Interindividual Age-Independent Differences in Human CX43 Impact Ventricular Arrhythmic Risk  

作　　者：Laura García-Mendívil María Pérez-Zabalza Antoni Oliver-Gelabert JoséMaría Vallejo-Gil Javier Fañanás-Mastral Manuel Vázquez-Sancho Javier AndréBellido-Morales Alexánder Sebastián Vaca-Núñez Carlos Ballester-Cuenca Emiliano Diez Laura Ordovás Esther Pueyo 

机构地区：[1]Biomedical Signal Interpretation and Computational Simulation group(BSICoS),Aragón Institute of Engineering Research,University of Zaragoza,Zaragoza 50018,Spain [2]BSICoS,Instituto de Investigación Sanitaria Aragón(IISA),Zaragoza 50018,Spain [3]Centro Universitario de la Defensa(CUD),Zaragoza 50090,Spain. [4]Department of Cardiovascular Surgery,University Hospital Miguel Servet,Zaragoza 50009,Spain. [5]Institute of Experimental Medicine and Biology of Cuyo(IMBECU),CONICET,Mendoza 5500,Argentina. [6]Fundación Agencia Aragonesa para la Investigación y el Desarrollo(ARAID),Zaragoza 50018,Spain. [7]Biomedical Research Networking Center in Bioengineering,Biomaterials and Nanomedicine(CIBER-BBN),Zaragoza 50018,Spain.

出　　处：《Research》2024年第3期417-432,共16页研究（英文）

基　　金：AEI-Ministerio de Ciencia e Innovación through projects PID2019-105674RB-I00,TED2021-130459B-I00,PID2022-140556OB-I00;PID2022-139859OB-I00 funded by MCIN/AEI/10.13039/501100011033;“ERDF A way of making Europe”,by Gobierno de Aragón through projects LMP94_21,LMP128_21,and BSICoS group T39_23R;the European Research Council through project ERC G.A.638284.Computations were performed using ICTS NANBIOSIS(HPC Unit,U.Zaragoza);L.G.-M.was supported by a predoctoral fellowship from the Departamento de Ciencia,Universidad y Sociedad del Conocimiento from the Gobierno de Aragón 2016-2020 cofounded by Programa Operativo del Fondo Social Europeo Aragón(C150/2016),EMBO Short-Term fellowship(7710),and Ibercaja-CAI Estancias de Investigación(IT18/18).

摘　　要：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.

关 键 词：CX43 RHYTHM INDEPENDENT 

分 类 号：R541.7[医药卫生—心血管疾病]