Novel therapeutic approaches to Mitral valve repair in ischemic heart disease

摘要： 这个R01应用程序的首要目标是定义 二尖瓣缩小后再发功能性二尖瓣反流的机制 心力衰竭患者的心脏瓣环成形术(UMA)，并将机械学上的见解转化为 消除这一问题的新外科技术。200-300万美国人患有FMR， 缺血性心肌病。FMR造成的容量超负荷不仅会升高肺压力和 会导致呼吸困难，但会对已经患有心肌病的患者施加独特的低压血流动力学压力 脑室。这种应激提高了交感神经的驱动力，导致心脏细胞外基质的分解，并 会导致快速的心功能不全。及时修复FMR现在被认为是必要的，患者正在 及时转诊手术修复，但修复耐久性差和修复后复发继续 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称，在患者 在接受FMR修复术时，FMR已完全修复。 手术时间，但在1年34%的患者发生复发的中度或更多的FMR，在2 年间曾有过一次维修失败。这种情况需要改善，但对反复出现的FMR的机械性见解 环状成形术后的心脏功能缺乏，因此缺乏改进的技术。我们开发并验证了 新型患者成像(3D ECHO+MRI)衍生生物力学建模平台研究机制 在接受瓣环成形术的患者中导致复发的FMR。使用这一方法进行了一项回顾性研究 在我们机构的一组精选的FMR患者图像上进行建模，这导致了一种假设，即 乳头肌外侧缩短控制着发生FMR的风险，手术上接近于 乳头肌可以消除复发的FMR。我们在体外二尖瓣模型中验证了我们的假设。 并在一个慢性猪模型中，最近发表了这些结果。在此R01应用程序中，我们建议 进行一项前瞻性试验，以确认乳头间肌侧向缩短不良的患者 二尖瓣环成形术后复发的FMR(目标1)；乳头间肌侧向缩短不良导致 二尖瓣前缘和后缘的栓扎力增加，收缩压降低 实现充分接合所必需的平行化(目标2)；最后提出乳头肌 逼近作为一种新技术减少心脏瓣膜成形术后复发的FMR并使之能够逆转 重塑(目标3)。已经组建了一个拥有心脏瓣膜生物力学专业知识的多学科团队， 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提供 开展这项工作的良好环境。最终，这项工作将提供前所未有的机械性 对瓣环成形术后复发的FMR的洞察，并验证使用新技术来解决这一问题 有问题。这项工作的翻译潜力很高，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.