Abstract P3093: Early Myocarditis In The Desmoglein 2 Mutant Mouse Model Of Arrhythmogenic Cardiomyopathy

Abstract

Arrhythmogenic cardiomyopathy (ACM) is an inherited disease caused by mutations in desmosome proteins. Patients with ACM are born with normal hearts but develop arrhythmias, fibrofatty infiltration, and sudden death. The desmoglein 2 (DSG2) mutant mouse is a well-established model of ACM that recapitulates the human phenotype of the disease. This mouse develops severe ventricular arrhythmias, systolic dysfunction, myocardial fibrosis and exercise induced sudden death. Here, we present evidence of early myocardial immune cell infiltration as well as an inverse relationship between cardiac function and adult myocardial cytokine expression in DSG2 mutant mice. We examined 20 week old adult DSG2 homozygote mice and wildtype littermate controls for systolic function using echocardiography, cytokine expression using rtPCR and fibrosis using masons trichrome staining. Consistent with previous studies we found ventricular fibrosis is significantly increased in mutant hearts (p=0.003). We demonstrate that osteopontin, an inflammatory cytokine released by macrophages, is highly expressed in these hearts (p=2.0x10 -4 ). We detected an inverse correlation between systolic function and the osteopontin expression levels in these mutant mice (p=0.0015, r=-0.8315, R 2 =0.6914). These results lead us to suspect that immune cell infiltration may contribute to the disease progression. Subsequently, we examined immune cell populations in 3 week old DSG2 hearts, a period of time before the development of fibrosis, systolic dysfunction or arrhythmias. We measured >40-fold higher number of CD45 + leukocytes (with increased Ly6G + neutrophils and Ly6C + monocytes) within the heart muscle of DSG2 homozygotes via flow cytometry (p=7.4x10 -5 ), consistent with myocarditis. These results suggest myocarditis precedes fibrosis in the DSG2 mutant mouse model. Our ongoing work is focused on further characterizing the immune response in early post-natal life in the DSG2 mouse heart and determining whether early myocarditis contributes to the phenotype in ACM. Our results highlight potentially novel therapeutic targets to prevent disease progression in ACM.