The critical role of the coronary microcirculation in heart failure

冠状动脉微循环在心力衰竭中的关键作用

• 批准号: 9383841
• 负责人: WILLIAM M CHILIAN
• 金额: $ 45.63万
• 依托单位: NORTHEAST OHIO MEDICAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9383841
• 关键词: Address; Adrenergic Antagonists; Apoptosis; Area; Blood flow; Cardiac; Cardiac Myocytes; Caring; Cell Death; Cells; Cessation of life; Congestive; Contractile Proteins; Coronary; Coupling; Deterioration; Development; Disease; Disease Progression; Doxycycline; Electron Spin Resonance Spectroscopy; Evaluation; Failure; Fatty Acids; Goals; Health; Heart; Heart failure; Hypoxia; Impairment; Infarction; Inflammation; Injury; Intervention; Knockout Mice; Laboratories; Lead; Long-Term Effects; Measurement; Measures; Metabolic; Metabolism; Microcirculation; Microscopic; Modeling; Mus; Muscle Cells; Mutation; Myocardial; Myocardial Infarction; Myocardial Ischemia; Myocardial dysfunction; Myocardial perfusion; Myocarditis; Myocardium; Outcome; Perfusion; Pharmacology; Plasma; Play; Positron-Emission Tomography; Principal Investigator; Regulation; Role; Smooth Muscle; Societies; Structural Protein; Sudden Death; Testing; Thinking; Time; Tissues; Troponin I; Vasodilation; Vasodilator Agents; Ventricular Function; Wild Type Mouse; Work; cardiogenesis; constriction; conventional therapy; design; experimental study; gene therapy; glucose metabolism; heart metabolism; in vivo; prevent; therapy design; tissue oxygenation

The goal of this proposal is to test the hypothesis that impaired regulation of the coronary microcirculation— more specifically, an inadequate connection between coronary blood flow and the metabolic needs of the myocardium—underlies the development of some types of heart failure (HF). The sequence we propose is that impaired coupling between coronary blood flow and cardiac work results in minute areas of hypoxia in cardiac myocytes, which induces apoptosis in small numbers of cardiac myocytes. Over time these minute areas of tissue death accumulate to an extent that cardiac function is compromised. Current treatments for heart failure are designed to reduce cardiac work, but not directly produce coronary vasodilation. None of these therapies stop or reverse the progression of the disease—progression is only slowed. We speculate that the reason these treatments do not stop or reverse the progression of the disease is that they are not targeting the causal problem of insufficient blood flow to the heart. We propose that by correcting the myocardial perfusion deficiencies in heart failure, we will stop and potentially reverse the progression of heart failure. We propose two aims. Aim 1 will determine if impaired regulation of myocardial blood flow, i.e., inadequate coupling of flow to metabolism, plays a critical role in the development of heart failure. In this aim we will measure myocardial perfusion, plasma BNP and cardiac troponin I, tissue oxygenation, cardiac metabolism and cardiac myocyte hypoxia (using hypoxia fate mapping) and myocyte apoptosis in the murine transaortic constriction model of heart failure. Measurements will be made at various points during the progression of the disease and in wild type mice and mice with an impairment in myocardial blood flow (Kv1.5 null mice). These measurements will enable precise evaluation of failure and also whether myocardial ischemia occurs during heart failure. Aim 2 will analyze if the progression of heart failure can be stopped or reversed by increasing blood flow to the heart. In this aim we will increase blood flow to the heart by increasing expression of Kv1.5 channels in smooth muscle or will administer a pharmacological vasodilator at varying times during the progression of the disease. We will compare these interventions to one of the current standards of care for heart failure (beta1-adrenergic antagonist). We will establish if increases in myocardial blood flow to the heart can stop, and/or reverse, the progression of heart failure resulting in a better outcome than the conventional therapy. This application builds upon the expertise of the Principal Investigator, and that of additional laboratories via subcontracts enabling corroborative, interdisciplinary measurements to definitely test whether subtle levels of myocardial ischemia lead to heart failure and if therapies that increase flow to the heart hold promise as a cure.

这项提议的目标是检验这样一种假设，即冠状动脉微循环调节受损- 更具体地说，冠脉血流和代谢需求之间的联系不充分 心肌--是某些类型心力衰竭(HF)发生的基础。我们提出的顺序是 冠脉血流和心脏做功之间的偶联受损导致心脏微小缺氧区 心肌细胞，可诱导少量心肌细胞的凋亡。随着时间的推移，这些微小的区域 组织死亡累积到心脏功能受损的程度。目前心力衰竭的治疗方法 旨在减少心脏做功，但不直接产生冠状动脉血管扩张。所有这些疗法都不是 阻止或逆转疾病的进展-进展只是缓慢。我们推测原因是 这些治疗方法不能阻止或逆转疾病的发展，因为它们不是针对病因 流向心脏的血液不足的问题。我们建议通过校正心肌灌注 在心力衰竭的缺陷中，我们将停止并有可能逆转心力衰竭的进展。我们建议 两个目标。目标1将确定心肌血流调节受损，即血流耦合不足 对新陈代谢，在心力衰竭的发展中起着至关重要的作用。在这个目标中，我们将测量心肌 灌注、血浆BNP和心肌肌钙蛋白I、组织氧合、心脏代谢和心肌细胞 低氧(利用低氧命运图)与小鼠经主动脉缩窄模型中的心肌细胞凋亡 心力衰竭。将在疾病发展过程中的不同时间点和在野外进行测量 型小鼠和心肌血流量受损的小鼠(Kv1.5缺失小鼠)。这些测量结果将 能够准确地评估心力衰竭以及心力衰竭期间是否发生心肌缺血。目标2 将分析是否可以通过增加流向心脏的血液来阻止或逆转心力衰竭的进展。 在这个目标中，我们将通过增加Kv1.5通道的表达来增加流向心脏的血流量 在疾病发展的不同时期，肌肉或将给予药物血管扩张剂。 我们将把这些干预措施与目前心力衰竭护理标准之一(β1-肾上腺素能)进行比较 拮抗者)。我们将确定流向心脏的心肌血流量增加是否可以阻止和/或逆转 心力衰竭的进展导致比传统治疗更好的结果。此应用程序构建 根据首席调查员的专业知识，以及通过分包合同增加实验室的专业知识， 确凿的、跨学科的测量，以确定心肌缺血的细微程度 会导致心力衰竭，如果增加流向心脏的治疗方法有望治愈。