P676Mechanisms of sinoatrial node dysfunction in RyR2(R420Q) mice model of catecholaminergic polymorphic ventricular tachycardia

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Abstract

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a genetic disease characterized by stress-induced syncope and/or sudden death in young individuals with structurally normal heart. More than 150 mutations located in the cardiac Ca2+ release channel (type-2 ryanodine receptor, RyR2) gene are related to CPVT. Besides ventricular tachycardia (VT) under stress, sinoatrial node (SAN) dysfunction is frequently observed in CPVT patients. However, the cellular mechanisms remain underexplored. We created a KI mice model bearing a mutation in the N-terminal portion of the RyR2 found in a CPVT family, RyR2(R420Q). ECGs were recorded in KI and WT littermates in resting condition and after epinephrine/caffeine (2/120 mg/kg) challenge (i.p. injection). All KI mice (n=7) showed sustained bidirectional VT, validating the model. Moreover, resting heart rhythm was slower in KI mice during rest period (525.3±9.0 bpm n=4 and 498.5±4.9 bpm n=3, P<0.05), denoting alteration in SAN function. To examine the mechanisms of this dysfunction, SANs were dissected from WT and KI mice, loaded with the cell-permeant Ca2+ dye, Fluo-4 AM, and viewed by confocal microscopy using a white light laser fitted to 500 nm and resonant scanning. The cycle length of spontaneous [Ca2+]i transients was significantly longer in KI mice (696±2ms in 70 WT cells vs. 994±5ms in 48 KI cells, P<0.0001). [Ca2+]i transient amplitudes were reduced in KI cells (peak F/F0: 3.2±0.2, n= 43, p<0.05) compared to WT cells (peak F/F0: 3.7±0.1, n= 67), but with similar kinetics. Ca2+ sparks frequency between spontaneous beats was similar between KI and WT but the time to peak (22.8±0.4ms in 938 WT Ca2+ sparks vs. 41.2±0.7ms in 1617 KI Ca2+ sparks, P<0.0001) and duration were prolonged in KI mice (duration at half maximum: 34.1±0.5ms, n=1135 WT; vs. 57.8±0.6ms n=2237 KI, P<0.0001). In conclusion, our data show that RYR2R420Q SAN mutation: 1) induce CPVT phenotype in mice, 2) decreases the SAN rhythm, 3) promotes more [Ca2+]i leak during diastole. These alterations may contribute to supraventricular arrhythmia in CPVT.

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