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Abstract:

Background: Rate-varying S1S2 stimulation protocols can be used for restitution studies to characterize atrial substrate, ionic remodeling, and atrial fibrillation risk. Clinical restitution studies with numerous patients create large amounts of these data. Thus, an automated pipeline to evaluate clinically acquired S1S2 stimulation protocol data necessitates consistent, robust, reproducible, and precise evaluation of local activation times, electrogram amplitude, and conduction velocity. Here, we present the CVAR-Seg pipeline, developed focusing on three challenges: (i) No previous knowledge of the stimulation parameters is available, thus, arbitrary protocols are supported. (ii) The pipeline remains robust under different noise conditions. (iii) The pipeline supports segmentation of atrial activities in close temporal proximity to the stimulation artifact, which is challenging due to larger amplitude and slope of the stimulus compared to the atrial activity. Methods and Results: The S1 basic cycle length was estimated by time interval detection. Stimulation time windows were segmented by detecting synchronous peaks in different channels surpassing an amplitude threshold and identifying time intervals between detected stimuli. Elimination of the stimulation artifact by a matched filter allowed detection of local activation times in temporal proximity. A non-linear signal energy operator was used to segment periods of atrial activity. Geodesic and Euclidean inter electrode distances allowed approximation of conduction velocity. The automatic segmentation performance of the CVAR-Seg pipeline was evaluated on 37 synthetic datasets with decreasing signal-to-noise ratios. Noise was modeled by reconstructing the frequency spectrum of clinical noise. The pipeline retained a median local activation time error below a single sample (1 ms) for signal-to-noise ratios as low as 0 dB representing a high clinical noise level. As a proof of concept, the pipeline was tested on a CARTO case of a paroxysmal atrial fibrillation patient and yielded plausible restitution curves for conduction speed and amplitude. Conclusion: The proposed openly available CVAR-Seg pipeline promises fast, fully automated, robust, and accurate evaluations of atrial signals even with low signal-to-noise ratios. This is achieved by solving the proximity problem of stimulation and atrial activity to enable standardized evaluation without introducing human bias for large data sets.

Abstract:

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

Abstract:

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.

Abstract:

In patients with atrial fibrillation, intracardiac electrogram signal amplitude is known to decrease with increased structural tissue remodeling, referred to as fibrosis. In addition to the isolation of the pulmonary veins, fibrotic sites are considered a suitable target for catheter ablation. However, it remains an open challenge to find fibrotic areas and to differentiate their density and transmurality. This study aims to identify the volume fraction and transmurality of fibrosis in the atrial substrate. Simulated cardiac electrograms, combined with a generalized model of clinical noise, reproduce clinically measured signals. Our hybrid dataset approach combines and clinical electrograms to train a decision tree classifier to characterize the fibrotic atrial substrate. This approach captures different dynamics of the electrical propagation reflected on healthy electrogram morphology and synergistically combines it with synthetic fibrotic electrograms from experiments. The machine learning algorithm was tested on five patients and compared against clinical voltage maps as a proof of concept, distinguishing non-fibrotic from fibrotic tissue and characterizing the patient's fibrotic tissue in terms of density and transmurality. The proposed approach can be used to overcome a single voltage cut-off value to identify fibrotic tissue and guide ablation targeting fibrotic areas.

Abstract:

Identification of atrial sites that perpetuate atrial fibrillation (AF), and ablation thereof terminates AF, is challenging. We hypothesized that specific electrogram (EGM) characteristics identify AF-termination sites (AFTS). Twenty-one patients in whom low-voltage-guided ablation after pulmonary vein isolation terminated clinical persistent AF were included. Patients were included if short RF-delivery for <8sec at a given atrial site was associated with acute termination of clinical persistent AF. EGM-characteristics at 21 AFTS, 105 targeted sites without termination and 105 non-targeted control sites were analyzed. Alteration of EGM-characteristics by local fibrosis was evaluated in a three-dimensional high resolution (100 µm)-computational AF model. AFTS demonstrated lower EGM-voltage, higher EGM-cycle-length-coverage, shorter AF-cycle-length and higher pattern consistency than control sites (0.49 ± 0.39 mV vs. 0.83 ± 0.76 mV, p < 0.0001; 79 ± 16% vs. 59 ± 22%, p = 0.0022; 173 ± 49 ms vs. 198 ± 34 ms, p = 0.047; 80% vs. 30%, p < 0.01). Among targeted sites, AFTS had higher EGM-cycle-length coverage, shorter local AF-cycle-length and higher pattern consistency than targeted sites without AF-termination (79 ± 16% vs. 63 ± 23%, p = 0.02; 173 ± 49 ms vs. 210 ± 44 ms, p = 0.002; 80% vs. 40%, p = 0.01). Low voltage (0.52 ± 0.3 mV) fractionated EGMs (79 ± 24 ms) with delayed components in sinus rhythm ('atrial late potentials', respectively 'ALP') were observed at 71% of AFTS. EGMs recorded from fibrotic areas in computational models demonstrated comparable EGM-characteristics both in simulated AF and sinus rhythm. AFTS may therefore be identified by locally consistent, fractionated low-voltage EGMs with high cycle-length-coverage and rapid activity in AF, with low-voltage, fractionated EGMs with delayed components/ 'atrial late potentials' (ALP) persisting in sinus rhythm.

Abstract:

Under persistent atrial fibrillation (peAF), cardiac tissue experiences electrophysiological and structural remodeling. Fibrosis in the atrial tissue has an important impact on the myocyte action potential and its propagation. The objective of this work is to explore the effect of heterogeneities present in the fibrotic tissue and their impact on the intracardiac electrogram (EGM). Human atrial myocyte and fibroblast electrophysiology was simulated using mathematical models proposed by Koivumäki et al. to represent electrical remodeling under peAF and the paracrine effect of the transforming grow factor 1 (TGF-1). 2D tissue simulations were computed varying the density of fibrosis (10%, 20% and 40%), myofibroblasts and collagen were randomly distributed with different ratios (0%-100%, 50%-50% and 100%- 0%). Results show that increasing the fibrosis density changes the re-entry dynamics from functional to anatomical due to a block in conduction in regions with high fibrosis density (40%). EGM morphology was affected by different ratios of myofibroblasts-collagen. For low myofibroblast densities (below 50%) the duration of active segments was shorter compared to higher myofibroblasts densities (above 50%). Our results show that fibrosis heterogeneities can alter the dynamics of the re-entry and the morphology of the EGM.

Abstract:

Heterogeneous atrial substrate can induce, maintain and promote cardiac arrhythmias. The level of heterogeneity may be used to assess disease progression. One key parameter, suspected to be correlated with tissue vitality is the conduction velocity (CV). By measuring not only the current CV of the patient but rather its rate dependent changes, restitution information is gained. In the following, we show our approach towards a patient-specific quantitative atrial substrate characterization by combining sets of local and global CV restitution measurements to create a parametrization of the individual patient substrate characteristics.

Abstract:

Atrial fibrillation is the most common cardiac arrhythmia characterized by a rapid and irregular atrial excitation rate. Mimicking this behaviour, the S1-S2 stimulation protocol is currently the clinically established method for measuring tissue rate dependency, leading to a need for an automated segmentation method. We propose a method for stimulus artefact removal tailored towards the S1-S2 protocol. We show that this method results in the detection of atrial signals minimizing distortion by the stimulus artefact and is therefore an effective segmentation tool and a building block for automation of signal analysis.

Abstract:

Introduction: Multi-scale computational models of cardiac electrophysiology are used to investigate complex phenomena such as cardiac arrhythmias, its therapies and the testing of drugs or medical devices. While a couple of software solutions exist, none fully meets the needs of the community. In particular, newcomers to the field often have to go through a very steep learning curve which could be facilitated by dedicated user interfaces, documentation, and training material. Outcome: openCARP is an open cardiac electrophysiology simulator, released to the community to advance the computational cardiology field by making state-of-the-art simulations accessible. It aims to achieve this by supporting self-driven learning. To this end, an online platform is available containing educational video tutorials, user and developer-oriented documentation, detailed examples, and a question-and-answer system. The software is written in C++. We provide binary packages, a Docker container, and a CMake-based compilation workflow, making the installation process simple. The software can fully scale from desktop to high-performance computers. Nightly tests are run to ensure the consistency of the simulator based on predefined reference solutions, keeping a high standard of quality for all its components. openCARP interoperates with different input/output standard data formats. Additionally, sustainability is achieved through automated continuous integration to generate not only software packages, but also documentation and content for the community platform. Furthermore, carputils provides a user-friendly environment to create complex, multi-scale simulations that are shareable and reproducible. Conclusion: In conclusion, openCARP is a tailored software solution for the scientific community in the cardiac electrophysiology field and contributes to increasing use and reproducibility of in-silico experiments.