Advances in Clinical Medicine
Vol.
11
No.
08
(
2021
), Article ID:
44610
,
4
pages
10.12677/ACM.2021.118514
小而密低密度脂蛋白与冠心病的最新进展
李国霖,王治平
长治医学院附属和平医院,山西 长治
![](http://html.hanspub.org/file/31-1572474x1_hanspub.png?20210818181253918)
收稿日期:2021年7月11日;录用日期:2021年8月11日;发布日期:2021年8月18日
![](http://html.hanspub.org/file/31-1572474x2_hanspub.png?20210818181253918)
摘要
综述冠心病的危险因素以及小而密低密度脂蛋白的分类方式、致动脉粥样硬化机制、与甘油三脂的关系、及治疗方法,为临床上的诊断及治疗提供更全面的方法。
关键词
小而密低密度脂蛋白,冠状动脉粥样硬化性心脏病,甘油三脂
![](http://html.hanspub.org/file/31-1572474x3_hanspub.png?20210818181253918)
Determination of Small and Dense of Low-Density Lipoprotein and Coronary Heart Disease
Goulin Li, Zhiping Wang
Affiliated Heping Hospital, Changzhi Medical College, Changzhi Shanxi
Received: Jul. 11th, 2021; accepted: Aug. 11th, 2021; published: Aug. 18th, 2021
ABSTRACT
The risk factors of coronary heart disease, the classification of small dense low density lipoprotein, the mechanism of atherosclerosis, the relationship with triglycerides, and the treatment methods were reviewed to provide a more comprehensive approach for clinical diagnosis and treatment.
Keywords:Small and Dense of Low-Density Lipoprotein, Coronary Heart Disease, Triglycerides
Copyright © 2021 by author(s) and Hans Publishers Inc.
This work is licensed under the Creative Commons Attribution International License (CC BY 4.0).
http://creativecommons.org/licenses/by/4.0/
1. 引言
冠状动脉粥样硬化性心脏病(CAD)是影响全球人口的主要心血管疾病之一。这种疾病已被证明是发达国家和发展中国家的主要死亡原因。根据美国心脏协会/美国大学心脏病学指南,主要的心血管危险因素包括年龄增加、男性、高血压、糖尿病、吸烟、总胆固醇升高和高密度脂蛋白胆固醇(HDL-C)降低 [1]。有研究表明,遗传和环境因素相互作用来决定心血管疾病的临床表型,生活方式对疾病的发展起着重要的作用 [2]。了解相关的风险因素,采取健康的生活方式和预防策略以及早期诊断对于管理和根除此类心血管疾病至关重要。目前的指南以降低LDL水平为首要目标,但在大多数临床研究中实现的心血管风险降低不超过30%,由于动脉粥样硬化残留风险的存在,识别其他脂质靶点仍是现在的研究热点 [3]。残余风险包括:导致动脉粥样硬化的血脂异常复合体、高密度脂蛋白胆固醇(HDL-C)降低、富含甘油三酯(TRL)的脂蛋白(TRL)升高以及小而密低密度脂蛋白(SdLDL) [4]。2016年ECS/EAS指南 [5] 和国际动脉粥样硬化学会立场文件 [6] 建议在达到LDL-C目标后将非HDL-C作为首选的二级目标,非高密度脂蛋白胆固醇本质上是低密度脂蛋白、中密度脂蛋白和极低密度脂蛋白颗粒中胆固醇的总和,其中极低密度脂蛋白是甘油三酯的主要载体 [6]。目前认为高密度脂蛋白(HDL)颗粒功能紊乱而不是低浓度对心血管疾病 [7] 很重要,但缺乏对这一假设的验证数据。重大不良心血管事件(MACE)的风险与残余胆固醇水平呈负相关,残余胆固醇水平降低0.8 mmol/L可使MACE风险降低20% [8]。
2. 小而密低密度脂蛋白与冠心病
目前有几种关于低密度脂蛋白亚类的分类方法,导致小而密低密度脂蛋白的根据目前的共识,根据血浆低密度脂蛋白谱定义了两种主要的表型,A和B,中间的A/B表型介于两者 [9] 之间。A型以大浮力低密度脂蛋白(LbLDL)为主,B型以小而密低密度脂蛋白(sdLDL)为主。sdLDL比其他LDL亚组分具有更大的致动脉粥样硬化潜能,sdLDL胆固醇(sdLDL-C)比例是比总LDL-C更好的心血管疾病预测指标。sdLDL胆固醇浓度高的个体有更高的心肌梗死和动脉粥样硬化性心血管疾病ASCVD风险 [10]。研究表明,天然低密度脂蛋白不会导致培养细胞中的脂质堆积,sdLDL比其他LDL亚组循环时间更长,循环中的sdLDL很容易在血浆中经历多种致动脉粥样硬化的修饰,如脱脂、糖基化和氧化,修饰的sdLDL是与心血管疾病相关的炎症过程的有效诱导物 [11]。首先,与较大尺寸的对应物相比,sdLDL-C颗粒对LDL受体的亲和力较低 [12],在循环中的停留时间较长 [13]。其次,由于sdLDL-C颗粒较小且具有较大的比表面积,它们更容易穿透动脉壁 [14]。第三,sdLDL-C是致动脉粥样硬化程度最高的脂蛋白之一,对氧化修饰的敏感性更高 [15]。最后,sdLDL-C水平可能是动脉粥样硬化风险的综合标志 [16]。从而进一步增加其致动脉粥样硬化的能力。在一项前瞻性研究中,正常血压人群中,sdLDL-C和TG/HDL-C比值可以独立预测动脉硬化进展,且sdLDL-C和TG/HDL-C比值越高,发生动脉硬化的风险越高 [17]。颈动脉–股动脉脉搏波速度(cf-pwv)目前被认为是测定动脉硬度的金标准,CF-PWV直接反映主动脉僵硬,并与主动脉僵硬有最好的临床相关性 [18]。流行病学研究证实,cf-PWV是心血管事件的预测因子,是与心血管发病率和死亡率直接相关的为数不多的动脉僵硬指标之一 [18]。sdLDL水平升高在许多与动脉粥样硬化有关的疾病中,如血脂异常、糖尿病和代谢综合征(METS),以及许多其他疾病 [19]。一项前瞻性纵向队列研究对39例(前期)糖尿病患者进行了2年的随访,结果表明,sdLDL颗粒比例及其变化可以预测颈动脉内膜–中膜厚度(cIMT)和胰岛素抵抗的变化。在代谢综合征患者中,sdLDL水平的升高对未来有独立的预测价值。
3. 小而密低密度脂蛋白与甘油三脂Small and Dense Low Density Lipoprotein Cholesterol
来自流行病学和遗传学研究的越来越多的证据表明,血液中甘油三酯或残留的富含胆固醇和富甘油三酯的脂蛋白水平升高是心血管疾病的一个风险因素 [20]。富含甘油三酯的脂蛋白通常与动脉粥样硬化性血脂异常有关,被认为是引起CVD脂质相关风险的主要因素之一 [21]。2016年发表的一项研究首次表明,在接受降脂治疗的患者中,即使在低密度脂蛋白胆固醇水平得到很好控制,血甘油三酯水平与冠状动脉斑块进展有关,特别是>200毫克/分升(>2.3 mmol/l),较低的甘油三酯水平与心血管疾病风险的斑块消退有关 [22]。高甘油三酯血症通常与HDL-胆固醇水平降低和sdLDL颗粒增加有关。sdLDL可能有多种来源。在最近一项针对健康人和高甘油三酯血症患者的研究中,研究了apoE和apoC-III脂蛋白在apoB代谢中的调节作用 [23]。当血浆甘油三脂(TG)水平正常时,肝脏主要分泌富含载脂蛋白E的极低密度脂蛋白(VLDL),这些极低密度脂蛋白(VLDL)被迅速从循环中清除。然而,在高甘油三酯血症中,平衡向含有载脂蛋白C-III (apoC-III)的富含TG的脂蛋白转移,这种脂蛋白循环时间更长,并被转化为sdLDL。含载脂蛋白E的脂蛋白清除率也降低。结果,sdLDL的高形成率和清除率降低导致了sdLDL水平升高的B型表型的发展。有研究表明,超速离心分离的极低密度脂蛋白分为两个亚类(极低密度脂蛋白1和极低密度脂蛋白2),在大小和代谢功能上各不相同,极低密度脂蛋白-1 (VLDL-1)较大,TG含量较高,而极低密度脂蛋白2 (VLDL-2)较小密度较高。据报道极低密度脂蛋白1更有利于动脉粥样硬化,因为它们能产生sdLDL [24]。几项大型研究的结果表明,甘油三酯(禁食或非禁食)水平升高,富含甘油三酯的脂蛋白及其残留物水平升高,与心血管疾病的风险增加独立相关。这种关联的可能机制包括过度释放游离脂肪酸、产生促炎细胞因子、凝血因子和纤溶功能障碍。因此,高甘油三酯血症的靶向治疗可以减少心血管疾病和心血管事件,而不是通过降低低密度脂蛋白来实现。但是目前降低甘油三酯水平对心血管疾病的影响的研究结果不一致,因此通过降低甘油三酯来降低死亡率仍是目前讨论的问题 [25]。
4. 降低小而密低密度脂蛋白的方式
降低sdLDL水平可以预防和治疗动脉粥样硬化,降低胆固醇和低密度脂蛋白的化合物在降低sdLDL水平方面也是有效的。此外,改善血脂状况,特别是降低甘油三酯水平,适当的养生法和生活方式可以降低sdLDL水平。包括药理学和非药理学药物。药物制剂包括:他汀类药物、依折麦布、贝特、多沙唑嗪、奥利司他汀、烟酸、西洛他唑、生长激素、二甲双胍、SGLT2抑制剂、GLP-1RAs、DPP-4抑制剂和格列酮;饮食制剂和生活方式包括:中性食品、植物甾醇、草本材料、吸烟和胆红素。其主要机制是降低TG水平和VLDL1的生成 [26]。他汀类药物的作用是剂量依赖性的,应该使用最大剂量。根据临床试验,瑞舒伐他汀和匹伐他汀比阿托伐他汀更适合降低sdLDL水平 [27]。将他汀类药物与降胆固醇药物(如依折麦布)和降甘油三酯药物(包括贝特类和二十碳五烯酸(EPA))联合使用可以避免使用高剂量的他汀类药物 [28]。2型糖尿病患者死亡和发病的主要原因之一是血脂异常。在这些患者中,患心血管疾病的风险大约是健康人的三倍。建议糖尿病患者在治疗的第一阶段使用降糖药物,以改善胰岛素抵抗,降低动脉粥样硬化的风险。然后,在疾病的晚期,对这些患者最好的药物是胰岛素疗法 [29]。在患有代谢综合征和左心室肥厚的患者中,服用营养食品(包括膳食纤维、益生菌、益生菌、多不饱和脂肪酸、抗氧化剂和其他不同类型的草本/天然食品)可以显著降低血清sdLDL,证实了营养食品在改善脂质状况、血管内皮功能障碍和最终减少心血管疾病,特别是动脉粥样硬化方面的有效性 [30]。omega-3脂肪酸,目前可作为降脂剂处方的药物补充剂使用,建议每天服用1.8 g (纯度 > 98%)。由于抗氧化活性和可能增强一氧化氮合酶活性,这些补充剂减少了sdLDL的氧化,改善了内皮功能 [31]。甲亢症患者和高胆固醇血症患者每天摄入植物甾醇可能通过降低sdLDL水平来降低动脉粥样硬化的风险。因此,在改变饮食习惯的同时,植物甾醇可以被认为是改善脂肪状况和降低心血管疾病风险的一个非常好的选择。草本材料可以被认为是预防和治疗心血管疾病的一个很好的选择。由于含有多种生物活性成分,这些材料可以降低sdLDL,改善血脂状况。然而,关于它们对sdLDL水平的有益影响的信息似乎很少。因此,应该建立进一步的随机对照试验,使用足够的参与者和持续时间,以便能够引入草本材料作为降低心血管疾病风险的有效药物 [32]。尽管吸烟通常会增加动脉粥样硬化的风险,但吸烟导致血清sdLDL水平显著降低 [33]。但需要更多的研究才能证明吸烟对sdLDL的影响。直接胆红素可以通过提高抗氧化能力和降低sdLDL来降低动脉粥样硬化的发生率 [34]。因此,直接血清胆红素可作为预测和预防动脉粥样硬化的有价值的生物标志物。这需要进一步的研究。
5. 小结
小而密低密度脂蛋白比其他的低密度脂蛋白亚类有更强的致动脉粥样硬化能力,其来源目前认为与甘油三脂有关,但需要更进一步的研究来证明,降低小而密低密度脂蛋白的方法很多,甘油三脂与致动脉粥样硬化的残留风险有关,但降低其水平与冠心病的死亡率目前处于争议中。
文章引用
李国霖,王治平. 小而密低密度脂蛋白与冠心病的最新进展
Determination of Small and Dense of Low-Density Lipoprotein and Coronary Heart Disease[J]. 临床医学进展, 2021, 11(08): 3525-3528. https://doi.org/10.12677/ACM.2021.118514
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