The Effect of Exercise on the Pathogenesis of ARVC in a Mouse Model and the Comparability to Patient Specific Cardiac Myocytes from Induced Pulripotent Stem Cells

致心律失常性右心室心肌病属于原发性心肌病组，与心脏健康的年轻患者的心源性猝死相关，主要发生在高强度活动期间的运动员中。它伴随沿着结构变化，如心肌萎缩、纤维脂肪替代和室壁厚度减少，但仍然不清楚心肌梗死是如何发展的，以及基因突变如何与体力活动相结合导致心脏的病理变化。我们假设，PKP2的变化引起的钠通道定位及其调节剂CaMKII的变化与身体活动的底物是ARVC中的一个主要触发因素。因此，我们计划运动具有杂合功能丧失突变的小鼠，每天8小时，持续8周。在此培训期后，我们将分析体内和体外心脏。首先，将通过超声心动图检查动物，随后，将分析分离的心肌细胞和分离的心脏，以识别和分析心肌发生过程中的关键参与者。首先，将使用免疫荧光分析离子通道和调节剂的定位，并通过膜片钳和钙成像技术进一步研究这些蛋白的功能。将分析来自这些具有改变的桥粒形态的动物的离体心脏中的细胞间通讯和来自具有ARVC 9突变的患者的患者特异性诱导多能干细胞的组织楔中的细胞间通讯，以更好地理解桥粒疾病对收缩性和细胞间通讯的影响。这项研究的结果将首次显示PKP2突变如何导致心律失常以及运动如何影响发病机制。这些数据将为更好的诊断系统和预防性治疗方案奠定基础。

Arrhythmogenic Right Ventricular Cardiomyopathy belongs to the group of primary cardiomyopathies und is associated to sudden cardiac death in young, apparently heart-healthy patients, with a predominant occurrence among athletic persons during high intensity activity. It comes along with structural changes such as myocardial atrophy, fibro-fatty replacement and a reduced wall thickness with an enlarged chamber.However, it remains elusive how arrhythmogenesis is progressing and how the genetic mutations in combination with physical activity lead to pathological changes in the heart. We hypothesize that, caused by the changes in PKP2, the changes in sodium channel localization and its modulator CaMKII build the substrate with physical activity being a main trigger for arrhythmogenesis in ARVC.Thus, we plan to exercise mice with a heterozygous loss-of-function mutation for 8 hours per day for a period of 8 weeks. After this training period, we will analyze the hearts in vivo and in vitro. First, the animals will be examined by echocardiography and subsequently, isolated cardiac myocytes and isolated hearts will be analyzed to identify and analyze the key players during arrhythmogenesis. First, the localization of ion channels and modulators will be analyzed using immunofluorescene and the function of these proteins will be further studied by patch clamp and Ca imaging techniques. The intercellular communication in isolated hearts from these animals with altered desmosomal morphology and in tissue wedges from patient specific induced pluripotent stem cells from patients with an ARVC9 mutation will be analyzed to better understand the impact of the desmosomal disorders on the contractility and intercellular communication. The results from this study will show for the first time how a PKP2 mutation can cause arrhythmia and how the pathogenesis can be influenced by physical activity. These data will set the basis for a better diagnosis system and preventive treatment options.