Mark J. McPate

Increased vulnerability of human ventricle to re-entrant excitation in hERG-linked variant 1 short QT syndrome.

The short QT syndrome (SQTS) is a genetically heterogeneous condition characterized by abbreviated QT intervals and an increased susceptibility to arrhythmia and sudden death. This simulation study identifies arrhythmogenic mechanisms in the rapid-delayed rectifier K+ current (IKr)-linked SQT1 variant of the SQTS. Markov chain (MC) models were found to be superior to Hodgkin-Huxley (HH) models in reproducing experimental data regarding effects of the N588K mutation on KCNH2-encoded hERG. These ionic channel models were then incorporated into human ventricular action potential (AP) models and into 1D and 2D idealised and realistic transmural ventricular tissue simulations and into a 3D anatomical model. In single cell models, the N588K mutation abbreviated ventricular cell AP duration at 90% repolarization (APD90) and decreased the maximal transmural voltage heterogeneity (δV) during APs. This resulted in decreased transmural heterogeneity of APD90 and of the effective refractory period (ERP): effects that are anticipated to be anti-arrhythmic rather than pro-arrhythmic. However, with consideration of transmural heterogeneity of IKr density in the intact tissue model based on the ten Tusscher-Noble-Noble-Panfilov ventricular model, not only did the N588K mutation lead to QT-shortening and increases in T-wave amplitude, but δV was found to be augmented in some local regions of ventricle tissue, resulting in increased tissue vulnerability for uni-directional conduction block and predisposing to formation of re-entrant excitation waves. In 2D and 3D tissue models, the N588K mutation facilitated and maintained re-entrant excitation waves due to the reduced substrate size necessary for sustaining re-entry. Thus, in SQT1 the N588K-hERG mutation facilitates initiation and maintenance of ventricular re-entry, increasing the lifespan of re-entrant spiral waves and the stability of scroll waves in 3D tissue.

Inhibition of the HERG K+ channel by the antifungal drug ketoconazole depends on channel gating and involves the S6 residue F656

The mechanism of human ether‐à‐go‐go‐related gene (HERG) K+ channel blockade by the antifungal agent ketoconazole was investigated using patch‐clamp recording from mammalian cell lines. Ketoconazole inhibited whole‐cell HERG current (I HERG) with a clinically relevant half‐maximal inhibitory drug concentration (IC50) value of 1.7 μM. The voltage‐ and time‐dependent characteristics of I HERG blockade by ketoconazole indicated dependence of block on channel gating, ruling out a significant role for closed‐state channel inhibition. The S6 HERG mutations Y652A and F656A produced ∼4‐fold and ∼21‐fold increases in IC50 for I HERG blockade, respectively. Thus, ketoconazole accesses the HERG channel pore‐cavity on channel gating, and the S6 residue F656 is an important determinant of ketoconazole binding.

Action potential clamp and chloroquine sensitivity of mutant Kir2.1 channels responsible for variant 3 short QT syndrome.

Recently identified genetic forms of short QT syndrome (SQTS) are associated with an increased risk of arrhythmia and sudden death. The SQT3 variant is associated with an amino-acid substitution (D172N) in the KCNJ2-encoded Kir2.1 K+ channel. In this study, whole-cell action potential (AP) clamp recording from transiently transfected Chinese Hamster Ovary cells at 37 °C showed marked augmentation of outward Kir2.1 current through D172N channels, associated with right-ward voltage-shifts of peak repolarizing current during both ventricular and atrial AP commands. Peak outward current elicited by ventricular AP commands was inhibited by chloroquine with an IC50 of 2.45 μM for wild-type (WT) Kir2.1, of 3.30 μM for D172N-Kir2.1 alone and of 3.11 μM for co-expressed WT and D172N (P > 0.05 for all). These findings establish chloroquine as an effective inhibitor of SQT3 mutant Kir2.1 channels.

Acidosis Impairs the Protective Role of hERG K+ Channels Against Premature Stimulation

Acidosis and the hERG K+ Channel. Introduction: Potassium channels encoded by human ether‐à‐go‐go‐related gene (hERG) underlie the cardiac rapid delayed rectifier K+ channel current (IKr). Acidosis occurs in a number of pathological situations and modulates a range of ionic currents including IKr. The aim of this study was to characterize effects of extracellular acidosis on hERG current (IhERG), with particular reference to quantifying effects on IhERG elicited by physiological waveforms and upon the protective role afforded by hERG against premature depolarizing stimuli.

Short QT syndrome

The idiopathic short QT syndrome (SQTS) is a recently identified condition characterized by abbreviated QT intervals (typically 300 ms or less) and in affected families is associated with an increased incidence of atrial and ventricular arrhythmias and sudden cardiac death. Genetic analysis has, to date, identified three distinct forms of the condition, involving gain-of-function mutations to three different cardiac potassium channel genes: KCNH2 (SQT1), KCNQ1 (SQT2) and KCNJ2 (SQT3). This article reviews recent advances in understanding this syndrome, discussing the basis of QT interval shortening, possible mechanisms for the associated arrhythmogenic risk in SQT1, current approaches to treatment of the SQTS (focusing on SQT1) and avenues for future investigation.