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

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 $\beta$ - 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 μ M 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 $\beta$ - Adrenoceptor blocker carvedilol as a potential drug for SQTS treatment.