Patient-Tailored In Silico 3D Simulations and Models From Electroanatomical Maps of the Left Atrium

Proceeding of 2018 Computing in Cardiology Conference (CinC), September 23-26, 2018, Maastricht, The NetherlandsThe mechanisms underlying atrial fibrillation (AF) are still under debate, making treatments for this arrhythmia remain suboptimal, with most treatments applied in a standard fashion with no patient personalization. Recent technological advances in electroanatomical mapping (EAM) using multi-electrode catheter allow the physicians to better characterize the substrate, thanks to a better spatial resolution and higher density of acquisition points. Taking advantage of this technology, we describe a workflow to build personalized electrophysiological atrial models for AF patients. We seek to better predict the outcome of a treatment and study the AF problem in a more specific scenario. We generated physiological 3D models from the EAM data using hexahedral meshing of element size 300μm, and added fiber orientation based on a generic model. We used the local activation time (LAT) maps performed in sinus rhythm (SR) to estimate the conduction velocity (CV) of the regions in the atrium with a new method that combines the LATs of neighboring tissue as the average CV of triplets of points. We also characterized the cellular model by Maleckar et al. in terms of longitudinal conductivity and CV to personalize the atrial models. We were able to simulate SR and AF scenarios on the personalized models, and we generated a database of atrial models for future analysis.This work has been partly supported by MINECO/FEDER (ADVENTURE, id. TEC2015-69868-C2-1-R), Co munidad de Madrid (CASI-CAM-CM, id. S2013/ICE-2845), Centro de Investigación Biomédica en Red (CIBER), proyecto DPI2016-75458, and the Programa Prometeo, Generalitat Valenciana, Award Number: 2016/088.Publicad

Omnipolar EGM Voltage Mapping for Atrial Fibrosis Identification Evaluated with an Electrophysiological Model

[EN] Atrial fibrillation (AF) is the most spread heart arrhythmia, whose mechanisms are not completely clear yet. Catheter ablation is a standard treatment, which isolates the area involved in the arrhythmia. Intracardiac electrograms (EGMs) are used to better understand the AF mechanisms and to find appropriate ablation sites. Bipolar EGMs (b-EGMs) are often employed, but their amplitude and shape depend on catheter orientation, limiting reliability. To avoid this uncertainty, an approach insensitive to catheter orientation, referred as Omnipolar EGM (OP-EGM) method, has been introduced, which uses an estimation of the electric field within a group of electrodes, referred as clique. In this work, we compare different mapping approaches based on b-EGMs and OPEGM signals in simulation including fibrosis, so to evaluate their ability to detect fibrosis and reproduce the spatial distribution of the voltage. Maps have been computed using two clique configurations (square and triangular), introducing or not a previous time alignment of the bEGMs. OP-EGM signals have been obtained by projecting the electric field along directions of its maximal excursion and its principal components. Results show that both cliques configurations present good performance, in terms of fibrosis detection and correlation with the reference voltage maps. In addition, the proposed alignment of b-EGMS improves maps based on OP-EGM signals, especially when square cliques are used.This work is part of a project that has received funding from the European Union¿s Horizon 2020 research and innovation program under the Marie Sk¿odowska-Curie grant agreement No 766082 (MY-ATRIA).Riccio, J.; Alcaine, A.; Rocher-Ventura, S.; Laguna, P.; Saiz Rodríguez, FJ.; Martínez, JP. (2021). Omnipolar EGM Voltage Mapping for Atrial Fibrosis Identification Evaluated with an Electrophysiological Model. IEEE. 920-924. https://doi.org/10.23919/Eusipco47968.2020.9287670S92092

Unipolar Electrogram Eigenvalue Distribution Analysis for the Identification of Atrial Fibrosis

[EN] Atrial fibrosis plays an important role in the pathogenesis of atrial fibrillation (AF). Low bipolar electrograms (b-EGMs) peak-to-peak voltage areas indicate scar tissue and are considered targets for AF substrate ablation. However, this approach ignores the spatiotemporal information embedded in the signal and the dependence of b-EGMs on catheter orientation. This work proposes an approach to detect fibrosis based on the eigenvalue dominance ratio (EIGDR) in an ensemble (clique) of unipolar electrograms (u-EGMs). A 2-D tissue with a central circular patch of fibrosis has been simulated using the Courtemanche cellular model. Maps of EIGDR have been computed using two sizes of electrode cliques, from the original u-EGMs within the ensemble or after a time alignment of these signals. Performance of each map in detecting fibrosis has been evaluated using receiver operating characteristic curves and detection accuracy. Best results achieve an area under the curve (AUC) of 0.98 and an accuracy (ACC) of 1 when we use as marker the gain in eigenvalue dominance produced by the ensemble alignmentFunding comes from EU Programme H2020 under the Marie Sklodowska-Curie Grant No 766082 (MY-ATRIA), Gobierno de Aragon (BSICoS Group T39-20R) cofunded by FEDER 2014-2020 "Building Europe from Aragon", fellowship ACIF/2018/174 from Generalitat Valenciana, and PID2019-104881RB-I00 from MICINN, SpainRiccio, J.; Rocher-Ventura, S.; Martínez-Mateu, L.; Alcaine, A.; Saiz Rodríguez, FJ.; Martínez, JP.; Laguna, P. (2020). Unipolar Electrogram Eigenvalue Distribution Analysis for the Identification of Atrial Fibrosis. IEEE. 1-4. https://doi.org/10.22489/CinC.2020.434S1

Atrial fibrosis identification with unipolar electrogram eigenvalue distribution analysis in multi-electrode arrays

Atrial fbrosis plays a key role in the initiation and progression of atrial fbrillation (AF). Atrial fbrosis is typically identifed by a peak-to-peak amplitude of bipolar electrograms (b-EGMs) lower than 0.5 mV, which may be considered as ablation targets. Nevertheless, this approach disregards signal spatiotemporal information and b-EGM sensitivity to catheter orientation. To overcome these limitations, we propose the dominant-to-remaining eigenvalue dominance ratio (EIGDR) of unipolar electrograms (u-EGMs) within neighbor electrode cliques as a waveform dispersion measure, hypothesizing that it is correlated with the presence of fbrosis. A simulated 2D tissue with a fbrosis patch was used for validation. We computed EIGDR maps from both original and time-aligned u-EGMs, denoted as R and RA, respectively, also mapping the gain in eigenvalue concentration obtained by the alignment, ΔRA. The performance of each map in detecting fbrosis was evaluated in scenarios including noise and variable electrode-tissue distance. Best results were achieved by RA, reaching 94% detection accuracy, versus the 86% of b-EGMs voltage maps. The proposed strategy was also tested in real u-EGMs from fbrotic and non-fbrotic areas over 3D electroanatomical maps, supporting the ability of the EIGDRs as fbrosis markers, encouraging further studies to confrm their translation to clinical settings

Hypoxic pulmonary vasoconstriction, carotid body function and erythropoietin production in adult rats perinatally exposed to hyperoxia

Adult mammalians possess three cell systems that are activated by acute bodily hypoxia: pulmonary artery smooth muscle cells (PASMC), carotid body chemoreceptor cells (CBCC) and erythropoietin (EPO)-producing cells. In rats, chronic perinatal hyperoxia causes permanent carotid body (CB) atrophy and functional alterations of surviving CBCC. There are no studies on PASMC or EPO-producing cells. Our aim is to define possible long-lasting functional changes in PASMC or EPO-producing cells (measured as EPO plasma levels) and, further, to analyse CBCC functional alterations. We used 3- to 4-month-old rats born and reared in a normal atmosphere or exposed to perinatal hyperoxia (55–60% O2 for the last 5–6 days of pregnancy and 4 weeks after birth). Perinatal hyperoxia causes an almost complete loss of hypoxic pulmonary vasoconstriction (HPV), which was correlated with lung oxidative status in early postnatal life and prevented by antioxidant supplementation in the diet. O2-sensitivity of K+ currents in the PASMC of hyperoxic animals is normal, indicating that their inhibition is not sufficient to trigger HPV. Perinatal hyperoxia also abrogated responses elicited by hypoxia on catecholamine and cAMP metabolism in the CB. An increase in EPO plasma levels elicited by hypoxia was identical in hyperoxic and control animals, implying a normal functioning of EPO-producing cells. The loss of HPV observed in adult rats and caused by perinatal hyperoxia, comparable to oxygen therapy in premature infants, might represent a previously unrecognized complication of such a medical intervention capable of aggravating medical conditions such as regional pneumonias, atelectases or general anaesthesia in adult life.This work was supported by Grants BFU2012-37459 from the Ministry of Economy and Competitiveness (Spain) and Grant CIBER CB06/06/0050 from the Institute of Health Carlos III (Spain) to C. G. Also supported by Grants SAF2011-28150 to F.P-V and SAF2010-22066-C02-02 to AC from the Ministry of Economy and Competitiveness (Spain).Peer Reviewe

Characterization of Atrial Propagation Patterns and Fibrotic Substrate With a Modified Omnipolar Electrogram Strategy in Multi-Electrode Arrays

[EN] Introduction: The omnipolar electrogram method was recently proposed to try to generate orientation-independent electrograms. It estimates the electric field from the bipolar electrograms of a clique, under the assumption of locally plane and homogeneous propagation. The local electric field evolution over time describes a loop trajectory from which omnipolar signals in the propagation direction, substrate and propagation features, are derived. In this work, we propose substrate and conduction velocity mapping modalities based on a modified version of the omnipolar electrogram method, which aims to reduce orientation-dependent residual components in the standard approach. Methods: A simulated electrical propagation in 2D, with a tissue including a circular patch of diffuse fibrosis, was used for validation. Unipolar electrograms were calculated in a multi-electrode array, also deriving bipolar electrograms along the two main directions of the grid. Simulated bipolar electrograms were also contaminated with real noise, to assess the robustness of the mapping strategies against noise. The performance of the maps in identifying fibrosis and in reproducing unipolar reference voltage maps was evaluated. Bipolar voltage maps were also considered for performance comparison. Results: Results show that the modified omnipolar mapping strategies are more accurate and robust against noise than bipolar and standard omnipolar maps in fibrosis detection (accuracies higher than 85 vs. 80% and 70%, respectively). They present better correlation with unipolar reference voltage maps than bipolar and original omnipolar maps (Pearson's correlations higher than 0.75 vs. 0.60 and 0.70, respectively). Conclusion: The modified omnipolar method improves fibrosis detection, characterization of substrate and propagation, also reducing the residual sensitivity to directionality over the standard approach and improving robustness against noise. Nevertheless, studies with real electrograms will elucidate its impact in catheter ablation interventions.This study has received funding from the European Union's Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement No 766082 (MY-ATRIA project), from projects PID2019-104881RB-I00, and PID2019-105674RB-I00 from MICINN, Spain, from Gobierno de Aragon (BSICoS Group T39-20R) cofunded by FEDER 20142020 Building Europe from Aragon and from Generalitat Valenciana through the fellowship ACIF/2018/174 and the grant PROMETEO/2020/043.Riccio, J.; Alcaine, A.; Rocher-Ventura, S.; Martínez-Mateu, L.; Laranjo, S.; Saiz Rodríguez, FJ.; Laguna, P.... (2021). Characterization of Atrial Propagation Patterns and Fibrotic Substrate With a Modified Omnipolar Electrogram Strategy in Multi-Electrode Arrays. Frontiers in Physiology. 12:1-21. https://doi.org/10.3389/fphys.2021.674223S1211

Fernando de Castro and the discovery of the arterial chemoreceptors

Producción CientíficaWhen de Castro entered the carotid body(CB)field,the organ was considered to be a small autonomic ganglion,a gland,a glomusorglomerulus,or a paraganglion. In his 1928 paper,de Castro concluded:“Insum,the Glomuscarotic umisinnervated by centripetal fibers,whose trophic center sare located in thesensory ganglia of the glossopharyngeal, and not by centrifugal[efferent] or secret o motor fibers a sisthe case for glands ; these are precisely the facts which lead to suppose that the Glomuscaroticumisa sensory organ.”A few pages down,de Castro wrote:“The Glomus represents an organ with multiplereceptors furnished with specialized receptor cells like those of the sensory organs [tastebuds?]...As aplausible hypothesis we propos et hattheGlomuscaroti cum represents a sensory organ, at present the only one in its kind, dedicated to capture certain qualitative variations in the composition of blood, a function that,possibly by are flex mechanism would have an effect on the functionalactivity of other organs... Therefore, thesensory fiber would not be directly stimulated by blood, but via the intermediation of the epithelial cell soft he organ, which, as their structures suggests, possess a secretory function which would participate in the stimulation of the centripetal fibers.”In our article we will recreat et he experiments that allowed Fernando de Castrotoreach this first conclusion. Also, we will scrutinize the natural endowment sand the scientific knowledge that drove de Castrotomaket the triple hypotheses : the CBaschemoreceptor (variationsinbloodcomposition),as a secondary sensory receptor which functioning involves a chemical synapse, and as a center, origin of systemicreflexes. After a brief account of the systemic reflex effects resulting from the CB stimulation, we wil lcomplete our article with a general view of the cellular-molecular mechanisms currently thought to be involved in the functionin go fthis arterial chemoreceptor

Enhanced Extinction of Aversive Memories by High-Frequency Stimulation of the Rat Infralimbic Cortex

Electrical stimulation of the rodent medial prefrontal cortex (mPFC), including the infralimbic cortex (IL), immediately prior to or during fear extinction training facilitates extinction memory. Here we examined the effects of high-frequency stimulation (HFS) of the rat IL either prior to conditioning or following retrieval of the conditioned memory, on extinction of Pavlovian fear and conditioned taste aversion (CTA). IL-HFS applied immediately after fear memory retrieval, but not three hours after retrieval or prior to conditioning, subsequently reduced freezing during fear extinction. Similarly, IL-HFS given immediately, but not three hours after, retrieval of a CTA memory reduced aversion during extinction. These data indicate that HFS of the IL may be an effective method for reducing both learned fear and learned aversion

Tau association with synaptic vesicles causes presynaptic dysfunction

Tau is implicated in more than 20 neurodegenerative diseases, including Alzheimer's disease. Under pathological conditions, Tau dissociates from axonal microtubules and missorts to pre- and postsynaptic terminals. Patients suffer from early synaptic dysfunction prior to Tau aggregate formation, but the underlying mechanism is unclear. Here we show that pathogenic Tau binds to synaptic vesicles via its N-terminal domain and interferes with presynaptic functions, including synaptic vesicle mobility and release rate, lowering neurotransmission in fly and rat neurons. Pathological Tau mutants lacking the vesicle binding domain still localize to the presynaptic compartment but do not impair synaptic function in fly neurons. Moreover, an exogenously applied membrane-permeable peptide that competes for Tau-vesicle binding suppresses Tau-induced synaptic toxicity in rat neurons. Our work uncovers a presynaptic role of Tau that may be part of the early pathology in various Tauopathies and could be exploited therapeutically.status: publishe