Mechanism of Sinus Bradycardia in Carriers of the A414G Mutation in the HCN4 Gene

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Abstract

Heterozygous carriers of the A414G mutation in the HCN4 gene, which encodes the HCN4 protein, show moderate to severe sinus bradycardia. Tetramers of HCN4 subunits constitute the ion channels that conduct the cardiac hyperpolarization-activated 'funny current' (If), which plays an important modulating role in the pacemaker activity of sinus node cells.We assessed the mechanism by which the A414G mutation in HCN4 causes sinus bradycardia. We carried out voltage clamp experiments on HCN4 channels expressed in Chinese hamster ovary (CHO) cells and incorporated the experimentally observed mutation-induced changes in If into the Fabbri-Severi model of a single human sinus node cell.In the Fabbri-Severi model, the experimentally observed effects on If increased the cycle length from 813 to 1004 ms, corresponding with a 19% decrease in beating rate from 74 to 60 beats/min. These mutation effects became more prominent at 10 nM ACh (vagal tone) and in the presence of a hyperpolarizing atrial load.We conclude that the experimentally identified mutation-induced changes in If can explain the clinically observed sinus bradycardia in carriers of the A414G mutation in the HCN4 gene.
Original languageEnglish
Title of host publication2019 Computing in Cardiology, CinC 2019
PublisherIEEE Computer Society
Number of pages4
Volume2019-September
ISBN (Electronic)9781728169361
DOIs
Publication statusPublished - 2019
Event2019 Computing in Cardiology, CinC 2019 - Singapore, Singapore
Duration: 8 Sept 201911 Sept 2019

Publication series

NameComputing in Cardiology

Conference

Conference2019 Computing in Cardiology, CinC 2019
Country/TerritorySingapore
CitySingapore
Period8/09/201911/09/2019

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