2015
DOI: 10.1073/pnas.1419795112
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Arrhythmogenesis in a catecholaminergic polymorphic ventricular tachycardia mutation that depresses ryanodine receptor function

Abstract: Current mechanisms of arrhythmogenesis in catecholaminergic polymorphic ventricular tachycardia (CPVT) require spontaneous Ca 2+ release via cardiac ryanodine receptor (RyR2) channels affected by gain-of-function mutations. Hence, hyperactive RyR2 channels eager to release Ca 2+ on their own appear as essential components of this arrhythmogenic scheme. This mechanism, therefore, appears inadequate to explain lethal arrhythmias in patients harboring RyR2 channels destabilized by loss-of-function mutations. We a… Show more

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Cited by 92 publications
(105 citation statements)
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“…Twenty minutes later, 120 mg/kg caffeine was injected i.p. to simulate a catecholaminergic surge and assess the incidence of ventricular arrhythmias (29,30). For ex vivo experiments, pseudo-ECGs were recorded from isolated Langendorff-perfused mouse hearts using published methods (4, 23, 26).…”
Section: Methodsmentioning
confidence: 99%
See 1 more Smart Citation
“…Twenty minutes later, 120 mg/kg caffeine was injected i.p. to simulate a catecholaminergic surge and assess the incidence of ventricular arrhythmias (29,30). For ex vivo experiments, pseudo-ECGs were recorded from isolated Langendorff-perfused mouse hearts using published methods (4, 23, 26).…”
Section: Methodsmentioning
confidence: 99%
“…To assess the effect of the p.Asn1768Asp mutation on cardiac excitability, we recorded ventricular myocyte action potentials (APs) under current clamp. The duration of the early phases of AP repolarization [action potential duration (APD); APD 30 and APD 50 ] was prolonged in Scn8a N1768D/+ myocytes (Fig. 2, red), with no difference in total duration (Fig.…”
Section: Altered Action Potential Morphology and Delayed Afterdepolarmentioning
confidence: 99%
“…The mutation depresses RyR2 channel activity during E-C coupling, but also results in random bursts of Ca 2+ release during systole. Therefore, the myocytes are affected by a specific Ca 2+ metabolism imbalance, resulting in a form of catecholaminergic polymorphic ventricular tachycardia (24). The unique mitochondrial Significance Nanotunnels are long, thin mitochondrial extensions that have been implied in direct long-distance (1 to >5 μm) communication between mitochondria of cardiac myocytes.…”
Section: Camentioning
confidence: 99%
“…On the other hand, it has been shown that the zipping-unzipping mechanism (mediated by the N-terminal and central region interaction) was disturbed by the RyR 2 R2474S mutation, which induces conformational changes and favors the unzipped state. Although most proposed functional alterations caused by the RyR 2 mutations result in a gain of function, a loss-offunction mutation in the C-terminal portion has been recently reported in a mice model (42).…”
Section: R420qmentioning
confidence: 99%