脂蛋白（a）与缺血性卒中的研究进展

doi:10.3969/j.issn.1673-5765.2025.06.014

摘要/Abstract

摘要： 脂蛋白（a）[lipoprotein(a)，Lp(a)]是一种具有高度遗传性的脂蛋白，其在心血管疾病中的作用已被广泛研究，但与缺血性卒中的关联尚未完全明确。本文回顾了Lp(a)的生物学特性，以及不同种族、地域、年龄和性别人群中Lp(a)水平的差异，并探讨了Lp(a)与遗传因素的关系，阐述了其在缺血性卒中的发生和复发中的作用，重点讨论了Lp(a)在动脉粥样硬化、炎症反应和血栓形成中的病理生理作用。目前，传统的降脂药物降低Lp(a)水平的作用有限，但RNA靶向治疗等新兴治疗策略显示出了降低Lp(a)水平的潜力。这些新兴的治疗策略为降低卒中风险提供了新的靶点与思路。

文章导读： Lp(a)作为一种具有高度遗传性的脂蛋白，其水平可影响缺血性卒中的发生和复发。传统降脂药物降低Lp(a)的效果有限，而新兴治疗策略（如PCSK9抑制剂、RNA靶向治疗药物）显示出了降低Lp(a)水平的潜力，为降低卒中风险提供了新的靶点与思路。

关键词: 脂蛋白（a）; 缺血性卒中; 动脉粥样硬化; 氧化应激; 炎症反应

Abstract: Lipoprotein(a) [Lp(a)] is a highly heritable lipoprotein whose role in cardiovascular disease has been extensively studied. However, its association with ischemic stroke remains incompletely understood. This review summarizes the biological characteristics of Lp(a) and its variability across different ethnicities, geographic regions, age groups, and genders. It also explores the relationship between Lp(a) and genetic factors, highlighting its role in the onset and recurrence of ischemic stroke. Special emphasis is placed on the pathophysiological mechanisms of Lp(a) in atherosclerosis, inflammatory responses, and thrombogenesis. While conventional lipid-lowering therapies have shown limited efficacy in reducing Lp(a) levels, emerging strategies such as RNA-targeted therapies demonstrate promising potential in lowering Lp(a). These novel therapeutic strategies provide new targets and ideas for reducing stroke risk.

Key words: Lipoprotein(a); Ischemic stroke; Atherosclerosis; Oxidative stress; Inflammatory reaction

中图分类号:

何讯, 陈心怡, 胡杰, 李佳璇, 贾新会, 吴君仓. 脂蛋白（a）与缺血性卒中的研究进展[J]. 中国卒中杂志, 2025, 20(6): 775-780.

HE Xun, CHEN Xinyi, HU Jie, LI Jiaxuan, JIA Xinhui, WU Juncang. Research Progress on Lipoprotein(a) and Ischemic Stroke[J]. Chinese Journal of Stroke, 2025, 20(6): 775-780.

参考文献

[1] FESKE S K. Ischemic stroke[J]. Am J Med，2021，134（12）：1457-1464.
[2] TEKLE W G，HASSAN A E. Intracranial atherosclerotic disease：current concepts in medical and surgical management[J/OL]. Neurology，2021，97（20 Suppl 2）：S145-S157[2025-01-15]. https://doi.org/10.1212/WNL.0000000000012805.
[3] SAEED A，KINOUSH S，VIRANI S S. Lipoprotein（a）：recent updates on a unique lipoprotein[J/OL]. Curr Atheroscler Rep，2021，23（8）：41[2025-01-15]. https://doi.org/10.1007/s11883-021-00940-5.
[4] 林琳，李京秀，闫娜，等. 脂蛋白a的治疗现状及研究新方向[J]. 心血管病学进展，2021，42（6）：543-546.
LIN L，LI J X，YAN N，et al. Therapeutic status and research prospects of treatment of lipoprotein a[J]. Adv Cardiovasc Dis，2021，42（6）：543-546.
[5] DI FUSCO S A，MAGGIONI A P，SCICCHITANO P，et al. Lipoprotein(a)，inflammation，and atherosclerosis[J/OL]. J Clin Med，2023，12（7）：2529[2025-01-15]. https://doi.org/10.3390/jcm12072529.
[6] KATSANOS A H，HART R G. New horizons in pharmacologic therapy for secondary stroke prevention[J]. JAMA Neurol，2020，77（10）：1308-1317.
[7] KAMSTRUP P R. Lipoprotein(a) and cardiovascular disease[J]. Clin Chem，2021，67（1）：154-166.
[8] TSIMIKAS S，STROES E S G. The dedicated “Lp(a)clinic”：a concept whose time has arrived？[J/OL]. Atherosclerosis，2020，300：1-9[2025-01-15]. https://doi.org/10.1016/j.atherosclerosis.2020.03.003.
[9] COLANTONIO L D，BITTNER V，SAFFORD M M，et al. Lipoprotein(a) and the risk for coronary heart disease and ischemic stroke events among black and white adults with cardiovascular disease[J/OL]. J Am Heart Assoc，2022，11（11）：e025397[2025-01-15]. https://doi.org/10.1161/JAHA.121.025397.
[10] LANKTREE M B，RAJAKUMAR C，BRUNT J H，et al. Determination of lipoprotein(a) kringle repeat number from genomic DNA：copy number variation genotyping using qPCR[J]. J Lipid Res，2009，50（4）：768-772.
[11] ARSENAULT B J，KAMSTRUP P R. Lipoprotein(a) and cardiovascular and valvular diseases：a genetic epidemiological perspective[J/OL]. Atherosclerosis，2022，349：7-16[2025-01-15]. https://doi.org/10.1016/j.atherosclerosis.2022.04.015.
[12] KAR S. Elevated lipoprotein a in South Asians and the associated risk of cardiovascular disease：a systematic review[J/OL]. Curr Probl Cardiol，2021，46（3）：100581[2025-01-15]. https://doi.org/10.1016/j.cpcardiol.2020.100581.
[13] LI S Y，GAO Y，MA W N，et al. The relationship between serum lipoprotein(a) levels and ischemic stroke risk：a cohort study in the Chinese population[J]. Inflammation，2014，37（3）：686-693.
[14] ARORA P，KALRA R，CALLAS P W，et al. Lipoprotein(a) and risk of ischemic stroke in the REGARDS study[J]. Arterioscler Thromb Vasc Biol，2019，39（4）：810-818.
[15] YANG Y，HAN Y F，SUN W D，et al. Increased systemic immune-inflammation index predicts hemorrhagic transformation in anterior circulation acute ischemic stroke due to large-artery atherosclerotic[J]. Int J Neurosci，2023，133（6）：629-635.
[16] ZAFRIR B，AKER A，NAOUM I，et al. Guideline-directed low-density lipoprotein cholesterol management after acute ischemic stroke：findings from a national health care service[J/OL]. Am J Cardiol，2023，203：332-338[2025-01-15]. https://doi.org/10.1016/j.amjcard.2023.07.032.
[17] ARNOLD M，SCHWEIZER J，NAKAS C T，et al. Lipoprotein(a) is associated with large artery atherosclerosis stroke aetiology and stroke recurrence among patients below the age of 60 years：results from the BIOSIGNAL study[J]. Eur Heart J，2021，42（22）：2186-2196.
[18] XU J，HAO X W，ZHAN R，et al. Effect of lipoprotein(a) on stroke recurrence attenuates at low LDL-C（low-density lipoprotein）and inflammation levels[J]. Stroke，2022，53（8）：2504-2511.
[19] DING P F，ZHANG H S，WANG J，et al. Insulin resistance in ischemic stroke：mechanisms and therapeutic approaches[J/OL]. Front Endocrinol（Lausanne），2022，13：1092431[2025-01-15]. https://doi.org/10.3389/fendo.2022.1092431.
[20] 李世雨，张星，胡文立. 脂蛋白（a）与颈动脉粥样硬化不稳定斑块的关系[J]. 中国卒中杂志，2024，19（5）：539-544.
LI S Y，ZHANG X，HU W L. Relationship between lipoprotein(a) and unstable carotid atherosclerotic plaque[J]. Chin J Stroke，2024，19（5）：539-544.
[21] WU H，WANG Y，ZHANG Y P，et al. Breaking the vicious loop between inflammation，oxidative stress and coagulation，a novel anti-thrombus insight of nattokinase by inhibiting LPS-induced inflammation and oxidative stress[J/OL]. Redox Biol，2020，32：101500[2025-01-15]. https://doi.org/10.1016/j.redox.2020.101500.
[22] BARGIEL W，CIERPISZEWSKA K，MARUSZCZAK K，et al. Recognized and potentially new biomarkers-their role in diagnosis and prognosis of cardiovascular disease[J/OL]. Medicina（Kaunas），2021，57（7）：701[2025-01-15]. https://doi.org/10.3390/medicina57070701.
[23] SLOOP G D，POP G，WEIDMAN J J，et al. Apolipoprotein(a) is the product of a pseudogene：implications for the pathophysiology of lipoprotein(a) [J/OL]. Cureus，2018，10（5）：e2715[2025-01-15]. https://doi.org/10.7759/cureus.2715.
[24] TMOYAN N A，EZHOV M V，AFANASIEVA O I，et al. Association of lipoprotein(a) with ischemic stroke and stenotic carotid atherosclerosis[J]. S.S. Korsakov Journal of Neurology and Psychiatry，2020，120（3/2）：42-48.
[25] LI Z F，BI R T，SUN S，et al. The role of oxidative stress in acute ischemic stroke-related thrombosis[J/OL].
Oxid Med Cell Longev，2022，2022：8418820[2025-01-15]. https://doi.org/10.1155/2022/8418820.
[26] MARCOVINA S M. Lipoprotein(a)：a genetically determined risk factor for cardiovascular disease[J]. Crit Rev Clin Lab Sci，2023，60（8）：560-572.
[27] SCHWARTZ G G，STEG P G，SZAREK M，et al. Alirocumab and cardiovascular outcomes after acute coronary syndrome[J]. N Engl J Med，2018，379（22）：2097-2107.
[28] HADJIPHILIPPOU S，RAY K K. Evolocumab and clinical outcomes in patients with cardiovascular disease[J]. J R Coll Physicians Edinb，2017，47（2）：153-155.
[29] ALKHALIL M. Lipoprotein(a) reduction in persons with cardiovascular disease[J/OL]. N Engl J Med，2020，382（21）：e65[2025-01-15]. https://doi.org/10.1056/NEJMc2004861.
[30] O’DONOGHUE M L，ROSENSON R S，LÓPEZ J A G，et al. The off-treatment effects of olpasiran on lipoprotein(a) lowering：OCEAN(a)-DOSE extension period results[J]. J Am Coll Cardiol，2024，84（9）：790-797.
[31] KOSMAS C E，BOUSVAROU M D，PAPAKONSTANTINOU E J，et al. Lipoprotein(a) and cerebrovascular disease[J/OL]. J Int Med Res，2024，52（7）：3000605241264182[2025-01-15]. https://doi.org/10.1177/03000605241264182.
[32] KOSMAS C E，BOUSVAROU M D，PAPAKONSTANTINOU E J，et al. Novel pharmacological therapies for the management of hyperlipoproteinemia(a)[J/OL]. Int J Mol Sci，2023，24（17）：13622[2025-01-15]. https://doi.org/10.3390/ijms241713622.
[33] DIAZ N，PEREZ C，ESCRIBANO A M，et al. Discovery of potent small-molecule inhibitors of lipoprotein(a) formation[J]. Nature，2024，629（8013）：945-950.
[34] GRECO A，FINOCCHIARO S，SPAGNOLO M，et al. Lipoprotein(a) as a pharmacological target：premises，promises，and prospects[J]. Circulation，2025，151（6）：400-415.
[35] MAKRIS A，BARKAS F，SFIKAKIS P P，et al. Lipoprotein(a)，interleukin-6 inhibitors，and atherosclerotic cardiovascular disease：is there an association？[J/OL]. Atheroscler Plus，2023，54：1-6[2025-01-15].