Abstract
ABSTRACTAlthough 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.
Highlights
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a life-threatening inherited arrhythmia that predisposes young individuals with structurally normal hearts to cardiac arrest
A follow-up exercise stress test at nineteen months revealed that multiform ventricular arrhythmias persisted despite β-blockade (Fig. 1D), with ventricular ectopy starting during stage 1 exercise and progressing to couplets during stage 3 exercise at a maximum heart rate of 138 bpm
In a follow-up stress test three weeks after starting flecainide, the patient was able to exercise to exhaustion with a peak heart rate during stage 3 exercise of 168 bpm and no ventricular ectopy (Fig. 1D)
Summary
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a life-threatening inherited arrhythmia that predisposes young individuals with structurally normal hearts to cardiac arrest. Evidence suggests that the majority of RyR2 mutations promote catecholamine-driven spontaneous Ca2+ release from the SR during diastole by reducing the threshold for store overload-induced Ca2+ release (Jiang et al, 2005) These diastolic Ca2+-release events generate an electrogenic, depolarizing transient inward current that leads to delayed afterdepolarizations (DADs) and triggered arrhythmias in CPVT (Paavola et al, 2007). Several reports have demonstrated pharmacological rescue of mutant RyR2 function in human CPVT iPSC-CMs (Itzhaki et al, 2012; Jung et al, 2012; Di Pasquale et al, 2013; Zhang et al, 2013), few studies directly correlate in vitro patient-specific drug response differentials to in vivo clinical data. A notable proof-of-principle study for this paradigm demonstrated that CPVT patient-derived iPSC-CMs can replicate in vivo individual drug responses to dantrolene in a mutation-specific manner (Penttinen et al, 2015). Before patient-derived iPSC-CMs can be widely utilized for precision medicine, their capacity to model in vivo therapeutic idiosyncrasies must be comprehensively established
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