Abstract
Coordinated release of calcium (Ca2+) from the sarcoplasmic reticulum (SR) through cardiac ryanodine receptor (RYR2) channels is essential for cardiomyocyte function. In catecholaminergic polymorphic ventricular tachycardia (CPVT), an inherited disease characterized by stress-induced ventricular arrhythmias in young patients with structurally normal hearts, autosomal dominant mutations in RYR2 or recessive mutations in calsequestrin lead to aberrant diastolic Ca2+ release from the SR causing arrhythmogenic delayed after depolarizations (DADs). Here, we report the generation of induced pluripotent stem cells (iPSCs) from a CPVT patient carrying a novel RYR2 S406L mutation. In patient iPSC-derived cardiomyocytes, catecholaminergic stress led to elevated diastolic Ca2+ concentrations, a reduced SR Ca2+ content and an increased susceptibility to DADs and arrhythmia as compared to control myocytes. This was due to increased frequency and duration of elementary Ca2+ release events (Ca2+ sparks). Dantrolene, a drug effective on malignant hyperthermia, restored normal Ca2+ spark properties and rescued the arrhythmogenic phenotype. This suggests defective inter-domain interactions within the RYR2 channel as the pathomechanism of the S406L mutation. Our work provides a new in vitro model to study the pathogenesis of human cardiac arrhythmias and develop novel therapies for CPVT.
Highlights
RESULTSCatecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited life-threatening arrhythmia leading to syncope and sudden cardiac death at a young age
In catecholaminergic polymorphic ventricular tachycardia (CPVT), an inherited disease characterized by stress-induced ventricular arrhythmias in young patients with structurally normal hearts, autosomal dominant mutations in RYR2 or recessive mutations in calsequestrin lead to aberrant diastolic Ca2þ release from the sarcoplasmic reticulum (SR) causing arrhythmogenic delayed after depolarizations (DADs)
It may be possible that selected mutations alter FKBP12.6 binding to RYR2, this hypothesis has been recently challenged and increasing body of evidence clearly demonstrates that alterations in FKBP12.6-RYR2 interaction are unlikely to be the common cause of CPVT1 (George et al, 2003; Guo et al, 2010; Jiang et al, 2005; Liu et al, 2006; Xiao et al, 2007)
Summary
RESULTSCatecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited life-threatening arrhythmia leading to syncope and sudden cardiac death at a young age. Two genetic forms of the disease have been described: one accounting for at least 50% of all cases and associated with autosomal dominant mutations in the cardiac ryanodine receptor, RYR2 (CPVT1; Priori et al, 2001) and a very rare one linked to recessive mutations in calsequestrin (CPVT2; Postma et al, 2002) Both proteins belong to the multimolecular calcium (Ca2þ) release channel complex of the sarcoplasmic reticulum (SR) which supports myocyte Ca2þ cycling and contractile activity (Berridge, 2003; Bers, 2004; Gyorke & Terentyev, 2008; Kaye et al, 2008; Lanner et al, 2010). The molecular mechanisms underlying the pathogenesis of these mutations are still controversial
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