【作者】 王文静；

【导师】 祖秀光；

【作者基本信息】 河北医科大学 ， 内科学， 2014， 硕士

【摘要】 目的：原发性高血压与心脑血管事件发生率及致死率密切相关，而心脑血管事件严重影响着人类的生活质量。大量研究表明，原发性高血压可以导致并且加重血管内皮功能障碍，而血管内皮功能障碍又可以促进高血压的发生、发展，二者形成恶性循环。因而改善血管内皮功能在高血压治疗中的地位日益受到重视。大量临床研究证明阿托伐他汀钙除了具有调脂作用外，还具有改善血管内皮功能、抗炎、抗氧化等调脂外作用。而依折麦布作为新型的调脂药物，是否和他汀类调脂药物一样具有改善血管内皮功能、抗炎等调脂外作用，目前鲜有报道。本研究旨在观察阿托伐他汀钙联合依折麦布是否可以进一步改善原发性高血压患者血管内皮功能。方法：选取2013年1月至2013年8月就诊于河北医科大学第二医院的原发性高血压患者60例（符合2005年中国高血压治疗指南的原发性高血压的诊断标准，即血压≧140/90mmHg）。入选标准：原发性高血压1、2级的患者。排除标准：①肝、肾功能障碍或心力衰竭者。②严重胃肠疾病可能影响药物吸收患者。③对他汀类药物及依折麦布过敏者。④肌酸激酶＞正常值上限的2倍。⑤明确诊断的继发性高血压、原发性高血压分级3级的患者、冠心病、糖尿病及其他严重的器质性系统疾病患者。⑥未按规定用药、依从性差及不能定期回访的患者。将符合入选标准的60例患者随机分为两组，每组30例，降压药物均选用苯磺酸左旋氨氯地平。A组（单独用药组）：给予阿托伐他汀钙20mg1/晚；B组（联合用药组）：给予阿托伐他汀20mg1/晚、依折麦布10mg1/日，治疗期间保持用药前的饮食与生活习惯。所有入选患者分别于治疗前及治疗4周后抽取清晨空腹静脉血，测定血浆中血脂、NO、ET-1、Hs-CRP水平，肝肾功能等指标，进行治疗前后组内及组间比较。统计治疗前后Hs-CRP、NO、ET-1、血脂、血压变化情况。采用SPSS13.0软件包处理全部数据，P＜0.05有统计学意义。正态计量资料采用均数±标准差表示，组间、组内均数比较采用t检验。计数资料用百分比表示。结果：1、入组患者一般情况两组患者年龄、性别比例、体重指数、吸烟率、饮酒率、家族史、血脂、血压水平等均无统计学意义。2、两组患者治疗前后肝肾功能变化情况两组患者的ALT、Scr基线水平无统计学意义。组内比较：治疗前后ALT、Scr未见有意义升高。组间比较：ALT及Scr在治疗前后两组患者两两比较均无统计学意义。3、两组患者治疗前后Hs-CRP变化情况：组内比较：治疗前后两组Hs-CRP浓度（mg/L）分别为:治疗前，A组3.32±1.25；B组2.90±1.68；4周时，A组2.45±1.41，B组2.10±0.71。4周时与治疗前相比，A组降幅△da=0.48±0.45(P<0.05)，B组降幅△db=1.21±0.68(P <0.05)。两组Hs-CRP均降低，与治疗前相比差异存在统计学意义。组间比较：两组治疗前后Hs-CRP△d相比较，A组降幅da=0.48±0.45(P<0.05)，B组降幅△db=1.21±0.68(P <0.05）。阿托伐他汀钙联合依折麦布组Hs-CRP降低幅度更显著，差异存在统计学意义（P=0.00）。4、治疗前后血管内皮功能变化情况：ET-1组内比较：治疗前后两组ET-1浓度(ng/L)分别为:治疗前，A组68.23±6.70，B组71.68±6.62；4周时，A组62.90±5.88，B组61.62±6.79。A组降幅△da=5.32±3.88（P<0.05）; B组降幅△db=9.94±5.68(P<0.05)。两组ET-1均降低，与治疗前相比差异存在统计学意义。ET-1组间比较：两组治疗前后ET-1△d相比较，A组降幅△da=5.32±3.88（P<0.05），B组降幅△db=9.94±5.68(P<0.05)。阿托伐他汀钙联合依折麦布组ET-1降低幅度更显著，差异存在统计学意义（P=0.002）。NO组内比较：治疗前后NO浓度(umol/L)分别为:治疗前，A组52.28±5.45，B组50.42±4.72；4周时，A组56.83±5.92，B组58.08±5.24。A组降幅△da=-4.55±4.12（P<0.05），B组降幅△db=-7.43±7.77（P<0.05）；两组NO均升高，与治疗前相比差异有统计学意义。NO组间比较：两组治疗前后NO△d相比较，A组降幅△da=-4.55±4.12（P<0.05）;B组降幅△db=-7.43±7.77(P<0.05)。阿托伐他汀钙联合依折麦布组NO升高幅度更显著，差异存在统计学意义(P=0.015)。5、两组患者治疗前后血压变化情况血压情况组内比较：A组治疗前后血压（mmHg）分别为：治疗前收缩压153.87±8.43，4周时收缩压140.10±8.15；治疗前舒张压105.00±96.3,4周时舒张压84.90±5.44。治疗后收缩压与舒张压均降低，与治疗前相比差异存在统计学意义B组治疗前后血压（mmHg）分别为：治疗前收缩压153.13±8.47，4周时收缩压140.23±7.52；治疗前舒张压95.03±8.52，4周时舒张压85.77±5.18。治疗后收缩压与舒张压均降低，与治疗前相比差异存在统计学意义。血压情况组间比较：两组收缩压降幅：△da=13.77±5.70（P<0.05），△db=12.90±4.55（P<0.05），两组收缩压降低幅度差异不存在统计学意义。两组舒张压降幅：△da=11.4±5.29（P<0.05），△db=9.27±4.08（P<0.05），两组舒张压降低幅度不存在统计学意义。6、两组患者治疗前后血脂变化情况LDL-C组内比较：治疗前后两组LDL-C浓度(mmol/L)分别为:治疗前，A组1.99±1.20，B组2.33±1.18；4周时，A组1.55±1.00，B组1.36±0.56。A组降幅△da=0.44±0.56(P<0.05）; B组降幅△db=0.97±0.84(P<0.05)。两组LDL-C均降低，与治疗前相比差异存在统计学意义。LDL-C组间比较：治疗前后两组△d LDL-C浓度(mmol/L)分别为: A组降幅△da=0.44±0.56(P<0.05），B组降幅△db=0.97±0.84(P<0.05)。阿托伐他汀钙联合依折麦布组LDL-C降低幅度更显著，差异存在统计学意义(P=0.027)。CHOL组内比较：治疗前后两组CHOL浓度(mmol/L)分别为:治疗前，A组4.39±1.26，B组4.67±0.79；4周时，A组3.51±0.1，B组3.08±1.01。A组降幅△da=0.84±0.45(P<0.05); B组降幅△db=1.47±0.68(P<0.05)。两组CHOL均降低，与治疗前相比差异存在统计学意义。CHOL组间比较：治疗前后两组△d CHOL浓度(mmol/L)分别为: A组降幅△da=0.84±0.45(P<0.05)，B组降幅△db=1.47±0.68(P<0.05)。阿托伐他汀钙联合依折麦布组CHOL降低幅度更显著，差异存在统计学意义。结论：1、原发性高血压患者应用阿托伐他汀钙后，血管内皮炎性因子ET-1、Hs-CRP下降，NO升高。表明阿托伐他汀钙可以有效改善原发性高血压患者血管内皮功能。2、原发性高血压患者联合应用阿托伐他汀钙与依折麦布后，Hs-CRP、ET-1下降的幅度、NO升高的幅度更显著。表明加用依折麦布可以更好的改善原发性高血压患者血管内皮功能。3、联合依折麦布用药与单独用药比较，肝肾毒性未见明显增加。4、联合依折麦布与单独用药比较，血脂下降幅度更显著。更多还原

【Abstract】 Objective: Essential hypertension is closely related to the incidenceand mortality of cardiovascular events, cardiovascular and cerebrovascular events have seriously affected the quality of human life. Many studies show that essential hypertension can lead to and increased endothelialdysfunction, and hypertension can accelerate the development endothelial dysfunction, then they form a vicious circle. So improving endothelialfunction status more attention in the treatment of essential hypertension.Numerous clinical trials have certified that atorvastatin calcium not only has slowed lipid effects, but also has improved endothelial function, anti-inflammatory and antioxidant function. The ezetimibe as a new lipidlowering drugs, whether has the function of improving endothelial, anti-inflammatory lipid external action, which is currently rarely reported. This study aimed to view atorvastatin calcium combined with ezetimibe whether can be further improve endothelial function in patients with essential hypertension.Methods: Choose60patients diagnosed as hypertension in SecondHospital of Hebei Medical University from January2013to August2013.Inclusion criteria：hypertension diagnostic criteria in line with2005Chinese Hypertension Prevention Guide recommended method: blood pressure≥140/90mmHg (1,2-level selected patients with hypertension).Exclusion criteria:①liver, kidney dysfunction or heart failure.②severe gastrointestinal disease may affect the absorption of the drug in patient.③on statins and ezetimibe allergies.④creatine kinase>2times the upperlimit of normal.⑤diagnosis of secondary hypertension,coronary heart disease, diabetes and other serious diseases organic systems.⑥The patien t who is failing to medication and cannot regularly visit.The60patientsmet the inclusion criteria were randomly divided into two groups.Bothgroups have30patients. Group A(monotherapy group):given levamlodipine lesylate tablets2.5mg1/QD,atorvastatin calcium20mg1/QN;Group B(combination group):given levamlodipine lesylate tablets2.5mg1/QD,atorvastatin20mg1/QN and ezetimibe tablets10mg/QD, diet and lifestyle is same as before medication during treatment.All enrolled patients were obtained fasting blood samples before treatment and after4weeks oftreatment, which is used to evaluate the level plasma lipids,NO,ET-1,Hs-CRP levels, liver and kidney function. The statistics of Hs-CRP,NO,ET-1was observed before and after treatment.The experimental data will be dealed with by using SPSS13.0software for statistical analysis.“P <0.05”is considered statistically significant. Measurement data were expressed as mean±standard deviation.While between the two groups were compared using t test. Count datawas expressed as a percentage.Results:1,the general condition of enrolled patientsBasic information (age,gender,body mass index,smoking rates,drinking rates,family history,blood lipids,blood pressure levels) in patients doesnot have statistically significant difference between two groups (P>0.05).2,the changes of liver and kidney function in the two groups，patientsbefore and after treatment:The level of ALT and Scr in Two groups’ patients has no significant difference in baseline. Within groups: two groups of patients after treatment had varying degrees of elevated ALT, and then gradually declined (P<0.05);Scr levels showed no significant change in each period. Between the two groups:ALT and Scr patients in each group at different times pair wise comparisons showed no significant difference.3, the changes of Hs-CRP before and after treatment:Within the group:Hs-CRP concentrations in two groups(mg/L) were a s follows before and after treatment:pre-treatment, groupA3.32±1.25; groupB2.90±1.68;4weeks, group A2.45±1.41,group B2.10±0.71;4weeks compared with before treatment, groupA dropped△da=0.48±0.45（P<0.05）,groupB fell△db=1.21±0.68(P<0.05);therefore can be summarized as follows:Hs-CRP in two groups appear lower since the application of the drug in patients, while the difference has statistically significant.Between the two groups: two groups before and after treatment compared△d, groupA dropped△da=0.48±0.45(P<0.05), groupB fell△db=1.21±0.68(P<0.05),it can be summed up as, in atorvastatin calcium combinedwith ezetimibe group Hs-CRP is lower magnitude more obvious, whichhas statistically significant.4, the changes of vascular endothelial function before and after treatment:Within the group:ET-1concentrations in two groups (mg/L) beforeand after treatment were as follows:before treatment, group A68.23±6.70, GroupB71.68±6.62;4weeks,groupA62.90±5.88, groupB61.62±6.79;4weeks compared with before treatment, groupA drop△da=5.32±3.88(P<0.05), groupB fell△db=9.94±5.68(P<0.05); therefore it can be summarized as that: ET-1in two groups appear lower since the application of the drug in patients, while the difference has statistically significant.Between the two groups:two groups before and after treatment compared△da=5.32±3.88(P<0.05),group B fell△db=9.94±5.68(P<0.05),it can besummed up as, in atorvastatin calcium combined with ezetimibe groupET-1is lower magnitude more obvious, which has statistically significant.Within the group: NO concentrations in two groups before and after treatment were as follows:pre-treatment, group A52.28±5.45,group B50.42±4.72:4weeks, groupA56.83±5.92, groupB58.08±5.24;4weeks compared with before treatment,groupA drop△da=-4.55±4.12(P<0.05), group Bfell△db=-7.43±7.77(P<0.05);therefore can be summarized as that: Noun two groups appear lower since the application of the drug in patients, while the difference has statistically significant.Between the two groups: two groups before and after treatment compared△d, groupA dropped△da=-4.55±4.12(P<0.05), groupB fell△db=-7.43±7.77(P<0.05),it can be summed up as, in atorvastatin calcium combined with ezetimibe group NO is lower magnitude more obvious, whichhas statistically significant.5、the changes of blood pressure before and after treatment：Blood pressure within the group:The blood pressure(mmHg) of groupA before and after treatment was as follows: systolic blood pressure before treatment was153.87±8.43,4weeks was140.10±8.15;while diastolic blood pressure before treatmentwas105.00±96.3,4weeks diastolic was84.90±5.44. After treatment, systolic and diastolic blood pressures were both lower, compared with before treatment there were statistically significant differences.Blood pressure (mmHg) of group B Blood pressure before and aftertreatment was: systolic blood pressure before treatment was153.13±8.47,4weeks140.23±7.52;diastolic blood pressure before treatment was105.00±96.3, diastolic blood pressure at4weeks was84.90±5.44. After treatment, systolic and diastolic blood pressures were both lower, comparedwith pre-treatment differences statistically significant.Blood pressure between the two groups:systolic blood pressure drop in two groups:△da=13.77±5.70(P<0.05),△db=12.90±4.55(P<0.05), the magnitude of differences of systolicblood pressure do not exist statistically significant in the two groups.Two diastolic decline:△da=11.4±5.29(P<0.05),△db=9.27±4.08(P<0.05),the magnitude of differences of systolic blood pressure do notexist statistically significant in the two groups.6、the lipid changes of two groups before and after treatment：The level of LDL-C within group: the level of LDL-C concentrations(mmol/L) in two groups before and after treatment were as follows: before treatment, groupA1.99±1.20, group2.33±1.18;4weeks, groupA1.55 ±1.00, groupB1.36±0.56. group A dropped△da=0.44±0.56(P<0.05);groupB fell△db=0.97±0.84(P<0.05). LDL-C was lower in both groupscompared with pre-treatment differences existed statistically significant.The level of LDL-C between groups: the level of LDL-C concentrations (mmol/L) in two groups before and after treatment were as follows:groupA dropped△da=0.44±0.56(P<0.05), groupB fell△db=0.97±0.84(P<0.05). Atorvastatin calcium and ezetimibe reduced LDL-C group magnitude more obviously,differences existed statistically significant.The level of CHOL within group: the level of CHOL concentrations(mmol/L) in two groups before and after treatment were as follows: before treatment, group A4.39±1.26, Group B4.67±0.79;4weeks, groupA3.51±0.10, GroupB3.08±1.01. groupA dropped△da=0.84±0.45(P<0.05); groupB dropped△db=1.47±0.68(P<0.05). CHOL was lower inboth groups compared with pre-treatment differences existed statisticallysignificant.The level of CHOL between groups: the level of LDL-C concentrations (mmol/L) in two groups before and after treatment were as follows:groupA dropped△da=0.84±0.45(P<0.05), groupB dropped△db=1.47±0.68(P<0.05).Atorvastatin calcium ezetimibe group CHOL lower magnitude more obviously,differences existed statistically significant.Conclusions:1,The factors of vascular endothelial inflammatory ET-1,Hs-CRP decreased,NO increased after the patients with essential hypertension taking atorvastatin calcium.Atorvastatin calcium can improve endothelial function in patients with essential hypertension.2,in atorvastatin calcium combined with ezetimibe,Hs-CRP,ET-1decreased more obviously andNO elevated more obviously in the patients with essential hypertension.Combined treatment showed better improvement in endothelial function in essential hypertensive patients with primary aspects.3,The combinationtherapy compared to immunotherapy groups in the patients with essential hypertension.; there is no significant increase in liver and kidney toxicity.4,In atorvastatin calcium combined with ezetimibe,lipid decreased mor e obviously.更多还原