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）：二尖瓣返流（MR）是心肌梗死（MI）和左心室（LV）功能障碍的常见并发症，死亡率加倍，但标准瓣环缩小术的生存获益存在激烈争议。左心室重塑通常在成形环复位后进展，导致复发性二尖瓣返流。因此，我们必须以受控的方式解决二尖瓣返流是否有助于重塑;修复的益处是否因通常较晚而受到限制;以及为什么修复后继续进行积极的重塑。在最初的资助期，我们开发了一个心尖心肌梗死模型（无固有MR），通过左心室至左心房分流的标准化MR型血流。在该绵羊模型中，与MI或单独MR相比，MI后患者典型的中度MR血流在整个心脏、细胞和分子水平上强烈增加了LV重构，具有代偿失败的双相模式（肥大、抗凋亡信号上升，然后耗尽）。通过分流关闭进行的早期MR修复逆转了重构，而肌浆网Ca+2-ATP酶（SERCA 2a）的早期转基因过表达改善了重构。在此基础上，目前的建议提出了一个中心假设，即通过适当定时的分子或机械干预可以减少MI后左心室重构的恶化，具体目标如下：1）检验MR修复逆转重塑随时间减少的假设，同时逆转重塑的分子“动量”减少，强调早期修复的益处。2)为了检验这一假设，即通过转基因调节MI+ MR失代偿期耗尽的应激敏感性钙循环途径可以减少重塑。在具有MR的前壁和下壁MI的临床相关谱中，将测试这种分子干预在延迟MR修复中改善重塑逆转的能力。这将对应于术后功能的改善，延长了由于延迟修复而导致的任何“不可逆点”之外的逆向重塑窗口。重新提交的重点是延迟修复和分子干预之间的相互作用，由SERCA 2a基因转移研究的定量数据支持。该研究团队结合了手术建模（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博士）的专业知识。这些目标集中在当前关于MR修复对LV功能的中心影响的问题上，以增加我们对机制的理解并确定潜在的治疗靶点。 公共卫生相关性：二尖瓣返流（MR）是心肌梗死（MI）和左心室（LV）功能障碍的常见并发症，其死亡率加倍，但标准瓣环缩小术的生存获益存在激烈争议，并且LV重塑通常在之后进展，心脏增大，收缩减弱。因此，研究这种适应不良反应是至关重要的，它如何与瓣膜修复相对于分子变化的时机，以及分子干预是否可以为延迟修复后的LV改善“争取时间”。该提案组建了一个拥有关键专业知识和资源的研究团队，通过使用基因转移技术来剖析MR导致心肌变弱的原因并加强其功能，以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，并增加我们对机制的理解，以确定新的治疗靶点。