前蛋白转化酶枯草溶菌素9抑制剂在急性冠脉综合征患者中的研究进展

doi:10.3969/j.issn.1674-490X.2024.06.001

摘要/Abstract

摘要： 低密度脂蛋白胆固醇是冠心病的主要危险因素之一,与冠心病的不良预后密切相关。前蛋白转化酶枯草溶菌素9在调节胆固醇代谢中具有重要作用。前蛋白转化酶枯草溶菌素9抑制剂能够通过抑制前蛋白转化酶枯草溶菌素9增加细胞膜表面低密度脂蛋白胆固醇受体,显著降低血浆低密度脂蛋白胆固醇水平,从而减少冠心病患者不良心血管事件发生。现通过归纳应用前蛋白转化酶枯草溶菌素9抑制剂改善动脉粥样硬化的理论依据,同时列举其在急性冠脉综合征患者中的临床获益,为该类人群实施前蛋白转化酶枯草溶菌素9抑制剂强化降脂治疗提供依据。

关键词: 前蛋白转化酶枯草溶菌素9抑制剂, 急性冠脉综合征, 低密度脂蛋白胆固醇, 炎症反应, 血小板, 主要不良心血管事件

Abstract: Low-density lipoprotein cholesterol(LDL-C)is one of the major risk factors for coronary heart disease(CHD)and is closely related to adverse outcomes in CHD patients. Proprotein convertase subtilisin/kexin type 9(PCSK9)plays an important role in regulating cholesterol metabolism. PCSK9 inhibitors can increase the number of LDL-C receptors on cell membranes by inhibiting PCSK9, significantly lowering plasma LDL-C levels. This reduction helps to decrease the occurrence of adverse cardiovascular events in CHD patients. This study summarizes the theoretical basis for using PCSK9 inhibitors to improve atherosclerosis and highlights their clinical benefits in patients with acute coronary syndrome. This provides justification for implementing intensified lipid-lowering therapy with PCSK9 inhibitors in this patient population.

Key words: proprotein convertase subtilisin/kexin type 9 inhibitors, acute coronary syndrome, low density lipoprotein cholesterol, inflammatory response, platelets, major adverse cardiac events

中图分类号:

冯荣,鲁佳慧,胡晋滔,杨迪,李亚芹,崔红根. 前蛋白转化酶枯草溶菌素9抑制剂在急性冠脉综合征患者中的研究进展[J]. 医学研究与教育, 2024, 41(6): 1-8.

参考文献

[1] 《中国心血管健康与疾病报告》编写组. 《中国心血管健康与疾病报告2022》要点解读[J]. 中国心血管杂志, 2023, 28(4): 297-312. DOI: 10.3969/j.issn.1007-5410.2023.04.001.
[2] RAY K K, COLHOUN H M, SZAREK M, et al. Effects of alirocumab on cardiovascular and metabolic outcomes after acute coronary syndrome in patients with or without diabetes: a prespecified analysis of the ODYSSEY OUTCOMES randomised controlled trial[J]. Lancet Diabetes Endocrinol, 2019, 7(8): 618-628. DOI: 10.1016/S2213-8587(19)30158-5.
[3] ERVITI J, WRIGHT J, BASSETT K, et al. Restoring mortality data in the FOURIER cardiovascular outcomes trial of evolocumab in patients with cardiovascular disease: a reanalysis based on regulatory data[J]. BMJ Open, 2022, 12(12): e060172. DOI: 10.1136/bmjopen-2021-060172.
[4] WRIGHT R S, KOENIG W, LANDMESSER U, et al. Safety and tolerability of inclisiran for treatment of hypercholesterolemia in 7 clinical trials[J]. J Am Coll Cardiol, 2023, 82(24): 2251-2261. DOI: 10.1016/j.jacc.2023.10.007.
[5] MOMTAZI-BOROJENI A A, SABOURI-RAD S, GOTTO A M, et al. PCSK9 and inflammation: a review of experimental and clinical evidence[J]. Eur Heart J Cardiovasc Pharmacother, 2019, 5(4): 237-245. DOI: 10.1093/ehjcvp/pvz022.
[6] SEIDAH N G, PRAT A. The multifaceted biology of PCSK9[J]. Endocr Rev, 2022, 43(3): 558-582. DOI: 10.1210/endrev/bnab035.
[7] VALENTI V, NOTO D, GIAMMANCO A, et al. PCSK9-D374Y mediated LDL-R degradation can be functionally inhibited by EGF-A and truncated EGF-a peptides: an in vitro study[J]. Atherosclerosis, 2020, 292: 209-214. DOI: 10.1016/j.atherosclerosis.2019.09.009.
[8] COPPINGER C, MOVAHED M R, AZEMAWAH V, et al. A comprehensive review of PCSK9 inhibitors[J]. J Cardiovasc Pharmacol Ther, 2022, 27: 10742484221100107. DOI: 10.1177/10742484221100107.
[9] 中国血脂管理指南修订联合专家委员会. 中国血脂管理指南(2023年)[J]. 中华心血管病杂志, 2023, 51(3): 221-255. DOI: 10.3760/cma.j.cn112148-20230119-00038.
[10] 中华医学会心血管病学分会动脉粥样硬化与冠心病学组, 中华心血管病杂志编辑委员会. 超高危动脉粥样硬化性心血管疾病患者血脂管理中国专家共识[J]. 中华心血管病杂志, 2020, 48(4): 280-286. DOI: 10.3760/cma.j.cn112148-20200121-00036.
[11] 中华医学会老年医学分会, 高龄老年冠心病诊治中国专家共识写作组. 高龄老年冠心病诊治中国专家共识[J]. 中华老年医学杂志, 2016, 35(7): 683-691. DOI: 10.3760/cma.j.issn.0254-9026.2016.07.001.
[12] 韩雅玲, 马颖艳, 苏国海, 等. 阿利西尤单抗与依折麦布治疗高胆固醇血症合并心血管高危患者的疗效及安全性比较: ODYSSEY EAST研究中国地区亚组分析[J]. 中华心血管病杂志, 2020, 48(7): 7. DOI: 10.3760/cma.j.cn112148-20191216-00755.
[13] DEEDWANIA P, MURPHY S A, SCHEEN A, et al. Efficacy and safety of PCSK9 inhibition with evolocumab in reducing cardiovascular events in patients with metabolic syndrome receiving statin therapy: secondary analysis from the FOURIER randomized clinical trial[J]. JAMA Cardiol, 2021, 6(2): 139-147. DOI: 10.1001/jamacardio.2020.3151.
[14] HUO Y, LESOGOR A, LEE C W, et al. Efficacy and safety of inclisiran in Asian patients: results from ORION-18[J]. JACC Asia, 2023, 4(2): 123-134. DOI: 10.1016/j.jacasi.2023.09.006.
[15] DALGIC Y, ABACI O, KOCAS C, et al. The relationship between protein convertase subtilisin kexin type-9 levels and extent of coronary artery disease in patients with non-ST-elevation myocardial infarction[J]. Coron Artery Dis, 2020, 31(1): 81-86. DOI: 10.1097/M-CA.0000000000000774.
[16] GAO J, YANG Y N, CUI Z, et al. Pcsk9 is associated with severity of coronary artery lesions in male patients with premature myocardial infarction[J]. Lipids Health Dis, 2021, 20(1): 56. DOI: 10.1186/s12944-021-01478-w.
[17] LI H Y, WEI Y D, YANG Z H, et al. Safety, tolerability, pharmacokinetics, and pharmacodynamics of alirocumab in healthy Chinese subjects: a randomized, double-blind, placebo-controlled, ascending single-dose study[J]. Am J Cardiovasc Drugs, 2020, 20(5): 489-503. DOI: 10.1007/s40256-020-00394-1.
[18] RAY K K, TROQUAY R P T, VISSEREN F L J, et al. Long-term efficacy and safety of inclisiran in patients with high cardiovascular risk and elevated LDL cholesterol(ORION-3): results from the 4-year open-label extension of the ORION-1 trial[J]. Lancet Diabetes Endocrinol, 2023, 11(2): 109-119. DOI: 10.1016/S2213-8587(22)00353-9.
[19] FERRI N, RUSCICA M, LUPO M G, et al. Pharmacological rationale for the very early treatment of acute coronary syndrome with monoclonal antibodies anti-PCSK9[J]. Pharmacol Res, 2022, 184: 106439. DOI: 10.1016/j.phrs.2022.106439.
[20] PATRIKI D, SARAVI S S S, CAMICI G G, et al. PCSK 9: a link between inflammation and atherosclerosis[J]. Curr Med Chem, 2022, 29(2): 251-267. DOI: 10.2174/0929867328666210707192625.
[21] WANG F F, LI M, ZHANG A D, et al. PCSK9 modulates macrophage polarization-mediated ventricular remodeling after myocardial infarction[J]. J Immunol Res, 2022, 2022: 7685796. DOI: 10.1155/2022/7685796.
[22] DING Z F, POTHINENI N V K, GOEL A, et al. PCSK9 and inflammation: role of shear stress, pro-inflammatory cytokines, and LOX-1[J]. Cardiovasc Res, 2020, 116(5): 908-915. DOI: 10.1093/cvr/cvz313.
[23] HASSANZADEH-MAKOUI R, RAZI B, ASLANI S, et al. The association between matrix metallo-proteinases-9(MMP-9)gene family polymorphisms and risk of coronary artery disease(CAD): a systematic review and meta-analysis[J]. BMC Cardiovasc Disord, 2020, 20(1): 232. DOI: 10.1186/s12872-020-01510-4.
[24] POLAK D, TALAR M, WATALA C, et al. Intravital assessment of blood platelet function. A review of the methodological approaches with examples of studies of selected aspects of blood platelet function[J]. Int J Mol Sci, 2020, 21(21): 8334. DOI: 10.3390/ijms21218334.
[25] BARALE C, BONOMO K, FRASCAROLI C, et al. Platelet function and activation markers in primary hypercholesterolemia treated with anti-PCSK9 monoclonal antibody: a 12-month follow-up[J]. Nutr Metab Cardiovasc Dis, 2020, 30(2): 282-291. DOI: 10.1016/j.numecd.2019.09.012.
[26] CAMMISOTTO V, BARATTA F, CASTELLANI V, et al. Proprotein convertase subtilisin kexin type 9 inhibitors reduce platelet activation modulating ox-LDL pathways[J]. Int J Mol Sci, 2021, 22(13): 7193. DOI: 10.3390/ijms22137193.
[27] QI Z Y, HU L, ZHANG J J, et al. PCSK9(proprotein convertase subtilisin/kexin 9)enhances platelet activation, thrombosis, and myocardial infarct expansion by binding to platelet CD36[J]. Circulation, 2021, 143(1): 45-61. DOI: 10.1161/CIRCULATIONAHA.120.046290.
[28] GUEDENEY P, SORRENTINO S, GIUSTINO G, et al. Indirect comparison of the efficacy and safety of alirocumab and evolocumab: a systematic review and network meta-analysis[J]. Eur Heart J Cardiovasc Pharmacother, 2021, 7(3): 225-235. DOI: 10.1093/ehjcvp/pvaa024.
[29] BLOM D J, CHEN J Y, YUAN Z Y, et al. Effects of evolocumab therapy and low LDL-C levels on vitamin E and steroid hormones in Chinese and global patients with type 2 diabetes[J]. Endocrinol Diabetes Metab, 2020, 3(2): e00123. DOI: 10.1002/edm2.123.
[30] GAUDET D, LÓPEZ-SENDÓN J L, AVERNA M, et al. Safety and efficacy of alirocumab in a real-life setting: the ODYSSEY APPRISE study[J]. Eur J Prev Cardiol, 2022, 28(17): 1864-1872. DOI: 10.1093/eurjpc/zwaa097.
[31] CALAPAI F, MANNUCCI C, CURRÒ M, et al. Adverse reactions to evolocumab: analysis of real-world data from EudraVigilance[J]. Pharmaceuticals, 2024, 17(3): 364. DOI: 10.3390/ph17030364.
[32] RAY K K, WRIGHT R S, KALLEND D, et al. Two phase 3 trials of inclisiran in patients with elevated LDL cholesterol[J]. N Engl J Med, 2020, 382(16): 1507-1519. DOI: 10.1056/NEJMoa1912387.
[33] RÄBER L, UEKI Y, OTSUKA T, et al. Effect of alirocumab added to high-intensity statin therapy on coronary atherosclerosis in patients with acute myocardial infarction: the PACMAN-AMI randomized clinical trial[J]. JAMA, 2022, 327(18): 1771-1781. DOI: 10.1001/jama.2022.5218.
[34] NICHOLLS S J, KATAOKA Y, NISSEN S E, et al. Effect of evolocumab on coronary plaque phenotype and burden in statin-treated patients following myocardial infarction[J]. JACC Cardiovasc Imaging, 2022, 15(7): 1308-1321. DOI: 10.1016/j.jcmg.2022.03.002.
[35] HAO Y, YANG Y L, WANG Y C, et al. Effect of the early application of evolocumab on blood lipid profile and cardiovascular prognosis in patients with extremely high-risk acute coronary syndrome[J]. Int Heart J, 2022, 63(4): 669-677. DOI: 10.1536/ihj.22-052.
[36] ZHANG Y H, ZHANG Y H, ZHANG B, et al. Early initiation of evolocumab treatment in Chinese patients with acute coronary syndrome undergoing percutaneous coronary intervention[J]. Clin Ther, 2022, 44(6): 901-912. DOI: 10.1016/j.clinthera.2022.04.010.
[37] LUAN Y, WANG M, ZHAO L D, et al. Safety and efficacy of perioperative use of evolocumab in myocardial infarction patients: study protocol for a multicentre randomized controlled trial[J]. Adv Ther, 2021, 38(4): 1801-1810. DOI: 10.1007/s12325-021-01662-5.