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: 6862312
• 负责人: ROBERT A LEVINE
• 金额: $ 7.61万
• 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 2007-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6862312
• 关键词: Effect; Mitral; Regurgitation; Ischemic; LV

DESCRIPTION (provided by applicant): This supplement will use human embryonic stem cells (ESCs) to address the adverse effects of left ventricular (LV) remodeling following myocardial infarction (MI) on ventricular size and function, with particular focus on how such remodeling augments volume overload by causing mitral regurgitation (MR). These are the scientific questions in the parent R01, Effect of Mitral Regurgitation on Ischemic LV Remodeling, and the related R21, Active Patch Therapy of Ischemic MR. Following MI, localized distortion of the heart wall restricts the ability of the attached mitral leaflets to close, causing MR that exacerbates LV remodeling and doubles late mortality. Our initial studies have shown that passive external constraints applied to the MI zone can reverse its shape change and eliminate MR; however, an entire region of myocardium remains immobilized. With collaborating investigators, we have been studying the possibility that injecting autologous skeletal myoblasts into the infarcted wall to thicken and re-shape it can reverse MR, with potential for augmenting contraction as well. However, there may be some limitations of using skeletal myoblasts for this purpose, including absence of connecting gap junctions between grafted and host cells needed for concerted contraction. The next logical step would therefore be to test whether we can reduce LV remodeling and ischemic MR and, at the same time, provide the added benefit of functional tissue by using human embryonic stem cells instead of skeletal myoblasts in a post-infarct MR model. Our colleagues have shown that such undifferentiated cells, under the influence of tissue growth factors, can be committed to a cardiac lineage, with evidence for sarcomeric striations and expression of gap junction protein, allowing integration with surrounding myocardium. Cells derived from embryonic stem cells would therefore be the best candidates to replace damaged muscle with true myocytes, with the greatest potential for actually increasing contractility. Specific aims include: 1) To establish simple protocols for cardiac commitment of human ESCs and to understand the molecular mechanisms underlying this process to prevent tumor formation; 2) To investigate the fate and immunocompatibility of cardiac-committed ESCs transplanted into post-MI and failing sheep hearts; and 3) To evaluate the improvement of cardiac function after engraftment of cardiac-committed ESCs in sheep with heart failure worsened by MR. NIH cell registry number TE03 (training available). This supplement brings together unique resources and expertise to address this challenge, including groups with extensive experience in cell transplantation into infarcted regions, successful cardiac differentiation of ESCs in other species, and quantitative three-dimensional evaluation of cardiac function.

描述（由申请人提供）：本补品将使用人类胚胎干细胞（ESCs）来解决心肌梗死（MI）后左心室（LV）重构对心室大小和功能的不利影响，特别关注这种重构如何通过引起二尖瓣反流（MR）而增加容量过载。这些都是母体R01《二尖瓣返流对缺血性左室重构的影响》和相关R21《缺血性MR的主动贴片治疗》中提出的科学问题。心肌梗死后，心壁的局部扭曲限制了附着的二尖瓣小叶的闭合能力，导致MR加剧左室重构，使晚期死亡率加倍。我们的初步研究表明，应用于MI区的被动外部约束可以逆转其形状变化并消除MR；然而，整个心肌区域仍处于固定状态。与合作研究人员一起，我们一直在研究将自体骨骼肌母细胞注射到梗死壁中以增厚和重塑其形状的可能性，这种方法可以逆转MR，并有可能增强收缩。然而，将骨骼肌母细胞用于此目的可能存在一些局限性，包括移植物细胞和宿主细胞之间缺乏协调收缩所需的连接间隙连接。因此，下一个合乎逻辑的步骤将是测试我们是否可以减少左室重塑和缺血性MR，同时，通过在梗死后MR模型中使用人类胚胎干细胞而不是骨骼肌母细胞，提供功能性组织的额外好处。我们的同事已经证明，在组织生长因子的影响下，这种未分化的细胞可以转化为心脏谱系，有证据表明，肌瘤条纹和间隙连接蛋白的表达，允许与周围心肌整合。因此，从胚胎干细胞中提取的细胞将是用真正的肌细胞代替受损肌肉的最佳候选者，具有实际增加收缩性的最大潜力。具体目标包括：1)建立人类ESCs心脏功能的简单方案，并了解其分子机制