RESUMEN
Hypertrophic cardiomyopathy (HCM) is an inherited heart muscle disease that is characterised by left ventricular wall thickening, cardiomyocyte disarray and fibrosis, and is associated with arrhythmias, heart failure and sudden death. However, it is unclear to what extent the electrophysiological disturbances that lead to sudden death occur secondary to structural changes in the myocardium or as a result of HCM cardiomyocyte electrophysiology. In this study, we used an induced pluripotent stem cell model of the R403Q variant in myosin heavy chain 7 (MYH7) to study the electrophysiology of HCM cardiomyocytes in electrically coupled syncytia, revealing significant conduction slowing and increased spatial dispersion of repolarisation - both well-established substrates for arrhythmia. Analysis of rhythmonome protein expression in MYH7 R403Q cardiomyocytes showed reduced expression of connexin-43 (also known as GJA1), sodium channels and inward rectifier potassium channels - a three-way hit that reduces electrotonic coupling and slows cardiac conduction. Our data represent a previously unreported, biophysical basis for arrhythmia in HCM that is intrinsic to cardiomyocyte electrophysiology. Later in the progression of the disease, these proarrhythmic phenotypes may be accentuated by myocyte disarray and fibrosis to contribute to sudden death.
Asunto(s)
Cardiomiopatía Hipertrófica , Conexina 43 , Sistema de Conducción Cardíaco , Miocitos Cardíacos , Cadenas Pesadas de Miosina , Conexina 43/metabolismo , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Humanos , Cardiomiopatía Hipertrófica/patología , Cardiomiopatía Hipertrófica/metabolismo , Cardiomiopatía Hipertrófica/fisiopatología , Cadenas Pesadas de Miosina/metabolismo , Cadenas Pesadas de Miosina/genética , Sistema de Conducción Cardíaco/metabolismo , Sistema de Conducción Cardíaco/fisiopatología , Células Madre Pluripotentes Inducidas/metabolismo , Miosinas Cardíacas/metabolismo , Miosinas Cardíacas/genética , Células Gigantes/metabolismo , Células Gigantes/patología , Arritmias Cardíacas/patología , Arritmias Cardíacas/metabolismo , Arritmias Cardíacas/fisiopatología , Potenciales de AcciónRESUMEN
Variants in the sodium voltage-gated channel alpha subunit 5 gene (SCN5A) produce variable cardiac phenotypes including Brugada syndrome, conduction disease and cardiomyopathy. These phenotypes can lead to life-threatening arrhythmias, heart failure, and sudden cardiac death. Novel variants in splice-site regions of SCN5A require functional studies to characterise their pathogenicity as they are poorly understood. The generation of an induced pluripotent stem cell line provides a valuable resource to investigate the functional effects of potential splice-disrupting variants in SCN5A.