000125889 001__ 125889 000125889 005__ 20241125101134.0 000125889 0247_ $$2doi$$a10.1016/j.compbiomed.2023.106719 000125889 0248_ $$2sideral$$a133420 000125889 037__ $$aART-2023-133420 000125889 041__ $$aeng 000125889 100__ $$aCelotto, Ch.$$uUniversidad de Zaragoza 000125889 245__ $$aSteady-state and transient effects of SK channel block and adrenergic stimulation to counteract acetylcholine-induced arrhythmogenic effects in the human atria: a computational study 000125889 260__ $$c2023 000125889 5060_ $$aAccess copy available to the general public$$fUnrestricted 000125889 5203_ $$aHyperactivity of the parasympathetic nervous system has been linked to the development of paroxysmal atrial fibrillation (AF). The parasympathetic neurotransmitter acetylcholine (ACh) causes a reduction in action potential (AP) duration (APD) and an increase in resting membrane potential (RMP), both of which contribute to enhance the risk for reentry. Research suggests that small-conductance calcium activated potassium (SK) channels may be an effective target for treating AF. Therapies targeting the autonomic nervous system, either alone or in combination with other drugs, have been explored and have been shown to decrease the incidence of atrial arrhythmias. This study uses computational modeling and simulation to examine the impact of SK channel block (SKb) and-adrenergic stimulation through Isoproterenol (Iso) on countering the negative effects of cholinergic activity in human atrial cell and 2D tissue models. The steady-state effects of Iso and/or SKb on AP shape, APD at 90% repolarization (APD90) and RMP were evaluated. The ability to terminate stable rotational activity in cholinergically-stimulated 2D tissue models of AF was also investigated. A range of SKb and Iso application kinetics, which reflect varying drug binding rates, were taken into consideration. The results showed that SKb alone prolonged APD90 and was able to stop sustained rotors in the presence of ACh concentrations up to 0.01 M. Iso terminated rotors under all tested ACh concentrations, but resulted in highly-variable steady-state outcomes depending on baseline AP morphology. Importantly, the combination of SKb and Iso resulted in greater APD90 prolongation and showed promising anti-arrhythmic potential by stopping stable rotors and preventing re-inducibility. 000125889 536__ $$9info:eu-repo/grantAgreement/EUR/MICINN/TED2021-130459B-I00$$9info:eu-repo/grantAgreement/ES/MICINN/PID2019-104881RB-I00$$9This project has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No H2020 766082-MY-ATRIA$$9info:eu-repo/grantAgreement/EC/H2020/766082/EU/MultidisciplinarY training network for ATrial fibRillation monItoring, treAtment and progression/MY-ATRIA$$9This project has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No H2020 638284-MODELAGE$$9info:eu-repo/grantAgreement/EC/H2020/638284/EU/Is your heart aging well? A systems biology approach to characterize cardiac aging from the cell to the body surface/MODELAGE$$9info:eu-repo/grantAgreement/ES/DGA/T39-23R$$9info:eu-repo/grantAgreement/ES/DGA/LMP94_21$$9info:eu-repo/grantAgreement/ES/AEI/PID2019-105674RB-I00 000125889 540__ $$9info:eu-repo/semantics/openAccess$$aby-nc-nd$$uhttp://creativecommons.org/licenses/by-nc-nd/3.0/es/ 000125889 590__ $$a7.0$$b2023 000125889 592__ $$a1.481$$b2023 000125889 591__ $$aBIOLOGY$$b7 / 109 = 0.064$$c2023$$dQ1$$eT1 000125889 593__ $$aHealth Informatics$$c2023$$dQ1 000125889 591__ $$aMATHEMATICAL & COMPUTATIONAL BIOLOGY$$b2 / 66 = 0.03$$c2023$$dQ1$$eT1 000125889 593__ $$aComputer Science Applications$$c2023$$dQ1 000125889 591__ $$aENGINEERING, BIOMEDICAL$$b16 / 123 = 0.13$$c2023$$dQ1$$eT1 000125889 591__ $$aCOMPUTER SCIENCE, INTERDISCIPLINARY APPLICATIONS$$b19 / 170 = 0.112$$c2023$$dQ1$$eT1 000125889 594__ $$a11.7$$b2023 000125889 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/publishedVersion 000125889 700__ $$0(orcid)0000-0003-4273-5403$$aSánchez, C.$$uUniversidad de Zaragoza 000125889 700__ $$aMountris, K. A. 000125889 700__ $$0(orcid)0000-0003-3434-9254$$aLaguna, P.$$uUniversidad de Zaragoza 000125889 700__ $$0(orcid)0000-0002-1960-407X$$aPueyo, E.$$uUniversidad de Zaragoza 000125889 7102_ $$15007$$2520$$aUniversidad de Zaragoza$$bDpto. Informát.Ingenie.Sistms.$$cÁrea Ingen.Sistemas y Automát. 000125889 7102_ $$15008$$2800$$aUniversidad de Zaragoza$$bDpto. Ingeniería Electrón.Com.$$cÁrea Teoría Señal y Comunicac. 000125889 773__ $$g157 (2023), 106719 [14 pp.]$$pComput. biol. med.$$tComputers in biology and medicine$$x0010-4825 000125889 8564_ $$s3208579$$uhttps://zaguan.unizar.es/record/125889/files/texto_completo.pdf$$yVersión publicada 000125889 8564_ $$s2585881$$uhttps://zaguan.unizar.es/record/125889/files/texto_completo.jpg?subformat=icon$$xicon$$yVersión publicada 000125889 909CO $$ooai:zaguan.unizar.es:125889$$particulos$$pdriver 000125889 951__ $$a2024-11-22-11:59:52 000125889 980__ $$aARTICLE