Optimization of anti-tachycardia pacing efficacy through scar-specific delivery and minimization of re-initiation: a virtual study on a cohort of infarcted porcine hearts.

AIMS: Anti-tachycardia pacing (ATP) is a reliable electrotherapy to painlessly terminate ventricular tachycardia (VT). However, ATP is often ineffective, particularly for fast VTs. The efficacy may be enhanced by optimized delivery closer to the re-entrant circuit driving the VT. This study aims to compare ATP efficacy for different delivery locations with respect to the re-entrant circuit, and further optimize ATP by minimizing failure through re-initiation. METHODS AND RESULTS: Seventy-three sustained VTs were induced in a cohort of seven infarcted porcine ventricular computational models, largely dominated by a single re-entrant pathway. The efficacy of burst ATP delivered from three locations proximal to the re-entrant circuit (septum) and three distal locations (lateral/posterior left ventricle) was compared. Re-initiation episodes were used to develop an algorithm utilizing correlations between successive sensed electrogram morphologies to automatically truncate ATP pulse delivery. Anti-tachycardia pacing was more efficacious at terminating slow compared with fast VTs (65 vs. 46%, P = 0.000039). A separate analysis of slow VTs showed that the efficacy was significantly higher when delivered from distal compared with proximal locations (distal 72%, proximal 59%), being reversed for fast VTs (distal 41%, proximal 51%). Application of our early termination detection algorithm (ETDA) accurately detected VT termination in 79% of re-initiated cases, improving the overall efficacy for proximal delivery with delivery inside the critical isthmus (CI) itself being overall most effective. CONCLUSION: Anti-tachycardia pacing delivery proximal to the re-entrant circuit is more effective at terminating fast VTs, but less so slow VTs, due to frequent re-initiation. Attenuating re-initiation, through ETDA, increases the efficacy of delivery within the CI for all VTs.

Late Gadolinium Enhancement Cardiovascular Magnetic Resonance Assessment of Substrate for Ventricular Tachycardia With Hemodynamic Compromise.

Background: The majority of data regarding tissue substrate for post myocardial infarction (MI) VT has been collected during hemodynamically tolerated VT, which may be distinct from the substrate responsible for VT with hemodynamic compromise (VT-HC). This study aimed to characterize tissue at diastolic locations of VT-HC in a porcine model. Methods: Late Gadolinium Enhancement (LGE) cardiovascular magnetic resonance (CMR) imaging was performed in eight pigs with healed antero-septal infarcts. Seven pigs underwent electrophysiology study with venous arterial-extra corporeal membrane oxygenation (VA-ECMO) support. Tissue thickness, scar and heterogeneous tissue (HT) transmurality were calculated at the location of the diastolic electrograms of mapped VT-HC. Results: Diastolic locations had median scar transmurality of 33.1% and a median HT transmurality 7.6%. Diastolic activation was found within areas of non-transmural scar in 80.1% of cases. Tissue activated during the diastolic component of VT circuits was thinner than healthy tissue (median thickness: 5.5 mm vs. 8.2 mm healthy tissue, p < 0.0001) and closer to HT (median distance diastolic tissue: 2.8 mm vs. 11.4 mm healthy tissue, p < 0.0001). Non-scarred regions with diastolic activation were closer to steep gradients in thickness than non-scarred locations with normal EGMs (diastolic locations distance = 1.19 mm vs. 9.67 mm for non-diastolic locations, p < 0.0001). Sites activated late in diastole were closest to steep gradients in tissue thickness. Conclusions: Non-transmural scar, mildly decreased tissue thickness, and steep gradients in tissue thickness represent the structural characteristics of the diastolic component of reentrant circuits in VT-HC in this porcine model and could form the basis for imaging criteria to define ablation targets in future trials.

An in-silico assessment of efficacy of two novel intra-cardiac electrode configurations versus traditional anti-tachycardia pacing therapy for terminating sustained ventricular tachycardia.

The implanted cardioverter defibrillator (ICD) is an effective direct therapy for the treatment of cardiac arrhythmias, including ventricular tachycardia (VT). Anti-tachycardia pacing (ATP) is often applied by the ICD as the first mode of therapy, but is often found to be ineffective, particularly for fast VTs. In such cases, strong, painful and damaging backup defibrillation shocks are applied by the device. Here, we propose two novel electrode configurations: "bipolar" and "transmural" which both combine the concept of targeted shock delivery with the advantage of reduced energy required for VT termination. We perform an in silico study to evaluate the efficacy of VT termination by applying one single (low-energy) monophasic shock from each novel configuration, comparing with conventional ATP therapy. Both bipolar and transmural configurations are able to achieve a higher efficacy (93% and 85%) than ATP (45%), with energy delivered similar to and two orders of magnitudes smaller than conventional ICD defibrillation shocks, respectively. Specifically, the transmural configuration (which applies the shock vector directly across the scar substrate sustaining the VT) is most efficient, requiring typically less than 1 J shock energy to achieve a high efficacy. The efficacy of both bipolar and transmural configurations are higher when applied to slow VTs (100% and 97%) compared to fast VTs (57% and 29%). Both novel electrode configurations introduced are able to improve electrotherapy efficacy while reducing the overall number of required therapies and need for strong backup shocks.

OpenEP: A Cross-Platform Electroanatomic Mapping Data Format and Analysis Platform for Electrophysiology Research.

BACKGROUND: Electroanatomic mapping systems are used to support electrophysiology research. Data exported from these systems is stored in proprietary formats which are challenging to access and storage-space inefficient. No previous work has made available an open-source platform for parsing and interrogating this data in a standardized format. We therefore sought to develop a standardized, open-source data structure and associated computer code to store electroanatomic mapping data in a space-efficient and easily accessible manner. METHODS: A data structure was defined capturing the available anatomic and electrical data. OpenEP, implemented in MATLAB, was developed to parse and interrogate this data. Functions are provided for analysis of chamber geometry, activation mapping, conduction velocity mapping, voltage mapping, ablation sites, and electrograms as well as visualization and input/output functions. Performance benchmarking for data import and storage was performed. Data import and analysis validation was performed for chamber geometry, activation mapping, voltage mapping and ablation representation. Finally, systematic analysis of electrophysiology literature was performed to determine the suitability of OpenEP for contemporary electrophysiology research. RESULTS: The average time to parse clinical datasets was 400 ± 162 s per patient. OpenEP data was two orders of magnitude smaller than compressed clinical data (OpenEP: 20.5 ± 8.7 Mb, vs clinical: 1.46 ± 0.77 Gb). OpenEP-derived geometry metrics were correlated with the same clinical metrics (Area: R 2 = 0.7726, P < 0.0001; Volume: R 2 = 0.5179, P < 0.0001). Investigating the cause of systematic bias in these correlations revealed OpenEP to outperform the clinical platform in recovering accurate values. Both activation and voltage mapping data created with OpenEP were correlated with clinical values (mean voltage R 2 = 0.8708, P < 0.001; local activation time R 2 = 0.8892, P < 0.0001). OpenEP provides the processing necessary for 87 of 92 qualitatively assessed analysis techniques (95%) and 119 of 136 quantitatively assessed analysis techniques (88%) in a contemporary cohort of mapping studies. CONCLUSIONS: We present the OpenEP framework for evaluating electroanatomic mapping data. OpenEP provides the core functionality necessary to conduct electroanatomic mapping research. We demonstrate that OpenEP is both space-efficient and accurately representative of the original data. We show that OpenEP captures the majority of data required for contemporary electroanatomic mapping-based electrophysiology research and propose a roadmap for future development.

Moderate but not severe hypothermia causes pro-arrhythmic changes in cardiac electrophysiology.

AIMS: Treatment of arrhythmias evoked by hypothermia/rewarming remains challenging, and the underlying mechanisms are unclear. This in vitro experimental study assessed cardiac electrophysiology in isolated rabbit hearts at temperatures occurring in therapeutic and accidental hypothermia. METHODS AND RESULTS: Detailed ECG, surface electrogram, and panoramic optical mapping were performed in isolated rabbit hearts cooled to moderate (31°C) and severe (17°C) hypothermia. Ventricular activation was unchanged at 31°C while action potential duration (APD) was significantly prolonged (176.9 ± 4.2 ms vs. 241.0 ± 2.9 ms, P < 0.05), as was ventricular repolarization. At 17°C, there were proportionally similar delays in both activation and repolarization. These changes were reflected in the QRS and QT intervals of ECG recordings. Ventricular fibrillation threshold was significantly reduced at 31°C (16.3 ± 3.1 vs. 35 ± 3.5 mA, P < 0.05) but increased at 17°C (64.2 ± 9.9, P < 0.05). At 31°C, transverse conduction was relatively unchanged by cooling compared to longitudinal conduction, but at 17°C both transverse and longitudinal conduction were proportionately reduced to a similar extent. The gap junction uncoupler heptanol had a larger relative effect on transverse than longitudinal conduction and was able to restore the transverse/longitudinal conduction ratio, returning ventricular fibrillation threshold to baseline values (16.3 ± 3.1 vs. 36.3 ± 4.3 mA, P < 0.05) at 31°C. Rewarming to 37°C restored the majority of the electrophysiological parameters. CONCLUSIONS: Moderate hypothermia does not significantly change ventricular conduction time but prolongs repolarization and is pro-arrhythmic. Further cooling to severe hypothermia causes parallel changes in ventricular activation and repolarization, changes which are anti-arrhythmic. Therefore, relative changes in QRS and QT intervals (QR/QTc) emerge as an ECG-biomarker of pro-arrhythmic activity. Risk for ventricular fibrillation appears to be linked to the relatively low temperature sensitivity of ventricular transmural conduction, a conclusion supported by the anti-arrhythmic effect of heptanol at 31°C.

Improved co-registration of ex-vivo and in-vivo cardiovascular magnetic resonance images using heart-specific flexible 3D printed acrylic scaffold combined with non-rigid registration.

BACKGROUND: Ex-vivo cardiovascular magnetic resonance (CMR) imaging has played an important role in the validation of in-vivo CMR characterization of pathological processes. However, comparison between in-vivo and ex-vivo imaging remains challenging due to shape changes occurring between the two states, which may be non-uniform across the diseased heart. A novel two-step process to facilitate registration between ex-vivo and in-vivo CMR was developed and evaluated in a porcine model of chronic myocardial infarction (MI). METHODS: Seven weeks after ischemia-reperfusion MI, 12 swine underwent in-vivo CMR imaging with late gadolinium enhancement followed by ex-vivo CMR 1 week later. Five animals comprised the control group, in which ex-vivo imaging was undertaken without any support in the LV cavity, 7 animals comprised the experimental group, in which a two-step registration optimization process was undertaken. The first step involved a heart specific flexible 3D printed scaffold generated from in-vivo CMR, which was used to maintain left ventricular (LV) shape during ex-vivo imaging. In the second step, a non-rigid co-registration algorithm was applied to align in-vivo and ex-vivo data. Tissue dimension changes between in-vivo and ex-vivo imaging were compared between the experimental and control group. In the experimental group, tissue compartment volumes and thickness were compared between in-vivo and ex-vivo data before and after non-rigid registration. The effectiveness of the alignment was assessed quantitatively using the DICE similarity coefficient. RESULTS: LV cavity volume changed more in the control group (ratio of cavity volume between ex-vivo and in-vivo imaging in control and experimental group 0.14 vs 0.56, p < 0.0001) and there was a significantly greater change in the short axis dimensions in the control group (ratio of short axis dimensions in control and experimental group 0.38 vs 0.79, p < 0.001). In the experimental group, prior to non-rigid co-registration the LV cavity contracted isotropically in the ex-vivo condition by less than 20% in each dimension. There was a significant proportional change in tissue thickness in the healthy myocardium (change = 29 ± 21%), but not in dense scar (change = - 2 ± 2%, p = 0.034). Following the non-rigid co-registration step of the process, the DICE similarity coefficients for the myocardium, LV cavity and scar were 0.93 (±0.02), 0.89 (±0.01) and 0.77 (±0.07) respectively and the myocardial tissue and LV cavity volumes had a ratio of 1.03 and 1.00 respectively. CONCLUSIONS: The pattern of the morphological changes seen between the in-vivo and the ex-vivo LV differs between scar and healthy myocardium. A 3D printed flexible scaffold based on the in-vivo shape of the LV cavity is an effective strategy to minimize morphological changes in the ex-vivo LV. The subsequent non-rigid registration step further improved the co-registration and local comparison between in-vivo and ex-vivo data.

Generation of a cohort of whole-torso cardiac models for assessing the utility of a novel computed shock vector efficiency metric for ICD optimisation.

Implanted cardiac defibrillators (ICDs) seek to automatically detect and terminate potentially lethal ventricular arrhythmias by applying strong internal electric shocks across the heart. However, the optimisation of the specific electrode design and configurations represents an intensive area of research in the pursuit of reduced shock strengths and fewer device complications and risks. Computational whole-torso simulations play an important role in this endeavour, although knowing which specific metric should be used to assess configuration efficacy and assessing the impact of different patient anatomies and pathologies, and the corresponding effect this may have on different metrics has not been investigated. We constructed a cohort of CT-derived high-resolution whole torso-cardiac computational models, including variants of cardiomyopathies and patients with differing torso dimensions. Simulations of electric shock application between electrode configurations corresponding to transveneous (TV-ICD) and subcutaneous (S-ICD) ICDs were modelled and conventional metrics such as defibrillation threshold (DFT) and impedance computed. In addition, we computed a novel metric termed the shock vector efficiency (η), which quantifies the fraction of electrical energy dissipated in the heart relative to the rest of the torso. Across the cohort, S-ICD configurations showed higher DFTs and impedances than TV-ICDs, as expected, although little consistent difference was seen between healthy and cardiomyopathy variants. η was consistently <2% for S-ICD configurations, becoming as high as 13% for TV-ICD setups. Simulations also suggested that a total torso height of approximately 20 cm is required for convergence in η. Overall, η was seen to be approximately negatively correlated with both DFT and impedance. However, important scenarios were identified in which certain values of DFT (or impedance) were associated with a range of η values, and vice-versa, highlighting the heterogeneity introduced by the different torsos and pathologies modelled. In conclusion, the shock vector efficiency represents a useful additional metric to be considered alongside DFT and impedance in the optimisation of ICD electrode configurations, particularly in the context of differing torso anatomies and cardiac pathologies, which can induce significant heterogeneity in conventional metrics of ICD efficacy.

Conceptual Intra-Cardiac Electrode Configurations That Facilitate Directional Cardiac Stimulation for Optimal Electrotherapy.

OBJECTIVE: Electrotherapy remains the most effective direct therapy against lethal cardiac arrhythmias. When an arrhythmic event is sensed, either strong electric shocks or controlled rapid pacing is automatically applied directly to the heart via an implanted cardioverter defibrillator (ICDs). Despite their success, ICDs remain a highly non-optimal therapy: the strong shocks required for defibrillation cause significant extra-cardiac stimulation, resulting in pain and long-term tissue damage, and can also limit battery life. When used in anti-tachycardia pacing mode, ICDs are also often ineffective, as the pacing electrode can be far away from the centre of the arrhythmia, making it hard for the paced wave to interrupt and terminate it. METHODS: In this paper, we present two conceptual intra-cardiac directional electrode configurations in silico based on novel arrangements of pairs of positive-negative electrodes. Both configurations have the potential to cause preferential excitation on specific regions of the heart. RESULTS: We demonstrate how the properties of the induced field varies spatially around the electrodes and how it depends upon the specific arrangements of dipole electrode pairs. The results show that when tested within anatomically-realistic rabbit ventricular models, both electrode configurations produce strong virtual electrodes on the targeted endocardial surfaces, with weaker virtual electrodes produced elsewhere. CONCLUSIONS: The proposed electrode configurations may facilitate targeted far-field anti-tachycardia pacing and/or defibrillation, which may be useful in cases where conventional anti-tachycardia pacing fails. In addition, the conceptual electrode designs intrinsically confine the electric field to the immediate vicinity of the electrodes, and may, thus, minimize pain due to unnecessary extra-cardiac stimulation.

Ventricular Endocardial Tissue Geometry Affects Stimulus Threshold and Effective Refractory Period.

BACKGROUND: Understanding the biophysical processes by which electrical stimuli applied to cardiac tissue may result in local activation is important in both the experimental and clinical electrophysiology laboratory environments, as well as for gaining a more in-depth knowledge of the mechanisms of focal-trigger-induced arrhythmias. Previous computational models have predicted that local myocardial tissue architecture alone may significantly modulate tissue excitability, affecting both the local stimulus current required to excite the tissue and the local effective refractory period (ERP). In this work, we present experimental validation of this structural modulation of local tissue excitability on the endocardial tissue surface, use computational models to provide mechanistic understanding of this phenomena in relation to localized changes in electrotonic loading, and demonstrate its implications for the capture of afterdepolarizations. METHODS AND RESULTS: Experiments on rabbit ventricular wedge preparations showed that endocardial ridges (surfaces of negative mean curvature) had a stimulus capture threshold that was 0.21 ± 0.03 V less than endocardial grooves (surfaces of positive mean curvature) for pairwise comparison (24% reduction, corresponding to 56.2 ± 6.4% of the energy). When stimulated at the minimal stimulus strength for capture, ridge locations showed a shorter ERP than grooves (n = 6, mean pairwise difference 7.4 ± 4.2 ms). When each site was stimulated with identical-strength stimuli, the difference in ERP was further increased (mean pairwise difference 15.8 ± 5.3 ms). Computational bidomain models of highly idealized cylindrical endocardial structures qualitatively agreed with these findings, showing that such changes in excitability are driven by structural modulation in electrotonic loading, quantifying this relationship as a function of surface curvature. Simulations further showed that capture of delayed afterdepolarizations was more likely in trabecular ridges than grooves, driven by this difference in loading. CONCLUSIONS: We have demonstrated experimentally and explained mechanistically in computer simulations that the ability to capture tissue on the endocardial surface depends upon the local tissue architecture. These findings have important implications for deepening our understanding of excitability differences related to anatomical structure during stimulus application that may have important applications in the translation of novel experimental optogenetics pacing strategies. The uncovered preferential vulnerability to capture of afterdepolarizations of endocardial ridges, compared to grooves, provides important insight for understanding the mechanisms of focal-trigger-induced arrhythmias.

Normal interventricular differences in tissue architecture underlie right ventricular susceptibility to conduction abnormalities in a mouse model of Brugada syndrome.

Aims: Loss-of-function of the cardiac sodium channel NaV1.5 is a common feature of Brugada syndrome. Arrhythmias arise preferentially from the right ventricle (RV) despite equivalent NaV1.5 downregulation in the left ventricle (LV). The reasons for increased RV sensitivity to NaV1.5 loss-of-function mutations remain unclear. Because ventricular electrical activation occurs predominantly in the transmural axis, we compare RV and LV transmural electrophysiology to determine the underlying cause of the asymmetrical conduction abnormalities in Scn5a haploinsufficient mice (Scn5a+/-). Methods and results: Optical mapping and two-photon microscopy in isolated-perfused mouse hearts demonstrated equivalent depression of transmural conduction velocity (CV) in the LV and RV of Scn5a+/- vs. wild-type littermates. Only RV transmural conduction was further impaired when challenged with increased pacing frequencies. Epicardial dispersion of activation and beat-to-beat variation in activation time were increased only in the RV of Scn5a+/- hearts. Analysis of confocal and histological images revealed larger intramural clefts between cardiomyocyte layers in the RV vs. LV, independent of genotype. Acute sodium current inhibition in wild type hearts using tetrodotoxin reproduced beat-to-beat activation variability and frequency-dependent CV slowing in the RV only, with the LV unaffected. The influence of clefts on conduction was examined using a two-dimensional monodomain computational model. When peak sodium channel conductance was reduced to 50% of normal the presence of clefts between cardiomyocyte layers reproduced the activation variability and conduction phenotype observed experimentally. Conclusions: Normal structural heterogeneities present in the RV are responsible for increased vulnerability to conduction slowing in the presence of reduced sodium channel function. Heterogeneous conduction slowing seen in the RV will predispose to functional block and the initiation of re-entrant ventricular arrhythmias.

Highly trabeculated structure of the human endocardium underlies asymmetrical response to low-energy monophasic shocks.

Novel low-energy defibrillation therapies are thought to be driven by virtual-electrodes (VEs), due to the interaction of applied monophasic electric shocks with fine-scale anatomical structures within the heart. Significant inter-species differences in the cardiac (micro)-anatomy exist, however, particularly with respect to the degree of endocardial trabeculations, which may underlie important differences in response to low-energy defibrillation protocols. Understanding the interaction of monophasic electric fields with the specific human micro-anatomy is therefore imperative in facilitating the translation and optimisation of these promising experimental therapies to the clinic. In this study, we sought to investigate how electric fields from implanted devices interact with the highly trabeculated human endocardial surface to better understand shock success in order to help optimise future clinical protocols. A bi-ventricular human computational model was constructed from high resolution (350 µm) ex-vivo MR data, including anatomically accurate endocardial structures. Monophasic shocks were applied between a basal right ventricular catheter and an exterior ground. Shocks of varying strengths were applied with both anodal [positive right ventricle (RV) electrode] and cathodal (negative RV electrode) polarities at different states of tissue refractoriness and during induced arrhythmias. Anodal shocks induced isolated positive VEs at the distal side of "detached" trabeculations, which rapidly spread into hyperpolarised tissue on the surrounding endocardial surfaces following the shock. Anodal shocks thus depolarised more tissue 10 ms after the shock than cathodal shocks where the propagation of activation from VEs induced on the proximal side of "detached" trabeculations was prevented due to refractory endocardium. Anodal shocks increased arrhythmia complexity more than cathodal shocks during failed anti-arrhythmia shocks. In conclusion, multiple detached trabeculations in the human ventricle interact with anodal stimuli to induce multiple secondary sources from VEs, facilitating more rapid shock-induced ventricular excitation compared to cathodal shocks. Such a mechanism may help explain inter-species differences in response to shocks and help to develop novel defibrillation strategies.

Bidomain Predictions of Virtual Electrode-Induced Make and Break Excitations around Blood Vessels.

INTRODUCTION AND BACKGROUND: Virtual electrodes formed by field stimulation during defibrillation of cardiac tissue play an important role in eliciting activations. It has been suggested that the coronary vasculature is an important source of virtual electrodes, especially during low-energy defibrillation. This work aims to further the understanding of how virtual electrodes from the coronary vasculature influence defibrillation outcomes. METHODS: Using the bidomain model, we investigated how field stimulation elicited activations from virtual electrodes around idealized intramural blood vessels. Strength-interval curves, which quantify the stimulus strength required to elicit wavefront propagation from the vessels at different states of tissue refractoriness, were computed for each idealized geometry. RESULTS: Make excitations occurred at late diastolic intervals, originating from regions of depolarization around the vessel. Break excitations occurred at early diastolic intervals, whereby the vessels were able to excite surrounding refractory tissue due to the local restoration of excitability by virtual electrode-induced hyperpolarizations. Overall, strength-interval curves had similar morphologies and underlying excitation mechanisms compared with previous experimental and numerical unipolar stimulation studies of cardiac tissue. Including the presence of the vessel wall increased the field strength required for make excitations but decreased the field strength required for break excitations, and the field strength at which break excitations occurred was generally greater than 5 V/cm. Finally, in a more realistic ventricular slice geometry, the proximity of virtual electrodes around subepicardial vessels was seen to cause break excitations in the form of propagating unstable wavelets to the subepicardial layer. CONCLUSION: Representing the blood vessel wall microstructure in computational bidomain models of defibrillation is recommended as it significantly alters the electrophysiological response of the vessel to field stimulation. Although vessels may facilitate excitation of relatively refractory tissue via break excitations, the field strength required for this is generally greater than those used in the literature on low-energy defibrillation. However, the high-intensity shocks used in standard defibrillation may elicit break excitation propagation from the coronary vasculature.

Virtual electrodes around anatomical structures and their roles in defibrillation.

BACKGROUND: Virtual electrodes from structural/conductivity heterogeneities are known to elicit wavefront propagation, upon field-stimulation, and are thought to be important for defibrillation. In this work we investigate how the constitutive and geometrical parameters associated with such anatomical heterogeneities, represented by endo/epicardial surfaces and intramural surfaces in the form of blood-vessels, affect the virtual electrode patterns produced. METHODS AND RESULTS: The steady-state bidomain model is used to obtain, using analytical and numerical methods, the virtual electrode patterns created around idealized endocardial trabeculations and blood-vessels. The virtual electrode pattern around blood-vessels is shown to be composed of two dominant effects; current traversing the vessel surface and conductivity heterogeneity from the fibre-architecture. The relative magnitudes of these two effects explain the swapping of the virtual electrode polarity observed, as a function of the vessel radius, and aid in the understanding of the virtual electrode patterns predicted by numerical bidomain modelling. The relatively high conductivity of blood, compared to myocardium, is shown to cause stronger depolarizations in the endocardial trabeculae grooves than the protrusions. CONCLUSIONS: The results provide additional quantitative understanding of the virtual electrodes produced by small-scale ventricular anatomy, and highlight the importance of faithfully representing the physiology and the physics in the context of computational modelling of field stimulation.

Computational Representations of Myocardial Infarct Scars and Implications for Arrhythmogenesis.

Image-based computational modeling is becoming an increasingly used clinical tool to provide insight into the mechanisms of reentrant arrhythmias. In the context of ischemic heart disease, faithful representation of the electrophysiological properties of the infarct region within models is essential, due to the scars known for arrhythmic properties. Here, we review the different computational representations of the infarcted region, summarizing the experimental measurements upon which they are based. We then focus on the two most common representations of the scar core (complete insulator or electrically passive tissue) and perform simulations of electrical propagation around idealized infarct geometries. Our simulations highlight significant differences in action potential duration and focal effective refractory period (ERP) around the scar, driven by differences in electrotonic loading, depending on the choice of scar representation. Finally, a novel mechanism for arrhythmia induction, following a focal ectopic beat, is demonstrated, which relies on localized gradients in ERP directly caused by the electrotonic sink effects of the neighboring passive scar.

Local Gradients in Electrotonic Loading Modulate the Local Effective Refractory Period: Implications for Arrhythmogenesis in the Infarct Border Zone.

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.

Structural heterogeneity modulates effective refractory period: a mechanism of focal arrhythmia initiation.

Reductions in electrotonic loading around regions of structural and electrophysiological heterogeneity may facilitate capture of focal triggered activity, initiating reentrant arrhythmias. How electrotonic loading, refractoriness and capture of focal ectopics depend upon the intricate nature of physiological structural anatomy, as well as pathological tissue remodelling, however, is not well understood. In this study, we performed computational bidomain simulations with anatomically-detailed models representing the rabbit left ventricle. We used these models to quantify the relationship between local structural anatomy and spatial heterogeneity in action potential (AP) characteristics, electrotonic currents and effective refractory periods (ERPs) under pacing and restitution protocols. Regions surrounding vessel cavities, in addition to tissue surfaces, had significantly lower peak downstream electrotonic currents than well coupled myocardium (72.6 vs 220.4 µA/cm2), with faster maximum AP upstroke velocities (257.3 vs 147.3 mV/ms), although noticeably very similar APDs (167.7 vs 168.4 ms) and AP restitution properties. Despite similarities in APDs, ERPs in regions of low electrotonic load in the vicinity of surfaces, intramural vessel cavities and endocardial structures were up to 40 ms shorter compared to neighbouring well-coupled tissue, leading to regions of sharp ERP gradients. Consequently, focal extra-stimuli timed within this window of ERP heterogeneity between neighbouring regions readily induced uni-directional block, inducing reentry. Most effective induction sites were within channels of low ERPs between large vessels and epicardium. Significant differences in ERP driven by reductions in electrotonic loading due to fine-scale physiological structural heterogeneity provides an important mechanism of capture of focal activity and reentry induction. Application to pathological ventricles, particularly myocardial infarction, will have important implications in anti-arrhythmia therapy.