The Role of Inflammation and Autoimmunity in Long QT Syndrome

Abstract

Inflammation and autoimmunity are increasingly recognized as novel pathogenic mechanisms of acquired long QT syndrome (LQTS), actively cooperating with classical risk factors to increase the risk of torsades de pointes (TdP), and sudden cardiac death (SCD). Accumulating evidence points to inflammatory cytokines, particularly TNFα, IL-1, and IL-6, as the key mediators linking inflammatory activation to heart rate-corrected QT interval (QTc) prolongation, primarily via direct electrophysiological effects on the myocardium. Experimental studies provided evidence that such molecules can prolong ventricular action potential duration (APD) by modulating the expression and/or function of several ion channels of the cardiomyocyte (inflammatory channelopathies). In addition, different types of arrhythmogenic autoantibodies have been identified, able to cross-react, and functionally interfere with specific ion channels critically involved in ventricular APD (autoimmune channelopathies), leading to acquired forms of LQTS of autoimmune origin. The most investigated are anti-Ro/SSA antibodies, acting via an inhibition of the human Ether-a-go-go-Related Gene (hERG) potassium channel. To date, the potential impact of inflammatory and autoimmune channelopathies on ventricular repolarization is largely overlooked in the clinical practice and therefore poorly considered in terms of diagnostic and therapeutic implications in LQTS. In this view, increased awareness to the existence of these forms is essential to identify and adequately manage affected patients. By integrating basic and clinical research, in this chapter we provide an updated overview of this subject, also discussing practical implications and future therapeutic perspectives.