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 2

KI mice show SAN dysfunction after emotional stress.

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KI mice show SAN dysfunction after emotional stress. (A) RR intervals du...
(A) RR intervals during emotional stress protocol in a WT (top) and a KI (bottom) mouse. Black rectangles represent the 15 s of warm air blowing. Forty-five seconds of rest was allowed before the next air blowing. This experiment was repeated in 8 WT and in 7 KI mice. (B) Percentage of mice dead after this protocol in WT and KI mice. (C) An example of ECG recorded from a KI mouse, which died after the emotional stress. First line is the ECG during air blowing. Below, ECG 3 hours after the beginning of the protocol (time after the beginning of the protocol on the left). After ventricular tachycardia and a progressively slower ventricular escape rhythm, the mouse died of asystolia. KI, heterozygous for the RyR2R420Q mutation.