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[EN] Atrial fibrillation (AF) is the most common tachyarrhythmia. It has been demonstrated that extra-stimuli could act as triggers for AF. In many patients it is possible that multiple ectopic foci co-exist, and their interactions may generate complex conduction patterns. Our goal is to investigate the influence of the focus frequency, conduction velocity, and anisotropy on fibrillatory pattern generation during the interaction of multiple ectopic activities under electrical remodeling conditions. Our results support the broadly accepted theory that ectopic activity acting in remodeled tissue is an initiator of reentrant mechanisms. These reentrant circuits can generate fibrillatory activity when interacting with other rapid ectopic foci and under the following conditions: high ectopic focus frequency, slow conduction velocity, and anisotropic tissue. Analyses of electrogram polymorphism allow determination of which zones of tissue permit one to know in which zone of tissue unstable activity exists. Our results give useful insights into the electrophysiological parameters that determine the initiation and maintenance of fibrillatory conduction by two ectopic foci interaction in a simulated two-dimensional sheet of human atrial cells, under chronic AF conditions. ; This work was partially supported by the Direccion General de Politica Cientifica de la Generalitat Valenciana (PROMETEU 2016/088) and the University of Medellin ; Tobón, C.; Saiz Rodríguez, FJ. (2019). Fibrillatory conduction in a simulated two-dimensional model of human atrial tissue: effect of the interaction of two ectopic foci. Transactions of the Society for Computer Simulation. 95(7):577-591. https://doi.org/10.1177/0037549718782401 ; S ; 577 ; 591 ; 95 ; 7 ; Fuster, V., Rydén, L. E., Cannom, D. S., Crijns, H. J., Curtis, A. B., … Ellenbogen, K. A. (2006). ACC/AHA/ESC 2006 Guidelines for the Management of Patients With Atrial Fibrillation—Executive Summary. Circulation, 114(7), 700-752. doi:10.1161/circulationaha.106.177031 ; Stewart, S., ...

[EN] Genetic mutations affecting genes encoding for ion channel protein structures have been associated with the presence of atrial fibrillation (AF) in healthy individuals. The aim of this study is to model and simulate the effects of two gain-of-function mutations found in literature, T895M and T436M, and affecting the rapid delayed rectifier potassium current. Courtemanche human atrial model has been chosen to reproduce myocytes behaviour and an optimization algorithm has been employed to fit model parameters to experimental data. Single cell and tissue patch simulations have been performed to study the effects of the two mutations in control, paroxysmal and permanent AF conditions, both in right and left atrium. 0D simulations revealed that both mutations cause an increase in IKr current, leading to action potential duration shortening and flattening of restitution curves, especially in presence of the mutation T895M. Initiation of a re-entrant activity in 2D simulations were possible both in case of T895M and T436M. The study reports the arrhythmogenicity of the two mutants and reveals T895M having a stronger effect with respect to T436M, in particular in control rather than in paroxysmal and permanent AF conditions. Differences in the dynamics of the two mutations highlight the importance of a patient-specific approach in planning targeted drug therapies. ; I acknowledge this work to the European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie gran agreement No.766082 and to Generalitat Valenciana, Prometeo programme 2020/043 ; Belletti, R.; Martínez-Mateu, L.; Romero Pérez, L.; Saiz Rodríguez, FJ. (2020). Simulation Study of the Arrhythmogenic Effects of Two Missense Mutations in Human Atrial Fibrillation. IEEE. 1-4. https://doi.org/10.22489/CinC.2020.420 ; S ; 1 ; 4

[EN] During atrial fibrillation, cardiac tissue undergoes different remodeling processes at different scales from the molecular level to the tissue level. One central player that contributes to both electrical and structural remodeling is the myofibroblast. Based on recent experimental evidence on myofibroblasts' ability to contract, we extended a biophysical myofibroblast model with Ca2+ handling components and studied the effect on cellular and tissue electrophysiology. Using genetic algorithms, we fitted the myofibroblast model parameters to the existing in vitro data. In silico experiments showed that Ca2+ currents can explain the experimentally observed variability regarding the myofibroblast resting membrane potential. The presence of an L-type Ca2+ current can trigger automaticity in the myofibroblast with a cycle length of 799.9 ms. Myocyte action potentials were prolonged when coupled to myofibroblasts with Ca2+ handling machinery. Different spatial myofibroblast distribution patterns increased the vulnerable window to induce arrhythmia from 12 ms in non-fibrotic tissue to 22 & PLUSMN; 2.5 ms and altered the reentry dynamics. Our findings suggest that Ca2+ handling can considerably affect myofibroblast electrophysiology and alter the electrical propagation in atrial tissue composed of myocytes coupled with myofibroblasts. These findings can inform experimental validation experiments to further elucidate the role of myofibroblast Ca2+ handling in atrial arrhythmogenesis. ; We gratefully acknowledge financial support by the Deutsche Forschungsgemeinschaft (DFG) through DO637/22-3 and LO2093/1-1 and by the KIT-Publication Fund of the Karlsruhe Institute of Technology. This work was supported by the European High-Performance Computing Joint Undertaking EuroHPC under grant agreement No 955495 (MICROCARD) co-funded by the Horizon 2020 programme of the European Union (EU), the French National Research Agency ANR, the German Federal Ministry of Education and Research, and the Research Council of Norway. ...

[EN] Atrial fibrillation (AF) is the most common cardiac arrhythmia characterized by disorganized electrical activations of the upper chambers of the heart, leading to uncoordinated contraction and compromising the pumping action of the organ. AF risk factors include cardiovascular pathologies, endocrine disorders, advanced age, obesity, smoking and heritability. Genetic mutations affecting gene encoding for ion channel protein structures are in fact considered as cause of fibrillatory events in individuals who do not present any other co-morbidities. In this work, two genetic mutations found in literature and affecting the alpha-subunit of the rapid delayed rectifier potassium channel are modelled, by reparametrizing the IKr current formulation and by fitting it to mutant experimental data. The modified potassium current was then incorporated into the Courtemanche-Ramirez-Nattel (CRN) model and single cell simulations have been performed to study the mutations¿ effects on action potential and current traces, as well as, restitution properties, in right and left atrium. Both mutations produced a shortening of the action potential duration at 90% of repolarization (APD90), a higher current peak and lower APD values in the restitution curves. T895M yielded also to a reduction in the maximum slope of restitution curve. Tissue patch simulations revealed that T895M and T436M provide a substrate to initiate and maintain re-entries during the 5 seconds of simulation. Rotor¿s meandering in T895M appears more stable with a less extended area and more regular pattern than in T436M. Investigation on 3D atria and torso models will be necessary to provide further insights in understanding the mechanisms behind these genetic mutations. ; I am grateful to the teams at GaTech, who helped me in the realization of this work. This project has been funded by the European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie gran agreement No.766082 and by Generalitat Valenciana, Prometeo programme ...

[EN] Drug-induced proarrhythmicity is a major concern for regulators and pharmaceutical companies. For novel drug candidates, the standard assessment involves the evaluation of the potassium hERG channels block and the in vivo prolongation of the QT interval. However, this method is known to be too restrictive and to stop the development of potentially valuable therapeutic drugs. The aim of this work is to create an in silico tool for early detection of drug-induced proarrhythmic risk. The system is based on simulations of how different compounds affect the action potential duration (APD) of isolated endocardial, midmyocardial, and epicardial cells as well as the QT prolongation in a virtual tissue. Multiple channel-drug interactions and state-of-the-art human ventricular action potential models (O'Hara, T., et al. PLos Comput. Biol. 2011, 7, e1002061) were used in our simulations. Specifically, 206.766 cellular and 7072 tissue simulations were performed by blocking the slow and the fast components of the delayed rectifier current (I-Ks and I-Kr, respectively) and the L-type calcium current (I-CaL) at different levels. The performance of our system was validated by classifying the proarrhythmic risk of 84 compounds, 40 of which present torsadogenic properties. On the basis of these results, we propose the use of a new index (Tx) for discriminating torsadogenic compounds, defined as the ratio of the drug concentrations producing 10% prolongation of the cellular endocardial, midmyocardial, and epicardial APDs and the QT interval, over the maximum effective free therapeutic plasma concentration (EFTPC). Our results show that the Tx index outperforms standard methods for early identification of torsadogenic compounds. Indeed, for the analyzed compounds, the Tx tests accuracy was in the range of 87-88% compared with a 73% accuracy of the hERG IC50 based test. ; L.R, J.C., J.G., B.T., J.S.: This work was partially supported by the Direccion General de Politica Cientifica de la Generalitat Valenciana (PROMETEU2016/088) ...

[EN] 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 in silico and clinical electrograms to train a decision tree classifier to characterize the fibrotic atrial substrate. This approach captures different in vivo dynamics of the electrical propagation reflected on healthy electrogram morphology and synergistically combines it with synthetic fibrotic electrograms from in silico 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. ; We gratefully acknowledge financial support by the Deutsche Forschungsgemeinschaft (DFG) through DO637/22-3, LO2093/1-1 and LU 2294/1-1, by the European Union's Horizon 2020 programme (grant agreement No.766082, MY-ATRIA project), by the KIT-Publication Fund of the Karlsruhe Institute of Technology and by the Plan Estatal de Investigacion Cientifica y Tecnica y de Innovacion 2017-2020 from the Ministerio de Ciencia e Innovacion y Universidades (PID2019-104356RB-C41/AEI/10.13039/501100011033) ; Sánchez Arciniegas, JP.; Luongo, G.; Nothstein, M.; Unger, LA.; Saiz Rodríguez, FJ.; Trenor Gomis, BA.; Luik, A. ...

[EN] In clinical practice, reducing the burden of persistent atrial fibrillation by pharmacological means is challenging. We explored if blocking the background and the acetylcholine-activated inward rectifier potassium currents (I-K1 and I-KACh) could be antiarrhythmic in persistent atrial fibrillation. We thus tested the hypothesis that blocking I-K1 and I-KACh with chloroquine decreases the burden of persistent atrial fibrillation. We used patch clamp to determine the IC50 of I-K1 and I-KACh block by chloroquine and molecular modeling to simulate the interaction between chloroquine and Kir2.1 and Kir3.1, the molecular correlates of I-K1 and I-KACh. We then tested, as a proof of concept, if oral chloroquine administration to a patient with persistent atrial fibrillation can decrease the arrhythmia burden. We also simulated the effects of chloroquine in a 3D model of human atria with persistent atrial fibrillation. In patch clamp the IC50 of I-K1 block by chloroquine was similar to that of I-KACh. A 14-day regimen of oral chloroquine significantly decreased the burden of persistent atrial fibrillation in a patient. Mathematical simulations of persistent atrial fibrillation in a 3D model of human atria suggested that chloroquine prolonged the action potential duration, leading to failure of reentrant excitation, and the subsequent termination of the arrhythmia. The combined block of I-K1 and I-KACh can be a targeted therapeutic strategy for persistent atrial fibrillation. ; This work was supported in part by National Institutes of Health grants R21HL138064, R01HL129136, by the Direccion General de Politica Cientifica de la Generalitat Valenciana (PROMETEO 2016/088), and by the ACM SIGHPC/Intel Computational & Data Science fellowship. ; Tobón, C.; Palacio, LC.; Chidipi, B.; Slough, DP.; Tran, T.; Tran, N.; Reiser, M. (2019). The Antimalarial Chloroquine Reduces the Burden of Persistent Atrial Fibrillation. Frontiers in Pharmacology. 10:1-12. https://doi.org/10.3389/fphar.2019.01392 ; S ; 1 ; 12 ; 10 ...