Surgical Revascularization's Impact on Hibernating Myoacrdium

血运重建手术对冬眠心肌的影响

• 批准号: 9357365
• 负责人: EDWARD O. MCFALLS
• 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/9357365
• 关键词: Aldehydes; Animal Model; Anterior; Antioxidants; Apoptosis; Arteries; Biochemical Markers; Bioenergetics; Blood; Blood flow; Bypass; Cardiac; 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; 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; Pharmacology; Physiological; Process; Proteins; Proteome; Proteomics; Pump; Recovery; Recovery of Function; Regional Blood Flow; Reperfusion Therapy; Reproducibility; Research; Respiration; Risk; Spasm; Stress; Study models; Sudden Death; Superoxide Dismutase; Supplementation; Techniques; Testing; Thrombosis; Time; Tissue Viability; 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; predictive marker; protein expression; protein transport; 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）： 背景资料：冬眠心肌是存活的、持续性功能障碍的心肌，其发生是对持续或重复缺血的反应，其特征是灌注不足而无坏死证据。本课题组成功地建立了一种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，我们现在已经建立了一种新的方法，其中（a）我们进行非体外循环单血管旁路手术，使缺血心肌再血管化，（B）我们测试了再血管化后从冬眠心肌恢复的时间过程，（c）我们测试了补充辅酶Q10（CoQ10）（一种已知的心脏保护剂）作为再血管化后恢复的辅助手段的功效。研究方法：在冬眠心肌的猪模型中，将使用左乳内动脉（LIMA）进行外科血运重建（与假手术相比），以使用跳动心脏、非体外循环技术（与临床技术相同）绕过慢性阻塞的左前降支（LAD）动脉。在第12周和第16周，将获得旁路手术前和旁路手术后的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、局部室壁增厚的恢复、内膜下灌注的恢复和收缩功能。此外，冬眠手术血运重建诱导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改变，这些研究将在终末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，这项研究将研究辅酶Q10形式的药理学干预的潜力。这项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：由于缺乏合适的动物模型来识别和测试所谓的预测手术获益的标志物，对冬眠心肌潜在恢复的临床理解受到限制。适应冬眠是复杂的，涉及线粒体的生物能量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缺血应激有动态蛋白质组学反应，这与晚期心力衰竭中能量底物代谢和功能的整体变化相似。这些蛋白质组学变化可能限制氧化损伤和细胞凋亡，并影响血运重建后的功能恢复。我们认为冬眠心肌是一种以牺牲心肌收缩力为代价的生存适应。临床上，冬眠心肌的血运重建可导致广泛的结局，从功能几乎完全恢复到致密梗死。血运重建后恢复的时间过程以及药物干预的疗效尚未得到表征，心脏恢复的机制仍然未知。

项目成果

Recovery of hibernating myocardium: what is the role of surgical revascularization?

冬眠心肌的恢复：血运重建手术的作用是什么？

• DOI: 10.1111/jocs.12477
• 发表时间: 2015
• 期刊: Journal of cardiac surgery
• 影响因子: 1.6
• 作者: Holley,ChristopherT;Long,EricK;Lindsey,MeganE;McFalls,EdwardO;Kelly,RosemaryF
• 通讯作者: Kelly,RosemaryF

Hibernating myocardium: is the program to survive a pathway to failure?

冬眠的心肌：生存程序是否会走向失败？

• DOI: 10.1161/circresaha.107.168278
• 发表时间: 2008
• 期刊: Circulation research
• 影响因子: 20.1
• 作者: Kelly,RosemaryF;Sluiter,Wim;McFalls,EdwardO
• 通讯作者: McFalls,EdwardO

Recovery of hibernating myocardium using stem cell patch with coronary bypass surgery.

使用干细胞补片和冠状动脉搭桥手术恢复冬眠心肌。

• DOI: 10.1016/j.jtcvs.2019.12.073
• 发表时间: 2021
• 期刊: The Journal of thoracic and cardiovascular surgery
• 作者: HocumStone,LauraL;Swingen,Cory;Wright,Christin;Qi,StevenS;Rassette,Matt;McFalls,EdwardO;Kelly,RosemaryF
• 通讯作者: Kelly,RosemaryF

Magnetic resonance imaging assessment of cardiac function in a swine model of hibernating myocardium 3 months following bypass surgery.

磁共振成像评估搭桥手术后 3 个月冬眠心肌猪模型的心脏功能。

• DOI: 10.1016/j.jtcvs.2016.10.089
• 发表时间: 2017
• 期刊: The Journal of thoracic and cardiovascular surgery
• 作者: HocumStone,LauraL;Swingen,Cory;Holley,Christopher;Wright,Christin;Chappuis,Erin;Ward,HerbertB;McFalls,EdwardO;Kelly,RosemaryF
• 通讯作者: Kelly,RosemaryF

Cardiac Strain in a Swine Model of Regional Hibernating Myocardium: Effects of CoQ10 on Contractile Reserve Following Bypass Surgery.

猪区域冬眠心肌模型中的心脏应变：CoQ10 对搭桥手术后收缩储备的影响。

• DOI: 10.1007/s12265-016-9696-y
• 发表时间: 2016
• 期刊: Journal of cardiovascular translational research
• 影响因子: 3.4
• 作者: HocumStone,Laura;Butterick,TammyA;Duffy,Cayla;Swingen,Corey;Ward,HerbertB;Kelly,RosemaryF;McFalls,EdwardO
• 通讯作者: McFalls,EdwardO