Steady-state and transient effects of SK channel block and adrenergic stimulation to counteract acetylcholine-induced arrhythmogenic effects in the human atria: a computational study

Celotto, Ch. (Universidad de Zaragoza) ; Sánchez, C. (Universidad de Zaragoza) ; Mountris, K. A. ; Laguna, P. (Universidad de Zaragoza) ; Pueyo, E. (Universidad de Zaragoza)

Resumen: Hyperactivity 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.

Idioma: Inglés

DOI: 10.1016/j.compbiomed.2023.106719

Año: 2023

Publicado en: Computers in biology and medicine 157 (2023), 106719 [14 pp.]
ISSN: 0010-4825

Factor impacto JCR: 7.0 (2023)

Categ. JCR: BIOLOGY rank: 7 / 109 = 0.064 (2023) - Q1 - T1
Categ. JCR: MATHEMATICAL & COMPUTATIONAL BIOLOGY rank: 2 / 66 = 0.03 (2023) - Q1 - T1
Categ. JCR: ENGINEERING, BIOMEDICAL rank: 16 / 123 = 0.13 (2023) - Q1 - T1
Categ. JCR: COMPUTER SCIENCE, INTERDISCIPLINARY APPLICATIONS rank: 19 / 170 = 0.112 (2023) - Q1 - T1

Factor impacto CITESCORE: 11.7 - Health Informatics (Q1) - Computer Science Applications (Q1)

Factor impacto SCIMAGO: 1.481 - Health Informatics (Q1) - Computer Science Applications (Q1)

Financiación: info:eu-repo/grantAgreement/ES/AEI/PID2019-105674RB-I00
Financiación: info:eu-repo/grantAgreement/ES/DGA/LMP94_21
Financiación: info:eu-repo/grantAgreement/ES/DGA/T39-23R
Financiación: info: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
Financiación: info:eu-repo/grantAgreement/EC/H2020/766082/EU/MultidisciplinarY training network for ATrial fibRillation monItoring, treAtment and progression/MY-ATRIA
Financiación: info:eu-repo/grantAgreement/ES/MICINN/PID2019-104881RB-I00
Financiación: info:eu-repo/grantAgreement/EUR/MICINN/TED2021-130459B-I00

Tipo y forma: Article (Published version)

Área (Departamento): Área Ingen.Sistemas y Automát. (Dpto. Informát.Ingenie.Sistms.)
Área (Departamento): Área Teoría Señal y Comunicac. (Dpto. Ingeniería Electrón.Com.)