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Cardiac electrophysiological disorders, in particular arrhythmias, are a key cause of morbidity and mortality throughout the world. There are two basic requirements for arrhythmogenesis: an underlying substrate and a trigger. Altered conduction velocity (CV) provides a key substrate for arrhythmogenesis, with slowed CV increasing the probability of re-entrant arrhythmias by reducing the length scale over which re-entry can occur. In this review, we examine methods to measure cardiac CV in vivo and ex vivo, discuss underlying determinants of CV, and address how pathological variations alter CV, potentially increasing arrhythmogenic risk. Finally, we will highlight future directions both for methodologies to measure CV and for possible treatments to restore normal CV.

Whole electrocardiogram (ECG) waveform analysis is a technique for evaluating aggregate arrhythmic risks of drugs. In this paper, we propose methods for exploring changes to ECG morphology due to drug effects using Gaussian model parameters, and predict patient specific post-drug ECG based on pre-drug ECG. We evaluate the proposed methods using clinical ECG recordings from subjects under the effect of anti-arrhythmic drugs Dofetilide, Quinidine, Ranolazine, and Verapamil, from the ECGRVDQ database on PhysioNet. Paired-sample t-test p-values (>0.05) suggest the proposed method can achieve similar results when compared to expert annotated J to T peak and T peak to T end intervals for all four drug states. We employed a leave-one-out cross validation strategy to train the prediction model and produce the results. Mean Pearson correlations between all predicted and recorded post-drug waveform morphologies for all drug states across both the vector magnitude lead and Lead II is 0.94±0.05, with p-values <0.01 for all predictions; indicating significant predictions. Parameters from ECG models with Gaussian basis can be used to calculate clinically useful information and to capture or predict changes in cardiac signals due to drug effects., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Ectopic electrical activity that originates in the peri-infarct region can give rise to potentially lethal re-entrant arrhythmias. The spatial variation in electrotonic loading that results from structural remodelling in the infarct border zone may increase the probability that focal activity will trigger electrical capture, but this has not previously been investigated systematically. This study uses in-silico experiments to examine the structural modulation of effective refractory period on ectopic beat capture. Informed by 3-D reconstructions of myocyte organization in the infarct border zone, a region of rapid tissue expansion is abstracted to an idealized representation. A novel metric is introduced that defines the local electrotonic loading as a function of passive tissue properties and boundary conditions. The effective refractory period correlates closely with local electrotonic loading, while the action potential duration, conduction, and upstroke velocity reduce in regions of increasing electrotonic load. In the presence of focal ectopic stimuli, spatial variation in effective refractory period can cause unidirectional conduction block providing a substrate for reentrant arrhythmias. Consequently, based on the observed results, a possible novel mechanism for arrhythmogenesis in the infarct border zone is proposed.

Impulse propagation in the heart depends on the excitability of individual cardiomyocytes, impulse transmission between adjacent myocytes, and the 3-dimensional arrangement of those cells. Here, we review the role of each of these factors in normal and aberrant cardiac electric activation, with particular emphasis on the effects of 3-dimensional myocyte architecture at the tissue scale. The analysis draws on findings from in vivo and in vitro experiments, as well as biophysically based computer models that have been used to integrate and interpret these experimental data. It indicates that discontinuous arrangement of myocytes and extracellular connective tissue at the tissue scale can give rise to current source-to-sink mismatch, spatiotemporal distribution of refractoriness, and rate-sensitive electric instability, which contribute to the initiation and maintenance of reentrant cardiac arrhythmia. This exacerbates the risk of rhythm disturbance associated with heart disease. We conclude that structure-based, multiscale computer models that incorporate accurate information about local cellular electric activity provide a powerful platform for investigating the basis of reentrant cardiac arrhythmia. However, it is important that these models capture key features of structure and related electric function at the tissue scale.

Background: Marked changes in ventricular APD restitution and associated alternans rhythm have been demonstrated in structural heart disease (SHD). However, whether this is due to structural heterogeneity or regional variation in cellular properties remains uncertain. In this study, we address the hypothesis that the structural heterogeneity associated with SHD is sufficient to alter dynamic restitution and increase the probability of electric instability., Methods and Results: Activation was simulated in a 14x14 mm(2) domain in the presence and absence (control) of a central region containing nonuniform discontinuities resembling patchy fibrosis. A modified LR1 cardiac activation model was used in a bidomain formulation with isotropic conductivities. Bipolar stimulation was imposed above the central region with coupling intervals decreasing progressively from 500 ms and then maintained at 105 ms. Structural discontinuities had little effect on electric activation at low stimulus rates, but activation time and APD distributions became highly nonuniform within and adjacent to the discontinuous region at high rates. Discordant APD alternans occurred in both "fibrosis" and control, but at lower stimulus rates and with markedly greater extent in the former. Tortuous conduction through the discontinuous region resulted in large fluctuations of diastolic intervals giving rise to regional electric instability, which modulates dynamic conduction velocity and APD restitution. This led to heterogeneous conduction block and reentry not observed in control., Conclusions: We show that structural discontinuities can amplify discordant alternans and provide a rate-dependent substrate for reentry. This work provides new insights into the mechanisms by which fibrosis may contribute to arrhythmogenesis.

Two-dimensional in silico models have been constructed for investigating electrical dynamics arising due to pacing rates and tissue discontinuities. Discontinuities (structures) are introduced explicitly through flux discontinuities in the intracellular space. These models use isotropic electrophysiological properties with heterogeneity arising solely from tissue structure. Both simplified and tissue-specific structures can be used together with membrane models with varying restitution properties. Stimuli are delivered at increasing pacing rates, and solution restarts enable the investigation of repeat stimulation at any of the rates. Investigations using these models are providing new insights into mechanisms leading to conduction block and arrhythmogenesis in cardiac tissue.