Novel therapeutic approaches to Mitral valve repair in ischemic heart disease

缺血性心脏病二尖瓣修复的新治疗方法

• 批准号: 9756450
• 负责人: Sai Muralidhar Padala
• 金额: $ 63.89万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9756450
• 关键词: 3-Dimensional; Address; American; Anterior; Biomechanics; Cardiac; Cardiac Surgery procedures; Cardiac Volume; Chronic; Clinical; Clinical Trials; Computer Simulation; Development; Dyspnea; Environment; Extracellular Matrix; Failure; Family suidae; Goals; Gold; Heart Valves; Heart failure; Human; Image; Institution; Laboratories; Lateral; Lesion; Lung; Magnetic Resonance Imaging; Mitral Valve; Mitral Valve Insufficiency; Modeling; Myocardial Ischemia; Operative Surgical Procedures; Outcome; Patient imaging; Patient-Focused Outcomes; Patients; Pilot Projects; Postoperative Period; Publishing; Randomized Controlled Trials; Recurrence; Reporting; Research; Research Personnel; Retrospective Studies; Risk; Role; Stress; Surgeon; Surgical sutures; Techniques; Time; Translating; Universities; Ventricular Dysfunction; Ventricular Remodeling; Work; biomechanical model; cardiovascular health; heart imaging; hemodynamics; improved; indexing; insight; ischemic cardiomyopathy; multidisciplinary; novel; novel strategies; novel therapeutic intervention; overtreatment; papillary muscle; parallelization; patient stratification; pre-clinical; pressure; prospective; repaired; valve replacement

ABSTRACT: The overarching goal of this R01 application from a collaborative new and early stage investigator, is to define the mechanistic basis for recurrent functional mitral regurgitation (FMR) after undersizing mitral annuloplasty(UMA) in heart failure patients, and translate the mechanistic insights into the development of a new surgical technique that eliminates this problem. 2-3 million Americans suffer from FMR developing from ischemic cardiomyopathy. Volume overload imposed by FMR not only elevates pulmonary pressures and causes dyspnea, but imposes a unique low pressure hemodynamic stress on the already cardiomyopathic ventricle. This stress elevates sympathetic drive and causes breakdown of cardiac extracellular matrix and leads to rapid ventricular dysfunction. Timely repair of FMR is now considered necessary and patients are promptly referred for surgical repair, but poor repair durability and post-repair recurrence of FMR continue to haunt these patients and their cardiologists. A recent randomized controlled trial reported that in patients receiving FMR repair with an undersizing annuloplasty ring (current gold standard), FMR was fully repaired at the time of surgery, but at 1 year 34% of the patients developed recurrent moderate or greater FMR, and at 2 years 64% had repair failure. This situation needs to be improved, but mechanistic insights into recurrent FMR after annuloplasty are scarce and thus techniques for improvement are lacking. We developed and validated a novel patient imaging (3D echo+MRI) derived biomechanical modeling platform to investigate the mechanism causing recurrent FMR in patients receiving annuloplasty. A retrospective study was performed using this model on a select set of FMR patient images at our institution, which resulted in a hypothesis that poor inter- papillary muscle lateral shortening governs the risk of developing FMR, and that surgically approximating the papillary muscles can eliminate recurrent FMR. We validated our hypothesis in an ex-vivo mitral valve model and in a chronic swine model, and recently published these results. In this R01 application, we propose to conduct a prospective trial to confirm that patients with poor inter-papillary muscle lateral shortening develop recurrent FMR after mitral annuloplasty (Aim 1); that poor-inter papillary muscle lateral shortening leads to elevated tethering forces on the anterior and posterior mitral leaflet edges that reduces their systolic parallelization that is essential to achieve adequate coaptation (Aim 2); and finally propose papillary muscle approximation as a new technique to reduce recurrent FMR after annuloplasty, and enable reverse ventricular remodeling(Aim 3). A multi-disciplinary team has been assembled with expertise in heart valve biomechanics, cardiac surgery, cardiac imaging and clinical trials, in a high volume cardiac surgery center that provides an excellent environment to conduct this work. Ultimately, this work would provide unprecedented mechanistic insights into recurrent FMR after annuloplasty, and validate the use of a new technique to address this problem. The translational potential of this work is high and these patients will benefit from the outcomes.

抽象的： 此R01应用程序的总体目标是合作新的和早期阶段调查员，是为了定义 二尖瓣降低二尖瓣后，复发性二尖瓣反流（FMR）的机械基础 心力衰竭患者的环形成形术（UMA），并将机械洞察力转化为A的发展 消除此问题的新外科手术技术。 2-300万美国人患有FMR的发展 缺血性心肌病。 FMR施加的体积超负荷不仅会提高肺部压力和 引起呼吸困难，但对已经心肌疗法施加独特的低压血液动力学应力 心室。这种应力提高了交感神经驱动，并导致心脏外基质的崩溃和 导致快速心室功能障碍。现在认为FMR的及时维修是必要的，患者是 立即转介手术修复，但修复耐用性和修复后FMR的复发继续继续 困扰着这些患者及其心脏病学家。最近的一项随机对照试验报告说，患者 接受FMR维修，并用较低的环形成形术环（当前金标准）进行全面修复。 手术时间，但在1年中，有34％的患者出现了中度或更高的FMR，在2岁时 64％的年度维修失败。这种情况需要改善，但是对经常性FMR的机械见解 过整形成形术后稀缺后，缺乏改进的技术。我们开发并验证了 新型患者成像（3D Echo+MRI）衍生的生物力学建模平台，以研究机制 导致接受环形成形术的患者的复发性FMR。使用此研究进行了回顾性研究 在我们机构的一组FMR患者图像中的模型，这导致了一个假设，即较差 乳头状肌肉侧向缩短控制FMR的风险，并通过手术近似 乳头状肌肉可以消除复发性FMR。我们在前二尖瓣模型中验证了我们的假设 并在慢性猪模型中，最近发布了这些结果。在此R01应用程序中，我们建议 进行一项前瞻性试验，以确认毛皮间肌肉间侧向缩短的患者发展 二尖瓣环形成形术后的复发FMR（AIM 1）；那个较差的乳头状肌肉侧向缩短导致 在二尖瓣后边缘和后二尖瓣边缘上升高的绑扎力，减少其收缩压 对实现足够的仪式至关重要的并行化（AIM 2）；最后提出乳头状肌肉 近似作为一种新技术，以减少环形成形术后复发性FMR，并启用反向心室 重塑（AIM 3）。一支多学科团队已经在心脏瓣膜生物力学方面拥有专业知识， 心脏外科手术，心脏成像和临床试验，在大容量心脏手术中心提供 出色的环境来进行这项工作。最终，这项工作将提供前所未有的机械 对环形成形术后复发性FMR的见解，并验证使用新技术解决此问题 问题。这项工作的翻译潜力很高，这些患者将从结果中受益。