Abstract 18012: Modeling of a Rare SCN10A Variant (A1886V) Linked with Early-Onset Atrial Fibrillation Shortens Atrial Action Potential Duration
Introduction: SCN10A encodes the tetrodotoxin-resistant sodium channel isoform Nav1.8, which is variably expressed in neuronal tissue and heart and has been associated with atrial fibrillation (AF). We resequenced the SCN10A gene in 274 early-onset AF probands and identified a rare non-synonymous variant (A1886V) that co-segregated with AF in a kindred. In-vitro electrophysiological studies revealed that this variant displayed a “gain-of-function” phenotype with increased peak (INa-peak) and late (INa-L) sodium currents.
Hypothesis: Here, we hypothesized that the increased peak and late INa associated with A1886V variant might modulate atrial action potential duration (APD) and thus increase susceptibility to AF.
Methods: We used 2 Clancy-Rudy INa Markov models modified to fit wild-type (WT) and A1886V variant. Modeled currents were incorporated into the Courtemanche-Ramirez-Nattel model of human atrial AP. The overall SCN10A/Nav1.8 contribution to the total INa was simulated in the 5-50% range of WT-SCN5A/Nav1.5 current, and for each overall SCN10A magnitude, the contribution of A1886V compared to WT was simulated in the 0-to-100% range. Cycle-length used was 1000 ms (frequency 1 Hz).
Results: While the precise magnitude of SCN10A atrial expression (WT and A1886V) has not yet been determined, simulation of a range of contributions of each component to atrial AP demonstrated incremental morphology changes with removal of the “spike and dome” and triangularization of AP associated with progressive shortening of APD90 (301 ms at 0% SCN10A contribution; 281 ms at 10% SCN10A [100% WT, 0% A1886V]; 261 ms at 10% SCN10A [0% WT, 100% A1886V]) (Table).
Conclusion: Computational modeling of A1886V-SCN10A rare variant linked with familial AF surprisingly shortened atrial APD by removal of phase 1 “spike and dome” and augmentation of atrial AP “triangularization”, providing a potential mechanism for increased AF susceptibility.
Author Disclosures: R.L. Abraham: None. E. Savio-Galimberti: None. T. Yang: None. D.M. Roden: None. D. Darbar: None.
- © 2014 by American Heart Association, Inc.