Proteomic and Mechanistic Analysis of Spironolactone in Patients at Risk for HF
Proteomic and Mechanistic Analysis of Spironolactone in Patients at Risk for HF
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DOI：
10.1016/j.jchf.2020.11.010
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发表时间：
2021-03-29
影响因子：
13
通讯作者：
Zannad, Faiez
中科院分区：
文献类型：
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作者：
Ferreira, Joao Pedro;Verdonschot, Job;Zannad, Faiez
目的 本研究旨在进一步了解螺内酯作用的潜在机制，并评估其对多种血浆蛋白生物标志物及其各自的潜在生物学途径的影响。 背景 除了对已确定的心力衰竭 (HF) 的有益作用外，盐皮质激素受体拮抗剂还可能在机制上游发挥作用，预防心力衰竭的发生。在有心力衰竭风险的人群中，HOMAGE（AGEing 中的心脏 OMics）试验表明，螺内酯治疗可以提供抗纤维化和抗重塑作用，可能减缓心力衰竭的进展。 方法 使用 Olink Proseek-Multiplex 心血管和炎症面板（Olink，瑞典乌普萨拉）。通过协方差分析评估螺内酯对生物标志物的影响，并通过基于知识的网络分析进行探索。结果 共有 527 名参与者入组； 265 名患者被随机分配至螺内酯（25 至 50 毫克/天），262 名患者被随机分配至标准护理（“对照”）。中位年龄（四分位距）为 73 岁（69 至 79 岁），其中 26% 为女性。螺内酯降低胶原代谢的生物标志物（例如 COL1A1、MMP-2）；脑钠肽；以及与代谢过程（例如 PAPPA）、炎症和血栓形成（例如 IL17A、VEGF 和尿激酶）相关的生物标志物。螺内酯增加反映盐皮质激素受体（例如肾素）阻断的生物标志物，并增加参与抗炎反应（例如 RARRES2）的脂肪因子和止血维持生物标志物（例如 tPA、UPAR）、骨髓抑制活性（例如 CCL16）、胰岛素抑制（例如 RETN）和炎症调节的水平（例如，IL-12B）。结论蛋白质组学分析表明螺内酯发挥多效性作用，包括减少纤维化、炎症、血栓形成、充血和改善血管功能，所有这些都可能介导心血管保护作用，可能减缓心力衰竭的进展。 （HOMAGE [盐皮质激素受体拮抗剂预防心力衰竭的生物分析反应]；NCT02556450）(C) 2021，美国心脏病学会基金会。
OBJECTIVES This study sought to further understand the mechanisms underlying effect of spironolactone and assessed its impact on multiple plasma protein biomarkers and their respective underlying biologic pathways.BACKGROUND In addition to their beneficial effects in established heart failure (HF), mineralocorticoid receptor antagonists may act upstream on mechanisms, preventing incident HF. In people at risk for developing HF, the HOMAGE (Heart OMics in AGEing) trial showed that spironolactone treatment could provide antifibrotic and antiremodeling effects, potentially slowing the progression to HF.METHODS Baseline, 1-month, and 9-month (or last visit) plasma samples of HOMAGE participants were measured for protein biomarkers (n = 276) by using Olink Proseek-Multiplex cardiovascular and inflammation panels (Olink, Uppsala, Sweden). The effect of spironolactone on biomarkers was assessed by analysis of covariance and explored by knowledgebased network analysis. RESULTS A total of 527 participants were enrolled; 265 were randomized to spironolactone (25 to 50 mg/day) and 262 to standard care ("control"). The median (interquartile range) age was 73 years (69 to 79 years), and 26% were female. Spironolactone reduced biomarkers of collagen metabolism (e.g., COL1A1, MMP-2); brain natriuretic peptide; and biomarkers related to metabolic processes (e.g., PAPPA), inflammation, and thrombosis (e.g., IL17A, VEGF, and urokinase). Spironolactone increased biomarkers that reflect the blockade of the mineralocorticoid receptor (e.g., renin) and increased the levels of adipokines involved in the anti-inflammatory response (e.g., RARRES2) and biomarkers of hemostasis maintenance (e.g., tPA, UPAR), myelosuppressive activity (e.g., CCL16), insulin suppression (e.g., RETN), and inflammatory regulation (e.g., IL-12B).CONCLUSIONS Proteomic analyses suggest that spironolactone exerts pleiotropic effects including reduction in fibrosis, inflammation, thrombosis, congestion, and vascular function improvement, all of which may mediate cardiovascular protective effects, potentially slowing progression toward heart failure. (HOMAGE [Bioprofiling Response to Mineralocorticoid Receptor Antagonists for the Prevention of Heart Failure]; NCT02556450) (C) 2021 by the American College of Cardiology Foundation.