L. Azzolin, S. Schuler, O. Dössel, and A. Loewe. A Reproducible Protocol to Assess Arrhythmia Vulnerability : Pacing at the End of the Effective Refractory Period.. In Frontiers in Physiology, vol. 12, pp. 656411, 2021
In both clinical and computational studies, different pacing protocols are used to induce arrhythmia and non-inducibility is often considered as the endpoint of treatment. The need for a standardized methodology is urgent since the choice of the protocol used to induce arrhythmia could lead to contrasting results, e.g., in assessing atrial fibrillation (AF) vulnerabilty. Therefore, we propose a novel method-pacing at the end of the effective refractory period (PEERP)-and compare it to state-of-the-art protocols, such as phase singularity distribution (PSD) and rapid pacing (RP) in a computational study. All methods were tested by pacing from evenly distributed endocardial points at 1 cm inter-point distance in two bi-atrial geometries. Seven different atrial models were implemented: five cases without specific AF-induced remodeling but with decreasing global conduction velocity and two persistent AF cases with an increasing amount of fibrosis resembling different substrate remodeling stages. Compared with PSD and RP, PEERP induced a larger variety of arrhythmia complexity requiring, on average, only 2.7 extra-stimuli and 3 s of simulation time to initiate reentry. Moreover, PEERP and PSD were the protocols which unveiled a larger number of areas vulnerable to sustain stable long living reentries compared to RP. Finally, PEERP can foster standardization and reproducibility, since, in contrast to the other protocols, it is a parameter-free method. Furthermore, we discuss its clinical applicability. We conclude that the choice of the inducing protocol has an influence on both initiation and maintenance of AF and we propose and provide PEERP as a reproducible method to assess arrhythmia vulnerability.
L. Azzolin, L. Dedè, A. Gerbi, and A. Quarteroni. Effect of fibre orientation and bulk modulus on the electromechanical modelling of human ventricles. In Mathematics in Engineering, vol. 2(4) , pp. 614-638, 2020
This work concerns the mathematical and numerical modeling of the heart. The aim is to enhance the understanding of the cardiac function in both physiological and pathological conditions. Along this road, a challenge arises from the multi-scale and multi-physics nature of the mathematical problem at hand. In this paper, we propose an electromechanical model that, in bi-ventricle geometries, combines the monodomain equation, the Bueno-Orovio minimal ionic model, and the Holzapfel-Ogden strain energy function for the passive myocardial tissue modelling together with the active strain approach combined with a model for the transmurally heterogeneous thickening of the myocardium. Since the distribution of the electric signal is dependent on the fibres orientation of the ventricles, we use a Laplace-Dirichlet Rule-Based algorithm to determine the myocardial fibres and sheets configuration in the whole bi-ventricle. In this paper, we study the influence of different fibre directions and incompressibility constraint and penalization on the compressibility of the material (bulk modulus) on the pressure-volume relation simulating a full heart beat. The coupled electromechanical problem is addressed by means of a fully segregated scheme. The numerical discretization is based on the Finite Element Method for the spatial discretization and on Backward Differentiation Formulas for the time discretization. The arising non-linear algebraic system coming from application of the implicit scheme is solved through the Newton method. Numerical simulations are carried out in a patient-specific biventricle geometry to highlight the most relevant results of both electrophysiology and mechanics and to compare them with physiological data and measurements. We show how various fibre configurations and bulk modulus modify relevant clinical quantities such as stroke volume, ejection fraction and ventricle contractility.
The arrhythmogenesis of atrial fibrillation is associated with the presence of fibrotic atrial tissue. Not only fibrosis but also physiological anatomical variability of the atria and the thorax reflect in altered morphology of the P wave in the 12-lead electrocardiogram (ECG). Distinguishing between the effects on the P wave induced by local atrial substrate changes and those caused by healthy anatomical variations is important to gauge the potential of the 12-lead ECG as a non-invasive and cost-effective tool for the early detection of fibrotic atrial cardiomyopathy to stratify atrial fibrillation propensity. In this work, we realized 54,000 combinations of different atria and thorax geometries from statistical shape models capturing anatomical variability in the general population. For each atrial model, 10 different volume fractions (0-45%) were defined as fibrotic. Electrophysiological simulations in sinus rhythm were conducted for each model combination and the respective 12-lead ECGs were computed. P wave features (duration, amplitude, dispersion, terminal force in V1) were extracted and compared between the healthy and the diseased model cohorts. All investigated feature values systematically in- or decreased with the left atrial volume fraction covered by fibrotic tissue, however value ranges overlapped between the healthy and the diseased cohort. Using all extracted P wave features as input values, the amount of the fibrotic left atrial volume fraction was estimated by a neural network with an absolute root mean square error of 8.78%. Our simulation results suggest that although all investigated P wave features highly vary for different anatomical properties, the combination of these features can contribute to non-invasively estimate the volume fraction of atrial fibrosis using ECG-based machine learning approaches.
AIMS: The treatment of atrial fibrillation beyond pulmonary vein isolation has remained an unsolved challenge. Targeting regions identified by different substrate mapping approaches for ablation resulted in ambiguous outcomes. With the effective refractory period being a fundamental prerequisite for the maintenance of fibrillatory conduction, this study aims at estimating the effective refractory period with clinically available measurements. METHODS AND RESULTS: A set of 240 simulations in a spherical model of the left atrium with varying model initialization, combination of cellular refractory properties, and size of a region of lowered effective refractory period was implemented to analyse the capabilities and limitations of cycle length mapping. The minimum observed cycle length and the 25% quantile were compared to the underlying effective refractory period. The density of phase singularities was used as a measure for the complexity of the excitation pattern. Finally, we employed the method in a clinical test of concept including five patients. Areas of lowered effective refractory period could be distinguished from their surroundings in simulated scenarios with successfully induced multi-wavelet re-entry. Larger areas and higher gradients in effective refractory period as well as complex activation patterns favour the method. The 25% quantile of cycle lengths in patients with persistent atrial fibrillation was found to range from 85 to 190 ms. CONCLUSION: Cycle length mapping is capable of highlighting regions of pathologic refractory properties. In combination with complementary substrate mapping approaches, the method fosters confidence to enhance the treatment of atrial fibrillation beyond pulmonary vein isolation particularly in patients with complex activation patterns.
Clinical and computational studies highlighted the role of atrial anatomy for atrial fibrillation vulnerability. However, personalized computational models are often generated from electroanatomical maps, which might lack important anatomical structures like the appendages, or from imaging data which are potentially affected by segmentation uncertainty. A bi-atrial statistical shape model (SSM) covering relevant structures for electrophysiological simulations was shown to cover atrial shape variability. We hypothesized that it could, therefore, also be used to infer the shape of missing structures and deliver ready-to-use models to assess atrial fibrillation vulnerability in silico. We implemented a highly automatized pipeline to generate a personalized computational model by fitting the SSM to the clinically acquired geometries. We applied our framework to a geometry coming from an electroanatomical map and one derived from magnetic resonance images (MRI). Only landmarks belonging to the left atrium and no information from the right atrium were used in the fitting process. The left atrium surface-to-surface distance between electroanatomical map and a fitted instance of the SSM was 2.26+-1.95 mm. The distance between MRI segmentation and SSM was 2.07+-1.56 mm and 3.59+-2.84 mm in the left and right atrium, respectively. Our semi-automatic pipeline provides ready-to-use personalized computational models representing the original anatomy well by fitting a SSM. We were able to infer the shape of the right atrium even in the case of using information only from the left atrium.
This work uses a highly detailed computational model of human atria to investigate the effect of spatial gradient and smoothing of atrial wall thickness on inducibility and maintenance of atrial fibrillation (AF) episodes. An atrial model with homogeneous thickness (HO) was used as baseline for the generation of different atrial models including either a low (LG) or high thickness gradient between left/right atrial free wall and the other regions. Since the model with high spatial gradient presented non-natural sharp edges between regions, either 1 (HG1) or 2 (HG2) Laplacian smoothing iterations were applied. Arrhythmic episodes were initiated using a rapid pacing protocol and long-living rotors were detected and tracked over time. Thresholds optimised with receiver operating characteristic analysis were used to define high gradient/curvature regions. Greater spatial gradients increased the atrial model inducibility and unveiled additional regions vulnerable to maintain AF drivers. In the models with heterogeneous wall thickness (LG, HG2 and HG1), 73.5 ± 8.7% of the long living rotors were found in areas within 1.5 mm from nodes with high thickness gradient, and 85.0 ± 3.4% in areas around high endocardial curvature. These findings promote wall thickness gradient and endocardial curvature as measures of AF vulnerability.
L. Azzolin, O. Dössel, and A. Loewe. Influence of the protocol used to induce arrhythmia on atrial fibrillation vulnerability. In 41 Annual International Conference of the IEEE Engineering in Medicine and Biology Society (EMBC), 2019
Several works have studied arrhythmogenicity of a given atrial model using different methods to initiate and simulate the perpetuation of re-entrant activity. We evaluated and compared two state-of-the-art methods showing their influence on the estimated vulnerability to arrhythmia of an atrial model.
L. Azzolin, D. Olaf, and L. Axel. Influence of the protocol used to induce arrhythmia on atrial fibrillation vulnerability. In Atrial Signals Conference, 2019
Nowadays, a large share of the global population is affected by heart rhythm disorders. Computational modelling is a useful tool for understanding the dynamics of cardiac arrhythmias. Several recent clinical and experimental studies suggest that atrial fibrillation is maintained by re-entrant drivers (e.g. rotors). As a consequence, numerous works have addressed atrial arrhythmogenicity of a given electrophysiological model using different methods to simulate the perpetuation of re-entrant activity. However, no common procedure to test atrial fibrillation vulnerability has yet been defined. Here, we systematically evaluate and compare two state-of-the-art methods. The first one is rapid extrastimulus pacing from rim of the four pulmonary veins. The second consists of placing phase singularities in the atria, estimating an activation time map by solving the Eikonal equation and finally using this as initial condition for the electrical cardiac propagation simulation. In this way, we are forcing the wavefronts to follow re-entrant circuits with low computational cost thus less simulation time. We aim to identify a methodology to quantify arrhythmia vulnerability on patient-specific atrial geometries and substrates. We will proceed with in-silico experiments, comparing the results of these two methods to initiate re-entrant activity, checking the influence of the different parameters on the dynamics on the re-entrant drivers and finally extracting a valid set of parameters allowing to reliably assess re-entry vulnerability. The final objective is to come up with an easily reproducible minimal set of simulations to assess vulnerability of a particular atrial substrate (cellular and tissue model) or of distinct anatomical atrial geometries to arrhythmic episodes. Given the great need of exploring susceptibility to atrial arrhythmias, i.e. after a first ablation procedure, this study can provide a useful tool to test new treatment strategies and to learn how to prevent the onset and progression of atrial fibrillation.
T. Zheng, L. Azzolin, J. Sánchez, O. Dössel, and A. Loewe. An automate pipeline for generating fiber orientation and region annotation in patient specific atrial models. In Current Directions in Biomedical Engineering, vol. 7(2) , pp. 136-139, 2021
The fast conduction system, in particular the HisPurkinje-System (HPS), is a key element for coordinated electrical activation of the heart. However, it is often omitted in computational studies. We hypothesized that the inclusion of the HPS is necessary when investigating arrhythmia maintenance and termination in an ischemic heart. We used a computational model of regionally-ischemic human ventricles reconstructed from magnetic resonance imaging data, and combined this with a rule-based HPS that produced a realistic activation pattern. Simulations using a high-frequency pacing protocol showed that re-entrant waves through the ischemic region may retrogradely activate the HPS, leading to self-terminating ventricular tachycardia (VT). Simulations without the HPS maintained the ischemia-induced VT, highlighting the role of the HPS in arrhythmia termination. Optical mapping recordings from isolated Langendorf-perfused rabbit hearts during regional ischemia and ischemia-reperfusion are compatible with the conclusions from the in-silico model, showing patterns of re-entry and termination that may be generated from retrograde HPS conduction.
Atrial fibrillation (AF) is an irregular heart rhythm due to disorganized atrial electrical activity, often sustained by rotational drivers called rotors. In the present work, we sought to characterize and discriminate whether simulated single stable rotors are located in the pulmonary veins (PVs) or not, only by using non-invasive signals (i.e., the 12-lead ECG). Several features have been extracted from the signals, such as Hjort descriptors, recurrence quantification analysis (RQA), and principal component analysis. All the extracted features have shown significant discriminatory power, with particular emphasis to the RQA parameters. A decision tree classifier achieved 98.48% accuracy, 83.33% sensitivity, and 100% specificity on simulated data. Clinical relevance— This study might guide ablation proce- dures, suggesting doctors to proceed directly in some patients with a pulmonary veins isolation, and avoiding the prior use of an invasive atrial mapping system.
Atrial fibrillation (AF) is the most frequent irregular heart rhythm due to disorganized atrial electrical activity, often sustained by rotational drivers called rotors. The non-invasive localization of AF drivers can lead to improved personalized ablation strategy, suggesting pulmonary vein (PV) isolation or more complex extra- PV ablation procedures in case the driver is on other atrial regions. We used a Machine Learning approach to characterize and discriminate simulated single stable rotors (1R) location: PVs, left atrium (LA) excluding the PVs, and right atrium (RA), utilizing solely non-invasive signals (i.e., the 12-lead ECG). 1R episodes sustaining AF were simulated. 128 features were extracted from the signals. Greedy forward algorithm was implemented to select the best feature set which was fed to a decision tree classifier with hold-out cross-validation technique. All tested features showed significant discriminatory power, especially those based on recurrence quantification analysis (up to 80.9% accuracy with single feature classification). The decision tree classifier achieved 89.4% test accuracy with 18 features on simulated data, with sensitivities of 93.0%, 82.4%, and 83.3% for RA, LA, and PV classes, respectively. Our results show that a machine learning approach can potentially identify the location of 1R sustaining AF using the 12-lead ECG.