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

International Journal of Molecular Sciences
Ronald Wilders

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. Furthe...Continue Reading

References

Mar 1, 1992·Journal of the American College of Cardiology·T J TobéH Wesseling
Nov 1, 1991·Biophysical Journal·R WildersA C van Ginneken
Dec 11, 1999·Circulation Research·C BezzinaA A Wilde
May 16, 2000·Circulation Research·M W VeldkampJ R Balser
Jul 19, 2000·American Journal of Physiology. Heart and Circulatory Physiology·H ZhangM R Boyett
Sep 7, 2000·Cardiovascular Research·M R BoyettI Kodama
May 28, 2002·Journal of Cardiovascular Electrophysiology·Henggui ZhangMark R Boyett
Apr 5, 2003·Circulation Research·Marieke W VeldkampArthur A M Wilde
Jul 19, 2005·Journal of the American College of Cardiology·Gertie C M Beaufort-KrolMargreet Th E Bink-Boelkens
Mar 28, 2006·American Journal of Physiology. Heart and Circulatory Physiology·Vadim V FedorovIgor R Efimov
Aug 1, 2006·American Journal of Physiology. Heart and Circulatory Physiology·Zhu-Shan ZhangAugustus O Grant
Sep 19, 2006·American Journal of Physiology. Heart and Circulatory Physiology·Stefania VecchiettiSilvio Cavalcanti
Mar 21, 2007·Cardiovascular Research·Ming LeiChristopher L-H Huang
Jun 9, 2007·Heart Rhythm : the Official Journal of the Heart Rhythm Society·Sarah N FlaimAndrew D McCulloch
Sep 8, 2007·European Heart Journal·Arie O VerkerkHanno L Tan
Apr 26, 2008·Trends in Cardiovascular Medicine·Carol Ann RemmeConnie R Bezzina
May 6, 2008·American Journal of Physiology. Heart and Circulatory Physiology·Markéta BébarováPaul G A Volders
Jul 9, 2008·Orphanet Journal of Rare Diseases·Lia CrottiPeter J Schwartz
Jul 29, 2008·Bioinformatics·Catherine M LloydPoul F Nielsen
Nov 26, 2008·Progress in Biophysics and Molecular Biology·Ming LeiYanmin Zhang
Feb 26, 2009·International Journal of Biological Sciences·Arie O VerkerkHanno L Tan
Apr 2, 2009·Circulation Journal : Official Journal of the Japanese Circulation Society·Naomasa Makita
Apr 21, 2009·Nature Reviews. Cardiology·Yanfei RuanSilvia G Priori
Sep 12, 2009·Journal of Molecular and Cellular Cardiology·Hugues Abriel
Oct 8, 2009·Circulation. Arrhythmia and Electrophysiology·Augustus O Grant
Oct 21, 2009·Circulation·Peter J SchwartzCarla Spazzolini
Oct 31, 2009·Heart Rhythm : the Official Journal of the Heart Rhythm Society·Ahmad S AminArthur A M Wilde
Dec 2, 2009·Netherlands Heart Journal : Monthly Journal of the Netherlands Society of Cardiology and the Netherlands Heart Foundation·P G PostemaA Wilde
Jan 22, 2010·Pflügers Archiv : European journal of physiology·Ahmad S AminHanno L Tan

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Citations

Oct 18, 2018·Frontiers in Cardiovascular Medicine·Arie O VerkerkCarol Ann Remme
Oct 27, 2018·Frontiers in Physiology·Wenjia LiAijun Sun
Aug 21, 2018·Frontiers in Cardiovascular Medicine·Ronald Wilders, Arie O Verkerk

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Methods Mentioned

BETA
transfection

Software Mentioned

Windows
Cellular Open Resource ( COR ) environment
CellML

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