Research progress on the protective mechanism of proprotein convertase subtilisin/kexin type 9 inhibitors on vascular endothelium
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摘要:
前蛋白转化酶枯草溶菌素-kexin9型抑制剂(PCSK9抑制剂)不仅具有良好的降脂作用, 还具有改善心血管结局、减轻氧化应激及改善血管内皮等多效性作用。近年来, PCSK9抑制剂的不断研发为心血管疾病治疗提供了新思路，本文就PCSK9抑制剂的多效性作用机制研究，尤其是对于血管内皮功能的作用机制研究予以综述。
Abstract:Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors not only have good lipid-lowering effects, but also have pleiotropic effects such as improving cardiovascular outcomes, relieving anti-inflammation, relieving oxidative stress and improving vascular endothelium. In recent years, the continuous development of PCSK9 inhibitors provides new ideas for the treatment of cardiovascular diseases. This article reviewed the pleiotropic mechanisms of PCSK9 inhibitors, especially on vascular endothelial function.
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H型高血压是卒中的危险因素之一[1-2], 18岁以上居民H型高血压患病率约38.6%, 占高血压患者的75.0%。家庭医生对H型高血压普遍重视不足、管理不足。研究[3-4]表明，基层就诊的H型高血压规范管理率仅为30.3%, 远远低于高血压规范管理率的46.4%。本研究选取社区卫生服务中心家庭医生签约管理的高血压患者，通过横断面研究分析签约管理的H型高血压的患病情况及其危险因素，为基层医疗卫生机构全科医生对H型高血压进行更精准、有效的管理提供参考，以进一步降低脑血管病的疾病风险，改善患者预后。
1. 资料与方法
1.1 一般资料
选取2020年1月—2021年12月在宛平社区卫生服务中心就诊并接受家庭医生签约管理的高血压患者769例。纳入标准: 建立居民健康档案并纳入社区慢病管理者; 年龄≥18岁者; 无严重肝、肾等器质性疾病和肿瘤等恶性疾病者; 无甲亢等代谢性疾病者; 签署知情同意书者; 能完成本研究所需检查项目者。排除标准: 继发性高血压者; 患有精神疾病、肿瘤以及严重心、肝、肺、肾疾病者; 妊娠和哺乳妇女; 近3个月有感染或创伤等应激状况者; 不同意签署知情同意书并参加此研究者; 既往明确诊断H型高血压且规律应用叶酸者; 近期服用抗癫痫药物者(卡马西平、苯妥英钠等)。
根据《H型高血压诊断与治疗专家共识》[3], 将血浆同型半胱氨酸(Hcy)≥10 μmol/L的高血压定义为H型高血压。以血浆Hcy水平将患者分为H型高血压组(n=362, Hcy≥10 μmol/L)和非H型高血压组(n=407, Hcy < 10 μmol/L)。本研究经北京市丰台区中西医结合医院伦理委员会批准，所有患者均知情同意并签署知情同意书。
1.2 方法
采用一对一问卷调查记录患者一般资料、生活方式、慢性病情况、用药情况等。由经过研究培训的超声医师采用东芝660A彩色多普勒超声诊断仪行颈部血管超声检查，检测入选患者颈动脉内膜中层厚度(IMT)和颈动脉斑块厚度。入组患者均采用爱安德牌TM-2430动态血压监测仪，监测24 h动态血压，根据夜间血压(22: 00—6: 00)较白天血压(6: 00—22: 00)的下降率，把血压的昼夜节律分为杓型(10%~20%)、非杓型(< 10%)、超杓型(>20%)和反杓型(夜间血压高于白天)。
1.3 观察指标
患者禁食12 h以上，清晨抽取患者空腹静脉血3 mL, 采用酶循环法(东芝全自动生化分析仪)测定血清Hcy水平。采用荧光偏振免疫分析法(东芝自动生化分析仪)测定血清总胆固醇(TC)、甘油三酯(TG)、低密度脂蛋白胆固醇(LDL-C)、高密度脂蛋白胆固醇(HDL-C)、C反应蛋白(CRP)、血糖(GLU)、糖化血红蛋白(HbAlc)、尿酸(UA)、尿素氮(BUN)、估算肾小球滤过率(eGFR)。
1.4 统计学分析
采用SPSS 26.0统计软件分析数据，符合正态分布的计量资料以(x±s)表示，行t检验或方差分析; 不符合正态分布的计量资料以[M(P25, P75)]表示，采用秩和检验。计数资料以[n(%)]表示，行χ2检验。采用多因素Logistic回归分析探讨H型高血压的危险因素。P < 0.05为差异有统计学意义。
2. 结果
2.1 入选患者人口学特征
本研究共纳入家庭医生签约管理的高血压患者769例，其中男272例(35.4%), 中位年龄62岁。H型高血压组患者362例(检出率47.1%), 男性检出率为55.5%(151/272), 高于女性检出率的42.5%(211/497), 差异有统计学意义(P < 0.05)。H型高血压组中男性、吸烟者、本地居民、老年人占比高于非H型高血压组，差异有统计学意义(P < 0.05)。见表 1。
表 1 入选患者人口学特征[n(%)]人口学特征 分类 n H型高血压组(n=362) 非H型高血压组(n=407) P 性别 男性 272 151(41.7) 121(29.7) 0.001 女性 497 211(58.3) 286(70.3) 吸烟 吸烟 274 216(59.7) 58(14.3) < 0.001 非吸烟 495 146(40.3) 349(85.7) 居民类型 本地 677 329(90.9) 348(85.5) 0.022 外地 92 33(9.1) 59(14.5) 年龄段 19~35岁(青年) 8 0 8(2.0) < 0.001 36~59岁(中年) 299 121(33.4) 178(43.7) ≥60岁(老年) 462 241(66.6) 221(54.3) 2.2 H型高血压与非H型高血压患者临床特征
H型高血压组患者IMT、腰围、HbAlc、UA、BUN、TG高于非H型高血压组，HDL-C、eGFR低于非H型高血压组，差异有统计学意义(P < 0.05)。见表 2。
表 2 H型高血压组与非H型高血压组患者临床特征(x±s)临床特征 H型高血压(n=362) 非H型高血压(n=407) P 腰围/cm 89.92±11.06 87.60±10.02 0.002 IMT/mm 2.42±0.81 1.62±0.84 0.001 HbAlc/% 6.89±1.34 6.42±1.40 0.001 eGFR/[mL/(min·1.73 m2)] 74.14±30.14 81.63±30.76 0.001 BUN/(mmol/L) 5.78±2.23 4.83±1.51 0.001 UA/(μmol/L) 350.80±109.69 291.76±80.04 0.001 HDL-C/(mmol/L) 1.47±0.30 1.55±0.34 0.001 TG/(mmol/L) 1.90±1.60 1.61±1.01 0.040 体质量指数/(kg/m2) 26.19±4.07 25.76±3.65 0.126 收缩压/mmHg 127.20±8.39 126.60±8.70 0.332 舒张压/mmHg 76.83±6.29 77.17±6.48 0.464 总胆固醇/(mmol/L) 4.63±1.40 4.70±1.13 0.340 LDL-C/(mmol/L) 2.58±0.87 2.68±0.87 0.108 空腹血糖/(mmol/L) 6.54±2.16 6.26±2.23 0.075 CK-MB/(U/L) 18.18±12.05 17.66±16.99 0.624 ALT/(U/L) 26.03±10.17 25.77±13.11 0.762 GGT/(U/L) 32.70±31.17 34.24±63.96 0.676 IMT: 颈动脉内膜中层厚度; HbAlc: 糖化血红蛋白; eGFR: 估算肾小球滤过率; BUN: 尿素氮; UA: 尿酸;
HDL-C: 高密度脂蛋白胆固醇; TG: 甘油三酯; LDL-C: 低密度脂蛋白胆固醇; CK-MB: 肌酸激酶同工酶;
ALT: 丙氨酸氨基转移酶; GGT: 谷氨酰胺转移酶。2.3 H型高血压与非H型高血压患者血压变异曲线分类特征
24 h血压变异曲线分类结果显示, H型高血压组非杓型和超杓型占比高于非H型高血压组，差异有统计学意义(P < 0.05)。见表 3。
表 3 非H型高血压组与H型高血压组血压变异分类结果[n(%)]血压变异类型 n H型高血压组(n=362) 非H型高血压组(n=407) χ2 P 非杓型 146 133(91.1) 13(8.9) 164.165 < 0.001 杓型 532 174(32.7) 358(67.3) 超杓型 91 55(60.4) 36(39.6) 2.4 H型高血压影响因素分析
以H型高血压为因变量，以表 2中差异有统计学意义的因素为自变量行影响因素分析，结果显示，男性、吸烟、老年人、IMT增厚、eGFR下降、腰围增大、BUN升高、UA升高、HbAlc升高是H型高血压的危险因素(P < 0.05)。见表 4。
表 4 H型高血压logistics回归分析自变量 B Wald OR 95%CI P 男性 2.592 37.225 13.357 5.812~30.723 < 0.001 吸烟 3.695 85.665 0.025 26.881~70.354 < 0.001 本地居民 0.184 0.342 1.202 0.652~2.234 0.559 年龄/岁 0.923 8.212 1.321 0.684~4.323 0.040 颈动脉斑块厚度/mm 1.068 70.803 2.909 2.274~3.732 < 0.001 估算肾小球滤过率/[mL/(min·1.73 m2)] -0.005 1.550 0.912 0.721~1.993 0.030 腰围/mm 0.645 6.354 1.861 1.121~4.946 0.020 尿素氮/(mmol/L) 0.209 8.526 1.233 1.071~1.425 0.004 尿酸/(μmol/L) 0.060 23.846 1.006 1.004~1.009 < 0.001 糖化血红蛋白/% 0.235 9.799 1.265 1.093~1.474 0.002 甘油三酯/(mmol/L) 0.005 0.004 1.005 0.845~1.185 0.720 低密度脂蛋白胆固醇/(mmol/L) -0.063 0.299 0.939 0.745~1.176 0.590 总胆固醇/(mmol/L) 0.212 0.813 1.182 0.777~2.889 0.682 高密度脂蛋白胆固醇/(mmol/L) -0.314 0.777 0.730 0.362~1.473 0.378 3. 讨论
高血压作为家庭医生管理的重点慢性病之一，其控制率并不理想, H型高血压管理不佳尤为严重。流行病学资料[5-7]表明，中国H型高血压患病率为47.24%~96.98%。本研究纳入社区卫生服务中心就诊、家庭医生签约管理的高血压人群，对比20年前流行病学调查中北京城乡人群血浆Hcy(男性为15.4 μmol/L、女性为12.2 μmol/L)的均值水平[8], 发现本研究高血压人群Hcy水平[男性为(12.46±9.46) μmol/L、女性为(9.50±5.67) μmol/L)]有所降低，同时低于上海闵行区35岁及以上人群Hcy水平[男性为(16.63±7.39) μmol/L, 女性为(12.88±4.50) μmol/L)][9]。
既往研究[10]证实, Hcy是人体内蛋氨酸的代谢中间产物，通过损害血管内皮细胞、炎症反应、脂质斑块形成，导致心脑血管疾病。H型高血压是脑卒中重要的危险因素，可导致患者肾功能恶化，甚至肾功能衰竭。H型高血压是脑梗死发生的独立危险因素，同时也是糖尿病视网膜病变的危险因素之一[11-14]。本研究中，H型高血压组患者包括eGFR及BUN水平在内的肾脏功能指标均比非H型高血压组差，颈动脉斑块形成比例显著高于非H型高血压组。H型高血压组患者的血压变异性高于非H型高血压组，非杓型及超杓型患者更多。变异性高会损害内皮功能，引起炎症反应及氧化效应激活，促进动脉粥样硬化[15], 进而导致心脑血管风险增加。
H型高血压患者常伴随多种代谢紊乱，同时高Hcy、高UA与脂代谢紊乱共同参与高血压的发生发展过程，且可能存在交互作用[16]。本研究也显示, H型高血压组患者UA、TG、HbAlc显著高于非H型高血压组, HDL-C低于非H型高血压组。本研究中还发现腰围与H型高血压的相关性，腹型肥胖高血压患者更易合并H型高血压。本研究中，男性H型高血压检出率高于女性。分析原因可能为男性体内缺少雌激素对Hcy的调节作用，从而导致男性H型高血压的患病率高于女性[17]。另一个可能因素是女性更偏爱蔬菜和水果，这类食物含有更多的叶酸。此外，本研究表明，吸烟、老年是H型高血压的风险因素。分析原因可能为年龄越大机体吸收叶酸的能力越差，体内Hcy叶酸依赖的代谢途径受限，导致老年患者体内Hcy水平升高; 吸烟可抑制血管内皮舒张功能和降低一氧化氮(NO)活性，引起血压升高; 同时吸烟增加体内氧自由基，降低亚甲基四氢叶酸还原酶活性，导致血Hcy水平升高[18]。
综上所述, H型高血压在家庭医生签约管理的高血压患者中检出率高，同时容易伴随多种代谢紊乱和靶器官损害。性别、年龄、肥胖、吸烟等因素与H型高血压发病密切相关。家庭医生应加强对高危人群的定期筛查以及时诊断H型高血压，并采取积极的干预措施，包括合理膳食、控制患者体质量、戒烟，以提高H型高血压的控制率和规范管理率，进而改善患者临床预后。
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