The Prolonged QT Interval: Role of Pro-inflammatory Cytokines, Reactive Oxygen Species and the Ceramide and Sphingosine-1 Phosphate Pathways

Patients with QT prolongation have delayed cardiac repolarization and may suffer fatal ventricular arrhythmias. To determine the role of cytokines in causing this syndrome, we reviewed reports on patients with rheumatoid arthritis, psoriasis and other inflammatory conditions. These patients frequently have prolonged QT, which correlates with increases in tumor necrosis factor alpha, and interleukin-1β and 6. Studies in experimental models have shown that these cytokines act through stimulation of reactive oxygen species. Our review of data on phospholipidosis and on QT-shortening agents suggests a key role in QT prolongation for the ceramide/sphingosine-1- phosphate rheostat. We conclude that the cause of prolonged QT in inflammatory conditions is cytokine induction of reactive oxygen species and then ceramides, and believe that QT-prolonging agents bypass initial steps of this pathway and directly affect ceramides. Since both pro-inflammatory cytokines and numerous medications cause QT prolongation and ventricular arrhythmias by this mechanism, extra caution is needed when using these agents in patients with inflammatory conditions. An increase in the levels of pro-inflammatory cytokines plays a role in the morbidity of numerous diseases. Marked elevations in levels of tumor necrosis factor-alpha (TNFα), and interleukins IL1β and IL6, in particular, have been found in diseases as diverse as diabetes (1), Alzheimer's disease (2), inflammatory bowel disease (3) and cancer (4). When elevation of these cytokines becomes massive, a 'cytokine storm' may develop and cause death of the patient (5-7). These pro-inflammatory cytokines are also found to be increased in autoimmune diseases, and blockers of these cytokines are now standard therapies for patients with rheumatoid arthritis (RA) and many other diseases (8-10). In long QT syndrome, there is delayed repolarization secondary to abnormalities in the potassium, sodium and calcium ion channels in myocardial cells. This may be caused by a genetic abnormality, coexisting cardiac diseases, hypokalemia or hypomagnesemia, or by one of numerous pharmaceutical agents, including commonly used antihistamines, sedatives, antibiotics, antiarrhythmics and psychiatric drugs. Ventricular tachycardia and sudden death secondary to delay in repolarization may occur (11-15). There is now increasing evidence suggesting that overexpression of IL1β, IL6, TNFα, and other cytokines plays a role in the pathogenesis of the long QT syndrome.