Investigating ventricular arrhythmia development in hypertrophic cardiomyopathy in a mouse model and patient samples

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Hypertrophic cardiomyopathy (HCM) is one of the most frequently inherited cardiac diseases. Its most prominent feature is a thickening of the left ventricle, which can cause an impairment of the pump function of the heart. Furthermore, HCM patients often suffer from rhythm disturbances in atria as well as ventricles. Ventricular arrhythmias are acutely life-threatening and can occur in patients which had been asymptomatic before. It is unknown how these arrhythmias are elicited. Findings from a study on mice which carry a HCM causing mutation in the gene for cardiac troponin T indicate that an increased myofilament calcium sensitivity, which is caused by the mutation, could be a cause for the arrhythmias. These mice did not have thickened ventricles, but showed an increased susceptibility for arrhythmias when beta-adrenergically stimulated. At the same time, ventricular action potentials were shortened. Cardiac muscle cells and strips isolated from the Mybpc3-KI mouse model used in our laboratory, which is based on a mutation found in patients in the gene encoding cardiac myosin-binding protein C, also showed increased arrhythmia susceptibility when beta-adrenergically stimulated. These mice also display increased myofilament calcium sensitivity, but when they carry the disease-causing mutation homozygously, they develop a thickening of the left ventricle and ventricular action potentials are prolonged. This is contrary to the findings made in the troponin T model and indicates that not all HCM mutations which cause increased myofilament calcium sensitivity do influence ventricular action potentials similarly. Additionally, it seems likely that hearts of homozygous Mybpc3-KI mice undergo changes which additionally influence the action potential. In this project, we want to investigate the characteristics of these changes and evaluate if they contribute to the increased arrhythmia susceptibility or if the increased myofilament calcium sensitivity is sufficient to explain it. For this, it will be helpful that mice which are heterozygous for the Mybpc3 mutation do display an increased calcium sensitivity of the myofilament, but do not develop a thickening of the heart. Our results will be validated in experiments using heart samples of HCM patients. This will help us to find possible causes for the increased incidence of ventricular arrhythmias and to clarify, if these causes are different in patients with and without a thickening of the heart. With the help of this project, we hope to find new effective pharmacological therapies for ventricular arrhythmias.