130146 20251009133839.0 doi 10.34133/research.0254 sideral 136465 ART-2023-136465 eng García-Mendívil, Laura Universidad de Zaragoza (orcid)0000-0002-2954-1068 Interindividual Age-Independent Differences in Human CX43 Impact Ventricular Arrhythmic Risk 2023 Access copy available to the general public Unrestricted Connexin 43 (CX43) is one of the major components of gap junctions, the structures responsible for the intercellular communication and transmission of the electrical impulse in the left ventricle. There is limited information on the histological changes of CX43 with age and their effect on electrophysiology, especially in humans. Here, we analyzed left ventricular biopsies from living donors starting at midlife to characterize age-related CX43 remodeling. We assessed its quantity, degree of lateralization, and spatial heterogeneity together with fibrotic deposition. We observed no significant age-related remodeling of CX43. Only spatial heterogeneity increased slightly with age, and this increase was better explained by biological age than by chronological age. Importantly, we found that CX43 features varied considerably among individuals in our population with no relevant relationship to age or fibrosis content, in contrast to animal species. We used our experimental results to feed computational models of human ventricular electrophysiology and to assess the effects of interindividual differences in specific features of CX43 and fibrosis on conduction velocity, action potential duration, and arrhythmogenicity. We found that larger amounts of fibrosis were associated with the highest arrhythmic risk, with this risk being increased when fibrosis deposition was combined with a reduction in CX43 amount and/or with an increase in CX43 spatial heterogeneity. These mechanisms underlying high arrhythmic risk in some individuals were not associated with age in our study population. In conclusion, our data rule out CX43 remodeling as an age-related arrhythmic substrate in the population beyond midlife, but highlight its potential as a proarrhythmic factor at the individual level, especially when combined with increased fibrosis. info:eu-repo/grantAgreement/ES/DGA/LMP128_21 info:eu-repo/grantAgreement/ES/DGA/LMP94_21 info:eu-repo/grantAgreement/ES/DGA/T39-23R info:eu-repo/grantAgreement/ES/MICINN/PID2019-105674RB-I00 info:eu-repo/grantAgreement/ES/MICINN/PID2022-140556OB-I00 info:eu-repo/grantAgreement/EUR/MICINN/TED2021-130459B-I00 info:eu-repo/semantics/openAccess by https://creativecommons.org/licenses/by/4.0/deed.es 8.5 2023 MULTIDISCIPLINARY SCIENCES 14 / 134 = 0.104 2023 Q1 T1 2.102 2023 Multidisciplinary 2023 Q1 13.3 2023 info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion Pérez-Zabalza, María (orcid)0000-0002-3194-7796 Oliver-Gelabert, Antoni Vallejo-Gil, José María Fañanás-Mastral, Javier Vázquez-Sancho, Manuel Bellido-Morales, Javier André Vaca-Núñez, Alexánder Sebastián Ballester-Cuenca, Carlos Universidad de Zaragoza (orcid)0000-0002-2225-308X Diez, Emiliano Ordovás, Laura (orcid)0000-0003-3982-1263 Pueyo, Esther Universidad de Zaragoza (orcid)0000-0002-1960-407X 1013 090 Universidad de Zaragoza Dpto. Cirugía Área Cirugía 5008 800 Universidad de Zaragoza Dpto. Ingeniería Electrón.Com. Área Teoría Señal y Comunicac. 6 (2023), 0254 [17 pp.] Research 2096-5168 4275925 http://zaguan.unizar.es/record/130146/files/texto_completo.pdf Versión publicada 3005512 http://zaguan.unizar.es/record/130146/files/texto_completo.jpg?subformat=icon icon Versión publicada oai:zaguan.unizar.es:130146 articulos driver 2025-10-09-13:25:45 ARTICLE