Cell to whole organ global sensitivity analysis on a four-chamber heart electromechanics model using Gaussian processes emulators.

Cardiac pump function arises from a series of highly orchestrated events across multiple scales. Computational electromechanics can encode these events in physics-constrained models. However, the large number of parameters in these models has made the systematic study of the link between cellular, tissue, and organ scale parameters to whole heart physiology challenging. A patient-specific anatomical heart model, or digital twin, was created. Cellular ionic dynamics and contraction were simulated with the Courtemanche-Land and the ToR-ORd-Land models for the atria and the ventricles, respectively. Whole heart contraction was coupled with the circulatory system, simulated with CircAdapt, while accounting for the effect of the pericardium on cardiac motion. The four-chamber electromechanics framework resulted in 117 parameters of interest. The model was broken into five hierarchical sub-models: tissue electrophysiology, ToR-ORd-Land model, Courtemanche-Land model, passive mechanics and CircAdapt. For each sub-model, we trained Gaussian processes emulators (GPEs) that were then used to perform a global sensitivity analysis (GSA) to retain parameters explaining 90% of the total sensitivity for subsequent analysis. We identified 45 out of 117 parameters that were important for whole heart function. We performed a GSA over these 45 parameters and identified the systemic and pulmonary peripheral resistance as being critical parameters for a wide range of volumetric and hemodynamic cardiac indexes across all four chambers. We have shown that GPEs provide a robust method for mapping between cellular properties and clinical measurements. This could be applied to identify parameters that can be calibrated in patient-specific models or digital twins, and to link cellular function to clinical indexes.

A computational study on the influence of antegrade accessory pathway location on the 12-lead electrocardiogram in Wolff-Parkinson-White syndrome.

Wolff-Parkinson-White syndrome is a cardiovascular disease characterized by abnormal atrio-ventricular conduction facilitated by accessory pathways (APs). Invasive catheter ablation of the AP represents the primary treatment modality. Accurate localization of APs is crucial for successful ablation outcomes, but current diagnostic algorithms based on the 12 lead electrocardiogram (ECG) often struggle with precise determination of AP locations. In order to gain insight into the mechanisms underlying localization failures observed in current diagnostic algorithms, we employ a virtual cardiac model to elucidate the relationship between AP location and ECG morphology. We first introduce a cardiac model of electrophysiology that was specifically tailored to represent antegrade APs in the form of a short atrio-ventricular bypass tract. Locations of antegrade APs were then automatically swept across both ventricles in the virtual model to generate a synthetic ECG database consisting of 9271 signals. Regional grouping of antegrade APs revealed overarching morphological patterns originating from diverse cardiac regions. We then applied variance-based sensitivity analysis relying on polynomial chaos expansion on the ECG database to mathematically quantify how variation in AP location and timing relates to morphological variation in the 12 lead ECG. We utilized our mechanistic virtual model to showcase limitations of AP localization using standard ECG-based algorithms and provide mechanistic explanations through exemplary simulations. Our findings highlight the potential of virtual models of cardiac electrophysiology not only to deepen our understanding of the underlying mechanisms of Wolff-Parkinson-White syndrome but also to potentially enhance the diagnostic accuracy of ECG-based algorithms and facilitate personalized treatment planning.

Effect of scar and His-Purkinje and myocardium conduction on response to conduction system pacing.

INTRODUCTION: Conduction system pacing (CSP), in the form of His bundle pacing (HBP) or left bundle branch pacing (LBBP), is emerging as a valuable cardiac resynchronization therapy (CRT) delivery method. However, patient selection and therapy personalization for CSP delivery remain poorly characterized. We aim to compare pacing-induced electrical synchrony during CRT, HBP, LBBP, HBP with left ventricular (LV) epicardial lead (His-optimized CRT [HOT-CRT]), and LBBP with LV epicardial lead (LBBP-optimized CRT [LOT-CRT]) in patients with different conduction disease presentations using computational modeling. METHODS: We simulated ventricular activation on 24 four-chamber heart geometries, including His-Purkinje systems with proximal left bundle branch block (LBBB). We simulated septal scar, LV lateral wall scar, and mild and severe myocardium and LV His-Purkinje system conduction disease by decreasing the conduction velocity (CV) down to 70% and 35% of the healthy CV. Electrical synchrony was measured by the shortest interval to activate 90% of the ventricles (90% of biventricular activation time [BIVAT-90]). RESULTS: Severe LV His-Purkinje conduction disease favored CRT (BIVAT-90: HBP 101.5 ± 7.8 ms vs. CRT 93.0 ± 8.9 ms, p < .05), with additional electrical synchrony induced by HOT-CRT (87.6 ± 6.7 ms, p < .05) and LOT-CRT (73.9 ± 7.6 ms, p < .05). Patients with slow myocardium CV benefit more from CSP compared to CRT (BIVAT-90: CRT 134.5 ± 24.1 ms; HBP 97.1 ± 9.9 ms, p < .01; LBBP: 101.5 ± 10.7 ms, p < .01). Septal but not lateral wall scar made CSP ineffective, while CRT was able to resynchronize the ventricles in the presence of septal scar (BIVAT-90: baseline 119.1 ± 10.8 ms vs. CRT 85.1 ± 14.9 ms, p < .01). CONCLUSION: Severe LV His-Purkinje conduction disease attenuates the benefits of CSP, with additional improvements achieved with HOT-CRT and LOT-CRT. Septal but not lateral wall scars make CSP ineffective.

Modelling the interaction between stem cells derived cardiomyocytes patches and host myocardium to aid non-arrhythmic engineered heart tissue design.

Application of epicardial patches constructed from human-induced pluripotent stem cell- derived cardiomyocytes (hiPSC-CMs) has been proposed as a long-term therapy to treat scarred hearts post myocardial infarction (MI). Understanding electrical interaction between engineered heart tissue patches (EHT) and host myocardium represents a key step toward a successful patch engraftment. EHT retain different electrical properties with respect to the host heart tissue due to the hiPSC-CMs immature phenotype, which may lead to increased arrhythmia risk. We developed a modelling framework to examine the influence of patch design on electrical activation at the engraftment site. We performed an in silico investigation of different patch design approaches to restore pre-MI activation properties and evaluated the associated arrhythmic risk. We developed an in silico cardiac electrophysiology model of a transmural cross section of host myocardium. The model featured an infarct region, an epicardial patch spanning the infarct region and a bath region. The patch is modelled as a layer of hiPSC-CM, combined with a layer of conductive polymer (CP). Tissue and patch geometrical dimensions and conductivities were incorporated through 10 modifiable model parameters. We validated our model against 4 independent experimental studies and showed that it can qualitatively reproduce their findings. We performed a global sensitivity analysis (GSA) to isolate the most important parameters, showing that the stimulus propagation is mainly governed by the scar depth, radius and conductivity when the scar is not transmural, and by the EHT patch conductivity when the scar is transmural. We assessed the relevance of small animal studies to humans by comparing simulations of rat, rabbit and human myocardium. We found that stimulus propagation paths and GSA sensitivity indices are consistent across species. We explored which EHT design variables have the potential to restore physiological propagation. Simulations predict that increasing EHT conductivity from 0.28 to 1-1.1 S/m recovered physiological activation in rat, rabbit and human. Finally, we assessed arrhythmia risk related to increasing EHT conductivity and tested increasing the EHT Na+ channel density as an alternative strategy to match healthy activation. Our results revealed a greater arrhythmia risk linked to increased EHT conductivity compared to increased Na+ channel density. We demonstrated that our modeling framework could capture the interaction between host and EHT patches observed in in vitro experiments. We showed that large (patch and tissue dimensions) and small (cardiac myocyte electrophysiology) scale differences between small animals and humans do not alter EHT patch effect on infarcted tissue. Our model revealed that only when the scar is transmural do EHT properties impact activation times and isolated the EHT conductivity as the main parameter influencing propagation. We predicted that restoring physiological activation by tuning EHT conductivity is possible but may promote arrhythmic behavior. Finally, our model suggests that acting on hiPSC-CMs low action potential upstroke velocity and lack of IK1 may restore pre-MI activation while not promoting arrhythmia.

Correction: Linking statistical shape models and simulated function in the healthy adult human heart.

[This corrects the article DOI: 10.1371/journal.pcbi.1008851.].

Arrhythmogenic vulnerability of re-entrant pathways in post-infarct ventricular tachycardia assessed by advanced computational modelling.

AIMS: Substrate assessment of scar-mediated ventricular tachycardia (VT) is frequently performed using late gadolinium enhancement (LGE) images. Although this provides structural information about critical pathways through the scar, assessing the vulnerability of these pathways for sustaining VT is not possible with imaging alone.This study evaluated the performance of a novel automated re-entrant pathway finding algorithm to non-invasively predict VT circuit and inducibility. METHODS: Twenty post-infarct VT-ablation patients were included for retrospective analysis. Commercially available software (ADAS3D left ventricular) was used to generate scar maps from 2D-LGE images using the default 40-60 pixel-signal-intensity (PSI) threshold. In addition, algorithm sensitivity for altered thresholds was explored using PSI 45-55, 35-65, and 30-70. Simulations were performed on the Virtual Induction and Treatment of Arrhythmias (VITA) framework to identify potential sites of block and assess their vulnerability depending on the automatically computed round-trip-time (RTT). Metrics, indicative of substrate complexity, were correlated with VT-recurrence during follow-up. RESULTS: Total VTs (85 ± 43 vs. 42 ± 27) and unique VTs (9 ± 4 vs. 5 ± 4) were significantly higher in patients with- compared to patients without recurrence, and were predictive of recurrence with area under the curve of 0.820 and 0.770, respectively. VITA was robust to scar threshold variations with no significant impact on total and unique VTs, and mean RTT between the four models. Simulation metrics derived from PSI 45-55 model had the highest number of parameters predictive for post-ablation VT-recurrence. CONCLUSION: Advanced computational metrics can non-invasively and robustly assess VT substrate complexity, which may aid personalized clinical planning and decision-making in the treatment of post-infarction VT.

Non-invasive localization of post-infarct ventricular tachycardia exit sites to guide ablation planning: a computational deep learning platform utilizing the 12-lead electrocardiogram and intracardiac electrograms from implanted devices.

AIMS: Existing strategies that identify post-infarct ventricular tachycardia (VT) ablation target either employ invasive electrophysiological (EP) mapping or non-invasive modalities utilizing the electrocardiogram (ECG). Their success relies on localizing sites critical to the maintenance of the clinical arrhythmia, not always recorded on the 12-lead ECG. Targeting the clinical VT by utilizing electrograms (EGM) recordings stored in implanted devices may aid ablation planning, enhancing safety and speed and potentially reducing the need of VT induction. In this context, we aim to develop a non-invasive computational-deep learning (DL) platform to localize VT exit sites from surface ECGs and implanted device intracardiac EGMs. METHODS AND RESULTS: A library of ECGs and EGMs from simulated paced beats and representative post-infarct VTs was generated across five torso models. Traces were used to train DL algorithms to localize VT sites of earliest systolic activation; first tested on simulated data and then on a clinically induced VT to show applicability of our platform in clinical settings. Localization performance was estimated via localization errors (LEs) against known VT exit sites from simulations or clinical ablation targets. Surface ECGs successfully localized post-infarct VTs from simulated data with mean LE = 9.61 ± 2.61 mm across torsos. VT localization was successfully achieved from implanted device intracardiac EGMs with mean LE = 13.10 ± 2.36 mm. Finally, the clinically induced VT localization was in agreement with the clinical ablation volume. CONCLUSION: The proposed framework may be utilized for direct localization of post-infarct VTs from surface ECGs and/or implanted device EGMs, or in conjunction with efficient, patient-specific modelling, enhancing safety and speed of ablation planning.

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.

Linking statistical shape models and simulated function in the healthy adult human heart.

Cardiac anatomy plays a crucial role in determining cardiac function. However, there is a poor understanding of how specific and localised anatomical changes affect different cardiac functional outputs. In this work, we test the hypothesis that in a statistical shape model (SSM), the modes that are most relevant for describing anatomy are also most important for determining the output of cardiac electromechanics simulations. We made patient-specific four-chamber heart meshes (n = 20) from cardiac CT images in asymptomatic subjects and created a SSM from 19 cases. Nine modes captured 90% of the anatomical variation in the SSM. Functional simulation outputs correlated best with modes 2, 3 and 9 on average (R = 0.49 ± 0.17, 0.37 ± 0.23 and 0.34 ± 0.17 respectively). We performed a global sensitivity analysis to identify the different modes responsible for different simulated electrical and mechanical measures of cardiac function. Modes 2 and 9 were the most important for determining simulated left ventricular mechanics and pressure-derived phenotypes. Mode 2 explained 28.56 ± 16.48% and 25.5 ± 20.85, and mode 9 explained 12.1 ± 8.74% and 13.54 ± 16.91% of the variances of mechanics and pressure-derived phenotypes, respectively. Electrophysiological biomarkers were explained by the interaction of 3 ± 1 modes. In the healthy adult human heart, shape modes that explain large portions of anatomical variance do not explain equivalent levels of electromechanical functional variation. As a result, in cardiac models, representing patient anatomy using a limited number of modes of anatomical variation can cause a loss in accuracy of simulated electromechanical function.

An accurate, robust, and efficient finite element framework with applications to anisotropic, nearly and fully incompressible elasticity.

Fiber-reinforced soft biological tissues are typically modeled as hyperelastic, anisotropic, and nearly incompressible materials. To enforce incompressibility a multiplicative split of the deformation gradient into a volumetric and an isochoric part is a very common approach. However, the finite element analysis of such problems often suffers from severe volumetric locking effects and numerical instabilities. In this paper, we present novel methods to overcome volumetric locking phenomena for using stabilized P1-P1 elements. We introduce different stabilization techniques and demonstrate the high robustness and computational efficiency of the chosen methods. In two benchmark problems from the literature as well as an advanced application to cardiac electromechanics, we compare the approach to standard linear elements and show the accuracy and versatility of the methods to simulate anisotropic, nearly and fully incompressible materials. We demonstrate the potential of this numerical framework to accelerate accurate simulations of biological tissues to the extent of enabling patient-specific parameterization studies, where numerous forward simulations are required.

Using machine learning to identify local cellular properties that support re-entrant activation in patient-specific models of atrial fibrillation.

AIMS: Atrial fibrillation (AF) is sustained by re-entrant activation patterns. Ablation strategies have been proposed that target regions of tissue that may support re-entrant activation patterns. We aimed to characterize the tissue properties associated with regions that tether re-entrant activation patterns in a validated virtual patient cohort. METHODS AND RESULTS: Atrial fibrillation patient-specific models (seven paroxysmal and three persistent) were generated and validated against local activation time (LAT) measurements during an S1-S2 pacing protocol from the coronary sinus and high right atrium, respectively. Atrial models were stimulated with burst pacing from three locations in the proximity of each pulmonary vein to initiate re-entrant activation patterns. Five atria exhibited sustained activation patterns for at least 80 s. Models with short maximum action potential durations (APDs) were associated with sustained activation. Phase singularities were mapped across the atria sustained activation patterns. Regions with a low maximum conduction velocity (CV) were associated with tethering of phase singularities. A support vector machine (SVM) was trained on maximum local conduction velocity and action potential duration to identify regions that tether phase singularities. The SVM identified regions of tissue that could support tethering with 91% accuracy. This accuracy increased to 95% when the SVM was also trained on surface area. CONCLUSION: In a virtual patient cohort, local tissue properties, that can be measured (CV) or estimated (APD; using effective refractory period as a surrogate) clinically, identified regions of tissue that tether phase singularities. Combing CV and APD with atrial surface area further improved the accuracy in identifying regions that tether phase singularities.

Automatic reconstruction of the left atrium activation from sparse intracardiac contact recordings by inverse estimate of fibre structure and anisotropic conduction in a patient-specific model.

AIMS: Electric conduction in the atria is direction-dependent, being faster in fibre direction, and possibly heterogeneous due to structural remodelling. Intracardiac recordings of atrial activation may convey such information, but only with high-quality data. The aim of this study was to apply a patient-specific approach to enable such assessment even when data are scarce, noisy, and incomplete. METHODS AND RESULTS: Contact intracardiac recordings in the left atrium from nine patients who underwent ablation therapy were collected before pulmonary veins isolation and retrospectively included in the study. The Personalized Inverse Eikonal Model from cardiac Electro-Anatomical Maps (PIEMAP), previously developed, has been used to reconstruct the conductivity tensor from sparse recordings of the activation. Regional fibre direction and conduction velocity were estimated from the fitted conductivity tensor and extensively cross-validated by clustered and sparse data removal. Electrical conductivity was successfully reconstructed in all patients. Cross-validation with respect to the measurements was excellent in seven patients (Pearson correlation r > 0.93) and modest in two patients (r = 0.62 and r = 0.74). Bland-Altman analysis showed a neglectable bias with respect to the measurements and the limit-of-agreement at -22.2 and 23.0 ms. Conduction velocity in the fibre direction was 82 ± 25 cm/s, whereas cross-fibre velocity was 46 ± 7 cm/s. Anisotropic ratio was 1.91±0.16. No significant inter-patient variability was observed. Personalized Inverse Eikonal model from cardiac Electro-Anatomical Maps correctly predicted activation times in late regions in all patients (r = 0.88) and was robust to a sparser dataset (r = 0.95). CONCLUSION: Personalized Inverse Eikonal model from cardiac Electro-Anatomical Maps offers a novel approach to extrapolate the activation in unmapped regions and to assess conduction properties of the atria. It could be seamlessly integrated into existing electro-anatomic mapping systems. Personalized Inverse Eikonal model from cardiac Electro-Anatomical Maps also enables personalization of cardiac electrophysiology models.

Combining endocardial mapping and electrocardiographic imaging (ECGI) for improving PVC localization: A feasibility study.

INTRODUCTION: Accurate reconstruction of cardiac activation wavefronts is crucial for clinical diagnosis, management, and treatment of cardiac arrhythmias. Furthermore, reconstruction of activation profiles within the intramural myocardium has long been impossible because electrical mapping was only performed on the endocardial surface. Recent advancements in electrocardiographic imaging (ECGI) have made endocardial and epicardial activation mapping possible. We propose a novel approach to use both endocardial and epicardial mapping in a combined approach to reconstruct intramural activation times. OBJECTIVE: To implement and validate a combined epicardial/endocardial intramural activation time reconstruction technique. METHODS: We used 11 simulations of ventricular activation paced from sites throughout myocardial wall and extracted endocardial and epicardial activation maps at approximate clinical resolution. From these maps, we interpolated the activation times through the myocardium using thin-plate-spline radial basis functions. We evaluated activation time reconstruction accuracy using root-mean-squared error (RMSE) of activation times and the percent of nodes within 1 ms of the ground truth. RESULTS: Reconstructed intramural activation times showed an RMSE and percentage of nodes within 1 ms of the ground truth simulations of 3 ms and 70%, respectively. In the worst case, the RMSE and percentage of nodes were 4 ms and 60%, respectively. CONCLUSION: We showed that a simple, yet effective combination of clinical endocardial and epicardial activation maps can accurately reconstruct intramural wavefronts. Furthermore, we showed that this approach provided robust reconstructions across multiple intramural stimulation sites.

Quantifying the spatiotemporal influence of acute myocardial ischemia on volumetric conduction velocity.

INTRODUCTION: Acute myocardial ischemia occurs when coronary perfusion to the heart is inadequate, which can perturb the highly organized electrical activation of the heart and can result in adverse cardiac events including sudden cardiac death. Ischemia is known to influence the ST and repolarization phases of the ECG, but it also has a marked effect on propagation (QRS); however, studies investigating propagation during ischemia have been limited. METHODS: We estimated conduction velocity (CV) and ischemic stress prior to and throughout 20 episodes of experimentally induced ischemia in order to quantify the progression and correlation of volumetric conduction changes during ischemia. To estimate volumetric CV, we 1) reconstructed the activation wavefront; 2) calculated the elementwise gradient to approximate propagation direction; and 3) estimated conduction speed (CS) with an inverse-gradient technique. RESULTS: We found that acute ischemia induces significant conduction slowing, reducing the global median speed by 20 cm/s. We observed a biphasic response in CS (acceleration then deceleration) early in some ischemic episodes. Furthermore, we noted a high temporal correlation between ST-segment changes and CS slowing; however, when comparing these changes over space, we found only moderate correlation (corr. = 0.60). DISCUSSION: This study is the first to report volumetric CS changes (acceleration and slowing) during episodes of acute ischemia in the whole heart. We showed that while CS changes progress in a similar time course to ischemic stress (measured by ST-segment shifts), the spatial overlap is complex and variable, showing extreme conduction slowing both in and around regions experiencing severe ischemia.

A computationally efficient physiologically comprehensive 3D-0D closed-loop model of the heart and circulation.

Computer models of cardiac electro-mechanics (EM) show promise as an effective means for the quantitative analysis of clinical data and, potentially, for predicting therapeutic responses. To realize such advanced applications methodological key challenges must be addressed. Enhanced computational efficiency and robustness is crucial to facilitate, within tractable time frames, model personalization, the simulation of prolonged observation periods under a broad range of conditions, and physiological completeness encompassing therapy-relevant mechanisms is needed to endow models with predictive capabilities beyond the mere replication of observations. Here, we introduce a universal feature-complete cardiac EM modeling framework that builds on a flexible method for coupling a 3D model of bi-ventricular EM to the physiologically comprehensive 0D CircAdapt model representing atrial mechanics and closed-loop circulation. A detailed mathematical description is given and efficiency, robustness, and accuracy of numerical scheme and solver implementation are evaluated. After parameterization and stabilization of the coupled 3D-0D model to a limit cycle under baseline conditions, the model's ability to replicate physiological behaviors is demonstrated, by simulating the transient response to alterations in loading conditions and contractility, as induced by experimental protocols used for assessing systolic and diastolic ventricular properties. Mechanistic completeness and computational efficiency of this novel model render advanced applications geared towards predicting acute outcomes of EM therapies feasible.

Scar shape analysis and simulated electrical instabilities in a non-ischemic dilated cardiomyopathy patient cohort.

This paper presents a morphological analysis of fibrotic scarring in non-ischemic dilated cardiomyopathy, and its relationship to electrical instabilities which underlie reentrant arrhythmias. Two dimensional electrophysiological simulation models were constructed from a set of 699 late gadolinium enhanced cardiac magnetic resonance images originating from 157 patients. Areas of late gadolinium enhancement (LGE) in each image were assigned one of 10 possible microstructures, which modelled the details of fibrotic scarring an order of magnitude below the MRI scan resolution. A simulated programmed electrical stimulation protocol tested each model for the possibility of generating either a transmural block or a transmural reentry. The outcomes of the simulations were compared against morphological LGE features extracted from the images. Models which blocked or reentered, grouped by microstructure, were significantly different from one another in myocardial-LGE interface length, number of components and entropy, but not in relative area and transmurality. With an unknown microstructure, transmurality alone was the best predictor of block, whereas a combination of interface length, transmurality and number of components was the best predictor of reentry in linear discriminant analysis.

Personalization of electro-mechanical models of the pressure-overloaded left ventricle: fitting of Windkessel-type afterload models.

Computer models of left ventricular (LV) electro-mechanics (EM) show promise as a tool for assessing the impact of increased afterload upon LV performance. However, the identification of unique afterload model parameters and the personalization of EM LV models remains challenging due to significant clinical input uncertainties. Here, we personalized a virtual cohort of N = 17 EM LV models under pressure overload conditions. A global-local optimizer was developed to uniquely identify parameters of a three-element Windkessel (Wk3) afterload model. The sensitivity of Wk3 parameters to input uncertainty and of the EM LV model to Wk3 parameter uncertainty was analysed. The optimizer uniquely identified Wk3 parameters, and outputs of the personalized EM LV models showed close agreement with clinical data in all cases. Sensitivity analysis revealed a strong dependence of Wk3 parameters on input uncertainty. However, this had limited impact on outputs of EM LV models. A unique identification of Wk3 parameters from clinical data appears feasible, but it is sensitive to input uncertainty, thus depending on accurate invasive measurements. By contrast, the EM LV model outputs were less sensitive, with errors of less than 8.14% for input data errors of 10%, which is within the bounds of clinical data uncertainty. This article is part of the theme issue 'Uncertainty quantification in cardiac and cardiovascular modelling and simulation'.

Factors Promoting Conduction Slowing as Substrates for Block and Reentry in Infarcted Hearts.

The development of effective and safe therapies for scar-related ventricular tachycardias requires a detailed understanding of the mechanisms underlying the conduction block that initiates electrical re-entries associated with these arrhythmias. Conduction block has been often associated with electrophysiological changes that prolong action potential duration (APD) within the border zone (BZ) of chronically infarcted hearts. However, experimental evidence suggests that remodeling processes promoting conduction slowing as opposed to APD prolongation mark the chronic phase. In this context, the substrate for the initial block at the mouth of an isthmus/diastolic channel leading to ventricular tachycardia is unclear. The goal of this study was to determine whether electrophysiological parameters associated with conduction slowing can cause block and re-entry in the BZ. In silico experiments were conducted on two-dimensional idealized infarct tissue as well as on a cohort of postinfarction porcine left ventricular models constructed from ex vivo magnetic resonance imaging scans. Functional conduction slowing in the BZ was modeled by reducing sodium current density, whereas structural conduction slowing was represented by decreasing tissue conductivity and including fibrosis. The arrhythmogenic potential of APD prolongation was also tested as a basis for comparison. Within all models, the combination of reduced sodium current with structural remodeling more often degenerated into re-entry and, if so, was more likely to be sustained for more cycles. Although re-entries were also detected in experiments with prolonged APD, they were often not sustained because of the subsequent block caused by long-lasting repolarization. Functional and structural conditions associated with slow conduction rather than APD prolongation form a potent substrate for arrhythmogenesis at the isthmus/BZ of chronically infarcted hearts. Reduced excitability led to block while slow conduction shortened the wavelength of propagation, facilitating the sustenance of re-entries. These findings provide important insights for models of patient-specific risk stratification and therapy planning.

Sex-Dependent QRS Guidelines for Cardiac Resynchronization Therapy Using Computer Model Predictions.

Cardiac resynchronization therapy (CRT) is an important treatment for heart failure. Low female enrollment in clinical trials means that current CRT guidelines may be biased toward males. However, females have higher response rates at lower QRS duration (QRSd) thresholds. Sex differences in the left ventricle (LV) size could provide an explanation for the improved female response at lower QRSd. We aimed to test if sex differences in CRT response at lower QRSd thresholds are explained by differences in LV size and hence predict sex-specific guidelines for CRT. We investigated the effect that LV size sex difference has on QRSd between male and females in 1093 healthy individuals and 50 CRT patients using electrophysiological computer models of the heart. Simulations on the healthy mean shape models show that LV size sex difference can account for 50-100% of the sex difference in baseline QRSd in healthy individuals. In the CRT patient cohort, model simulations predicted female-specific guidelines for CRT, which were 9-13 ms lower than current guidelines. Sex differences in the LV size are able to account for a significant proportion of the sex difference in QRSd and provide a mechanistic explanation for the sex difference in CRT response. Simulations accounting for the smaller LV size in female CRT patients predict 9-13 ms lower QRSd thresholds for female CRT guidelines.

Inverse localization of earliest cardiac activation sites from activation maps based on the viscous Eikonal equation.

In this study we propose a novel method for identifying the locations of earliest activation in the human left ventricle from activation maps measured at the epicardial surface. Electrical activation is modeled based on the viscous Eikonal equation. The sites of earliest activation are identified by solving a minimization problem. Arbitrary initial locations are assumed, which are then modified based on a shape derivative based perturbation field until a minimal mismatch between the computed and the given activation maps on the epicardial surface is achieved. The proposed method is tested in two numerical benchmarks, a generic 2D unit-square benchmark, and an anatomically accurate MRI-derived 3D human left ventricle benchmark to demonstrate potential utility in a clinical context. For unperturbed input data, our localization method is able to accurately reconstruct the earliest activation sites in both benchmarks with deviations of only a fraction of the used spatial discretization size. Further, with the quality of the input data reduced by spatial undersampling and addition of noise, we demonstrate that an accurate identification of the sites of earliest activation is still feasible.