Background: Hibernating myocardium is viable, persistently dysfunctional myocardium that occurs in response to continuing or repetitive myocardial 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 and (b) we test the success of such surgery in recovering myocardial function using physiologic and proteomic approaches. Surgical revascularization of chronically ischemic myocardium with survival has never been studied in an animal model and so it has significant implications in understanding heart failure and the potential for recovery. Methods: In a swine model of hibernating myocardium, surgical revascularization (vesus sham operation) will be performed using the left internal mammary artery to bypass the chronically obstructed left anterior descending artery using a beating heart, off-pump technique, which is identical to the clinical technique. At 12 and 20 weeks, a prebypass and postbypass multi-detector computer tomography (MDCT) and transthoracic echocardiogram (TTE) in both groups will be obtained to determine LIMA patency, recovery of regional wall thickening, and recovery of subendocardial perfusion. Also, studies of the recovery induced by surgical revascularization of hibernating myocardial blood flow, mitochondrial bioenergetics and protein alterations are simultaneous analyzed at the terminal study to more accurately understand the spectrum of myocardial functional recovery. Proteomic mitochondrial responses following revascularization will be compared to the control group of chronic ischemia (hibernation) using, western blot analysis and proteomic analysis [isobaric Tags for Relative and Absolute Quantification (iTRAQ)].
Aims :
The aim of this study is to understand the changes that are induced upon the hibernating myocardium of the swine model when it is successfully surgically revascularized. In this model we will evaluate whether surgical revascularization normalizes regional blood flow at rest and with increased work load (dobutamine stress) by measuring blood flow (microsphere analysis) and cardiac function (2D ECHO, MDCT).
A second aim i s to understand the alteration in the oxygen consumption of the hibernating myocardium following revascularization. We will evaluate this aim by comparing the bioenergic state of the revascularized myocardium to the hibernating myocardium, quantifying the proteomic changes in the mitochondria of both groups and evaluating enzymatic protein activity as directed by the proteomic changes. 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 proteomics 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 mechanisms of hibernating myocardium to restore complete and reliable myocardial function and mitochondrial bioenergetics following the reestablishing blood flow through coronary revascularization remain unknown and require study.

Public Health Relevance

Patients with episodic chest pain prior to a heart attack suffer less damage to the heart than individuals presenting with the same type of heart attack but without prior warning attacks. The warning attacks, called angina, indicate that the heart is transiently stressed by increased work load demands, by spasm or fluctuating thrombosis in one of the arteries prior to its complete closure. These periods of increased demand or of decreased blood flow stimulate the heart to adapt favorably to a more prolonged episode of oxygen deprivation. This concept, referred to as the """"""""smart heart,"""""""" relies on alterations in the energy producing parts of the heart cells, the mitochondria. We propose that mitochondria in chronically ischemic heart cells have acquired protection against low blood flow. By performing a surgical operation to resupply blood to the heart, our research will test whether these adaptations to ischemia are reversible and allow the heart to return to normal function, or if the adaptations are permanent.

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Veterans Affairs (VA)
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Cardiovascular Studies A (CARA)
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Minneapolis VA Medical Center
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Hocum Stone, Laura; Wright, Christin; Chappuis, Erin et al. (2018) Surgical Swine Model of Chronic Cardiac Ischemia Treated by Off-Pump Coronary Artery Bypass Graft Surgery. J Vis Exp :
Hocum Stone, Laura L; Swingen, Cory; Holley, Christopher et al. (2017) Magnetic resonance imaging assessment of cardiac function in a swine model of hibernating myocardium 3 months following bypass surgery. J Thorac Cardiovasc Surg 153:582-590
Swingen, Cory; Hocum Stone, Laura; Kelly, Rosemary F (2017) Cardiac magnetic resonance imaging for ischemic mitral regurgitation: A guide through complex surgical terrain. J Thorac Cardiovasc Surg 154:159-160
Butterick, Tammy A; Hocum Stone, Laura; Duffy, Cayla et al. (2016) Pioglitazone increases PGC1-? signaling within chronically ischemic myocardium. Basic Res Cardiol 111:37
Hocum Stone, Laura; Butterick, Tammy A; Duffy, Cayla et al. (2016) Cardiac Strain in a Swine Model of Regional Hibernating Myocardium: Effects of CoQ10 on Contractile Reserve Following Bypass Surgery. J Cardiovasc Transl Res 9:368-73
Holley, Christopher T; Long, Eric K; Butterick, Tammy A et al. (2015) Mitochondrial fusion proteins in revascularized hibernating hearts. J Surg Res 195:29-36
Holley, Christopher T; Duffy, Cayla M; Butterick, Tammy A et al. (2015) Expression of uncoupling protein-2 remains increased within hibernating myocardium despite successful coronary artery bypass grafting at 4 wk post-revascularization. J Surg Res 193:15-21
Holley, Christopher T; Long, Eric K; Lindsey, Megan E et al. (2015) Recovery of hibernating myocardium: what is the role of surgical revascularization? J Card Surg 30:224-31
Colbert, Robert W; Holley, Christopher T; Stone, Laura Hocum et al. (2015) The Recovery of Hibernating Hearts Lies on a Spectrum: from Bears in Nature to Patients with Coronary Artery Disease. J Cardiovasc Transl Res 8:244-52
Cabrera, Jesús A; Butterick, Tammy A; Long, Eric K et al. (2013) Reduced expression of mitochondrial electron transport chain proteins from hibernating hearts relative to ischemic preconditioned hearts in the second window of protection. J Mol Cell Cardiol 60:90-6

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