Automated Framework for the Inclusion of a His-Purkinje System in Cardiac Digital Twins of Ventricular Electrophysiology.

Personalized models of cardiac electrophysiology (EP) that match clinical observation with high fidelity, referred to as cardiac digital twins (CDTs), show promise as a tool for tailoring cardiac precision therapies. Building CDTs of cardiac EP relies on the ability of models to replicate the ventricular activation sequence under a broad range of conditions. Of pivotal importance is the His-Purkinje system (HPS) within the ventricles. Workflows for the generation and incorporation of HPS models are needed for use in cardiac digital twinning pipelines that aim to minimize the misfit between model predictions and clinical data such as the 12 lead electrocardiogram (ECG). We thus develop an automated two stage approach for HPS personalization. A fascicular-based model is first introduced that modulates the endocardial Purkinje network. Only emergent features of sites of earliest activation within the ventricular myocardium and a fast-conducting sub-endocardial layer are accounted for. It is then replaced by a topologically realistic Purkinje-based representation of the HPS. Feasibility of the approach is demonstrated. Equivalence between both HPS model representations is investigated by comparing activation patterns and 12 lead ECGs under both sinus rhythm and right-ventricular apical pacing. Predominant ECG morphology is preserved by both HPS models under sinus conditions, but elucidates differences during pacing.

The openCARP simulation environment for cardiac electrophysiology.

BACKGROUND AND OBJECTIVE: Cardiac electrophysiology is a medical specialty with a long and rich tradition of computational modeling. Nevertheless, no community standard for cardiac electrophysiology simulation software has evolved yet. Here, we present the openCARP simulation environment as one solution that could foster the needs of large parts of this community. METHODS AND RESULTS: openCARP and the Python-based carputils framework allow developing and sharing simulation pipelines which automate in silico experiments including all modeling and simulation steps to increase reproducibility and productivity. The continuously expanding openCARP user community is supported by tailored infrastructure. Documentation and training material facilitate access to this complementary research tool for new users. After a brief historic review, this paper summarizes requirements for a high-usability electrophysiology simulator and describes how openCARP fulfills them. We introduce the openCARP modeling workflow in a multi-scale example of atrial fibrillation simulations on single cell, tissue, organ and body level and finally outline future development potential. CONCLUSION: As an open simulator, openCARP can advance the computational cardiac electrophysiology field by making state-of-the-art simulations accessible. In combination with the carputils framework, it offers a tailored software solution for the scientific community and contributes towards increasing use, transparency, standardization and reproducibility of in silico experiments.

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.

Wide-area low-energy surface stimulation of large mammalian ventricular tissue.

The epicardial and endocardial surfaces of the heart are attractive targets to administer antiarrhythmic electrotherapies. Electrically stimulating wide areas of the surfaces of small mammalian ventricles is straightforward given the relatively small scale of their myocardial dimensions compared to the tissue space constant and electrical field. However, it has yet to be proven for larger mammalian hearts with tissue properties and ventricular dimensions closer to humans. Our goal was to address the feasibility and impact of wide-area electrical stimulation on the ventricular surfaces of large mammalian hearts at different stimulus strengths. This was accomplished by placing long line electrodes on the ventricular surfaces of pig hearts that span wide areas, and activating them individually. Stimulus efficacy was assessed and compared between surfaces, and tissue viability was evaluated. Activation time was dependent on stimulation strength and location, achieving uniform linear stimulation at 9x threshold strength. Endocardial stimulation activated more tissue transmurally than epicardial stimulation, which could be considered a potential target for future cardiac electrotherapies. Overall, our results indicate that electrically stimulating wide areas of the ventricular surfaces of large mammals is achievable with line electrodes, minimal tissue damage, and energies under the human pain threshold (100 mJ).

Compartmentalized Structure of the Moderator Band Provides a Unique Substrate for Macroreentrant Ventricular Tachycardia.

Background Papillary muscles are an important source of ventricular tachycardia (VT). Yet little is known about the role of the right ventricular (RV) endocavity structure, the moderator band (MB). The aim of this study was to determine the characteristics of the MB that may predispose to arrhythmia substrates. Methods Ventricular wedge preparations with intact MBs were studied from humans (n=2) and sheep (n=15; 40-50 kg). RV endocardium was optically mapped, and electrical recordings were measured along the MB and septum. S1S2 pacing of the RV free wall, MB, or combined S1-RV S2-MB sites were assessed. Human (n=2) and sheep (n=4) MB tissue constituents were assessed histologically. Results The MB structure was remarkably organized as 2 excitable, yet uncoupled compartments of myocardium and Purkinje. In humans, action potential duration heterogeneity between MB and RV myocardium was found (324.6±12.0 versus 364.0±8.4 ms; P<0.0001). S1S2-MB pacing induced unidirectional propagation via MB myocardium, permitting sustained macroreentrant VT. In sheep, the incidence of VT for RV, MB, and S1-RV S2-MB pacing was 1.3%, 5.1%, and 10.3%. Severing the MB led to VT termination, confirming a primary arrhythmic role. Inducible preparations had shorter action potential duration in the MB than RV (259.3±45.2 versus 300.7±38.5 ms; P<0.05), whereas noninducible preparations showed no difference (312.0±30.3 versus 310.0±24.6 ms, respectively). Conclusions The MB presents anatomic and electrical compartmentalization between myocardium and Purkinje fibers, providing a substrate for macroreentry. The vulnerability to sustain VT via this mechanism is dependent on MB structure and action potential duration gradients between the RV free wall and MB.

Determinants of atrial bipolar voltage: Inter electrode distance and wavefront angle.

BACKGROUND: Local bipolar electrogram (EGM) peak-to-peak voltage (Vpp) is currently used to characterise mapped myocardial substrate. However, how interelectrode distance and angle of wavefront incidence affect bipolar, Vpp values, in the current era of multi-electrode mapping is unknown. OBJECTIVES: To elucidate the effects of tissue and electrode geometry on bipolar Vpp measurements, when mapping healthy versus diseased atrial regions. METHODS: A bidomain model of human atrial tissue was used to quantify the influence on Vpp values of various electrode configurations in healthy tissue, and tissue containing an unexcitable region. The orientation angle and interelectrode spacing of a surface bipole, and thickness and depth of the unexcitable core were serially varied. Results were validated with data obtained from isolated porcine hearts. RESULTS: In healthy tissue, bipolar Vpp values increased with increasing interelectrode spacing and plateaued beyond a spacing of approximately 4 mm. The bipolar Vpp values in healthy tissue were relatively less sensitive to wavefront orientation angle with large interelectrode spacing. In diseased tissue, on the contrary, with increasing interelectrode spacing, bipolar Vpp values increased linearly without a plateau and were more sensitive to orientation angle. The bipolar Vpp values decreased with increasing thickness of the scar, with larger relative decrease in small bipoles than larger ones. Bipolar Vpp values increased with a progressively intramural location of fixed-size scar and became less distinguishable from healthy tissue especially for smaller interelectrode spacings. CONCLUSIONS: The scalable relationship established for interelectrode distances favour an electric-field-based assessment as opposed to traditional Vpp values as a tool for physiologically relevant measurement for mapping catheters with interelectrode spacing up to 4 mm. This will allow for universal assessment of myocardial health across catheters with varied spacing.

Spatial Resolution Requirements for Accurate Identification of Drivers of Atrial Fibrillation.

BACKGROUND: Recent studies have demonstrated conflicting mechanisms underlying atrial fibrillation (AF), with the spatial resolution of data often cited as a potential reason for the disagreement. The purpose of this study was to investigate whether the variation in spatial resolution of mapping may lead to misinterpretation of the underlying mechanism in persistent AF. METHODS AND RESULTS: Simulations of rotors and focal sources were performed to estimate the minimum number of recording points required to correctly identify the underlying AF mechanism. The effects of different data types (action potentials and unipolar or bipolar electrograms) and rotor stability on resolution requirements were investigated. We also determined the ability of clinically used endocardial catheters to identify AF mechanisms using clinically recorded and simulated data. The spatial resolution required for correct identification of rotors and focal sources is a linear function of spatial wavelength (the distance between wavefronts) of the arrhythmia. Rotor localization errors are larger for electrogram data than for action potential data. Stationary rotors are more reliably identified compared with meandering trajectories, for any given spatial resolution. All clinical high-resolution multipolar catheters are of sufficient resolution to accurately detect and track rotors when placed over the rotor core although the low-resolution basket catheter is prone to false detections and may incorrectly identify rotors that are not present. CONCLUSIONS: The spatial resolution of AF data can significantly affect the interpretation of the underlying AF mechanism. Therefore, the interpretation of human AF data must be taken in the context of the spatial resolution of the recordings.

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.

Patient-derived models link re-entrant driver localization in atrial fibrillation to fibrosis spatial pattern.

AIMS: The mechanisms underlying persistent atrial fibrillation (AF) in patients with atrial fibrosis are poorly understood. The goal of this study was to use patient-derived atrial models to test the hypothesis that AF re-entrant drivers (RDs) persist only in regions with specific fibrosis patterns. METHODS AND RESULTS: Twenty patients with persistent AF (PsAF) underwent late gadolinium-enhanced MRI to detect the presence of atrial fibrosis. Segmented images were used to construct personalized 3D models of the fibrotic atria with biophysically realistic atrial electrophysiology. In each model, rapid pacing was applied to induce AF. AF dynamics were analysed and RDs were identified using phase mapping. Fibrosis patterns in RD regions were characterized by computing maps of fibrosis density (FD) and entropy (FE). AF was inducible in 13/20 models and perpetuated by few RDs (2.7 ± 1.5) that were spatially confined (trajectory of phase singularities: 7.6 ± 2.3 mm). Compared with the remaining atrial tissue, regions where RDs persisted had higher FE (IQR: 0.42-0.60 vs. 0.00-0.40, P < 0.05) and FD (IQR: 0.59-0.77 vs. 0.00-0.33, P < 0.05). Machine learning classified RD and non-RD regions based on FD and FE and identified a subset of fibrotic boundary zones present in 13.8 ± 4.9% of atrial tissue where 83.5 ± 2.4% of all RD phase singularities were located. CONCLUSION: Patient-derived models demonstrate that AF in fibrotic substrates is perpetuated by RDs persisting in fibrosis boundary zones characterized by specific regional fibrosis metrics (high FE and FD). These results provide new insights into the mechanisms that sustain PsAF and could pave the way for personalized, MRI-based management of PsAF.

Defibrillation success is not associated with near field electrogram complexity or shock timing.

BACKGROUND: It has been suggested that more-complex fibrillation requires higher energy shocks to terminate. Furthermore, animal studies have demonstrated that shock timing also plays a role. The objective of this study was to test these assertions in a clinical context. METHODS: Near- and far-field electrograms were collected during defibrillation threshold testing. Fibrillation complexity was measured by quantifying the organization in the signals with wavelet-based methods, scaling exponent, and cross-correlation analysis. Receiver operator characteristic curves were used to determine predictive value. The effect of the phase at which defibrillation shocks were applied was also determined. RESULTS: No measure was able to classify whether a particular shock would be successful. All performed very poorly. Shock timing played no role in defibrillation outcome. CONCLUSIONS: Signal organization of a local electrogram and phase of shock delivery do not relate to minimum defibrillation shock energy immediately after ventricular fibrillation onset.

Fusion during entrainment of orthodromic reciprocating tachycardia is enhanced for basal pacing sites but diminished when pacing near Purkinje system end points.

BACKGROUND: In the electrophysiological laboratory, orthodromic atrioventricular reciprocating tachycardia (ORT) can be distinguished from atrial tachycardia and atrioventricular node reentry tachycardia by identifying orthodromic and antidromic wavefront fusion during ventricular overdrive pacing (VOP). Previous work has shown that basal VOP near the accessory pathway (AP) increases the likelihood of observing fusion; however, in a third of cases, fusion is not appreciable regardless of VOP location. OBJECTIVE: To explore the hypothesis that pacing near His-Purkinje system (PS) end points reduces fusion quality, which may explain patients with nonresponsive ORT. METHODS: In a novel computer model of ORT, simulations were performed with a variety of AP locations and pacing sites; results were analyzed to assess factors influencing fusion quality in pseudo-electrocardiogram signals. RESULTS: Entrainment by basal VOP near the AP was more likely to produce fusion visible on simulated electrocardiograms compared to entrainment by apical VOP, but this advantage was dramatically diminished when the pacing site was also near PS end points. Prediction of fusion quality based on AP proximity alone was dramatically improved when corrected to penalize for PS proximity. CONCLUSIONS: These results suggest that basal VOP near the AP and far from the PS is optimal; this could be tested in patients. A denser basal ramification of PS fibers is known to exist in a minority of human hearts; our findings indicate that this unusual PS configuration is a plausible explanation for ORT cases where fusion is never observed in spite of entrainment by basal VOP near the AP.

Automatically generated, anatomically accurate meshes for cardiac electrophysiology problems.

Significant advancements in imaging technology and the dramatic increase in computer power over the last few years broke the ground for the construction of anatomically realistic models of the heart at an unprecedented level of detail. To effectively make use of high-resolution imaging datasets for modeling purposes, the imaged objects have to be discretized. This procedure is trivial for structured grids. However, to develop generally applicable heart models, unstructured grids are much preferable. In this study, a novel image-based unstructured mesh generation technique is proposed. It uses the dual mesh of an octree applied directly to segmented 3-D image stacks. The method produces conformal, boundary-fitted, and hexahedra-dominant meshes. The algorithm operates fully automatically with no requirements for interactivity and generates accurate volume-preserving representations of arbitrarily complex geometries with smooth surfaces. The method is very well suited for cardiac electrophysiological simulations. In the myocardium, the algorithm minimizes variations in element size, whereas in the surrounding medium, the element size is grown larger with the distance to the myocardial surfaces to reduce the computational burden. The numerical feasibility of the approach is demonstrated by discretizing and solving the monodomain and bidomain equations on the generated grids for two preparations of high experimental relevance, a left ventricular wedge preparation, and a papillary muscle.

Estimating atrial action potential duration from electrograms.

Electrogram analysis is important in clinical and experimental settings. Activation recovery interval (ARI) has been used to measure ventricular action potential duration (APD) but its suitability for the atria has not been addressed. Mapping of atrial repolarization may be especially important during nerve stimulation since large heterogenous APD changes may manifest. This study assessed the utility of estimating APD in the atria using electrograms. A computer model of the atria was used to compute electrograms. Two different atrial waveforms were used, as well as two ventricular. APD was modulated with an acetylcholine- (ACh) dependent potassium channel and varying the spatial ACh distribution. ARI was computed, as well as the area under the repolarization wave (ATa). APD was measured by four methods. Atrial electrograms were also compared to monophasic action potentials recorded from a dog. ARI computed from atrial action potentials was not very precise, with errors ranging over 30 ms. Determining changes in APD induced by changing [ACh] yielded larger errors. Conversely, ventricular action potentials produced ARIs that very closely correlated with APD, and changes in APD . Positive ATa indicated regions of shortened APD, and islands of ACh release were clearly demarcated by ATa polarity. Experimentally, ARI was able to detect changes in APD, but did not measure APD well. The faster rate of ventricular repolarization produces larger currents that are less susceptible to electrotonic coupling effects, improving correlation with APD. ARI most closely correlated with APD measured as a fixed threshold above rest. Atrial APs produce electrograms that can be used to detect changes in APD. This may be improved by decreasing coupling. The ATa is a robust measure for precisely identifying spatial APD heterogeneities.

Mechanistic basis of differential conduction in skeletal muscle arteries.

The goal of this investigation was to probe intercellular conduction in skeletal muscle feed arteries and to address why smooth muscle-initiated responses fail to robustly spread like their endothelial counterpart. Using computational and experimental approaches, two interrelated rationales were developed to explain this apparent discrepancy in cell-to-cell communication. The first rationale stressed that smooth muscle electrical responses, if initiated, will be actively dissipated as they spread from cell-to-cell along the arterial wall. Charge dissipation is promoted within arteries by the structural and connectivity properties of vascular cells. The second rationale centred on the idea that when agents other than KCl stimulate a limited number of smooth muscle cells, they fail to generate the currents required to elicit a localized membrane potential (V(M)) response. This insufficiency results in part from charge loss, via gap junctions, to neighbouring unstimulated cells. Experiments confirmed the latter rationale by showing that focal phenylephrine application: (1) elicited a localized constriction insensitive to L-type Ca(2+) channel blockade; and (2) failed to substantially depolarize vascular smooth muscle cells. Further investigation revealed that while focal phenylephrine-induced constriction was V(M) independent, it was reliant on internal Ca(2+) mobilization and the activation of inositol 1,4,5-trisphosphate (IP(3)) receptors. The preceding findings illustrate that by using computational modelling and experimentation in a complementary manner, one can isolate key cellular properties and rationally examine their role in limiting the conduction of smooth muscle-initiated responses. Functionally, these observations enable investigators to assign the concept of 'local and global' blood flow control to the electrical and/or non-electrical behaviour of specific cell types.