【作者】 姚丽；

【导师】 刘坤申； 籍振国；

【作者基本信息】 河北医科大学 ， 内科学， 2007， 硕士

【摘要】 背景:冠状动脉粥样硬化性心脏病(冠心病)是一种多危险因素影响的常见疾病,其高危患者病死率、致残率高。近年来对冠心病防治的重点已逐渐转移至一级和二级预防。有研究表明,内皮功能障碍是冠心病的临床前期的标志,而颈动脉内-中层厚度(IMT)增加可作为冠心病患病率及病死率的独立危险因素。阿托伐他汀作为新型组织选择性3-羟基3-甲基戊二酰辅酶A(HMG-CoA)还原酶抑制剂,能在降低总胆固醇(TC)和低密度脂蛋白(LDL-C)胆固醇的同时,发挥其非调脂作用,改善内皮功能、降低血小板聚集性和血栓沉积,减轻血管炎症反应,能更有效地降低冠心病发病率、冠脉事件发生率和提高生存率。目的:探讨阿托伐他汀强化降脂与常规剂量降脂对冠心病高危患者内皮功能及颈动脉IMT的影响。方法:入选标准:选择2005年3月-2006年3月我科住院的冠心病高危患者:包括冠心病及冠心病等危症患者,冠心病等危症是指,发生主要冠脉事件的危险性与已患冠心病者等同,即10年内患“硬性冠心病(”指心肌梗死和冠脉死亡)危险大于20%者,包括:①糖尿病;②动脉粥样硬化的其他临床表现形式(周围动脉性疾病、腹主动脉瘤和症状性颈动脉疾病),③存在多项危险因素,估计10年冠心病危险大于20%者;并且低密度脂蛋白胆固醇(LDL-C)≥3.4mmol/L。入院前停服降脂药物大于4周,共入选81例,其中男性49,女性32例,年龄为45-78岁;平均年龄(63.82土8.69)。排除标准:除外怀孕或哺乳期妇女;原发性甲状腺功能减退(TSH>5.5mU/L);肾病综合征或肾功能损害,尿素氮(BUN)≥10.71mmol/L(30mg/dL)或肌酐(Cr)≥176μmol/L(2.0mg/dL);阻塞性黄疸,活动性肝病,慢性肝炎或肝功能不全,天冬氨酸转氨酶(AST)或丙氨酸转氨酶(ALT)大于或等于正常上限3倍,或高胆红素血症;肌病,肌酸激酶(CK)超过正常上限5倍或不明原因的CK升高;有酗酒或药物滥用史;对他汀类药物过敏或有禁忌症者;仍在服用以下任何药物者:调血脂药,免疫抑制剂,其他已知影响血脂水平或与研究药物存在相互作用或影响临床实验室参数(如红霉素,异维A酸,类固醇药物),已知与他汀类药物合用增加横纹肌溶解危险的药物;严重肺部疾病;恶性肿瘤(除外可治愈的皮肤癌症);慢性胰腺炎;胶原病。按随机数字表法随机将81例患者分为10mg/d阿托伐他汀组(入选40例,其中男性25例,女性15例,平均年龄63.56土8.47岁),及40mg/d阿托伐他汀组(入选41例,其中男性24例,女性17例,平均年龄64.13土8.04岁)。两组均每晚顿服一次。服药期间患者饮食习惯和生活方式基本不变。如AST或ALT大于或等于正常上限3倍,可减少药量或停止药物。CK超过正常上限10倍应停药。检测治疗前及治疗后1、3、6个月时血清低密度脂蛋白胆固醇(LDL-C)、总胆固醇(TC)、甘油三脂(TG)、高密度脂蛋白胆固醇(HDL-C)、血糖(GLU)、激酸肌酶(CK)和肝肾功能。血脂测定采用酶法在全自动生化仪测定血清TC、TG、GLU、CK和肝肾功能,免疫比浊法测定血清HDL-C。按Friedewald公式计算血LDL-C浓度。LDL-C:LDL-C=TC-HDL-C-TG/2.2(如TG值>4.52 mmol/L,不采用此公式,采用免疫比浊法)。每次取血化验前1天晚上不宜进高脂饮食及饮酒,晚餐后不宜再进食,保证空腹12h以上,抽取静脉血测定血脂。测定治疗前及治疗后6个月及12个月肱动脉血流介导舒张功能。肱动脉血流介导舒张功能的测定,采用德国SEQUOIAS-512型超声诊断仪,参照Celermajor等方法。检测时患者取仰卧位,右上肢外展15度,用二维超声成像纵向扫描肘上2~15cm的肱动脉,于心室舒张末期测量前后内膜之间的垂直距离,测3个心动周期,取平均值为肱动脉内径。每例受试者分别测量其基础状态、反应性充血后肱动脉的内径。受试者测试前休息10min,在测定基础值(D0)后进行反应性充血试验,将血压计袖带置于肘下,充气加压300mmHg,4min后放气减压,60~90s内测肱动脉的内径(D1)。反应性充血后内径的变化(D1-D0)/D0*100%,代表肱动脉内皮依赖性血管舒张功能(FMD)。在测试过程中,超声探头处于固定位置,每次测量肱动脉内径均取同一部位。测定治疗前及治疗后6个月及12个月颈动脉内膜-中层厚度的变化。颈动脉超声检测采用德国SEQUOIAS-512型超声诊断仪,行两侧颈动脉检查,由专人测定,探头频率7.0MHZ。患者仰卧位,从锁骨的内侧端横向扫查颈总动脉,在心室舒张末期(即同步ECG波时)固定颈动脉窦以下1cm处的图像,每侧测3个心动周期,颈总动脉后壁表现为由相对较低回声分隔的2条平行亮线,取其间垂直距离计算左右两侧颈动脉测量的6次检测平均值即为颈动脉内-中膜厚度(IMT),IMT≥0.9mm即为增厚。同时并记录各项指标及不良反应(头晕、肌痛、胃肠道反应等)。所用数据输入SAS6.12统计软件包进行统计,计量资料用均数±标准差表示,组间比较采用t检验,组内治疗前后比较用配对t检验,计数资料采用X2检验。P<0.05为统计学意义。结果:1两组间基线年龄、性别、疾病种类、体重指数等无统计学差异(P均>0.05),两组资料均衡,具有可比性。(见table 1)2治疗第1、3、6个月时,与治疗前相比,两组TC、LDL-C、TG水平均有显著性差异(P均<0.01)。两组HDL-C水平与治疗前相比均有升高,但无统计学差异(P均>0.05)。(见table2)两组组间比较:治疗第1、3、6个月时,40mg/d组降低LDL-C较10mg/d组更显著(40.78% vs 31.71%,P <0.05;47.17% vs 36.27%,P <0.01;49.14% vs 38.04%,P <0.01)。40mg/d组降低TC也较10mg/d组显著(32.83% vs 25.13%,P <0.01;36.85% vs 28.01%,P <0.01;37.69% vs 29.37%,P <0.01)。TG两组间同期相比无显著性差异(21.69% vs 15.95%,P >0.05;26.79% vs 19.68%,P >0.05;26.98% vs 20.74%,P >0.05)。HDL-C两组间同期相比无显著性差异(2.61% vs 4.27%,P >0.05;3.48% vs 5.13%,P >0.05;3.48% vs 5.98%,P>0.05)。3治疗第6、12个月时,两组FMD均较治疗前明显改善(P<0.05),12个月较6个月时改善更为明显(P<0.05)。两组组间比较:治疗第6、12个月时FMD比较,40mg/d组改善更为明显(P<0.05)。4治疗后6个月,10mg/d组IMT较治疗前有所改善,但无统计学差异(P>0.05),治疗后12个月较治疗前及治疗后6个月明显改善(P<0.05)。40mg/d组治疗第6、12个月时,IMT均较治疗前明显改善(P<0.05),12个月较6个月时改善更为明显(P<0.05)。两组组间比较:治疗后12个月IMT比较,40mg/d组改善更为明显(P<0.05)。(见table 3)5单因素相关分析显示,基线FMD与IMT数值无相关关系(r=0.0685,p>0.05);两组用药6个月后,FMD及IMT改善的程度与患者LDL-C降低的程度亦无相关关系(r分别为-0.06和0.1188,p值均>0.05)(见Fig.1、2、3)6服药第1、3、6个月时复查肝功能,40mg/d组ALT及AST值升高率高于10mg/d组,但两组间相比无统计学差异。检测CK两组均无超出正常上限者。两组均无横纹肌溶解现象。两组间副反应发生率无统计学差异(P>0.05)。(见table 4)结论:对于冠心病高危患者,40mg/d阿托伐他汀与10mg/d阿托伐他汀相比,能更有效调脂,同时能更有效的发挥其非调脂作用,逆转或延迟颈动脉IMT的进程,改善内皮功能。且其对内皮功能及IMT的改善作用独立于其降脂作用。两组间相比有一致的安全性。更多还原

【Abstract】 Background: Coronary atherosclerosis heart disease (CHD) is a disease caused by several risk factors with high morbidity and mortality, especially in the population with high risk factors. For the past few years, the emphasis of how to prevent and cure CHD has been transfer to first and second class prevention. There are studies indicated that endodermis functional impairment is the labeling of the preclinical phase of CHD,and the intra-medio layer thickness augment of carotis has been as the independent risk factor of morbidity and fatality in the CHD pationt. Atorvastatin as a new type tissue selectivity 3-hydroxy-3-methyl glutaryl CoA reductases-stat,can lower TC and LDL-C, and educe its non-lower lipin effection,improve endodermis functional impairment,lower platelet aggregation and lesson angio-inflammatory, should lower the morbility of CHD,coronet arteries even and elevate survival effectively.Objective: Investigate the effection of Intensive Lipid Lowering and routine Lipid Lowering With Atorvastatin in HighRisk Coronary Heart Disease, to the endodermis functional and intra-medio layer thickness of carotis. Methods: selection critria: Patients with high CHD risk facotrs in our hospital between March 2005 and october 2006 were enrolled in the study .High CHD risk was defined as CHD and CHD risk equivalent. CHD risk equivalent is defined a person without established CHD, whose absolute 10-year risk for developing major coronary events (myocardial infarction and coronary death) is equal to that of persons with CHD, i.e, >20 percent per 10 years. CHD equivelant include (1). diabetes, (2). other forms of clinical atherosclerotic diseases (peripheral arterial disease, abdominal aortic aneurysm, carotid artery disease), (3). high-risk persons with multiple risk factors who can be diagnosed CHD, or with 10-year risk>20 percent ; and with LDL cholesterol level≥3.4mmol/L. They all did not received statins four weeks before treatment, and the eighty-one patients aged 45 to 78 years (48 male and 32 female). Average age is(63.82土8.69).Exclusion critria: pregnancy or breastfeeding women, primary hypothyroidism (TSH>5.5mU/L), nephrotic syndrome or renal disfunction, blood urea nitrogen (BUN)≥10.71mmol/L (30mg/dL) or serum creatinine(Cr)≥176mol/L (2.0mg/dL), obstructive biliary disease, active liver disease, chronic viral hepatitis or hepatic disfunction, Alanine aminotransferase(ALT) or Asparatate aminotransferase (AST)≥3 times upper limit of normal or Hyperbilirubinemia, myopathies, creatine kinase(CK)>5 times upper limit of normal or creatine kinase >upper limit of normal that its cause was indefinitely, alcohol or drug abuse, participation in another study within 1 months before randomization or concomitant use of the following drugs: lipid-lowering agents expect for the study medication, immunosuppressants, any drugs known to affect lipid levels or drugs that interfere with study medication or drugs that affect clinical laboratory parameters (e.g., systemic steroids or isotretinoin, erythromycin), drugs associated with rhabdomyolysis in combination with statins,severe lung disease, malignant tumor (with exception for skin cancer that can be cured), chronic pancreatitis,collagenoses.The patients were randomized into 10mg/d atorvastatin group (in all 40 patients, 25 male and 15 female, with age of 63.56土8.47 years) and 40mg/d atorvastatin group(in all 41 patients, 24 male and 17 female, with age of 64.13±8.04 years).The patients of two groups received atorvastatin orally once at night leaving diet habit, lifestyle and other medical treatment unchanged. Patients were permited to decrease atorvastatin dosage or withdraw from the trial if their ALT or AST≥3 times upper limit of normal and CK>10 times upper limit of normal .TC, LDL-C, HDL-C, TG, Glucose, creatine kinase,hepatic function and renal function were measured regularly before study entry and at month 1, 3, 6 during the study period. TG、TC、GLU、CK、hepatic function and renal function by enzymic method determined at hol- automatic biochemistrict meter and HDL-C by immunoturbidimetry. LDL-C were measured by Formula of Friedewald: LDL-C=TC - HDL-C - TG/2.2 (LDL-C dose not adopt the Formula if value of TG >4.52mmol/L, LDL-C by immunoturbidimetry). All the patients were not suitable eat high fat diet and drinking pro-evening ,inadvisable eating after dinner, must fast over 12 hours before the venous blood samples were obtained every time.Determin the variation of diastolic function mediated by arteria brachialis bloodstream, at pretherapy and post-treatment six and twelve month. These determinion apply germany SEQUOIAS-512 type diagnostic ultrasound meter, Celermajor and reference Celermajor method. Patients take dorsal position, abducens right upper extremity fifteen degrees, portait scan arteria brachialis above elbow with 2D-ultrasonic imaging, measure vertical dimension of circa endomembrane in ventricular diastasis, measure three cardiac cycle,take general average,is arteria brachialis inner diameter. Every subjects measure its arteria brachialisinner diameter in ground condition and after reactive hyperemia. Subjects recess ten mintues before test, march reactive hyperemia test after ground value(D0) was determined,put the blood pressure gauge cuff in below elbow, charge and pressurize to 300mmHg, deflate and deboost after four minute,measure arteria brachialis inner diameter in 60~90s( D1) represent。The change of inner diameter after reactive hyperemia (D1-D0)/D0*100%, represent blood vessel diastolic function dependented by arteria brachialis endodermis (FMD). In these test process, supersound transducer be in fixed position,and take same place in every time.Determin the variation of the intra-medio layer thickness of carotis, at pretherapy and post-treatment six and twelve month. These determinion apply germany SEQUOIAS-512 type diagnostic ultrasound meter,take test with two sides carotid by special messenger, transducer frequency is 7.0MHZ. Patients take supine position, explorate arteria carotis communis transversally from clavicular wall, fix the picture below one centimeter of bulbus caroticus in ventricles diastasis(i.e synchronization ECG wave), measure three cardiac cycle every side, the arteria carotis communis posterior wall appearant two strip parallel bright line separated by relative lower level echo,take vertical dimension in between, calculate average value of six times of the carotid’s two sides,this is the intra-medio layer thickness of carotis(IMT),IMT≥0.9mm is thickening.Chief complaints such as vertigo, myalgia, gastrointestinal events were recorded durng the follow-up.All statistical tests were performed with two-sided alternatives and a typeⅠerror of 0.05 and with the use of SAS software (version 6.12). Initially the homogeneity of variance among all the groups was analyzed. All the measurement data was expressed as mean±standard deviation (mean±SD) and students t test was used to explore statistical significance. Chi-square test was used for analysis of categorical data.Results: 1 The two groups of patients were well matched with regard to baseline characteristics of age, sex、disease variety and body mass index (P>0.05) (Table 1).2 After 1, 3, 6 months treatment, TC, LDL-C, TG were significantly reduced striking (P<0.01) and HDL-C was increased (P>0.05) compared with baseline in two groups (Table2). Two sets group comparison:Atorvastatin of 40mg yielded significantly reduction from baseline in LDL-C compared with Atorvastatin 10mg at month 1(40.78% vs 31.71%; P<0.05), at month 3 (47.17% vs 36.27%; P<0.01) and at month 6 (49.14% vs 38.04%; P<0.01) respectively. The data also showed there was a significant recuduction in TC in the group given atorvastatin 40mg daily compared with the group given atorvastatin 10mg daily after1-month treatment (32.83% vs 25.13%; P<0.01), after 3-month treatment (36.85% vs 28.01%; P<0.01) and after 6-month treatment (37.69% vs 29.37%; P<0.01). However, there was no significant reduction in TG between two groups at month 1(21.69% in atorvastatin of 40mg/day group vs 15.95% in atorvastatin of 40mg/day group; P>0.05), month 3 (26.79% in atorvastatin of 40mg/day group vs 19.68% in atorvastatin of 10mg/day group; P>0.05), and month 6 (26.98% in atorvastatin of 40mg/day group vs 20.74% in atorvastatin of 10mg/day group; P>0.05), respectively. There was also no significant difference in HDL-C between atrovastatin 40mg daily group and atrovastatin 10mg daily group after 1-month treatment (2.61% vs 4.27%; P>0.05), after 3-month treatment (3.48% vs 5.13%; P>0.05) and after 6-month treatment (3.48% vs 5.98%; P >0.05).3 After treatment in six and twelve month, FMD of the two sets improved obviously all compare to pretherapy P<0.05,compare to six month , the FMD of twelve month improved obviously P<0.05.Two sets group comparison: .after treatment in six and twelve month, FMD of the 40mg/d group improved obviously P<0.05. (Table 3)4 After treatment in six month, IMT of the 10mg/d group has improved compare to pretherapy,but without statistics difference P >0.05,compare to pretherapy and six month treatment, the twelve month treatment improved obviously P<0.05。After treatment in six and twelve month, IMT of the 40mg/d group improved obviously compare to pretherapy P<0.05,compare to six month , the IMT of twelve month improved obviously P<0.05。Two sets group comparison: .after treatment in twelve month, IMT of the 40mg/d group improved obviously P<0.05 (Table 3)5 Mono-agentcorrelation analysis display that , the baseline numerus of FMD and IMT without correlativity(r=0.0685,p>0.05);After treatment in six month of the two sets , the improved degree of FMD and IMT have no correlativity with the depressed degree of LDL-C(r= -0.06 p>0.05;r=0.1188,p >0.05)(Fig.1、2、3)6 During study period, the data showed both groups had a similar safety profile. The proportion of patients with elevation of ALT and AST was slightly high in the group given atorvastatin 40mg/day during the study period, However, there was no stastical significance. CK level in all patients was in normal limit during the study period. Rhabdomyolysis was not observed in both groups. There was no siginifcant difference in adverse effects between both groups (P>0.05) (Table 4).Concolusions: For patients with high CHD risk factors, Atorvastatin at 40mg/day is more effective in Lipid-modifying compared with atorvastatin 10mg/day,and educe its non- lipid-modifying effect more effective in the same time, reverse or delay the proceeding of the carotid’s IMT,improve endodermis fuction.And the improved fuction to endodermis fuction and carotid’s IMT are independent to Lipid-modifying. However, safety was similar in two groups.更多还原