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Metformin Preconditioning Attenuates Apoptosis and Augments Cardiac Function in a Large Animal Model of Chronic Myocardial Ischemia
*Christopher R. Stone, *Dwight D. Harris, *Sharif Sabe, *Mark Broadwin, *Meghamsh Kanuparthy, *M. Ruhul Abid, Frank Sellke
Cardiothoracic Surgery, Brown University, Providence, RI

Objective: Although surgical and endovascular revascularization are durably efficacious for many patients with chronic myocardial ischemia (CMI), up to one-third of patients are poor candidates for these standard therapies. For such patients, many of whom are afflicted with the multiple comorbidities referred to as metabolic syndrome (MS), there is an urgent need to elucidate novel therapeutic mechanisms. Extracellular vesicle (EV) therapy has been shown to be efficacious in this context, improving cardiac output, augmenting blood flow, and fostering angiogenesis in the ischemic myocardium in a high-fidelity large animal model of CMI. These effects are attenuated, however, in the presence MS. Accordingly, we sought to determine whether pretreatment with metformin could ameliorate the therapeutic decrement associated with MS. Methods: Yorkshire swine aged 5-6 weeks (n=29) were administered a high-fat diet for four weeks in accordance with a regimen shown to effectively induce MS, whereupon a mini-thoracotomy was performed for ameroid constrictor placement around the left circumflex coronary artery to induce CMI. Over the succeeding two weeks, animals were given either 500 mg PO metformin BID or placebo; all then underwent a repeat mini-thoracotomy for injection of either bone marrow-derived EVs or saline. This sequence ultimately generated four animal groups: placebo+saline controls (CON, n=6), placebo+EVs (EV, n=8), metformin+saline (MET, n=7), and metformin+EVs (MEV, n=8). Swine were maintained thereafter for five weeks before acquisition of functional and perfusion data through use of pressure-volume catheter placement and transduction immediately prior to terminal myocardial harvest. Immunoblotting was utilized on tissue lysates derived from the most ischemic myocardial sections of animals from all groups, as delineated by microsphere distribution studies; markers of apoptosis were probed. To characterize apopotosis histologically, ischemic myocardial sections were subjected to TUNEL staining. Results: Compared with control animals, those administered metformin experienced a significant augmentation in left ventricular ejection fraction, both at rest (EF, p=0.0255) and when externally paced at 150 beats per minute (p=0.0289). While there were no differences in caspase 3 or 9 expression between groups, apoptosis-inducing factor was significantly decreased in both metformin and metformin+EV groups (p=0.0063 and p=0.0261, respectively). TUNEL staining mirrored these latter changes, with immunofluorescent intensity markedly decreased in both aforementioned metformin groups (p=0.0004 and p=0.0200, respectively). Conclusions: Metformin preconditioning reduces apoptotic cell death in the chronically ischemic myocardium of a porcine model of metabolic syndrome. The promise possessed by metformin as a therapeutic agent in this context is further supported by concomitant improvements in the ejection fraction of treated aniamals.


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