A human pluripotent stem cell model of catecholaminergic polymorphic ventricular tachycardia recapitulates patient-specific drug responses

Abstract

Although β-blockers can be used to eliminate stress-induced ventricular arrhythmias in patients with catecholaminergic polymorphic ventricular tachycardia (CPVT), this treatment is unsuccessful in ∼25% of cases. Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) generated from these patients have potential for use in investigating the phenomenon, but it remains unknown whether they can recapitulate patient-specific drug responses to β-blockers. This study assessed whether the inadequacy of β-blocker therapy in an individual can be observed in vitro using patient-derived CPVT iPSC-CMs. An individual with CPVT harboring a novel mutation in the type 2 cardiac ryanodine receptor (RyR2) was identified whose persistent ventricular arrhythmias during β-blockade with nadolol were abolished during flecainide treatment. iPSC-CMs generated from this patient and two control individuals expressed comparable levels of excitation-contraction genes, but assessment of the sarcoplasmic reticulum Ca2+ leak and load relationship revealed intracellular Ca2+ homeostasis was altered in the CPVT iPSC-CMs. β-adrenergic stimulation potentiated spontaneous Ca2+ waves and unduly frequent, large and prolonged Ca2+ sparks in CPVT compared with control iPSC-CMs, validating the disease phenotype. Pursuant to the patient's in vivo responses, nadolol treatment during β-adrenergic stimulation achieved negligible reduction of Ca2+ wave frequency and failed to rescue Ca2+ spark defects in CPVT iPSC-CMs. In contrast, flecainide reduced both frequency and amplitude of Ca2+ waves and restored the frequency, width and duration of Ca2+ sparks to baseline levels. By recapitulating the improved response of an individual with CPVT to flecainide compared with β-blocker therapy in vitro, these data provide new evidence that iPSC-CMs can capture basic components of patient-specific drug responses.

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

“…47 Using hiPSC-CMs to establish disease-in-a-dish models may allow the study of diseased human cardiomyocytes in a patient-specific manner. Subsequently, many hiPSC-CMs models of both CPVT types [20][21][22][23][24][25][26][27][28][29] were shown to recapitulate the clinical phenotype in the culture-dish by displaying abnormal Ca 2+ handling and arrhythmias. Here, we focused on CPVT2 and found, similar to previous reports, 24,25,29 21,30 We recently investigated this phenomenon in a CPVT1-hiPSC-CMs model demonstrating a reduced SOICR threshold in the affected cells.…”

“…These findings may suggest that hiPSC-based models could potentially aid in predicting patient/specific clinical response, as was also evident from a recent report comparing the flecainide clinical response with in vitro findings using hiPSC-CMs from a CPVT1 patient. 28 Although of significant potential, hiPSC-CM-based disease models of arrhythmogenic syndromes are not flawless. One limitation of such models, including our current work, is that cells are usually obtained from only a small number of individuals (because of the rare incidence of such syndromes and to the large amount of work associated with creation and detailed characterization of the generated cell lines), and hence, the results of these studies cannot necessarily be generalized to differences between patient populations.…”

“…7,8 In the cardiac field, hiPSCs were established from healthy individuals and from patients inflicted with acquired 9 and several types of inherited cardiac disorders. 10,11 Patient-specific hiPSC-derived cardiomyocyte (hiPSC-CM) models of different inherited arrhythmogenic syndromes (including the long-QT, [12][13][14][15] Brugada, 16 and sodium channel overlap 17 syndromes; arrhythmogenic right ventricular cardiomyopathy 18,19 ; and both types of CPVT [20][21][22][23][24][25][26][27][28][29] ) were…”

Modeling Inherited Arrhythmia Disorders Using Induced Pluripotent Stem Cell-Derived Cardiomyocytes

“…In addition, inositol-3-phosphate receptor contributes to a much greater proportion of calcium transients that in adult CMs, another feature consistent with immaturity. 52,53 Despite these differences in calcium handling between hiPSC-CMs and adult ventricular CMs, hiPSC-CMs have been productively used to model diseases such as CPVT that are caused by mutations that affect calcium handling 54–57 (Table 2). …”

“…To date, there are five hiPSC-CM models of RYR2 mutations have been described 54,55,57,84,85 . These cover three of the four regions of RYR2 where the vast majority of pathogenic mutations have been described 8 .…”