RyR₂^R420Q catecholaminergic polymorphic ventricular tachycardia mutation induces bradycardia by disturbing the coupled clock pacemaker mechanism

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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 RyR₂^R420Q 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 (I_f ). 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