Slow Conduction Velocity Revealed in Hypertrophic Cardiomyopathy Modelled With Patient-Derived Induced Pluripotent Stem Cell Cardiomyocytes

Hypertrophic cardiomyopathy (HCM) is an inherited cardiac disorder characterised by left ventricular hypertrophy ≥15 mm, resulting in arrhythmias, heart failure, and sudden cardiac death. In this study, we used an induced pluripotent stem cell model to identify the molecular basis of electrophysical changes resulting from HCM. We modelled HCM using cardiomyocytes from induced pluripotent stem cells (iPSC-CMs) derived from a patient carrying the HCM disease-causing Arg403Gln variant in myosin heavy chain 7 (MYH7403/+) compared with CRISPR-corrected isogenic iPSC-CMs (MYH7-C+/+). Electrical phenotypes in iPSC-CM monolayers were screened on a high-throughput multi-electrode array (MEA) platform. MYH7403/+ iPSC-CMs was associated with slowed conduction velocity, prolonged field potential duration, increased spatial dispersion of repolarisation, beating irregularities and pro-arrhythmia. Analysis of rhythmonome protein expression identified altered levels of gap-junction protein connexin-43 as well as Nav1.5, Cav1.2, Kir2.1 and Kir6.2 in MYH7403/+ iPSC-CMs relative to isogenic controls, consistent with the observed electrophysiological phenotypes. We show high-throughput screening platforms such as the MEA reveal phenotypic changes in MYH7403/+ iPSC-CMs associated with HCM. Our data indicate that altered conduction velocity and increased spatial dispersion of repolarisation may contribute to arrhythmia formation.