论文 9 intervention is one of the most commonly used animal models of experimental, the early 60 s Dahl was successfully established in 1960, salt sensitivity genetic hypertension Rats then Kawasaki and Luft in the late 1970 s successively put forward the concept of salt sensitivity of blood pressure, the study of development mechanism, relationship between salt and hypertension in [4-5] has entered a new stage, in the domestic Han Yunfeng et al. [6] for the first time successfully established sensory nerve dependence of salt sensitivity Hypertensive rat model. However, research progress on exploring the relationship between salt and cardiovascular disease are not many in the crowd. So on the different number of sodium excretion of elderly male patients with high blood pressure, low sodium excretion and higher sodium excretion in patients with hypertension and what is the effect of target organs? Objective: (1) the follow-up comparing elderly male patients with high blood pressure, high sodium excretion and the incidence of low sodium excretion in patients with cardiovascular disease; (2) in elderly male patients with high blood pressure as the research object, according to the 24 h urine sodium level grouping, observe their carotid intima - middle thickness (IMT), heart, left ventricular mass index (LVMI), microalbuminuria (MAU) and the level of blood pressure (BP) target organs such as the change of the structure and function, discusses different urinary sodium excretion in patients with target organ damage, for subsequent provides some references for the further study of mechanisms and intervention. Methods: (1) the elderly male patients with essential hypertension (N = 400) observational analysis. Let into the group of patients in the group before and after 2 weeks, and into the group of patients with the determination of 24 h urinary sodium excretion, take the average. The subjects the urine normal diet. Record the urine start and end time, measuring record urine output. Through all the participants' fasting urine for 24 hours urinary sodium excretion, it is concluded that the baseline average estimate sodium 上海交通大学医学院硕士学位论文 10 excretion, 24 hours a day and through the 24 h sodium excretion of three digits in population can be divided into: low sodium excretion, baseline sodium excretion group with high sodium excretion. Cox regression analysis the relationship between the urinary sodium excretion cardiovascular events. (2) the elderly male patients with essential hypertension (N = 400) determination of 24 hours urinary sodium value, divided into low sodium excretion, baseline urinary sodium excretion group and high sodium excretion, and all subjects was detected in carotid intima - middle thickness (IMT), heart, left ventricular mass index (LVMI) and 24 hours of microalbuminuria (MAU) and blood pressure (BP) levels, analysis the correlation among the indexes. Results: (1) at baseline, estimate the 24 hours urinary sodium excretion of 6.74 g (the standard deviation is 1.81). After follow-up of 18 months, a total of 62 (17.9%) of the object in cardiovascular events, including 20 cases of acute coronary syndrome (acs), 18 cases of stroke, 24 patients with CHF in hospital. With baseline estimation of urinary sodium excretion is 4.93 ~ 8.55 g/day of control group (n = 136; 4.6% of acute coronary syndrome (acs), and stroke 4.2%, 3.8% for CHF hospital), compared to a higher baseline estimation of urinary sodium excretion and acute coronary syndrome (> 8.55 g/day increased by 6.8%; HR, 1.48; 95% CI, 1.11 1.98), stroke (> 8.55 g/day increased by 6.6%; HR, 1.48; 95% CI, 1.09 2.01), and because of CHF hospital risk (> 8.55 g/day increased by 6.5%; HR, 1.51; 1.12 to 2.05). Low risk of urinary sodium excretion from CHF also admitted to hospital (< 4.93 g/day increased by 8.2%; HR, 1.23; 95% CI, 1.01 1.49). In respect of acute coronary syndrome and stroke, the comparison has no obvious statistical significance (P > 0.05). (2) the study found that higher sodium excretion of carotid intima - middle thickness (IMT) levels, heart, left ventricular mass index (LVMI) and 24 hours of microalbuminuria (MAU) and blood pressure (BP) were higher than baseline urinary sodium excretion group (P < 0.05) and low sodium excretion group (P < 0.01). The baseline urinary sodium excretion 上海交通大学医学院硕士学位论文 11 and low sodium excretion group compared with no significant difference (P > 0.05). Conclusion: 1. Compared with the baseline group urinary sodium excretion, high urinary sodium excretion (sodium intake of high substitution index) and acute coronary syndrome (including angina and myocardial infarction), stroke, and heart failure caused by increased risk of hospitalization; Low urinary sodium excretion is associated with an increased risk of heart failure caused by hospital, and acute coronary syndrome (including angina and myocardial infarction) and the incidence of stroke. (2) in elderly male patients with high blood pressure, high sodium excretion set a baseline urinary sodium excretion group and the low sodium excretion and the blood pressure, the structure and function of the heart, kidney, and degree of arteriosclerosis target-organ damage has increased significantly, while the baseline urinary sodium excretion and low sodium excretion group compared with no significant difference. Key words: high blood pressure in older men; Sodium excretion; Target organ damage 上海交通大学医学院硕士学位论文 12 中英文缩写词对照表 英文缩写英文全称中文全称 EH essentialhyPertension 原发性高血压 SHBG sex hormone binding globulin 性激素结合球蛋白 AR androgen receptor 核内雄激素受体 CHD coronary heart disease 冠状动脉粥样硬化性心脏病 IMT intima-media thickness 颈动脉内膜-中层厚度 SBP systolic blood pressure 收缩压 DBP diastolic blood pressure 舒张压 INTERSALT International Study of Salt and Blood Pressure 国际盐与高血压研究 SPSS statistical package for the social science 社会科学统计软件包 LVEF left ventricular ejection fraction 左室射血分数 LVEDD left ventricular end-diastolic dimension 左心室舒张末期内径 IVST interventricular septal thickness 室间隔厚度 E Early diastolic mitral transvalvular flow rate 二尖瓣舒张早期跨瓣流速 A Late diastolic flow velocity across the mitral valve 二尖瓣舒张晚期跨瓣流速 LVPWD left ventricular posterior wall thickness 左心室后壁厚度 BMI body mass index 体重指数 BSA body surface area 体表面积 LVM left ventricular mass 左心室质量 LVMI left ventricular mass index 左心室质量指数 WC waist circumference 腰围 FBG fasting blood glucose 空腹血糖 HDL-C high density lipoprotein-cholesterol 高密度脂蛋白-胆固醇 LDL-C low density lipoprotein-cholesterol 低密度脂蛋白-胆固醇 TG triglyceride 甘油三酯 TC total cholesterol 总胆固醇 MAU microscale albuminuria 微量白蛋白尿 SHR spontaneous hypertensive rat 自发性高血压大鼠 Sham sham-operation group 假手术组 上海交通大学医学院硕士学位论文 13 Cas castration group 去势组 RAAS renin-angiotensin-aldosteronesystem 肾素-血管紧张素-醛固酮系统 ARB Angiotensin II receptor antagonist 血管紧张素Ⅱ受体阻滞剂 上海交通大学医学院硕士学位论文 14 目录 英文缩略词对表………………………………………………………………...……12 第一章 引言………………………………………………………………………….16 第二章 尿钠排泄与心血管事件风险关系的临床研究…………………………….19 2.1.对象和方法……………………………………………………………………….19 2.1.1 研究对象………………………………………………………………………..19 2.1.2 研究方案………………………………………………………………………..20 2.2 统计学分析……………………………………………………………………….22 2.3 结果……………………………………………………………………………….22 2.3.1 不同尿钠排泄量的老年高血压男性患者各参数之间的比较………………..22 2.3.2 急性冠脉综合症、卒中和因 CHF 入院率与 24 小时尿钠的 COX 回归分析结果……………………………………………………………………………………...23 第三章不同尿钠排泄量对老年高血压男性靶器官的影响………………………...24 3.1 对象和方法…………………………………………………………………..…..24 3.1.1 研究对象………………………………………………………………………..24 3.1.2 研究方案…………………………………………………………………..……24 3.2.统计学分析……………………………………………………………………….26 3.3.结果…………………………………………………………………………….…26 3.3.1 各组受试对象的一般情况…………………………………………..…………26 3.3.2 3 组患者心脏超声测定结果及左室重量指数(LVMI)比较…………………...27 第四章讨论…………………………………………………………………………...28 4.1 钠盐摄入与钠泵(Na+/K+-ATP 酶)的关系………………………………………28 上海交通大学医学院硕士学位论文 15 4.2 盐敏感性高血压………………………………………………………………….29 4.3高钠排泄与心血管事件及靶器官损害的关系…………………………………..31 4.3.1 高盐摄入与高血压……………………………………………………………..31 4.3.2 高盐摄入与心肌损伤…………………………………………………………..35 4.3.3 高盐摄入与大动脉损伤………………………………………………………..36 4.3.4高盐摄入与肾脏损伤…………………………………………………………...38 4.3.5 高盐摄入与脑血管疾病………………………………………………………..39 4.4尿钠水平与慢性心力衰竭的关系………………………………………………..40 4.5 低钠排泄增加心血管事件发生的可能机制…………………………………….41 第五章小结………………………………………………….………………………..46 参考文献…………………………………………………………………...…………47 致谢………………………………………….………………………………………..58 攻读硕士学位期间已发表或录用的论文………………………………………...…59 上海交通大学医学院硕士学位论文 16 尿钠排泄量与老年男性高血压患者心血管疾病的相关性研究 引言 高血压是现今社会上最常见的心血管疾病,全世界每年约有 1700 万人死于高血压及相关疾病 [7] 。2005 年世界卫生组织调查显示,全世界范围内约有 10 亿以上的高血压患者,估计到 2025 年,高血压人数将达到 15.6 亿 [8] ,据 2010 年调查数据,我国约有 2.3 亿高血压患者,约占全球高血压总人数的 1/5,每 5 个成年人中就有 1 个高血压病患者,且呈逐年上升的趋势 [9] 。2010 年中国心血管病报告估计全国约有心血管病人2.3亿,每年心血管病死亡人数达300万(占全年疾病死亡人数的30%以上),每 10.5 秒就有 1 人死于心血管病,而高血压是导致心、脑血管疾病发生率和死亡率升高的重要原因。与正常人群比较,高血压患者卒中发生率增加 2.6~2.8 倍,心绞痛发生率增加 2~2.2 倍,充血性心力衰竭发生率增加 3~4 倍。高血压引起约 60%的脑卒中和 50%的冠心病,收缩压每升高 20mmHg 或舒张压每升高 10mmHg,心、脑血管并发症发生的风险倍增 [10] ,所以国内外学者研究均认为,高血压在基因和环境因素共同影响下已经成为现今社会威胁人类健康的严重公共卫生问题和沉重负担 [1] 。 高血压发生的主要危险因素有高钠低钾膳食、吸烟、过量饮酒、高血糖、高血脂、肥胖超重、年龄、长期过度精神紧张、高血压病家族遗传史及缺乏体力活动等 [11] 。其中膳食钠摄入量与血压水平和高血压患病率呈正相关,而膳食钾摄入量与血压水平呈负相关,膳食钠/钾比值与血压的相关性更强。我国各地区均存在较严重的高钠摄入问题,全国大部分地区人均每天膳食钠摄入量都在 12g 以上 [12] ,我国 14 组人群研究表明,膳食钠盐摄入量平均每天增加 2g,收缩压和舒张压将分别增高 2.0mmHg和 1.2mmHg [13] 。 大量研究显示人类原发性高血压(EH)是在一定遗传背景的基础上,由多种环境因素刺激造成血压调节的失衡。这其中,盐被国内外学者公认为是影响血压的重要因素。高盐及盐敏感性高一直是我国高血压人群的流行病特点之一。2007 年以来多项动物实验、流行病学、临床试验和遗传学研究的结果证明,高盐饮食的摄入是 上海交通大学医学院硕士学位论文 17 导致高血压的原因之一。日常生活中,成人每天膳食摄取钠 1-2g(相当于食盐 3-5g)就足以满足一般生理需要,但目前人均钠盐摄入量远远高于此数值。中国国内普遍存在高盐摄入食习惯,“2002 年中国居民营养与健康调查”指出我国居民每日盐摄入量平均为 12g,有 81.6%的居民食盐消费量超过世界卫生组织和中国居民膳食指南建议的消费水平(6g) [14-15] 。流行病学和临床观察均示食盐摄入量与高血压发生密切相关,即高钠高血压,尤其是盐敏感者更明显。盐摄入量与血压水平呈正相关,与每日盐摄入量<6g 比较,摄入量≥12g 者高血压患病风险增高 14%,摄入量≥18g 者风险增高 27%。有研究显示,平均 24 h 尿钠排泄量与血压均随着年龄增长呈显著相关,个体排钠量与血压显著相关,同时发现血压升高随年龄增长与大量盐摄入密切相关。高钠饮食可影响血管功能,导致血管动脉硬化,从而出现血压脉压差的增大以及血压昼夜节律的改变。高钠可引起水钠潴留,激活组织中的肾素-血管紧张素-醛固酮系统(RAAS)活性为主,引起血压升高,而循环中肾素活性水平是降低的。研究证实,盐不仅可以使血压升高,而且还可直接作用于靶器官,并造成损害。高血压患者限盐饮食可呈剂量依赖而显著降低血压,降低心血管事件的发生率。 自发性高血压大鼠(Spontaneously HypertensiveRat,SHR)是日本学者 Okamoto 和Aoki1 于 1963 年首先从普通 Wistar 大鼠中通过连续多代近亲交配筛选得到的,并于1969 年在美国国家卫生研究所(National Institutes of Health,NIH)正式建立品系。因为 SHR 的高血压自然发生,且高血压发生发展过程中伴随的一系列靶器官病理生理改变与原发性高血压患者非常相似,故 SHR 成为研究原发性高血压的理想动物模型,应用也最为广泛。在实验研究中,常选用来自 SHR 发源地的京都 Wistar 大鼠(WistarKyotorats,WKY)作为正常对照组。因此,SHR 的出现是高血压研究史的一个重要里程碑。目前高盐导致其他心血管病靶器官损害的直接证据大多来自于国内外的大量动物实验。 日常生活中,成人每天膳食摄取钠 1-2g(相当于食盐 3-5g)就足以满足一般生理需要 [16] ,但目前人均钠盐摄入量远远高于此数值。流行病学和临床观察均示食盐摄入量与高血压发生密切相关,即高钠高血压,尤其是盐敏感者更明显。盐敏感性高血压是高血压重要类型之一,近百年围绕盐敏感性高血压进行了大量研究。