Sinus Bradycardia in Carriers of the SCN5A-1795insD Mutation: Unraveling the Mechanism through Computer Simulations
AbstractThe 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
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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.
Wilders R. Sinus Bradycardia in Carriers of the SCN5A-1795insD Mutation: Unraveling the Mechanism through Computer Simulations. International Journal of Molecular Sciences. 2018; 19(2):634.Chicago/Turabian Style
Wilders, Ronald. 2018. "Sinus Bradycardia in Carriers of the SCN5A-1795insD Mutation: Unraveling the Mechanism through Computer Simulations." Int. J. Mol. Sci. 19, no. 2: 634.
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