Reduced Apolipoprotein M and Adverse Outcomes across the Spectrum of Human Heart Failure

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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.


  • Julio A. Chirinos
  • Lei Zhao
  • Yi Jia
  • Luigi Adamo
  • Douglas Mann
  • Swapnil V. Shewale
  • John S. Millar
  • Daniel J. Rader
  • Benjamin French
  • Jeff Brandimarto
  • Kenneth B. Margulies
  • John S. Parks
  • Zhaoqing Wang
  • Dietmar A. Seiffert
  • James Fang
  • Nancy Sweitzer
  • Christina Chistoffersen
  • Bruce D. Car
  • David A. Gordon
  • Thomas P. Cappola
  • Ali Javaheri
Enheter & grupper
Externa organisationer
  • Bristol-Myers Squibb
  • Washington University in St. Louis
  • Wake Forest University
  • University of Utah
  • University of Arizona
  • Copenhagen University Hospital
  • University of Pennsylvania
  • Hospital of the University of Pennsylvania
  • SomaLogic
  • University of Copenhagen

Ämnesklassifikation (UKÄ) – OBLIGATORISK

  • Kardiologi


Sidor (från-till)1463-1476
Antal sidor14
StatusPublished - 2020
Peer review utfördJa