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，可使死亡率加倍，但标准瓣环缩小治疗的生存益处存在激烈争论。左心室重塑通常在环复位后进展，导致复发性 MR。因此，我们必须以可控的方式确定 MR 是否有助于重塑；维修的好处是否因通常迟到而受到限制；以及为什么修复后继续进行积极的改造。在初始资助期间，我们开发了心尖 MI 模型（无内在 MR），具有通过 LV-to-LA 分流的标准化 MR 型血流。在该绵羊模型中，与单独的 MI 或 MR 相比，MI 后患者典型的中度 MR 血流在全心、细胞和分子水平上强烈增加左室重塑，并具有补偿尝试失败的双相模式（升高，然后耗尽肥大的抗凋亡信号）。通过分流闭合进行的早期 MR 修复逆转了重塑，而肌浆网 Ca+2-ATPase (SERCA2a) 的早期转基因过度表达则改善了重塑。在此基础上，当前的提案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 MR 导致的 MI 后左心室重塑的恶化，具体目标如下：1）检验 MR 修复对重塑的逆转随着时间的推移而减少的假设，同时逆转重塑的分子“动力”减少，强调早期修复的益处。 2) 检验以下假设：通过转基因调节在 MI+MR 失代偿阶段耗尽的应激敏感钙循环途径，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是否能够改善因 MR 修复延迟而逆转重塑的能力。这将对应于术后功能的改善，将逆向重塑的窗口延长到超出由于延迟修复而导致的任何“不归点”。重新提交的重点是延迟修复和分子干预之间的相互作用，并得到 SERCA2a 基因转移研究的定量数据的支持。该研究团队结合了手术建模（Gus Vlahakes 博士）、定量 3D 心脏成像以及左心室重塑的分子生物学和转基因修饰（Roger Hajjar 博士和 Ronen Beeri 博士）方面的专业知识。这些目标重点关注当前关于 MR 修复对左室功能的核心影响的问题，以增加我们对机制的理解并确定潜在的治疗靶点。 公众健康相关性：二尖瓣反流 (MR) 是心肌梗死 (MI) 和左心室 (LV) 功能障碍的常见并发症，可使死亡率加倍，但标准瓣环缩小治疗的生存益处存在激烈争议，并且 LV 重塑通常会在随后进展，导致心脏扩大和收缩减弱。因此，研究这种适应不良反应、它与分子变化相关的瓣膜修复时间有何关系，以及分子干预是否可以为延迟修复后的左心室改善“争取时间”至关重要。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 导致心肌变弱和强化的原因，以解决这一公共卫生问题。这项工作将重点关注 MR 修复对左室功能的核心影响（作为预后的关键决定因素），并加强我们对机制的理解，以确定新的治疗靶点。