Surgical Revascularization's Impact on Hibernating Myoacrdium

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DESCRIPTION (provided by applicant): Background: Hibernating myocardium is viable, persistently dysfunctional myocardium that occurs in response to continuing or repetitive ischemia and is characterized by hypoperfusion without evidence of necrosis. Our group has successfully established a reproducible swine model of hibernating myocardium and has studied this model extensively. As an extension of this work, we have now established a novel method whereby (a) we perform off-pump single vessel bypass surgery with survival to revascularize ischemic myocardium, (b) we test the time course of recovery from hibernating myocardium following revascularization, and (c) we test the efficacy of supplementation with coenzyme Q10 (CoQ10), a known cardioprotectant, as an aid to recovery following revascularization. Methods: In a swine model of hibernating myocardium, surgical revascularization (versus sham operation) will be performed using the left internal mammary artery (LIMA) to bypass the chronically obstructed left anterior descending (LAD) artery using a beating heart, off-pump technique, which is identical to the clinical technique. At 12 and 16 weeks, a prebypass and postbypass multi-detector computer tomography (MDCT) and magnetic resonance imaging (MRI) will be obtained to determine LIMA patency, recovery of regional wall thickening, recovery of subendocardial perfusion, and contractile function. Also, studies of the recovery induced by surgical revascularization of hibernating include myocardial blood flow, mitochondrial bioenergetics and respiration, and protein alterations, which will be simultaneously analyzed at the terminal study to more accurately, understand the spectrum of myocardial functional recovery. Aims: The aim of this study is to characterize the time course of recovery from hibernating myocardium following successful revascularization. Furthermore, this study will examine the potential for pharmacological intervention in the form of coenzyme Q10. This study will evaluate the effects of revascularization and CoQ10 on mitochondrial function, protein expression, and antioxidant status as well as improvement of physiological parameters such as cardiac strain, ejection fraction, and regional blood flow. Conclusion: Clinical understanding of potential recovery of hibernating myocardium is limited by the lack of an appropriate animal model to identify and test alleged markers predicting benefit with surgery. Adaptations to hibernation are complex and involve alterations in the bioenergetics and proteome of the mitochondria that allow the tissue to maintain its viability while sacrificing myocardial function. Hibernating myocardium appears to have dynamic proteomic responses to persistent ischemic stress, which has similarities to the global changes in energy substrate metabolism and function seen in advanced heart failure. These proteomic changes may limit oxidative injury and apoptosis and impact functional recovery after revascularization. We believe that hibernating myocardium is an adaptation to promote survival but at the expense of contractility. Clinically, revascularization of hibernating myocardium results in a wide spectrum of outcomes from near total recovery of function to dense infarction. The time course of recovery following revascularization as well as the efficacy of pharmacological intervention have not been characterized and the mechanisms by which the heart recovers remain unknown.