PCSK9抑制剂通过靶向调控低密度脂蛋白受体(LDLR)降解,已成为动脉粥样硬化性心血管疾病(ASCVD)治疗的革命性策略。本文结合国内外研究进展,从以下三方面进行系统阐述:1) 分子机制:PCSK9通过催化结构域与LDLR结合,介导其溶酶体降解,而抑制剂可恢复LDLR再循环,降低LDL-C达60%~70%;2) 药物研发:单克隆抗体(Alirocumab、Evolocumab)显著降低MACE风险15%~20%,RNA干扰疗法(Inclisiran)实现半年一次给药,口服小分子(MK-0616)突破生物制剂限制;3) 多途径保护:除降脂外,PCSK9抑制剂通过抑制炎症(hs-CRP降低37%)、调节免疫(Treg/Th17平衡)及改善内皮功能(FMD提升12%)发挥协同效应。未来需聚焦长期安全性验证、成本效益优化及联合疗法开发,以全面提升ASCVD的防治水平。PCSK9 inhibitors have become a revolutionary strategy for the treatment of atherosclerotic cardiovascular disease (ASCVD) by targeting and regulating low-density lipoprotein receptor (LDLR) degradation. Based on the research progress at home and abroad, this paper systematically describes the following three aspects: 1) Molecular mechanism: PCSK9 binds to LDLR through catalytic domain, mediates lysosomal degradation, while inhibitors can restore LDLR recycling and reduce LDL-C by 60%~70%;2) Drug development: Monoclonal antibodies (Alirocumab, Evolocumab) significantly reduced the risk of MACE by 15%~20%, RNA interference therapy (Inclisiran) achieved semi-annual administration, and oral small molecules (MK0616) broke the limit of biologics;3) Multipathway protection: In addition to lipid-lowering, PCSK9 inhibitors play a synergistic role by inhibiting inflammation (37% reduction in hs-CRP), modulating immunity (Treg/Th17 balance), and improving endothelial function (12% increase in FMD). The future needs to focus on long-term safety validation, cost-effectiveness optimization, and combination therapy development to comprehensively improve the level of ASCVD prevention and treatment.
冠状动脉微血管疾病(CMD)是心肌缺血的独立病因,其机制涉及内皮功能障碍、微血管痉挛、炎症及血管重构等多因素。临床表现为非阻塞性心绞痛,与心血管事件风险升高相关。诊断依赖侵入性功能指标(如CFR、IMR)与非侵入性影像(心脏磁共振、PET),但标准化不足。治疗以改善微循环为核心,传统药物包括硝酸酯类、尼可地尔(KATP通道开放剂)、雷诺嗪(钠通道抑制剂)及ACEI/ARB,新兴疗法如sGC激动剂和SGLT-2抑制剂展现潜力。目前证据多基于小样本研究,缺乏具体指南,且长期预后仍存在争议。未来需整合多组学、影像标志物与AI技术,建立精准诊疗体系,并通过大规模临床试验验证分层治疗策略。Coronary microvascular disease (CMD) is an independent cause of myocardial ischemia, and its mechanism involves multiple factors such as endothelial dysfunction, microvascular spasm, inflammation and vascular remodeling. The clinical manifestation is non-obstructive angina, which is associated with an increased risk of cardiovascular events. Diagnosis relies on invasive functional indicators (such as CFR, IMR) and non-invasive imaging (cardiac magnetic resonance, PET), but the standardization is insufficient. The core treatment is to improve microcirculation. Traditional drugs include nitrates, nicorandil (KATP channel opener), ranolazine (sodium channel inhibitor) and ACEI/ARB. Emerging therapies such as sGC agonists and SGLT-2 inhibitors show potential. The current evidence is mostly based on small sample studies, lacks specific guidelines, and long-term prognosis is still controversial. In the future, it is necessary to integrate multi-omics, imaging markers and AI technology to establish a precise diagnosis and treatment system, and to verify the stratified treatment strategy through large-scale clinical trials.
