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）和左室（LV）功能障碍的常见并发症，可使死亡率增加一倍，但标准环复位治疗的生存益处存在激烈争议。左室重构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是否有助于重构；修理的好处是否因为通常迟到而受到限制；以及为什么修复后侵略性的重塑会继续。在最初的授权期间，我们开发了一个根尖心肌梗死模型（无本征磁共振），通过lvto - la分流器进行标准化的磁共振型血流。在该羊模型中，心肌梗死后患者典型的中度MR血流在全心脏、细胞和分子水平上强烈增加左室重构，与心肌梗死或单独MR相比，具有补偿失败的双相模式（上升，然后衰竭肥厚，抗凋亡信号）。早期通过分流关闭修复MR可逆转重构，而早期转基因过表达肌浆网Ca+2- atp酶（SERCA2a）可改善重构。在此基础上，目前的建议解决了核心假设，即通过适当的时间分子或机械干预可以减少心肌梗死后左室重构的加剧，具体目的如下：1)验证MR修复的重塑逆转随着时间的推移而减少的假设，与此同时，逆转重塑的分子“动量”也在减少，强调早期修复的好处。2)通过转基因调节在MI+MR失代偿期耗尽的应激敏感钙循环通路，可以减少重塑的假设。在临床相关的前段和下段MIs磁共振频谱中，将测试这种分子干预在延迟MR修复后改善重塑逆转的能力。这将与术后功能的改善相对应，延长了由于延迟修复而导致的任何“不归点”的逆转重塑窗口。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SERCA2a基因转移研究的定量数据支持。该研究团队结合了外科建模（Gus Vlahakes博士）、定量3D心脏成像、左室重塑的分子生物学和转基因修饰(dr。Roger Hajjar和Ronen Beeri)。这些目标集中在当前关于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。

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