Practice Update: Cardiology

ARRHYTHMIAS/HEART RHYTHM DISORDERS 14

Systemic inflammation as a novel QT-prolonging risk factor in patients with torsades de pointes

Heart (British Cardiac Society)

(acute infections, n=31; immune-mediated diseases, n=12; others, n=3) and elevated CRP (inflammatory cohort) were prospectively enrolled, and corrected QT (QTc) and cytokine levels were measured during active disease and after a CRP decrease of >75%subsequent to therapy. RESULTS In the TdP cohort, 80% of patients showed elevated CRP levels (median: ~3mg/ dL), with a definite inflammatory disease iden- tifiable in 18/40 cases (acute infections, n=12; immune-mediated diseases, n=5; others, n=1). In these subjects, IL-6, but not TNFα and IL-1, was ~15–20 times higher than in controls, and comparable to RA patients. In the inflammatory cohort, where QTc prolongation was common (mean values: 456.6±30.9 ms), CRP reduction was associated with IL-6 level decrease and significant QTc shortening (-22.3 ms). CONCLUSION The data are first to show that sys- temic inflammation via elevated IL-6 levels may represent a novel QT-prolonging risk factor contributing to TdP occurrence in the presence of other classical risk factors. If confirmed, this could open new avenues in antiarrhythmic therapy. Systemic inflammationas anovel QT-prolonging risk factor in patients with Torsades de Pointes. Heart 2017 May 10;[EPub Ahead of Print], PE Lazzerini, F Laghi-Pasini, I Bertolozzi, et al. study, suggesting that multiple factors are required for arrhythmia initiation. Whether IL-6 can directly alter cardiac repolariza- tion, and therefore QTc, or if it’s a surrogate for other causative factors, remains to be elucidated. This study should also be interpreted in the broader context of sys- temic inflammation and infection, which are not only accompanied by sympathetic activation affecting cardiac repolarization and arrhythmia development, but also by parasympathetic withdrawal, which, via the cholinergic anti-inflammatory path- way, can further amplify production of inflammatory cytokines and affect cardiac repolarization. Dr Vaseghi is Assistant Professor of Medicine and Director of Clinical and Translational Research at UCLA Cardiac Arrhythmia Center in California.

Take-home message • In this study, 40 consecutive patients experiencing torsade de pointes (TdP) were enrolled, and their levels of CRP and proinflammatory cytokines were compared with those of patients with rheumatoid arthritis and healthy controls to determine whether systemic inflammation may be an overlooked risk factor contributing to TdP development. Of the patients with TdP, 80% had elevated CRP levels and 18 patients had identifiable inflammatory disease. These patients had IL-6 levels approximately 15 to 20 times higher than levels in the control group. An additional 46 patients with inflammatory conditions and elevated CRP were enrolled. In these patients, CRP reduction was associated with decreased IL-6 levels and significant QTc shortening. • These results suggest that elevated IL-6 levels may represent a novel QT-prolonging risk factor related to TdP occurrence, which may introduce new areas for antiarrhythmic therapy.

systemic inflammation may represent a currently overlooked risk factor contributing to TdP devel- opment in the general population. METHODS Forty consecutive patients who experienced TdP (TdP cohort) were consecutively enrolled and circulating levels of C-reactive protein (CRP) and proinflammatory cytokines (interleukin-6 [IL-6],tumour necrosis factor alpha [TNFα], interleukin-1 [IL-1]) were compared with patients with active rheumatoid arthritis (RA), comorbidity or healthy controls. An additional 46 patients with different inflammatory conditions

Abstract OBJECTIVE Increasing evidence indicates sys- temic inflammation as a new potential cause of acquired long QT syndrome (LQTS), via cytokine-mediated changes in cardiomyo- cyte ion channels. Torsade de pointes (TdP) is a life-threatening polymorphic ventricular tachycardia occurring in patients with LQTS, usually when multiple QT-prolonging factors are simultaneously present. Since classical risk factors cannot fully explain TdP events in a number of patients, we hypothesised that COMMENT By Marmar Vaseghi MD, PhD C ardiac repolarization and the QT interval are controlled by myriad factors, ranging from cardiac ion channel function to the cardiac autonomic nervous system. Specifically, defects in certain ion channels, including potas- sium channels, are known to cause QT prolongation, whereas sympathetic acti- vation can also affect QT interval, cardiac repolarization, and increase the risk of ventricular arrhythmias. It is also known that patients with systemic inflamma- tion are at risk for cardiac disease and arrhythmias, although much of this work has previously focused on coronary artery disease. In this study by Lazzerini and colleagues, patients who developed torsade de pointes not only had prolonged QTc inter- vals but also were more likely to have

elevated CRP and IL-6 levels, equivalent to those in patients with active rheuma- toid arthritis. Acute or chronic infection or inflammation was observed in 45%. Fur- thermore, CRP and IL-6 reduction were associated with a significant reduction in QTc interval. Interestingly, TNF-α and IL-1 levels were not significantly elevated in torsade de pointes patients and were comparable to age-, gender-, and comor- bidity-matched controls. Although this study does not provide a causative link, it is intriguing in that it points to additional factors, including specific cytokines, which may affect cardiac repolarization and con- tribute to initiation of arrhythmias. It’s also important to note that patients with rheumatoid arthritis who had equiva- lent CRP and IL-6 levels were not reported to develop torsade de pointes in this

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