The long QT syndromes: genetic basis and clinical implications

Abstract

It is becoming clear that mutations in the KVLQT1, human "ether-a-go-go" related gene, cardiac voltage-dependent sodium channel gene, minK and MiRP1 genes, respectively, are responsible for the LQT1, LQT2, LQT3, LQT5 and LQT6 variants of the Romano-Ward syndrome, characterized by autosomal dominant transmission and no deafness. The much rarer Jervell-Lange-Nielsen syndrome (with marked QT prolongation and sensorineural deafness) arises when a child inherits mutant KVLQT1 or minK alleles from both parents. In addition, some families are not linked to the known genetic loci. Cardiac voltage-dependent sodium channel gene encodes the cardiac sodium channel, and long QT syndrome (LQTS) mutations prolong action potentials by increasing inward plateau sodium current. The other mutations cause a decrease in net repolarizing current by reducing potassium currents through "dominant negative" or "loss of function" mechanisms. Polymorphic ventricular tachycardia (torsade de pointes) is thought to be initiated by early after-depolarizations in the Purkinje system and maintained by reentry in the myocardium. Clinical presentations vary with the specific gene affected and the specific mutation. Nevertheless, patients with identical mutations can also present differently, and some patients with LQTS mutations may have no manifest baseline phenotype. The question of whether the latter situation is one of high risk for administration of QT prolonging drugs or during myocardial ischemia is under active investigation. More generally, the identification of LQTS genes has provided tremendous new insights for our understanding of normal cardiac electrophysiology and its perturbation in a wide range of conditions associated with sudden death. It seems likely that the approach of applying information from the genetics of uncommon congenital syndromes to the study of common acquired diseases will be an increasingly important one in the next millennium.

Sevoflurane Inhibition of the Slowly Activating Delayed Rectifier K+ Current in Guinea Pig Ventricular Cells

“…2). The finding is consistent with the recent report that halothane inhibited HERG (human ether-a-go-go-related gene) channels, which are partly responsible for cardiac I Kr (22). Sevoflurane and halothane may act on I Kr channels in a different manner.…”

“…Both currents play an important role for repolarization of action potential, and a congenital or acquired prolongation of the QT interval in ECG is often brought about by a loss of function of the above current systems (2). Excessive prolongation of the QT interval may trigger the development of lethal tachyarrhythmia torsade de pointes, resulting in syncope and sudden cardiac death (2).…”

“…This is particularly important since I Ks and I Kr are known to exhibit pharmacologically distinct properties. I Kr is not only a target of class III antiarrhythmic agents (14) but is also blocked by various, structurally unrelated drugs such as antipsychotics, H 1 -antihitamines, and fluoroquinolones (2). The most common mechanism of QT interval prolongation by pharmaceuticals appears to be inhibition of I Kr (2).…”

“…I Kr is not only a target of class III antiarrhythmic agents (14) but is also blocked by various, structurally unrelated drugs such as antipsychotics, H 1 -antihitamines, and fluoroquinolones (2). The most common mechanism of QT interval prolongation by pharmaceuticals appears to be inhibition of I Kr (2). On the other hand, I Ks is blocked by chromanol derivatives (15,16) and some general anesthetics including propofol and barbiturates (17).…”

Ischemic, genetic and pharmacological origins of cardiac arrhythmias: The contribution of the Quebec Heart Institute

“…These arrhythmias are most commonly associated with heart disease (2). They are also characteristic of the relatively rare congenital long QT syndrome (LQTS), an inherited group of conditions associated with prolongation of the QT interval on the surface electrocardiogram, syncope and sudden death (3). Genetic studies of LQTS have led to the hypothesis THE QUEBEC HEART INSTITUTE ©2007 Pulsus Group Inc. All rights reserved Research in the field of basic electrophysiology at the Quebec Heart Institute (Laval Hospital, Quebec City, Quebec) has evolved since its beginning in the 1990s.…”