Effect of Mitral Regurgitation on Ischemic LV Remodeling

二尖瓣反流对缺血性左室重构的影响

• 批准号: 7784799
• 负责人: ROBERT A LEVINE
• 金额: $ 46.62万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-15 至 2013-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7784799
• 关键词: ATP phosphohydrolase; Address; Adult; Affect; Animals; Anterior; Apical; Apical Myocardial Infarction; Apoptosis; Apoptotic; Area; Biphasic Pattern; Calcium; Cardiac; Cardiac Myocytes; Cardiomegaly; Cardiopulmonary Bypass; Cell Survival; Cellular Morphology; Clinical; Complication; Congestive Heart Failure; Coronary; Data; Dilatation - action; Extracellular Matrix; Failure; Fibrosis; Financial compensation; Functional disorder; Gene Delivery; Gene Transfer; Gene Transfer Techniques; Grant; Heart; Heart failure; Hypertrophy; Image; Infarction; Inferior; Inferior Myocardial Infarction; Infusion procedures; Intention; Intervention; Laboratories; Lead; Left; Left Ventricular Dysfunction; Left Ventricular Function; Left Ventricular Remodeling; Mechanics; Methods; Mitral Valve Insufficiency; Modeling; Modification; Molecular; Molecular Biology; Myocardial Infarction; Myocardial Ischemia; Myocardium; Natural History; Nitroglycerin; Pathway interactions; Patients; Phase; Phenotype; Postoperative Period; Process; Progress Reports; Public Health; Publishing; Recovery; Recovery of Function; Recurrence; Relative (related person); Research; Resources; SERCA2a; Sarcoplasmic Reticulum; Sheep; Shunt Device; Signal Pathway; Signal Transduction; Standardization; Stress; Surface; Surgical Models; Techniques; Testing; Time; Transgenic Organisms; Translating; Up-Regulation; Ventricular; Work; base; clinically relevant; exhaust; exhaustion; improved; mortality; myocardial infarct sizing; new therapeutic target; outcome forecast; overexpression; public health relevance; repaired; research study; response; therapeutic target

DESCRIPTION (provided by applicant): Mitral regurgitation (MR) is a frequent complication of myocardial infarction (MI) and left ventricular (LV) dysfunction that doubles mortality, but the survival benefit of standard annular ring reduction therapy is intensely debated. LV remodeling often progresses after ring reduction, causing recurrent MR. We must therefore resolve in a controlled fashion whether MR contributes to remodeling; whether the benefit of repair is limited by being typically late; and why aggressive remodeling continues post-repair. In the initial grant period, we developed an apical MI model (no intrinsic MR) with standardized MR-type flow through an LV-to-LA shunt. In that sheep model, moderate MR flow typical of post-MI patients strongly increased LV remodeling at the whole-heart, cellular and molecular levels versus MI or MR alone, with a biphasic pattern of failed attempts at compensation (rise, then exhaustion of hypertrophic, anti-apoptotic signals). Early MR repair by shunt closure reversed remodeling, while early transgenic overexpression of sarcoplasmic reticulum Ca+2-ATPase (SERCA2a) improved it. Building on that, the current proposal addresses the central hypothesis that exacerbation of post-MI LV remodeling by MR can be reduced by appropriately timed molecular or mechanical interventions, with the following specific aims: 1) To test the hypothesis that the reversal of remodeling by MR repair decreases over time, in parallel with a reduced molecular "momentum" for reverse remodeling, emphasizing the benefit of early repair. 2) To test the hypothesis that remodeling can be reduced by transgenically modulating the stress-sensitive calcium cycling pathway that is exhausted in the decompensated phase of MI+MR. In a clinically relevant spectrum of anterior and inferior MIs with MR, this molecular intervention will be tested for its ability to improve reversal of remodeling in response to delayed MR repair. This would correspond to improved postoperative function, extending the window for reverse remodeling beyond any "point of no return" due to delayed repair. The resubmission is focused on the interaction between delayed repair and molecular interventions, supported by quantitative data from SERCA2a gene transfer studies. The research team combines expertise in surgical modeling (Dr. Gus Vlahakes), quantitative 3D cardiac imaging, and the molecular biology and transgenic modification of LV remodeling (Drs. Roger Hajjar and Ronen Beeri). These aims focus on the current questions regarding the central impact of MR repair on LV function to increase our mechanistic understanding and identify potential therapeutic targets. PUBLIC HEALTH RELEVANCE: Mitral regurgitation (MR) is a frequent complication of myocardial infarction (MI) and left ventricular (LV) dysfunction that doubles mortality, but the survival benefit of standard annular ring reduction therapy is intensely debated, and LV remodeling often progresses afterwards, with enlargement of the heart and weakened contraction. It is therefore critical to investigate this maladaptive response, how it relates to the timing of valve repair relative to molecular changes, and whether molecular interventions can "buy time" for LV improvement following delayed repair. This proposal has assembled a research team with the key expertise and resources to address this public health problem by using gene transfer techniques to dissect why MR causes the heart muscle to become weak and to strengthen it. The work will focus on the central impact of MR repair on LV function as the key determinant of prognosis, and on increasing our mechanistic understanding to identify new therapeutic targets.

描述（由申请人提供）：二尖瓣反流（MR）是心肌梗塞（MI）和左心室（LV）功能障碍的常见并发症，使死亡率增加了一倍，但是标准环形环还原疗法的存活率受到了激烈的辩论。 LV重塑经常在降压后进行，导致复发性MR。因此，我们必须以受控的方式解决是否有助于改建；维修的好处是否受到通常迟到的限制；以及为什么积极的重塑继续进行后修复。在最初的赠款期间，我们开发了一个顶端MI模型（无固有的MR），其标准化MR型通过LV-TO-LA分流器。在该绵羊模型中，MI后患者的典型中等MR流动在全心脏，细胞和分子水平上与单独使用MI或MR的LV重塑大大增加，并具有双相的赔偿尝试（增加，肥大，然后耗尽）的双相模式，抗凋亡信号）。分流闭合的早期MR修复逆转了重塑，而核质网Ca+2-ATPase（SERCA2A）的早期转基因过表达改善了它。在此基础上，当前的提案解决了以下中心假设：MR会加剧MI后MI LV重塑的加重可以通过适当定时的分子或机械干预措施来减少，并具有以下具体目的：1）测试以下假设：随着时间的流逝，MR修复会减少，与分子“动量”降低以进行反向重塑，强调了早期修复的益处。 2）要测试可以通过转基因调节在MI+MR的代偿阶段耗尽的应力敏感钙循环途径来减少重塑的假设。在与MR的临床相关范围内和较低的临床范围内，该分子干预措施将因其改善响应延迟MR修复而改善重塑逆转的能力。这将对应于改进的术后功能，将窗口扩展到由于修复延迟而导致的任何“无返回点”的反向重塑的窗口。重新提交的重点是延迟修复和分子干预措施之间的相互作用，并由SERCA2A基因转移研究的定量数据支持。研究小组结合了手术建模（Gus Vlahakes博士），定量3D心脏成像以及LV重塑的分子生物学和转基因修饰（Roger Hajjar和Ronen Beeri）。这些目的集中于有关MR修复对LV功能的核心影响的当前问题，以提高我们的机械理解并确定潜在的治疗靶标。 公共卫生相关性：二尖瓣反流（MR）是心肌梗塞（MI）和左心室（LV）功能障碍的常见并发症，使死亡率增加了一倍，但是标准环形环还原疗法的生存益处是强烈的争论，并且经常进行LV重塑的进展，LV重塑经常会发生。 ，随着心脏的扩大和收缩减弱。因此，研究这种不良适应反应，与分子变化相对于阀修复的时机的关系以及分子干预措施是否可以“购买时间”以改善延迟修复后，这一点至关重要。该提案通过使用基因转移技术来剖析为什么先生会导致心肌变得虚弱并加强它，从而召集了一个研究团队，以关键的专业知识和资源来解决这一公共卫生问题。这项工作将集中于MR修复对LV功能的核心影响，作为预后的关键决定因素，并提高我们的机械理解以识别新的治疗靶标。