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Advances in Clinical Medicine
Vol. 09  No. 04 ( 2019 ), Article ID: 29823 , 5 pages
10.12677/ACM.2019.94070

Advances in New Marker ST2 for Heart Failure

Yajiao Xing, Chenxia Wang

Yanan University Affiliated Hospital, Yan’an Shaanxi

Received: Apr. 1st, 2019; accepted: Apr. 15th, 2019; published: Apr. 23rd, 2019

ABSTRACT

With the successful integration of natriuretic peptide into the clinical practice of heart failure (HF) treatment, the possibility that the new biomarker supplement BNP and its n-terminal equivalent (nt-proBNP) may further promote patient management is being explored. Defects in natriuretic peptides (such as high biological variability and age dependence), and multiple comorbidities in heart failure patients can affect the concentration of BNP or nt-proBNP (such as sepsis, kidney disease and obesity), opening the door to new biomarker additions for clinical judgment. Therefore, this paper reviews the research progress of HF patients’ promising biomarker ST2. In order to rely on the unique pathophysiological information it provides patients with specific selection and monitoring of treatment.

Keywords:Heart Failure, ST2, The Research Progress, BNP (Brain Natriuretic Peptide)

心力衰竭新型标志物ST2的研究进展

邢亚娇，王晨霞

延安大学附属医院，陕西 延安

收稿日期：2019年4月1日；录用日期：2019年4月15日；发布日期：2019年4月23日

摘 要

随着利钠肽成功地整合到心力衰竭(HF)治疗的临床实践中，新的生物标记物补充BNP (B型脑利钠肽Brain natriuretic peptide)及其n端等效物(NT-proBNP)并进一步促进患者管理的可能性正在探索中。利钠肽的缺陷(如高生物变异和年龄依赖性)，心力衰竭患者的多种共病可影响BNP或NT-proBNP的浓度(如败血症、肾病和肥胖)，这为新的生物标志物补充临床判断打开了大门。因此，本文对HF患者有希望的新型生物标志物ST2 (生长刺激表达基因2蛋白)的研究进展进行做一阐述，以期依赖于其提供的独特的病理生理学信息，对患者进行特定的选择和监测治疗。

关键词 :心力衰竭，生长刺激表达基因2蛋白，研究进展，BNP

Copyright © 2019 by author(s) and Hans Publishers Inc.

This work is licensed under the Creative Commons Attribution International License (CC BY).

http://creativecommons.org/licenses/by/4.0/

1. 关于ST2

关于ST2在心肌生物学中的心血管作用早已被证实，ST2中的两种亚型：可溶性(ST2)和跨膜配体(ST2L)与心血管疾病的关系最为密切 [1] 。当心肌细胞和成纤维细胞受到牵拉时，sST2基因则高度表达 [2] ，在这种情况下，ST2L变得易于接受白细胞介素-33 (IL-33也被细胞拉伸诱导)。IL-33具有ST2L转导的抗增生性和抗纤维化作用，而sST2可阻断IL-33的良好影响。这表明sST2可能作为IL-33循环的诱饵受体。支持这一假设的是，在压力超负荷的体内模型中，ST2小鼠在主动脉束带4周后，心肌细胞肥大和纤维化程度明显高于野生型小鼠，左室功能也较差 [3] 。此外，还提出了ST2在血管重构过程中的作用 [4] 。

2. ST2与急性和慢性心衰

美国心脏病学会/美国心脏协会(ACC/AHA)最近更新的临床实践指南为急性失代偿性心力衰竭(ADHF) (证据水平a)和慢性心力衰竭(证据水平B)的sST2测量提供了IIb类建议，目的是对心力衰竭患者进行风险分层 [5] 。

数据证明ST2在心衰管理方面是强有力的竞争者。在急诊科对593例急性呼吸困难患者的分析中发现，209例急性心力衰竭患者sST2浓度较高。在对1年死亡预测因子的完全调整分析中，sST2是PRIDE研究中检测到的最强的生物标志物，其危险比为4.6，而NT-proBNP为2.3，这一观察扩展到了4年的结果 [6] 。sST2浓度越高，左室体积越大，LVEF越差，右心功能越差，肺压力越大，血流动力学特征越失代偿 [7] 。sST2对保留射血分数(HFpEF)的HF患者的预后与射血分数(HFrEF)下降的患者相同 [8] 。

在另一项研究中，高浓度sST2和NT-proBNP水平的病人面临死亡的风险也最高，1年(>40%)，然而，重要的是，在那些较低数水平浓度的病人，根据sST2的升高水平对死亡的可能性进行重新分级，表明即使是在那些利钠肽值较低的病人，sST2也可提供有用的信息。类似的结果在ADHF队列中也有报道，使用高度敏感(hs)肌钙蛋白T、NT-proBNP和sST2进行多标记检测，可以精确地将受试者分层，从低(<5%的死亡率)到非常高(>50%)的风险。

与其他生物标志物相比 [9] ，sST2对预后的重要性在其他几项分析中也得到了证实。在PRIDE研究中，除了NT-proBNP外，sST2在预后方面优于其他几种生物标志物，包括炎性生物学标志物，肌钙蛋白，半乳糖凝集素-3。在一项大规模meta分析ADHF患者中，大量的生物标志物相互偏离，sST2在预测死亡方面提供了与最强的预后生物标志物相媲美的价值，改善了包含其他生物标志物和临床变量的临床模型之外的风险重新分类。此外，在进展期HF患者中，只有sST2可预测90天死亡或移植(危险比5.53)，而pro-BNP、肾标志物、超敏肌钙蛋白和炎症标志物均不能预测90天死亡或移植(危险比5.53) [10] 。

新出现的数据显示，使用sST2序列水平来监测患者的预后，而不是依赖单一的ADHF预后测量。在一项研究中，住院进行药物治疗后sST2值仍>76 ng/mL的患者，其死亡、移植或再次住院的风险为50%。

在慢性心力衰竭的门诊患者中，sST2具有相当强的预后价值，再次对利钠肽进行了补充，对HFpEF和HFrEF患者的预后也同样有用。在最近一次sST2与半乳糖凝集素-3的面对面比较中，sST2对动态HF的预后有更好的鉴别、校正和分类 [11] 。与ADHF一样，慢性HF中sST2的连续测量增加了大量的预后信息，与其他标志物相比(包括超敏肌钙蛋白T、生长分化因子-15 (GDF-15)和NT-proBNP)具有更好的预后表现 [12] 。

3. ST2在有心力衰竭风险的个体中

弗雷明汉心脏研究的3428名受试者，在平均11年的随访中，有33例sST2浓度升高与HF、CV事件或死亡独立相关 [13] 。这一预测价值可以解释为sST2预测收缩期高血压发病的能力，这与血管重建的作用是一致的 [14] 。芬兰一项基于人群研究的最新数据显示，基线sST2水平不能预测调整后模型中的HF或CV事件，但可以预测全因死亡率 [15] ，该研究包括8444名受试者，随访15年，除了以社区为基础的研究对象，sST2还预测急性冠状动脉综合征患者中HF的发病。例如，在4426例非st段抬高型急性冠状动脉综合征患者中，sST2 > 35 ng/mL的患者，即使在调整了临床协变量和生物标志物(危险比1.90)之后，在30天和1年后仍会增加HF并发症的风险，并将sST2添加到基础模型中，对其分类进行了相当大的改进 [16] [17] [18] 。

4. ST2在心力衰竭管理中的潜在作用

sST2与HF治疗干预之间的几个重要相互作用最近被提出，所有这些建议都是基于回顾性数据，在慢性心力衰竭患者中，使用更高剂量的β-受体阻滞剂治疗后，sST2浓度下降，而在sST2 > 35 ng/mL的环境中滴定时，高剂量β-受体阻滞剂的疗效明显高于低浓度sST2 [19] 。在缬沙坦HF试验(缬沙坦-heft)中，缬沙坦治疗组sST2浓度低于安慰剂组，而Maisel和他的同事则认为，sST2升高与盐皮质激素受体拮抗剂(MRA)治疗的益处之间存在相互作用，相反，在利钠肽和半乳糖凝集素-3之间没有发现这种相互作用 [20] 。sST2可预测可植入性心律转复除颤器(ICD)治疗和慢性心衰猝死，sST2测量还可以用于检测心脏移植后的排斥反应以及预测预后，最后，初步数据表明，对急性心肌梗死(MI)患者sST2的测量可能有助于治疗决策。Weir and colleagues研究表明高浓度的sST2有可能可以认证心梗后血管重建风险获益于依普利酮，而半乳糖凝集素-3并没有相关结果 [20] 。

5. 结语

综上，ST2作为新型心衰标志物，依据其病理生理机制，有其独特的优势，有望与BNP联合应用于临床以对心衰诊断及治疗以其预后提供参考依据。

文章引用

邢亚娇,王晨霞. 心力衰竭新型标志物ST2的研究进展
Advances in New Marker ST2 for Heart Failure[J]. 临床医学进展, 2019, 09(04): 451-455. https://doi.org/10.12677/ACM.2019.94070

参考文献

  1. 1. Iwahana, H., Yanagisawa, K., Ito-Kosaka, A., Kuroiwa, K., Tago, K., Komatsu, N., Katashima, R., Itakura, M. and Tominaga, S. (1999) Different Promoter Usage and Multiple Transcription Initiation Sites of the Interleukin-1 Recep-tor-Related Human ST2 Gene in UT-7 and TM12 Cells. European Journal of Biochemistry, 264, 397-406. https://doi.org/10.1046/j.1432-1327.1999.00615.x

  2. 2. Weinberg, E.O., Shimpo, M., De Keulenaer, G.W., Mac-Gillivray, C., Tominaga, S., Solomon, S.D., Rouleau, J.L. and Lee, R.T. (2002) Expression and Regulation of ST2, an Interleukin-1 Receptor Family Member, in Cardiomyocytes and Myocardial Infarction. Circulation, 106, 2961-2966. https://doi.org/10.1161/01.CIR.0000038705.69871.D9

  3. 3. Sanada, S., Hakuno, D., Higgins, L.J., Schreiter, E.R., McKenzie, A.N. and Lee, R.T. (2007) IL-33 and ST2 Comprise a Critical Biomechanically Induced and Cardioprotective Signaling System. Journal of Clinical Investigation, 117, 1538-1549. https://doi.org/10.1172/JCI30634

  4. 4. Demyanets, S., Kaun, C., Pentz, R., Krychtiuk, K.A., Rauscher, S., Pfaffenberger, S., Zuckermann, A., Aliabadi, A., Groger, M., Maurer, G., Huber, K. and Wojta, J. (2013) Components of the Interleukin-33/ST2 System Are Differentially Expressed and Regulated in Human Cardiac Cells and in Cells of the Cardiac Vasculature. Journal of Molecular and Cellular Cardiology, 60, 16-26. https://doi.org/10.1016/j.yjmcc.2013.03.020

  5. 5. Yancy, C.W., Jessup, M., Bozkurt, B., Masoudi, F.A., Butler, J., McBride, P.E., Casey, D.E., McMurray, J.J., Drazner, M.H., Mitchell, J.E., Fonarow, G.C., Peterson, P.N., Geraci, S.A., Horwich, T., Januzzi, J.L., Johnson, M.R., Kasper, E.K., Levy, W.C., Riegel, B., Sam, F., Stevenson, L.W., Tang, W.H., Tsai, E.J. and Wilkoff, B.L. (2013) ACCF/AHA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Journal of the American College of Cardiology, 62, e147-e239. https://doi.org/10.1016/j.jacc.2013.05.019

  6. 6. Januzzi, J.L., Peacock, W.F., Maisel, A.S., Chae, C.U., Jesse, R.L., Baggish, A.L., O’Donoghue, M., Sakhuja, R., Chen, A.A., van Kimmenade, R.R., Lewandrowski, K.B., Lloyd-Jones, D.M. and Wu, A.H. (2007) Measurement of the Interleukin Family Member ST2 in Patients with Acute Dyspnea: Results from the PRIDE (ProBrain Natriuretic Peptide Investigation of Dyspneain the Emergency Department) Study. Journal of the American College of Cardiology, 50, 607-613. https://doi.org/10.1016/j.jacc.2007.05.014

  7. 7. Januzzi, J.L., Rehman, S., Mueller, T., van Kimmenade, R.R. and Lloyd-Jones, D.M. (2010) Importance of Biomarkers for Long-Term Mortality Prediction in Acutely Dyspneic Patients. Clinical Chemistry, 56, 1814-1821. https://doi.org/10.1373/clinchem.2010.146506

  8. 8. Shah, R.V., Chen-Tournoux, A.A., Picard, M.H., van Kim-menade, R.R. and Januzzi, J.L. (2009) Serum Levels of the Interleukin-1 Receptor Family Member ST2, Cardiac Structure and Function, and Long-Term Mortality in Patients with Acute Dyspnea. Circulation: Heart Failure, 2, 311-319. https://doi.org/10.1161/CIRCHEARTFAILURE.108.833707

  9. 9. Manzano-Fernandez, S., Mueller, T., Pascu-al-Figal, D., Truong, Q.A. and Januzzi, J.L. (2011) Usefulness of Soluble Concentrations of Interleukin Family Member ST2 as Predictor of Mortality in Patients with Acutely Decompensated Heart Failure Relative to Left Ventricular Ejection Fraction. American Journal of Cardiology, 107, 259-267. https://doi.org/10.1016/j.amjcard.2010.09.011

  10. 10. Rehman, S.U., Mueller, T. and Januzzi, J.L. (2008) Charac-teristics of the Novel Interleukin Family Biomarker ST2 in Patients with Acute Heart Failure. JACC: Journal of the American College of Cardiology, 52, 1458-1465. https://doi.org/10.1016/j.jacc.2008.07.042

  11. 11. Pascual-Figal, D.A., Manzano-Fernandez, S., Boronat, M., Casas, T., Garrido, I.P., Bonaque, J.C., Pastor-Perez, F., Valdes, M. and Januzzi, J.L. (2011) Soluble ST2, High-Sensitivity, Troponin-T and N-Terminal pro-B-type Natriuretic Peptide, Complementary Role for Risk Stratification in Acutely Decompensated Heart Failure. European Journal of Heart Failure, 13, 718-725. https://doi.org/10.1093/eurjhf/hfr047

  12. 12. Lassus, J., Gayat, E., Mueller, C., Peacock, W.F., Spinar, J., Harjola, V.P., van Kimmenade, R., Pathak, A., Mueller, T., Disomma, S., Metra, M., Pascual-Figal, D., Laribi, S., Logeart, D., Nouira, S., Sato, N., Potocki, M., Parenica, J., Collet, C., Cohen-Solal, A., Januzzi, J.L. and Mebazaa, A. (2013) In-cremental Value of Biomarkers to Clinical Variables for Mortality Prediction in Acutely Decompensated Heart Failure: The Multinational Observational Cohort on Acute Heart Failure (MOCA) Study. International Journal of Cardiology, 168, 2186-2194. https://doi.org/10.1016/j.ijcard.2013.01.228

  13. 13. Zilinski, J.L., Shah, R.V., Gaggin, H.K., Gantzer, M.L., Wang, T.J. and Januzzi, J.L. (2012) Measurement of Multiple Biomarkers in Advanced Stage Heart Failure Patients Treated with Pulmonary Artery Catheter Guided Therapy. Critical Care, 16, r135. https://doi.org/10.1186/cc11440

  14. 14. Boisot, S., Beede, J., Isakson, S., Chiu, A., Clopton, P., Januzzi, J., Maisel, A.S. and Fitzgerald, R.L. (2008) Serial Sampling of ST2 Predicts 90-Day Mortality Following Destabilized Heart Failure. Journal of Cardiac Failure, 14, 732-738. https://doi.org/10.1016/j.cardfail.2008.06.415

  15. 15. Manzano-Fernandez, S., Januzzi, J.L., Pastor-Perez, F.J., Bonaque-Gonzalez, J.C., Boronat-Garcia, M., Pascual-Figal, D.A., Montalban-Larrea, S., Navarro-Penalver, M., An-dreu-Cayuelas, J.M. and Valdes, M. (2012) Serial Monitoring of Soluble Interleukin Family Member ST2 in Patients with Acutely Decompensated Heart Failure. Cardiology, 122, 158-166. https://doi.org/10.1159/000338800

  16. 16. Ky, B., French, B., McCloskey, K., Rame, J.E., McIntosh, E., Shahi, P., Dries, D.L., Tang, W.H., Wu, A.H., Fang, J.C., Boxer, R., Sweitzer, N.K., Levy, W.C., Goldberg, L.R., Jessup, M. and Cappola, T.P. (2011) High-Sensitivity ST2 for Prediction of Adverse Outcomes in Chronic Heart Failure. Circulation: Heart Failure, 4, 180-187. https://doi.org/10.1161/CIRCHEARTFAILURE.110.958223

  17. 17. Bayes-Genis, A., de Antonio, M., Vila, J., Penafiel, J., Galan, A., Barallat, J., Zamora, E., Urrutia, A. and Lupon, J. (2014) Head-to-Head Comparison of 2 Myo-cardial Fibrosis Biomarkers for Long-Term Heart Failure Risk Stratification: ST2 versus Galectin-3. Journal of the American College of Cardiology, 63, 158-166. https://doi.org/10.1016/j.jacc.2013.07.087

  18. 18. Gaggin, H.K., Szymonifka, J., Bhardwaj, A., Belcher, A., De Berardinis, B., Motiwala, S., Wang, T.J. and Januzzi, J.L. (2014) Head-to-Head Comparison of Serial Soluble ST2, Growth Differentiation Factor-15, and Highly-Sensitive Troponin T Measurements in Patients with Chronic Heart Failure. JACC Heart Fail, 2, 65-72. https://doi.org/10.1016/j.jchf.2013.10.005

  19. 19. Gaggin, H.K., Motiwala, S., Bhardwaj, A., Parks, K.A. and Januzzi, J.L. (2013) Soluble Concentrations of the Interleukin Receptor Family Member ST2 and Beta-Blocker Therapy in Chronic Heart Failure. Circulation: Heart Failure, 6, 1206-1213. https://doi.org/10.1161/CIRCHEARTFAILURE.113.000457

  20. 20. Anand, I.S., Rector, T.S., Kuskowski, M., Snider, J. and Cohn, J.N. (2014) Prognostic Value of Soluble ST2 in the Valsartan Heart Failure Trial. Circulation: Heart Failure, 7, 418-426. https://doi.org/10.1161/CIRCHEARTFAILURE.113.001036

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