Induced Pluripotent Stem Cell-Derived Cardiomyocytes Recapitulate Clinically Observed Refractoriness to Therapeutic beta-Blockade in a Patient Specific Model of Catecholaminergic Polymorphic Ventricular Tachycardia

Introduction: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmia syndrome characterized by diastolic store overload-induced Ca2+ waves during β-adrenergic receptor (β-AR) stimulation. Mysteriously, β-blockers are ineffective at abolishing stress-induced ventricular arrhythmias in ~25% of patients. Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) generated from these CPVT patients offer an attractive system for investigating the phenomenon, but it remains unknown whether iPSC-CMs can recapitulate clinically observed patient-specific drug responses. Hypothesis: This study assessed the hypothesis that patient-specific refractoriness to β-blocker therapy can be observed in vitro using CPVT iPSC-CMs. Methods: We generated iPSC-CMs from a control individual and a CPVT patient insensitive to the widely prescribed β-blocker nadolol, but responsive to flecainide, and compared the efficacy of the two drugs in vitro in diminishing diastolic Ca2+ waves and restoring...