In silico Assessment of Pharmacotherapy for Human Atrial Patho-Electrophysiology Associated With hERG-Linked Short QT Syndrome

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.

Complementarity between Arrhythmia Mechanisms Found in Silico and in Genetic Models of N588K-hERG Linked Short QT Syndrome

“…Such findings are qualitatively consistent with modest systolic changes observed using Doppler imaging and speckle-tracking echocardiography in SQTS patients [23]. A simulation approach has also been used to explore the atrial arrhythmia substrate and its susceptibility to modification by Class I antiarrhythmic drugs in N588K-linked SQTS [24].…”

Proarrhythmia in the p.Met207Val PITX2c-Linked Familial Atrial Fibrillation-Insights From Modeling

“…The mechanisms by which ionic and structural remodeling induced by the PITX2c p.Met207Val mutation promotes and perpetuates AF have not yet been elucidated. Complex electrical wave dynamics observed during AF is determined by AP morphology, APD, conduction velocity (CV) restitution, wavelength (WL), vulnerable window (VW) for unidirectional conduction block, and the minimal substrate size required to induce re-entry (Bai et al, 2016b; Ni et al, 2017; Whittaker et al, 2017, 2018a,b). Therefore, utilizing a multi-scale computational model of the human atria based on experimental data on the PITX2c p.Met207Val mutation, we simulated electrical activity to quantify its potential impact at the cellular, 1D fiber tissue and 2D sheet tissue levels.…”

Short QT Syndrome: A Comprehensive Genetic Interpretation and Clinical Translation of Rare Variants

“…The p.(Asn588Lys) variant (rs104894021, CM040082/CM040083) was identified in KCNH2 . Conclusive data concerning pathogenicity was recently reported [23], even using human-induced pluripotent stem cell–derived cardiomyocytes (hiPSC-CMs) [24,25] supporting a deleterious role previously proposed in 2003. Considering all data, including in silico analysis (Table 2), p.(Asn588Lys) should be classified as Pathogenic for SQTS following ACMG/AMP recommendations (Table 1 and Table 3, Figure 1).…”