title: Ion channels, long QT syndrome and arrhythmogenesis in ageing.
abstract: Ageing is associated with increased prevalences of both atrial and ventricular arrhythmias, reflecting disruption of the normal sequence of ion channel activation and inactivation generating the propagated cardiac action potential. Experimental models with specific ion channel genetic modifications have helped clarify the interacting functional roles of ion channels and how their dysregulation contributes to arrhythmogenic processes at the cellular and systems level. They have also investigated interactions between these ion channel abnormalities and age-related processes in producing arrhythmic tendency. Previous reviews have explored the relationships between age and loss-of-function Nav1.5 mutations in producing arrhythmogenicity. The present review now explores complementary relationships arising from gain-of-function Nav1.5 mutations associated with long QT3 (LQTS3). LQTS3 patients show increased risks of life-threatening ventricular arrhythmias, particularly after 40 years of age, consistent with such interactions between the ion channel abnormailities and ageing. In turn clinical evidence suggests that ageing is accompanied by structural, particularly fibrotic, as well as electrophysiological change. These abnormalities may result from biochemical changes producing low-grade inflammation resulting from increased production of reactive oxygen species and superoxide. Experimental studies offer further insights into the underlying mechanisms underlying these phenotypes. Thus, studies in genetically modified murine models for LQTS implicated action potential recovery processes in arrhythmogenesis resulting from functional ion channel abnormalities. In addition, ageing wild type (WT) murine models demonstrated both ion channel alterations and fibrotic changes with ageing. Murine models then suggested evidence for interactions between ageing and ion channel mutations and provided insights into potential arrhythmic mechanisms inviting future exploration.
authors.affiliation: Faculty of Health and Medical Sciences, University of Surrey, Guildford, UK.|School of Medicine, Perdana University-Royal College of Surgeons Ireland, Serdang, Selangor Darul Ehsan, Malaysia.
authors.forename: Kamalan
authors.identifier: 0000-0002-6232-388X
authors.initials: K
authors.lastname: Jeevaratnam
authors.affiliation: Faculty of Health and Medical Sciences, University of Surrey, Guildford, UK.|Physiological Laboratory, University of Cambridge, Cambridge, UK.
authors.forename: Karan R
authors.initials: KR
authors.lastname: Chadda
authors.affiliation: Department of Biochemistry, University of Cambridge, Cambridge, UK.
authors.forename: Samantha C
authors.initials: SC
authors.lastname: Salvage
authors.affiliation: Physiological Laboratory, University of Cambridge, Cambridge, UK.
authors.forename: Haseeb
authors.initials: H
authors.lastname: Valli
authors.affiliation: Physiological Laboratory, University of Cambridge, Cambridge, UK.
authors.forename: Shiraz
authors.initials: S
authors.lastname: Ahmad
authors.affiliation: Division of Cardiovascular Biology, Department of Biochemistry, University of Cambridge, Cambridge, UK.
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Grace
authors.affiliation: Physiological Laboratory, University of Cambridge, Cambridge, UK.|Division of Cardiovascular Biology, Department of Biochemistry, University of Cambridge, Cambridge, UK.
authors.forename: Christopher L-H
authors.initials: CL
authors.lastname: Huang
mesh_terms: D000200:Action Potentials / Q000235:genetics*; D000367:Age Factors; D000375:Aging / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D020022:Genetic Predisposition to Disease; D006339:Heart Rate / Q000235:genetics*; D006801:Humans; D015994:Incidence; D007700:Kinetics; D008133:Long QT Syndrome / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D009154:Mutation; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D012307:Risk Factors
chemical_list: D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; C568321:Scn5a protein, mouse
keywords: ageing; cardiac arrhythmia; fibrotic change; long QT syndrome; murine models; sodium channel