Pharmacological approach to the treatment of long and short QT syndromes

Abstract

Inherited channelopathies have received increasing attention in recent years. The past decade has witnessed impressive progress in our understanding of the molecular and cellular basis of arrhythmogenesis associated with inherited channelopathies. An imbalance in ionic forces induced by these channelopathies affects the duration of ventricular repolarization and amplifies the intrinsic electrical heterogeneity of the myocardium, creating an arrhythmogenic milieu. Today, many of the channelopathies have been linked to mutations in specific genes encoding either components of ion channels or membrane or regulatory proteins. Many of the channelopathies are genetically heterogeneous with a variable degree of expression of the disease. Defining the molecular basis of channelopathies can have a profound impact on patient management, particularly in cases in which genotype-specific pharmacotherapy is available.The long QT syndrome (LQTS) is one of the first identified and most studied channelopathies where abnormal prolongation of ventricular repolarization predisposes an individual to life threatening ventricular arrhythmia called Torsade de Pointes. On the other hand of the spectrum, molecular defects favoring premature repolarization lead to Short QT syndrome (SQTS), a recently described inherited channelopathy. Both of these channelopathies are associated with a high risk of sudden cardiac death due to malignant ventricular arrhythmia. Whereas pharmacological therapy is first line treatment for LQTS, defibrillators are considered as primary treatment for SQTS. This review provides a comprehensive review of the molecular genetics, clinical features, genotype-phenotype correlations and genotype-specific approach to pharmacotherapy of these two mirror-image channelopathies, SQTS and LQTS.

Cardiac Potassium Channel Subtypes: New Roles in Repolarization and Arrhythmia

“…A clear antiarrhythmic effect was observed in the rabbit wedge and included the expected action potential shortening, but also reduced dispersion. In contrast, canine wedge studies resulted in increased dispersion and pacing-induced polymorphic ventricular tachycardia (334,498). In intact isolated hearts, NS3623 has demonstrated antiarrhythmic properties such as a decrease in QT variability, and a tendency towards reduced global dispersion when addressed as a reduction in T peak -T end intervals, as well as a marked reduction in number of extrasystoli (170).…”

The genetic basis of long QT and short QT syndromes: A mutation update

“…The standard treatment of SQTS, on the other hand, is implantation of an ICD [Boriani et al, 2006], which has been shown to save patients from sudden arrhythmic death, despite a considerable risk of inappropriate discharges due to misinterpretation of frequent short-coupled tall T-waves as an arrhythmia [Schimpf et al, 2003[Schimpf et al, , 2005. The use of pharmacological treatment, e.g., quinidine, which inhibits both I Kr and I Ks [Patel and Antzelevitch, 2008], or disopyramide, which may be effective for SQT1 [Schimpf et al, 2007], is normally only considered in cases where ICD treatment is difficult to institute, e.g., in young children [Patel and Antzelevitch, 2008].…”

Class IV Antiarrhythmic Agents: New Compounds Using an Old Strategy

“…Bepridil is an exception but due to its I to and I K,Ach and certainly not its calcium channel blocking action [139]. CCAs should also be avoided in the treatment of short QT syndrome as in some genetic, congenital forms of the disease (SQT4 and 5) the calcium channels are already conduct a smaller current [140], [141]. Moreover, together with other drugs, verapamil is used to model early repolarization in animal studies [142].…”