Abstract GS.12: A New Mouse Model To Investigate The Early Steps Of Arrhythmogenic Cardiomyopathy

Abstract

Arrhythmogenic Cardiomyopathy (ACM) is characterized by progressive loss of cardiomyocytes with fibrosis, systolic dysfunction and life-threatening arrhythmias. Mutations in genes of the desmosomal adhesion complex such as desmoglein-2 (Dsg2) are the major cause, but the underlying mechanisms leading to the disease are not well understood. Accordingly, only symptomatic treatment is available. Here, we establish an inducible Dsg2-W2A knock-in mouse model with temporal control of disease onset as new approach to analyse the early processes underlying the ACM phenotype. We have previously characterized a constitutive Dsg2-W2A knock-in model which develops a cardiac phenotype bearing all major criteria of ACM directly after birth. To control the onset of disease, we now generated a mouse line bearing the Dsg2-W2A mutation and a loxP -flanked Dsg2 on separate alleles, leading to functional hemizygosity of the Dsg2-W2A mutation upon tamoxifen-induced Cre expression. Detailed characterization of this iDsg2-W2A model revealed early repolarization changes in ECG recordings starting directly after induction and progression to extensive impairment of electrical conduction over 10 weeks. These changes were paralleled with the appearance of ventricular and supraventricular arrhythmias. Starting two weeks after induction, reduced cardiac output function of the right and later of the left ventricle was detectable via echocardiography. Finally, these mice developed structural changes with loss of cardiomyocytes and ventricular fibrosis similar to ACM patients. This study gives detailed insight on the early steps of ACM showing a sequence from changes in conduction, occurrence of arrhythmia to functional impairment, starting in the right and progressing to the left ventricle, together with structural changes of the heart. We expect this model to be valuable to discern patho-mechanisms in detail and to identify and test novel treatment options for ACM.