Interleukin-6 Elevation Is a Key Pathogenic Factor Underlying COVID-19-Associated Heart Rate-Corrected QT Interval Prolongation

Figures

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  FIGURE 1. Heart rate-corrected QT interval (QTc), C-reactive protein (CRP), and interleukin-6 (IL-6) in patients with COVID-19, during active disease and recovery. (A) Heart rate-corrected QT interval based on Bazett’s formula (QTc); two-tail paired t-test, ***p < 0.001. (B) Comparison of QTc in patients with COVID-19, during active disease and recovery, and controls; two-tailed unpaired t-test, ***p < 0.001, n.s. not significant. (C) CRP; two-tailed paired t-test, ***p < 0.0001. (D) IL-6; two-tailed Wilcoxon matched pairs test, ***p < 0.001. Patients, n = 33; controls, n = 20.

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  FIGURE 2. Correlation between QTc, CRP, and IL-6 in patients with COVID-19 over time. (A) Relationship between heart rate-corrected QT interval based on Bazett’s formula (QTc) and CRP levels. (B) Relationship between QTc and Il-6 levels.Spearman’s rank correlation. Patients, n = 33.

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  FIGURE 3. Impact of IL-6 on QTc in guinea pigs. (A) Representative lead-II ECG from a guinea pig during the basal condition (a) with a normal sinus rhythm at 250 beats/min with a QTc = 219 ms, and (b) at 40 min after intravenous injection with IL-6 (184 μg/kg) in the same guinea pig, demonstrating a sinus rhythm at 227 beats/min with a QTc = 232 ms; the shaded area in light blue and the black arrows indicate the QT interval at baseline, while the red arrows indicate the QT interval after IL-6. (B) Changes in QTc levels at baseline and 40 min after IL-6 injection for each guinea pig (n = 5); two-tailed paired t-test, *p < 0.05. (C) Changes in QRS interval observed at baseline and 40 min after IL-6 injection for each guinea pig (n = 5); two-tailed Wilcoxon matched pairs test, n.s. not significant.

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  FIGURE 4. Effects of IL-6 on action potential and IKr in guinea pig ventricular myocytes. Representative action potentials (A) and IKr (B) recorded from a separate set of control myocytes (black traces) and from another set of myocytes preincubated with IL-6 (200 μg/L) for 40 min (blue traces). In panel (A), action potentials were recorded in ventricular myocytes (n = 18) without IL-6 (black traces, control) and in ventricular myocytes (n = 11) preincubated with IL-6 (200 μg/L) for 40 min (blue traces) using the current-clamp mode. In panel (B), IKr tail currents were recorded in ventricular myocytes (n = 10) without IL-6 (black traces) and in ventricular myocytes (n = 9) preincubated with IL-6 (200 μg/L) for 40 min (blue traces) using voltage-clamp mode.

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  FIGURE 5. Systemic inflammatory activation may per se promote QTc prolongation in patients with severe COVID-19 via IL-6 elevation, leading to ventricular electric remodeling. (A) In patients with active severe COVID-19 and elevated IL-6 levels, QTc is significantly prolonged but rapidly normalized during recovery in correlation with IL-6 decrease. (B) Direct injection of IL-6 in an in vivo guinea pig model acutely prolongs QTc duration. (C) Guinea pig ventricular myocytes incubated in vitro with IL-6 show evident APD prolongation, along with significant inhibition in the IKr current. APD, action potential duration; COVID-19, coronavirus disease 2019; ERG, ether-a-go-go-related gene K+ channel; IL-6, interleukin-6; IKr: rapid delayed rectifier potassium current; QTc, heart rate-corrected QT interval.