Electrophysiological and antiarrhythmic benefit of cell therapy for heart disease

描述(申请人提供)：在美国，缺血性心脏病(IHD)是导致死亡的主要原因，会对心肌造成不可逆转的损害。最近的研究表明，通过添加新的、健康的细胞，如骨骼肌成肌细胞(SKMB)或骨髓来源的间充质干细胞(MSC)，可以恢复心脏功能。细胞治疗的早期结果令人鼓舞，表明血流动力学有所改善；然而，细胞治疗是否能降低与IHD相关的心脏性猝死(SCO)的风险尚不清楚。此外，由于心律失常风险增加的报道，已经提出了重大的安全问题。到目前为止，几项研究表明，移植细胞与宿主细胞电耦合的能力是心律失常风险的重要决定因素。此外，通过加强干细胞对受损心肌部位的归巢来增强自然组织再生过程可能会提供进一步的好处。总的来说，我们假设细胞治疗降低心律失常易感性的能力将取决于它通过植入形成功能性电连接的存活细胞来增强梗死区的电生理活性的能力。因此，这项建议的一个主要目标是确定细胞治疗IHD的电生理益处，从而确定抗心律失常的结果，并通过利用基因治疗增强细胞间偶联和细胞归巢/植入来优化细胞治疗。为了实现这些目标，将利用新的光学标测技术和大鼠IHD模型来解决以下具体目标：1)开发和验证光学标测系统以研究大鼠心肌梗死(ML)相关SCD的细胞治疗。2)用ML确定细胞治疗对心脏电生理有益或有害的机制。3)建立与ML细胞治疗相关的全心抗心律失常或致心律失常机制。4)确定过表达连接蛋白(Cx40、Cx43和Cx45)和SDF-1(干细胞归巢因子)是否能显著增强SKMB和MSC对多发性骨髓瘤相关SCD的治疗作用。总体而言，这项研究将提高对细胞疗法治疗IHD的电生理学的理解，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与IHD相关的SCD的治疗方法。

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.