Autosomal Recessive Cardiomyopathy Presenting as Acute Myocarditis

被引:90
作者
Belkaya, Serkan [1 ]
Kontorovich, Amy R. [2 ,3 ,4 ]
Byun, Minji [1 ]
Mulero-Navarro, Sonia [2 ,3 ]
Bajolle, Fanny [5 ]
Cobat, Aurelie [6 ]
Josowitz, Rebecca [2 ,3 ]
Itan, Yuval [1 ]
Quint, Raphaelle [1 ]
Lorenzo, Lazaro [6 ]
Boucherit, Soraya [6 ,7 ]
Stoven, Cecile [8 ]
Di Filippo, Sylvie [9 ]
Abel, Laurent [1 ,6 ,7 ]
Zhang, Shen-Ying [1 ,6 ,7 ]
Bonnet, Damien
Gelb, Bruce D. [2 ,3 ]
Casanova, Jean-Laurent [1 ,6 ,7 ,10 ,11 ]
机构
[1] Rockefeller Univ, St Giles Lab Human Genet Infect Dis, Rockefeller Branch, 1230 York Ave, New York, NY 10021 USA
[2] Icahn Sch Med Mt Sinai, Mindich Child Hlth & Dev Inst, Dept Pediat, New York, NY 10029 USA
[3] Icahn Sch Med Mt Sinai, Mindich Child Hlth & Dev Inst, Dept Genet & Genom Sci, New York, NY 10029 USA
[4] Icahn Sch Med Mt Sinai, Zena & Michael A Wiener Cardiovasc Inst, New York, NY 10029 USA
[5] Paris Descartes Univ, Ctr Reference Malformat Cardiaques Congenitales C, Necker Hosp Sick Children, AP HP,Sorbonne Paris Cite, Paris, France
[6] INSERM, U1163, Necker Branch, Lab Human Genet Infect Dis, Paris, France
[7] Paris Descartes Univ, Sorbonne Paris Cite, Imagine Inst, Paris, France
[8] CHU Reunion, Site GHSR, Serv Pediat Gen, St Denis, La Reunion, France
[9] Hosp Civils Lyon, Cardiovasc Louis Pradel Hosp, Pediat Cardiol & Congenital Heart Dis Dept, Lyon, France
[10] Necker Hosp Sick Children, AP HP, Pediat Immunol Hematol Unit, Paris, France
[11] Rockefeller Univ, Howard Hughes Med Inst, New York, NY 10021 USA
基金
美国国家卫生研究院;
关键词
cardiomyocytes; children; genetics; immunity; sequencing; virus; RIGHT-VENTRICULAR DYSPLASIA/CARDIOMYOPATHY; CARDIOVASCULAR MAGNETIC-RESONANCE; TOLL-LIKE RECEPTOR-3; DILATED CARDIOMYOPATHY; GENETIC-VARIANTS; HYPERTROPHIC CARDIOMYOPATHY; ENDOMYOCARDIAL BIOPSY; MUSCULAR-DYSTROPHY; VIRAL MYOCARDITIS; INNATE IMMUNITY;
D O I
10.1016/j.jacc.2017.01.043
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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)-alpha/beta 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-alpha/beta and IFN-alpha/beta-stimulated genes in control cardiomyocytes. Finally, exogenous IFN-alpha did not substantially protect cardiomyocytes against CVB3. We did not observe a significant enrichment of rare variations in TLR3-or IFN-alpha/beta-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. (C) 2017 by the American College of Cardiology Foundation.
引用
收藏
页码:1653 / 1665
页数:13
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