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）：本补充品将使用人类胚胎干细胞（ESC）来解决心肌梗塞（MI）后左心室（LV）重塑对心室大小和功能的不利影响，特别关注这种重塑如何通过引起二尖瓣反流（MR）来增加容量超负荷。这些是母版 R01“二尖瓣反流对缺血性左心室重构的影响”和相关 R21“缺血性 MR 的主动贴片治疗”中的科学问题。心肌梗死后，心壁的局部变形限制了附着的二尖瓣关闭的能力，导致心肌梗死，加剧左心室重塑并使晚期死亡率加倍。我们的初步研究表明，施加于 MI 区的被动外部约束可以逆转其形状变化并消除 MR；然而，整个心肌区域仍然不动。我们与合作研究人员一起研究了将自体骨骼肌母细胞注射到梗死壁以增厚和重塑其形状可以逆转 MR 的可能性，并有可能增强收缩。然而，使用骨骼肌细胞用于此目的可能存在一些限制，包括移植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是测试我们是否可以减少左心室重塑和缺血性 MR，同时通过在梗塞后 MR 模型中使用人类胚胎干细胞而不是骨骼肌母细胞来提供功能组织的额外益处。我们的同事已经证明，这种未分化的细胞在组织生长因子的影响下，可以分化为心脏谱系，有证据表明肌节条纹和间隙连接蛋白的表达，从而可以与周围的心肌整合。因此，源自胚胎干细胞的细胞将是用真正的肌细胞替代受损肌肉的最佳候选者，最有可能真正增加收缩性。具体目标包括： 1) 建立人类 ESC 心脏承诺的简单方案并了解其分子机制 这一过程的基础是防止肿瘤形成； 2) 研究命运和免疫相容性 将心脏相关的 ESC 移植到 MI 后和衰竭的绵羊心脏中； 3) 评估 MR 导致心力衰竭恶化的绵羊植入心脏定向 ESC 后心脏功能得到改善。 NIH 细胞登记号 TE03（可提供培训）。该补充品汇集了独特的资源和专业知识来应对这一挑战，包括在梗塞区域细胞移植、其他物种的 ESC 成功心脏分化以及心脏功能定量三维评估方面拥有丰富经验的小组。