Modeling Human Atrial Patho-Electrophysiology from Ion Channels to ECG - Substrates, Pharmacology, Vulnerability, and P-Waves

Half of the patients suffering from atrial fibrillation (AF) cannot be treated adequately, today. This thesis presents multi-scale computational methods to advance our understanding of patho-mechanisms, to improve the diagnosis of patients harboring an arrhythmogenic substrate, and to tailor therapy. The modeling pipeline ranges from ion channels on the subcellular level up to the ECG on the body surface. The tailored therapeutic approaches carry the potential to reduce the burden of AF

Modeling Human Atrial Patho-Electrophysiology from Ion Channels to ECG - Substrates, Pharmacology, Vulnerability, and P-Waves

Half of the patients suffering from atrial fibrillation (AF) cannot be treated adequately, today. This book presents multi-scale computational methods to advance our understanding of patho-mechanisms, to improve the diagnosis of patients harboring an arrhythmogenic substrate, and to tailor therapy. The modeling pipeline ranges from ion channels on the subcellular level up to the ECG on the body surface. The tailored therapeutic approaches carry the potential to reduce the burden of AF

Modeling Human Atrial Patho-Electrophysiology from Ion Channels to ECG - Substrates, Pharmacology, Vulnerability, and P-Waves

Half of the patients suffering from atrial fibrillation (AF) cannot be treated adequately, today. This book presents multi-scale computational methods to advance our understanding of patho-mechanisms, to improve the diagnosis of patients harboring an arrhythmogenic substrate, and to tailor therapy. The modeling pipeline ranges from ion channels on the subcellular level up to the ECG on the body surface. The tailored therapeutic approaches carry the potential to reduce the burden of AF

A Review of Healthy and Fibrotic Myocardium Microstructure Modeling and Corresponding Intracardiac Electrograms

Computational simulations of cardiac electrophysiology provide detailed information on the depolarization phenomena at different spatial and temporal scales. With the development of new hardware and software, in silico experiments have gained more importance in cardiac electrophysiology research. For plane waves in healthy tissue, in vivo and in silico electrograms at the surface of the tissue demonstrate symmetric morphology and high peak-to-peak amplitude. Simulations provided insight into the factors that alter the morphology and amplitude of the electrograms. The situation is more complex in remodeled tissue with fibrotic infiltrations. Clinically, different changes including fractionation of the signal, extended duration and reduced amplitude have been described. In silico, numerous approaches have been proposed to represent the pathological changes on different spatial and functional scales. Different modeling approaches can reproduce distinct subsets of the clinically observed electrogram phenomena. This review provides an overview of how different modeling approaches to incorporate fibrotic and structural remodeling affect the electrogram and highlights open challenges to be addressed in future research

Sensitivity and Generalization of a Neural Network for Estimating Left Atrial Fibrotic Volume Fractions from the 12-lead ECG

Features extracted from P waves of the 12-lead electrocardiogram (ECG) have proven valuable for non-invasively estimating the left atrial fibrotic volume fraction associated with the arrhythmogenesis of atrial fibrillation. However, feature extraction in the clinical context is prone to errors and oftentimes yields unreliable results in the presence of noise. This leads to inaccurate input values provided to machine learning algorithms tailored at estimating the amount of atrial fibrosis with clinical ECGs.Another important aspect for clinical translation is the network’s generalization ability regarding newECGs.To quantify a network’s sensitivity to inaccurately extracted P wave features, we added Gaussian noise to the features extracted from 540,000 simulated ECGs consisting of P wave duration, dispersion, terminal force in lead V1, peak-to-peak amplitudes, and additionallythoracic and atrial volumes. For assessing generalization, we evaluated the network performance for train-validation-test splits divided such that ECGs simulated with the same atria or torso geometry only belongedto either the trainingand validationor the test set. The root mean squared error (RMSE) of the network increased the most in case of noisy torso volumes and P wave durations. Large generalization errors witha RMSEdifference between training and test set of more than 2% fibrotic volume fraction only occurred ifveryhigh or low atria and torso volumes were left out during training.Our results suggest that P wave duration and thoracic volume are features that have to be measured accurately if employed for estimating atrial fibrosis with a neural network. Furthermore, our method is capable of generalizing wellto ECGs simulated with anatomical models excluded during training and thus meets an important requirement for clinical translation

The Impact of Standard Ablation Strategies for Atrial Fibrillation on Cardiovascular Performance in a Four-Chamber Heart Model

Purpose: Atrial fibrillation is one of the most frequent cardiac arrhythmias in the industrialized world and ablation therapy is the method of choice for many patients. However, ablation scars alter the electrophysiological activation and the mechanical behavior of the affected atria. Different ablation strategies with the aim to terminate atrial fibrillation and prevent its recurrence exist but their impact on the performance of the heart is often neglected. Methods: In this work, we present a simulation study analyzing five commonly used ablation scar patterns and their combinations in the left atrium regarding their impact on the pumping function of the heart using an electromechanical whole-heart model. We analyzed how the altered atrial activation and increased stiffness due to the ablation scars affect atrial as well as ventricular contraction and relaxation. Results: We found that systolic and diastolic function of the left atrium is impaired by ablation scars and that the reduction of atrial stroke volume of up to 11.43% depends linearly on the amount of inactivated tissue. Consequently, the end-diastolic volume of the left ventricle, and thus stroke volume, was reduced by up to 1.4 and 1.8%, respectively. During ventricular systole, left atrial pressure was increased by up to 20% due to changes in the atrial activation sequence and the stiffening of scar tissue. Conclusion: This study provides biomechanical evidence that atrial ablation has acute effects not only on atrial contraction but also on ventricular performance. Therefore, the position and extent of ablation scars is not only important for the termination of arrhythmias but is also determining long-term pumping efficiency. If confirmed in larger cohorts, these results have the potential to help tailoring ablation strategies towards minimal global cardiovascular impairment

Characterization of the pace-and-drive capacity of the human sinoatrial node: A 3D in silico study

The sinoatrial node (SAN) is a complex structure that spontaneously depolarizes rhythmically (“pacing”) and excites the surrounding non-automatic cardiac cells (“drive”) to initiate each heart beat. However, the mechanisms by which the SAN cells can activate the large and hyperpolarized surrounding cardiac tissue are incompletely understood. Experimental studies demonstrated the presence of an insulating border that separates the SAN from the hyperpolarizing influence of the surrounding myocardium, except at a discrete number of sinoatrial exit pathways (SEPs). We propose a highly detailed 3D model of the human SAN, including 3D SEPs to study the requirements for successful electrical activation of the primary pacemaking structure of the human heart. A total of 788 simulations investigate the ability of the SAN to pace and drive with different heterogeneous characteristics of the nodal tissue (gradient and mosaic models) and myocyte orientation. A sigmoidal distribution of the tissue conductivity combined with a mosaic model of SAN and atrial cells in the SEP was able to drive the right atrium (RA) at varying rates induced by gradual If block. Additionally, we investigated the influence of the SEPs by varying their number, length, and width. SEPs created a transition zone of transmembrane voltage and ionic currents to enable successful pace and drive. Unsuccessful simulations showed a hyperpolarized transmembrane voltage (−66 mV), which blocked the L-type channels and attenuated the sodium-calcium exchanger. The fiber direction influenced the SEPs that preferentially activated the crista terminalis (CT). The location of the leading pacemaker site (LPS) shifted toward the SEP-free areas. LPSs were located closer to the SEP-free areas (3.46 1.42 mm), where the hyperpolarizing influence of the CT was reduced, compared with a larger distance from the LPS to the areas where SEPs were located (7.17 0.98 mm). This study identified the geometrical and electrophysiological aspects of the 3D SAN-SEP-CT structure required for successful pace and drive in silico

The Impact of Standard Ablation Strategies for Atrial Fibrillation on Cardiovascular Performance in a Four-chamber Heart Model

Atrial fibrillation is one of the most frequent cardiac arrhythmias in the industrialized world and ablation therapy is the method of choice for many patients. However, ablation scars alter the electrophysiological activation and the mechanical behavior of the affected atria. Different ablation strategies with the aim to terminate atrial fibrillation and prevent its recurrence exist but their impact on the hemodynamic performance of the heart has not been investigated thoroughly. In this work, we present a simulation study analyzing five commonly used ablation scar patterns and their combinations in the left atrium regarding their impact on the pumping function of the heart using an electromechanical whole-heart model. We analyzed how the altered atrial activation and increased stiffness due to the ablation scar affect atrial as well as ventricular contraction and relaxation. We found that systolic and diastolic function of the left atrium is impaired by ablation scars and that the reduction of atrial stroke volume of up to 11.43% depends linearly on the amount of inactivated tissue. Consequently, the end-diastolic volume of the left ventricle, and thus stroke volume, was reduced by up to 1.4% and 1.8%, respectively. During ventricular systole, left atrial pressure was increased by up to 20% due to changes in the atrial activation sequence and the stiffening of scar tissue. This study provides biomechanical evidence that atrial ablation has acute effects not only on atrial contraction but also on ventricular pumping function. Our results have the potential to help tailoring ablation strategies towards minimal global hemodynamic impairment

A bi-atrial statistical shape model for large-scale in silico studies of human atria: model development and application to ECG simulations

Large-scale electrophysiological simulations to obtain electrocardiograms (ECG) carry the potential to produce extensive datasets for training of machine learning classifiers to, e.g., discriminate between different cardiac pathologies. The adoption of simulations for these purposes is limited due to a lack of ready-to-use models covering atrial anatomical variability. We built a bi-atrial statistical shape model (SSM) of the endocardial wall based on 47 segmented human CT and MRI datasets using Gaussian process morphable models. Generalization, specificity, and compactness metrics were evaluated. The SSM was applied to simulate atrial ECGs in 100 random volumetric instances. The first eigenmode of our SSM reflects a change of the total volume of both atria, the second the asymmetry between left vs. right atrial volume, the third a change in the prominence of the atrial appendages. The SSM is capable of generalizing well to unseen geometries and 95% of the total shape variance is covered by its first 23 eigenvectors. The P waves in the 12-lead ECG of 100 random instances showed a duration of 104ms in accordance with large cohort studies. The novel bi-atrial SSM itself as well as 100 exemplary instances with rule-based augmentation of atrial wall thickness, fiber orientation, inter-atrial bridges and tags for anatomical structures have been made publicly available. The novel, openly available bi-atrial SSM can in future be employed to generate large sets of realistic atrial geometries as a basis for in silico big data approaches