Ion channels, long QT syndrome and arrhythmogenesis in ageing

Abstract

SummaryAgeing 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.

Systemic inflammation as a novel QT-prolonging risk factor in patients with torsades de pointes

“…Although this primarily points to occult inflammatory diseases, the fact that patients with TdP are rather old (median 80 years) and age-matched CC patients show slightly higher CRP and IL-6 levels versus HC, suggests that also ‘inflammaging’ (ie, low-grade chronic systemic inflammation due to the normal ageing process)26 may play a role. More intriguingly, according to recent data,27 inflammaging could contribute to explain why advanced age is a recognised TdP risk factor 1. In any case, these findings point to the concept that regardless of the specific aetiology, pathogenesis and targeted organs, systemic inflammation may per se represent the true risk factor for TdP development, via the action of common basic mediators involved in the different inflammatory processes.…”

The impact of age on long QT syndrome

“…This is relevant for LQTS3 patients, who account for 5 to 10% of cases of congenital LQTS, whose LQT phenomenon is caused by a gain-offunction mutation in the SCN5A gene, which encodes the α subunit of the Na + channel (Nav1.5). LQTS3 patients show increased risk of life-threatening ventricular arrhythmias, particularly after 40 years of age, consistent with ion channel abnormalities caused by aging [4,5]. The QTc interval in general increases with age, with the age-related increase is more evident in men than in women.…”

Mitochondrial Dysfunction Increases Arrhythmic Triggers and Substrates; Potential Anti-arrhythmic Pharmacological Targets

“…Mice, often with electrophysiologically stable 129/Sv or C57BL/6 genetic backgrounds, have thus far represented the main transgenic system for modeling arrhythmic syndromes ( 61 , 62 ) typically via well-defined mutations strategically positioned to reflect the genotypes associated with these syndromes and reliably reflecting their phenotype ( 9 , 23 , 63 ). From a practical aspect, mice are inexpensive, easily maintained, and reproduce rapidly thus allowing provision of aged mice over relatively short periods ( 25 ). Mice also reflect the human aging process such that they complete their growth before reproduction commences ( 1 , 64 ).…”

“…Interestingly, arrhythmic risk in individuals with many inherited channelopathies, such as BrS and LQT3, increases markedly with age, despite these individuals carrying the proarrhythmic mutation from birth ( 25 ). For example, LQT3 patients show significantly increased arrhythmic risk after the 40 years of age ( 26 , 27 ).…”