Elevated Interleukin‐6 Levels Are Associated With an Increased Risk of QTc Interval Prolongation in a Large Cohort of US Veterans

Abstract

Background Although accumulating data indicate that IL‐6 (interleukin‐6) can promote heart rate‐corrected QT interval (QTc) prolongation via direct and indirect effects on cardiac electrophysiology, current evidence comes from basic investigations and small clinical studies only. Therefore, IL‐6 is still largely ignored in the clinical management of long‐QT syndrome and related arrhythmias. The aim of this study was to estimate the risk of QTc prolongation associated with elevated IL‐6 levels in a large population of unselected subjects. Methods and Results An observational study using the Veterans Affairs Informatics and Computing Infrastructure was performed. Participants were US veterans who had an ECG and were tested for IL‐6. Descriptive statistics and univariate and multivariate regression analyses were performed to study the relationship between IL‐6 and QTc prolongation risk. Study population comprised 1085 individuals, 306 showing normal (<5 pg/mL), 376 moderately high (5–25 pg/mL), and 403 high (>25 pg/mL) IL‐6 levels. Subjects with elevated IL‐6 showed a concentration‐dependent increase in the prevalence of QTc prolongation, and those presenting with QTc prolongation exhibited higher circulating IL‐6 levels. Stepwise multivariate regression analyses demonstrated that increased IL‐6 level was significantly associated with a risk of QTc prolongation up to 2 times the odds of the reference category of QTc (e.g. QTc >470 ms men/480 ms women ms: odds ratio, 2.28 [95% CI, 1.12–4.50] for IL‐6 >25 pg/mL) regardless of the underlying cause. Specifically, the mean QTc increase observed in the presence of elevated IL‐6 was quantitatively comparable (IL‐6 >25 pg/mL:+6.7 ms) to that of major recognized QT‐prolonging risk factors, such as hypokalemia and history of myocardial infarction. Conclusions Our data provide evidence that a high circulating IL‐6 level is a robust risk factor for QTc prolongation in a large cohort of US veterans, supporting a potentially important arrhythmogenic role for this cytokine in the general population.