@article{10.1172/jci.insight.91872, author = {Yue Yi Wang AND Pietro Mesirca AND Elena Marqués-Sulé AND Alexandra Zahradnikova Jr. AND Olivier Villejoubert AND Pilar D’Ocon AND Cristina Ruiz AND Diana Domingo AND Esther Zorio AND Matteo E. Mangoni AND Jean-Pierre Benitah AND Ana María Gómez}, journal = {JCI Insight}, publisher = {The American Society for Clinical Investigation}, title = {RyR2R420Q catecholaminergic polymorphic ventricular tachycardia mutation induces bradycardia by disturbing the coupled clock pacemaker mechanism}, year = {2017}, month = {4}, volume = {2}, url = {https://insight.jci.org/articles/view/91872}, 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.}, number = {8}, doi = {10.1172/jci.insight.91872}, url = {https://doi.org/10.1172/jci.insight.91872}, }