Prolonged ventricular repolarization acts as an independent predictor of sepsis prognosis: a cohort study and insights into intracardiac electrophysiology

Abstract Background Sepsis-induced myocardial injury is a serious complication of sepsis, which requires identification in the early stage. The abnormality of ventricular repolarization is related to myocardial injury in a group of heterogeneous disorders. Prolongation of QT interval (QTP) is a proarrhythmic status reflecting the increased ventricular activation duration. However, the study on the clinical value of QT prolongation in sepsis and their potential mechanism is limited. Purpose We aimed to investigate the clinical characteristics, predictors of new-onset QT prolongation in sepsis and its relationship with outcomes in a multicenter cohort study, and exploration of the underlying mechanism of changes of ventricular repolarization in sepsis-induced myocardial injury. Methods Electrocardiograms were collected from septic patients after exclusion of QT-influencing medications and electrolyte abnormalities. The characteristics and predictive factors of QT prolongation (QTc>450ms) were analyzed, and so was its impact on prognosis. Ventricular depolarization and repolarization were observed in lipopolysaccharide-treated mice with optical mapping. Bulk-RNA sequencing of septic myocardium and pathway enrichment were also performed. The ion channel-related gene expression was thereafter determined. Results QT prolongation occurred in 235/1024 (22.9%) patients from 4 centers. The majority demonstrated similar pattern as type I long QT syndrome. Patients with QT prolongation had a higher 15-day and 30-day in-hospital mortality (P<0.001), which was demonstrated as an independent predictor for prognosis (P=0.044) after multivariate analysis. History of coronary artery disease (P=0.001), septic shock (P=0.008), acute respiratory (P<0.001), heart (P=0.021) and renal dysfunction (P=0.013) were independent predictors of QT prolongation in sepsis. Optical mapping demonstrated longer QT interval and global action potential duration in lipopolysaccharide-treated mice without an increase in its dispersion within the ventricles. Sequencing of septic myocardium revealed significant downregulation of multiple potassium channel genes, consistent with the results of quantitative PCR. Conclusion New-onset QT prolongation in sepsis was associated with increased mortality as well as atrial and ventricular arrhythmias, which was predicted by disease severity and organ dysfunction. The prolongation of ventricular repolarization can be explained by the downregulation of potassium channel-related genes and the subsequent lengthening of activation potential duration.Graphic Abstract