Electrocardiography provides some information useful for ischemic diagnosis. However, more recently there has been substantial growth in the area of ECG imaging, which by solving the inverse problem of electrocardiography aims to produce high-resolution mapping of the electrical and magnetic dynamics of the heart. Most inverse studies use the full resolution of the body surface potential (BSP) to reconstruct the epicardial potentials, however using a limited number of torso electrodes to interpolate the BSP is more clinically relevant and has an important effect on the reconstruction which must be quantified. A circular ischemic lesion on the right ventricle lateral wall 27 mm in radius is reconstructed using three Tikhonov methods along with 6 different electrode configurations ranging from 32 leads to 1,024 leads. The 2nd order Tikhonov solution performed the most accurately (~80% lesion identified) followed by the 1st (~50% lesion identified) and then the 0 order Tikhonov solution performed the worst with a maximum of ~30% lesion identified regardless of how many leads were used. With an increasing number of leads the solution produces less error, and the error becomes more localised around the lesion for all three regularisation methods. In noisy conditions, the relative performance gap of the 1st and 2nd order Tikhonov solutions was reduced, and determining an accurate regularisation parameter became relatively more difficult. Lesions located on the left ventricle walls were also able to be identified but comparatively to the right ventricle lateral wall performed marginally worse with lesions located on the interventricular septum being able to be indicated by the reconstructions but not successfully identified against the error. The quality of reconstruction was found to decrease as the lesion radius decreased, with a lesion radius of <20 mm becoming difficult to correctly identify against the error even when using >512 torso electrodes.

Atrial fibrillation (AF) and sinus bradycardia have been reported in patients with short QT syndrome variant 2 (SQT2), which is underlain by gain-of-function mutations in KCNQ1 encoding the α subunit of channels carrying slow delayed rectifier potassium current, I Ks. However, the mechanism(s) underlying the increased atrial arrhythmogenesis and impaired cardiac pacemaking activity arising from increased I Ks remain unclear. Possible pharmacological interventions of AF in the SQT2 condition also remain to be elucidated. Using computational modelling, we assessed the functional impact of SQT2 mutations on human sinoatrial node (SAN) pacemaking, atrial repolarisation and arrhythmogenesis, and efficacy of the anti-arrhythmic drug quinidine. Markov chain formulations of I Ks describing two KCNQ1 mutations - V141M and V307L - were developed from voltage-clamp experimental data and then incorporated into contemporary action potential (AP) models of human atrial and SAN cells, the former of which were integrated into idealised and anatomically detailed tissue models. Both mutations shortened atrial AP duration (APD) through distinct I Ks gain-of-function mechanisms, whereas SAN pacemaking rate was slowed markedly only by the V141M mutation. Differences in APD restitution steepness influenced re-entry dynamics in tissue - the V141M mutation promoted stationary and stable spiral waves whereas the V307L mutation promoted non-stationary and unstable re-entrant waves. Both mutations shortened tissue excitation wavelength through reduced effective refractory period but not conduction velocity, which served to increase the lifespan of re-entrant excitation in a 3D anatomical human atria model, as well as the dominant frequency (DF), which was higher for the V141M mutation. Quinidine was effective at terminating arrhythmic excitation waves associated with the V307L but not V141M mutation, and reduced the DF in a dose-dependent manner under both mutation conditions. This study provides mechanistic insights into different AF/bradycardia phenotypes in SQT2 and the efficacy of quinidine pharmacotherapy.

A recent experimental study investigating patients with lone atrial fibrillation identified six novel mutations in the KCNA5 gene. The mutants exhibited both gain- and loss-of-function of the atrial specific ultra-rapid delayed rectifier K+ current, IKur. The aim of this study is to elucidate and quantify the functional impact of these KCNA5 mutations on atrial electrical activity. A multi-scale model of the human atria was updated to incorporate detailed experimental data on IKur from both wild-type and mutants. The effects of the mutations on human atrial action potential and rate dependence were investigated at the cellular level. In tissue, we assessed the effects of the mutations on the vulnerability to unidirectional conduction patterns and dynamics of re-entrant excitation waves. Gain-of-function mutations shortened the action potential duration in single cells, and stabilised and accelerated re-entrant excitation in tissue. Loss-of-function mutations had heterogeneous effects on action potential duration and promoted early-after-depolarisations following beta-adrenergic stimulation. In the tissue model, loss-of-function mutations facilitated breakdown of excitation waves at more physiological excitation rates than the wild-type, and the generation of early-after-depolarisations promoted unidirectional patterns of excitation. Gain- and loss-of-function IKur mutations produced multiple mechanisms of atrial arrhythmogenesis, with significant differences between the two groups of mutations. This study provides new insights into understanding the mechanisms by which mutant IKur contributes to atrial arrhythmias. In addition, as IKur is an atrial-specific channel and a number of IKur-selective blockers have been developed as anti-AF agents, this study also helps to understand some contradictory results on both pro- and anti-arrhythmic effects of blocking IKur.

We investigate the effect of mechano-electrical feedback and atrial fibrillation induced electrical remodelling (AFER) of cellular ion channel properties on the dynamics of spiral waves in a discrete 2D model of human atrial tissue. The tissue electro-mechanics are modelled using the discrete element method (DEM). Millions of bonded DEM particles form a network of coupled atrial cells representing 2D cardiac tissue, allowing simulations of the dynamic behaviour of electrical excitation waves and mechanical contraction in the tissue. In the tissue model, each cell is modelled by nine particles, accounting for the features of individual cellular geometry; and discrete inter-cellular spatial arrangement of cells is also considered. The electro-mechanical model of a human atrial single-cell was constructed by strongly coupling the electrophysiological model of Colman et al. to the mechanical myofilament model of Rice et al., with parameters modified based on experimental data. A stretch-activated channel was incorporated into the model to simulate the mechano-electrical feedback. In order to investigate the effect of mechano-electrical feedback on the dynamics of spiral waves, simulations of spiral waves were conducted in both the electromechanical model and the electrical-only model in normal and AFER conditions, to allow direct comparison of the results between the models. Dynamics of spiral waves were characterized by tracing their tip trajectories, stability, excitation frequencies and meandering range of tip trajectories. It was shown that the developed DEM method provides a stable and efficient model of human atrial tissue with considerations of the intrinsically discrete and anisotropic properties of the atrial tissue, which are challenges to handle in traditional continuum mechanics models. This study provides mechanistic insights into the complex behaviours of spiral waves and the genesis of atrial fibrillation by showing an important role of the mechano-electrical feedback in facilitating and promoting atrial fibrillation.

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 OHara-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.

[This corrects the article DOI: 10.3389/fphys.2019.00050.].

Gain-of-function mutations in KCNJ2-encoded Kir2.1 channels underlie variant 3 (SQT3) of the short QT syndrome, which is associated with atrial fibrillation (AF). Using biophysically-detailed human atria computer models, this study investigated the mechanistic link between SQT3 mutations and atrial arrhythmogenesis, and potential ion channel targets for treatment of SQT3. A contemporary model of the human atrial action potential (AP) was modified to recapitulate functional changes in IK1 due to heterozygous and homozygous forms of the D172N and E299V Kir2.1 mutations. Wild-type (WT) and mutant formulations were incorporated into multi-scale homogeneous and heterogeneous tissue models. Effects of mutations on AP duration (APD), conduction velocity (CV), effective refractory period (ERP), tissue excitation threshold and their rate-dependence, as well as the wavelength of re-entry (WL) were quantified. The D172N and E299V Kir2.1 mutations produced distinct effects on IK1 and APD shortening. Both mutations decreased WL for re-entry through a reduction in ERP and CV. Stability of re-entrant excitation waves in 2D and 3D tissue models was mediated by changes to tissue excitability and dispersion of APD in mutation conditions. Combined block of IK1 and IKr was effective in terminating re-entry associated with heterozygous D172N conditions, whereas IKr block alone may be a safer alternative for the E299V mutation. Combined inhibition of IKr and IKur produced a synergistic anti-arrhythmic effect in both forms of SQT3. In conclusion, this study provides mechanistic insights into atrial proarrhythmia with SQT3 Kir2.1 mutations and highlights possible pharmacological strategies for management of SQT3-linked AF.

Elucidating the function of specific cell types in a highly complex multicellular system such as the heart often requires detailed anatomic reconstruction. We recently described a distinctive class of phenylethanolamine n-methyltransferase (Pnmt+) cell-derived cardiomyocytes (PdCMs), a new cardiomyocyte population with a potential endocrine role. In this dataset, a 3D reconstruction was carried out to visualise the distribution of PdCMs throughout the murine heart. Rigid registration (stiff rotation and translation) was applied to properly align the fused heart slice images based on landmarks using TrakEM2, an open source plug-in in Fiji. The registered slices were then analysed and reconstructed using MATLAB (MATLAB®. Version 8.3.0.532). The final reconstructed 3D volume was 561×866×48 pixels (corresponding to spatial resolutions of 5.8, 8.9 and 2.5 mm in the x-, y- and z-direction respectively), and visualised in Paraview. The reconstruction allows for detailed analyses of morphology, projections and cellular features of different cell types, enabling further geometrical and topological analyses. Image data can be accessed and viewed through Figshare.

Myocardial ventricular ischemia arises from a lack of blood supply to the heart, which may cause abnormal repolarization and excitation wave conduction patterns in the tissue, leading to cardiac arrhythmias and even sudden death. Current diagnosis of cardiac ischemia by the 12-lead electrocardiogram (ECG) has limitations as they are insensitive in many cases and may show unnoticeable differences to normal patterns. As the magnetic field provides extra information on cardiac excitation and is more sensitive to tangential currents to the surface of the chest, whereas the electric field is more sensitive to flux currents, it has been hypothesized that the magnetocardiogram (MCG) may provide a complementary method to the ECG in ischemic diagnosis. However, it is unclear yet about the differences in sensitivity regions of body surface ECG and MCG signals to ischemic conditions. The aim of this study was to investigate such differences by using 12-, 36- ECG and 36-MCG computed from multi-scale biophysically detailed computational models of the human ventricles and torso in both control and ischemic conditions. It was shown that ischemia produced changes in the ECG and MCG signals in the QRS complex, T-wave and ST-segment, with greater relative differences seen in the 36-lead ECG and MCG as compared to the 12-leads ECG (34% and 37% vs 26%, respectively). The 36-lead ECG showed more averaged sensitivity than the MCG in the change of T-wave due to ischemia (37% vs 32%, respectively), whereas the MCG showed greater sensitivity than the ECG in the change of the ST-segment (50% vs 40%, respectively). In addition, both MCG and ECG showed regional-dependent changes to ischemia, but with MCG showing a stronger correlation between ischemic region in the heart. In conclusion, MCG shows more sensitivity than ECG in response to ischemia, which may provide an alternative method for the diagnosis of ischemia.

Atrial fibrillation (AF) is the most common cardiac arrhythmia. Developing effective and safe anti-AF drugs remains an unmet challenge. Simultaneous block of both atrial-specific ultra-rapid delayed rectifier potassium (K+) current (IKur) and the Na+ current (INa) has been hypothesized to be anti-AF, without inducing significant QT prolongation and ventricular side effects. However, the antiarrhythmic advantage of simultaneously blocking these two channels vs. individual block in the setting of AF-induced electrical remodeling remains to be documented. Furthermore, many IKur blockers such as acacetin and AVE0118, partially inhibit other K+ currents in the atria. Whether this multi-K+-block produces greater anti-AF effects compared with selective IKur-block has not been fully understood. The aim of this study was to use computer models to (i) assess the impact of multi-K+-block as exhibited by many IKur blokers, and (ii) evaluate the antiarrhythmic effect of blocking IKur and INa, either alone or in combination, on atrial and ventricular electrical excitation and recovery in the setting of AF-induced electrical-remodeling. Contemporary mathematical models of human atrial and ventricular cells were modified to incorporate dose-dependent actions of acacetin (a multichannel blocker primarily inhibiting IKur while less potently blocking Ito, IKr, and IKs). Rate- and atrial-selective inhibition of INa was also incorporated into the models. These single myocyte models were then incorporated into multicellular two-dimensional (2D) and three-dimensional (3D) anatomical models of the human atria. As expected, application of IKur blocker produced pronounced action potential duration (APD) prolongation in atrial myocytes. Furthermore, combined multiple K+-channel block that mimicked the effects of acacetin exhibited synergistic APD prolongations. Synergistically anti-AF effects following inhibition of INa and combined IKur/K+-channels were also observed. The attainable maximal AF-selectivity of INa inhibition was greatly augmented by blocking IKur or multiple K+-currents in the atrial myocytes. This enhanced anti-arrhythmic effects of combined block of Na+- and K+-channels were also seen in 2D and 3D simulations; specially, there was an enhanced efficacy in terminating re-entrant excitation waves, exerting improved antiarrhythmic effects in the human atria as compared to a single-channel block. However, in the human ventricular myocytes and tissue, cellular repolarization and computed QT intervals were modestly affected in the presence of actions of acacetin and INa blockers (either alone or in combination). In conclusion, this study demonstrates synergistic antiarrhythmic benefits of combined block of IKur and INa, as well as those of INa and combined multi K+-current block of acacetin, without significant alterations of ventricular repolarization and QT intervals. This approach may be a valuable strategy for the treatment of AF.