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Autosomal Recessive Cardiomyopathy Presenting as Acute Myocarditis.

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)-?/? 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-?/? and IFN-?/?-stimulated genes in control cardiomyocytes. Finally, exogenous IFN-? did not substantially protect cardiomyocytes against CVB3. We did not observe a significant enrichment of rare variations in TLR3- or IFN-?/?-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.

SUBMITTER: Belkaya S

PROVIDER: S-EPMC5551973 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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Autosomal Recessive Cardiomyopathy Presenting as Acute Myocarditis.

Belkaya Serkan S Kontorovich Amy R AR Byun Minji M Mulero-Navarro Sonia S Bajolle Fanny F Cobat Aurelie A Josowitz Rebecca R Itan Yuval Y Quint Raphaelle R Lorenzo Lazaro L Boucherit Soraya S Stoven Cecile C Di Filippo Sylvie S Abel Laurent L Zhang Shen-Ying SY Bonnet Damien D Gelb Bruce D BD Casanova Jean-Laurent JL

Journal of the American College of Cardiology 20170401 13

<h4>Background</h4>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 ...[more]

PMID: 28359509

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Project description:Acute myocarditis is an inflammatory disease of the myocardium, and it can present as severe heart failure in children. Differential diagnosis with genetic cardiomyopathy can be difficult. The objective of this study is to identify patterns of clinical presentation and to assess invasive and non-invasive measures to differentiate patients with acute myocarditis from patients with dilated genetic cardiomyopathy. We performed a retrospective descriptive study of all paediatric patients (0-16 years old) that presented with new-onset heart failure with left ventricle ejection fraction < 35% in whom we performed an endomyocardial biopsy (EMB) during the period from April 2007 to December 2020. The patients were classified into two groups: Group 1 included 18 patients with myocarditis. Group 2 included 9 patients with genetic cardiomyopathy. Findings favouring a diagnosis of myocarditis included a fulminant or acute presentation (77.8% vs 33.3%, p = 0.01), higher degree of cardiac enzyme elevation (p = 0.011), lower left ventricular dimension z-score (2.2 vs 5.4, p = 0.03) increase of ventricular wall thickness (88.8% vs 33.3%, p = 0.03) and oedema in the EMB. Seven (77.8%) patients with genetic cardiomyopathy had inflammation in the endomyocardial biopsy fulfilling the diagnostic criteria of inflammatory cardiomyopathy.Conclusion: Differentiating patients with a myocarditis from those with genetic cardiomyopathy can be challenging, even performing an EMB. Some patients with genetic cardiomyopathy fulfil the diagnostic criteria of inflammatory cardiomyopathy. Using invasive and non-invasive measures may be useful to develop a predictive model to differentiate myocarditis from genetic cardiomyopathy. What is Known: • Acute myocarditis could present with cardiogenic shock in paediatric patients. • Parvovirus B19 is the main cause of myocarditis in this population. What is New: • Current diagnostic criteria for myocarditis have limited use in paediatric patients presenting with new-onset heart failure. • Some patients with a genetic cardiomyopathy and a new-onset heart failure fulfill the diagnostic criteria of inflammatory cardiomyopathy.

Dataset Information

Autosomal Recessive Cardiomyopathy Presenting as Acute Myocarditis.

Publications

Autosomal Recessive Cardiomyopathy Presenting as Acute Myocarditis.

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