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 aimed to elucidate arrhythmia mechanisms in a RyR2-linked CPVT mutation (RyR2-A4860G) that depresses channel activity. Recombinant RyR2-A4860G protein was expressed equally as wild type (WT) RyR2, but channel activity was dramatically inhibited, as inferred by [ ) exhibited basal bradycardia but no cardiac structural alterations; in contrast, no homozygotes were detected at birth, suggesting a lethal phenotype. Sympathetic stimulation elicited malignant arrhythmias in RyR2-A4860G +/− hearts, recapitulating the phenotype originally described in a human patient with the same mutation. In isoproterenol-stimulated ventricular myocytes, the RyR2-A4860G mutation decreased the peak of Ca 2+ release during systole, gradually overloading the sarcoplasmic reticulum with Ca 2+. The resultant Ca 2+ overload then randomly caused bursts of prolonged Ca 2+ release, activating electrogenic Na + -Ca 2+ exchanger activity and triggering early afterdepolarizations. The RyR2-A4860G mutation reveals novel pathways by which RyR2 channels engage sarcolemmal currents to produce life-threatening arrhythmias.ryanodine receptor | heart | cardiac arrhythmias | CPVT | sarcoplasmic reticulum

Cardiac arrhythmia in a mouse model of sodium channel SCN8A epileptic encephalopathy

“…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).…”

“…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.…”

Increased mitochondrial nanotunneling activity, induced by calcium imbalance, affects intermitochondrial matrix exchanges

“…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.…”

RyR2R420Q catecholaminergic polymorphic ventricular tachycardia mutation induces bradycardia by disturbing the coupled clock pacemaker mechanism

“…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).…”