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Int. J. Mol. Sci. 2018, 19(2), 634; https://doi.org/10.3390/ijms19020634

Sinus Bradycardia in Carriers of the SCN5A-1795insD Mutation: Unraveling the Mechanism through Computer Simulations

Department of Medical Biology, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands
Received: 8 January 2018 / Revised: 13 February 2018 / Accepted: 19 February 2018 / Published: 23 February 2018
(This article belongs to the Special Issue Ion Transporters and Channels in Physiology and Pathophysiology)
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Abstract

The SCN5A gene encodes the pore-forming α-subunit of the ion channel that carries the cardiac fast sodium current (INa). The 1795insD mutation in SCN5A causes sinus bradycardia, with a mean heart rate of 70 beats/min in mutation carriers vs. 77 beats/min in non-carriers from the same family (lowest heart rate 41 vs. 47 beats/min). To unravel the underlying mechanism, we incorporated the mutation-induced changes in INa into a recently developed comprehensive computational model of a single human sinoatrial node cell (Fabbri–Severi model). The 1795insD mutation reduced the beating rate of the model cell from 74 to 69 beats/min (from 49 to 43 beats/min in the simulated presence of 20 nmol/L acetylcholine). The mutation-induced persistent INa per se resulted in a substantial increase in beating rate. This gain-of-function effect was almost completely counteracted by the loss-of-function effect of the reduction in INa conductance. The further loss-of-function effect of the shifts in steady-state activation and inactivation resulted in an overall loss-of-function effect of the 1795insD mutation. We conclude that the experimentally identified mutation-induced changes in INa can explain the clinically observed sinus bradycardia. Furthermore, we conclude that the Fabbri–Severi model may prove a useful tool in understanding cardiac pacemaker activity in humans. View Full-Text
Keywords: heart; sinoatrial node; electrophysiology; long-QT syndrome; sinus bradycardia; sick sinus syndrome; genetics; sodium current; ion channels; computer simulations heart; sinoatrial node; electrophysiology; long-QT syndrome; sinus bradycardia; sick sinus syndrome; genetics; sodium current; ion channels; computer simulations
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).
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Wilders, R. Sinus Bradycardia in Carriers of the SCN5A-1795insD Mutation: Unraveling the Mechanism through Computer Simulations. Int. J. Mol. Sci. 2018, 19, 634.

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