Electrophysiological and antiarrhythmic benefit of cell therapy for heart disease

描述（由申请人提供）：缺血性心脏病（IHD）是美国死亡的主要原因，对心肌造成不可逆转的损害。最近的研究表明，心脏功能可以通过添加新的健康细胞，如骨骼肌成肌细胞（SKMB）或骨髓来源的间充质干细胞（MSC）来恢复。细胞治疗的早期结果令人鼓舞，并表明血液动力学改善；然而，尚不清楚细胞疗法是否能降低与IHD相关的心源性猝死（SCO）风险。此外，由于心律失常风险增加的报道，严重的安全性问题已经提出。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，通过增强干细胞在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益处。总的来说，我们假设细胞疗法降低心律失常易感性的能力将取决于其通过植入形成功能性电连接的活细胞来增强梗死区电生理活力的能力。因此，本提案的主要目标是确定IHD细胞治疗的电生理益处，从而确定抗心律失常的结果，并通过使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，将利用新的光学定位技术和IHD大鼠模型来实现以下具体目标：1)开发和验证光学定位系统，以研究大鼠心肌梗死（Ml）相关SCD的细胞治疗。2)确定细胞治疗对心肌梗死心脏电生理有益或有害的机制。3)建立与全心脏心肌梗死细胞治疗相关的抗心律失常或促心律失常机制。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细胞治疗Ml相关性SCD的效果。总的来说，本研究将提高对IHD细胞治疗电生理的认识，为更广泛、更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.