Autosomal Recessive Cardiomyopathy Presenting as Acute Myocarditis.

J Am Coll Cardiol

St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, New York; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Paris, France; Paris Descartes University, Sorbonne Paris Cité, Imagine Institute, Paris, France; Pediatric Immunology-Hematology Unit, AP-HP, Necker Hospital for Sick Children, Paris, France; Howard Hughes Medical Institute, The Rockefeller University, New York, New York.

Published: April 2017

AI Article Synopsis

  • Myocarditis is inflammation of the heart muscle typically following viral infections, but it's unclear why only a small number of children develop life-threatening forms of this condition despite the commonality of the viruses.
  • The study aimed to explore whether genetic factors, particularly involving TLR3 and interferon immunity, contribute to acute viral myocarditis in previously healthy children.
  • Findings showed that while certain rare gene variants linked to inherited heart diseases were more common in children with acute myocarditis, there was no significant evidence that TLR3 or interferon-related pathways were directly involved in increased susceptibility to the virus in heart muscle cells.

Article Abstract

Background: Myocarditis is inflammation of the heart muscle that can follow various viral infections. Why children only rarely develop life-threatening acute viral myocarditis (AVM), given that the causal viral infections are common, is unknown. Genetic lesions might underlie such susceptibilities. Mouse genetic studies demonstrated that interferon (IFN)-α/β immunity defects increased susceptibility to virus-induced myocarditis. Moreover, variations in human TLR3, a potent inducer of IFNs, were proposed to underlie AVM.

Objectives: This study sought to evaluate the hypothesis that human genetic factors may underlie AVM in previously healthy children.

Methods: We tested the role of TLR3-IFN immunity using human induced pluripotent stem cell-derived cardiomyocytes. We then performed whole-exome sequencing of 42 unrelated children with acute myocarditis (AM), some with proven viral causes.

Results: We found that TLR3- and STAT1-deficient cardiomyocytes were not more susceptible to Coxsackie virus 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. We did not observe a significant enrichment of rare variations in TLR3- or IFN-α/β-related genes. Surprisingly, we 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 42 patients (16.7%) carried rare biallelic (homozygous or compound heterozygous) nonsynonymous or splice-site variations in 6 cardiomyopathy-associated genes (BAG3, DSP, PKP2, RYR2, SCN5A, or TNNI3).

Conclusions: Previously silent recessive defects of the myocardium may predispose to acute heart failure presenting as AM, notably after common viral infections in children.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5551973PMC
http://dx.doi.org/10.1016/j.jacc.2017.01.043DOI Listing

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