ACTIVE PATCH THERAPY FOR ISCHEMIC MITRAL REGURGITATION

描述(由申请人提供)： 缺血性二尖瓣返流(MR)是心肌梗死的常见并发症，可使其晚期死亡率增加一倍。从根本上说，它是由受损的心壁扭曲引起的，这会拉住二尖瓣瓣叶，限制它们关闭的能力。我们已经证明，这一过程可以通过手术或使用外部补片重塑心脏来逆转；然而，这些方法会使心脏的很大一部分固定，需要心内直视手术。我们建议探索两种创新的方法来实现这一目标，并为患者带来更多好处：(1)通过将自体成肌细胞移植到梗死壁中来再生组织，通过变厚，组织再生将抵抗变形，并呈现更正常的形状，从而缓解二尖瓣叶上的张力(这是一种有可能实现微创实施的方法)；以及(2)使用由聚合物人工肌肉组成的外部补片来提供正常形状(较少MR)以及收缩和松弛的额外好处，以帮助心脏功能。人造肌肉的开发将需要对替代材料和设计进行计算、体外和体内测试。这两种方法都将在已建立的具有适当对照的缺血性MR模型中进行测试。这些研究通过被动贴片的有希望的结果来证明是合理的，并且需要探索性的工作来开发功能性贴片。 为了实现临床问题和开发技术的综合，这一建议将汇集几个领域的专业知识：通过三维超声心动图对动物模型中的二尖瓣进行定量分析(已在波士顿和巴黎实验室提供)；成肌细胞的收获和心肌再生(Menasche教授)；开发制造人造肌肉的创新方法(麻省理工学院的Hunter教授)；以及心血管外科(Vlahakes博士和Menasche教授)。

DESCRIPTION (provided by applicant): Ischemic mitral regurgitation (MR) is a common complication of myocardial infarction that doubles its late mortality. It is fundamentally caused by distortion of the damaged heart wall, which pulls on the mitral valve leaflets and restricts their ability to close. We have shown this process can be reversed by re-shaping the heart surgically or with an external patch; these approaches, however, immobilize a large portion of the heart and require open-heart surgery. We propose exploring two innovative ways to achieve this goal with additional benefits to the patient: (1) tissue regeneration by autologous myoblast transplantation into the infarcted wall, which, by becoming thicker, would resist deformation and assume a more normal shape that relieves the tension on the mitral leaflets (an approach with potential for minimally invasive implementation); and (2) using an external patch composed of polymer-based artificial muscle to provide both normal shape (less MR) and the additional benefits of contraction and relaxation to assist heart function. The artificial muscle development will require computational, in vitro and in vivo testing of alternative materials and designs. Both approaches will be tested in established models of ischemic MR with appropriate controls. These studies are justified by promising results with passive patches, and require exploratory work to develop functional patches. To achieve this synthesis of clinical problem and developmental techniques, this proposal will bring together expertise in several areas: quantitative analysis of the mitral valve in animal models by three-dimensional echocardiography, available in both Boston and Paris laboratories; myoblast harvesting and myocardial repopulation (Professor Menasche); developing innovative approaches to create artificial muscle (Professor Hunter at MIT); and cardiovascular surgery (Dr. Vlahakes and Prof. Menasche).