Abstract 12604: Potassium-dependence of Arrhythmias due to the SCN5A Variant R222Q
Background: R222Q is a charge-neutralizing mutation in domain I/S4 voltage sensor of the cardiac sodium channel. Mutation carriers display very frequent ectopy and dilated cardiomyopathy (DCM). To probe mechanisms for the ectopy, DCM, and the relationship between the two, we have generated mice carrying humanized wild-type (H) or mutant (RQ) channels.
Methods and results: RQ/RQ pups are viable but typically die by 7 days postnatally, so the data reported here compare RQ/H and H/H. Consistent with previous heterologous expression studies, RQ/H myocytes displayed hyperpolarizing shifts in both inactivation (V1/2: -107.1±1.2 mV vs -94.7±1.3, p<0.01) and activation (V1/2: -70.1±1.3 mV vs -53.8±1.6, p<0.01) resulting in increased window current. RQ/H myocytes also displayed accelerated INa fast inactivation (1.5±0.1 ms vs 2.1±0.2 at -40 mV, p<0.01), recovery from inactivation, and unusually short action potential duration (APD90: 12.6±1.3 ms vs 29.1±1, p<0.01). However, at 3 and 6 months RQ/H mice exhibited only infrequent ectopy. Surface ECGs and echocardiograms were normal. Previous reports have identified an outward pore current with DCM-associated SCN5A voltage sensor domain mutations, and in analogous SCN4A mutations associated with hypokalemic periodic paralysis. Decreasing [K+]o from 4 to 2 mM increased R222Q-associated pore current from 11.9±2.0 pA/pF to 19.1±2.1 at +40 mV (p<0.05); there was minimal pore current in H/H myocytes at either potassium concentration. Decreasing [K+]o also elicited afterdepolarizations in 9/14 RQ/H myocytes compared to 0/10 H/H. With Langendorff perfusion of 2 mM [K+]o, ectopy was present in 0.2±0.6% of beats in H/H hearts but was markedly enhanced to 24.3±9.6% in RQ/H (n=6-9; P<0.05).
Conclusion: Despite striking INa dysfunction, RQ/H mice displayed minimal ectopy. The lack of DCM in the absence of frequent ectopy supports the hypothesis that frequent ectopy causes the DCM in human mutation carriers. Hypokalemia increased pore current in R222Q myocytes, and was highly arrhythmogenic in vitro and ex vivo. We speculate that frequent ectopy in human mutation carriers could be responsive to potassium supplements, and this in turn could prevent or ameliorate the DCM phenotype.
Author Disclosures: L. Daniel: None. T. Yang: None. D. Roden: Research Grant; Modest; NIH.
- © 2016 by American Heart Association, Inc.