Interleukin-6 inhibition of hERG underlies risk for acquired long QT in cardiac and systemic inflammation

Abstract

Increased proinflammatory interleukin-6 (IL-6) levels are associated with acquired long QT-syndrome (LQTS) in patients with systemic inflammation, leading to higher risks for life-threatening polymorphic ventricular tachycardia such as Torsades de Pointes. However, the functional and molecular mechanisms of this association are not known. In most cases of acquired LQTS, the target ion channel is the human ether-á-go-go-related gene (hERG) encoding the rapid component of the delayed rectifier K current, IKr, which plays a critical role in cardiac repolarization. Here, we tested the hypothesis that IL-6 may cause QT prolongation by suppressing IKr. Electrophysiological and biochemical assays were used to assess the impact of IL-6 on the functional expression of IKr in HEK293 cells and adult guinea-pig ventricular myocytes (AGPVM). In HEK293 cells, IL-6 alone or in combination with the soluble IL-6 receptor (IL-6R), produced a significant depression of IKr peak and tail current densities. Block of IL-6R or Janus kinase (JAK) reversed the inhibitory effects of IL-6 on IKr. In AGPVM, IL-6 prolonged action potential duration (APD) which was further prolonged in the presence of IL-6R. Similar to heterologous cells, IL-6 reduced endogenous guinea pig ERG channel mRNA and protein expression. The data are first to demonstrate that IL-6 inhibition of IKr and the resulting prolongation of APD is mediated via IL-6R and JAK pathway activation and forms the basis for the observed clinical QT interval prolongation. These novel findings may guide the development of targeted anti-arrhythmic therapeutic interventions in patients with LQTS and inflammatory disorders.

Associations between QT interval subcomponents, HIV serostatus, and inflammation

“…The paucity of HIV‐related disease factor relationships with the T‐wave subcomponents raised the possibility of contributions from other factors, of which inflammation was a leading contender based on our prior work pertaining to the total QTc (Wu et al, ). Attenuation of the HIV association with T‐onset to T‐peak by higher inflammatory levels supports a potential mechanistic role of cytokine‐induced potassium channelopathies suggested by findings from cohort studies and supported by recent experimental studies (Aromolaran et al, ; Capecchi et al, ; Lazzerini, Laghi‐Pasini, Boutjdir, & Capecchi, ). Among patients with systemic inflammatory diseases but who are HIV−, QTc prolongation correlates with higher IL‐6 concentrations (Capecchi et al, ).…”

Can atmospheric pollution be considered a co-factor in extremely high level of SARS-CoV-2 lethality in Northern Italy?

“…Among the other more common pollutants, ozone (O 3 ) and sulfur dioxide (SO 2 ) have also a prominent role in inducing systemic and respiratory system inflammation, particularly via IL-8 (Kurai et al, 2018), IL-17 (Che et al, 2016) and TNF-a (Cho et al, 2007), both in vitro and in vivo (Knorst et al, 1996). All these modifications are well known to contribute to atherogenesis, chronic respiratory diseases and cardiovascular events, the latter strictly correlated with IL-6 serum levels (Aromolaran et al, 2018). Nevertheless, aside of "classical" pollution-related conditions, several recent studies have pointed out a possible correlation between poor air quality and development and worsening of chronic inflammatory disease, such as systemic lupus erythematous (Alves et al, 2018;Gulati and Brunner, 2018) and rheumatoid arthritis (Sigaux et al, 2019).…”

Considerations for Drug Interactions on QTc in Exploratory COVID-19 Treatment

“…These include hypokalemia, hypomagnesemia, fever, 16 and an inflammatory state. 17 Mechanisms to minimize arrhythmia risk include: o In patients critically ill with COVID-19 infection, frequent caregiver contact may need to be minimized, so optimal electrocardiographic interval and rhythm monitoring may not be possible.…”