Transcriptome and proteome mapping in the sheep atria reveal molecular featurets of atrial fibrillation progression Álvarez Franco, Alba Cogliati, Sara Atrial fibrillation RNA-Seq Proteomics Mitochondria Chromatin This work was supported by the Spanish government (BFU2017-84914-P to M.M.; FPI Fellowship to A.A.-F.; FPU Fellowship to R.R.), and in part by grants to J.J. from the National Heart, Lung and Blood Institute (R01 grant HL122352 NIH/NHLBI), the Leducq Foundation (Transatlantic Network of Excellence Program on Structural Alterations in the Myocardium and the Substrate for Cardiac Fibrillation), and the University of Michigan Health System-Peking University Health Science Center Joint Institute for Translational and Clinical Research (UMHS-PUHSC; project: Molecular Mechanisms of Fibrosis and the Progression from Paroxysmal to Persistent Atrial Fibrillation). The CNIC is supported by the Instituto de Salud Carlos III (ISCIII), the Ministerio de Ciencia e Innovacio ' n and the Pro CNIC Foundation and is a Severo Ochoa Center of Excellence (SEV-2015-0505). Aims Atrial fibrillation (AF) is a progressive cardiac arrhythmia that increases the risk of hospitalization and adverse cardiovascular events. There is a clear demand for more inclusive and large-scale approaches to understand the molecular drivers responsible for AF, as well as the fundamental mechanisms governing the transition from paroxysmal to persistent and permanent forms. In this study, we aimed to create a molecular map of AF and find the distinct molecular programmes underlying cell type-specific atrial remodelling and AF progression. Methods and results We used a sheep model of long-standing, tachypacing-induced AF, sampled right and left atrial tissue, and isolated cardiomyocytes (CMs) from control, intermediate (transition), and late time points during AF progression, and performed transcriptomic and proteome profiling. We have merged all these layers of information into a meaningful three-component space in which we explored the genes and proteins detected and their common patterns of expression. Our data-driven analysis points at extracellular matrix remodelling, inflammation, ion channel, myofibril structure, mitochondrial complexes, chromatin remodelling, and genes related to neural function, as well as critical regulators of cell proliferation as hallmarks of AF progression. Most important, we prove that these changes occur at early transitional stages of the disease, but not at later stages, and that the left atrium undergoes significantly more profound changes than the right atrium in its expression programme. The pattern of dynamic changes in gene and protein expression replicate the electrical and structural remodelling demonstrated previously in the sheep and in humans, and uncover novel mechanisms potentially relevant for disease treatment. Conclusions Transcriptomic and proteomic analysis of AF progression in a large animal model shows that significant changes occur at early stages, and that among others involve previously undescribed increase in mitochondria, changes to the chromatin of atrial CMs, and genes related to neural function and cell proliferation. 2021-09-14T08:51:45Z 2021-09-14T08:51:45Z 2020-10-29 info:eu-repo/semantics/article Alba Alvarez-Franco... [et al.]. Transcriptome and proteome mapping in the sheep atria reveal molecular featurets of atrial fibrillation progression, Cardiovascular Research, Volume 117, Issue 7, 15 June 2021, Pages 1760–1775, [https://doi.org/10.1093/cvr/cvaa307] http://hdl.handle.net/10481/70198 10.1093/cvr/cvaa307 eng http://creativecommons.org/licenses/by-nc/3.0/es/ info:eu-repo/semantics/openAccess Atribución-NoComercial 3.0 España Oxford University Press