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

Julio A. Chirinos, Lei Zhao, Yi Jia, Cecilia Frej, 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, Björn Dahlbäck, Bruce D. CarDavid A. Gordon, Thomas P. Cappola, Ali Javaheri

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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.

Original languageEnglish (US)
Pages (from-to)1463-1476
Number of pages14
JournalCirculation
DOIs
StateAccepted/In press - 2020

Keywords

  • apolipoproteins M
  • heart failure
  • lipoproteins, HDL
  • sphingosine-1-phosphate
  • survival

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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    Chirinos, J. A., Zhao, L., Jia, Y., Frej, C., Adamo, L., Mann, D., Shewale, S. V., Millar, J. S., Rader, D. J., French, B., Brandimarto, J., Margulies, K. B., Parks, J. S., Wang, Z., Seiffert, D. A., Fang, J., Sweitzer, N., Chistoffersen, C., Dahlbäck, B., ... Javaheri, A. (Accepted/In press). Reduced Apolipoprotein M and Adverse Outcomes across the Spectrum of Human Heart Failure. Circulation, 1463-1476. https://doi.org/10.1161/CIRCULATIONAHA.119.045323