect of MET prior to ischemia. MET had no effect on non-ischemic AP duration. At 15 min ischemia, [ATP] was higher in MET than CTL (4.1 vs 3.5 μmol/g, p=0.039), with less AP shortening from baseline in MET (4±2%) than in CTL (13±2%, p<0.001). Survival free of VF was greater in MET pigs than CTL (Figure).
Conclusions: Chronic treatment with a clinically relevant dose of MET activates AMPK, preserves [ATP] and prevents AP shortening during ischemia, and diminishes the propensity for ischemic VF in metabolically normal pigs. Based on these findings, MET may have therapeutic utility beyond type 2 diabetes, extending to ischemic protection of the normal heart.
Author Disclosures: G.G. Schwartz: None. L. Lu: None. S. Ye: None. C.R. Greyson: None.
- © 2015 by American Heart Association, Inc.