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.

• Authors: 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 Car, David A Gordon, Thomas P Cappola, Ali Javaheri
• Journal: Circulation (Circulation) Vol. 141 Issue 18 Pg. 1463-1476 (05 05 2020) ISSN: 1524-4539 [Electronic] United States
• PMID: 32237898 (Publication Type: Journal Article, Multicenter Study, Observational Study, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• APOM protein, human
• Apolipoproteins M
• Biomarkers
• Lipoproteins, HDL
• Lysophospholipids
• Proteome
• sphingosine 1-phosphate
• Sphingosine

Topics

• Aged
• Apolipoproteins M (blood)
• Biomarkers (blood)
• Down-Regulation
• Female
• Heart Failure (blood, diagnosis, mortality, therapy)
• Humans
• Lipoproteins, HDL (blood)
• Lysophospholipids (blood)
• Male
• Middle Aged
• Prognosis
• Proteome
• Proteomics
• Randomized Controlled Trials as Topic
• Registries
• Risk Assessment
• Risk Factors
• Sphingosine (analogs & derivatives, blood)
• Time Factors
• United States