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.

Keywords: anti-Ro/SSA; autoantibodies; cytokines; immunity; inflammation; long QT syndrome.

Figure 1

Molecular and electrophysiological basis of QT interval. INa, sodium current; Ito, transient outward current; ICaL, L(long-lasting)-type calcium current; IKr, rapid component of the delayed rectifier potassium current; IKs, slow component of the delayed rectifier potassium current; IK1, inward rectifier potassium current.

Figure 2

Potential mechanisms responsible for inflammation-mediated QTc prolongation. CRP, C-reactive protein.

Figure 3

Autoantibody-mediated QTc prolongation: molecular targets and electrophysiological consequences. Anti-β1, anti β1-adrenergic receptor antibodies; Ito, transient outward potassium current; IKr, rapid component of the delayed rectifier current; IKs, slow component of the delayed rectifier current; ICaL, L-type calcium current; APD, action potential duration.

Figure 4

Putative pathways involved in exacerbating myocardial electrical instability in patients with congenital LQTS during an acute inflammatory illness. LQTS, long QT syndrome; APD, action potential duration.