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

Background: Apolipoprotein M (APOM) mediates the physical interaction between high-density lipoprotein (HDL) particles and sphingosine-1-phosphate (S1P). APOM exerts anti-inflammatory and cardio-protective effects in animal models. Methods: In a subset of Penn-HF study (PHFS) participants (n=297), we measured APOM by ELISA. We also measured total S1P by liquid chromatography-mass spectrometry and isolated HDL particles to test the association between APOM and HDL-associated S1P. We confirmed the relationship between APOM and outcomes using modified aptamer-based APOM measurements, among 2,170 adults in the PHFS and 2 independent cohorts: the Washington University HF registry (n=173) and a subset of the TOPCAT trial (n=218). Finally, we examined the relationship between APOM and ~5000 other proteins (SomaScan assay) to identify biological pathways associated with APOM in HF. Results: In the PHFS, APOM 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 or heart transplant (Standardized HR=0.62; 95%CI=0.58-0.67; P<0.0001). This relationship was independent of HDL-C or APOA-I levels. APOM remained associated with death (HR=0.78; 0.69-0.88; P<0.0001) and the composite of death/ventricular assist device/heart transplant (HR=0.85; 95%CI=0.76-0.94; P=0.001) in models that adjusted for multiple confounders. This association was present in both HF with reduced (HFrEF) and preserved (HFpEF) ejection fraction, and was replicated in the Washington University cohort and a HFpEF-only cohort (TOPCAT). The S1P and APOM content of isolated HDL particles strongly correlated (R=0.81; P<0.0001). The top canonical pathways associated with APOM were inflammation (negative association), the coagulation system (negative association) and LXR/RXR activation (positive association). The relationship with inflammation was validated with multiple inflammatory markers measured with independent assays. Conclusions: Reduced circulating APOM is independently associated with adverse outcomes across the spectrum of human HF. Further research is needed to assess whether the APOM/S1P axis is a suitable therapeutic target in HF.