{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T21:26:13Z","timestamp":1790630773883,"version":"4.1.0"},"reference-count":51,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"18","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2020,5,5]]},"abstract":"<jats:sec>\n                    <jats:title>Background:<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods:<\/jats:title>\n                    <jats:p>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\u2013mass 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 \u22485000 other proteins (SomaScan assay) to identify biological pathways associated with apo M in heart failure.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>\n                      In the PHFS, apo M was inversely associated with the risk of death (standardized hazard ratio, 0.56 [95% CI, 0.51\u20130.61];\n                      <jats:italic>P<\/jats:italic>\n                      &lt;0.0001) and the composite of death\/ventricular assist device implantation\/heart transplantation (standardized hazard ratio, 0.62 [95% CI, 0.58\u20130.67];\n                      <jats:italic>P<\/jats:italic>\n                      &lt;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\u20130.88];\n                      <jats:italic>P<\/jats:italic>\n                      &lt;0.0001) and the composite of death\/ventricular assist device\/heart transplantation (hazard ratio, 0.85 [95% CI, 0.76\u20130.94];\n                      <jats:italic>P<\/jats:italic>\n                      =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 (\n                      <jats:italic>R<\/jats:italic>\n                      =0.81,\n                      <jats:italic>P<\/jats:italic>\n                      &lt;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.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions:<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circulationaha.119.045323","type":"journal-article","created":{"date-parts":[[2020,4,2]],"date-time":"2020-04-02T05:00:34Z","timestamp":1585803634000},"page":"1463-1476","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":81,"title":["Reduced Apolipoprotein M and Adverse Outcomes Across the Spectrum of Human Heart Failure"],"prefix":"10.1161","volume":"141","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9035-5670","authenticated-orcid":false,"given":"Julio A.","family":"Chirinos","sequence":"first","affiliation":[{"name":"Perelman School of Medicine. University of Pennsylvania School of Medicine\/Hospital of the University of Pennsylvania (J.A.C., S.V.S., J.S.M., D.J.R., B.F., J.B., K.B.M., T.P.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Zhao","sequence":"additional","affiliation":[{"name":"Bristol-Myers Squibb Co, Lawrenceville, NJ (L.Z., Z.W., D.A.S., B.D.C., D.A.G.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Jia","sequence":"additional","affiliation":[{"name":"SomaLogic Inc, Boulder, CO (Y.J.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cecilia","family":"Frej","sequence":"additional","affiliation":[{"name":"Lund University, Malmo, Sweden (C.F., B.D.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luigi","family":"Adamo","sequence":"additional","affiliation":[{"name":"Washington University School of Medicine, St Louis, MO (L.A., D.M., A.J.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Douglas","family":"Mann","sequence":"additional","affiliation":[{"name":"Washington University School of Medicine, St Louis, MO (L.A., D.M., A.J.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Swapnil V.","family":"Shewale","sequence":"additional","affiliation":[{"name":"Perelman School of Medicine. University of Pennsylvania School of Medicine\/Hospital of the University of Pennsylvania (J.A.C., S.V.S., J.S.M., D.J.R., B.F., J.B., K.B.M., T.P.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John S.","family":"Millar","sequence":"additional","affiliation":[{"name":"Perelman School of Medicine. University of Pennsylvania School of Medicine\/Hospital of the University of Pennsylvania (J.A.C., S.V.S., J.S.M., D.J.R., B.F., J.B., K.B.M., T.P.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel J.","family":"Rader","sequence":"additional","affiliation":[{"name":"Perelman School of Medicine. University of Pennsylvania School of Medicine\/Hospital of the University of Pennsylvania (J.A.C., S.V.S., J.S.M., D.J.R., B.F., J.B., K.B.M., T.P.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin","family":"French","sequence":"additional","affiliation":[{"name":"Perelman School of Medicine. University of Pennsylvania School of Medicine\/Hospital of the University of Pennsylvania (J.A.C., S.V.S., J.S.M., D.J.R., B.F., J.B., K.B.M., T.P.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeff","family":"Brandimarto","sequence":"additional","affiliation":[{"name":"Perelman School of Medicine. University of Pennsylvania School of Medicine\/Hospital of the University of Pennsylvania (J.A.C., S.V.S., J.S.M., D.J.R., B.F., J.B., K.B.M., T.P.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth B.","family":"Margulies","sequence":"additional","affiliation":[{"name":"Perelman School of Medicine. University of Pennsylvania School of Medicine\/Hospital of the University of Pennsylvania (J.A.C., S.V.S., J.S.M., D.J.R., B.F., J.B., K.B.M., T.P.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John S.","family":"Parks","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine\u2013Molecular Medicine, Wake Forest School of Medicine, Winston Salem, NC (J.S.P.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhaoqing","family":"Wang","sequence":"additional","affiliation":[{"name":"Bristol-Myers Squibb Co, Lawrenceville, NJ (L.Z., Z.W., D.A.S., B.D.C., D.A.G.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dietmar A.","family":"Seiffert","sequence":"additional","affiliation":[{"name":"Bristol-Myers Squibb Co, Lawrenceville, NJ (L.Z., Z.W., D.A.S., B.D.C., D.A.G.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"Fang","sequence":"additional","affiliation":[{"name":"University of Utah, Salt Lake City (J.F.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nancy","family":"Sweitzer","sequence":"additional","affiliation":[{"name":"Sarver Heart Institute, University of Arizona, Tucson (N.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina","family":"Chistoffersen","sequence":"additional","affiliation":[{"name":"Department of Clinical Biochemistry, Rigshospitalet and Department of Biomedical Sciences, Copenhagen, Denmark (C.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bj\u00f6rn","family":"Dahlb\u00e4ck","sequence":"additional","affiliation":[{"name":"Lund University, Malmo, Sweden (C.F., B.D.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruce D.","family":"Car","sequence":"additional","affiliation":[{"name":"Bristol-Myers Squibb Co, Lawrenceville, NJ (L.Z., Z.W., D.A.S., B.D.C., D.A.G.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David A.","family":"Gordon","sequence":"additional","affiliation":[{"name":"Bristol-Myers Squibb Co, Lawrenceville, NJ (L.Z., Z.W., D.A.S., B.D.C., D.A.G.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas P.","family":"Cappola","sequence":"additional","affiliation":[{"name":"Perelman School of Medicine. University of Pennsylvania School of Medicine\/Hospital of the University of Pennsylvania (J.A.C., S.V.S., J.S.M., D.J.R., B.F., J.B., K.B.M., T.P.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6657-331X","authenticated-orcid":false,"given":"Ali","family":"Javaheri","sequence":"additional","affiliation":[{"name":"Washington University School of Medicine, St Louis, MO (L.A., D.M., 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