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.

Keywords: apolipoproteins M; heart failure; lipoproteins, HDL; sphingosine-1-phosphate; survival.

Figure 1.. Risk of adverse outcomes among Penn Heart Failure Study participants and textiles APOM, measured by ELISA.

Kaplan-Meier survival curves for all-cause mortality (A) or the composite outcome of death, ventricular assist device or heart transplant (B) are shown. The number of patients at risk at each timepoint is presented below the graph.

Figure 1.. Risk of adverse outcomes among Penn Heart Failure Study participants and textiles APOM, measured by ELISA.

Kaplan-Meier survival curves for all-cause mortality (A) or the composite outcome of death, ventricular assist device or heart transplant (B) are shown. The number of patients at risk at each timepoint is presented below the graph.

Figure 2.. Risk of adverse outcomes among Penn Heart Failure Study participants stratified by tertiles of APOM.

Kaplan-Meier survival curves for all-cause mortality (A) or the composite outcome of death, ventricular assist device or heart transplant (B) are shown. The number of patients at risk at each timepoint is presented below the graph.

Figure 2.. Risk of adverse outcomes among Penn Heart Failure Study participants stratified by tertiles of APOM.

Kaplan-Meier survival curves for all-cause mortality (A) or the composite outcome of death, ventricular assist device or heart transplant (B) are shown. The number of patients at risk at each timepoint is presented below the graph.

Figure 3.. Risk of adverse outcomes among Penn Heart Failure Study participants with HFpEF stratified by tertiles of APOM.

Kaplan-Meier survival curves for all-cause mortality (A) or the composite outcome of death or heart failure-related hospitalization (B) are shown. The number of patients at risk at each timepoint is presented below the graph.

Figure 3.. Risk of adverse outcomes among Penn Heart Failure Study participants with HFpEF stratified by tertiles of APOM.

Kaplan-Meier survival curves for all-cause mortality (A) or the composite outcome of death or heart failure-related hospitalization (B) are shown. The number of patients at risk at each timepoint is presented below the graph.

Figure 4.. Top 20 canonical pathways associated with APOM.

Red bars indicate a negative z-score (negative correlation). Green bars indicate positive z-scores (i.e., positive correlations). Gray bars denote pathways in which there is significant overlap with ApoM, but the directionality of the relationship is unclear.

Figure 5.. Proposed protective effects of apolipoprotein M in heart failure.

APOM is associated with HDL and binds S1P. S1P signaling enhances cardiomyocyte survival, activates endothelial protective pathways, and is anti-inflammatory. The culmination of these effects may result in improved survival in heart failure. However, whether the relationship between APOM and outcomes is causal remains to be determined.