RyR2R420Q catecholaminergic polymorphic ventricular tachycardia mutation induces bradycardia by disturbing the coupled clock pacemaker mechanism
Yue Yi Wang, Pietro Mesirca, Elena Marqués-Sulé, Alexandra Zahradnikova Jr., Olivier Villejoubert, Pilar D’Ocon, Cristina Ruiz, Diana Domingo, Esther Zorio, Matteo E. Mangoni, Jean-Pierre Benitah, Ana María Gómez
Yue Yi Wang, Pietro Mesirca, Elena Marqués-Sulé, Alexandra Zahradnikova Jr., Olivier Villejoubert, Pilar D’Ocon, Cristina Ruiz, Diana Domingo, Esther Zorio, Matteo E. Mangoni, Jean-Pierre Benitah, Ana María Gómez
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Research Article Cardiology

RyR2R420Q catecholaminergic polymorphic ventricular tachycardia mutation induces bradycardia by disturbing the coupled clock pacemaker mechanism

Abstract

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a lethal genetic arrhythmia that manifests syncope or sudden death in children and young adults under stress conditions. CPVT patients often present bradycardia and sino-atrial node (SAN) dysfunction. However, the mechanism remains unclear. We analyzed SAN function in two CPVT families and in a novel knock-in (KI) mouse model carrying the RyR2R420Q mutation. Humans and KI mice presented slower resting heart rate. Accordingly, the rate of spontaneous intracellular Ca2+ ([Ca2+]i) transients was slower in KI mouse SAN preparations than in WT, without any significant alteration in the “funny” current (If ). The L-type Ca2+ current was reduced in KI SAN cells in a [Ca2+]i-dependent way, suggesting that bradycardia was due to disrupted crosstalk between the “voltage” and “Ca2+” clock, and the mechanisms of pacemaking was induced by aberrant spontaneous RyR2- dependent Ca2+ release. This finding was consistent with a higher Ca2+ leak during diastolic periods produced by long-lasting Ca2+ sparks in KI SAN cells. Our results uncover a mechanism for the CPVT-causing RyR2 N-terminal mutation R420Q, and they highlight the fact that enhancing the Ca2+ clock may slow the heart rhythm by disturbing the coupling between Ca2+ and voltage clocks.

Authors

Yue Yi Wang, Pietro Mesirca, Elena Marqués-Sulé, Alexandra Zahradnikova Jr., Olivier Villejoubert, Pilar D’Ocon, Cristina Ruiz, Diana Domingo, Esther Zorio, Matteo E. Mangoni, Jean-Pierre Benitah, Ana María Gómez

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Figure 3

Cycle length (CL) in sinoatrial node (SAN) in KI is longer than in WT.

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Cycle length (CL) in sinoatrial node (SAN) in KI is longer than in WT. (...
(A) Examples of 2-D confocal images (left) of SAN cells within the intact SAN, and the corresponding fluorescence traces (right) in WT (upper) and KI (lower) SAN cell. Fluorescence traces are expressed as F/F0, where F is the fluorescence signal and F0 the fluorescence during the diastolic period. (B) KI mice have markedly longer cycle lengths (CL; time between two consecutive spontaneous [Ca2+]i transients) than WT, from n = 14 WT and n = 14 KI SAN cells. (C) Isoproterenol (ISO, 20 nM) decreases SAN CL, although irrespective to the clinical group, as the response in KI SAN (n = 6) is larger than in WT (n = 6). (D) Carbachol (CCH, 500 nM) increases CL in each SAN, and no statistical difference was observed between WT (n = 7) and KI (n = 6) SAN cells. Each bar displays mean value ± SEM of the node (white for WT and red for KI) with individual data shown on the columns, while each SAN is averaged from several cells (4–13 cells in each SAN). Stars correspond to the comparisons between groups, while crosses show the comparisons inside each group before and after the administration of the drug. †P < 0.05; **P < 0.01; †††P < 0.001 by two (stars) or one (crosses) sample t test. KI, heterozygous for the RyR2R420Q mutation.