Long QT Syndrome and Sinus Bradycardia-A Mini Review

Abstract

Congenital long-QT syndrome (LQTS) is an inherited cardiac disorder characterized by the prolongation of ventricular repolarization, susceptibility to Torsades de Pointes (TdP), and a risk for sudden death. Various types of congenital LQTS exist, all due to specific defects in ion channel-related genes. Interestingly, almost all of the ion channels affected by the various types of LQTS gene mutations are also expressed in the human sinoatrial node (SAN). It is therefore not surprising that LQTS is frequently associated with a change in basal heart rate (HR). However, current data on how the LQTS-associated ion channel defects result in impaired human SAN pacemaker activity are limited. In this mini-review, we provide an overview of known LQTS mutations with effects on HR and the underlying changes in expression and kinetics of ion channels. Sinus bradycardia has been reported in relation to a large number of LQTS mutations. However, the occurrence of both QT prolongation and sinus bradycardia on a family basis is almost completely limited to LQTS types 3 and 4 (LQT3 and Ankyrin-B syndrome, respectively). Furthermore, a clear causative role of this sinus bradycardia in cardiac events seems reserved to mutations underlying LQT3.

Keywords: computer simulation; heart rate; human; ion channel; long-QT syndrome; mutations; sinoatrial node; sinus bradycardia.

Figure 1

Effect of the 1795insD mutation in SCN5A on the electrical activity of the Fabbri–Severi model cell of a human SAN pacemaker cell (A–D) under control conditions (normal autonomic activity) and (E–H) during vagal activity [based on data from recent computer simulations (29)]. (A,E) Membrane potential (V_m) of wild-type and mutant cell (solid blue and dotted red trace, respectively). (B,F) Associated net membrane current (I_net). (C,G) Associated fast Na⁺ current (I_Na). (D,H) Contribution of wild-type and mutant channels (solid green and orange trace, respectively) to I_Na of the mutant cell (dotted red trace).