The SCN5A gene encodes the pore-forming α-subunit of the cardiac fast sodium channel (INa channel). Carriers of the 1795insD mutation in SCN5A show sinus bradycardia, with a mean heart rate of 70 bpm in mutation carriers vs. 77 bpm in non-carriers from the same family (lowest heart rate 41 vs. 47 bpm). We assessed the mechanism by which the 1795insD mutation causes sinus bradycardia by incorporating the mutation-induced changes in INa into the comprehensive computational model of a single human sinoatrial node cell that was recently developed by Fabbri et al. The 1795insD mutation reduced the beating rate of the model cell from 74 to 69 bpm (from 49 to 43 bpm in the presence of 20 nM acetylcholine). The mutation-induced persistent INa per se resulted in a large increase in beating rate. This gain-of-function effect was almost completely counteracted by the loss-of-function effect of the reduction in INa amplitude. The further loss-of-function effect of the shifts in (in) activation 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 et al. model may prove a useful tool in understanding cardiac pacemaker activity in human.
|Number of pages||4|
|Publication status||Published - 2017|
|Event||44th Computing in Cardiology Conference, CinC 2017 - Rennes, France|
Duration: 24 Sep 2017 → 27 Sep 2017
|Conference||44th Computing in Cardiology Conference, CinC 2017|
|Period||24/09/17 → 27/09/17|