Electrophysiological and antiarrhythmic benefit of cell therapy for heart disease

描述（由申请方提供）：缺血性心脏病（IHD）是美国的主要死亡原因，并导致心肌不可逆损伤。最近的研究表明，心脏功能可以通过添加新的健康细胞来恢复，如骨骼肌成肌细胞（SKMB）或骨髓来源的间充质干细胞（MSC）。细胞疗法的早期结果令人鼓舞，表明血流动力学改善;然而，尚不清楚细胞疗法是否可以降低与IHD相关的心源性猝死（SCO）的风险。此外，由于心律失常风险增加的报告，引起了重大的安全性问题。迄今为止，一些研究表明，移植细胞与宿主细胞电偶联的能力是心律失常风险的重要决定因素。此外，通过增强干细胞归巢到受损心肌部位来增强自然组织再生过程可以提供进一步的益处。在一般情况下，我们假设，细胞疗法的能力，以减少心律失常的脆弱性将由其能力，以提高梗死区的电生理活力，通过植入形成功能性电连接的活细胞。因此，本建议的主要目标是确定电生理学的好处，因此，IHD的细胞治疗的抗肿瘤的后果，并优化细胞治疗，通过增强细胞间的耦合和细胞归巢/植入使用基因治疗。为了实现这些目标，将利用新的光学映射技术和IHD的大鼠模型来解决以下具体目标：1）开发和验证光学映射系统以研究用于大鼠中与心肌梗死（MI）相关的SCD的细胞疗法。2)确定细胞疗法在MI心脏中提供电生理益处或损害的机制。3)在整个心脏中建立与MI的细胞疗法相关的抗心律失常或预防心律失常机制。4)确定连接蛋白蛋白（Cx40、Cx43和Cx45）和SDF-1（干细胞归巢因子）的过表达是否可以显著增强SKMB和MSC细胞治疗与MI相关的SCD。总的来说，这项研究将提高对IHD细胞治疗电生理学的理解，并为更广泛的，基于科学的临床试验奠定重要的基础。这项研究的长期目标是开发一种治疗与IHD相关的SCD的方法。

DESCRIPTION (provided by applicant): Ischemic heart disease (IHD) is the leading cause of death in the USA and results in irreversible damage to the myocardium. Recent studies suggest that cardiac function can be restored by adding new, healthy cells such as skeletal muscle myoblasts (SKMB) or bone marrow-derived mesenchymal stem cells (MSC). Early results of cell therapy are encouraging and indicate hemodynamic improvement; however, it is unknown if cell therapy can reduce the risk of sudden cardiac death (SCO) associated with IHD. Moreover, significant safety concerns have been raised due to reports of increased arrhythmia risk. To date, several studies suggest that the ability of transplanted cells to electrically couple with host cells is an important determinant of arrhythmia risk. In addition, augmenting the natural tissue regeneration process by enhancing stem cell homing to the site of damaged myocardium may provide further benefit. In general, we hypothesize that the ability of cell therapy to reduce arrhythmia vulnerability will be determined by its ability to enhance electrophysiological viability of the infarct zone through the engraftment of viable cells that form functional electrical connections. Therefore a major goal of this proposal is to determine the electrophysiological benefit and, thus, the antiarrhythmic consequence of cell therapy for IHD, and to optimize cell therapy by enhancement of intercellular coupling and cell homing/engraftment using gene therapy. To achieve these goals, novel optical mapping techniques and a rat model of IHD will be utilized to address the following specific aims: 1) Develop and validate an optical mapping system to investigate cell therapy for SCD associated with myocardial infarction (Ml) in rat. 2) Determine the mechanisms by which cell therapy provides electrophysiological benefit or detriment in hearts with Ml. 3) Establish the antiarrhythmic or proarrhythmic mechanisms associated with cell therapy for Ml in the whole heart. 4) Determine if overexpression of connexin protein (Cx40, Cx43, and Cx45) and SDF-1 (stem cell homing factor) can significantly enhance SKMB and MSC cell therapy for SCD associated with Ml. Overall, this study will improve the understanding of the electrophysiology of cell therapy for IHD, and lay important basic groundwork for more extensive, science-based, clinical trials. The long-term goal of this study is to develop a cure for SCD associated with IHD.