|
|
PCSK9及其抑制剂在急性缺血性卒中预防和治疗中的应用
|
Abstract:
在缺血性卒中的多种风险原因中，高脂血症特别是高胆固醇血症始终占有着很关键的地位，通过降低血浆中胆固醇特别是低密度脂蛋白胆固醇的水平，可以很有效地减少缺血性卒中发生的风险，这一观点已是世界神经科专家的普遍共识。他汀类药物是缺血性卒中二级预防的基石，被广泛应用于临床，然而，他汀类药物也有其自身的局限性。首先，如果他汀类药物剂量增加一倍，其降脂效果仅增加6%，这使得许多患者仅靠他汀类药物很难达到LDL-C目标。其次，有些患者不能耐受他汀类药物，这一现象在接受大剂量他汀类药物治疗的中国患者中尤为明显。近几年新上市的新型降脂药物–前蛋白转化酶枯草溶菌素9 (proprotein convertase subtilisin/kexin type 9, PCSK9)抑制剂则为缺血性卒中的治疗提供了新的策略。
Among the myriad risk factors for ischemic stroke, hyperlipidemia, particularly hypercholesterolemia, consistently holds a pivotal role. The reduction of plasma cholesterol levels, notably low-density lipoprotein cholesterol (LDL-C), has been recognized as an effective strategy to mitigate the risk of ischemic stroke. This perspective has garnered widespread acceptance among neurology experts globally. Statins, as the mainstay of secondary prevention for ischemic stroke, are extensively utilized in clinical settings. However, statins are not without their inherent limitations. Firstly, the lipid-lowering efficacy of statins plateaus with increased dosage; doubling the dose results in a mere 6% increase in cholesterol reduction, making it challenging for many patients to achieve their LDL-C targets with statin monotherapy. Secondly, statin intolerance is not uncommon, with a pronounced incidence observed among Chinese patients undergoing high-dose statin therapy. In this context, the advent of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, a novel class of lipid-lowering agents, offers a promising alternative for the management of ischemic stroke, presenting a new therapeutic horizon in the field.
| [1] | Cui, C., Li, S. and Li, J. (2015) PCSK9 and Its Modulation. Clinica Chimica Acta, 440, 79-86. https://doi.org/10.1016/j.cca.2014.10.044 |
| [2] | Moustafa, B. and Testai, F.D. (2021) Efficacy and Safety of PCSK9 Inhibitors in Stroke Prevention. Journal of Stroke and Cerebrovascular Diseases, 30, Article 106057. https://doi.org/10.1016/j.jstrokecerebrovasdis.2021.106057 |
| [3] | Kent, S.T., Rosenson, R.S., Avery, C.L., Chen, Y.I., Correa, A., Cummings, S.R., et al. (2017) PCSK9 Loss-of-Function Variants, Low-Density Lipoprotein Cholesterol, and Risk of Coronary Heart Disease and Stroke. Circulation: Cardiovascular Genetics, 10, 1-9. https://doi.org/10.1161/circgenetics.116.001632 |
| [4] | Rao, A.S., Lindholm, D., Rivas, M.A., Knowles, J.W., Montgomery, S.B. and Ingelsson, E. (2018) Large-Scale Phenome-Wide Association Study of PCSK9 Variants Demonstrates Protection against Ischemic Stroke. Circulation: Genomic and Precision Medicine, 11, e002162. https://doi.org/10.1161/circgen.118.002162 |
| [5] | Au, A., Griffiths, L.R., Cheng, K., Wee Kooi, C., Irene, L. and Keat Wei, L. (2015) The Influence of OLR1 and PCSK9 Gene Polymorphisms on Ischemic Stroke: Evidence from a Meta-Analysis. Scientific Reports, 5, Article No. 18224. https://doi.org/10.1038/srep18224 |
| [6] | Lei, J. (2014) Correlation of PCSK9 Gene Polymorphism with Cerebral Ischemic Stroke in Xinjiang Han and Uygur Populations. Medical Science Monitor, 20, 1758-1767. https://doi.org/10.12659/msm.892091 |
| [7] | Abboud, S., Karhunen, P.J., Lütjohann, D., Goebeler, S., Luoto, T., Friedrichs, S., et al. (2007) Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Gene Is a Risk Factor of Large-Vessel Atherosclerosis Stroke. PLOS ONE, 2, e1043. https://doi.org/10.1371/journal.pone.0001043 |
| [8] | Slimani, A., Harira, Y., Trabelsi, I., Jomaa, W., Maatouk, F., Hamda, K.B., et al. (2014) Effect of E670G Polymorphism in PCSK9 Gene on the Risk and Severity of Coronary Heart Disease and Ischemic Stroke in a Tunisian Cohort. Journal of Molecular Neuroscience, 53, 150-157. https://doi.org/10.1007/s12031-014-0238-2 |
| [9] | Andreadou, I., Tsoumani, M., Vilahur, G., Ikonomidis, I., Badimon, L., Varga, Z.V., et al. (2020) PCSK9 in Myocardial Infarction and Cardioprotection: Importance of Lipid Metabolism and Inflammation. Frontiers in Physiology, 11, Article 602497. https://doi.org/10.3389/fphys.2020.602497 |
| [10] | Tang, Z., Peng, J., Ren, Z., Yang, J., Li, T., Li, T., et al. (2017) New Role of PCSK9 in Atherosclerotic Inflammation Promotion Involving the TLR4/NF-κB Pathway. Atherosclerosis, 262, 113-122. https://doi.org/10.1016/j.atherosclerosis.2017.04.023 |
| [11] | Ricci, C., Ruscica, M., Camera, M., Rossetti, L., Macchi, C., Colciago, A., et al. (2018) PCSK9 Induces a Pro-Inflammatory Response in Macrophages. Scientific Reports, 8, Article No. 2267. https://doi.org/10.1038/s41598-018-20425-x |
| [12] | Marfella, R., Prattichizzo, F., Sardu, C., Paolisso, P., D’Onofrio, N., Scisciola, L., et al. (2023) Evidence of an Anti-Inflammatory Effect of PCSK9 Inhibitors within the Human Atherosclerotic Plaque. Atherosclerosis, 378, Article 117180. https://doi.org/10.1016/j.atherosclerosis.2023.06.971 |
| [13] | Libby, P., Ridker, P.M. and Hansson, G.K. (2011) Progress and Challenges in Translating the Biology of Atherosclerosis. Nature, 473, 317-325. https://doi.org/10.1038/nature10146 |
| [14] | Kataoka, H., Kume, N., Miyamoto, S., Minami, M., Morimoto, M., Hayashida, K., et al. (2001) Oxidized LDL Modulates Bax/Bcl-2 through the Lectinlike Ox-LDL Receptor-1 in Vascular Smooth Muscle Cells. Arteriosclerosis, Thrombosis, and Vascular Biology, 21, 955-960. https://doi.org/10.1161/01.atv.21.6.955 |
| [15] | Wu, C., Tang, Z., Jiang, L., Li, X., Jiang, Z. and Liu, L. (2011) PCSK9 siRNA Inhibits HUVEC Apoptosis Induced by ox-LDL via Bcl/Bax-Caspase9-Caspase3 Pathway. Molecular and Cellular Biochemistry, 359, 347-358. https://doi.org/10.1007/s11010-011-1028-6 |
| [16] | Ziogos, E., Chelko, S.P., Harb, T., Engel, M., Vavuranakis, M.A., Landim-Vieira, M., et al. (2023) Platelet Activation and Endothelial Dysfunction Biomarkers in Acute Coronary Syndrome: The Impact of PCSK9 Inhibition. European Heart Journal—Cardiovascular Pharmacotherapy, 9, 636-646. https://doi.org/10.1093/ehjcvp/pvad051 |
| [17] | Sabatine, M.S., Giugliano, R.P., Keech, A.C., Honarpour, N., Wiviott, S.D., Murphy, S.A., et al. (2017) Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. New England Journal of Medicine, 376, 1713-1722. https://doi.org/10.1056/nejmoa1615664 |
| [18] | Jukema, J.W., Zijlstra, L.E., Bhatt, D.L., Bittner, V.A., Diaz, R., Drexel, H., et al. (2019) Effect of Alirocumab on Stroke in ODYSSEY Outcomes. Circulation, 140, 2054-2062. https://doi.org/10.1161/circulationaha.119.043826 |
| [19] | Du, H., Li, X., Su, N., Li, L., Hao, X., Gao, H., et al. (2019) Proprotein Convertase Subtilisin/Kexin 9 Inhibitors in Reducing Cardiovascular Outcomes: A Systematic Review and Meta-Analysis. Heart, 105, 1149-1159. https://doi.org/10.1136/heartjnl-2019-314763 |
| [20] | Ridker, P.M., Revkin, J., Amarenco, P., Brunell, R., Curto, M., Civeira, F., et al. (2017) Cardiovascular Efficacy and Safety of Bococizumab in High-Risk Patients. New England Journal of Medicine, 376, 1527-1539. https://doi.org/10.1056/nejmoa1701488 |
| [21] | Cheng, J.M., Oemrawsingh, R.M., Garcia-Garcia, H.M., Boersma, E., van Geuns, R., Serruys, P.W., et al. (2016) PCSK9 in Relation to Coronary Plaque Inflammation: Results of the ATHEROREMO-IVUS Study. Atherosclerosis, 248, 117-122. https://doi.org/10.1016/j.atherosclerosis.2016.03.010 |
| [22] | Nicholls, S.J., Puri, R., Anderson, T., Ballantyne, C.M., Cho, L., Kastelein, J.J.P., et al. (2016) Effect of Evolocumab on Progression of Coronary Disease in Statin-Treated Patients. Journal of the American Medical Association, 316, 2373-2384. https://doi.org/10.1001/jama.2016.16951 |
| [23] | Nicholls, S.J., Kataoka, Y., Nissen, S.E., Prati, F., Windecker, S., Puri, R., et al. (2022) Effect of Evolocumab on Coronary Plaque Phenotype and Burden in Statin-Treated Patients Following Myocardial Infarction. JACC: Cardiovascular Imaging, 15, 1308-1321. https://doi.org/10.1016/j.jcmg.2022.03.002 |
| [24] | Chen, J., Zhao, F., Lei, C., Qi, T., Xue, X., Meng, Y., et al. (2023) Effect of Evolocumab on the Progression of Intraplaque Neovascularization of the Carotid Based on Contrast-Enhanced Ultrasonography (EPIC Study): A Prospective Single-Arm, Open-Label Study. Frontiers in Pharmacology, 13, Article 999224. https://doi.org/10.3389/fphar.2022.999224 |
| [25] | Barale, C., Melchionda, E., Morotti, A. and Russo, I. (2021) PCSK9 Biology and Its Role in Atherothrombosis. International Journal of Molecular Sciences, 22, Article 5880. https://doi.org/10.3390/ijms22115880 |
| [26] | Pastori, D., Nocella, C., Farcomeni, A., Bartimoccia, S., Santulli, M., Vasaturo, F., et al. (2017) Relationship of PCSK9 and Urinary Thromboxane Excretion to Cardiovascular Events in Patients with Atrial Fibrillation. Journal of the American College of Cardiology, 70, 1455-1462. https://doi.org/10.1016/j.jacc.2017.07.743 |
| [27] | Navarese, E.P., Kolodziejczak, M., Winter, M., Alimohammadi, A., Lang, I.M., Buffon, A., et al. (2017) Association of PCSK9 with Platelet Reactivity in Patients with Acute Coronary Syndrome Treated with Prasugrel or Ticagrelor: The PCSK9-REACT Study. International Journal of Cardiology, 227, 644-649. https://doi.org/10.1016/j.ijcard.2016.10.084 |
| [28] | Barale, C., Bonomo, K., Frascaroli, C., Morotti, A., Guerrasio, A., Cavalot, F., et al. (2020) Platelet Function and Activation Markers in Primary Hypercholesterolemia Treated with Anti-PCSK9 Monoclonal Antibody: A 12-Month Follow-Up. Nutrition, Metabolism and Cardiovascular Diseases, 30, 282-291. https://doi.org/10.1016/j.numecd.2019.09.012 |
| [29] | Wang, H., Wang, Q., Wang, J., Guo, C., Kleiman, K., Meng, H., et al. (2017) Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Deficiency Is Protective against Venous Thrombosis in Mice. Scientific Reports, 7, Article No. 14360. https://doi.org/10.1038/s41598-017-14307-x |
| [30] | Sabatine, M.S., Leiter, L.A., Wiviott, S.D., Giugliano, R.P., Deedwania, P., De Ferrari, G.M., et al. (2017) Cardiovascular Safety and Efficacy of the PCSK9 Inhibitor Evolocumab in Patients with and without Diabetes and the Effect of Evolocumab on Glycaemia and Risk of New-Onset Diabetes: A Prespecified Analysis of the FOURIER Randomized Controlled Trial. The Lancet Diabetes & Endocrinology, 5, 941-950. https://doi.org/10.1016/s2213-8587(17)30313-3 |
| [31] | Koren, M.J., Sabatine, M.S., Giugliano, R.P., Langslet, G., Wiviott, S.D., Kassahun, H., et al. (2017) Long-Term Low-Density Lipoprotein Cholesterol-Lowering Efficacy, Persistence, and Safety of Evolocumab in Treatment of Hypercholesterolemia. JAMA Cardiology, 2, 598-607. https://doi.org/10.1001/jamacardio.2017.0747 |
| [32] | Taskinen, M., Del Prato, S., Bujas-Bobanovic, M., Louie, M.J., Letierce, A., Thompson, D., et al. (2018) Efficacy and Safety of Alirocumab in Individuals with Type 2 Diabetes Mellitus with or without Mixed Dyslipidaemia: Analysis of the Odyssey Long Term Trial. Atherosclerosis, 276, 124-130. https://doi.org/10.1016/j.atherosclerosis.2018.07.017 |
| [33] | Monami, M., Sesti, G. and Mannucci, E. (2018) PCSK9 Inhibitor Therapy: A Systematic Review and Meta-Analysis of Metabolic and Cardiovascular Outcomes in Patients with Diabetes. Diabetes, Obesity and Metabolism, 21, 903-908. https://doi.org/10.1111/dom.13599 |
| [34] | Blom, D.J., Hala, T., Bolognese, M., Lillestol, M.J., Toth, P.D., Burgess, L., et al. (2014) A 52-Week Placebo-Controlled Trial of Evolocumab in Hyperlipidemia. New England Journal of Medicine, 370, 1809-1819. https://doi.org/10.1056/nejmoa1316222 |
| [35] | Moriarty, P.M., Jacobson, T.A., Bruckert, E., Thompson, P.D., Guyton, J.R., Baccara-Dinet, M.T., et al. (2014) Efficacy and Safety of Alirocumab, a Monoclonal Antibody to PCSK9, in Statin-Intolerant Patients: Design and Rationale of Odyssey Alternative, a Randomized Phase 3 Trial. Journal of Clinical Lipidology, 8, 554-561. https://doi.org/10.1016/j.jacl.2014.09.007 |
| [36] | Nissen, S.E., Stroes, E., Dent-Acosta, R.E., Rosenson, R.S., Lehman, S.J., Sattar, N., et al. (2016) Efficacy and Tolerability of Evolocumab vs Ezetimibe in Patients with Muscle-Related Statin Intolerance. Journal of the American Medical Association, 315, Article 1580. https://doi.org/10.1001/jama.2016.3608 |
| [37] | Giugliano, R.P., Mach, F., Zavitz, K., Kurtz, C., Im, K., Kanevsky, E., et al. (2017) Cognitive Function in a Randomized Trial of Evolocumab. New England Journal of Medicine, 377, 633-643. https://doi.org/10.1056/nejmoa1701131 |
| [38] | Qin, J., Liu, L., Su, X.D., Wang, B.B., Fu, B.S., Cui, J.Z., et al. (2021) The Effect of PCSK9 Inhibitors on Brain Stroke Prevention: A Systematic Review and Meta-Analysis. Nutrition, Metabolism and Cardiovascular Diseases, 31, 2234-2243. https://doi.org/10.1016/j.numecd.2021.03.026 |
| [39] | Gaba, P., O’Donoghue, M.L., Park, J., Wiviott, S.D., Atar, D., Kuder, J.F., et al. (2023) Association between Achieved Low-Density Lipoprotein Cholesterol Levels and Long-Term Cardiovascular and Safety Outcomes: An Analysis of Fourier-Ole. Circulation, 147, 1192-1203. https://doi.org/10.1161/circulationaha.122.063399 |
| [40] | Grundy, S.M., Stone, N.J., Bailey, A.L., et al. (2019)2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/ APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: Executive Summary. Circulation, 139, e1082-e1143. Https://doi.org/10.1161/CIR.0000000000000625 |
| [41] | Mach, F., Baigent, C., Catapano, A.L., Koskinas, K.C., Casula, M., Badimon, L., et al. (2019) 2019 ESC/EAS Guidelines for the Management of Dyslipidaemias: Lipid Modification to Reduce Cardiovascular Risk. European Heart Journal, 41, 111-188. https://doi.org/10.1093/eurheartj/ehz455 |
| [42] | 王增武, 刘静, 李建军, 等. 中国血脂管理指南(2023年) [J]. 中国循环杂志, 2023, 38(3): 237-271. |
