【作者】 JOEL MULUNGU（周伟穆伦古）；

【导师】 袁洪；

【作者基本信息】 中南大学 ， 内科学， 2010， 硕士

【摘要】 目前,心脑血管疾病已经成为我国居民死亡的首要原因,而高血压作为一种常见的心血管综合征,与脑卒中、冠心病、心力衰竭及肾脏疾病等多种危害人民生命健康的重大疾病息息相关,根据已有的流行病学资料显示,我国目前已经有超过2亿高血压患者,且这个数字正以每年1000万的速度增长,全国每年用于高血压的直接治疗费用逾400亿元。高血压业已成为我国重大的公共卫生问题。长期的高血压主要引起全身小动脉病变,与伴之而来的其它危险因素共同作用促进动脉粥样硬化的形成,最终导致心、脑、肾等靶器官的损害和多种并发症的产生。而动脉硬化病变为多种心血管疾病的共同病理生理基础,是高血压患者发生心血管事件的独立预测因子。众多研究表明早期诊断和干预动脉硬化能有效降低心血管事件发生率。诸如动脉脉搏波传导速度测定(PWV)、踝臂指数(ABI)、反射波增强指数(AI)等一系列检测技术相继问世,为早期诊断动脉硬化性疾病创造了有利的条件。防治动脉硬化、减少心血管风险需多种渠道、多个方位综合干预,其中控制血压是重要环节,而就“最合理”降压药物方案选择上来看,如何确定“最佳”方案以有效控制血压及改善血管功能仍然是悬而未决的难题。踝臂指数(Ankle-Brachial Index, ABI)为踝部动脉收缩压和双侧肱动脉收缩压的最高值之比。ABI基于的原理是外周动脉狭窄达到临界水平并导致狭窄远端灌注压的降低程度大致与病变的严重程度成正比。AHA公布的测算方法如下：先测量双侧肱动脉收缩期血压并取其平均值,若两侧血压差值大于10 mmHg(1 mmHg=0.133kPa),则以高值作为肱动脉收缩压；再测同侧胫后动脉和足背动脉,取其中的高值作为踝部收压;最后用选定的踝部收缩压除以选定的肱动脉收缩压,所得的值即这一侧的ABI,ABI的降低常提示踝部以上血管有狭窄或闭塞。而PWV指的是脉搏波在动脉的传导速度。动脉弹性的减低可导致脉搏波在动脉系统的传播速度加快。它与动脉壁的生物力学特性、血管的几何特性以及血液的密度等因素有一定的关系。PWV的数值虽然随着年龄的增加而增大,其基准值为1400cm/s。PWV与动脉硬度存在一定的正相关性,且测量方法简便易行、无创,被广泛应用于临床。PWV可以良好地反映大动脉的扩张性,PWV越快,动脉的扩张性越差、僵硬度越高、弹性越差。PWV的测定是通过测量脉搏波传导时间和两个记录部位的距离求得,计算公式为PWV(m/s)=L/t。通过检测ABI、PWV等指标可了解动脉弹性及血管功能,有助于诊断动脉硬化、并可预测心血管事件风险。目前我国高血压的知晓率、治疗率及控制率依然在较低水平,各类降压药物单一的有效率仅为42%-59%。实践证明,联合用药有利于有效控制血压、减少药物不良反应的发生。FEVER研究表明,钙拮抗剂加上利尿剂疗效要优于单用利尿剂。而进一步的研究发现,不同的联合用药方案在降压和减少心血管危险事件上存在差异。ASCOT-BPLA研究结果显示氨氯地平联用培哚普利治疗高血压合并高危因素的患者优于阿替洛尔加苄氟噻嗪。美国高血压协会最近正式发表了降压联合治疗方案意见书,推荐钙拮抗剂／利尿剂、ACEI/利尿剂、血管紧张素Ⅱ受体拮抗剂／钙拮抗剂、ACEI/钙拮抗剂作为优先选择的联合方案。ACCOMPLISH研究表明贝拉普利联合氨氯地平方案较之贝拉普利联合氢氯噻嗪方案治疗高血压合并高危因素的患者能更显著减少心血管危险事件的发生,但钙拮抗剂与血管紧张素Ⅱ受体拮抗剂联用的疗效是否优于钙拮抗剂与利尿剂尚不清楚。钙拮抗剂,作为一线降压药物,在我国高血压患者应用非常广泛,Syst-China、FEVER等研究均以二氢吡啶类钙拮抗剂为基础用药,本研究采用以氨氯地平为基础的不同联合降压方案,观察氨氯地平联合复方阿米洛利及氨氯地平联合替米沙坦在两组高血压患者中的疗效及不良反应发生率,探讨这两种方案对以上患者血压、动脉硬度的影响及其安全性。1.研究对象随机入选湖南省3个社区的106名老年高血压患者,男女不限,年龄为60-79岁。试验期间两组共有7名脱落(原因均系受试者要求退出药物临床试验)至试验结束时共获得99名受试者资料。将受试者随机分配到两个药物治疗组,即替米沙坦／氨氯地平组或阿米洛利／氨氯地平组,进行随机前瞻性开放性盲法治疗(PROBE)12周服药：替米沙坦组用替米沙坦40mg和氨氯地平2.5mg,每日早一次；阿米洛利组用复方阿米洛利半片(含阿米洛利1.25mg+氢氯噻嗪12.5mg)和氨氯地平2.5mg,每日早一次。2.实验室检查试验前后,每位受试者都进行全面的体格健康检查和实验室测试,包括血脂测试(总胆固醇,甘油三酯,高密度脂蛋白,低密度脂蛋白)、肝功能测试(谷丙转氨酶,谷草转氨酶)和肾功能检测(肌酐,尿酸)。另检测受试者的血压、踝臂指数及脉搏波速度以评价疗效。应用动脉硬化诊断仪测量肱-踝动脉PWV(brachial-ankle artery PWV, baPWV),双侧PWV中取较高一侧。单侧ABI的计算为该侧踝动脉(即胫后动脉或足背动脉)收缩压与双侧肱动脉收缩压的最高值之比,最后取左右两侧ABI的低值作为该患者的ABI。3.统计学方法采用SPSS for Windows Ver.11.5统计软件进行分析。计量资料用均数±标准差(x±s)表示,两组治疗前后自身对照采用配对t检验,组间比较采用两样本t检验, (若方差不齐,则采用两个独立样本比较的Mann-WhitneyU检验。)有效率及达标率比较采用χ2检验。以P<0.05为差异有统计学意义,P<0.01为差异有非常显著意义。经治疗后,两组人群PWV、ABI与起始基础值比较,PWV均明显降低(P<0.05),而ABI值均无明显变化(P>0.05)。而对治疗后PWV值降低幅度和ABI值上升幅度进行组间比较,结果表明,组间比较差异均无统计学意义(P>0.05)。治疗12周后,氨氯地平+替米沙坦组有效率90.0%(45／50),氨氯地平+阿米洛利组有效率89.8%(44/49),两组降压有效率统计分析结果显示：差别无统计学意义(P>0.05)。治疗12周后,氨氯地平+替米沙坦组达标率70.0%(35／50),氨氯地平+阿米洛利组达标率55.1%(27／49),两组降压达标率统计分析结果显示：差别无统计学意义(P>0.05)。经治疗后,替米沙坦组收缩压下降幅度为(29.1±13.1)1nmHg,阿米洛利组收缩压下降幅度为(26.3±16.4)mmHg,存在统计学差异(P<0.05)；替米沙坦组舒张压下降幅度为(11.5±7.8)]mmHg,阿米洛利组舒张压下降幅度为(10.5±9.5)1nmHg,两组组间比较差异均无统计学意义(P>0.05)。(表3)106例患者无明显不良反应停药者,替米沙坦组脱落3人,阿米洛利组脱落4人,原因均系受试者要求退出药物临床试验。两组不良反应发生均较少,分别为替米沙坦组头晕2例,头痛2例,不良反应发生率为8.0%；阿米洛利组头晕4例,皮疹1例,不良反应发生率为10.2%。经χ2检验,两组不良反应发生率无统计学意义(P>0.05)。所有不良反应均经对症处理后,症状消失,未影响继续治疗。替米沙坦组治疗前尿酸平均为(329.3±12.0)mmol/L,治疗后为(288.3±12.2)mmol/L,存在统计学差异(P<0.05),而阿米洛利组治疗前后尿酸水平无显著变化(P>0.05)。电解质、血脂等其它生化项两组治疗前后均无明显改变(P>0.05)。(表4)。1.两种用药方案均有助于降低动脉硬度、改善血管顺应性,但短期应用未能获得改善ABI的证据。2.以氨氯地平为基础的两种联合用药方案(替米沙坦／氨氯地平、阿米洛利／氨氯地平)对高血压患者的血压控制同样安全、有效；且氨氯地平联合替米沙坦可能更利于收缩压的降低。3.较之阿米洛利／氨氯地平,替米沙坦／氨氯地平治疗可能在尿酸水平降低上有更多获益。更多还原

【Abstract】 BACKGROUND:Currently, cardio and cerebrovascular diseases have become the leading cause of death among the Chinese population, and hypertension is one common type of cardiovascular syndrome, in addition to multiple others like stroke, coronary heart disease, heart failure, kidney disease that are harmful to people’s lives and health.According to existing epidemiological data, China now has more than 200 million people suffering from hypertension, and this number is growing by 10 million every year, china’s national annual direct cost of treatment for high blood pressure exceeds 40 billion yuan(Chinese currency). Hypertension has become a major public health problem in china.However, currently hypertension awareness, treatment and control rates have remained at low levels; various types of antihypertensive drugs are effective only for about 42%-59%. Practice has proved that combination therapy is conducive to effective control of blood pressure; reduce the incidence of adverse drug reactions. The Felodipine Event Reduction (FEVER) study shows that calcium antagonist in combination with diuretics is superior to a single diuretic effect. The study further found that there are differences in incidence in the use of different drug combination programs to reduce blood pressure and cardiovascular risk events. The anglo-scandinavian cardiac outcome trial-blood pressure lowering arm (ASCOT-BPLA) study showed that amlodipine combined with perindopril in patients with risk factors for hypertension is superior to Atenolol combined with bendrofluazide. The American Society of Hypertension recently published a blood pressure lowering drug combination treatment program formal submission, recommended calcium antagonist/ diuretic, ACEI/diuretics, angiotensinⅡreceptor antagonist/calcium antagonists, ACEI /calcium antagonists as first choice combination therapyThe Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) study shows that benazepril-amlodipine combination was superior to the benazepril-hydrochlorothiazide combination in reducing cardiovascular events in patients with hypertension who were at high risk for such events. However the superior effect of calcium antagonists and angiotensin II antagonist combination over that of calcium antagonists and diuretics is not clear.The main cause of long standing hypertension is systemic small artery disease changes coupled with other risk factors, promotes the formation of atherosclerosis, ultimately leading to heart, brain, kidney and other target organ damage and multiple complications. The atherosclerotic pathological changes and multiple common cardiovascular pathophysiological disease basis, are independent predictors of cardiovascular events in hypertensive patients.Many studies show that early diagnosis and intervention can reduce atherosclerosis incidence of cardiovascular events. Such as the determination of arterial pulse wave velocity (PWV), ankle brachial index (ABI), reflected wave augmentation index (AI) and a series of detection technology have been brought forth for the early diagnosis of atherosclerotic diseases has created favorable conditions. ABI (Ankle-Brachial Index, ABI) is the ratio of the systolic blood pressure measured at the ankle to the systolic blood pressure measured at the brachial artery. ABI is based on the principle of peripheral arterial stenosis reaches a critical level and lead to a narrow distal perfusion pressure in the lower level which is roughly proportional to the severity of disease. AHA published estimates as follows:first, bilateral brachial artery systolic blood pressure measurement is done and there should be a difference of 10 mmHg (1 mmHg=0.133 kPa) between each brachial B.P, The brachial systolic pressure in both arms is measured and patient is first allowed to rest for 5-10 minutes in the supine position. BP cuff is placed on the patient’s upper arm with the lower edge approximately 1 inch above the antecubital fossa.Brachial pulse is palpated for and conductivity gel is applied over the brachial artery. The tip of the probe is placed into the gel at a 45-60-degree angle until clear arterial pulse sounds are heard. The cuff is inflated to the point that pulse sounds disappear, then go 20 mm Hg above that point. Slowly deflate at a rate of 2 mm Hg per sec and the point where arterial pulse sounds resume is recorded. This is the brachial systolic pressure. This procedure is repeated in the other arm. The higher of the two brachial systolic pressure readings will be used to calculate the ABI. There should be a difference of less than 10 mm Hg between each brachial BP.The posterior tibial and dorsalis pedis systolic pressure in both legs is measured. The BP Cuff is placed on the patient’s leg approximately 2 inches above the ankle’s medial malleolus.The posterior tibial (PT) pulse is located, a gel is applied, and the Doppler probe is positioned. Systolic pressure is then measured following the same procedure described for the brachial artery. On the same leg, the dorsalis pedis (DP) pulse is located and systolic pressure measured. Measurement of both the PT and DP systolic pressures on the other leg is repeated. The higher of the two ankle readings for each leg (PT or DP) is selected These numbers will serve as the ankle systolic pressures in the ABI calculation. If either the PT or DP ankle pulse is absent, then the measurable reading is used to calculate the ABI.To calculate the ABI, each ankle systolic pressure is divided by the brachial systolic pressure. The higher of the two systolic pressures for each leg is divided by the higher of the two arm pressures to get the right and left ABI respectively.ABI may be an independent predictor of mortality, as it reflects the burden of atherosclerosis. A normal ABI is>0.9. An ABI<0.9 suggests significant narrowing of one or more blood vessels in the leg. The majority of patients with claudication have ABIs ranging from 0.3 to 0.9. Rest pain or severe occlusive disease typically occurs with an ABI <0.5. ABIs<0.2 are associated with ischemic or gangrenous extremities. Conditions such as diabetes mellitus or end stage-renal disease can give falsely elevated ABIs (1.3-1.5). The ABI test approaches 95% accuracy in detecting PAD. However, a normal ABI value does not absolutely rule out the possibility of PAD. Some patients with normal or near-normal ABI results may have symptoms suggesting PAD. If the resting ABI is normal, an exercise ABI should be conducted. PWV is velocity of pulse wave within the blood vessel. It is the velocity at which the pressure wave propagates because it is directly related to arterial stiffness. It is an independent predictive index of arterial stiffness. Reduction of arterial elasticity may lead to a faster transmission of arterial pulse wave velocity. The biomechanical properties of arterial walls, blood vessels geometric properties and density of blood factors to a certain extent have a relationship with arterial stiffness. PWV values change with many physiological factors. Age, respiration and cardiovascular health are some of the factors. As a person ages, his arteries harden gradually and the PWV of an arterial segment increases gradually following a relatively smooth curve. When a person develops cardiovascular problems the PWV deviates from the normal curve.PWV varies with respiration. It is slightly higher during expiration than inspiration due to the fact that blood pressure is slightly increased during the expiratory phase.The baseline value is< 1400cm/s(Normal). there is a certain degree of positive correlation between PWV and arterial stiffness, and the method of measurement is simple, noninvasive, widely used in clinical practice. PWV may well reflect stiffness in large arteries, faster PWV, the difference in the distensibility of arteries, the higher the stiffness, the lesser the flexibility. PWV was measured by measuring the pulse wave transit time and the distance between the two recording sites on the body obtained, calculated as PWV (m/s)= L(distance of two positions on the body) divided by t(time taken to travel in the two positions).for the prevention and treatment of atherosclerosis, there is need to avoid cardiovascular risk through multiple channels, involving a comprehensive intervention, which is an important part of controlling blood pressure, and selecting the "most reasonable" choice of antihypertensive drug programs, on how to determine the "best" program that could effectively control blood pressure and improve vascular function are still unresolved problems.Calcium channel blockers are widely used in china as first-line antihypertensive drugs in patients with hypertension, Syst-China, FEVER and other studies are some of the examples where dihydropyridine calcium antagonist-based drugs have been used. In this study we used different amlodipine-based drug combination program that lower Blood pressure, we evaluated the efficacy, adverse drug reactions and safety of amlodipine based drug programs (compound amiloride/amlodipine and telmisartan/amlodipine) on arterial stiffness in patients with hypertension.Objective:explore the effectiveness of different drug combination programs based on amlodipine to arterial stiffness in hypertensive patients.Materials and Methods:1. Study subjects and methods: In a randomized Prospective Study,106 elderly dyslipidemic hypertensive patients aged 60-79 years were enrolled, from three different communities in Hunan province out of which 99 subjects completed the study and 7 subjects dropped out (lost to follow up due to unclear reasons). A comprehensive physical and medical examination was carried out on them and laboratory tests which included:-Lipid profiles (TC, TG, HDL-C, LDL-C), liver function tests (AST, ALT), renal function tests (creatinine & uric acid) done on all the subjects. In addition, their B.P, brachial-ankle PWV and ABI were measured to assess the degree of arterial stiffness in order to predict cardiovascular events.They were later randomly assigned to two different groups of medications viz:-to telmisartan/amlodipine or amiloride/amlodipine. Subjects were followed up for 12 months of randomized prospective open blind ended treatment(PROBE).In the telmisartan group, oral doses of,(telmisartan 40mg+amlodipine 2.5mg) were administered, taken once daily, every morning, and in the amiloride group (amilodipine 2.5mg+compound amiloride plain tablets-amiloride 1.25mg,hydrochlorothiazide 12.5mg),one tablet once every morning were administered to the study subjects.2. Laboratory examination: Each subject underwent a comprehensive physical and medical examination, and then laboratory examinations where a lipid profile, renal and liver function tests were done. Blood pressure was taken and to measure the degree of arterial sclerosis, BaPWV and ABI measurements were done.3. Statistical Analysis: SPSS for windows version 11.5 soft ware was used for statistical analysis. Data is expressed as mean x±S; to compare and contrast between the two treatment groups before and after treatment,paired t test was performed. (If the variance is incomplete, then it would be compared using two independent samples by the Mann-Whitney U test.).efficiency was compared by using theχ2 test. significant level (P value) was P <0.05 for a statistically significant difference, and if P<0.01 showed an even more significant statistical difference.The effectiveness of these drug programs were assessed by quantification of the stiffness and other properties of the arterial wall which included measurements of the following indicators:-brachial-ankle PWV, ABI, systolic & diastolic blood pressures, lipid profile, liver and renal function tests and relating them to the traditional cardiovascular risk factors. In the final analysis, we compared:-(ⅰ) the effectiveness of B.P reduction in the two treatment groups, (ⅱ) B.P reduction rate in the two groups, (ⅲ) extent of B.P reduction before and after treatment in the two groups, (ⅳ) PWV and ABI for both groups before and after treatment, (ⅴ) treatment compliance in the two treatment groups, (ⅵ) laboratory test results for the two groups before and after treatment.Results:Arterial stiffness comparison for the two groups (2.1) PWV and ABI for both groups after treatment was compared with the baseline values, and PWV was significantly lower (P<0.05), whereas ABI values were not significantly changed (P>0.05). Comparing the values for both groups after treatment, PWV values reduced whereas ABI values increased. The results shows that the difference between the two groups were not statistically significant (P> 0.05) 2.2 Blood pressure comparison for the two groups was2.2.1 Comparison of efficiency in blood pressure reduction for the two groups was that after 12 weeks of treatment the efficiency in the amlodipine/telmisartan group was 90% (45/50), while the efficiency in the amlodipine/amiloride group was 89.8%(44/49).The efficiency rate in blood pressure reduction for the two groups showed no statistically significant difference (P>0.05).2.2.2 Comparison of Blood pressure reduction for the two groups that reached target levels (standard rates)After 12 weeks of treatment, rate of blood pressure reduction that reached target levels in the amlodipine+telmisartan group was 70.0%(35/50), while that in the amlodipine+ amiloride group was 55.1%(27/49), there was no statistically significant difference in blood pressure reduction for both groups that reached target levels (standard rates).The results showed:no significant difference (P> 0.05).2.2.3 Comparison of blood pressure reduction for the two groups before and after treatment.after the treatment, systolic blood pressure in the amlodipine+telmisartan group decreased by (29.1±13.1) mmHg, systolic blood pressure decrease in the amiloride group was (26.3±16.4) mmHg, there was significant difference (P<0.05); in the telmisartan group decrease in diastolic blood pressure was (11.5±7.8) mmHg, diastolic blood pressure decrease in the amiloride group was (10.5±9.5) mmHg, difference between the two groups were not statistically significant (P> 0.05).2.3 Comparison of occurrence of adverse drug reactions in the two groups 106 cases of patients with no history of drug discontinuation due to obvious harmful effects. In the telmisartan group,3 patients dropped out,4 dropped out from the amiloride group. These 7 patients were lost to follow-up. Occurrence of adverse drug reactions was less in both groups. In the telmisartan group, there were 2 cases of dizziness and 2 cases of headache whereas in the amiloride group, there were 4 cases of dizziness and 1 case of headache. The rate of occurrence of ADR in the telmisartan group was 8.0% and 10.2% in the amiloride group respectively.By using X2 test in both groups, the rate of occurrence of Adverse drug reaction was not statistically significant (P>0.05). All adverse drug reaction were characterized by dizziness and headache. These reactions improved on symptomatic treatment, the symptoms disappeared and did not affect further treatment.2.4 Comparison of laboratory results for both groups before and after treatment In the telmisartan group average uric acid before treatment was (329.3±12.0) mmol/L, after treatment it was (288.3±12.2) mmol/L, there was significant difference (P <0.05), while in the amiloride group uric acid levels before and after treatment showed no significant change (P>0.05). Electrolytes, lipids and other biochemistry items before and after treatment had no significant changes (P> 0.05).Conclusion:1. Both combination drug programs help reduce arterial stiffness and improve vascular compliance but failed to improve ABI in the short term.2. Both combination groups are safe & effective in hypertensive patients but telmisartan/amlodipine was more beneficial in lowering systolic blood pressure3. Compared with amiloride/amlodipine, telmisartan/amlodipine may be of more benefit in reducing uric acid levels.更多还原