FL 956/1-1: Investigation of mechanisms of ventricular arrhythmias in hypertrophic cardiomyopathy in a mouse model and patient specimen

Hypertrophic cardiomyopathy (HCM) is one of the most common inherited cardiac diseases. It is mainly characterized by a thickening of primarily the left ventricle, which can impair the pump function of the heart. Furthermore, patients often suffer from cardiac arrhythmias, which can occur in both the atria and the ventricles. Ventricular arrhyhthmias are life-threatening events which can occur before any other indication of HCM has occured. How these arrhythmias are caused is unknown. Findings in mice which carry a disease-casuing mutation in the gene encoding cardiac troponin T indicate that an increased calcium sensitivity of the myofilaments in cardiac myocytes could cause arrhythmias. These mice do not show a thickening of the heart, but have an increased susceptibility to arrhythmia occurence under beta-adrenergic stimulation. This was accompanied by a shortening of ventricular action potentials. We are working with Mybpc3-KI mice, which develop HCM because they carry a patient-found mutation in the gene encoding cardiac myosin-binding protein c. Cardiac myocytes and muscle strips of these mice also developed an increased number of arrhythmias under beta-adrenergic stimulation compared to controls. This model also shows an increased calcium sensitivity of the myofilaments and, other than the troponin T model, a thickening of the heart and a prolongation of ventricular action potentials, at least if mice carry the Mybpc3 mutation homozygously. This indicates that not all mutations which cause an increased calcium sensitivity of the myofilaments influence ventricular action potentials in the same way. Furthermore it seems like there are changes in homozygous Mybpc3-KI which additionally modulate the action potential. This project aims at identifying these changes and at clarifying if they add to increased arrhythmia susceptibility or if this is solely caused by increased calcium sensitivity of the myofilaments. Mice which carry the Mybpc3 mutation heterozygously develop increased calcium sensitivity of the myofilaments without a thickening of the heart and are therefore helpful for the study. The findings made in the mouse model will be verified in specimen from hearts of HCM patients. This will help to identify mechanisms which cause arrhythmias and to clarify if these mechanisms differ in patients with and without a thickening of the heart muscle. With the help of this project we hope to find new targets for pharmacological therapy of ventricular arrhythmias.