AMP-Dependent Protein Kinase Activators

A patent inability to properly use glycolytic and fatty acid substrates and progressive insulin resistance characterize non–insulin dependent diabetes mellitus. Curiously, the failing myocardium may also share these unfavorable characteristics. Insights from the clinical arena indicate a significant relationship between insulin resistance and New York Heart Association heart failure classification.1 In fact, insulin resistance may beget heart failure and heart failure may beget insulin resistance.2 Fueled by a recent resurgence in studies of the metabolic derangements contributing to cardiovascular disease, we are beginning to comprehend the complexities of metabolism or at least appreciate the bounds of our ignorance. Our understanding of such issues surrounding diabetes and heart failure is predicated on identifying the proximal regulators of substrate availability, sensing, and utilization. One potentially satisfying candidate appears to be AMPdependent protein kinase (AMPK)3,4 and is the focus of the study by Gundewar et al in this issue of Circulation Research.5 AMPK has emerged as a principal figure in the story of metabolic regulation and dysregulation in diabetes, exercise, and, to a lesser extent, myocardial ischemia. AMPK activation appears to be beneficial in the context of myocardial ischemia and reperfusion, at least in terms of infarct size reduction. Such findings are confirmed by the present5 and previous studies.6 However, the intriguing element of the present study5 is the significant effect of chronic, postischemic treatment with the AMPK-activating biguanide metformin in the context of the failing heart (Figure). Despite a prior contraindication for heart failure because of concerns about the generation of lactic acidosis, interest has been renewed (although it actually never waned for some determined investigators) for the potential use of the insulin “sensitizer” metformin in diabetics with heart failure. Such interest is based not simply on the pretext that metformin should mitigate the severity of the diabetic endocrine defect. Again, there may be significant interplay between diabetes and heart failure with common ground in the insulin resistant heart. A recently initiated and ongoing clinical trial (TAYSIDE) is directed at understanding the precise role of metformin treatment in the failing, insulin-resistant heart (ClinicalTrials.gov identifier NCT00473876). In the present study,5 the authors evaluate the efficacy of metformin in attenuating the severity of infarct-induced heart failure in reperfused and nonreperfused nondiabetic mouse models. So, how does metformin promote such beneficial effects during experimental myocardial infarction and heart failure? Metformin exerts an infarct sparing effect, even if given at reperfusion, and seems to require an AMPK–endothelial nitric oxide synthase (eNOS) axis.6 One might argue that reduction of infarct size would be sufficient to improve long-term cardiac function, but the data of the authors do not support such a contention. First, the data from the nonreperfused model show no difference in infarct size, yet, a significant improvement in survival. Second, the reperfused model shows a significant reduction in infarct size with a single early reperfusion dose of metformin without any functional improvements after four weeks. In additional groups of mice, daily postischemic metformin treatment significantly improved cardiac function at four weeks. This tells us that infarct size reduction in the murine model may not necessarily predict chronic improvements in cardiac function but, more importantly, that metformin can improve cardiac function in a nondiabetic and dysfunctional heart. One question that remains unanswered is how metformin activates AMPK. Others have demonstrated the pharmacological capacity of metformin to impair complex I in the mitochondria.7,8 Such an effect might elevate cytosolic AMP levels and consequently enable activation of AMPK by an upstream kinase, although others have proposed unrelated mechanisms of AMPK activation by metformin.9 What is clear from the present study is the obligatory nature of intact AMPK activity to generate the benefits of metformin in the failing heart. The specific requirement of cardiac AMPK suggests that the relevant effects of metformin may not be entirely systemic in the present in vivo model. Metformin treatment could improve cardiac metabolism thereby improving cardiac function and potentially do so in the absence of extracardiac effects. Mitochondria isolated from infarcted, metformin-treated hearts respiring on succinate produced more ATP at a lower oxygen cost than vehicle, consistent with improved coupling of oxidative phosphorylation. It is not clear why the metformin mitochondria were more efficient than the vehicle group, but the finding that PGC-1 was elevated yields at least one clue. Based on work from Kelly and colleagues10 and Spiegelman and colleagues,11 we know that deficiency of PGC-1 exacerbates the development of heart failure in mice and that PPAR/PGC activities are largely reduced in heart failure. In the study by Gundewar et al,5 the authors find that chronic metformin therapy boosts PGC-1 levels while improving ventricular function. Although the The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the Institute of Molecular Cardiology, University of Louisville, Ky. Correspondence to Steven P. Jones, PhD, Institute of Molecular Cardiology, University of Louisville, 580 S Preston St, Baxter II–404C, Louisville, KY 40202. E-mail [email protected] (Circ Res. 2009;104:282-284.) © 2009 American Heart Association, Inc.