Genetics of myocarditis in arrhythmogenic right ventricular dysplasia

Lopez-Ayala, Jose Maria; Pastor-Quirante, Francisco; González-Carrillo, Josefa; López-Cuenca, David; Sánchez-Muñoz, Juan J.; Oliva-Sandoval, María José; Gimeno, Juan R.

doi:10.1016/j.hrthm.2015.01.001

Cited by 114 publications

(100 citation statements)

References 22 publications

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“…It also highlights the possibility of overlapping between clinical phenotypes induced by desmin mutations, as has been reported for mutations in other genes 7, 8. This clinical presentation of “pseudo-myocarditis” has already been reported in other genetic cardiomyopathies, such as arrhythmogenic right ventricular cardiomyopathy 9, 10. Acute myocarditis may reflect an “active phase” of the underlying genetic cardiomyopathy and may play a role in the acceleration of myocardial involvement 11, 12.…”

Section: Discussionsupporting

confidence: 61%

Recurrent suspected myocarditis combined with infrahisian conduction disturbances revealing a desminopathy

Boulé

Richard

Groote

et al. 2015

HeartRhythm Case Reports

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Section: Discussionsupporting

confidence: 61%

Recurrent suspected myocarditis combined with infrahisian conduction disturbances revealing a desminopathy

Boulé

Richard

Groote

et al. 2015

HeartRhythm Case Reports

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“…A viral etiology has been directly implicated in acute deteriorations in hypertrophic cardiomyopathy (33) and DMD-associated DCM (34) through polymerase chain reaction identification of viral genomes in myocardial samples. For ARVC, myocarditis has been documented histologically in association with clinical deterioration (19), and viral genomes have been detected in ARVC myocardial samples at higher rates than in controls (35). …”

Section: Discussionmentioning

confidence: 99%

Autosomal Recessive Cardiomyopathy Presenting as Acute Myocarditis

Belkaya

Kontorovich

Byun

et al. 2017

Journal of the American College of Cardiology

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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 We evaluated the hypothesis that human genetic factors might underlie AVM in previously healthy children. METHODS We tested the role of TLR3-IFN immunity utilizing 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 etiologies. RESULTS We 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. 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 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.

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“…This study identified a small molecule that rescues the phenotype, moving ever closer to a therapeutic target in humans that addresses the molecular basis of disease. An intriguing recent finding by the Lopez-Ayala et al 132 circles back to the role of myocarditis in ARVC, notably reporting an association between acute episodes of myocarditis and the progression of underlying disease. Furthermore, it may be the case that certain mutations increase susceptibility to an environmental insult, such as viral myocarditis.…”

Section: Cause Of Cardiomyopathy: Role Of Deep Phenotyping and Precismentioning

confidence: 98%

“…Furthermore, it may be the case that certain mutations increase susceptibility to an environmental insult, such as viral myocarditis. 132 The theme of abnormal genotypic backdrop and subsequent environmental insult triggering presentation or progression of phenotype is likely to be common among many forms of cardiomyopathy on further investigation. Certainly, there are emerging associations reclassifying peripartum cardiomyopathy as part of familial dilated cardiomyopathy.…”

Section: Cause Of Cardiomyopathy: Role Of Deep Phenotyping and Precismentioning

confidence: 99%