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Desmoplakin cardiomyopathy-an inherited cardiomyopathy presenting with recurrent episodes of acute myocardial injury.

ABSTRACT: We present two female patients with recurrent episodes of myocardial injury, consisting of acute chest pain and elevated cardiac markers without coronary artery disease. Cardiovascular magnetic resonance imaging identified extensive late gadolinium enhancement suggestive of an inherited cardiomyopathy. Genetic testing showed heterozygous pathogenic variants in the desmoplakin (DSP) gene, the gene coding for the desmoplakin protein, a structural protein found in the cardiac desmosome. Pathogenic variants in the DSP gene are associated with dilated and arrhythmogenic cardiomyopathy. DSP cardiomyopathies may cause recurring myocardial injury mimicking an acute coronary syndrome or myocarditis. Cardiac magnetic resonance imaging is key in its diagnosis due to its specifying imaging features. Genetic testing is essential for the evaluation and confirmation of the diagnosis.

SUBMITTER: Schoonvelde SAC

PROVIDER: S-EPMC10400739 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature

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Desmoplakin cardiomyopathy-an inherited cardiomyopathy presenting with recurrent episodes of acute myocardial injury.

Schoonvelde S A C SAC Hirsch A A Yap S C SC Verhagen J M A JMA van Slegtenhorst M A MA Segers D D van Loon J E JE Michels M M

Netherlands heart journal : monthly journal of the Netherlands Society of Cardiology and the Netherlands Heart Foundation 20221126 7-8

We present two female patients with recurrent episodes of myocardial injury, consisting of acute chest pain and elevated cardiac markers without coronary artery disease. Cardiovascular magnetic resonance imaging identified extensive late gadolinium enhancement suggestive of an inherited cardiomyopathy. Genetic testing showed heterozygous pathogenic variants in the desmoplakin (DSP) gene, the gene coding for the desmoplakin protein, a structural protein found in the cardiac desmosome. Pathogenic ...[more]

PMID: 36434384

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Project description: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.

Dataset Information

Desmoplakin cardiomyopathy-an inherited cardiomyopathy presenting with recurrent episodes of acute myocardial injury.

Publications

Desmoplakin cardiomyopathy-an inherited cardiomyopathy presenting with recurrent episodes of acute myocardial injury.

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