Autosomal Recessive Cardiomyopathy and Acute Myocarditis

Study Questions:

Are there genetic factors that increase susceptibility to develop life-threatening acute viral myocarditis (AVM) in previously healthy children?


The investigators tested the role of TLR3-IFN immunity utilizing human-induced pluripotent stem cell-derived cardiomyocytes. They then performed whole exome sequencing of 42 unrelated children with acute myocarditis (AM), some with proven viral etiologies.


The investigators found that TLR3- and STAT1-deficient cardiomyocytes were not more susceptible to coxsackievirus B3 (CVB3) infection than control cells. Moreover, CVB3 did not induce IFN-α/β and IFN-α/β-stimulated genes in control cardiomyocytes. Finally, exogenous IFN-α did not substantially protect cardiomyocytes against CVB3. The authors did not observe a significant enrichment of rare variations in TLR3- or IFN-α/β-related genes. Surprisingly, they found that homozygous, but not heterozygous, rare variants in genes associated with inherited cardiomyopathies were significantly enriched in AM-AVM patients compared with healthy individuals (p = 2.22E-03) or patients with other diseases (p = 1.08E-04). Seven of forty-two patients (16.7%) carried rare biallelic nonsynonymous or splice-site variations in six cardiomyopathy-associated genes (BAG3, DSP, PKP2, RYR2, SCN5A, or TNNI3).


The authors concluded that silent recessive defects of the myocardium may predispose to acute heart failure presenting as acute viral myocarditis, notably after common viral infections.


This study reports that rare alleles altering cardiac-specific genes previously associated with typically dominant genetic cardiomyopathies are associated with AM and mediated through an autosomal recessive mechanism. It seems that AM is not primarily caused by inborn errors of TLR3-IFN immunity, but related to defects in cardiac structural proteins. Additional studies are needed to explore the mechanisms by which mutations altering structural cardiac proteins are associated with AM. Better understanding of whether the myocardium of such patients is more susceptible to viral infections per se, which may be related to defects in cell-intrinsic immunity or if viral infections indirectly destabilize vulnerable hearts, may lead to novel therapeutic and prophylactic strategies.

Clinical Topics: Arrhythmias and Clinical EP, Dyslipidemia, Heart Failure and Cardiomyopathies, Prevention, Genetic Arrhythmic Conditions, Lipid Metabolism, Acute Heart Failure

Keywords: Alleles, Cardiomyopathies, Coxsackievirus Infections, Exome, Heart Failure, Induced Pluripotent Stem Cells, Interferon-beta, Myocarditis, Myocardium, Myocytes, Cardiac, Ryanodine Receptor Calcium Release Channel, Secondary Prevention

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