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.

Fig. 1

Transmembrane action potentials and transmural electrocardiograms (ECG) in control and LQT1 (A), LQT2 (B), and LQT3 (C) models of LQTS (arterially-perfused canine left ventricular wedge preparations). Isoproterenol+chromanol 293B-an I_Ks blocker, d-sotalol+low [K⁺]_o, and ATX-II-an agent that slows inactivation of late I_Na are used to mimic the LQT1, LQT2 and LQT3 syndromes, respectively. Panels A–C depict action potentials simultaneously recorded from endocardial (Endo), M and epicardial (Epi) sites together with a transmural ECG. BCL=2000 ms. Transmural dispersion of repolarization across the ventricular wall, defined as the difference in the repolarization time between M and epicardial cells, is denoted below the ECG traces. Panels D–F: effect of isoproterenol in the LQT1, LQT2 and LQT3 models. In LQT1, isoproterenol (Iso) produces a persistent prolongation of the APD₉₀ of the M cell and of the QT interval (at both 2 and 10 min), whereas the APD₉₀ of the epicardial cell is always abbreviated, resulting in a persistent increase in TDR (D). In LQT2, isoproterenol initially prolongs (2 min) and then abbreviates the QT interval and the APD₉₀ of the M cell to the control level (10 min), whereas the APD₉₀ of epicardial cell is always abbreviated, resulting in a transient increase in TDR (E). In LQT3, isoproterenol produced a persistent abbreviation of the QT interval and the APD₉₀ of both M and epicardial cells (at both 2 and 10 min), resulting in a persistent decrease in TDR (F). *p<.0005 vs. Control; †p<.0005, ††p<.005, †††p<.05, vs. 293B, d-sotalol (d-Sot) or ATX-II. Modified from references (Shimizu & Antzelevitch, 1997, 1998, 2000a) with permission.

Fig. 2

Dose dependent effects of mexiletine (Mex) on APD and QT interval in chromanol 293B+isoproterenol (Iso) (LQT1,A), d-sotalol (LQT2, B) and ATX-II (LQT3, C) models of the arterially-perfused canine left ventricular wedge preparations. Each trace shows superimposed action potentials recorded simultaneously from M and epicardial (Epi) regions, together with a transmural ECG. BCL=2000 ms. Mexiletine (2 to 20 μmol/L) dose-dependently abbreviates the APD of both cells as well as the QT interval; 20 μmol/L mexiletine completely reverses the effects of ATX-II to prolong the QT interval, APD and to increase the TDR in the LQT3 model (C). Although 20 μmol/L mexiletine does not completely reverse the effect of the drug to prolong the QT interval and APD in the LQT1 (A) and LQT2 (B) models, mexiletine was effective in markedly reducing TDR due to a greater abbreviation of the APD of the M cell than that of Epi. Modified from references (Shimizu & Antzelevitch, 1997, 1998) with permission.