Interindividual Age-Independent Differences in Human CX43 Impact Ventricular Arrhythmic Risk
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 electroph...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
American Association for the Advancement of Science (AAAS)
2023-01-01
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| Series: | Research |
| Online Access: | https://spj.science.org/doi/10.34133/research.0254 |
| _version_ | 1797279743376097280 |
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| author | Laura García-Mendívil María Pérez-Zabalza Antoni Oliver-Gelabert José María Vallejo-Gil Javier Fañanás-Mastral Manuel Vázquez-Sancho Javier André Bellido-Morales Alexánder Sebastián Vaca-Núñez Carlos Ballester-Cuenca Emiliano Diez Laura Ordovás Esther Pueyo |
| author_facet | Laura García-Mendívil María Pérez-Zabalza Antoni Oliver-Gelabert José María Vallejo-Gil Javier Fañanás-Mastral Manuel Vázquez-Sancho Javier André Bellido-Morales Alexánder Sebastián Vaca-Núñez Carlos Ballester-Cuenca Emiliano Diez Laura Ordovás Esther Pueyo |
| author_sort | Laura García-Mendívil |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-07T16:31:28Z |
| format | Article |
| id | doaj.art-53dc7ecddc324f208d63aaeaa2a39b95 |
| institution | Directory Open Access Journal |
| issn | 2639-5274 |
| language | English |
| last_indexed | 2024-03-07T16:31:28Z |
| publishDate | 2023-01-01 |
| publisher | American Association for the Advancement of Science (AAAS) |
| record_format | Article |
| series | Research |
| spelling | doaj.art-53dc7ecddc324f208d63aaeaa2a39b952024-03-03T10:26:54ZengAmerican Association for the Advancement of Science (AAAS)Research2639-52742023-01-01610.34133/research.0254Interindividual Age-Independent Differences in Human CX43 Impact Ventricular Arrhythmic RiskLaura García-Mendívil0María Pérez-Zabalza1Antoni Oliver-Gelabert2José María Vallejo-Gil3Javier Fañanás-Mastral4Manuel Vázquez-Sancho5Javier André Bellido-Morales6Alexánder Sebastián Vaca-Núñez7Carlos Ballester-Cuenca8Emiliano Diez9Laura Ordovás10Esther Pueyo11Biomedical Signal Interpretation and Computational Simulation group (BSICoS), Aragón Institute of Engineering Research, University of Zaragoza, Zaragoza 50018, Spain.Biomedical Signal Interpretation and Computational Simulation group (BSICoS), Aragón Institute of Engineering Research, University of Zaragoza, Zaragoza 50018, Spain.Biomedical Signal Interpretation and Computational Simulation group (BSICoS), Aragón Institute of Engineering Research, University of Zaragoza, Zaragoza 50018, Spain.Department of Cardiovascular Surgery, University Hospital Miguel Servet, Zaragoza 50009, Spain.Department of Cardiovascular Surgery, University Hospital Miguel Servet, Zaragoza 50009, Spain.Department of Cardiovascular Surgery, University Hospital Miguel Servet, Zaragoza 50009, Spain.Department of Cardiovascular Surgery, University Hospital Miguel Servet, Zaragoza 50009, Spain.Department of Cardiovascular Surgery, University Hospital Miguel Servet, Zaragoza 50009, Spain.Department of Cardiovascular Surgery, University Hospital Miguel Servet, Zaragoza 50009, Spain.Institute of Experimental Medicine and Biology of Cuyo (IMBECU), CONICET, Mendoza 5500, Argentina.Biomedical Signal Interpretation and Computational Simulation group (BSICoS), Aragón Institute of Engineering Research, University of Zaragoza, Zaragoza 50018, Spain.Biomedical Signal Interpretation and Computational Simulation group (BSICoS), Aragón Institute of Engineering Research, University of Zaragoza, Zaragoza 50018, Spain.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.https://spj.science.org/doi/10.34133/research.0254 |
| spellingShingle | Laura García-Mendívil María Pérez-Zabalza Antoni Oliver-Gelabert José María Vallejo-Gil Javier Fañanás-Mastral Manuel Vázquez-Sancho Javier André Bellido-Morales Alexánder Sebastián Vaca-Núñez Carlos Ballester-Cuenca Emiliano Diez Laura Ordovás Esther Pueyo Interindividual Age-Independent Differences in Human CX43 Impact Ventricular Arrhythmic Risk Research |
| title | Interindividual Age-Independent Differences in Human CX43 Impact Ventricular Arrhythmic Risk |
| title_full | Interindividual Age-Independent Differences in Human CX43 Impact Ventricular Arrhythmic Risk |
| title_fullStr | Interindividual Age-Independent Differences in Human CX43 Impact Ventricular Arrhythmic Risk |
| title_full_unstemmed | Interindividual Age-Independent Differences in Human CX43 Impact Ventricular Arrhythmic Risk |
| title_short | Interindividual Age-Independent Differences in Human CX43 Impact Ventricular Arrhythmic Risk |
| title_sort | interindividual age independent differences in human cx43 impact ventricular arrhythmic risk |
| url | https://spj.science.org/doi/10.34133/research.0254 |
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