{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,7]],"date-time":"2025-11-07T09:22:35Z","timestamp":1762507355207,"version":"build-2065373602"},"reference-count":82,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2018,2,23]],"date-time":"2018-02-23T00:00:00Z","timestamp":1519344000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The SCN5A gene encodes the pore-forming \u03b1-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\u2013Severi 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\u2013Severi model may prove a useful tool in understanding cardiac pacemaker activity in humans.<\/jats:p>","DOI":"10.3390\/ijms19020634","type":"journal-article","created":{"date-parts":[[2018,2,23]],"date-time":"2018-02-23T12:17:39Z","timestamp":1519388259000},"page":"634","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Sinus Bradycardia in Carriers of the SCN5A-1795insD Mutation: Unraveling the Mechanism through Computer Simulations"],"prefix":"10.3390","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1340-0869","authenticated-orcid":false,"given":"Ronald","family":"Wilders","sequence":"first","affiliation":[{"name":"Department of Medical Biology, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2018,2,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1161\/CIRCEP.108.789081","article-title":"Cardiac ion channels","volume":"2","author":"Grant","year":"2009","journal-title":"Circ. 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