Sex Differences in Drug-Induced Arrhythmogenesis

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dc.article.number708435
dc.catalogadorgjm
dc.contributor.authorPeirlinck, Mathias
dc.contributor.authorSahli Costabal, Francisco
dc.contributor.authorKuhl, Ellen
dc.date.accessioned2024-05-30T16:23:26Z
dc.date.available2024-05-30T16:23:26Z
dc.date.issued2021
dc.description.abstractThe electrical activity in the heart varies significantly between men and women and results in a sex-specific response to drugs. Recent evidence suggests that women are more than twice as likely as men to develop drug-induced arrhythmia with potentially fatal consequences. Yet, the sex-specific differences in drug-induced arrhythmogenesis remain poorly understood. Here we integrate multiscale modeling and machine learning to gain mechanistic insight into the sex-specific origin of drug-induced cardiac arrhythmia at differing drug concentrations. To quantify critical drug concentrations in male and female hearts, we identify the most important ion channels that trigger male and female arrhythmogenesis, and create and train a sex-specific multi-fidelity arrhythmogenic risk classifier. Our study reveals that sex differences in ion channel activity, tissue conductivity, and heart dimensions trigger longer QT-intervals in women than in men. We quantify the critical drug concentration for dofetilide, a high risk drug, to be seven times lower for women than for men. Our results emphasize the importance of including sex as an independent biological variable in risk assessment during drug development. Acknowledging and understanding sex differences in drug safety evaluation is critical when developing novel therapeutic treatments on a personalized basis. The general trends of this study have significant implications on the development of safe and efficacious new drugs and the prescription of existing drugs in combination with other drugs.
dc.fechaingreso.objetodigital2024-12-17
dc.format.extent25 páginas
dc.fuente.origenORCID
dc.identifier.doi10.3389/fphys.2021.708435
dc.identifier.urihttps://doi.org/10.3389/fphys.2021.708435
dc.identifier.urihttp://www.scopus.com/inward/record.url?eid=2-s2.0-85114304890&partnerID=MN8TOARS
dc.identifier.urihttps://repositorio.uc.cl/handle/11534/86078
dc.identifier.wosidWOS:000692559800001
dc.information.autorucEscuela de Ingeniería; Sahli Costabal, Francisco; S/I; 154857
dc.language.isoen
dc.nota.accesocontenido completo
dc.revistaFrontiers in Physiology
dc.rightsacceso abierto
dc.rights.licenseCC BY 4.0 DEED Attribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectMultiscale modeling and simulation
dc.subjectCardiac electrophysiology
dc.subjectMachine learning
dc.subjectMulti-fidelity Gaussian process classification
dc.subjectActive learning
dc.subjectSex differences
dc.subjectArrhythmia
dc.subjectDrugs
dc.subject.ddc600
dc.subject.deweyTecnologíaes_ES
dc.subject.ods03 Good health and well-being
dc.subject.odspa03 Salud y bienestar
dc.titleSex Differences in Drug-Induced Arrhythmogenesis
dc.typeartículo
dc.volumen12
sipa.codpersvinculados154857
sipa.trazabilidadORCID;2024-05-27
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