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We apply virtual tissue engineering to the full term human uterus with a view to reconstruction of the spatiotemporal patterns of electrical activity of the myometrium that control mechanical activity via intracellular calcium. The three-dimensional geometry of the gravid uterus has been reconstructed from segmented in vivo magnetic resonance imaging as well as ex vivo diffusion tensor magnetic resonance imaging to resolve fine scale tissue architecture. A late-pregnancy uterine smooth muscle cell model is constructed and bursting analysed using continuation algorithms. These cell models are incorporated into partial differential equation models for tissue synchronisation and propagation. The ultimate objective is to develop a quantitative and predictive understanding of the mechanisms that initiate and regulate labour., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Despite a vast amount of experimental and clinical data on the underlying ionic, cellular and tissue substrates, the mechanisms of common atrial arrhythmias (such as atrial fibrillation, AF) arising from the functional interactions at the whole atria level remain unclear. Computational modelling provides a quantitative framework for integrating such multi-scale data and understanding the arrhythmogenic behaviour that emerges from the collective spatio-temporal dynamics in all parts of the heart. In this study, we have developed a multi-scale hierarchy of biophysically detailed computational models for the human atria--the 3D virtual human atria. Primarily, diffusion tensor MRI reconstruction of the tissue geometry and fibre orientation in the human sinoatrial node (SAN) and surrounding atrial muscle was integrated into the 3D model of the whole atria dissected from the Visible Human dataset. The anatomical models were combined with the heterogeneous atrial action potential (AP) models, and used to simulate the AP conduction in the human atria under various conditions: SAN pacemaking and atrial activation in the normal rhythm, break-down of regular AP wave-fronts during rapid atrial pacing, and the genesis of multiple re-entrant wavelets characteristic of AF. Contributions of different properties of the tissue to mechanisms of the normal rhythm and arrhythmogenesis were investigated. Primarily, the simulations showed that tissue heterogeneity caused the break-down of the normal AP wave-fronts at rapid pacing rates, which initiated a pair of re-entrant spiral waves; and tissue anisotropy resulted in a further break-down of the spiral waves into multiple meandering wavelets characteristic of AF. The 3D virtual atria model itself was incorporated into the torso model to simulate the body surface ECG patterns in the normal and arrhythmic conditions. Therefore, a state-of-the-art computational platform has been developed, which can be used for studying multi-scale electrical phenomena during atrial conduction and AF arrhythmogenesis. Results of such simulations can be directly compared with electrophysiological and endocardial mapping data, as well as clinical ECG recordings. The virtual human atria can provide in-depth insights into 3D excitation propagation processes within atrial walls of a whole heart in vivo, which is beyond the current technical capabilities of experimental or clinical set-ups., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Atrial fibrillation (AF) has been linked to increased inward rectifier potassium current, I(K1), either due to AF-induced electrical remodelling, or from functional changes due to the Kir2.1 V93I mutation. The aim of this simulation study was to identify at cell and tissue levels' mechanisms by which increased I(K1) facilitates and perpetuates AF. The Courtemanche et al. human atrial cell action potential (AP) model was modified to incorporate reported changes in I(K1) induced by the Kir2.1 V93I mutation in both heterozygous (Het) and homozygous (Hom) mutant forms. The modified models for wild type (WT), Het and Hom conditions were incorporated into homogeneous 1D, 2D and 3D tissue models. Restitution curves of AP duration (APD), effective refractory period (ERP) and conduction velocity (CV) were computed and both the temporal and the spatial vulnerability of atrial tissue to re-entry were measured. The lifespan and tip meandering pattern of re-entry were also characterised. For comparison, parallel simulations were performed by incorporating into the Courtmanche et al. model a linear increase in maximal I(K1) conductance. It was found that the gain-in-function of V93I 'mutant'I(K1) led to abbreviated atrial APs and flattened APD, ERP and CV restitution curves. It also hyperpolarised atrial resting membrane potential and slowed down intra-atrial conduction. V93I 'mutant'I(K1) reduced the tissue's temporal vulnerability but increased spatial vulnerability to initiate and sustain re-entry, resulting in an increased overall susceptibility of atrial tissue to arrhythmogenesis. In the 2D model, spiral waves self-terminated for WT (lifespan < 3.3 s) tissue, but persisted in Het and Hom tissues for the whole simulation period (lifespan > 10 s). The tip of the spiral wave meandered more in WT tissue than in Het and Hom tissues. Increased I(K1) due to augmented maximal conductance produced similar results to those of Het and Hom Kir2.1 V93I mutant conditions. In the 3D model the dynamic behaviour of scroll waves was stabilized by increased I(K1). In conclusion, increased I(K1) current, either by the Kir2.1 V93I mutation or by augmented maximal conductance, increases atrial susceptibility to arrhythmia by increasing the lifespan of re-entrant spiral waves and the stability of scroll waves in 3D tissue, thereby facilitating initiation and maintenance of re-entrant circuits.

We have constructed computational models of canine ventricular cells and tissues, ultimately combining detailed tissue architecture and heterogeneous transmural electrophysiology. The heterogeneity is introduced by modifying the Hund-Rudy canine cell model in order to reproduce experimentally reported electrophysiological properties of endocardial, midmyocardial (M) and epicardial cells. These models are validated against experimental data for individual ionic current and action potential characteristics, and their rate dependencies. 1D and 3D heterogeneous virtual tissues are constructed, with detailed tissue architecture (anisotropy and orthotropy, due to fibre orientation and sheet structure) of the left ventricular wall wedge extracted from a diffusion tensor imaging data set. The models are used to study the effects of tissue heterogeneity and class III drugs on transmural propagation and tissue vulnerability to re-entry. We have determined relationships between the transmural dispersion of action potential duration (APD) and the vulnerable window in the 1D virtual ventricular wall, and demonstrated how changes in the transmural heterogeneity, and hence tissue vulnerability, can lead to generation of re-entry in the 3D ventricular wedge. Two class III drugs with opposite qualitative effects on transmural APD heterogeneity are considered: d-sotalol that increases transmural APD dispersion, and amiodarone that decreases it. Simulations with the 1D virtual ventricular wall show that under d-sotalol conditions the vulnerable window is substantially wider compared to amiodarone conditions, primarily in the epicardial region where unidirectional conduction block persists until the adjacent M cells are fully repolarised. Further simulations with the 3D ventricular wedge have shown that ectopic stimulation of the epicardial region results in generation of sustained re-entry under d-sotalol conditions, but not under amiodarone conditions or in control. Again, APD increase in M cells was identified as the major contributor to tissue vulnerability--re-entry was initiated primarily due to ectopic excitation propagating around the unidirectional conduction block in the M cell region. This suggests an electrophysiological mechanism for the anti- and proarrhythmic effects of the class III drugs: the relative safety of amiodarone in comparison to d-sotalol can be explained by relatively low transmural APD dispersion, and hence, a narrow vulnerable window and low probability of re-entry in the tissue.

Idiopathic short QT syndrome (SQTS) is a recently identified, genetically heterogeneous condition characterised by abbreviated QT intervals and an increased susceptibility to arrhythmia and sudden death. This simulation study identifies mechanisms by which cellular electrophysiological changes in the SQT2 (slow delayed rectifier, IKs, -linked) SQTS variant increases arrhythmia risk. The channel kinetics of the V307L mutation of the KCNQ1 subunit of the IKs channel were incorporated into human ventricular action potential (AP) models and into 1D and 2D transmural tissue simulations. Incorporating the V307L mutation into simulations reproduced defining features of the SQTS: abbreviation of the QT interval, and increases in T wave amplitude and Tpeak-Tend duration. In the single-cell model, the V307L mutation abbreviated ventricular cell AP duration at 90% repolarisation (APD90) and increased the maximal transmural voltage heterogeneity (deltaV) during APs; this resulted in augmented transmural heterogeneity of APD90 and of the effective refractory period (ERP). In the intact tissue model, the vulnerable window for unidirectional conduction block was also increased. In 2D tissue the V307L mutation facilitated and maintained reentrant excitation. Thus, in SQT2 increases in transmural heterogeneity of APD, deltaV, ERP and an increased vulnerable window for unidirectional conduction block generate an electrical substrate favourable to reentrant arrhythmia.

Static magnetic fields induce flow potentials in arterial flows in and around the heart, that have been detected as distortions in the ECG. The resultant currents flowing through the myocardium could alter the rate or rhythm of the heart. No such changes have been seen in animal experiments, or with humans, in static fields up to 8 T. The possible effects of such currents induced by fields larger than 8 T on cardiac pacemaker rate, and arrhythmogenesis are reviewed, using virtual cardiac tissues-computational models of cardiac electrophysiology. Arrhythmogenesis can be by the initiation of ectopic beats, or by re-entry, whose probability of occurrence is increased by any increase in the electrical heterogeneity, in particular, the action potential duration heterogeneity of the ventricle. Focal ectopic activity would be readily detectable, but since re-entrant arrhythmias are very rare events, even a large increase in their probability of occurrence still leaves them unlikely to be observed. Both of these two arrhythmogenic mechanisms would show a steep sigmoidal, or threshold dependence on induced current intensity, with the threshold for increasing the vulnerability to re-entry less than the threshold for initiating activity. Failure to observe them at fields less than 8 T provides only a lower bound for any threshold for arrhythmogenesis.

There is substantial experimental evidence from studies using both intact tissue and isolated single cells to support the existence of different cell types within the ventricular wall of the heart, each possessing different electrical properties. However other studies have failed to find these differences, and instead support the idea that electrical coupling in vivo between regions with different cell types smoothes out differences in action potential shape and duration. In this study we have used a computational model of electrical activation in heterogenous 2D and 3D cardiac tissue to investigate the propagation of both normal beats and arrhythmias. We used the Luo-Rudy dynamic model for guinea pig ventricular cells, with simplified Ca2+ handling and transmural heterogeneity in IKs and Ito. With normal cell-to-cell coupling, a layer of M cells was not necessary for the formation of an upright T wave in the simulated electrocardiogram, and the amplitude and configuration of the T wave was not greatly affected by the thickness and configuration of the M cell layer. Transmural gradients in repolarisation pushed re-entrant waves with an intramural filament towards either the base or the apex of the ventricles, and caused transient break up of re-entry with a transmural filament., (Copyright 2004 Elsevier Ltd.)