A computational framework for testing arrhythmia marker sensitivities to model parameters in functionally calibrated populations of atrial cells.

Models of cardiac cell electrophysiology are complex non-linear systems which can be used to gain insight into mechanisms of cardiac dynamics in both healthy and pathological conditions. However, the complexity of cardiac models can make mechanistic insight difficult. Moreover, these are typically fitted to averaged experimental data which do not incorporate the variability in observations. Recently, building populations of models to incorporate inter- and intra-subject variability in simulations has been combined with sensitivity analysis (SA) to uncover novel ionic mechanisms and potentially clarify arrhythmogenic behaviors. We used the Koivumäki human atrial cell model to create two populations, representing normal Sinus Rhythm (nSR) and chronic Atrial Fibrillation (cAF), by varying 22 key model parameters. In each population, 14 biomarkers related to the action potential and dynamic restitution were extracted. Populations were calibrated based on distributions of biomarkers to obtain reasonable physiological behavior, and subjected to SA to quantify correlations between model parameters and pro-arrhythmia markers. The two populations showed distinct behaviors under steady state and dynamic pacing. The nSR population revealed greater variability, and more unstable dynamic restitution, as compared to the cAF population, suggesting that simulated cAF remodeling rendered cells more stable to parameter variation and rate adaptation. SA revealed that the biomarkers depended mainly on five ionic currents, with noted differences in sensitivities to these between nSR and cAF. Also, parameters could be selected to produce a model variant with no alternans and unaltered action potential morphology, highlighting that unstable dynamical behavior may be driven by specific cell parameter settings. These results ultimately suggest that arrhythmia maintenance in cAF may not be due to instability in cell membrane excitability, but rather due to tissue-level effects which promote initiation and maintenance of reentrant arrhythmia.

A feasibility study of arrhythmia risk prediction in patients with myocardial infarction and preserved ejection fraction.

AIM: To predict arrhythmia susceptibility in myocardial infarction (MI) patients with left ventricular ejection fraction (LVEF) >35% using a personalized virtual heart simulation approach. METHODS AND RESULTS: A total of four contrast enhanced magnetic resonance imaging (MRI) datasets of patient hearts with MI and average LVEF of 44.0 ± 2.6% were used in this study. Because of the preserved LVEF, the patients were not indicated for implantable cardioverter defibrillator (ICD) insertion. One patient had spontaneous ventricular tachycardia (VT) prior to the MRI scan; the others had no arrhythmic events. Simulations of arrhythmia susceptibility were blind to clinical outcome. Models were constructed from patient MRI images segmented to identify myocardium, grey zone, and scar based on pixel intensity. Grey zone was modelled as having altered electrophysiology. Programmed electrical stimulation (PES) was performed to assess VT inducibility from 19 bi-ventricular sites in each heart model. Simulations successfully predicted arrhythmia risk in all four patients. For the patient with arrhythmic event, in-silico PES resulted in VT induction. Simulations correctly predicted that VT was non-inducible for the three patients with no recorded VT events. CONCLUSIONS: Results demonstrate that the personalized virtual heart simulation approach may provide a novel risk stratification modality to non-invasively and effectively identify patients with LVEF >35% who could benefit from ICD implantation.

Fibrosis modeling choice affects morphology of ventricular arrhythmia in non-ischemic cardiomyopathy.

Introduction: Patients with non-ischemic cardiomyopathy (NICM) are at risk for ventricular arrhythmias, but diagnosis and treatment planning remain a serious clinical challenge. Although computational modeling has provided valuable insight into arrhythmic mechanisms, the optimal method for simulating reentry in NICM patients with structural disease is unknown. Methods: Here, we compare the effects of fibrotic representation on both reentry initiation and reentry morphology in patient-specific cardiac models. We investigate models with heterogeneous networks of non-conducting structures (cleft models) and models where fibrosis is represented as a dense core with a surrounding border zone (non-cleft models). Using segmented cardiac magnetic resonance with late gadolinium enhancement (LGE) of five NICM patients, we created 185 3D ventricular electrophysiological models with different fibrotic representations (clefts, reduced conductivity and ionic remodeling). Results: Reentry was induced by electrical pacing in 647 out of 3,145 simulations. Both cleft and non-cleft models can give rise to double-loop reentries meandering through fibrotic regions (Type 1-reentry). When accounting for fibrotic volume, the initiation sites of these reentries are associated with high local fibrotic density (mean LGE in cleft models: p< 0.001, core volume in non-cleft models: p = 0.018, negative binomial regression). In non-cleft models, Type 1-reentries required slow conduction in core tissue (non-cleftsc models) as opposed to total conduction block. Incorporating ionic remodeling in fibrotic regions can give rise to single- or double-loop rotors close to healthy-fibrotic interfaces (Type 2-reentry). Increasing the cleft density or core-to-border zone ratio in cleft and non-cleftc models, respectively, leads to increased inducibility and a change in reentry morphology from Type 2 to Type 1. Conclusions: By demonstrating how fibrotic representation affects reentry morphology and location, our findings can aid model selection for simulating arrhythmogenesis in NICM.

A universal biventricular coordinate system incorporating valve annuli: Validation in congenital heart disease.

Universal coordinate systems have been proposed to facilitate anatomic registration between three-dimensional images, data and models of the ventricles of the heart. However, current universal ventricular coordinate systems do not account for the outflow tracts and valve annuli where the anatomy is complex. Here we propose an extension to the 'Cobiveco' biventricular coordinate system that also accounts for the intervalvular bridges of the base and provides a tool for anatomically consistent registration between widely varying biventricular shapes. CobivecoX uses a novel algorithm to separate intervalvular bridges and assign new coordinates, including an inflow-outflow coordinate, to describe local positions in these regions uniquely and consistently. Anatomic consistency of registration was validated using curated three-dimensional biventricular shape models derived from cardiac MRI measurements in normal hearts and hearts from patients with congenital heart diseases. This new method allows the advantages of universal cardiac coordinates to be used for three-dimensional ventricular imaging data and models that include the left and right ventricular outflow tracts and valve annuli.

Regional Left Ventricular Fiber Stress Analysis for Cardiac Resynchronization Therapy Response.

Cardiac resynchronization therapy (CRT) is an effective treatment for a subgroup of heart failure (HF) patients, but more than 30% of those selected do not improve after CRT implantation. Imperfect pre-procedural criteria for patient selection and optimization are the main causes of the high non-response rate. In this study, we evaluated a novel measure for assessing CRT response. We used a computational modeling framework to calculate the regional stress of the left ventricular wall of seven CRT patients and seven healthy controls. The standard deviation of regional wall stress at the time of mitral valve closure (SD_MVC) was used to quantify dyssynchrony and compared between patients and controls and among the patients. The results show that SD_MVC is significantly lower in controls than patients and correlates with long-term response in patients, based on end-diastolic volume reduction. In contrast to our initial hypothesis, patients with lower SD_MVC respond better to therapy. The patient with the highest SD_MVC was the only non-responder in the patient cohort. The distribution of fiber stress at the beginning of the isovolumetric phase seems to correlate with the degree of response and the use of this measurement could potentially improve selection criteria for CRT implantation. Further studies with a larger cohort of patients are needed to validate these results.

Three-dimensional mechanisms of increased vulnerability to electric shocks in myocardial infarction: altered virtual electrode polarizations and conduction delay in the peri-infarct zone.

Defibrillation efficacy is decreased in infarcted hearts, but the mechanisms by which infarcted hearts are more vulnerable to electric shocks than healthy hearts remain poorly understood. The goal of this study was to provide insight into the 3D mechanisms for the increased vulnerability to electric shocks in infarcted hearts. We hypothesized that changes in virtual electrode polarizations (VEPs) and propagation delay through the peri-infarct zone (PZ) were responsible. We developed a micro anatomically detailed rabbit ventricular model with chronic myocardial infarction from magnetic resonance imaging and enriched the model with data from optical mapping experiments. We further developed a control model without the infarct. The simulation protocol involved apical pacing followed by biphasic shocks. Simulation results from both models were compared.The upper limit of vulnerability(ULV) was 8 V cm(-1) in the infarction model and 4 V cm(-1) in the control model. VEPs were less pronounced in the infarction model, providing a larger excitable area for postshock propagation but smaller transmembrane potential gradients to initiate new wavefronts. Initial post-shock transmural activation occurred at a later time in the infarction model, and the PZ served to delay propagation in subsequent beats. The presence of the PZ was found to be responsible for the increased vulnerability.

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.

Susceptibility to arrhythmia in the infarcted heart depends on myofibroblast density.

Fibroblasts are electrophysiologically quiescent in the healthy heart. Evidence suggests that remodeling following myocardial infarction may include coupling of myofibroblasts (Mfbs) among themselves and with myocytes via gap junctions. We use a magnetic resonance imaging-based, three-dimensional computational model of the chronically infarcted rabbit ventricles to characterize the arrhythmogenic substrate resulting from Mfb infiltration as a function of Mfb density. Mfbs forming gap junctions were incorporated into both infarct regions, the periinfarct zone (PZ) and the scar; six scenarios were modeled: 0%, 10%, and 30% Mfbs in the PZ, with either 80% or 0% Mfbs in the scar. Ionic current remodeling in PZ was also included. All preparations exhibited elevated resting membrane potential within and near the PZ and action potential duration shortening throughout the ventricles. The unique combination of PZ ionic current remodeling and different degrees of Mfb infiltration in the infarcted ventricles determines susceptibility to arrhythmia. At low densities, Mfbs do not alter arrhythmia propensity; the latter arises predominantly from ionic current remodeling in PZ. At intermediate densities, Mfbs cause additional action potential shortening and exacerbate arrhythmia propensity. At high densities, Mfbs protect against arrhythmia by causing resting depolarization and blocking propagation, thus overcoming the arrhythmogenic effects of PZ ionic current remodeling.

A Computational Study of the Effects of Tachycardia-Induced Remodeling on Calcium Wave Propagation in Rabbit Atrial Myocytes.

In atrial cardiomyocytes without a well-developed T-tubule system, calcium diffuses from the periphery toward the center creating a centripetal wave pattern. During atrial fibrillation, rapid activation of atrial myocytes induces complex remodeling in diffusion properties that result in failure of calcium to propagate in a fully regenerative manner toward the center; a phenomenon termed "calcium silencing." This has been observed in rabbit atrial myocytes after exposure to prolonged rapid pacing. Although experimental studies have pointed to possible mechanisms underlying calcium silencing, their individual effects and relative importance remain largely unknown. In this study we used computational modeling of the rabbit atrial cardiomyocyte to query the individual and combined effects of the proposed mechanisms leading to calcium silencing and abnormal calcium wave propagation. We employed a population of models obtained from a newly developed model of the rabbit atrial myocyte with spatial representation of intracellular calcium handling. We selected parameters in the model that represent experimentally observed cellular remodeling which have been implicated in calcium silencing, and scaled their values in the population to match experimental observations. In particular, we changed the maximum conductances of ICaL, INCX, and INaK, RyR open probability, RyR density, Serca2a density, and calcium buffering strength. We incorporated remodeling in a population of 16 models by independently varying parameters that reproduce experimentally observed cellular remodeling, and quantified the resulting alterations in calcium dynamics and wave propagation patterns. The results show a strong effect of ICaL in driving calcium silencing, with INCX, INaK, and RyR density also resulting in calcium silencing in some models. Calcium alternans was observed in some models where INCX and Serca2a density had been changed. Simultaneously incorporating changes in all remodeled parameters resulted in calcium silencing in all models, indicating the predominant role of decreasing ICaL in the population phenotype.

Optimal pacing sites in cardiac resynchronization by left ventricular activation front analysis.

Cardiac resynchronization therapy (CRT) can substantially improve dyssynchronous heart failure and reduce mortality. However, about one-third of patients who are implanted, derive no measurable benefit from CRT. Non-response may partly be due to suboptimal activation of the left ventricle (LV) caused by electrophysiological heterogeneities. The goal of this study is to investigate the performance of a newly developed method used to analyze electrical wavefront propagation in a heart model including myocardial scar and compare this to clinical benchmark studies. We used computational models to measure the maximum activation front (MAF) in the LV during different pacing scenarios. Different heart geometries and scars were created based on cardiac MR images of three patients. The right ventricle (RV) was paced from the apex and the LV was paced from 12 different sites, single site, dual-site and triple site. Our results showed that for single LV site pacing, the pacing site with the largest MAF corresponded with the latest activated regions of the LV demonstrated during RV pacing, which also agrees with previous markers used for predicting optimal single-site pacing location. We then demonstrated the utility of MAF in predicting optimal electrode placements in more complex scenarios including scar and multi-site LV pacing. This study demonstrates the potential value of computational simulations in understanding and planning CRT.

Combined In-silico and Machine Learning Approaches Toward Predicting Arrhythmic Risk in Post-infarction Patients.

Background: Remodeling due to myocardial infarction (MI) significantly increases patient arrhythmic risk. Simulations using patient-specific models have shown promise in predicting personalized risk for arrhythmia. However, these are computationally- and time- intensive, hindering translation to clinical practice. Classical machine learning (ML) algorithms (such as K-nearest neighbors, Gaussian support vector machines, and decision trees) as well as neural network techniques, shown to increase prediction accuracy, can be used to predict occurrence of arrhythmia as predicted by simulations based solely on infarct and ventricular geometry. We present an initial combined image-based patient-specific in silico and machine learning methodology to assess risk for dangerous arrhythmia in post-infarct patients. Furthermore, we aim to demonstrate that simulation-supported data augmentation improves prediction models, combining patient data, computational simulation, and advanced statistical modeling, improving overall accuracy for arrhythmia risk assessment. Methods: MRI-based computational models were constructed from 30 patients 5 days post-MI (the "baseline" population). In order to assess the utility biophysical model-supported data augmentation for improving arrhythmia prediction, we augmented the virtual baseline patient population. Each patient ventricular and ischemic geometry in the baseline population was used to create a subfamily of geometric models, resulting in an expanded set of patient models (the "augmented" population). Arrhythmia induction was attempted via programmed stimulation at 17 sites for each virtual patient corresponding to AHA LV segments and simulation outcome, "arrhythmia," or "no-arrhythmia," were used as ground truth for subsequent statistical prediction (machine learning, ML) models. For each patient geometric model, we measured and used choice data features: the myocardial volume and ischemic volume, as well as the segment-specific myocardial volume and ischemia percentage, as input to ML algorithms. For classical ML techniques (ML), we trained k-nearest neighbors, support vector machine, logistic regression, xgboost, and decision tree models to predict the simulation outcome from these geometric features alone. To explore neural network ML techniques, we trained both a three - and a four-hidden layer multilayer perceptron feed forward neural networks (NN), again predicting simulation outcomes from these geometric features alone. ML and NN models were trained on 70% of randomly selected segments and the remaining 30% was used for validation for both baseline and augmented populations. Results: Stimulation in the baseline population (30 patient models) resulted in reentry in 21.8% of sites tested; in the augmented population (129 total patient models) reentry occurred in 13.0% of sites tested. ML and NN models ranged in mean accuracy from 0.83 to 0.86 for the baseline population, improving to 0.88 to 0.89 in all cases. Conclusion: Machine learning techniques, combined with patient-specific, image-based computational simulations, can provide key clinical insights with high accuracy rapidly and efficiently. In the case of sparse or missing patient data, simulation-supported data augmentation can be employed to further improve predictive results for patient benefit. This work paves the way for using data-driven simulations for prediction of dangerous arrhythmia in MI patients.

A Novel Computational Model of the Rabbit Atrial Cardiomyocyte With Spatial Calcium Dynamics.

Models of cardiac electrophysiology are widely used to supplement experimental results and to provide insight into mechanisms of cardiac function and pathology. The rabbit has been a particularly important animal model for studying mechanisms of atrial pathophysiology and atrial fibrillation, which has motivated the development of models for the rabbit atrial cardiomyocyte electrophysiology. Previously developed models include detailed representations of membrane currents and intracellular ionic concentrations, but these so-called "common-pool" models lack a spatially distributed description of the calcium handling system, which reflects the detailed ultrastructure likely found in cells in vivo. Because of the less well-developed T-tubular system in atrial compared to ventricular cardiomyocytes, spatial gradients in intracellular calcium concentrations may play a more significant role in atrial cardiomyocyte pathophysiology, rendering common-pool models less suitable for investigating underlying electrophysiological mechanisms. In this study, we developed a novel computational model of the rabbit atrial cardiomyocyte incorporating detailed compartmentalization of intracellular calcium dynamics, in addition to a description of membrane currents and intracellular processes. The spatial representation of calcium was based on dividing the intracellular space into eighteen different compartments in the transversal direction, each with separate systems for internal calcium storage and release, and tracking ionic fluxes between compartments in addition to the dynamics driven by membrane currents and calcium release. The model was parameterized employing a population-of-models approach using experimental data from different sources. The parameterization of this novel model resulted in a reduced population of models with inherent variability in calcium dynamics and electrophysiological properties, all of which fall within the range of observed experimental values. As such, the population of models may represent natural variability in cardiomyocyte electrophysiology or inherent uncertainty in the underlying experimental data. The ionic model population was also able to reproduce the U-shaped waveform observed in line-scans of triggered calcium waves in atrial cardiomyocytes, characteristic of the absence of T-tubules, resulting in a centripetal calcium wave due to subcellular calcium diffusion. This novel spatial model of the rabbit atrial cardiomyocyte can be used to integrate experimental findings, offering the potential to enhance our understanding of the pathophysiological role of calcium-handling abnormalities under diseased conditions, such as atrial fibrillation.

Embedding high-dimensional Bayesian optimization via generative modeling: Parameter personalization of cardiac electrophysiological models.

The estimation of patient-specific tissue properties in the form of model parameters is important for personalized physiological models. Because tissue properties are spatially varying across the underlying geometrical model, it presents a significant challenge of high-dimensional (HD) optimization at the presence of limited measurement data. A common solution to reduce the dimension of the parameter space is to explicitly partition the geometrical mesh. In this paper, we present a novel concept that uses a generative variational auto-encoder (VAE) to embed HD Bayesian optimization into a low-dimensional (LD) latent space that represents the generative code of HD parameters. We further utilize VAE-encoded knowledge about the generative code to guide the exploration of the search space. The presented method is applied to estimating tissue excitability in a cardiac electrophysiological model in a range of synthetic and real-data experiments, through which we demonstrate its improved accuracy and substantially reduced computational cost in comparison to existing methods that rely on geometry-based reduction of the HD parameter space.

Multisite pacing and myocardial scars: a computational study.

Cardiac resynchronization therapy (CRT) is a frequently effective treatment modality for dyssynchronous heart failure, however, 30% of patients do not respond, usually due to suboptimal activation of the left ventricle (LV). Multisite pacing (MSP) may increase the response rate, but its effect in the presence of myocardial scars is not fully understood. We use a computational model to study the outcome of MSP in an LV with scars in two different locations and of two different sizes. The LV was stimulated from anterior, posterior and lateral locations individually and in pairs, while a septal stimulation site represented right ventricular (RV) pacing. Intraventricular pressures were measured, and outcomes evaluated in terms of maximum LV pressure gradient (dP/dtmax)- change compared to isolated RV pacing. The best result obtained using various LV pacing locations included a combination of sites remote from scars and the septum. The highest dP/dtmax increase was achieved, regardless of scar size, using MSP with one pacing site located on the LV free wall opposite to the scar and one site opposite to the septum. These in silico modelling results suggest that making placement of pacing electrodes dependent on location of scarring, may alter acute haemodynamics and that such modelling may contribute to future CRT optimization.

Towards predictive modelling of the electrophysiology of the heart.

The simulation of cardiac electrical function is an example of a successful integrative multiscale modelling approach that is directly relevant to human disease. Today we stand at the threshold of a new era, in which anatomically detailed, tomographically reconstructed models are being developed that integrate from the ion channel to the electromechanical interactions in the intact heart. Such models hold high promise for interpretation of clinical and physiological measurements, for improving the basic understanding of the mechanisms of dysfunction in disease, such as arrhythmias, myocardial ischaemia and heart failure, and for the development and performance optimization of medical devices. The goal of this article is to present an overview of current state-of-art advances towards predictive computational modelling of the heart as developed recently by the authors of this article. We first outline the methodology for constructing electrophysiological models of the heart. We then provide three examples that demonstrate the use of these models, focusing specifically on the mechanisms for arrhythmogenesis and defibrillation in the heart. These include: (1) uncovering the role of ventricular structure in defibrillation; (2) examining the contribution of Purkinje fibres to the failure of the shock; and (3) using magnetic resonance imaging reconstructed heart models to investigate the re-entrant circuits formed in the presence of an infarct scar.

Optimal contrast-enhanced MRI image thresholding for accurate prediction of ventricular tachycardia using ex-vivo high resolution models.

Patient specific models created from contrast-enhanced (i.e. late-gadolinium, LGE) MRI images can be used for prediction of reentry location and clinical ablation planning. However, there is still a need for direct and systematic comparison between characteristics of ventricular tachycardia (VT) morphologies predicted in computational models and those acquired in clinical or experimental protocols. In this study, we aimed to: 1) assess the differences in VT morphologies predicted by modeling and recorded in experiments in terms of patterns and location of reentries, earliest and latest activation sites, and cycle lengths; and 2) define the optimal range of infarct tissue threshold values which provide best match between simulation and experimental results. To achieve these goals, we utilized LGE-MRI images from 4 swine hearts with inducible monomorphic VT. The images were segmented to identify non-infarcted myocardium, semi viable gray zone (GZ), and core scar based on pixel intensity. Several models were reconstructed from each LGE-MRI scan, with voxels of intensity between that of non-infarcted myocardium and 20-50% of the maximum intensity (in 10% increments) in the infarct region classified as GZ. VT induction was simulated in each model. Our simulation results showed that using GZ intensity thresholds of 20% or 30% resulted in the best match of simulated propagation patterns and reentry locations with those from the experiment. Overall, we matched 70% (7/10) morphologies for all the hearts. Our simulation shows that MRI-based computational models of hearts with myocardial infarction can accurately reproduce the majority of experimentally recorded post-infarction VTs.

Computational Modeling of Electrophysiology and Pharmacotherapy of Atrial Fibrillation: Recent Advances and Future Challenges.

The pathophysiology of atrial fibrillation (AF) is broad, with components related to the unique and diverse cellular electrophysiology of atrial myocytes, structural complexity, and heterogeneity of atrial tissue, and pronounced disease-associated remodeling of both cells and tissue. A major challenge for rational design of AF therapy, particularly pharmacotherapy, is integrating these multiscale characteristics to identify approaches that are both efficacious and independent of ventricular contraindications. Computational modeling has long been touted as a basis for achieving such integration in a rapid, economical, and scalable manner. However, computational pipelines for AF-specific drug screening are in their infancy, and while the field is progressing quite rapidly, major challenges remain before computational approaches can fill the role of workhorse in rational design of AF pharmacotherapies. In this review, we briefly detail the unique aspects of AF pathophysiology that determine requirements for compounds targeting AF rhythm control, with emphasis on delimiting mechanisms that promote AF triggers from those providing substrate or supporting reentry. We then describe modeling approaches that have been used to assess the outcomes of drugs acting on established AF targets, as well as on novel promising targets including the ultra-rapidly activating delayed rectifier potassium current, the acetylcholine-activated potassium current and the small conductance calcium-activated potassium channel. Finally, we describe how heterogeneity and variability are being incorporated into AF-specific models, and how these approaches are yielding novel insights into the basic physiology of disease, as well as aiding identification of the important molecular players in the complex AF etiology.

Electromechanical Model to Predict Cardiac Resynchronization Therapy.

Cardiac resynchronization therapy (CRT) can substantially improve dyssynchronous heart failure and reduce mortality. However, one-third of the CRT patients derive no measurable benefit from CRT, due to suboptimal placement of the left ventricular (LV) lead. We introduce a pipeline for improved CRT-therapy by creating an electromechanical model using patient-specific geometric parameters allowing individualization of therapy. The model successfully mimics expected changes when variables for tension, stiffness, and conduction are entered. Changing LV pacing site had a notable effect on maximum pressure gradient (dP/dtmax) in the presence of cardiac scarring, causing non-uniform excitation propagation through the LV. Tailoring CRT to the individual requires simulations with patient-specific biventricular meshes including cardiac geometry and conductivity properties.

Quantifying the uncertainty in model parameters using Gaussian process-based Markov chain Monte Carlo in cardiac electrophysiology.

Model personalization requires the estimation of patient-specific tissue properties in the form of model parameters from indirect and sparse measurement data. Moreover, a low-dimensional representation of the parameter space is needed, which often has a limited ability to reveal the underlying tissue heterogeneity. As a result, significant uncertainty can be associated with the estimated values of the model parameters which, if left unquantified, will lead to unknown variability in model outputs that will hinder their reliable clinical adoption. Probabilistic estimation of model parameters, however, remains an unresolved challenge. Direct Markov Chain Monte Carlo (MCMC) sampling of the posterior distribution function (pdf) of the parameters is infeasible because it involves repeated evaluations of the computationally expensive simulation model. To accelerate this inference, one popular approach is to construct a computationally efficient surrogate and sample from this approximation. However, by sampling from an approximation, efficiency is gained at the expense of sampling accuracy. In this paper, we address this issue by integrating surrogate modeling of the posterior pdf into accelerating the Metropolis-Hastings (MH) sampling of the exact posterior pdf. It is achieved by two main components: (1) construction of a Gaussian process (GP) surrogate of the exact posterior pdf by actively selecting training points that allow for a good global approximation accuracy with a focus on the regions of high posterior probability; and (2) use of the GP surrogate to improve the proposal distribution in MH sampling, in order to improve the acceptance rate. The presented framework is evaluated in its estimation of the local tissue excitability of a cardiac electrophysiological model in both synthetic data experiments and real data experiments. In addition, the obtained posterior distributions of model parameters are interpreted in relation to the factors contributing to parameter uncertainty, including different low-dimensional representations of the parameter space, parameter non-identifiability, and parameter correlations.

Personalized virtual-heart technology for guiding the ablation of infarct-related ventricular tachycardia.

Ventricular tachycardia (VT), which can lead to sudden cardiac death, occurs frequently in patients with myocardial infarction. Catheter-based radiofrequency ablation of cardiac tissue has achieved only modest efficacy, owing to the inaccurate identification of ablation targets by current electrical mapping techniques, which can lead to extensive lesions and to a prolonged, poorly tolerated procedure. Here we show that personalized virtual-heart technology based on cardiac imaging and computational modelling can identify optimal infarct-related VT ablation targets in retrospective animal (5 swine) and human studies (21 patients) and in a prospective feasibility study (5 patients). We first assessed in retrospective studies (one of which included a proportion of clinical images with artifacts) the capability of the technology to determine the minimum-size ablation targets for eradicating all VTs. In the prospective study, VT sites predicted by the technology were targeted directly, without relying on prior electrical mapping. The approach could improve infarct-related VT ablation guidance, where accurate identification of patient-specific optimal targets could be achieved on a personalized virtual heart prior to the clinical procedure.