Abstract
Short QT syndrome variant 1 (SQT1) arises due to gain-of-function mutations to the human Ether-à-go-go-Related Gene (hERG), which encodes the α subunit of channels carrying rapid delayed rectifier potassium current, IKr. In addition to QT interval shortening and ventricular arrhythmias, SQT1 is associated with increased risk of atrial fibrillation (AF), which is often the only clinical presentation. However, the underlying basis of AF and its pharmacological treatment remain incompletely understood in the context of SQT1. In this study, computational modeling was used to investigate mechanisms of human atrial arrhythmogenesis consequent to a SQT1 mutation, as well as pharmacotherapeutic effects of selected class I drugs–disopyramide, quinidine, and propafenone. A Markov chain formulation describing wild type (WT) and N588K-hERG mutant IKr was incorporated into a contemporary human atrial action potential (AP) model, which was integrated into one-dimensional (1D) tissue strands, idealized 2D sheets, and a 3D heterogeneous, anatomical human atria model. Multi-channel pharmacological effects of disopyramide, quinidine, and propafenone, including binding kinetics for IKr/hERG and sodium current, INa, were considered. Heterozygous and homozygous formulations of the N588K-hERG mutation shortened the AP duration (APD) by 53 and 86 ms, respectively, which abbreviated the effective refractory period (ERP) and excitation wavelength in tissue, increasing the lifespan and dominant frequency (DF) of scroll waves in the 3D anatomical human atria. At the concentrations tested in this study, quinidine most effectively prolonged the APD and ERP in the setting of SQT1, followed by disopyramide and propafenone. In 2D simulations, disopyramide and quinidine promoted re-entry termination by increasing the re-entry wavelength, whereas propafenone induced secondary waves which destabilized the re-entrant circuit. In 3D simulations, the DF of re-entry was reduced in a dose-dependent manner for disopyramide and quinidine, and propafenone to a lesser extent. All of the anti-arrhythmic agents promoted pharmacological conversion, most frequently terminating re-entry in the order quinidine > propafenone = disopyramide. Our findings provide further insight into mechanisms of SQT1-related AF and a rational basis for the pursuit of combined IKr and INa block based pharmacological strategies in the treatment of SQT1-linked AF.
Highlights
The short QT syndrome (SQTS) is characterized primarily by a short QT interval on the ECG, which corresponds to abbreviated ventricular repolarisation
(green), and N588K conditions at a pacing frequency of 1 Hz, with corresponding current traces for (Aii) IKr, (Aiii) IK1, (Aiv) IKs, and (Av) ICaL, and (Avi) a summary of the measured APD90. (B) Activation-recovery interval (ARI) maps under (i) WT, (ii) WT-N588K, and (iii) N588K conditions. (Ci) View looking into the cavities of the 3D anatomical human atria model, with the following regions highlighted: crista terminalis (CT), left atrium (LA), pectinate muscles (PM), pulmonary veins (PV), and right atrium (RA). (Cii) Measured dispersion of activation-recovery interval, ARI, between different atrial regions under WT and SQTS variant 1 (SQT1) mutation conditions
Whilst several human Ether-à-go-go-Related gene (hERG) mutations have been identified in SQT1 (Hancox et al, 2018), the present study focused only on the N588K-hERG mutation, so the results here may not apply to all forms of SQT1
Summary
The short QT syndrome (SQTS) is characterized primarily by a short QT interval on the ECG, which corresponds to abbreviated ventricular repolarisation. A previous simulation study (Loewe et al, 2014b) used the Courtemanche-Ramirez-Nattel (CRN) mathematical model of the human atrial action potential (AP) (Courtemanche et al, 1998) to demonstrate shortening of the atrial effective refractory period (ERP) and tissue excitation wavelength (WL) consequent to the N588K-hERG mutation. This was shown to facilitate initiation and sustenance of spiral waves in idealized twodimensional (2D) sheets of human atrial tissue, which is a likely mechanism for increased susceptibility to AF. The first aim of the present study was to assess the arrhythmogenicity of the N588K-hERG mutation in anatomically-detailed models of the human atria with realistic structure and inclusion of regional differences in electrophysiology
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