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）：该补充剂将使用人类胚胎干细胞（ESC）来解决心肌梗塞（MI）对心室尺寸和功能后左心室（LV）重塑的不利影响，特别关注这种重塑如何通过导致米腹发出（MR）来增加体积超负荷（MR）。这些是父r01中的科学问题，二尖瓣反流对缺血性LV重塑的影响以及相关的R21缺血性MR的主动补丁治疗。 MI之后，心脏壁的局部变形限制了附着的二尖瓣关闭的能力，导致MR加剧了LV重塑并使晚期死亡率加倍。我们的最初研究表明，应用于MI区域的被动外部约束可以扭转其形状变化并消除MR。但是，整个心肌区域仍然固定。与合作的研究人员一起，我们一直在研究将自体骨骼肌细胞注射到梗塞壁中以使MR逆转MR的可能性，也有可能增加收缩的收缩。但是，在此目的中使用骨骼肌细胞可能存在一些局限性，包括没有连接的嫁接和宿主细胞之间需要的缝隙连接所需的缝隙连接。因此，下一个逻辑步骤将是测试我们是否可以减少LV重塑和缺血性MR，同时通过使用人类胚胎干细胞代替骨架后MR模型中的骨骼肌细胞来提供功能组织的额外好处。我们的同事表明，在组织生长因子的影响下，这种未分化的细胞可以致力于心脏谱系，并有证据表明肉瘤条纹和间隙连接蛋白的表达，从而使其与周围的心肌相结合。因此，源自胚胎干细胞的细胞将是用真正的肌细胞代替受损肌肉的最佳候选者，其实际上增加了收缩力的可能性最大。具体目的包括：1）建立人类ESC心脏承诺的简单方案并了解分子机制 这一过程以防止肿瘤形成； 2）研究命运和免疫相容性 通过移植到MI后和失败的绵羊心的心脏承诺的ESC； 3）评估 MR的心力衰竭恶化，心脏衰竭植入心脏的ESC后，心脏功能改善了心脏功能。 NIH细胞注册表号TE03（可用培训）。这种补充剂汇集了独特的资源和专业知识来应对这一挑战，包括在细胞移植到梗塞区域的丰富经验，其他物种中ESC的成功心脏分化以及对心脏功能的定量三维评估。