老年高血压病中医证候特征与血压变异相关性并中药干预研究
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摘要
新近公布的第六次全国人口普查数据显示60岁及以上人口占13.26%,65岁及以上人口占8.87%,我国已步入老龄社会,据2002年全国居民营养与健康状况调查显示,我国60岁及以上人群高血压的患病率为49%。高血压病是老年心脑血管疾病最主要的危险因素,其脑卒中、心肌梗死、心力衰竭及慢性肾脏病等主要并发症,致残、致死率高。
老年患者因动脉硬化,血管壁僵硬度增加,压力反射器敏感性下降等原因,血压变异性增大。近年来研究发现,血压变异性是卒中、冠心病等心血管风险事件的独立预测因子,血压的变异性越大,发生心血管事件的风险越大。
目前缺乏公认的老年高血压病的中医证候特征分布规律,而老年血压变异性与中医证候是否具有相关性,中药干预是否能够改善血压变异,进而减少心血管风险,亟待研究。本项课题首先对老年高血压病及其血压变异性近年来中西医研究进展进行了综述。其次也是课题重点,是通过因子分析法归纳老年高血压病的中医证候分布规律及其与血压变异的相关性,并对此进行了天麻舒心方干预的临床研究。旨在探讨老年高血压病的证治规律及中药干预的可行性与实用性。
第一部分：临床调查部分
1目的
通过因子分析法研究老年高血压病的中医证候分布规律,并进而探寻老年血压变异性与中医证候的相关性。
2方法
对60岁及以上的原发性高血压患者进行临床调查,采用自制问卷调查、临床查体及理化检查相结合方式进行。调查主要内容包括姓名、性别、年龄、病程、用药史等一般情况；眩晕、头痛、头胀等47个症状,舌脉、口唇紫暗、目眶发暗、手掌暗红等14个特征；心肺腹等常规体格检查；动态血压监测、颈动脉超声、心脏超声等。所有数据采用SPSS16.0进行数据管理及统计分析。
3结果
3.1一般资料
320例患者纳入调查,12例患者因缺少重要资料予以剔除,共有308例患者纳入统计分析。其中男性139例(45.1%),女性169例(54.9%)。年龄60～89岁(70.12±8.747),其中60～69岁患者154例(50%),70～79岁患者92例(29.9%),80岁以上患者62例(20.1%)。
3.2老年高血压病中医证候特征研究
3.2.1因子分析与证候特征
将调查表中出现频率在10%以上的44个变量纳入因子分析,以特征根大于1提取16个公因子,解释原有变量总方差变异71.122%,并进行方差最大化正交旋转(Varimax)。对16个公因子所代表的变量(症状群),请专家组判定中医证候,初始得出8种证候：阴虚阳亢,兼有血瘀(F3、F6、F8、F9、F10)；阴虚阳亢,兼有痰浊(F7)；阴阳两虚,兼有血瘀(F2)；气阴两虚,兼血瘀(F1)；气阴两虚,兼痰浊(F4、F12)；肝风痰浊(F13、F14)；肝风痰浊,兼有血瘀(F11)；痰瘀互阻证(F5、F15、F16)。再根据主证相同进行合并,最终归纳老年高血压病5种证候：阴虚阳亢证、气阴两虚证、阴阳两虚证、肝风痰浊证、痰瘀互阻证。
3.2.2老年高血压的证型分布规律
根据因子得分对患者进行分组,阴虚阳亢证119例(38.6%),气阴两虚证60例(19.4%),阴阳两虚证25例(8.1%),肝风痰浊证57例(18.4%),痰瘀互阻证47例(15.2%)。再将患者按痰瘀辨证分组统计,痰浊证(各证型兼夹痰浊及肝风痰浊证)105例,占34.1%,痰瘀互阻证(肝风痰浊证兼夹血瘀和痰瘀互阻证)59例,占19.1%,而兼血瘀者144例,达46.8%,可见阴虚阳亢是老年高血压病的主要证候特点,痰浊、血瘀是老年高血压的主要兼夹证。
3.3平均血压值与证型关系
全天、日间、夜间的收缩压、舒张压、平均动脉压的平均值在阴虚阳亢、气阴两虚、阴阳两虚、肝风痰浊、痰瘀互阻五种中医证型之间分布未见显著性差异,P>0.05。
3.4血压变异及变异系数与中医证型
全天、日间及夜间的收缩压变异(SBP-SD)在五种证型分布中具有差异(P<0.05),阴虚阳亢组血压变异性最大,而肝风痰浊型变异最小。呈现阴虚阳亢>气阴两虚>痰瘀互阻>阴阳两虚>肝风痰浊的趋势。而舒张压变异、平均动脉压变异在五种证型中未见显著差异(P>0.05)。
全天、日间及夜间的收缩压变异系数(SBP-CV)在五种证型中具有差异(P<0.05),阴虚阳亢型血压变异系数最大,肝风痰浊型变异最小。呈现阴虚阳亢>气阴两虚>痰瘀互阻>阴阳两虚>肝风痰浊的趋势。而舒张压变异系数、平均动脉压变异系数在五种证型中未见显著差异(P>0.05)。
3.5左心室重量指数(LVMI)与血压变异性及证候关系
血压变异与LVMI进行相关性分析,日间收缩压变异(DSBP SD)及变异系数(DSBP-CV)与LVMI正相关,相关系数为0.480和0.460。各时段舒张压变异及平均动脉压变异与LVMI未见相关。各证型组间比较LVMI具有统计学差异,P<0.05,阴虚阳亢组及气阴两虚组LVMI较重,P<0.05。
3.6颈动脉内中膜厚度(IMT)、动脉内径与中医证型
各证型组间比较颈动脉内径未见差异(P>0.05)；但IMT值具有显著差异,其中阴虚阳亢组IMT值最大(P<0.05)；颈动脉内膜光滑度及血流情况在各证型分布情况未见显著性差异(P>0.05)；但各证型间出现斑块情况具有统计学差异,气阴两虚组斑块更为多发(P<0.05)。
3.7中医症状积分
患者中医症状体征总积分最小4分,最大83分,平均23.95±1.35分。五个证型组总症状积分,具有显著性差异,P<0.05,从平均值来看,阴虚阳亢组积分最高,其次为气阴两虚组,可见这两组患者症状较多。
将308例患者依据全天收缩压变异系数(SBP-CV)的P50(0.112)分为血压变异性偏小组,和变异性偏大组,并据此进行中医症状积分的比较,经t检验,P50及以上组,中医症状积分更高(P<0.05),即血压变异大者症状主诉相对多。
4结论
老年高血压病呈现阴虚阳亢、气阴两虚、阴阳两虚、肝风痰浊、痰瘀互阻5种主要证型,以虚实夹杂为主要特征。其中阴虚阳亢是老年高血压病的主要证候特征及重要病机,痰浊、血瘀是重要的兼夹证。
收缩压变异及变异系数在不同证型间具有显著差异,阴虚阳亢组患者的收缩压变异及变异系数较其他组大,提示阴虚阳亢是老年血压变异的主要证候特征及病机要点。
阴虚阳亢组及气阴两虚组患者LVMⅠ值更大；阴虚阳亢组IMT最厚,气阴两虚组斑块更为多发。患者中医症状总积分在阴虚阳亢及气阴两虚组相对较高,而全天收缩压变异系数在P50及以上症状总积分更高,P<0.05。
提示,血压变异与中医证候具有相关性,特别是阴虚阳亢是老年高血压病血压变异的主要证候,也是老年高血压病的主要证候特征,临床辨证施治过程中应格外加以关注。
第二部分：临床观察部分
1.目的
评价天麻舒心方对老年高血压阴虚阳亢型患者血压变异性干预效果。
2.方法
年龄在60～85岁之间的原发性高血压患者,血压分级1级或2级,中医辨证属阴虚阳亢证者,签署知情同意书可纳入研究。入组患者以1：1比例随机分为对照组(西药组)30例,治疗组(西药+中药)30例。对照组：苯磺酸氨氯地平片5mg1/日；治疗组：苯磺酸氨氯地平片5mg1/日+天麻舒心方(中药配方颗粒,温水冲服),150ml,2/日,疗程均为4周。
观察过程中每周随诊1次,记录血压、症状、体征、用药情况、不良反应。疗程前后进行安全性及疗效性指标检测。安全性指标：血、尿常规,肝、肾功能。疗效性指标：平均血压值(诊室血压、动态血压监测),血压变异性(SD)、变异系数(CV)；中医症状体征积分；肾素(PRA)、血管紧张素Ⅱ(Ang Ⅱ)；总胆固醇(CHO)、甘油三酯(TG)、高密度脂蛋白(HDL)、低密度脂蛋白(LDL)。所有数据采用SPSS16.0进行数据管理及统计分析。
3结果
3.1一般资料
符合纳入标准的60例患者入组观察,其中门诊患者48例(80.0%),住院患者12例(20.0%)；男性31例(51.7%),女性29例(48.3%)；年龄60～75岁。
治疗前两组患者一般情况以及血压水平,肾素(PRA)、血管紧张素Ⅱ(AngⅡ)、总胆固醇(CHO)、甘油三酯(TG)、高密度脂蛋白(HDL)、低密度脂蛋白(LDL)等理化检查方面均未见统计学差异(P>0.05),具有可比性。
3.2治疗前后诊室血压值变化情况
治疗后两组收缩压及舒张压均较治疗前显著下降(P<0.05),显示两组药物均可较好的降低血压平均值；两组药物间比较,从第2周开始,治疗组降低收缩压的幅度较对照组大,具有统计学差异(P<0.05),显示治疗组药物更强劲的降低收缩压数值作用；但在舒张压数值方面两组间未见统计学差异(P>0.05),显示两组药物对舒张压的作用相当。
3.3动态血压各指标比较
3.3.1血压平均值变化
治疗后全天、日间及夜间的收缩压、舒张压平均值均有显著下降,具有统计学差异(P<0.05)；治疗后组间比较,治疗组在全天收缩压(24hSBP)及日间收缩压(DSBP)降低幅度更大,具有统计学意义(P<0.05)；结果显示两组药物均具有良好的降压效果,但治疗组在降低全天收缩压及日间收缩平均值方面更有优势。
3.3.2血压变异性(SD)情况
治疗后两组全天收缩压变异(24hSBP-SD)、舒张压变异(24hDBP-SD)均较前有显著降低(P<0.05)；两组日间收缩压变异较前均明显降低(P<0.05),但日间的舒张压变异(DDBP-SD)未见明显变化(P>0.05)；两组对夜间血压变异均有改善作用(P<0.05),但治疗组仅对夜间收缩压变异(NSBP-SD)具有降低作用(P<0.05),而对舒张压变异(NDBP-SD)未见降低(P>0.05)；以上结果显示：两组药物均有较好的改善血压变异作用,特别是对于收缩压的变异,改善作用明显。治疗后两组间比较：治疗组在24hSBP-SD及DSBP-SD的降低更明显(P<0.05),而在其他的血压变异方面,两组间未见差异(P>0.05)
3.3.3血压变异性系数(CV)情况
治疗后两组全天收缩压变异系数(24hSBP-CV)、舒张压变异系数(24hDBP-CV)均较前有显著降低(P<0.05)；两组日间收缩压变异系数较前均明显降低(P<0.05),但日间的舒张压变异系数(DDBP-CV)未见明显变化(P>0.05)；两组对夜间血压变异系数均未见降低(P>0.05)；以上结果显示：两组药物均有较好的改善血压变异系数作用,特别是对于收缩压的变异系数,改善作用明显。治疗后两组间比较：治疗组在24hSBP-CV及DSBP-CV的降低更明显(P<0.05),而在其他的血压变异方面系数,两组间未见差异(P>0.05)
3.4PRA, AngⅡ变化情况
治疗前后比较,对照组对PRA、AngⅡ均未见改善作用(P>0.05),而治疗组对PRA、AngⅡ改善作用明显(P<0.01)；疗后两组间比较,治疗组改善作用显著优于对照组(P<0.05),显示治疗组良好的降低PRA、AngⅡ活性的作用。
3.5两组血脂变化情况比较
两组治疗前后比较,治疗组对总胆固醇(CHO)、甘油三酯(TG)及低密度脂蛋白(LDL)具有降低作用,具有统计学差异(P<0.05),而对照组治疗前后对各项血脂指标未见影响(P>0.05)；治疗后两组间比较治疗组在TG及LDL的降低作用方面明显优于对照组(P<0.05)。
3.6两组中医症状体征积分变化情况
治疗后两组总积分均较前明显减少,均显现了较好的症状改善作用(P<0.05)；但是治疗后两组间积分比较,治疗组改善作用更为明显,具有统计学差异(P<0.05)
4.结论
具有滋阴潜阳,活血通脉的天麻舒心方具有降低老年高血压病阴虚阳亢型收缩压变异作用,并显示了降低血压数值作用,改善中医症状、体征积分,降低PRA、AngⅡ、CHO、TG、LDL水平,安全性良好。提示,辨证论治的中医药对血压变异具有改善作用,值得进一步深入研究。
本研究的创新点与临床意义
本项研究在国家中医药管理局中国中医药文献检索中心进行查新,结果在MEDLINE数据库联机检索表明：未查到与本项目相关的报道；U.S.PATENT DATABASE及中国专利数据库联机检索表明,未查到相关专利文献；中医药新闻数据库等检索表明,未查到相关新闻报道。并在以下3方面具有创新性及临床实用意义,1应用因子分析法对老年高血压病证候特征进行前瞻性研究,归纳出老年高血压病的5种证候特征(阴虚阳亢,气阴两虚,阴阳两虚,肝风痰浊,痰瘀互阻),是客观化证候研究的结果,可作为进一步研究或同类研究辨证分型的依据。2研究表明,老年高血压证候特征与血压变异具有相关性,同时发现老年高血压病及其收缩压变异阴虚阳亢为主要证候特征及重要的病机,提示临床辨证老年高血压病过程以阴虚为本,特别是肝肾阴虚为本,对于临床辨证论治具有指导性意义。3天麻舒心方有效降低血压,改善血压变异性,值得进一步的新药开发与推广；提示辨证论治的中医药,具有改善血压变异性作用,希冀减少心血管风险事件,改善预后,提高老年患者生活质量。中医药改善血压变异性或将是治疗高血压病的新靶点,或将为中医药治疗高血压的研究提供新的思路。
The data of Sixth national census showed that aged60and above accounted for13.26%of the population, aged65and above accounted for8.87%, China has entered the aging society. According to the data of National Health and Nutrition Examination Survey in2002, China's population aged60and above hypertension prevalence was49%. Hypertension is the most important risk factors of elderly cardiovascular disease. Stroke, myocardial infarction, heart failure and chronic kidney disease and other complications are the main reason of disability and death.
The prognostic significance of blood pressure variability has lately enjoyed considerable attention. Some post-hoc studies and meta-analysis indicate that blood pressure variability is the strong predictor of the risk in adverse vascular events, independent from mean blood pressure. Visit to visit blood pressure variability,24-h ambulatory blood pressure variability and home blood pressure monitoring variability show the same prognostic significance, especially in systolic blood pressure variability. Antihypertensive drugs have not the same effect of blood pressure variability as blood pressure readings. Calcium antagonists reduced between-subject BP variability, while b-blockers, ACE inhibitors and ARBs increased the variance ratio.
As the physiological function degradation, increasing in senile arteriosclerosis vascular wall stiffness, baroreflex control decreased, the blood pressure variability increases in elderly patients. Recent studies found that blood pressure variability is an independent predictor of cardiovascular events such as stroke, coronary heart disease, the greater the variability of blood pressure, the greater the risk the risk of the event.
Now, there has no recognized TCM syndrome distribution characteristics of the elderly patients with hypertension, and we do not know the relationship between blood pressure variability and syndromes characteristics of TCM, we also do not know the effect of traditional chinese medicine on changing blood pressure variability.
This study first conducted two literature reviews, one of blood pressure variability in elderly patients, and the other of elderly hypertension in TCM and Western research progress. And then we conducted two parts study to explore the relationship of blood pressure variability and TCM.
Part I:Clinical investigation
1. Objectives
To investigate TCM syndrome characters in elderly hypertensive patients by factor analysis, and then explore the relationship between blood pressure variability and TCM syndromes.
2. Methods
Hypertensive patients who aged60and over, signed informed consent were interviewed. We made clinical investigation through questionnaire and medical examination. Trained doctors completed questionnaires regarding to general states of health, treatment history, symptoms, physical signs, etc.Data were managed and statistically analyzed by SPSS16.0. Two-sample t test or the One-Way ANOVA tested normal distribution data. Non-normal distribution Data were tested by NPAR test, such as Mann-Whitney test, Kruskal—Wallis test, Chi-square and analyses.Symptom characters were tested by factor analysis.
3. Results
3.1General information
A total of320hypertensive patients were enrolled, but12patients were removed because of the lack of important information, so308patients were included in the statistical analysis. Among them,139are male (45.1%),169are female(54.9%); From age part, the youngest is60year-old, the oldest is89year-old, the mean age is70.12±8.747year-old.
3.2TCM Syndromes of elderly hypertensive patients
The44variables which Frequency was more than10%were included in the factor analysis.16common factors were selected, which could explain71.122%of the total variance of original variables. According to the stander of syndromes, expert group determined the TCM syndromes. At first, there were8kinds of syndromes, some of them had been united into one, and then5TCM syndromes were obtained. The5syndromes are yin deficiency with yang hyperactivity syndrome, dual deficiency of qi and yin syndrome, dual deficiency of yin and yang syndrome, liver-wind and phlegm syndrome, phlegm and blood stasis syndrome
Among the5syndrome, the yin deficiency with yang hyperactivity syndrome are the most common one, which are119cases (38.6%).60are dual deficiency of qi and yin syndrome(19.4%),25are dual deficiency of yin and yang syndrome (8.1%), liver wind phlegm in57are liver-wind and phlegm syndrome (18.4%),47are phlegm and blood stasis syndrome (15.2%).
According to syndrome of phlegm and blood stasis, there are105with phlegm syndrome (34.1%),59are with phlegm and blood stasis (19.1%),144are with blood stasis (46.8%).
Overall, the yin deficiency with yang hyperactivity syndrome is the most common syndrome in elderly hypertensive patients, phlegm syndrome and blood stasis syndrome are the chief plus syndrome.
3.3The relationship between blood pressure and TCM syndrome
The blood pressure of systolic and diastolic in all the time are no significant difference (P>0.05) between the5syndromes.
3.4The relationship between blood pressure variability and TCM syndrome
Systolic blood pressure variability (SBP-SD) is significant difference (P<0.05) in5syndromes. The yin deficiency with yang hyperactivity syndrome has the maximum SD, thus the SD of liver-wind and phlegm syndrome is the minimum. There are no significant difference (P>0.05) in Diastolic blood pressure SD, mean arterial blood pressure SD in the5syndromes.
Systolic blood pressure coefficient of variability (SBP-CV) is significant difference (P<0.05) in5syndromes. The yin deficiency with yang hyperactivity syndrome has the maximum CV, thus the CV of liver-wind and phlegm syndrome is the minimum. There are no significant difference (P>0.05) in Diastolic blood pressure CV, mean arterial blood pressure CV in the5syndromes.
3.5The relationship between LVMI and TCM syndrome
Blood pressure variability and LVMI correlation analysis, daytime systolic blood pressure variability (DSBP-SD) and coefficient of variation (DSBP-CV) are positive correlation with LVMI, a correlation coefficient of0.480and0.460. There has no relevant between LVMI and DBP-SD. LVMI is significant difference (P<0.05) in5syndromes. The yin deficiency with yang hyperactivity syndrome is heavier than other syndromes (P<0.05).
3.6The relationship between IMT and TCM syndrome
IMT is significant difference (P<0.05) in5syndromes. IMT of the yin deficiency with yang hyperactivity syndrome is thicker than other syndromes (P<0.05). The plaques are statistically significant in5syndromes, the plaques of dual deficiency of qi and yin syndrome are larger (P<0.05).
3.7The relationship between symptom scores and TCM syndrome
Symptom scores are significant differences (P<0.05) in5syndrome, scores of the yin deficiency with yang hyperactivity syndrome are the highest, and then scores of the dual deficiency of qi and yin syndrome. Scores of SBP-CV over P50are higher than others (P<0.05).
4Conclusions
Through factor analysis, there are5syndromes in elderly hypertensive patients which are yin deficiency with yang hyperactivity syndrome, dual deficiency of qi and yin syndrome, dual deficiency of yin and yang syndrome, liver-wind and phlegm syndrome and phlegm and blood stasis syndrome. Among the5syndromes the yin deficiency with yang hyperactivity syndrome are the most common syndrome in elderly hypertensive patients, phlegm syndrome and blood stasis are the chief plus syndrome.SBP-SD and SBP-CV are Significant difference between the5syndromes. SBP-SD and SBP-CV of yin deficiency with yang hyperactivity syndrome are larger than other syndromes.LVMI and IMT of yin deficiency with yang hyperactivity syndrome are thicker than other syndromes. The plaques of dual deficiency of qi and yin syndrome are larger.(P<0.05). Scores of the yin deficiency with yang hyperactivity syndrome are the highest. Scores of SBP-CV over P50are higher than others.
Part Ⅱ:Clinical study
1Objective
To evaluate the effect of Tianmashuxin decoction (TMSX) on decreasing the blood pressure variability of elderly hypertensive patients.
2Methods
A total of sixty hypertensive patients over the age of60years and below the age of85years with yin deficiency with yang hyperactivity syndrome were randomized into treated group(n=30) and control group(n=30).The treated group were treated with Amlodipinc+TMSX, the control group patient were distributed with Amlodipine only. The therapeutic course was4weeks. Security indicators:WBC, RBC, HGB, PLT, Cr, BUN, ALT, AST. Efficacy indicators:blood pressure (clinic blood pressure, ambulatory blood pressure monitoring), blood pressure variability (SD), coefficient of variation (CV); TCM symptoms and signs; renin (PRA), angiotensin Ⅱ (Ang Ⅱ); total cholesterol (CHO), triglyceride (TG), high density lipoprotein (HDL), low density lipoprotein (LDL). Data were managed and statistically analyzed by SPSS16.0. Two-sample t test tested normal distribution data. Non-normal distribution Data were tested by NPAR test, such as Mann-Whitney test, Chi-square and analyses.
3. Results
3.1General information
60cases were enrolled the study.48were outpatients (80.0%),12were hospitalized patients (20.0%);31are males (51.7%) and29are females (48.3%); aged range from60to75years old.
Before the course, there were no significant difference between two group in age, course, complications, blood pressure readings, classify of risks, BP-SD, BP-CV, PRA, Ang II, CHO, TG, HDL, LDL (P>0.05). The data of two groups were suit to campare.
3.2Visit to visit blood pressure readings
After the course, visit to visit blood pressure readings decreased significantly in two groups (P<0.05), and between the groups, SBP of treated group was lower than control group (P<0.05). But there were no significant difference in diastolic blood pressure values between the two groups (P>0.05). This result indicates that TMSX can decrease visit to visit blood pressure readings.
3.3ABPM blood pressure readings
After the course, all time ABPM pressure readings decreased significantly in two groups (P<0.05), and between the groups, SBP of treated group was lower than control group (P<0.05) in24-hour and daytime. But there were no significant difference in diastolic blood pressure values between the two groups (P>0.05). This result indicates that TMSX can decrease SBP readings of24-hour and daytime of ABPM.
3.4Blood pressure variability
The two groups'BP-SD of24-hours and nighttime were significant decreased after the course (P<0.05). But between the groups,24hSBP-SD,NSBP-SD of treated group was lower than control group (P<0.05), there were no difference in DBP-SD and DBP-CV (P>0.05). This result indicates that TMSX can decrease SBP-SDof24-hour and nighttime of ABPM.
3.5Blood pressure coefficient of variation
The two groups'BP-CV of24-hour and nighttime were significant decreased after the course (P<0.05). But between the groups,24hSBP-CV, NSBP-CV of treated group was lower than control group (P<0.05), there were no difference in DBP-SD and DBP-CV (P>0.05). This result indicates that TMSX can decrease SBP-CV of24-hour and nighttime of ABPM.
3.6PRA, Ang II, CHO, TG, HDL, LDL
There were not change of PRA, Ang II, CHO, TG, LDL within the control group (P>0.05), but the PRA, Ang II, CHO, TG, LDL in treated group were decreased significantly (P<0.01); This result indicates that TMSX can decrease PRA, Ang II, CHO,TG,LDL.
3.7Symptom scores
The two groups'symtom scores were significant decreased after the course (P<0.05). But between the groups, treated group significantly reduced the total score than the control group (P<0.05). This result indicates that TMSX can decrease symptom scores.
4Conclusions
TMSX can decrease the SBP-SD and SBP-CV efficiently, in the same time it also can decrease BP readings, PRA, Ang Ⅱ, CHO, TG, and LDL. Symptoms of yin deficiency with yang hyperactivity syndrome could be improved by TMSX. There has no significant side effect. This indicates that traditional chinese medicine can improve the BP-SD, but it also need to explore the mechanic of TCM on SD.
老年患者因动脉硬化,血管壁僵硬度增加,压力反射器敏感性下降等原因,血压变异性增大。近年来研究发现,血压变异性是卒中、冠心病等心血管风险事件的独立预测因子,血压的变异性越大,发生心血管事件的风险越大。
目前缺乏公认的老年高血压病的中医证候特征分布规律,而老年血压变异性与中医证候是否具有相关性,中药干预是否能够改善血压变异,进而减少心血管风险,亟待研究。本项课题首先对老年高血压病及其血压变异性近年来中西医研究进展进行了综述。其次也是课题重点,是通过因子分析法归纳老年高血压病的中医证候分布规律及其与血压变异的相关性,并对此进行了天麻舒心方干预的临床研究。旨在探讨老年高血压病的证治规律及中药干预的可行性与实用性。
第一部分：临床调查部分
1目的
通过因子分析法研究老年高血压病的中医证候分布规律,并进而探寻老年血压变异性与中医证候的相关性。
2方法
对60岁及以上的原发性高血压患者进行临床调查,采用自制问卷调查、临床查体及理化检查相结合方式进行。调查主要内容包括姓名、性别、年龄、病程、用药史等一般情况；眩晕、头痛、头胀等47个症状,舌脉、口唇紫暗、目眶发暗、手掌暗红等14个特征；心肺腹等常规体格检查；动态血压监测、颈动脉超声、心脏超声等。所有数据采用SPSS16.0进行数据管理及统计分析。
3结果
3.1一般资料
320例患者纳入调查,12例患者因缺少重要资料予以剔除,共有308例患者纳入统计分析。其中男性139例(45.1%),女性169例(54.9%)。年龄60～89岁(70.12±8.747),其中60～69岁患者154例(50%),70～79岁患者92例(29.9%),80岁以上患者62例(20.1%)。
3.2老年高血压病中医证候特征研究
3.2.1因子分析与证候特征
将调查表中出现频率在10%以上的44个变量纳入因子分析,以特征根大于1提取16个公因子,解释原有变量总方差变异71.122%,并进行方差最大化正交旋转(Varimax)。对16个公因子所代表的变量(症状群),请专家组判定中医证候,初始得出8种证候：阴虚阳亢,兼有血瘀(F3、F6、F8、F9、F10)；阴虚阳亢,兼有痰浊(F7)；阴阳两虚,兼有血瘀(F2)；气阴两虚,兼血瘀(F1)；气阴两虚,兼痰浊(F4、F12)；肝风痰浊(F13、F14)；肝风痰浊,兼有血瘀(F11)；痰瘀互阻证(F5、F15、F16)。再根据主证相同进行合并,最终归纳老年高血压病5种证候：阴虚阳亢证、气阴两虚证、阴阳两虚证、肝风痰浊证、痰瘀互阻证。
3.2.2老年高血压的证型分布规律
根据因子得分对患者进行分组,阴虚阳亢证119例(38.6%),气阴两虚证60例(19.4%),阴阳两虚证25例(8.1%),肝风痰浊证57例(18.4%),痰瘀互阻证47例(15.2%)。再将患者按痰瘀辨证分组统计,痰浊证(各证型兼夹痰浊及肝风痰浊证)105例,占34.1%,痰瘀互阻证(肝风痰浊证兼夹血瘀和痰瘀互阻证)59例,占19.1%,而兼血瘀者144例,达46.8%,可见阴虚阳亢是老年高血压病的主要证候特点,痰浊、血瘀是老年高血压的主要兼夹证。
3.3平均血压值与证型关系
全天、日间、夜间的收缩压、舒张压、平均动脉压的平均值在阴虚阳亢、气阴两虚、阴阳两虚、肝风痰浊、痰瘀互阻五种中医证型之间分布未见显著性差异,P>0.05。
3.4血压变异及变异系数与中医证型
全天、日间及夜间的收缩压变异(SBP-SD)在五种证型分布中具有差异(P<0.05),阴虚阳亢组血压变异性最大,而肝风痰浊型变异最小。呈现阴虚阳亢>气阴两虚>痰瘀互阻>阴阳两虚>肝风痰浊的趋势。而舒张压变异、平均动脉压变异在五种证型中未见显著差异(P>0.05)。
全天、日间及夜间的收缩压变异系数(SBP-CV)在五种证型中具有差异(P<0.05),阴虚阳亢型血压变异系数最大,肝风痰浊型变异最小。呈现阴虚阳亢>气阴两虚>痰瘀互阻>阴阳两虚>肝风痰浊的趋势。而舒张压变异系数、平均动脉压变异系数在五种证型中未见显著差异(P>0.05)。
3.5左心室重量指数(LVMI)与血压变异性及证候关系
血压变异与LVMI进行相关性分析,日间收缩压变异(DSBP SD)及变异系数(DSBP-CV)与LVMI正相关,相关系数为0.480和0.460。各时段舒张压变异及平均动脉压变异与LVMI未见相关。各证型组间比较LVMI具有统计学差异,P<0.05,阴虚阳亢组及气阴两虚组LVMI较重,P<0.05。
3.6颈动脉内中膜厚度(IMT)、动脉内径与中医证型
各证型组间比较颈动脉内径未见差异(P>0.05)；但IMT值具有显著差异,其中阴虚阳亢组IMT值最大(P<0.05)；颈动脉内膜光滑度及血流情况在各证型分布情况未见显著性差异(P>0.05)；但各证型间出现斑块情况具有统计学差异,气阴两虚组斑块更为多发(P<0.05)。
3.7中医症状积分
患者中医症状体征总积分最小4分,最大83分,平均23.95±1.35分。五个证型组总症状积分,具有显著性差异,P<0.05,从平均值来看,阴虚阳亢组积分最高,其次为气阴两虚组,可见这两组患者症状较多。
将308例患者依据全天收缩压变异系数(SBP-CV)的P50(0.112)分为血压变异性偏小组,和变异性偏大组,并据此进行中医症状积分的比较,经t检验,P50及以上组,中医症状积分更高(P<0.05),即血压变异大者症状主诉相对多。
4结论
老年高血压病呈现阴虚阳亢、气阴两虚、阴阳两虚、肝风痰浊、痰瘀互阻5种主要证型,以虚实夹杂为主要特征。其中阴虚阳亢是老年高血压病的主要证候特征及重要病机,痰浊、血瘀是重要的兼夹证。
收缩压变异及变异系数在不同证型间具有显著差异,阴虚阳亢组患者的收缩压变异及变异系数较其他组大,提示阴虚阳亢是老年血压变异的主要证候特征及病机要点。
阴虚阳亢组及气阴两虚组患者LVMⅠ值更大；阴虚阳亢组IMT最厚,气阴两虚组斑块更为多发。患者中医症状总积分在阴虚阳亢及气阴两虚组相对较高,而全天收缩压变异系数在P50及以上症状总积分更高,P<0.05。
提示,血压变异与中医证候具有相关性,特别是阴虚阳亢是老年高血压病血压变异的主要证候,也是老年高血压病的主要证候特征,临床辨证施治过程中应格外加以关注。
第二部分：临床观察部分
1.目的
评价天麻舒心方对老年高血压阴虚阳亢型患者血压变异性干预效果。
2.方法
年龄在60～85岁之间的原发性高血压患者,血压分级1级或2级,中医辨证属阴虚阳亢证者,签署知情同意书可纳入研究。入组患者以1：1比例随机分为对照组(西药组)30例,治疗组(西药+中药)30例。对照组：苯磺酸氨氯地平片5mg1/日；治疗组：苯磺酸氨氯地平片5mg1/日+天麻舒心方(中药配方颗粒,温水冲服),150ml,2/日,疗程均为4周。
观察过程中每周随诊1次,记录血压、症状、体征、用药情况、不良反应。疗程前后进行安全性及疗效性指标检测。安全性指标：血、尿常规,肝、肾功能。疗效性指标：平均血压值(诊室血压、动态血压监测),血压变异性(SD)、变异系数(CV)；中医症状体征积分；肾素(PRA)、血管紧张素Ⅱ(Ang Ⅱ)；总胆固醇(CHO)、甘油三酯(TG)、高密度脂蛋白(HDL)、低密度脂蛋白(LDL)。所有数据采用SPSS16.0进行数据管理及统计分析。
3结果
3.1一般资料
符合纳入标准的60例患者入组观察,其中门诊患者48例(80.0%),住院患者12例(20.0%)；男性31例(51.7%),女性29例(48.3%)；年龄60～75岁。
治疗前两组患者一般情况以及血压水平,肾素(PRA)、血管紧张素Ⅱ(AngⅡ)、总胆固醇(CHO)、甘油三酯(TG)、高密度脂蛋白(HDL)、低密度脂蛋白(LDL)等理化检查方面均未见统计学差异(P>0.05),具有可比性。
3.2治疗前后诊室血压值变化情况
治疗后两组收缩压及舒张压均较治疗前显著下降(P<0.05),显示两组药物均可较好的降低血压平均值；两组药物间比较,从第2周开始,治疗组降低收缩压的幅度较对照组大,具有统计学差异(P<0.05),显示治疗组药物更强劲的降低收缩压数值作用；但在舒张压数值方面两组间未见统计学差异(P>0.05),显示两组药物对舒张压的作用相当。
3.3动态血压各指标比较
3.3.1血压平均值变化
治疗后全天、日间及夜间的收缩压、舒张压平均值均有显著下降,具有统计学差异(P<0.05)；治疗后组间比较,治疗组在全天收缩压(24hSBP)及日间收缩压(DSBP)降低幅度更大,具有统计学意义(P<0.05)；结果显示两组药物均具有良好的降压效果,但治疗组在降低全天收缩压及日间收缩平均值方面更有优势。
3.3.2血压变异性(SD)情况
治疗后两组全天收缩压变异(24hSBP-SD)、舒张压变异(24hDBP-SD)均较前有显著降低(P<0.05)；两组日间收缩压变异较前均明显降低(P<0.05),但日间的舒张压变异(DDBP-SD)未见明显变化(P>0.05)；两组对夜间血压变异均有改善作用(P<0.05),但治疗组仅对夜间收缩压变异(NSBP-SD)具有降低作用(P<0.05),而对舒张压变异(NDBP-SD)未见降低(P>0.05)；以上结果显示：两组药物均有较好的改善血压变异作用,特别是对于收缩压的变异,改善作用明显。治疗后两组间比较：治疗组在24hSBP-SD及DSBP-SD的降低更明显(P<0.05),而在其他的血压变异方面,两组间未见差异(P>0.05)
3.3.3血压变异性系数(CV)情况
治疗后两组全天收缩压变异系数(24hSBP-CV)、舒张压变异系数(24hDBP-CV)均较前有显著降低(P<0.05)；两组日间收缩压变异系数较前均明显降低(P<0.05),但日间的舒张压变异系数(DDBP-CV)未见明显变化(P>0.05)；两组对夜间血压变异系数均未见降低(P>0.05)；以上结果显示：两组药物均有较好的改善血压变异系数作用,特别是对于收缩压的变异系数,改善作用明显。治疗后两组间比较：治疗组在24hSBP-CV及DSBP-CV的降低更明显(P<0.05),而在其他的血压变异方面系数,两组间未见差异(P>0.05)
3.4PRA, AngⅡ变化情况
治疗前后比较,对照组对PRA、AngⅡ均未见改善作用(P>0.05),而治疗组对PRA、AngⅡ改善作用明显(P<0.01)；疗后两组间比较,治疗组改善作用显著优于对照组(P<0.05),显示治疗组良好的降低PRA、AngⅡ活性的作用。
3.5两组血脂变化情况比较
两组治疗前后比较,治疗组对总胆固醇(CHO)、甘油三酯(TG)及低密度脂蛋白(LDL)具有降低作用,具有统计学差异(P<0.05),而对照组治疗前后对各项血脂指标未见影响(P>0.05)；治疗后两组间比较治疗组在TG及LDL的降低作用方面明显优于对照组(P<0.05)。
3.6两组中医症状体征积分变化情况
治疗后两组总积分均较前明显减少,均显现了较好的症状改善作用(P<0.05)；但是治疗后两组间积分比较,治疗组改善作用更为明显,具有统计学差异(P<0.05)
4.结论
具有滋阴潜阳,活血通脉的天麻舒心方具有降低老年高血压病阴虚阳亢型收缩压变异作用,并显示了降低血压数值作用,改善中医症状、体征积分,降低PRA、AngⅡ、CHO、TG、LDL水平,安全性良好。提示,辨证论治的中医药对血压变异具有改善作用,值得进一步深入研究。
本研究的创新点与临床意义
本项研究在国家中医药管理局中国中医药文献检索中心进行查新,结果在MEDLINE数据库联机检索表明：未查到与本项目相关的报道；U.S.PATENT DATABASE及中国专利数据库联机检索表明,未查到相关专利文献；中医药新闻数据库等检索表明,未查到相关新闻报道。并在以下3方面具有创新性及临床实用意义,1应用因子分析法对老年高血压病证候特征进行前瞻性研究,归纳出老年高血压病的5种证候特征(阴虚阳亢,气阴两虚,阴阳两虚,肝风痰浊,痰瘀互阻),是客观化证候研究的结果,可作为进一步研究或同类研究辨证分型的依据。2研究表明,老年高血压证候特征与血压变异具有相关性,同时发现老年高血压病及其收缩压变异阴虚阳亢为主要证候特征及重要的病机,提示临床辨证老年高血压病过程以阴虚为本,特别是肝肾阴虚为本,对于临床辨证论治具有指导性意义。3天麻舒心方有效降低血压,改善血压变异性,值得进一步的新药开发与推广；提示辨证论治的中医药,具有改善血压变异性作用,希冀减少心血管风险事件,改善预后,提高老年患者生活质量。中医药改善血压变异性或将是治疗高血压病的新靶点,或将为中医药治疗高血压的研究提供新的思路。
The data of Sixth national census showed that aged60and above accounted for13.26%of the population, aged65and above accounted for8.87%, China has entered the aging society. According to the data of National Health and Nutrition Examination Survey in2002, China's population aged60and above hypertension prevalence was49%. Hypertension is the most important risk factors of elderly cardiovascular disease. Stroke, myocardial infarction, heart failure and chronic kidney disease and other complications are the main reason of disability and death.
The prognostic significance of blood pressure variability has lately enjoyed considerable attention. Some post-hoc studies and meta-analysis indicate that blood pressure variability is the strong predictor of the risk in adverse vascular events, independent from mean blood pressure. Visit to visit blood pressure variability,24-h ambulatory blood pressure variability and home blood pressure monitoring variability show the same prognostic significance, especially in systolic blood pressure variability. Antihypertensive drugs have not the same effect of blood pressure variability as blood pressure readings. Calcium antagonists reduced between-subject BP variability, while b-blockers, ACE inhibitors and ARBs increased the variance ratio.
As the physiological function degradation, increasing in senile arteriosclerosis vascular wall stiffness, baroreflex control decreased, the blood pressure variability increases in elderly patients. Recent studies found that blood pressure variability is an independent predictor of cardiovascular events such as stroke, coronary heart disease, the greater the variability of blood pressure, the greater the risk the risk of the event.
Now, there has no recognized TCM syndrome distribution characteristics of the elderly patients with hypertension, and we do not know the relationship between blood pressure variability and syndromes characteristics of TCM, we also do not know the effect of traditional chinese medicine on changing blood pressure variability.
This study first conducted two literature reviews, one of blood pressure variability in elderly patients, and the other of elderly hypertension in TCM and Western research progress. And then we conducted two parts study to explore the relationship of blood pressure variability and TCM.
Part I:Clinical investigation
1. Objectives
To investigate TCM syndrome characters in elderly hypertensive patients by factor analysis, and then explore the relationship between blood pressure variability and TCM syndromes.
2. Methods
Hypertensive patients who aged60and over, signed informed consent were interviewed. We made clinical investigation through questionnaire and medical examination. Trained doctors completed questionnaires regarding to general states of health, treatment history, symptoms, physical signs, etc.Data were managed and statistically analyzed by SPSS16.0. Two-sample t test or the One-Way ANOVA tested normal distribution data. Non-normal distribution Data were tested by NPAR test, such as Mann-Whitney test, Kruskal—Wallis test, Chi-square and analyses.Symptom characters were tested by factor analysis.
3. Results
3.1General information
A total of320hypertensive patients were enrolled, but12patients were removed because of the lack of important information, so308patients were included in the statistical analysis. Among them,139are male (45.1%),169are female(54.9%); From age part, the youngest is60year-old, the oldest is89year-old, the mean age is70.12±8.747year-old.
3.2TCM Syndromes of elderly hypertensive patients
The44variables which Frequency was more than10%were included in the factor analysis.16common factors were selected, which could explain71.122%of the total variance of original variables. According to the stander of syndromes, expert group determined the TCM syndromes. At first, there were8kinds of syndromes, some of them had been united into one, and then5TCM syndromes were obtained. The5syndromes are yin deficiency with yang hyperactivity syndrome, dual deficiency of qi and yin syndrome, dual deficiency of yin and yang syndrome, liver-wind and phlegm syndrome, phlegm and blood stasis syndrome
Among the5syndrome, the yin deficiency with yang hyperactivity syndrome are the most common one, which are119cases (38.6%).60are dual deficiency of qi and yin syndrome(19.4%),25are dual deficiency of yin and yang syndrome (8.1%), liver wind phlegm in57are liver-wind and phlegm syndrome (18.4%),47are phlegm and blood stasis syndrome (15.2%).
According to syndrome of phlegm and blood stasis, there are105with phlegm syndrome (34.1%),59are with phlegm and blood stasis (19.1%),144are with blood stasis (46.8%).
Overall, the yin deficiency with yang hyperactivity syndrome is the most common syndrome in elderly hypertensive patients, phlegm syndrome and blood stasis syndrome are the chief plus syndrome.
3.3The relationship between blood pressure and TCM syndrome
The blood pressure of systolic and diastolic in all the time are no significant difference (P>0.05) between the5syndromes.
3.4The relationship between blood pressure variability and TCM syndrome
Systolic blood pressure variability (SBP-SD) is significant difference (P<0.05) in5syndromes. The yin deficiency with yang hyperactivity syndrome has the maximum SD, thus the SD of liver-wind and phlegm syndrome is the minimum. There are no significant difference (P>0.05) in Diastolic blood pressure SD, mean arterial blood pressure SD in the5syndromes.
Systolic blood pressure coefficient of variability (SBP-CV) is significant difference (P<0.05) in5syndromes. The yin deficiency with yang hyperactivity syndrome has the maximum CV, thus the CV of liver-wind and phlegm syndrome is the minimum. There are no significant difference (P>0.05) in Diastolic blood pressure CV, mean arterial blood pressure CV in the5syndromes.
3.5The relationship between LVMI and TCM syndrome
Blood pressure variability and LVMI correlation analysis, daytime systolic blood pressure variability (DSBP-SD) and coefficient of variation (DSBP-CV) are positive correlation with LVMI, a correlation coefficient of0.480and0.460. There has no relevant between LVMI and DBP-SD. LVMI is significant difference (P<0.05) in5syndromes. The yin deficiency with yang hyperactivity syndrome is heavier than other syndromes (P<0.05).
3.6The relationship between IMT and TCM syndrome
IMT is significant difference (P<0.05) in5syndromes. IMT of the yin deficiency with yang hyperactivity syndrome is thicker than other syndromes (P<0.05). The plaques are statistically significant in5syndromes, the plaques of dual deficiency of qi and yin syndrome are larger (P<0.05).
3.7The relationship between symptom scores and TCM syndrome
Symptom scores are significant differences (P<0.05) in5syndrome, scores of the yin deficiency with yang hyperactivity syndrome are the highest, and then scores of the dual deficiency of qi and yin syndrome. Scores of SBP-CV over P50are higher than others (P<0.05).
4Conclusions
Through factor analysis, there are5syndromes in elderly hypertensive patients which are yin deficiency with yang hyperactivity syndrome, dual deficiency of qi and yin syndrome, dual deficiency of yin and yang syndrome, liver-wind and phlegm syndrome and phlegm and blood stasis syndrome. Among the5syndromes the yin deficiency with yang hyperactivity syndrome are the most common syndrome in elderly hypertensive patients, phlegm syndrome and blood stasis are the chief plus syndrome.SBP-SD and SBP-CV are Significant difference between the5syndromes. SBP-SD and SBP-CV of yin deficiency with yang hyperactivity syndrome are larger than other syndromes.LVMI and IMT of yin deficiency with yang hyperactivity syndrome are thicker than other syndromes. The plaques of dual deficiency of qi and yin syndrome are larger.(P<0.05). Scores of the yin deficiency with yang hyperactivity syndrome are the highest. Scores of SBP-CV over P50are higher than others.
Part Ⅱ:Clinical study
1Objective
To evaluate the effect of Tianmashuxin decoction (TMSX) on decreasing the blood pressure variability of elderly hypertensive patients.
2Methods
A total of sixty hypertensive patients over the age of60years and below the age of85years with yin deficiency with yang hyperactivity syndrome were randomized into treated group(n=30) and control group(n=30).The treated group were treated with Amlodipinc+TMSX, the control group patient were distributed with Amlodipine only. The therapeutic course was4weeks. Security indicators:WBC, RBC, HGB, PLT, Cr, BUN, ALT, AST. Efficacy indicators:blood pressure (clinic blood pressure, ambulatory blood pressure monitoring), blood pressure variability (SD), coefficient of variation (CV); TCM symptoms and signs; renin (PRA), angiotensin Ⅱ (Ang Ⅱ); total cholesterol (CHO), triglyceride (TG), high density lipoprotein (HDL), low density lipoprotein (LDL). Data were managed and statistically analyzed by SPSS16.0. Two-sample t test tested normal distribution data. Non-normal distribution Data were tested by NPAR test, such as Mann-Whitney test, Chi-square and analyses.
3. Results
3.1General information
60cases were enrolled the study.48were outpatients (80.0%),12were hospitalized patients (20.0%);31are males (51.7%) and29are females (48.3%); aged range from60to75years old.
Before the course, there were no significant difference between two group in age, course, complications, blood pressure readings, classify of risks, BP-SD, BP-CV, PRA, Ang II, CHO, TG, HDL, LDL (P>0.05). The data of two groups were suit to campare.
3.2Visit to visit blood pressure readings
After the course, visit to visit blood pressure readings decreased significantly in two groups (P<0.05), and between the groups, SBP of treated group was lower than control group (P<0.05). But there were no significant difference in diastolic blood pressure values between the two groups (P>0.05). This result indicates that TMSX can decrease visit to visit blood pressure readings.
3.3ABPM blood pressure readings
After the course, all time ABPM pressure readings decreased significantly in two groups (P<0.05), and between the groups, SBP of treated group was lower than control group (P<0.05) in24-hour and daytime. But there were no significant difference in diastolic blood pressure values between the two groups (P>0.05). This result indicates that TMSX can decrease SBP readings of24-hour and daytime of ABPM.
3.4Blood pressure variability
The two groups'BP-SD of24-hours and nighttime were significant decreased after the course (P<0.05). But between the groups,24hSBP-SD,NSBP-SD of treated group was lower than control group (P<0.05), there were no difference in DBP-SD and DBP-CV (P>0.05). This result indicates that TMSX can decrease SBP-SDof24-hour and nighttime of ABPM.
3.5Blood pressure coefficient of variation
The two groups'BP-CV of24-hour and nighttime were significant decreased after the course (P<0.05). But between the groups,24hSBP-CV, NSBP-CV of treated group was lower than control group (P<0.05), there were no difference in DBP-SD and DBP-CV (P>0.05). This result indicates that TMSX can decrease SBP-CV of24-hour and nighttime of ABPM.
3.6PRA, Ang II, CHO, TG, HDL, LDL
There were not change of PRA, Ang II, CHO, TG, LDL within the control group (P>0.05), but the PRA, Ang II, CHO, TG, LDL in treated group were decreased significantly (P<0.01); This result indicates that TMSX can decrease PRA, Ang II, CHO,TG,LDL.
3.7Symptom scores
The two groups'symtom scores were significant decreased after the course (P<0.05). But between the groups, treated group significantly reduced the total score than the control group (P<0.05). This result indicates that TMSX can decrease symptom scores.
4Conclusions
TMSX can decrease the SBP-SD and SBP-CV efficiently, in the same time it also can decrease BP readings, PRA, Ang Ⅱ, CHO, TG, and LDL. Symptoms of yin deficiency with yang hyperactivity syndrome could be improved by TMSX. There has no significant side effect. This indicates that traditional chinese medicine can improve the BP-SD, but it also need to explore the mechanic of TCM on SD.
引文
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