Detection of focal source and arrhythmogenic substrate from body surface potentials to guide atrial fibrillation ablation.

Focal sources (FS) are believed to be important triggers and a perpetuation mechanism for paroxysmal atrial fibrillation (AF). Detecting FS and determining AF sustainability in atrial tissue can help guide ablation targeting. We hypothesized that sustained rotors during FS-driven episodes indicate an arrhythmogenic substrate for sustained AF, and that non-invasive electrical recordings, like electrocardiograms (ECGs) or body surface potential maps (BSPMs), could be used to detect FS and AF sustainability. Computer simulations were performed on five bi-atrial geometries. FS were induced by pacing at cycle lengths of 120-270 ms from 32 atrial sites and four pulmonary veins. Self-sustained reentrant activities were also initiated around the same 32 atrial sites with inexcitable cores of radii of 0, 0.5 and 1 cm. FS fired for two seconds and then AF inducibility was tested by whether activation was sustained for another second. ECGs and BSPMs were simulated. Equivalent atrial sources were extracted using second-order blind source separation, and their cycle length, periodicity and contribution, were used as features for random forest classifiers. Longer rotor duration during FS-driven episodes indicates higher AF inducibility (area under ROC curve = 0.83). Our method had accuracy of 90.6±1.0% and 90.6±0.6% in detecting FS presence, and 93.1±0.6% and 94.2±1.2% in identifying AF sustainability, and 80.0±6.6% and 61.0±5.2% in determining the atrium of the focal site, from BSPMs and ECGs of five atria. The detection of FS presence and AF sustainability were insensitive to vest placement (±9.6%). On pre-operative BSPMs of 52 paroxysmal AF patients, patients classified with initiator-type FS on a single atrium resulted in improved two-to-three-year AF-free likelihoods (p-value < 0.01, logrank tests). Detection of FS and arrhythmogenic substrate can be performed from ECGs and BSPMs, enabling non-invasive mapping towards mechanism-targeted AF treatment, and malignant ectopic beat detection with likely AF progression.

Impact of intraventricular septal fiber orientation on cardiac electromechanical function.

Cardiac fiber direction is an important factor determining the propagation of electrical activity, as well as the development of mechanical force. In this article, we imaged the ventricles of several species with special attention to the intraventricular septum to determine the functional consequences of septal fiber organization. First, we identified a dual-layer organization of the fiber orientation in the intraventricular septum of ex vivo sheep hearts using diffusion tensor imaging at high field MRI. To expand the scope of the results, we investigated the presence of a similar fiber organization in five mammalian species (rat, canine, pig, sheep, and human) and highlighted the continuity of the layer with the moderator band in large mammalian species. We implemented the measured septal fiber fields in three-dimensional electromechanical computer models to assess the impact of the fiber orientation. The downward fibers produced a diamond activation pattern superficially in the right ventricle. Electromechanically, there was very little change in pressure volume loops although the stress distribution was altered. In conclusion, we clarified that the right ventricular septum has a downwardly directed superficial layer in larger mammalian species, which can have modest effects on stress distribution.NEW & NOTEWORTHY A dual-layer organization of the fiber orientation in the intraventricular septum was identified in ex vivo hearts of large mammals. The RV septum has a downwardly directed superficial layer that is continuous with the moderator band. Electrically, it produced a diamond activation pattern. Electromechanically, little change in pressure volume loops were noticed but stress distribution was altered. Fiber distribution derived from diffusion tensor imaging should be considered for an accurate strain and stress analysis.

On the nature of delays allowing anatomical re-entry involving the Purkinje network: a simulation study.

AIMS: Clinical observations suggest that the Purkinje network can be part of anatomical re-entry circuits in monomorphic or polymorphic ventricular arrhythmias. However, significant conduction delay is needed to support anatomical re-entry given the high conduction velocity within the Purkinje network. METHODS AND RESULTS: We investigated, in computer models, whether damage rendering the Purkinje network as either an active lesion with slow conduction or a passive lesion with no excitable ionic channel, could explain clinical observations. Active lesions had compromised sodium current and a severe reduction in gap junction coupling, while passive lesions remained coupled by gap junctions, but modelled the membrane as a fixed resistance. Both types of tissue could provide significant delays of over 100 ms. Electrograms consistent with those obtained clinically were reproduced. However, passive tissue could not support re-entry as electrotonic coupling across the delay effectively increased the proximal refractory period to an extremely long interval. Active tissue, conversely, could robustly maintain re-entry. CONCLUSION: Formation of anatomical re-entry using the Purkinje network is possible through highly reduced gap junctional coupling leading to slowed conduction.

Variability in pulmonary vein electrophysiology and fibrosis determines arrhythmia susceptibility and dynamics.

Success rates for catheter ablation of persistent atrial fibrillation patients are currently low; however, there is a subset of patients for whom electrical isolation of the pulmonary veins alone is a successful treatment strategy. It is difficult to identify these patients because there are a multitude of factors affecting arrhythmia susceptibility and maintenance, and the individual contributions of these factors are difficult to determine clinically. We hypothesised that the combination of pulmonary vein (PV) electrophysiology and atrial body fibrosis determine driver location and effectiveness of pulmonary vein isolation (PVI). We used bilayer biatrial computer models based on patient geometries to investigate the effects of PV properties and atrial fibrosis on arrhythmia inducibility, maintenance mechanisms, and the outcome of PVI. Short PV action potential duration (APD) increased arrhythmia susceptibility, while longer PV APD was found to be protective. Arrhythmia inducibility increased with slower conduction velocity (CV) at the LA/PV junction, but not for cases with homogeneous CV changes or slower CV at the distal PV. Phase singularity (PS) density in the PV region for cases with PV fibrosis was increased. Arrhythmia dynamics depend on both PV properties and fibrosis distribution, varying from meandering rotors to PV reentry (in cases with baseline or long APD), to stable rotors at regions of high fibrosis density. Measurement of fibrosis and PV properties may indicate patient specific susceptibility to AF initiation and maintenance. PV PS density before PVI was higher for cases in which AF terminated or converted to a macroreentry; thus, high PV PS density may indicate likelihood of PVI success.

Opsin spectral sensitivity determines the effectiveness of optogenetic termination of ventricular fibrillation in the human heart: a simulation study.

KEY POINTS: Optogenetics-based defibrillation, a theoretical alternative to electrotherapy, involves expression of light-sensitive ion channels in the heart (via gene or cell therapy) and illumination of the cardiac surfaces (via implanted LED arrays) to elicit light-induced activations. We used a biophysically detailed human ventricular model to determine whether such a therapy could terminate fibrillation (VF) and identify which combinations of light-sensitive ion channel properties and illumination configurations would be effective. Defibrillation was successful when a large proportion (> 16.6%) of ventricular tissue was directly stimulated by light that was bright enough to induce an action potential in an uncoupled cell. While illumination with blue light never successfully terminated VF, illumination of red light-sensitive ion channels with dense arrays of implanted red light sources resulted in successful defibrillation. Our results suggest that cardiac expression of red light-sensitive ion channels is necessary for the development of effective optogenetics-based defibrillation therapy using LED arrays. ABSTRACT: Optogenetics-based defibrillation has been proposed as a novel and potentially pain-free approach to enable cardiomyocyte-selective defibrillation in humans, but the feasibility of such a therapy remains unknown. This study aimed to (1) assess the feasibility of terminating sustained ventricular fibrillation (VF) via light-induced excitation of opsins expressed throughout the myocardium and (2) identify the ideal (theoretically possible) opsin properties and light source configurations that would maximise therapeutic efficacy. We conducted electrophysiological simulations in an MRI-based human ventricular model with VF induced by rapid pacing; light sensitisation via systemic, cardiac-specific gene transfer of channelrhodopsin-2 (ChR2) was simulated. In addition to the widely used blue light-sensitive ChR2-H134R, we also modelled theoretical ChR2 variants with augmented light sensitivity (ChR2+), red-shifted spectral sensitivity (ChR2-RED) or both (ChR2-RED+). Light sources were modelled as synchronously activating LED arrays (LED radius: 1 mm; optical power: 10 mW mm-2 ; array density: 1.15-4.61 cm-2 ). For each unique optogenetic configuration, defibrillation was attempted with two different optical pulse durations (25 and 500 ms). VF termination was only successful for configurations involving ChR2-RED and ChR2-RED+ (for LED arrays with density ≥ 2.30 cm-2 ), suggesting that opsin spectral sensitivity was the most important determinant of optogenetic defibrillation efficacy. This was due to the deeper penetration of red light in cardiac tissue compared with blue light, which resulted in more widespread light-induced propagating wavefronts. Longer pulse duration and higher LED array density were associated with increased optogenetic defibrillation efficacy. In all cases observed, the defibrillation mechanism was light-induced depolarisation of the excitable gap, which led to block of reentrant wavefronts.

Modelling methodology of atrial fibrosis affects rotor dynamics and electrograms.

AIMS: Catheter ablation is an effective technique for terminating atrial arrhythmia. However, given a high atrial fibrillation (AF) recurrence rate, optimal ablation strategies have yet to be defined. Computer modelling can be a powerful aid but modelling of fibrosis, a major factor associated with AF, is an open question. Several groups have proposed methodologies based on imaging data, but no comparison to determine which methodology best corroborates clinically observed reentrant behaviour has been performed. We examined several methodologies to determine the best method for capturing fibrillation dynamics. METHODS AND RESULTS: Patient late gadolinium-enhanced magnetic resonance imaging data were transferred onto a bilayer atrial computer model and used to assign fibrosis distributions. Fibrosis was modelled as conduction disturbances (lower conductivity, edge splitting, or percolation), transforming growth factor-ß1 ionic channel effects, myocyte-fibroblast coupling, and combinations of the preceding. Reentry was induced through pulmonary vein ectopy and the ensuing rotor dynamics characterized. Non-invasive electrocardiographic imaging data of the patients in AF was used for comparison. Electrograms were computed and the fractionation durations measured over the surface. Edge splitting produced more phase singularities from wavebreaks than the other representations. The number of phase singularities seen with percolation was closer to the clinical values. Addition of fibroblast coupling had an organizing effect on rotor dynamics. Simple tissue conductivity changes with ionic changes localized rotors over fibrosis which was not observed with clinical data. CONCLUSION: The specific representation of fibrosis has a large effect on rotor dynamics and needs to be carefully considered for patient specific modelling.

Disrupted calcium release as a mechanism for atrial alternans associated with human atrial fibrillation.

Atrial fibrillation (AF) is the most common cardiac arrhythmia, but our knowledge of the arrhythmogenic substrate is incomplete. Alternans, the beat-to-beat alternation in the shape of cardiac electrical signals, typically occurs at fast heart rates and leads to arrhythmia. However, atrial alternans have been observed at slower pacing rates in AF patients than in controls, suggesting that increased vulnerability to arrhythmia in AF patients may be due to the proarrythmic influence of alternans at these slower rates. As such, alternans may present a useful therapeutic target for the treatment and prevention of AF, but the mechanism underlying alternans occurrence in AF patients at heart rates near rest is unknown. The goal of this study was to determine how cellular changes that occur in human AF affect the appearance of alternans at heart rates near rest. To achieve this, we developed a computational model of human atrial tissue incorporating electrophysiological remodeling associated with chronic AF (cAF) and performed parameter sensitivity analysis of ionic model parameters to determine which cellular changes led to alternans. Of the 20 parameters tested, only decreasing the ryanodine receptor (RyR) inactivation rate constant (kiCa) produced action potential duration (APD) alternans seen clinically at slower pacing rates. Using single-cell clamps of voltage, fluxes, and state variables, we determined that alternans onset was Ca2+-driven rather than voltage-driven and occurred as a result of decreased RyR inactivation which led to increased steepness of the sarcoplasmic reticulum (SR) Ca2+ release slope. Iterated map analysis revealed that because SR Ca2+ uptake efficiency was much higher in control atrial cells than in cAF cells, drastic reductions in kiCa were required to produce alternans at comparable pacing rates in control atrial cells. These findings suggest that RyR kinetics may play a critical role in altered Ca2+ homeostasis which drives proarrhythmic APD alternans in patients with AF.

A bilayer model of human atria: mathematical background, construction, and assessment.

AIMS: Atrial numerical modelling has generally represented the organ as either a surface or tissue with thickness. While surface models have significant computational advantages over tissue models, they cannot fully capture propagation patterns seen in vivo, such as dissociation of activity between endo- and epicardium. We introduce an intermediate representation, a bilayer model of the human atria, which is capable of recreating recorded activation patterns. METHODS AND RESULTS: We simultaneously solved two surface monodomain problems by formalizing an optimization method to set a coupling term between them. Two different asymptotically equivalent numerical implementations of the model are presented. We then built a geometrically and electrophysiologically detailed model of the human atria based on CT data, including two layers of fibre directions, major muscle bundles, and discrete atrial coupling. We adjusted parameters to recreate clinically measured activation times. Activation was compared with a monolayer model. Activation was fit to the physiological range measured over the entire atria. The crista terminalis and pectinate muscles were important for local right atrial activation, but did not significantly affect total activation time. Propagation in the bilayer model was similar to that of a monolayer, but with noticeable difference, due to three-dimensional propagation where fibre direction changed abruptly across the wall, resulting in a slight dissociation of activity. CONCLUSION: Atrial structure plays the dominant role in determining activation. A bilayer model is able to take into account transmural heterogeneities, while maintaining the low computational load associated with surface models.

A His bundle pacing protocol for suppressing ventricular arrhythmia maintenance and improving defibrillation efficacy.

BACKGROUND: The excitable gap (EG), defined as the excitable tissue between two subsequent wavefronts of depolarization, is critical for maintaining reentry that underlies deadly ventricular arrhythmias. EG in the His-Purkinje Network (HPN) plays an important role in the maintenance of electrical wave reentry that underlies these arrhythmias. OBJECTIVE: To determine if rapid His bundle pacing (HBP) during reentry reduces the amount of EG in the HPN and ventricular myocardium to suppress reentry maintenance and/or improve defibrillation efficacy. METHODS: In a virtual human biventricular model, reentry was initiated with rapid line pacing followed by HBP delivered for 3, 6, or 9 s at pacing cycle lengths (PCLs) ranging from 10 to 300 ms (n=30). EG was calculated independently for the HPN and myocardium over each PCL. Defibrillation efficacy was assessed for each PCL by stimulating myocardial surface EG with delays ranging from 0.25 to 9 s (increments of 0.25 s, n=36) after the start of HBP. Defibrillation was successful if reentry terminated within 1 s after EG stimulation. This defibrillation protocol was repeated without HBP. To test the approach under different pathological conditions, all protocols were repeated in the model with right (RBBB) or left (LBBB) bundle branch block. RESULTS: Compared to without pacing, HBP for >3 seconds reduced average EG in the HPN and myocardium across a broad range of PCLs for the default, RBBB, and LBBB models. HBP >6 seconds terminated reentrant arrhythmia by converting HPN activation to a sinus rhythm behavior in the default (6/30 PCLs) and RBBB (7/30 PCLs) models. Myocardial EG stimulation during HBP increased the number of successful defibrillation attempts by 3%-19% for 30/30 PCLs in the default model, 3%-6% for 14/30 PCLs in the RBBB model, and 3%-11% for 27/30 PCLs in the LBBB model. CONCLUSION: HBP can reduce the amount of excitable gap and suppress reentry maintenance in the HPN and myocardium. HBP can also improve the efficacy of low-energy defibrillation approaches targeting excitable myocardium. HBP during reentrant arrhythmias is a promising anti-arrhythmic and defibrillation strategy.

The circle of reentry: Characteristics of trigger-substrate interaction leading to sudden cardiac arrest.

Sudden cardiac death is often caused by ventricular arrhythmias driven by reentry. Comprehensive characterization of the potential triggers and substrate in survivors of sudden cardiac arrest has provided insights into the trigger-substrate interaction leading to reentry. Previously, a "Triangle of Arrhythmogenesis", reflecting interactions between substrate, trigger and modulating factors, has been proposed to reason about arrhythmia initiation. Here, we expand upon this concept by separating the trigger and substrate characteristics in their spatial and temporal components. This yields four key elements that are required for the initiation of reentry: local dispersion of excitability (e.g., the presence of steep repolarization time gradients), a critical relative size of the region of excitability and the region of inexcitability (e.g., a sufficiently large region with early repolarization), a trigger that originates at a time when some tissue is excitable and other tissue is inexcitable (e.g., an early premature complex), and which occurs from an excitable region (e.g., from a region with early repolarization). We discuss how these findings yield a new mechanistic framework for reasoning about reentry initiation, the "Circle of Reentry." In a patient case of unexplained ventricular fibrillation, we then illustrate how a comprehensive clinical investigation of these trigger-substrate characteristics may help to understand the associated arrhythmia mechanism. We will also discuss how this reentry initiation concept may help to identify patients at risk, and how similar reasoning may apply to other reentrant arrhythmias.

Computational cardiology: how computer simulations could be used to develop new therapies and advance existing ones.

This article reviews the latest developments in computational cardiology. It focuses on the contribution of cardiac modelling to the development of new therapies as well as the advancement of existing ones for cardiac arrhythmias and pump dysfunction. Reviewed are cardiac modelling efforts aimed at advancing and optimizing existent therapies for cardiac disease (defibrillation, ablation of ventricular tachycardia, and cardiac resynchronization therapy) and at suggesting novel treatments, including novel molecular targets, as well as efforts to use cardiac models in stratification of patients likely to benefit from a given therapy, and the use of models in diagnostic procedures.

Low-energy, single-pulse surface stimulation defibrillates large mammalian ventricles.

BACKGROUND: Strong electric shocks are the gold standard for ventricular defibrillation but are associated with pain and tissue damage. We hypothesized that targeting the excitable gap (EG) of reentry with low-energy surface stimulation is a less damaging and painless alternative for ventricular defibrillation. OBJECTIVE: The purpose of this study was to determine the conditions under which low-energy surface stimulation defibrillates large mammalian ventricles. METHODS: Low-energy surface stimulation was delivered with five electrodes that were 7 cm long and placed 1-2 cm apart on the endocardial and epicardial surfaces of perfused pig left ventricle (LV). Rapid pacing (>4 Hz) was used to induce reentry from a single electrode. A 2 ms defibrillation pulse ≤0.5 A was delivered from all electrodes with a varied time delay from the end of the induction protocol (0.1-5 seconds). Optical mapping was performed and arrhythmia dynamics analyzed. For mechanistic insight, simulations of the VF induction and defibrillation protocols were performed in silico with an LV model emulating the experimental conditions and electrodes placed 0.25-2 cm apart. RESULTS: In living LV, reentry was induced with varying complexity and dominant frequencies ranging between 3.5 to 6.2 Hz over 8 seconds postinitiation. Low-energy defibrillation was achieved with energy <60 mJ and electrode separations up to 2 cm for less complex arrhythmia. In simulations, defibrillation consistently occurred when stimulation captured >75% of the EG, which blocked reentry <2.9 mm in front of the leading reentrant wavefront. CONCLUSION: Defibrillation with low-energy, single-pulse surface stimulation is feasible with energies below the human pain threshold (100 mJ). Optimal defibrillation occurs when arrhythmia complexity is minimal and electrodes capture >75% of the EG.

The Purkinje network plays a major role in low-energy ventricular defibrillation.

BACKGROUND: During ventricular fibrillation (VF), targeting the excitable gap (EG) of reentry throughout the myocardium with low-energy surface stimulation shows promise for painless defibrillation. However, the Purkinje network may provide alternative pathways for reentry to evade termination. This study investigates the role of the Purkinje network in painless defibrillation. METHODS: In a computational human biventricular model featuring a Purkinje network, VF was initiated with 4 Hz epicardial pacing. Defibrillation was attempted by stimulating myocardial surface EG with a low-energy 2 ms duration pulse at 2x stimulus capture, which was administered at coupling intervals incremented by 0.25 s between 0.25 and 5 s after VF initiation. Defibrillation was accomplished if reentry ceased ≤ 1 s after the defibrillation pulse. The protocol was repeated with the Purkinje network and myocardial surface EG stimulated simultaneously, and again after uncoupling the Purkinje network from the myocardium. RESULTS: VF with the Purkinje network coupled and uncoupled had comparable dominant frequency in the left (3.81 ± 0.44 versus 3.77 ± 0.53 Hz) and right (3.80 ± 0.37 versus 3.76 ± 0.48 Hz) ventricles. When uncoupling the Purkinje network, myocardial surface EG stimulation terminated VF for all defibrillation pulses. When coupled, myocardial EG surface stimulation terminated VF for only 55% of the defibrillation pulses, but improved to 100% when stimulated simultaneously with Purkinje network EG. Defibrillation failures were attributed to EG evading stimulation in the Purkinje network. CONCLUSIONS: Defibrillation that exclusively targets myocardium can fail due to accessory pathways in the Purkinje network that allow for reentrant activity to evade termination and maintain VF. Painless defibrillation strategies should be adapted to include the Purkinje network.

Tissue Preparation Techniques for Contrast-Enhanced Micro Computed Tomography Imaging of Large Mammalian Cardiac Models with Chronic Disease.

Structural remodeling is a common consequence of chronic pathological stresses imposed on the heart. Understanding the architectural and compositional properties of diseased tissue is critical to determine their interactions with arrhythmic behavior. Microscale tissue remodeling, below the clinical resolution, is emerging as an important source of lethal arrhythmia, with high prevalence in young adults. Challenges remain in obtaining high imaging contrast at sufficient microscale resolution for preclinical models, such as large mammalian whole hearts. Moreover, tissue composition-selective contrast enhancement for three-dimensional high-resolution imaging is still lacking. Non-destructive imaging using micro-computed tomography shows promise for high-resolution imaging. The objective was to alleviate sufferance from X-ray over attenuation in large biological samples. Hearts were extracted from healthy pigs (N = 2), and sheep (N = 2) with either induced chronic myocardial infarction and fibrotic scar formation or induced chronic atrial fibrillation. Excised hearts were perfused with: a saline solution supplemented with a calcium ion quenching agent and a vasodilator, ethanol in serial dehydration, and hexamethyldisilizane under vacuum. The latter reinforced the heart structure during air-drying for 1 week. Collagen-dominant tissue was selectively bound by an X-ray contrast-enhancing agent, phosphomolybdic acid. Tissue conformation was stable in air, permitting long-duration microcomputed tomography acquisitions to obtain high-resolution (isotropic 20.7 µm) images. Optimal contrast agent loading by diffusion showed selective contrast enhancement of the epithelial layer and sub-endocardial Purkinje fibers in healthy pig ventricles. Atrial fibrillation (AF) hearts showed enhanced contrast accumulation in the posterior walls and appendages of the atria, attributed to greater collagen content. Myocardial infarction hearts showed increased contrast selectively in regions of cardiac fibrosis, which enabled the identification of interweaving surviving myocardial muscle fibers. Contrast-enhanced air-dried tissue preparations enabled microscale imaging of the intact large mammalian heart and selective contrast enhancement of underlying disease constituents.

Secretome of atrial epicardial adipose tissue facilitates reentrant arrhythmias by myocardial remodeling.

BACKGROUND: Epicardial adipose tissue (EAT) accumulation is associated with cardiac arrhythmias. The effect of EAT secretome (EATs) on cardiac electrophysiology remains largely unknown. OBJECTIVE: The purpose of this study was to investigate the arrhythmogenicity of EATs and its underlying molecular and electrophysiological mechanisms. METHODS: We collected atrial EAT and subcutaneous adipose tissue (SAT) from 30 patients with atrial fibrillation (AF), and EAT from 3 donors without AF. The secretome was collected after a 24-hour incubation of the adipose tissue explants. We cultured neonatal rat ventricular myocytes (NRVMs) with EATs, subcutaneous adipose tissue secretome (SATs), and cardiomyocytes conditioned medium (CCM) for 72 hours. We implemented the electrophysiological changes observed after EATs incubation into a model of human left atrium and tested arrhythmia inducibility. RESULTS: Incubation of NRVMs with EATs decreased expression of the potassium channel subunit Kcnj2 by 26% and correspondingly reduced the inward rectifier K+ current IK1 by 35% compared to incubation with CCM, resulting in a depolarized resting membrane of cardiomyocytes. EATs decreased expression of connexin43 (29% mRNA, 46% protein) in comparison to CCM. Cells incubated with SATs showed no significant differences in Kcnj2 or Gja1 expression in comparison to CCM, and their resting potential was not depolarized. Cardiomyocytes incubated with EATs showed reduced conduction velocity and increased conduction heterogeneity compared to SATs and CCM. Computer modeling of human left atrium revealed that the electrophysiological changes induced by EATs promote sustained reentrant arrhythmias if EAT partially covers the myocardium. CONCLUSION: EAT slows conduction, depolarizes the resting potential, alters electrical cell-cell coupling, and facilitates reentrant arrhythmias.

Critical repolarization gradients determine the induction of reentry-based torsades de pointes arrhythmia in models of long QT syndrome.

BACKGROUND: Torsades de pointes arrhythmia is a potentially lethal polymorphic ventricular tachyarrhythmia (pVT) in the setting of long QT syndrome. Arrhythmia susceptibility is influenced by risk factors modifying repolarization. OBJECTIVE: The purpose of this article was to characterize repolarization duration and heterogeneity in relation to pVT inducibility and maintenance. METHODS: Sotalol was infused regionally or globally in isolated Langendorff blood-perfused pig hearts (N = 7) to create repolarization time (RT) heterogeneities. Programmed stimulation and epicardial activation and repolarization mapping were performed. The role of RT (heterogeneities) was studied in more detail using a computer model of the human heart. RESULTS: pVTs (n = 11) were inducible at a critical combination of RT and RT heterogeneities. The pVT cycle lengths were similar in the short and long RT regions. Short-lasting pVTs were maintained by focal activity while longer-lasting pVTs by reentry wandering along the interface between the 2 regions. Local restitution curves from the long and short RT regions crossed. This was associated with T-wave inversion at coupling intervals at either side of the crossing point. These experimental observations were confirmed by the computer simulations. CONCLUSION: pVTs are inducible within a critical range of RT and RT heterogeneities and are maintained by reentry wandering along the repolarization gradient. Double potentials localize at the core of the reentrant circuit and reflect phase singularities. RT gradient and T waves invert with short-coupled premature beats in the long RT region as a result of the crossing of the restitution curves allowing reentry initiation.

A Framework for the generation of digital twins of cardiac electrophysiology from clinical 12-leads ECGs.

Cardiac digital twins (Cardiac Digital Twin (CDT)s) of human electrophysiology (Electrophysiology (EP)) are digital replicas of patient hearts derived from clinical data that match like-for-like all available clinical observations. Due to their inherent predictive potential, CDTs show high promise as a complementary modality aiding in clinical decision making and also in the cost-effective, safe and ethical testing of novel EP device therapies. However, current workflows for both the anatomical and functional twinning phases within CDT generation, referring to the inference of model anatomy and parameters from clinical data, are not sufficiently efficient, robust and accurate for advanced clinical and industrial applications. Our study addresses three primary limitations impeding the routine generation of high-fidelity CDTs by introducing; a comprehensive parameter vector encapsulating all factors relating to the ventricular EP; an abstract reference frame within the model allowing the unattended manipulation of model parameter fields; a novel fast-forward electrocardiogram (Electrocardiogram (ECG)) model for efficient and bio-physically-detailed simulation required for parameter inference. A novel workflow for the generation of CDTs is then introduced as an initial proof of concept. Anatomical twinning was performed within a reasonable time compatible with clinical workflows (<4h) for 12 subjects from clinically-attained magnetic resonance images. After assessment of the underlying fast forward ECG model against a gold standard bidomain ECG model, functional twinning of optimal parameters according to a clinically-attained 12 lead ECG was then performed using a forward Saltelli sampling approach for a single subject. The achieved results in terms of efficiency and fidelity demonstrate that our workflow is well-suited and viable for generating biophysically-detailed CDTs at scale.

Noninvasive detection of spatiotemporal activation-repolarization interactions that prime idiopathic ventricular fibrillation.

A comprehensive understanding of the interaction between triggers and electrical substrates leading to ventricular fibrillation (VF) and sudden cardiac arrest is lacking, and electrical substrates are difficult to detect and localize with current clinical tools. Here, we created repolarization time (RT) dispersion by regional drug infusion in perfused explanted human (n = 1) and porcine (n = 6) hearts and in a computational model of the human ventricle. Arrhythmia induction was tested with a single ventricular extrastimulus applied at the early or late RT region. Arrhythmias could only be induced from early RT regions. Vulnerability to VF increased with RT gradient steepness and with larger areas of early RT, but not with markers on the body-surface electrocardiogram. Noninvasive electrocardiographic imaging was performed in survivors of idiopathic VF (n = 11), patients with frequent premature ventricular complexes (PVCs) but no history of sudden cardiac arrest (n = 7), and controls (n = 10). In survivors of idiopathic VF, RT gradients were steeper than in controls, without differences in the clinical electrocardiogram, consistent with the ex vivo results. Patients with idiopathic VF also showed local myocardial regions with distinctly early-versus-late RT that were more balanced in size than in controls. Premature beats originated more often from the early RT regions in idiopathic VF survivors than in patients with frequent PVCs only. Thus, idiopathic VF emerges from the spatiotemporal interaction of a premature beat from an early-repolarization region with critical repolarization dispersion in that region. Electrocardiographic imaging can uncover the co-occurrence of these abnormalities.

Stretchable Conductive Fabric for Cardiac Electrophysiology Applications.

Stretchable conductive fabric (SCF) is a durable nontoxic textile material coated or blended with conductive metals. Unlike solid metal, SCF effectively conducts electricity with low resistance and maintains conductance when stretched. Thus, we hypothesized that SCF electrodes are more suitable for cardiac electrophysiology applications in beating hearts than traditional solid metal electrodes. Accordingly, we developed a straightforward protocol for fabricating customized SCF electrodes and then assessed their ability to electrically stimulate and record electrical signals from beating hearts. Compared to flexible copper electrodes, SCF electrodes had similar electrical resistance (112.50 ± 25.81 vs 157.85 ± 17.06 Ω, p = 0.09), activated cardiac tissue with lower stimulus strength (27.25 ± 3.52 vs 15.35 ± 2.15 mA, p = 0.0001), recorded stable electrograms with a higher signal-to-noise ratio (20.54 ± 1.09 vs 13.35 ± 1.46 dB, p = 0.04), and were noncorrosive and harmless to cardiac tissue or vasculature. These results support the use of SCF over metal electrodes for a wide range of cardiac electrophysiology applications in the beating heart.

An Inverse Eikonal Method for Identifying Ventricular Activation Sequences from Epicardial Activation Maps.

A key mechanism controlling cardiac function is the electrical activation sequence of the heart's main pumping chambers termed the ventricles. As such, personalization of the ventricular activation sequences is of pivotal importance for the clinical utility of computational models of cardiac electrophysiology. However, a direct observation of the activation sequence throughout the ventricular volume is virtually impossible. In this study, we report on a novel method for identification of activation sequences from activation maps measured at the outer surface of the heart termed the epicardium. Conceptually, the method attempts to identify the key factors governing the ventricular activation sequence - the timing of earliest activation sites (EAS) and the velocity tensor field within the ventricular walls - from sparse and noisy activation maps sampled from the epicardial surface and fits an Eikonal model to the observations. Regularization methods are first investigated to overcome the severe ill-posedness of the inverse problem in a simplified 2D example. These methods are then employed in an anatomically accurate biventricular model with two realistic activation models of varying complexity - a simplified trifascicular model (3F) and a topologically realistic model of the His-Purkinje system (HPS). Using epicardial activation maps at full resolution, we first demonstrate that reconstructing the volumetric activation sequence is, in principle, feasible under the assumption of known location of EAS and later evaluate robustness of the method against noise and reduced spatial resolution of observations. Our results suggest that the FIMIN algorithm is able to robustly recover the full 3D activation sequence using epicardial activation maps at a spatial resolution achievable with current mapping systems and in the presence of noise. Comparing the accuracy achieved in the reconstructed activation maps with clinical data uncertainties suggests that the FIMIN method may be suitable for the patient- specific parameterization of activation models.