Human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) are commonly used to model arrhythmogenic cardiomyopathy (ACM), a heritable cardiac disease characterized by severe ventricular arrhythmias, fibrofatty myocardial replacement and progressive ventricular dysfunction. Although ACM is inherited as an autosomal dominant disease, incomplete penetrance and variable expressivity are extremely common, resulting in different clinical manifestations. Here, we propose hiPSC-CMs as a powerful in vitro model to study incomplete penetrance in ACM. Six hiPSC lines were generated from blood samples of three ACM patients carrying a heterozygous deletion of exon 4 in the PKP2 gene, two asymptomatic (ASY) carriers of the same mutation and one healthy control (CTR), all belonging to the same family. Whole exome sequencing was performed in all family members and hiPSC-CMs were examined by ddPCR, western blot, Wes™ immunoassay system, patch clamp, immunofluorescence and RNASeq. Our results show molecular and functional differences between ACM and ASY hiPSC-CMs, including a higher amount of mutated PKP2 mRNA, a lower expression of the connexin-43 protein, a lower overall density of sodium current, a higher intracellular lipid accumulation and sarcomere disorganization in ACM compared to ASY hiPSC-CMs. Differentially expressed genes were also found, supporting a predisposition for a fatty phenotype in ACM hiPSC-CMs. These data indicate that hiPSC-CMs are a suitable model to study incomplete penetrance in ACM.

We present the case of a 17-year-old asymptomatic boy with a diagnosis of arrhythmogenic cardiomyopathy. Merging of cardiac magnetic resonance imaging and three-dimensional electroanatomic mapping provided striking visualization of the association between structural and electrical alterations and guided the decision to implant an implantable cardioverter defibrillator. (Level of Difficulty: Intermediate.).

The primary etiology of a diverse range of cardiomyopathies is now understood to be genetic, creating a new paradigm for targeting treatments on the basis of the underlying molecular cause. This review provides a genetic and etiologic context for the traditional clinical classifications of cardiomyopathy, including molecular subtypes that may exhibit differential responses to existing or emerging treatments. The authors describe several emerging cardiomyopathy treatments, including gene therapy, direct targeting of myofilament function, protein quality control, metabolism, and others. The authors discuss advantages and disadvantages of these approaches and indicate areas of high potential for short- and longer term efficacy.

Patients with familial arrhythmogenic cardiomyopathy typically present with ventricular arrhythmias or progressive heart failure. This paper characterizes a rare presentation of an underlying genetic cardiomyopathy with clinical manifestations mimicking an acute myocardial infarction in 2 siblings, each with the same mutation in the desmoplakin (DSP) gene. (Level of Difficulty: Advanced.).

Impairments in certain cardiac genes confer risk for myocarditis in children. To determine the extent of this association, we performed genomic sequencing in predominantly adult patients with acute myocarditis and matched control subjects. Putatively deleterious variants in a broad set of cardiac genes were found in 19 of 117 acute myocarditis cases vs 34 of 468 control subjects (P = 0.003). Thirteen genes classically associated with cardiomyopathy or neuromuscular disorders with cardiac involvement were implicated, including >1 associated damaging variant in DYSF, DSP, and TTN. Phenotypes of subjects who have acute myocarditis with or without deleterious variants were similar, indicating that genetic testing is necessary to differentiate them.

Nuclear envelope proteins have been shown to play an important role in the pathogenesis of inherited dilated cardiomyopathy. Here, we present a remarkable cardiac phenotype caused by a homozygous LEMD2 mutation in patients of the Hutterite population with juvenile cataract. Mutation carriers develop arrhythmic cardiomyopathy with mild impairment of left ventricular systolic function but severe ventricular arrhythmias leading to sudden cardiac death. Affected cardiac tissue from a deceased patient and fibroblasts exhibit elongated nuclei with abnormal condensed heterochromatin at the periphery. The patient fibroblasts demonstrate cellular senescence and reduced proliferation capacity, which may suggest an involvement of LEM domain containing protein 2 in chromatin remodeling processes and premature aging.