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

• Applicants: Dr. Karin Hammer, Ph.D.; Professor Dr. Stefan Wagner
• Subject Area: Cardiology, Angiology
• Term: from 2017 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 393118545

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.

• DFG Programme: Research Grants