Re-entry in models of cardiac ventricular tissue with scar represented as a Gaussian random field.

Introduction: Fibrotic scar in the heart is known to act as a substrate for arrhythmias. Regions of fibrotic scar are associated with slowed or blocked conduction of the action potential, but the detailed mechanisms of arrhythmia formation are not well characterised and this can limit the effective diagnosis and treatment of scar in patients. The aim of this computational study was to evaluate different representations of fibrotic scar in models of 2D 10 × 10 cm ventricular tissue, where the region of scar was defined by sampling a Gaussian random field with an adjustable length scale of between 1.25 and 10.0 mm. Methods: Cellular electrophysiology was represented by the Ten Tusscher 2006 model for human ventricular cells. Fibrotic scar was represented as a spatially varying diffusion, with different models of the boundary between normal and fibrotic tissue. Dispersion of activation time and action potential duration (APD) dispersion was assessed in each sample by pacing at an S1 cycle length of 400 ms followed by a premature S2 beat with a coupling interval of 323 ms. Vulnerability to reentry was assessed with an aggressive pacing protocol. In all models, simulated fibrosis acted to delay activation, to increase the dispersion of APD, and to generate re-entry. Results: A higher incidence of re-entry was observed in models with simulated fibrotic scar at shorter length scale, but the type of model used to represent fibrotic scar had a much bigger influence on the incidence of reentry. Discussion: This study shows that in computational models of fibrotic scar the effects that lead to either block or propagation of the action potential are strongly influenced by the way that fibrotic scar is represented in the model, and so the results of computational studies involving fibrotic scar should be interpreted carefully.

Evaluating pro-arrhythmogenic effects of the T634S-hERG mutation: insights from a simulation study.

A mutation to serine of a conserved threonine (T634S) in the hERG K+ channel S6 pore region has been identified as a variant of uncertain significance, showing a loss-of-function effect. However, its potential consequences for ventricular excitation and arrhythmogenesis have not been reported. This study evaluated possible functional effects of the T634S-hERG mutation on ventricular excitation and arrhythmogenesis by using multi-scale computer models of the human ventricle. A Markov chain model of the rapid delayed rectifier potassium current (IKr) was reconstructed for wild-type and T634S-hERG mutant conditions and incorporated into the ten Tusscher et al. models of human ventricles at cell and tissue (1D, 2D and 3D) levels. Possible functional impacts of the T634S-hERG mutation were evaluated by its effects on action potential durations (APDs) and their rate-dependence (APDr) at the cell level; and on the QT interval of pseudo-ECGs, tissue vulnerability to unidirectional conduction block (VW), spiral wave dynamics and repolarization dispersion at the tissue level. It was found that the T634S-hERG mutation prolonged cellular APDs, steepened APDr, prolonged the QT interval, increased VW, destablized re-entry and augmented repolarization dispersion across the ventricle. Collectively, these results imply potential pro-arrhythmic effects of the T634S-hERG mutation, consistent with LQT2.

Computational Analysis of the Mode of Action of Disopyramide and Quinidine on hERG-Linked Short QT Syndrome in Human Ventricles.

The short QT syndrome (SQTS) is a rare cardiac disorder associated with arrhythmias and sudden death. Gain-of-function mutations to potassium channels mediating the rapid delayed rectifier current, IKr, underlie SQTS variant 1 (SQT1), in which treatment with Na+ and K+ channel blocking class Ia anti-arrhythmic agents has demonstrated some efficacy. This study used computational modeling to gain mechanistic insights into the actions of two such drugs, disopyramide and quinidine, in the setting of SQT1. The O'Hara-Rudy (ORd) human ventricle model was modified to incorporate a Markov chain formulation of IKr describing wild type (WT) and SQT1 mutant conditions. Effects of multi-channel block by disopyramide and quinidine, including binding kinetics and altered potency of IKr/hERG channel block in SQT1 and state-dependent block of sodium channels, were simulated on action potential and multicellular tissue models. A one-dimensional (1D) transmural ventricular strand model was used to assess prolongation of the QT interval, effective refractory period (ERP), and re-entry wavelength (WL) by both drugs. Dynamics of re-entrant excitation waves were investigated using a 3D human left ventricular wedge model. In the setting of SQT1, disopyramide, and quinidine both produced a dose-dependent prolongation in (i) the QT interval, which was primarily due to IKr block, and (ii) the ERP, which was mediated by a synergistic combination of IKr and INa block. Over the same range of concentrations quinidine was more effective in restoring the QT interval, due to more potent block of IKr. Both drugs demonstrated an anti-arrhythmic increase in the WL of re-entrant circuits. In the 3D wedge, disopyramide and quinidine at clinically-relevant concentrations decreased the dominant frequency of re-entrant excitations and exhibited anti-fibrillatory effects; preventing formation of multiple, chaotic wavelets which developed in SQT1, and could terminate arrhythmias. This computational modeling study provides novel insights into the clinical efficacy of disopyramide and quinidine in the setting of SQT1; it also dissects ionic mechanisms underlying QT and ERP prolongation. Our findings show that both drugs demonstrate efficacy in reversing the SQT1 phenotype, and indicate that disopyramide warrants further investigation as an alternative to quinidine in the treatment of SQT1.

In silico investigation of the short QT syndrome, using human ventricle models incorporating electromechanical coupling.

INTRODUCTION: Genetic forms of the Short QT Syndrome (SQTS) arise due to cardiac ion channel mutations leading to accelerated ventricular repolarization, arrhythmias and sudden cardiac death. Results from experimental and simulation studies suggest that changes to refractoriness and tissue vulnerability produce a substrate favorable to re-entry. Potential electromechanical consequences of the SQTS are less well-understood. The aim of this study was to utilize electromechanically coupled human ventricle models to explore electromechanical consequences of the SQTS. METHODS AND RESULTS: The Rice et al. mechanical model was coupled to the ten Tusscher et al. ventricular cell model. Previously validated K(+) channel formulations for SQT variants 1 and 3 were incorporated. Functional effects of the SQTS mutations on [Ca(2+)] i transients, sarcomere length shortening and contractile force at the single cell level were evaluated with and without the consideration of stretch-activated channel current (I sac). Without I sac, at a stimulation frequency of 1Hz, the SQTS mutations produced dramatic reductions in the amplitude of [Ca(2+)] i transients, sarcomere length shortening and contractile force. When I sac was incorporated, there was a considerable attenuation of the effects of SQTS-associated action potential shortening on Ca(2+) transients, sarcomere shortening and contractile force. Single cell models were then incorporated into 3D human ventricular tissue models. The timing of maximum deformation was delayed in the SQTS setting compared to control. CONCLUSION: The incorporation of I sac appears to be an important consideration in modeling functional effects of SQT 1 and 3 mutations on cardiac electro-mechanical coupling. Whilst there is little evidence of profoundly impaired cardiac contractile function in SQTS patients, our 3D simulations correlate qualitatively with reported evidence for dissociation between ventricular repolarization and the end of mechanical systole.