{"doi":"10.3389/fcvm.2021.688396","title":"Integration of Functional Imaging, Cytometry, and Unbiased Proteomics Reveals New Features of Endothelial-to-Mesenchymal Transition in Ischemic Mitral Valve Regurgitation in Human Patients","abstract":"Background: Following myocardial infarction, mitral regurgitation (MR) is a common complication. Previous animal studies demonstrated the association of endothelial-to-mesenchymal transition (EndMT) with mitral valve (MV) remodeling. Nevertheless, little is known about how MV tissue responds to ischemic heart changes in humans. Methods: MVs were obtained by the Cardiothoracic Surgical Trials Network from 17 patients with ischemic mitral regurgitation (IMR). Echo-doppler imaging assessed MV function at time of resection. Cryosections of MVs were analyzed using a multi-faceted histology and immunofluorescence examination of cell populations. MVs were further analyzed using unbiased label-free proteomics. Echo-Doppler imaging, histo-cytometry measures and proteomic analysis were then integrated. Results: MVs from patients with greater MR exhibited proteomic changes associated with proteolysis-, inflammatory- and oxidative stress-related processes compared to MVs with less MR. Cryosections of MVs from patients with IMR displayed activated valvular interstitial cells (aVICs) and double positive CD31+ αSMA+ cells, a hallmark of EndMT. Univariable and multivariable association with echocardiography measures revealed a positive correlation of MR severity with both cellular and geometric changes (e.g., aVICs, EndMT, leaflet thickness, leaflet tenting). Finally, proteomic changes associated with EndMT showed gene-ontology enrichment in vesicle-, inflammatory- and oxidative stress-related processes. This discovery approach indicated new candidate proteins associated with EndMT regulation in IMR. Conclusion: We describe an atypical cellular composition and distinctive proteome of human MVs from patients with IMR, which highlighted new candidate proteins implicated in EndMT-related processes, associated with maladaptive MV fibrotic remodeling.","journal":"Frontiers in Cardiovascular Medicine","year":2021,"id":202732,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":6,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.957,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":316990,"name":"Yasufumi Nagata","orcid":"0000-0001-5481-7524","position":1,"is_corresponding":false},{"id":305053,"name":"Lívia Silva Araújo Passos","orcid":"0000-0001-9888-6206","position":2,"is_corresponding":false},{"id":783361,"name":"Dakota Beker-Greene","orcid":null,"position":3,"is_corresponding":false},{"id":446968,"name":"Katherine Kirkwood","orcid":"0000-0001-6994-7751","position":4,"is_corresponding":false},{"id":459583,"name":"Jill Wylie‐Sears","orcid":"0000-0003-3305-8578","position":5,"is_corresponding":false},{"id":782887,"name":"Zahra Alvandi","orcid":"0000-0003-0097-4713","position":6,"is_corresponding":false},{"id":364516,"name":"Hideyuki Higashi","orcid":"0000-0002-8286-8190","position":7,"is_corresponding":false},{"id":236188,"name":"Judy Hung","orcid":"0000-0003-3737-7584","position":8,"is_corresponding":false},{"id":364514,"name":"Sasha A. Singh","orcid":"0000-0003-0929-3164","position":9,"is_corresponding":false},{"id":381507,"name":"Joyce Bischoff","orcid":"0000-0002-6367-1974","position":10,"is_corresponding":false},{"id":286119,"name":"Robert A. Levine","orcid":"0000-0002-9484-8218","position":11,"is_corresponding":false},{"id":305056,"name":"Elena Aïkawa","orcid":"0000-0001-7835-2135","position":12,"is_corresponding":false},{"id":305054,"name":"Adrien Lupieri","orcid":"0000-0002-9245-0169","position":0,"is_corresponding":true}],"reference_count":59,"raw_metadata":null,"created_at":"2026-07-18T23:51:10.291262Z","pmid":"34458332","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}