Long QT Syndrome: An Emerging Role for Inflammation and Immunity

Abstract

The long QT syndrome (LQTS), classified as congenital or acquired, is a multi-factorial disorder of myocardial repolarization predisposing to life-threatening ventricular arrhythmias, particularly torsades de pointes. In the latest years, inflammation and immunity have been increasingly recognized as novel factors crucially involved in modulating ventricular repolarization. In the present paper, we critically review the available information on this topic, also analyzing putative mechanisms and potential interplays with the other etiologic factors, either acquired or inherited. Accumulating data indicate inflammatory activation as a potential cause of acquired LQTS. The putative underlying mechanisms are complex but essentially cytokine-mediated, including both direct actions on cardiomyocyte ion channels expression and function, and indirect effects resulting from an increased central nervous system sympathetic drive on the heart. Autoimmunity represents another recently arising cause of acquired LQTS. Indeed, increasing evidence demonstrates that autoantibodies may affect myocardial electric properties by directly cross-reacting with the cardiomyocyte and interfering with specific ion currents as a result of molecular mimicry mechanisms. Intriguingly, recent data suggest that inflammation and immunity may be also involved in modulating the clinical expression of congenital forms of LQTS, possibly triggering or enhancing electrical instability in patients who already are genetically predisposed to arrhythmias. In this view, targeting immuno-inflammatory pathways may in the future represent an attractive therapeutic approach in a number of LQTS patients, thus opening new exciting avenues in antiarrhythmic therapy.

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

“…In fact, by targeting autonomic centres of the brain, inflammatory cytokines can increase the sympathetic outflow, in turn controlling cytokine production via inhibitory β2-adrenergic receptors on circulating lymphomonocytes (inflammatory reflex) 5. Indeed, central sympathetic overactivity affects the whole body, including the heart where marked and complex changes in myocardial electrophysiology result in a net effect of APD prolongation 5 6.…”

“…In fact, both cardiac and systemic inflammation is associated with QTc prolongation and higher propensity to develop TdP, as demonstrated by accumulating data obtained in patients with myo/endocarditis,5 and systemic autoimmune diseases, particularly rheumatoid arthritis (RA)6 7 and connective tissue diseases,5 6 as well as in apparently healthy subjects 5 8 9. The putative underlying mechanisms are complex but essentially cytokine mediated including direct actions on cardiomyocyte ion channels expression and function 5 6.…”

“…In this scenario, mounting evidence indicates inflammatory activation as a new cause of acquired LQTS 5. In fact, both cardiac and systemic inflammation is associated with QTc prolongation and higher propensity to develop TdP, as demonstrated by accumulating data obtained in patients with myo/endocarditis,5 and systemic autoimmune diseases, particularly rheumatoid arthritis (RA)6 7 and connective tissue diseases,5 6 as well as in apparently healthy subjects 5 8 9.…”

Prevalence of QT interval prolongation in inflammatory bowel disease

“…The following six sequentially activated currents are responsible in AP: the sodium current, transient outward current, L (long-lasting)-type calcium current (ICaL), rapid component of the delayed rectifier potassium current (IKr), slow component of the delayed rectifier potassium current (IKs), and inward rectifier potassium current. AP is caused by transmembrane flow of ions, including inward depolarizing currents mainly through the sodium and calcium channels and outward repolarizing currents mainly through potassium channels (28). Inflammatory cytokines (particularly TNF-α, IL-6, and IL-1β) may affect the myocardium either directly by modulating specific ion channels critically involved in AP or indirectly by increasing the central nervous system sympathetic drive on the heart (28).…”

Ventricular Tachycardia due to Long QT Syndrome Associated to Non-Cardiac Pharmacological Agents

“…Third, there are several accessible sources, including Web sites that provide updated information on drug interactions and their direct effects on the QT interval. Fourth, the most important preventive measure is avoidance of drug interactions that prolong the QT interval, and the risk of torsade de pointes may be heightened by the direct effect of multiple drugs on the QT interval or by impaired metabolism of a QT prolonging medication by an additional drug [20][21][22][23][24]. To have these facts in mind will lead to simple precautions and preventive measures that can minimize the risk of serious ventricular arrhythmias in patients taking multiple medications.…”