Effects of the β-Adrenoceptor Blocker Carvedilol in Short QT Syndrome Caused by N588K Mutation in hERG: A Simulation Study

Abstract

The short QT syndrome (SQTS) is associated with shortening of QT interval resulting from an accelerated cardiac repolarization. The SQT1, SQTS variant, results from a gain-of-function N588K-KCNH2 mutation in the rapid delayed rectifier potassium current (I Kr) channels. Since β-Adrenoceptor blocker can block slow delayed rectifier potassium currents (I Ks) and I Kr , we used in silico approach to evaluate carvedilol's effects on SQT1. Mathematical models of human ventricular action potential (AP) developed by ten Tusscher et al. were modified to incorporate a Markov chain formulation of I Kr describing the SQT1 mutant condition. AP models were incorporated into a transmural strand for investigation of QT interval changes. In addition, the simulated I Ks and I Kr inhibition to prolong the QT interval in SQT1 was quantified. The blocking effects of carvedilol on I Ks and I Kr were modelled by using Hill coefficient and IC 50 from literatures (10 μM carvedilol reduced I Kr in Wild Type-and N588K-KCNH2 by 92.8% and 36.0%; it reduced I Ks by 36.5% in both conditions). At single cell level, carvedilol prolonged the AP duration (APD) in SQT1; at strand level, the effects of carvedilol normalized the QT interval in SQT1 from 286 ms to 364 ms. Simulations identified β-Adrenoceptor blocker carvedilol as a potential drug for SQTS treatment.

Effects of Taurine-Magnesium Coordination Compound on Type 2 Short QT Syndrome: A Simulation Study

“…To date, mutations in seven genes (KCNH2, KCNQ1, KCNJ2, CACN1Ac, CACNB2b, CACNA2D1, and SCN5A) have been identified as responsible for types 1 to 7 of SQTS (SQT1-SQT7) [2][3][4]. Therapies for SQTS include implantation of an implantable cardioverter defibrillator (ICD) and anti-arrhythmic drugs (quinidine, carvedilol, and disopyramide) [5][6][7][8][9][10]. However, ICD is not suitable for children.…”