{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T05:47:09Z","timestamp":1791352029411,"version":"4.3.1"},"reference-count":54,"publisher":"American Society for Clinical Investigation","issue":"8","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2017,4,20]]},"abstract":"<jats:p>\n                    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 RyR\n                    <jats:sub>2<\/jats:sub>\n                    <jats:sup>R420Q<\/jats:sup>\n                    mutation. Humans and KI mice presented slower resting heart rate. Accordingly, the rate of spontaneous intracellular Ca\n                    <jats:sup>2+<\/jats:sup>\n                    ([Ca\n                    <jats:sup>2+<\/jats:sup>\n                    ]\n                    <jats:sub>i<\/jats:sub>\n                    ) transients was slower in KI mouse SAN preparations than in WT, without any significant alteration in the \u201cfunny\u201d current (\n                    <jats:italic>\n                      I\n                      <jats:sub>f<\/jats:sub>\n                    <\/jats:italic>\n                    ). The L-type Ca\n                    <jats:sup>2+<\/jats:sup>\n                    current was reduced in KI SAN cells in a [Ca\n                    <jats:sup>2+<\/jats:sup>\n                    ]\n                    <jats:sub>i<\/jats:sub>\n                    -dependent way, suggesting that bradycardia was due to disrupted crosstalk between the \u201cvoltage\u201d and \u201cCa\n                    <jats:sup>2+<\/jats:sup>\n                    \u201d clock, and the mechanisms of pacemaking was induced by aberrant spontaneous RyR\n                    <jats:sub>2<\/jats:sub>\n                    - dependent Ca\n                    <jats:sup>2+<\/jats:sup>\n                    release. This finding was consistent with a higher Ca\n                    <jats:sup>2+<\/jats:sup>\n                    leak during diastolic periods produced by long-lasting Ca\n                    <jats:sup>2+<\/jats:sup>\n                    sparks in KI SAN cells. Our results uncover a mechanism for the CPVT-causing RyR\n                    <jats:sub>2<\/jats:sub>\n                    N-terminal mutation R420Q, and they highlight the fact that enhancing the Ca\n                    <jats:sup>2+<\/jats:sup>\n                    clock may slow the heart rhythm by disturbing the coupling between Ca\n                    <jats:sup>2+<\/jats:sup>\n                    and voltage clocks.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.91872","type":"journal-article","created":{"date-parts":[[2017,4,19]],"date-time":"2017-04-19T11:00:56Z","timestamp":1492599656000},"source":"Crossref","is-referenced-by-count":36,"title":["RyR2R420Q catecholaminergic polymorphic ventricular tachycardia mutation induces bradycardia by disturbing the coupled clock pacemaker mechanism"],"prefix":"10.1172","volume":"2","author":[{"given":"Yue Yi","family":"Wang","sequence":"first","affiliation":[{"name":"UMR-S 1180, Inserm, Universit\u00e9 Paris-Sud, 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