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

致心律失常性右室心肌病属于原发性心肌病组，与年轻的、明显心脏健康的患者心源性猝死有关，在高强度运动时运动员中占多数。它伴随着结构的变化，如心肌萎缩，纤维脂肪替代和室壁厚度减少，心腔扩大。然而，心律失常是如何进展的，以及基因突变和体力活动是如何导致心脏病理变化的，仍然难以捉摸。我们假设，由PKP2的变化引起的钠通道定位及其调节剂CaMKII的变化建立了以体力活动为主要触发因素的底物。因此，我们计划对具有杂合性功能丧失突变的小鼠进行为期8周的每天8小时的训练。在此训练期之后，我们将对体内和体外的心脏进行分析。首先，对动物进行超声心动图检查，然后对分离的心肌细胞和分离的心脏进行分析，以确定和分析心律失常发生的关键因素。首先，将利用免疫荧光法分析离子通道和调节剂的定位，并将利用膜片钳和钙成像技术进一步研究这些蛋白质的功能。将分析这些桥粒形态改变的动物的离体心脏的细胞间通讯，以及来自ARVC9突变患者的患者特异性诱导的多能干细胞的组织楔形组织中的细胞间通讯，以更好地了解桥粒疾病对收缩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，以及体育活动如何影响其发病机制。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.