载脂蛋白 M 减少与全谱心力衰竭不良结局相关。
Reduced Apolipoprotein M and Adverse Outcomes Across the Spectrum of Human Heart Failure.
机构信息
Perelman School of Medicine. University of Pennsylvania School of Medicine/Hospital of the University of Pennsylvania (J.A.C., S.V.S., J.S.M., D.J.R., B.F., J.B., K.B.M., T.P.C.).
Bristol-Myers Squibb Co, Lawrenceville, NJ (L.Z., Z.W., D.A.S., B.D.C., D.A.G.).
出版信息
Circulation. 2020 May 5;141(18):1463-1476. doi: 10.1161/CIRCULATIONAHA.119.045323. Epub 2020 Apr 2.
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]; <0.0001) and the composite of death/ventricular assist device implantation/heart transplantation (standardized hazard ratio, 0.62 [95% CI, 0.58-0.67]; <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]; <0.0001) and the composite of death/ventricular assist device/heart transplantation (hazard ratio, 0.85 [95% CI, 0.76-0.94]; =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 (=0.81, <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.
背景
载脂蛋白 M 介导高密度脂蛋白 (HDL) 颗粒与鞘氨醇 1-磷酸 (S1P) 之间的物理相互作用。载脂蛋白 M 在动物模型中具有抗炎和心脏保护作用。
方法
在 PHFS（宾夕法尼亚心力衰竭研究）参与者的亚组（n=297）中，我们通过酶联免疫吸附测定法（ELISA）测量载脂蛋白 M。我们还通过液相色谱-质谱法测量总 S1P，并分离 HDL 颗粒，以测试载脂蛋白 M 与 HDL 相关 S1P 之间的关联。我们使用 PHFS 中的 2170 名成年人和 2 个独立队列中的改良基于适配子的载脂蛋白 M 测量值（华盛顿大学心力衰竭登记处，n=173；TOPCAT 亚组，n=218）证实了载脂蛋白 M 与结局之间的关系。最后，我们检查了载脂蛋白 M 与约 5000 种其他蛋白质（SomaScan 测定法）之间的关系，以鉴定与心力衰竭中载脂蛋白 M 相关的生物学途径。
结果
在 PHFS 中，载脂蛋白 M 与死亡风险呈负相关（标准化风险比，0.56 [95%CI，0.51-0.61]；<0.0001）和死亡/心室辅助装置植入/心脏移植的复合终点（标准化风险比，0.62 [95%CI，0.58-0.67]；<0.0001）。这种关系独立于 HDL 胆固醇或载脂蛋白 AI 水平。在调整了多种混杂因素的模型中，载脂蛋白 M 与死亡（风险比，0.78 [95%CI，0.69-0.88]；<0.0001）和死亡/心室辅助装置/心脏移植的复合终点（风险比，0.85 [95%CI，0.76-0.94]；=0.001）仍相关。这种关联在射血分数降低和保留的心力衰竭中均存在，并在华盛顿大学队列和射血分数保留的心力衰竭队列（TOPCAT）中得到复制。分离的 HDL 颗粒中的 S1P 和载脂蛋白 M 含量呈强相关性（=0.81，<0.0001）。与载脂蛋白 M 相关的主要经典途径是炎症（负相关）、凝血系统（负相关）和肝 X 受体/视黄醇 X 受体激活（正相关）。通过使用独立检测法测量的多种炎症标志物验证了与炎症的关系。
结论
循环载脂蛋白 M 减少与人类心力衰竭谱中不良结局独立相关。需要进一步研究评估载脂蛋白 M/S1P 轴是否适合心力衰竭的治疗靶点。
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