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: 8420189
• 负责人: ROBERT A LEVINE
• 金额: $ 39.89万
• 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 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8420189
• 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.

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。

项目成果

Evidence of a vicious cycle in mitral regurgitation with prolapse: secondary tethering attributed to primary prolapse demonstrated by three-dimensional echocardiography exacerbates regurgitation.

二尖瓣反流伴脱垂恶性循环的证据：三维超声心动图显示，原发性脱垂引起的继发性束缚加剧了反流。

• DOI: 10.1161/circulationaha.111.084178
• 发表时间: 2012
• 期刊: Circulation
• 影响因子: 37.8
• 作者: Otani,Kyoko;Takeuchi,Masaaki;Kaku,Kyoko;Haruki,Nobuhiko;Yoshitani,Hidetoshi;Eto,Masataka;Tamura,Masahito;Okazaki,Masahiro;Abe,Haruhiko;Fujino,Yoshihisa;Nishimura,Yousuke;Levine,RobertA;Otsuji,Yutaka
• 通讯作者: Otsuji,Yutaka

New Mitral Valve Annuloplasty Concept: Optimizing Annular Dynamics and Force Distribution.

新二尖瓣瓣环成形术概念：优化瓣环动力学和力分布。

• 发表时间: 2018
• 期刊: The Journal of heart valve disease
• 作者: Jensen,MortenO;Jensen,Henrik;Skov,SørenN;Levine,RobertA;Nygaard,Hans;MHasenkam,J;Nielsen,StenL
• 通讯作者: Nielsen,StenL

A theoretical cardiac resynchronization therapy method to augment ventricular contraction using polymer-based actuators and mitral regurgitation reduction with devices over left ventricular endocardial pacing wire--an in-vitro study.

一种理论上的心脏再同步治疗方法，使用基于聚合物的执行器增强心室收缩，并使用左心室心内膜起搏线上的装置减少二尖瓣反流——一项体外研究。

• 发表时间: 2013
• 期刊: The Journal of invasive cardiology
• 作者: Arokiaraj,Mark;Guerrero,Luis;Levine,Robert;Palacios,Igor
• 通讯作者: Palacios,Igor

Mitral stenosis reversed by medical treatment for heart failure.

通过心力衰竭的药物治疗逆转二尖瓣狭窄。

• DOI: 10.1016/j.athoracsur.2013.04.132
• 发表时间: 2013
• 期刊: The Annals of thoracic surgery
• 作者: Yukawa,Sawami;Takeuchi,Masaaki;Nakazono,Akemi;Sakamoto,Kyoko;Araya,Kiyoshi;Eto,Masataka;Nishimura,Yosuke;Harada,Masaru;Levine,RobertA;Otsuji,Yutaka
• 通讯作者: Otsuji,Yutaka