Patient-Specific Drug Screening Using a Human Induced Pluripotent Stem Cell Model of Catecholaminergic Polymorphic Ventricular Tachycardia Type 2

Abstract

Background-Catecholaminergic polymorphic ventricular tachycardia type 2 (CPVT2) results from autosomal recessive CASQ2 mutations, causing abnormal Ca 2+ -handling and malignant ventricular arrhythmias. We aimed to establish a patient-specific human induced pluripotent stem cell (hiPSC) model of CPVT2 and to use the generated hiPSC-derived cardiomyocytes to gain insights into patient-specific disease mechanism and pharmacotherapy. Methods and Results-hiPSC cardiomyocytes were derived from a CPVT2 patient (D307H-CASQ2 mutation) and from healthy controls. Laser-confocal Ca 2+ and voltage imaging showed significant Ca 2+ -transient irregularities, marked arrhythmogenicity manifested by early afterdepolarizations and triggered arrhythmias, and reduced threshold for store overload-induced Ca 2+ -release events in the CPVT2-hiPSC cardiomyocytes when compared with healthy control cells. Pharmacological studies revealed the prevention of adrenergic-induced arrhythmias by β-blockers (propranolol and carvedilol), flecainide, and the neuronal sodium-channel blocker riluzole; a direct antiarrhythmic action of carvedilol (independent of its α/β-adrenergic blocking activity), flecainide, and riluzole; and suppression of abnormal Ca 2+ cycling by the ryanodine stabilizer JTV-519 and carvedilol. Mechanistic insights were gained on the different antiarrhythmic actions of the aforementioned drugs, with carvedilol and JTV-519 (but not flecainide or riluzole) acting primarily through sarcoplasmic reticulum stabilization. Finally, comparable outcomes were found between flecainide and labetalol antiarrhythmic effects in vitro and the clinical results in the same patient.Conclusions-These results demonstrate the ability of hiPSCs cardiomyocytes to recapitulate CPVT2 disease phenotype and drug response in the culture dish, to provide novel insights into disease and drug therapy mechanisms, and potentially to tailor patient-specific drug therapy. (Circ Arrhythm Electrophysiol. 2017;10:e004725.

Patient-Specific Induced Pluripotent Stem Cell–Based Disease Model for Pathogenesis Studies and Clinical Pharmacotherapy

“…The findings by Maizels et al 10 are consistent with prior findings of published iPSC-CM disease models of CPVT1 and CPVT2. Those studies found a propensity for diastolic Ca 2+ leak, increased incidence of EADs and DADs, and favorable therapeutic responses to beta blockers and flecainide.…”

“…In summary, Maizels et al 10 were able to demonstrate that iPSCs can recapitulate the disease phenotype of CPVT2. Their study provides important insights into disease and drug therapy mechanisms.…”

“…In this issue of the Journal, Maizels et al 10 established a patient- and disease-specific iPSC-cardiomyocyte (CM) model that recapitulates an autosomal-recessive type of catecholaminergic polymorphic ventricular tachycardia type 2 (CPVT2) with the D307H- CASQ2 mutation in vitro . By simultaneously recording Ca 2+ transients and optical action-potentials, they observed a complex interaction between Ca 2+ handling abnormalities and membrane potential changes.…”

“…To evaluate the potential of this CPVT2 iPSC-based model in prospectively predicting clinical drug effects in CPVT2, Maizels et al 10 then compared the in vitro drug testing findings in iPSC-CMs with the drug responses of the same patient. The authors found that flecainide significantly reduced isoproterenol and phenylephrine-induced arrhythmia in iPSC-CMs, which was congruent with patient exercise test results showing that treatment with flecainide ameliorated exercise-induced ventricular tachycardia.…”

Cardiac Conduction System in Congenitally Corrected Transposition of the Great Arteries and Its Clinical Relevance

“…Furthermore, the insights gained will likely also advance our understanding of the arrhythmogenicity of the failing right ventricle and risk stratification/prediction against sudden cardiac death. Finally it has become impossible to imagine a future of pacing without leadless systems and more importantly without biological therapies43, 44 that can restore automaticity or conduction so that current transvenous and epicardial systems become obsolete. This latter innovation is especially attractive for those patients with ccTGA, as they frequently require pacing at a much younger age than the conventional patient with AV block22 and therefore have many more years exposed to the risks of intravascular leads and generator replacement surgeries.…”