Modeling Cardiomyopathy and Arrhythmias in Induced Pluripotent Stem Cell–Derived Cardiomyocytes

See Article by El-Battrawy et al D ilated cardiomyopathy (DCM) are genetic heart diseases associated with arrhythmias, which are sometimes fatal, and progressive heart failure leading to heart transplantation. In some instances, a cardiac-only phenotype with heart failure and sudden cardiac death, X-linked DCM, results from DMD mutations. The discovery of DMD mutations leading to DCM and arrhythmias provided the connection between mutations in the lamin A/C gene (LMNA) and DCM. LMNA mutations are responsible for a variety of phenotypes including LGMD1B (limb-girdle muscular dystrophy type 1B), Emery-Dreifuss muscular dystrophy, and DCM with or without conduction disease and with or without subclinical muscle involvement. 3 DCM caused by LMNA mutations have been extensively studied, and it has been shown that LMNA can cause a particularly malignant phenotype both in terms of refractory heart failure and severe ventricular arrhythmias causing premature sudden cardiac death. The identification of a distinct arrhythmogenic phenotype in laminopathies had an important clinical impact and, in the new 2017 American Heart Association/American College of Cardiology/Heart Rhythm Society guidelines, prompted specific recommendations for the prevention of sudden cardiac death in patient with LMNA mutations. 4 However, the susceptibility to arrhythmias in LMNA mutations carriers and in general in muscle dystrophies is not well understood, is not fully explained by the progressive myocardial fibrosis in later stages of the disease, and is not well recapitulated by animal models.