Surgical Revascularization's Impact on Hibernating Myoacrdium

血运重建手术对冬眠心肌的影响

• 批准号: 8734738
• 负责人: Rosemary Frances Kelly
• 金额: --
• 依托单位: MINNEAPOLIS VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8734738
• 关键词: Aldehydes; Animal Model; Anterior; Antioxidants; Apoptosis; Arteries; Biochemical Markers; Bioenergetics; Blood; Blood flow; Bypass; Cardiac; Carrier Proteins; Chest Pain; Chronic; Clinical; Coenzyme Q10; Complex; Computers; Coronary Arteriosclerosis; Coronary Artery Bypass; EFRAC; Electron Transport; Electrons; Family suidae; Global Change; Heart; Heart failure; Hibernation; Individual; Infarction; Injury; Intervention; Ischemia; Lead; Left; Lipids; Magnetic Resonance Imaging; Metabolism; Methods; Mitochondria; Modeling; Morphology; Myocardial; Myocardial Infarction; Myocardial Ischemia; Myocardium; Necrosis; Operative Surgical Procedures; Outcome; Oxidants; Oxidative Stress; Oxygen; Oxygen Consumption; Patients; Perfusion; Physiological; Process; Proteins; Proteome; Proteomics; Pump; Recovery; Recovery of Function; Regional Blood Flow; Reperfusion Therapy; Research; Respiration; Risk; Spasm; Stress; Study models; Sudden Death; Superoxide Dismutase; Supplementation; Techniques; Testing; Thrombosis; Time; Tissues; UCP2 protein; Work; Workload; aldehyde dehydrogenases; deprivation; detector; efficacy testing; experience; glutathione peroxidase; heart cell; hypoperfusion; improved; internal thoracic artery; novel; operation; oxidant stress; protein expression; public health relevance; response; tomography

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.

描述（由申请人提供）： 背景：冬眠心肌是一种存活的、持续功能障碍的心肌，是对持续或反复缺血的反应，其特征是灌注不足，但没有坏死的证据。我们课题组成功建立了可重复的猪冬眠心肌模型，并对该模型进行了广泛的研究。作为这项工作的延伸，我们现在建立了一种新方法，通过该方法（a）我们进行非体外循环单血管搭桥手术以对缺血性心肌进行血运重建，（b）我们测试血运重建后从冬眠心肌中恢复的时间过程，以及（c）我们测试补充辅酶 Q10（CoQ10）（一种已知的心脏保护剂）作为术后恢复辅助手段的功效 血运重建。方法：在猪冬眠心肌模型中，使用左内乳动脉（LIMA）通过心脏跳动、非体外循环技术绕过长期阻塞的左前降支（LAD）进行外科血运重建（与假手术相比），这与临床技术相同。在第 12 周和第 16 周时，将进行搭桥前和搭桥后多探测器计算机断层扫描 (MDCT) 和磁共振成像 (MRI)，以确定 LIMA 通畅性、区域壁增厚的恢复、心内膜下灌注的恢复和收缩功能。此外，对冬眠手术血运重建引起的恢复的研究包括心肌血流、线粒体生物能和呼吸以及蛋白质改变，这些将在最终研究中同时进行分析，以更准确地了解心肌功能恢复的范围。目的：本研究的目的是描述成功血运重建后冬眠心肌恢复的时间过程。此外，本研究将探讨辅酶 Q10 进行药物干预的潜力。本研究将评估血运重建和辅酶 Q10 对线粒体功能、蛋白质表达和抗氧化状态以及心脏应变、射血分数和局部血流等生理参数改善的影响。结论：由于缺乏合适的动物模型来识别和测试预测手术获益的所谓标志物，对冬眠心肌潜在恢复的临床理解受到限制。对冬眠的适应是复杂的，涉及线粒体生物能学和蛋白质组的改变，使组织在牺牲心肌功能的同时保持其活力。冬眠心肌似乎对持续性缺血应激具有动态蛋白质组反应，这与晚期心力衰竭中看到的能量底物代谢和功能的整体变化相似。这些蛋白质组变化可能限制氧化损伤和细胞凋亡，并影响血运重建后的功能恢复。我们认为，冬眠心肌是一种促进生存的适应，但以牺牲收缩力为代价。临床上，冬眠心肌的血运重建会导致多种结果，从功能几乎完全恢复到致密梗塞。血运重建后恢复的时间过程以及药物干预的功效尚未确定，心脏恢复的机制仍不清楚。