{"doi":"10.1172/jci171874","title":"Impaired T cell IRE1α/XBP1 signaling directs inflammation in experimental heart failure with preserved ejection fraction","abstract":"Heart failure with preserved ejection fraction (HFpEF) is a widespread syndrome with limited therapeutic options and poorly understood immune pathophysiology. Using a 2-hit preclinical model of cardiometabolic HFpEF that induces obesity and hypertension, we found that cardiac T cell infiltration and lymphoid expansion occurred concomitantly with cardiac pathology and that diastolic dysfunction, cardiomyocyte hypertrophy, and cardiac phospholamban phosphorylation were T cell dependent. Heart-infiltrating T cells were not restricted to cardiac antigens and were uniquely characterized by impaired activation of the inositol-requiring enzyme 1α/X-box-binding protein 1 (IRE1α/XBP1) arm of the unfolded protein response. Notably, selective ablation of XBP1 in T cells enhanced their persistence in the heart and lymphoid organs of mice with preclinical HFpEF. Furthermore, T cell IRE1α/XBP1 activation was restored after withdrawal of the 2 comorbidities inducing HFpEF, resulting in partial improvement of cardiac pathology. Our results demonstrated that diastolic dysfunction and cardiomyocyte hypertrophy in preclinical HFpEF were T cell dependent and that reversible dysregulation of the T cell IRE1α/XBP1 axis was a T cell signature of HFpEF.","journal":"Journal of Clinical Investigation","year":2023,"id":320875,"datarank":0.5837730447165941,"base_score":3.8918202981106265,"endowment":3.8918202981106265,"self_citation_contribution":0.5837730447165941,"citation_network_contribution":0.0,"self_endowment_contribution":0.5837730447165941,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":48,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9552,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":636309,"name":"Abraham Bayer","orcid":"0000-0001-7534-6354","position":1,"is_corresponding":false},{"id":489948,"name":"Kuljeet Kaur","orcid":"0000-0002-8075-5678","position":2,"is_corresponding":false},{"id":894083,"name":"Erin Sanders","orcid":"0000-0002-1952-0941","position":3,"is_corresponding":false},{"id":155921,"name":"Mark Aronovitz","orcid":null,"position":4,"is_corresponding":false},{"id":892865,"name":"Mallory Filipp","orcid":"0000-0003-2957-3753","position":5,"is_corresponding":false},{"id":238277,"name":"Edward B. Thorp","orcid":"0000-0003-1387-7058","position":6,"is_corresponding":false},{"id":236835,"name":"Gabriele G. Schiattarella","orcid":"0000-0002-7582-7171","position":7,"is_corresponding":false},{"id":57436,"name":"Joseph A. Hill","orcid":"0000-0002-5379-1614","position":8,"is_corresponding":false},{"id":445054,"name":"Robert M. Blanton","orcid":"0000-0002-6837-2076","position":9,"is_corresponding":false},{"id":242940,"name":"Juan R. Cubillos‐Ruiz","orcid":"0000-0002-4267-4893","position":10,"is_corresponding":false},{"id":317914,"name":"Pilar Alcaide","orcid":"0000-0003-3013-3982","position":11,"is_corresponding":false},{"id":317913,"name":"Sasha Smolgovsky","orcid":"0000-0002-7735-9922","position":0,"is_corresponding":true}],"reference_count":44,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T01:07:27.434133Z","pmid":"37874641","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":[]}