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.

中文翻译：

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载脂蛋白 M 降低和人类心力衰竭的不良后果。


背景 Apo（载脂蛋白）M 介导高密度脂蛋白（HDL）颗粒和 1-磷酸鞘氨醇（S1P）之间的物理相互作用。 Apo M 在动物模型中发挥抗炎和心脏保护作用。方法 在 PHFS（宾夕法尼亚心力衰竭研究）参与者子集 (n=297) 中，我们通过酶联免疫吸附测定 (ELISA) 测量了 apo M。我们还通过液相色谱-质谱法测量了总 S1P，并分离了 HDL 颗粒，以测试 apo M 和 HDL 相关 S1P 之间的关联。我们使用改良的基于适体的 apo M 测量方法，对 PHFS 中的 2170 名成年人和 2 个独立队列（华盛顿大学心力衰竭登记处 (n=173) 和 TOPCAT（保留心脏功能的治疗）的一个子集）进行了修改，证实了 apo M 与结果之间的关系醛固酮拮抗剂引起的心力衰竭试验；n=218)。最后，我们检查了 apo M 与约 5000 种其他蛋白质之间的关系（SomaScan 测定），以确定与心力衰竭中 apo M 相关的生物途径。结果 在 PHFS 中，apo M 与死亡风险（标准化风险比，0.56 [95% CI，0.51-0.61]；P<0.0001）以及死亡/心室辅助装置植入/心脏移植的复合风险（标准化风险比）呈负相关。风险比，0.62 [95% CI，0.58-0.67]；P<0.0001）。这种关系与 HDL 胆固醇或载脂蛋白 AI 水平无关。 Apo M 仍然与死亡相关（风险比，0.78 [95% CI，0.69-0.88]；P<0.0001）以及死亡/心室辅助装置/心脏移植的复合因素（风险比，0.85 [95% CI，0.76-0.94] ]; P=0.001）在针对多个混杂因素进行调整的模型中。 这种关联在射血分数降低和保留的心力衰竭中都存在，并且在华盛顿大学队列和仅射血分数保留的心力衰竭队列（TOPCAT）中得到了复制。分离的HDL颗粒的S1P和apo M含量强相关（R=0.81，P<0.0001）。与 apo M 相关的最重要的经典途径是炎症（负相关）、凝血系统（负相关）和肝脏 X 受体/类视黄醇 X 受体激活（正相关）。通过独立测定测量的多种炎症标志物验证了与炎症的关系。结论 循环 apo M 减少与人类心力衰竭的不良后果独立相关。需要进一步的研究来评估 apo M/S1P 轴是否是心力衰竭的合适治疗靶点。