Novel therapeutic approaches to Mitral valve repair in ischemic heart disease

摘要： 来自合作的新的早期研究者的R 01应用程序的总体目标是定义 二尖瓣尺寸过小后功能性二尖瓣返流（FMR）复发的机制基础 在心力衰竭患者中进行瓣环成形术（UMA），并将机械见解转化为 新的外科技术可以消除这个问题。2-3数百万美国人患有FMR， 缺血性心肌病FMR造成的容量超负荷不仅会升高肺动脉压， 引起呼吸困难，但对已经患有心肌病的患者施加了独特的低压血流动力学压力， 脑室这种应激增强交感神经驱动并引起心脏细胞外基质的分解， 会导致心室功能快速紊乱现在认为及时修复FMR是必要的， 及时转诊进行手术修复，但修复耐久性差和修复后FMR复发仍在继续， 困扰着这些病人和他们的心脏病专家最近的一项随机对照试验报告， 使用尺寸过小的瓣膜成形环（当前金标准）接受FMR修复，FMR在 但在1年时，34%的患者出现复发性中度或重度FMR， 64%的患者出现了修复失败。这种情况需要改善，但对复发性FMR的机械见解 瓣环成形术后很少，因此缺乏改进的技术。我们开发并验证了 新型患者成像（3D回波+MRI）衍生生物力学建模平台，以研究机制 导致接受瓣环成形术的患者复发FMR。一项回顾性研究是使用这种方法进行的。 在我们的机构选择一组FMR患者图像模型，这导致了一个假设， 乳头肌横向缩短控制着发生FMR的风险，手术接近 乳头肌可以消除复发性FMR。我们在离体二尖瓣模型中验证了我们的假设 以及慢性猪模型，并于最近发表了这些结果。在R 01申请中，我们建议 进行一项前瞻性试验，以证实乳头肌间横向缩短不良的患者 二尖瓣环成形术后复发性FMR（目标1）;乳头肌间横向缩短不良导致 二尖瓣前叶和后叶边缘上的拴系力升高， 平行化是实现充分接合所必需的（目标2）;最后提出乳头肌 缝合作为一种新技术，可减少瓣环成形术后复发性FMR， 重塑（目标3）。一个多学科的团队已经组装了心脏瓣膜生物力学的专业知识， 心脏手术、心脏成像和临床试验，在一个高容量的心脏手术中心， 良好的工作环境来开展这项工作。最终，这项工作将提供前所未有的机械 对瓣环成形术后复发性FMR的见解，并验证使用新技术来解决这一问题 问题.这项工作的转化潜力很高，这些患者将从结果中受益。

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.