Surgical Revascularization's Impact on Hibernating Myoacrdium

描述(由申请人提供)： 背景：冬眠心肌是一种存活的、持续功能不全的心肌，可因持续或反复的缺血而发生反应，其特点是低灌注量而无坏死迹象。本课题组已成功建立了一种可复制的猪冬眠心肌模型，并对该模型进行了广泛的研究。作为这项工作的延伸，我们现在已经建立了一种新的方法，通过该方法：(A)我们进行存活的非体外循环单血管搭桥手术以重建缺血心肌，(B)我们测试血管重建后冬眠心肌恢复的时间进程，以及(C)我们测试补充已知的心脏保护剂辅酶Q10(CoQ10)作为血运重建后恢复的辅助作用的有效性。方法：在猪冬眠心肌模型上，采用心脏不停跳非体外循环技术，利用左乳内动脉(LIMA)绕过慢性闭塞的左前降支(LAD)，进行外科血运重建(与假手术比较)。在12周和16周时，分别进行搭桥前后多层计算机断层扫描(MDCT)和核磁共振成像(MRI)检查，以确定LIMA的通畅率、局部室壁增厚的恢复情况、心内膜下血流灌注的恢复情况和收缩功能。此外，冬眠手术血运重建引起的恢复研究包括心肌血流量、线粒体生物能量学和呼吸以及蛋白质变化，这些将在末期研究中同时进行分析，以更准确地了解心肌功能恢复的频谱。目的：本研究的目的是描述成功血管重建术后冬眠心肌恢复的时间进程。此外，这项研究将考察辅酶Q10形式的药物干预的可能性。本研究将评估血管重建术和辅酶Q10对线粒体功能、蛋白表达和抗氧化状态的影响，以及对心脏应变、射血分数和局部血流量等生理参数的改善。结论：冬眠心肌潜在恢复的临床认识受限于缺乏合适的动物模型来识别和测试预测手术益处的所谓标记物。对冬眠的适应是复杂的，涉及线粒体的生物能量学和蛋白质组的变化，使组织在牺牲心肌功能的同时保持其生存能力。冬眠心肌似乎对持续的缺血应激有动态的蛋白质组反应，这与晚期心力衰竭时能量底物代谢和功能的全球变化有相似之处。这些蛋白质组学变化可能限制氧化损伤和细胞凋亡，并影响血管重建后的功能恢复。我们认为冬眠心肌是一种促进生存的适应，但以收缩为代价。临床上，冬眠心肌血运重建可导致从功能几乎完全恢复到致密梗死的广泛预后。血运重建后恢复的时间进程以及药物干预的效果尚未确定，心脏恢复的机制仍不清楚。

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.