Pharmacological Modulation of Calcium Homeostasis in Familial Dilated Cardiomyopathy: An In Vitro Analysis From an RBM20 Patient‐Derived iPSC Model

For inherited cardiomyopathies, abnormal sensitivity to intracellular calcium (Ca 2+ ), incurred from genetic mutations, initiates subsequent molecular events leading to pathological remodeling. Here, we characterized the effect of β‐adrenergic stress in familial dilated cardiomyopathy (DCM) using human‐induced pluripotent stem cell (hiPSC)‐derived cardiomyocytes (CMs) from a patient with RBM20 DCM. Our findings suggest that β‐adrenergic stimulation accelerated defective Ca 2+ homeostasis, apoptotic changes, and sarcomeric disarray in familial DCM hiPSC‐CMs. Furthermore, pharmacological modulation of abnormal Ca 2+ handling by pretreatment with β‐blocker, carvedilol, or Ca 2+ ‐channel blocker, verapamil, significantly decreased the area under curve, reduced percentage of disorganized cells, and decreased terminal deoxynucleotidyl transferase‐mediated deoxyuridine triphosphate nick‐end labeling (TUNEL)‐positive apoptotic loci in familial DCM hiPSC‐CMs after β‐adrenergic stimulation. These translational data provide patient‐based in vitro analysis of β‐adrenergic stress in RBM20 ‐deficient familial DCM hiPSC‐CMs and evaluation of therapeutic interventions to modify heart disease progression, which may be personalized, but more importantly generalized in the clinic.