Effect of Mitral Regurgitation on Ischemic LV Remodeling

描述(申请人提供)：二尖瓣返流(MR)是心肌梗死(MI)和左心室(LV)功能不全的常见并发症，可使死亡率增加一倍，但标准环形环减少术的生存益处仍存在激烈争论。LV重塑通常在环减少后进展，导致复发的MR。因此，我们必须以可控的方式解决MR是否导致重塑；修复的益处是否因通常迟到而受限；以及为什么在修复后继续积极的重塑。在最初的资助期间，我们开发了一个心尖部心肌梗死模型(无固有MR)，其标准MR类型的血流通过LV到LA分流。在绵羊模型中，与单纯心肌梗死或MR相比，MI后患者典型的适度MR血流在全心、细胞和分子水平上强烈增加了LV重构，并出现了两种失败的代偿尝试模式(肥大、抗凋亡信号先升高，然后耗尽)。早期阻断分流的MR修复逆转了重塑，而肌浆网Ca+2-ATPase(SERCA2a)的早期转基因过表达改善了重塑。在此基础上，目前的建议解决了一个中心假设，即通过适当的时机的分子或机械干预可以减少MR对MI后左室重构的恶化，具体目的如下：1)测试MR修复对重构的逆转随着时间的推移而减少的假设，同时减少反向重构的分子“动量”，强调早期修复的好处。2)为了验证这一假说，即可以通过转基因调节在MI+MR失代偿期耗尽的应激敏感钙循环途径来减少重构的假设，这种分子干预将被测试其改善延迟MR修复反应的重构逆转的能力。这将对应于术后功能的改善，将反向重塑的窗口延长到任何由于修复延迟而无法恢复的点上。重新提交的重点是延迟修复和分子干预之间的相互作用，得到SERCA2a基因转移研究的定量数据的支持。研究团队结合了外科建模(Gus Vlahakes博士)、定量3D心脏成像以及分子生物学和左心室重塑转基因修改(Roger Hajjar博士和Ronen Beeri博士)方面的专业知识。这些目标集中在目前关于MR修复对左室功能的核心影响的问题上，以增加我们对机制的理解，并确定潜在的治疗靶点。 与公共卫生相关：二尖瓣返流(MR)是心肌梗死(MI)和左心室(LV)功能不全的常见并发症，可使死亡率增加一倍，但标准环形环减少术的生存益处仍存在激烈争论，而且LV重塑通常在随后进展，心脏增大，收缩减弱。因此，研究这种不适应反应，它与瓣膜修复的时机与分子变化的关系，以及分子干预能否为延迟修复后的左室改善“争取时间”，是至关重要的。这项提议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导致心肌变弱和增强的原因，以解决这一公共健康问题。这项工作将集中在MR修复对左心功能的核心影响，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。

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.