Understanding Early Drivers and Therapeutic Targets for Severe Forms of Arrhythmogenic Cardiomyopathy

Summary Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is an incurable genetic based cardiac disease that causes sudden death in young people, including pediatric populations. ARVD/C is termed a “disease of the desmosome” as majority of mutations are found in desmosomal (junctional anchor) genes. Cardiac inflammation, manifested as myocarditis, is an early component of ARVD/C, especially in pediatric patients and patients with mutations in the desmosomal gene, desmoplakin (DSP). However, no models and limited mechanistic insights exist of a direct causal relationship between inflammation and episodic myocardial injuries that drive DSP cardiomyopathy and what therapeutics would be impactful. We provide evidence for preclinical mouse models of DSP cardiomyopathy harboring inflammation, one of which is provoked by acute inflammatory stress to drive chronic myocarditis in DSP cardiomyopathy, providing platforms to dissect immune cell mediators. We show significant focal cardiac T cell infiltration in mice with DSP cardiomyopathy and that early use of CD4+T cell neutralizing antibodies can attenuate ensuing cardiac enlargement and pathology in these mice suggestive of T cells as mediators of DSP cardiomyopathy. We report the presence of human DSP peptides in a human immunopeptidome database suggesting DSP’s potential direct involvement as an antigens, which may explain T cell responses. We show T cell infiltration in explanted human heart tissue from a pediatric patient harboring two pathogenic DSP mutations, suggesting a T cell response that may be driven by DSP antigenic functions in the human heart. Early T cell involvement and as mediators of ARVD/C helps explain our report of asymptomatic patients with pathogenic DSP heterozygous mutations presenting early with recurrent myocarditis prior to the diagnosis of ARVD/C. Thus, understanding the immune response that underlies DSP cardiomyopathy can identify vulnerabilities in immune cell and antigen recognition that may drive disease and optimize immunotherapies for this subgroup. Loss of the gap junction protein, connexin43 (a primary target of DSP protein loss) is a key molecular alteration in DSP cardiomyopathy and we show that connexin43 upregulation via gene therapy is therapeutic and prevents myocarditis driven DSP cardiomyopathy. We hypothesize that DSP gene mutations/loss impact connexin43 loss, which disrupts cardiomyocyte junctional integrity and primes pathogenic T cells (via DSP antigen exposure) to drive chronic inflammation/myocarditis in ARVD/C. Connexin43 targeted strategies can therapeutically intervene with myocarditis driven DSP cardiomyopathy. We aim to define: (i) the immune cell mediators, (ii) triggers, and (iii) therapeutics that intervene with myocarditis in DSP cardiomyopathy.