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

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, and Esther Pueyo

Subjects
Science
Abstract

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.

Published
2023
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2. Analysis of age-related left ventricular collagen remodeling in living donors: Implications in arrhythmogenesis

Author

Laura García-Mendívil, María Pérez-Zabalza, Konstantinos Mountris, Sam Duwé, Nick Smisdom, Marta Pérez, Lluís Luján, Esther Wolfs, Ronald B. Driesen, José María Vallejo-Gil, Pedro Carlos Fresneda-Roldán, Javier Fañanás-Mastral, Manuel Vázquez-Sancho, Marta Matamala-Adell, Juan Fernando Sorribas-Berjón, Javier André Bellido-Morales, Francisco Javier Mancebón-Sierra, Alexánder Sebastián Vaca-Núñez, Carlos Ballester-Cuenca, Aida Oliván-Viguera, Emiliano Diez, Laura Ordovás, and Esther Pueyo

Subjects
Disease, Pathophysiology, Computational bioinformatics, Science
Abstract

Summary: Age-related fibrosis in the left ventricle (LV) has been mainly studied in animals by assessing collagen content. Using second-harmonic generation microscopy and image processing, we evaluated amount, aggregation and spatial distribution of LV collagen in young to old pigs, and middle-age and elder living donors. All collagen features increased when comparing adult and old pigs with young ones, but not when comparing adult with old pigs or middle-age with elder individuals. Remarkably, all collagen parameters strongly correlated with lipofuscin, a biological age marker, in humans. By building patient-specific models of human ventricular tissue electrophysiology, we confirmed that amount and organization of fibrosis modulated arrhythmia vulnerability, and that distribution should be accounted for arrhythmia risk assessment. In conclusion, we characterize the age-associated changes in LV collagen and its potential implications for ventricular arrhythmia development. Consistency between pig and human results substantiate the pig as a relevant model of age-related LV collagen dynamics.

Published
2022
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4. Age-associated changes in fibrosis amount and spatial organization and its effects on human ventricular electrophysiology.

Author

María Pérez-Zabalza, Laura García-Mendívil, Kostantinos A. Mountris, Nick Smisdom, José M. Vallejo-Gil, Pedro C. Fresneda-Roldán, Javier Fañanás-Mastral, Marta Matamala-Adell, Fernando Sorribas-Berjón, Manuel Vázquez-Sancho, Javier André Bellido-Morales, Francisco Javier Mancebón-Sierra, Alexánder Sebastián Vaca-Núñez, Carlos Ballester-Cuenca, Aida Oliván-Viguera, Laura Ordovás, and Esther Pueyo

Published
2021
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5. Caracterización del remodelado del colágeno asociado a la edad en el ventrículo izquierdo humano de donantes vivos y sus implicaciones en la generación de arritmias

Author

Laura García Mendívil, María Pérez Zabalza, Konstantinos Mountris, Francisco Javier Mancebón Sierra, Alexánder Sebastián Vaca Núñez, Sam Duwé, Laura Ordovás, and Esther Pueyo

Abstract

La edad es un factor de riesgo arrítmico que, en especies animales, está asociado a la remodelación del colágeno. En este trabajo caracterizamos la dinámica tisular del colágeno asociada a la edad en el ventrículo izquierdo humano y utilizamos estos resultados para simular su efecto sobre la generación de arritmias ventriculares.

Published
2022

6. Minimally invasive system to reliably characterize ventricular electrophysiology from living donors

Author

Carlos Ballester-Cuenca, Laura García-Mendívil, José María Vallejo-Gil, Francisco Javier Mancebón-Sierra, Emiliano Raúl Diez, Fernando Sorribas-Berjón, Miguel Angel Marigil, Sofía Orós-Rodrigo, Estel Ramos-Marquès, Manuel Vázquez-Sancho, Maria Perez-Zabalza, Javier André Bellido-Morales, Alexánder Sebastián Vaca-Núñez, Konstantinos A. Mountris, Aida Oliván-Viguera, Ralf Köhler, Laura Ordovás, Javier Fañanás-Mastral, Pedro Carlos Fresneda-Roldán, Cristina Pastor, Esther Pueyo, and Marta Matamala-Adell

Subjects
0301 basic medicine, Cell biology, Tissue architecture, Pathology, medicine.medical_specialty, Molecular biology, Swine, Heart Ventricles, Cardiology, lcsh:Medicine, Action Potentials, 030204 cardiovascular system & hematology, MYOCARDIAL SLICE, Article, Membrane Potentials, 03 medical and health sciences, 0302 clinical medicine, LIVING DONORS, Living Donors, Animals, Humans, Medicine, Cellular organization, lcsh:Science, Multidisciplinary, business.industry, lcsh:R, ACTION POTENTIALS, purl.org/becyt/ford/3.1 [https], ELECTROPHYSIOLOGY, Electrophysiological Phenomena, 3. Good health, Electrophysiology, 030104 developmental biology, Vital stain, Action potential duration, lcsh:Q, purl.org/becyt/ford/3 [https], Cardiac Electrophysiology, business, Core biopsy
Abstract

Cardiac tissue slices preserve the heterogeneous structure and multicellularity of the myocardium and allow its functional characterization. However, access to human ventricular samples is scarce. We aim to demonstrate that slices from small transmural core biopsies collected from living donors during routine cardiac surgery preserve structural and functional properties of larger myocardial specimens, allowing accurate electrophysiological characterization. In pigs, we compared left ventricular transmural core biopsies with transmural tissue blocks from the same ventricular region. In humans, we analyzed transmural biopsies and papillary muscles from living donors. All tissues were vibratomesliced. By histological analysis of the transmural biopsies, we showed that tissue architecture and cellular organization were preserved. Enzymatic and vital staining methods verifed viability. Optically mapped transmembrane potentials confrmed that action potential duration and morphology were similar in pig biopsies and tissue blocks. Action potential morphology and duration in human biopsies and papillary muscles agreed with published ranges. In both pigs and humans, responses to increasing pacing frequencies and β-adrenergic stimulation were similar in transmural biopsies and larger tissues. We show that it is possible to successfully collect and characterize tissue slices from human myocardial biopsies routinely extracted from living donors, whose behavior mimics that of larger myocardial preparations both structurally and electrophysiologically. Fil: Oliván Viguera, Aida. Universidad de Zaragoza; España Fil: Pérez Zabalza, María. Universidad de Zaragoza; España Fil: García Mendívil, Laura. Universidad de Zaragoza; España Fil: Mountris, Konstantinos A.. Universidad de Zaragoza; España Fil: Orós Rodrigo, Sofía. Universidad de Zaragoza; España Fil: Ramos Marquès, Estel. Universidad de Zaragoza; España Fil: Vallejo Gil, José María. University Hospital Miguel Servet; España Fil: Fresneda Roldán, Pedro Carlos. University Hospital Miguel Servet; España Fil: Fañanás Mastral, Javier. University Hospital Miguel Servet; España Fil: Vázquez Sancho, Manuel. University Hospital Miguel Servet; España Fil: Matamala Adell, Marta. University Hospital Miguel Servet; España Fil: Sorribas Berjón, Fernando. University Hospital Miguel Servet; España Fil: Bellido Morales, Javier André. University Hospital Miguel Servet; España Fil: Mancebón Sierra, Francisco Javier. University Hospital Miguel Servet; España Fil: Vaca Núñez, Alexánder Sebastián. University Hospital Miguel Servet; España Fil: Ballester Cuenca, Carlos. University Hospital Miguel Servet; España Fil: Marigil, Miguel Ángel. Hospital San Jorge; España Fil: Pastor, Cristina. Aragón Institute of Health Sciences; España Fil: Ordovás, Laura. Aragón Agency for Research and Development; España. Universidad de Zaragoza; España Fil: Köhler, Ralf. Aragón Institute of Health Sciences; España. Aragón Agency for Research and Development; España Fil: Diez, Emiliano Raúl. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Cátedra de Fisiología Humana Normal; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentina Fil: Pueyo, Esther. Centro de Investigación Biomédica en Red en Bioingeniería, Biomateriales y Nanomedicina; España. Universidad de Zaragoza; España

Published
2020

7. Chronological and biological aging of the human left ventricular myocardium: Analysis of microRNAs contribution

Author

Estel Ramos-Marquès, Elisa Garrido-Huéscar, Juan Carlos Oliveros, Javier André Bellido-Morales, Carlos Ballester-Cuenca, José María Vallejo-Gil, Francisco Javier Mancebón-Sierra, Gorka Muñiz, Javier Fañanás-Mastral, Aida Oliván-Viguera, Manuel F. Jiménez-Navarro, Carlos Gómez-González, Juan Fernando Sorribas-Berjón, Margarita Segovia-Roldan, Hazel Santander-Badules, Alberto Cebollada, Laura García-Mendívil, Maria Perez-Zabalza, Alexánder Sebastián Vaca-Núñez, Jose M. Villaescusa, Esther Pueyo, Marta Matamala-Adell, Laura Ordovás, Emiliano Raúl Diez, Manuel Vázquez-Sancho, Sabarathinam Srinivasan, Pedro Carlos Fresneda-Roldán, Rafael Torres-Pérez, [Ramos-Marquès,E, García-Mendívil,L, Pérez-Zabalza,M, Santander-Badules,H, Srinivasan,S, Garrido-Huéscar,E, Segovia-Roldán,M, Oliván-Viguera,A, Ordovás,L, Pueyo,E] Biomedical Signal Interpretation and Computational Simulation group (BSICoS), Aragón Institute of Engineering Research, University of Zaragoza, Zaragoza, Spain. [Ramos-Marquès,E, Pueyo,E] BSICoS, IIS Aragón, Zaragoza, Spain. [Oliveros,JC, Torres-Pérez,R] Bioinformatics for Genomics and Proteomics, National Center of Biotechnology- Spanish National Research Council, Madrid, Spain. [Cebollada,A] Biocomputation unit, IACS, Zaragoza, Spain. [Vallejo-Gil,JM, Fresneda-Roldán,PC, Fañanás-Mastral,J, Vázquez-Sancho,M, Matamala-Adell,M, Sorribas-Berjón,JF, Bellido-Morales,JA, Mancebón-Sierra,FJ, Vaca-Núñez,AS, Ballester-Cuenca,C] Department of Cardiovascular Surgery, University Hospital Miguel Servet, Zaragoza, Spain. [Jiménez-Navarro,M] Heart Area, Hospital Clínico Universitario Virgen de la Victoria, CIBERCV, IBIMA, Universidad de Málaga, UMA, Málaga, Spain. [Villaescusa,JM] UGC Heart Area, Cardiovascular Surgery Department, Hospital Universitario Virgen de la Victoria de Málaga, Fundación Pública Andaluza para la Investigación de Málaga en Biomedicina y Salud (FIMABIS), CIBERCV Enfermedades Cardiovasculares, Instituto de Salud Carlos III, University of Málaga, Madrid, Spain. [Gómez-González,C, Muñiz,G] Department of Pathology, San Jorge Hospital, Huesca, Spain. [Diez,E] Institute of Experimental Medicine and Biology of Cuyo (IMBECU), CONICET, Mendoza, Argentina. [Ordovás,L] ARAID Foundation, Zaragoza, Spain. [Pueyo,E] Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Zaragoza, Spain, and The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS.

Subjects
0301 basic medicine, Male, Aging, Phenomena and Processes::Genetic Phenomena::Phenotype [Medical Subject Headings], Cardiac fibrosis, Envejecimiento, Persons::Persons::Tissue Donors::Living Donors [Medical Subject Headings], Bioinformatics, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Statistics as Topic::Probability::Risk::Risk Factors [Medical Subject Headings], Transcriptome, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], 0302 clinical medicine, CDKN2A, Ventrículos cardíacos, Heart ventricles, Donadores vivos, MicroARNs, microRNA, transcriptomic age marker, Phenotype, Anatomy::Cardiovascular System::Heart::Heart Ventricles [Medical Subject Headings], 3. Good health, medicine.anatomical_structure, Heart aging, Disciplines and Occupations::Natural Science Disciplines::Biological Science Disciplines::Biology::Computational Biology [Medical Subject Headings], biological aging, Biomarker (medicine), Female, Redes reguladoras de genes, Senescence, gene regulation network, Heart Ventricles, Check Tags::Male [Medical Subject Headings], Phenomena and Processes::Genetic Phenomena::Genetic Structures::Base Sequence::Regulatory Sequences, Nucleic Acid::Gene Regulatory Networks [Medical Subject Headings], Biology, Phenomena and Processes::Chemical Phenomena::Biochemical Phenomena::Biochemical Processes::Transcription, Genetic::Transcriptome [Medical Subject Headings], 03 medical and health sciences, Biological aging, Phenomena and Processes::Physiological Phenomena::Physiological Processes::Growth and Development::Aging [Medical Subject Headings], medicine, Humans, Living donors, Gene regulation network, Original Paper, Myocardium, biomarkers, Cell Biology, Original Articles, Anatomy::Cardiovascular System::Heart::Myocardium [Medical Subject Headings], medicine.disease, Transcriptoma, Chemicals and Drugs::Nucleic Acids, Nucleotides, and Nucleosides::Antisense Elements (Genetics)::RNA, Antisense::MicroRNAs [Medical Subject Headings], MicroRNAs, 030104 developmental biology, Biomarcadores, Miocardio, Check Tags::Female [Medical Subject Headings], Ventricle, heart aging, Transcriptomic age marker, 030217 neurology & neurosurgery, Biomarkers
Abstract

Aging is the main risk factor for cardiovascular diseases. In humans, cardiac aging remains poorly characterized. Most studies are based on chronological age (CA) and disregard biological age (BA), the actual physiological age (result of the aging rate on the organ structure and function), thus yielding potentially imperfect outcomes. Deciphering the molecular basis of ventricular aging, especially by BA, could lead to major progresses in cardiac research. We aim to describe the transcriptome dynamics of the aging left ventricle (LV) in humans according to both CA and BA and characterize the contribution of microRNAs, key transcriptional regulators. BA is measured using two CA‐associated transcriptional markers: CDKN2A expression, a cell senescence marker, and apparent age (AppAge), a highly complex transcriptional index. Bioinformatics analysis of 132 LV samples shows that CDKN2A expression and AppAge represent transcriptomic changes better than CA. Both BA markers are biologically validated in relation to an aging phenotype associated with heart dysfunction, the amount of cardiac fibrosis. BA‐based analyses uncover depleted cardiac‐specific processes, among other relevant functions, that are undetected by CA. Twenty BA‐related microRNAs are identified, and two of them highly heart‐enriched that are present in plasma. We describe a microRNA‐gene regulatory network related to cardiac processes that are partially validated in vitro and in LV samples from living donors. We prove the higher sensitivity of BA over CA to explain transcriptomic changes in the aging myocardium and report novel molecular insights into human LV biological aging. Our results can find application in future therapeutic and biomarker research., The biological age, measured by transcriptional markers, explains better than the chronological age the transcriptional dynamics of the human aging myocardium. microRNAs that change expression in the aging left ventricle are identified. Such microRNAs potentially regulate genes with cardiac‐specific functions. Cardiac‐enriched microRNAs that increase or decrease with biological age are present in plasma. They are thus candidate biomarkers to represent the biological age of the heart.

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