Abstract 18289: Acute Myocarditis as a Presentation of Autosomal Recessive Cardiomyopathy

Myocarditis is inflammation of the heart muscle, often attributed to viral infections. It is unknown why children only rarely manifest acute viral myocarditis (AVM) as the causal viral infections are common. Mouse models and one affected patient with TLR3 mutations have implicated defects in IFN-α/β immunity in AVM susceptibility. Acute myocarditis (AM) has also been associated with the progression of myocardial dysfunction in certain inherited cardiomyopathies. To test the hypothesis that human genetic factors may underlie AVM, we first explored the impact of TLR3/IFN immunity against coxsackievirus B3 (CVB3) infections of human induced pluripotent stem cell (iPSC)-derived cardiomyocytes (CMs) from healthy donors and individuals with TLR3 or STAT1 mutations. No difference in CVB3 copies was observed between control and mutant CMs at different time points (2-24 h) post-infection at multiplicity of infection (MOI) of 1. Virus-induced cytotoxicity was also not elevated in mutant CMs compared to the control at 24 h post-infection at various MOIs. Finally, exogenous IFN-α did not provide a dramatic protection against CVB3 in CMs. In parallel, we performed whole exome sequencing of 42 unrelated children with AM, some with proven AVM. No enrichment of rare variants in TLR3/IFN-related genes was observed. Rather, we found that biallelic, but not monoallelic, damaging variants with allele frequency P =3.6E-07) or patients with diseases other than AVM ( P =6.6E-07). Seven of 42 patients (16.7%) carried biallelic nonsynonymous or essential splicing variants in six cardiomyopathy genes ( BAG3 , DSP , PKP2 , RYR2 , SCN5A , or TNNI3 ). The TNNI3 splicing variant was documented to result in exon skipping using an in vitro assay. Overall, our in vitro modeling with iPSC-derived CMs and human genetic data suggest that inborn errors of innate immunity are not the primary cause of AM. AVM appears to be more commonly related to defects in cardiac structural proteins. Previously silent recessive defects of the myocardium may predispose to acute heart failure presenting as AM, notably after common viral infections.