{"doi":"10.1161/circulationaha.119.045323","title":"Reduced Apolipoprotein M and Adverse Outcomes Across the Spectrum of Human Heart Failure","abstract":"Background: Apo (apolipoprotein) M mediates the physical interaction between high-density lipoprotein (HDL) particles and sphingosine-1-phosphate (S1P). Apo M exerts anti-inflammatory and cardioprotective effects in animal models. Methods: In a subset of PHFS (Penn Heart Failure Study) participants (n=297), we measured apo M by Enzyme-Linked ImmunoSorbent Assay (ELISA). We also measured total S1P by liquid chromatography–mass spectrometry and isolated HDL particles to test the association between apo M and HDL-associated S1P. We confirmed the relationship between apo M and outcomes using modified aptamer-based apo M measurements among 2170 adults in the PHFS and 2 independent cohorts: the Washington University Heart Failure Registry (n=173) and a subset of TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial; n=218). Last, we examined the relationship between apo M and ≈5000 other proteins (SomaScan assay) to identify biological pathways associated with apo M in heart failure. Results: In the PHFS, apo M was inversely associated with the risk of death (standardized hazard ratio, 0.56 [95% CI, 0.51–0.61]; P <0.0001) and the composite of death/ventricular assist device implantation/heart transplantation (standardized hazard ratio, 0.62 [95% CI, 0.58–0.67]; P <0.0001). This relationship was independent of HDL cholesterol or apo AI levels. Apo M remained associated with death (hazard ratio, 0.78 [95% CI, 0.69–0.88]; P <0.0001) and the composite of death/ventricular assist device/heart transplantation (hazard ratio, 0.85 [95% CI, 0.76–0.94]; P =0.001) in models that adjusted for multiple confounders. This association was present in both heart failure with reduced and preserved ejection fraction and was replicated in the Washington University cohort and a cohort with heart failure with preserved ejection fraction only (TOPCAT). The S1P and apo M content of isolated HDL particles strongly correlated ( R =0.81, P <0.0001). The top canonical pathways associated with apo M were inflammation (negative association), the coagulation system (negative association), and liver X receptor/retinoid X receptor activation (positive association). The relationship with inflammation was validated with multiple inflammatory markers measured with independent assays. Conclusions: Reduced circulating apo M is independently associated with adverse outcomes across the spectrum of human heart failure. Further research is needed to assess whether the apo M/S1P axis is a suitable therapeutic target in heart failure.","journal":"Circulation","year":2020,"id":57440,"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":78,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9583,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":228814,"name":"Lei Zhao","orcid":"0000-0001-5027-2379","position":1,"is_corresponding":false},{"id":299665,"name":"Yi Jia","orcid":"0000-0002-4563-917X","position":2,"is_corresponding":false},{"id":300570,"name":"Cecilia Frej","orcid":null,"position":3,"is_corresponding":false},{"id":263661,"name":"Luigi Adamo","orcid":"0000-0003-2704-978X","position":4,"is_corresponding":false},{"id":233712,"name":"Douglas L. Mann","orcid":"0000-0002-2516-0145","position":5,"is_corresponding":false},{"id":260475,"name":"Swapnil V. Shewale","orcid":"0000-0001-8373-9692","position":6,"is_corresponding":false},{"id":299666,"name":"John S. Millar","orcid":"0000-0002-1992-708X","position":7,"is_corresponding":false},{"id":33004,"name":"Daniel J. Rader","orcid":"0000-0002-9245-9876","position":8,"is_corresponding":false},{"id":299667,"name":"Benjamin French","orcid":"0000-0001-9265-5378","position":9,"is_corresponding":false},{"id":300571,"name":"Jeff Brandimarto","orcid":null,"position":10,"is_corresponding":false},{"id":30817,"name":"Kenneth B. Margulies","orcid":"0000-0002-8093-4465","position":11,"is_corresponding":false},{"id":299668,"name":"John S. Parks","orcid":"0000-0002-5227-8915","position":12,"is_corresponding":false},{"id":228815,"name":"Zhaoqing Wang","orcid":"0000-0003-1515-4945","position":13,"is_corresponding":false},{"id":228820,"name":"Dietmar Seiffert","orcid":"0009-0006-4818-2407","position":14,"is_corresponding":false},{"id":233711,"name":"James C. Fang","orcid":"0000-0003-2427-9504","position":15,"is_corresponding":false},{"id":260611,"name":"Nancy K. Sweitzer","orcid":"0000-0002-8117-6678","position":16,"is_corresponding":false},{"id":300572,"name":"Christina Chistoffersen","orcid":null,"position":17,"is_corresponding":false},{"id":299669,"name":"Björn Dahlbäck","orcid":"0000-0003-1546-0328","position":18,"is_corresponding":false},{"id":229923,"name":"Bruce D. Car","orcid":null,"position":19,"is_corresponding":false},{"id":212512,"name":"David A. Gordon","orcid":null,"position":20,"is_corresponding":false},{"id":30818,"name":"Thomas P. Cappola","orcid":"0000-0002-9630-7204","position":21,"is_corresponding":false},{"id":263663,"name":"Ali Javaheri","orcid":"0000-0001-6657-331X","position":22,"is_corresponding":false},{"id":228821,"name":"Julio A. Chirinos","orcid":"0000-0001-9035-5670","position":0,"is_corresponding":true}],"reference_count":52,"raw_metadata":null,"created_at":"2026-07-18T21:06:31.136481Z","pmid":"32237898","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":[]}