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.
Highlights
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 [1]
Because LQTS-related rhythm disorders can be triggered by slow or high heart rate (HR) and sinus pauses [4, 11], detailed knowledge of the relation between LQTS and sinoatrial node (SAN) function is required. 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 mutant channels
Several reports exist of mutations in the CALM1–CALM3 genes, each encoding the ubiquitous Ca2+ sensing protein calmodulin, in relation to LQTS and sinus bradycardia (Table 1 and Table S8)
Summary
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 [1]. Bradycardia is frequently observed in LQT1 mutation carriers, especially in the fetalneonatal period [12, 13]. The A341V mutation in KCNQ1 may result in sinus bradycardia [13], but may occur in absence of baseline HR changes compared to non-carriers [19]. Because LQTS-related rhythm disorders can be triggered by slow or high HR and sinus pauses [4, 11], detailed knowledge of the relation between LQTS and SAN function is required. 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 mutant channels
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