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Background: Heart rate-corrected QT interval (QTc) prolongation is prevalent in patients with severe coronavirus disease 2019 (COVID-19) and is associated with poor outcomes. Recent evidence suggests that the exaggerated host immune-inflammatory response characterizing the disease, specifically interleukin-6 (IL-6) increase, may have an important role, possibly via direct effects on cardiac electrophysiology. The aim of this study was to dissect the short-term discrete impact of IL-6 elevation on QTc in patients with severe COVID-19 infection and explore the underlying mechanisms. Methods: We investigated the following mechanisms: (1) the QTc duration in patients with COVID-19 during the active phase and recovery, and its association with C-reactive protein (CRP) and IL-6 levels; (2) the acute impact of IL-6 administration on QTc in an in vivo guinea pig model; and (3) the electrophysiological effects of IL-6 on ventricular myocytes in vitro. Results: In patients with active severe COVID-19 and elevated IL-6 levels, regardless of acute myocardial injury/strain and concomitant QT-prolonging risk factors, QTc was significantly prolonged and rapidly normalized in correlation with IL-6 decrease. The direct administration of IL-6 in an in vivo guinea pig model acutely prolongs QTc duration. Moreover, ventricular myocytes incubated in vitro with IL-6 show evident prolongation in the action potential, along with significant inhibition in the rapid delayed rectifier potassium current (IKr). Conclusion: For the first time, we demonstrated that in severe COVID-19, systemic inflammatory activation can per se promote QTc prolongation via IL-6 elevation, leading to ventricular electric remodeling. Despite being transitory, such modifications may significantly contribute to arrhythmic events and associated poor outcomes in COVID-19. These findings provide a further rationale for current anti-inflammatory treatments for COVID-19, including IL-6-targeted therapies.
RESUMEN
Objective To observe the effect of stress on the rapid component of delayed rectifier potassium current (IKr) in rat cardiomyocytes. Methods Forty male SD rats were randomly divided into four groups (10 each): control group (Ctrl), exhaustive group (ES), noise group (WN) and composite group (ES+WN). Stress animal models were prepared as follows: Rats in ES group were undergoing exhaustive swimming as the stress factor, in WN group undergoing white noise and in ES+WN group undergoing exhaustive swimming + white noise as the stress factor. Langendorff device was used to reversely perfuse collagenase for isolating the rat's ventricular myocytes. The effect of stress on IKr current and gating mechanism of single ventricular myocyte was recorded by whole-cell patch clamp technique. Results Compared with the Ctrl group, the tail current density of IKr (IKr,tail) of ventricular myocytes increased significantly in ES group and WN group (P<0.01). The IKr,tail current density of the ventricular myocytes in ES+WN group was significantly higher than that in ES group and WN group (P<0.01), and the effect was voltage dependent. Gating mechanism revealed that the half inactivation voltage of IKr,tail (V1/2,inact) can be shifted to the right in ES group, WN group and ES+WN group when compared with the Ctrl group, and the recovery time constant shortened after inactivation (P<0.01). However, the steady-state activation, fast inactivation constant and voltage dependence of IKr,tail were not statistically significant in ES group, WN group and ES+WN group when compared with the Ctrl group. Conclusion Stress increases the IKr current in rat cardiomyocytes, suggesting it be one of the electrophysiological bases of stress-induced arrhythmia.
