【作者】 张双伟；

【导师】 冼绍祥；

【作者基本信息】 广州中医药大学 ， 中医内科学， 2012， 博士

【摘要】 慢性心力衰竭,是各种心血管疾病由于长期负荷过重、心肌损害及收缩力减弱所致的心功能不全(失代偿期)的一种复杂综合征,是众多心脏疾病的终末阶段,死亡率极高。对心力衰竭发生发展机制的研究一直是全球心血管病防治的重点。一个世纪以来,心衰理论经历心肾学说、血流动力学学说、神经内分泌激素学说到现代的心室重构学说。现代分子生物学研究认为有关心衰的病理、生理机制涉及两方面内容：心室重构和神经内分泌细胞因子系统的激活。心室重塑是由于一系列复杂的分子和细胞机制引起的心肌细胞结构、功能及表型的改变,包括心肌细胞凋亡、心肌细胞肥大、胚胎基因再表达及心肌细胞外基质数量和组成变化等。而神经内分泌细胞因子系统的持续过度的激活是导致心室重塑和心衰恶化的重要原因。研究证实炎性因子与心力衰竭有着密切的关系：一方面,CHF的发生发展伴随着TNF-a、IL-1、IL-6等炎性细胞因子浓度的明显增加；另一方面,各种因素诱导的上述炎性因子浓度的增加可明显加重心衰的程度,甚至可以诱发心力衰竭。由此可见,心力衰竭的发生和发展是一个“进行性”的过程,在此过程中始终有着神经内分泌的激活,这种过度的激活对低下的心室功能起代偿的同时也加重了心肌的损害,加剧了心衰的恶化。同时,循环和组织中的多种细胞因子的水平也增加,这些因子和神经内分泌激活一起,可以损害心肌细胞的活性和功能,刺激心肌纤维化,促使心脏重塑。心力衰竭的发病机制非常复杂,随着对其发生机制的深入认识,心力衰竭的治疗决策也发生了相应的演变。其中关于阻断神经内分泌、细胞因子系统的激活和心肌重塑之间的恶性循环治疗CHF的观点已引起许多学者的关注,尽管调节神经内分泌因素治疗缺血性心衰的新药正在不断地被研制和评估,但是进一步通过抑制神经内分泌或体内其他系统改善死亡率的可能还很遥远,目前还没有确切方法能够用于干预CHF的慢性炎症状态。中医药方法治疗慢性炎症在长期临床实践中取得良好的临床疗效,中药抗炎药理研究已从“整体-器官-细胞”水平发展到在分子、基因水平探讨中药的作用机制,逐渐呈现出涉及中药品种更多、研究范围更广、研究水平比以往更高的局面。近年来随着对CHF发病机理的进一步阐述,特别是重视慢性炎症反应在CHF发生、发展中作用,以及抗炎症治疗对于改善CHF临床症状和预后重要帮助,许多学者重新开始认识到,中医治疗CHF不仅可以采用补气、活血、利水等方法,还可以针对CHF慢性炎症反应进行干预,特别是目前西医在这方面没有很好的方法。而中药毛冬青具备清热解毒和活血通脉之功效,现代药理研究表明其具有抗炎和多种心血管药理作用,中药人参具有大补元气、生津止渴、安神等功效,现代药理研究证明其活性成分对心血管系统的多种疾病有深远的临床意义。近年来中医界对心衰的病因病机认识趋于一致,即心衰为本虚标实之证,虚为气虚、阳虚,日久则累及心阳,涉及脾、肺、’肾,随着由气虚到阳虚,病情逐渐加重；标实为血瘀、水阻、痰饮；标本俱病、虚实夹杂,是心衰的病理特点。治疗以益气温阳治本,活血利水治标为主要的治疗方法。结合以往临床研究基础,我们认为中医治疗CHF不仅可以采用补气、活血、利水等传统方法,而且还可以采用益气活血解毒法,针对CHF的慢性炎症反应进行干预,从而改善CHF临床症状和预后。目的：1、临床研究：以西医规范治疗方案为对照,观察毛冬青与红参颗粒剂对慢性心力衰竭炎症状态的影响及其对慢性心力衰竭治疗的临床效果,探讨“益气活血解毒法”在慢性心力衰竭治疗中的作用。2、实验研究：观察毛冬青对SD大鼠慢性心力衰竭炎症状态的影响,进一步验证毛冬青对于慢性心力衰竭的改善作用。方法：1、临床研究：①将门诊和住院慢性心力衰竭患者101例随机分为2组,每组根据不同证型分为气阴亏虚、血瘀水停证和气阳亏虚、血瘀水停证。对照组49例单纯使用西医基础治疗；治疗组52例使用西医基础治疗+中药颗粒(毛冬青、红参),同时,选取20例正常健康体检者作为正常组空白对照。②观察治疗前和4周后查血、尿、便常规、肝、肾功能、血电解质、血糖和血脂等作为安全性指标,以确定毛冬青、红参是否有毒、副作用。③治疗前和4周后检测慢性心力衰竭患者血清超敏C反应蛋白(hs-CRP)、肿瘤坏死因子-α(TNF-α).白介素-1β(IL-1β).核因子K B和B型尿钠肽(BNP)水平,并进行比较,观察治疗前后慢性心力衰竭患者炎性状态及心功能状况。④治疗前4周后进行中医症候疗效、中医症候积分、心功能疗效、中医临床症状评分、明尼苏达心衰生活质量评分等比较,评价心功能改善情况。2、实验研究：①将60只雄性SD大鼠随机分为手术组和假手术组,手术组48只,假手术组12只。结扎腹主动脉建立心衰大鼠模型,造模成功的大鼠随机分为4组,分别为毛冬青低剂量组、毛冬青高剂量组,卡托普利组和对照组。②毛冬青低剂量组灌服毛冬青10g/kg/d；毛冬青高剂量组灌服毛冬青20g/kg/d；西药对照组灌服卡托普利100mg/kg/d；空白对照组及假手术组灌服生理盐水2ml/d。③各组均灌服2周后,行经胸超声心动图检测,将大鼠动脉血离心取血清,用Elisa酶联免疫法大鼠血清试剂盒测定白介素-1β(IL-1β).核因子kB指标并进行比较,观察毛冬青对SD大鼠慢性心力衰竭炎症状态和心功能的影响。结果：1、临床研究：①心衰患者血清hs-CRP、TNF-a、IL-1β、NF-κB及血浆BNP水平明显高于正常健康人群(P<0.05),且随着心力衰竭程度的加重上述指标进一步升高。②治疗后,两组患者血清hs-CRP、TNF-a、IL-1β、NF-κB等炎性因子水平、血浆BNP水平明显下降,与治疗前比较,其变化有统计学意义(P<0.05),两组治疗前后各指标的变化值比较,差别有统计学意义(P<0.05)。治疗前后两组患者不同证型间血清hs-CRP、TNF-a、IL-1β、NF-κB及血浆BNP水平的比较显示,治疗组两个证型治疗后各指标较治疗前降低,其变化有统计学意义(P<0.05)。③在西医常规治疗的基础上加入中药毛冬青和红参,能明显提高心功能疗效、明显降低中医症候积分、明尼苏达心衰生活质量评分,与对照组比较具有统计学意义(P<0.05)。2、实验研究：经灌服中药毛冬青的CHF大鼠其血清IL-1β、NF-KB水平明显低于对照组,差别有统计学意义(P<0.05)。心脏彩超相关指标显示,灌服毛冬青的CHF大鼠左心室舒张期内径(LVDd)、左心室收缩期内径(LVDs)、射血分数(EF)、短轴缩短率(FS)与其他各组比,其组间的差别有统计学意义(P<0.05)。结论：1、慢性心力衰竭过程中存在免疫和炎性系统的激活,慢性心衰患者血清炎性因子hs-CRP、TNF-a、IL-1、NF-κB水平明显高于正常组。2、慢性心衰患者血清炎性因子hs-CRP、TNF-a、IL-1、NF-κB水平随着心力衰竭程度的加重(血浆BNP水平升高)而升高,表明慢性心衰时机体炎性活动明显。3、毛冬青和红参可以改善不同证型慢性心衰患者的心功能和中医证候,减轻临床症状,经动物实验验证毛冬青可以缓解慢性心衰患者的炎症状态。4、益气活血解毒法可以改善慢性心力衰竭的炎症状态,改善CHF临床症状和预后。更多还原

【Abstract】 Chronic heart failure (CHF) is a complex syndrome, defined as a variety of cardiovascular diseases due to long-term overloading, myocardial damage and contractile force weakened making ventricular dysfunction (decompensated). CHF Is the end stage of many heart disease and mortality is extremely high. The study of heart failure (HF) development mechanism has been the focus of the global cardiovascular disease prevention. For a century, the HF theory developed from heart and kidney doctrine, the hemodynamic theory, neuroendocrine hormones doctrine to the modern theory of ventricular remodeling. Modern molecular biology holds that HF pathology and physiological mechanisms involved in the activation of two aspects:ventricular remodeling and neuroendocrine cytokine system. Ventricular remodeling is due to a series of complex molecular and cellular mechanisms of myocardial cell structure, function and phenotypic changes, including cardiomyocyte apoptosis, cardiac hypertrophy, the embryonic gene expression and myocardial extracellular matrix quantity and composition changes. Sustained excessive activation of the neuroendocrine cell factor system is the important reason of ventricular remodeling and worsening HF. The study confirmed that inflammatory factors and HF have a close relationship:on the one hand, the development of CHF, along with TNF-alpha, a significant increase of the concentration of IL-1, IL-6and other proinflammatory cytokines; the other hand, a variety of factorsinduced increase in the concentration of these inflammatory factors can significantly increase the degree of HF, and can even induce HF. Thus, the occurrence and development of HF is a progressive process. In this process, always with neuroendocrine activation. This excessive activation also increased, while the low ventricular function from compensatory myocardial damage, and aggravate HF deterioration. At the same time, a variety of cytokines in the circulation and tissue levels also increased, together, these factors and neuroendocrine activation can damage the activity of myocardial cells and stimulate myocardial fibrosis, to promote cardiac remodeling.The pathogenesis of HF is very complex, with the in-depth understanding of HF mechanism, the treatment decision making also produced corresponding change. The blocking of neuroendocrine, cytokine system activation and myocardial remodeling between the vicious spiral treatment of CHF view has attracted many scholars’attention, although the regulation of neuroendocrine factors in the treatment of ischemic HF drugs are constantly being developed and evaluated, but further by inhibiting neuroendocrine or other body systems to improve mortality may also very far away, there is no precise method can be used for CHF interventions of chronic inflammatory state.Traditional Chinese medicine for treatment of chronic inflammation in long-term clinical practice has good clinical curative effect of traditional Chinese medicine, anti-inflammatory pharmacologic research has shifted from" overall-organ-cell" level to develop at the molecular, genetic level of traditional Chinese medicine mechanism, gradually showing relates to traditional Chinese medicine breed more, research range wider, research level higher than in the past situation. In recent years, with further elaboration of the pathogenesis of CHF, especially the emphasis on chronic inflammatory response in the CHF occurred role in the development, as well as anti-inflammatory treatment for improving the CHF clinical symptoms and the prognosis is important to help, many scholars began to re-recognize Chinese medicine treatment of CHF can be used not only the method of气and blood circulation, dieresis, can also intervene in chronic inflammatory response in CHF, in particular, the current Western medicine is no good way in this regard. And Chinese traditional medicine hairy holly has heat clearing and detoxicating and promoting blood circulation pulse-beating. Modern pharmacological research founds that it has anti-inflammatory and multiple cardiovascular pharmacological effects of ginseng tonic, with vitality, quench thirst, sedative and other effects, modern pharmacological studies have shown its active components on cardiovascular system diseases have far-reaching significance.In recent years Chinese medicine pathogenesis of heart failure tend to be consistent, i.e. heart failure for this standard is false card, virtual as Qi, Yang long, involving the heart Yang, involving the spleen, lung, kidney, as by Qi to Yang, condition gradually worsened; Standard for water resistance, phlegm, blood stasis; specimens of all disease, the actual situation mixture, heart failure is the pathological features. Treatment of Qi and warm Yang cure, promote blood circulation and water solution as the main method of treatment. Combined with previous clinical research foundation, we suggest that Chinese medicine in the treatment of CHF can not only makes use of Qi, blood, water and other traditional methods, but also can use Detoxicating and activating blood method, according to the CHF chronic inflammatory response to intervention, thereby improving the CHF clinical symptoms and prognosis.Objective1. Clinical research:western medicine (WM) to standard treatment regimens for the control, the observation of hair holly and red ginseng granules on CHF inflammatory state and its effect on CHF treatment clinical effect, discuss Yiqi Huoxue Jiedu" in the treatment of CHF in rats.2. Experimental research:Observation of hairy holly on SD rats with CHF impact of inflammatory state, further validation of hairy holly for CHF effects.Methods1.Clinical research:①Randomly dividing101ambulatory and hospitalized patients with CHF into2groups, each group according to the different syndromes are divided into yin deficiency, blood stasis and Yang water stop credit deficiency, blood stasis syndrome of water stop.49cases of the control group simply use the basic treatment of Western medicine; treatment group of52cases using the conventional treatment plus traditional Chinese medicine granule (hairy holly, red ginseng), at the same time, we selected20cases of normal healthy subjects served as normal control group.②Observed before treatment and4weeks after a blood test, urine, stool routine, liver, renal function, electrolyte, blood glucose and lipids as safety index, to determine whether hair holly, red ginseng, toxic side effects.③Before treatment and4weeks after the detection of CHF patients serum high sensitive C reactive protein (hs-CRP), tumor necrosis factor alpha (TNF alpha), interleukin lbeta (beta IL-1), nuclear factor kappa B and B type natriuretic peptide (BNP) level, and carries on the comparison, were observed before and after treatment for CHF in patients with inflammatory status and functional status of the heart.④The first4weeks after the treatment effect of TCM, TCM syndrome integral, heart function, traditional Chinese medicine curative effect clinical symptom score, the Minnesota heart failure score of life quality comparison, evaluation of heart function improvement.2. Experimental research:①The60SD male rats were randomly divided into operation group and sham operation group, operation group48, sham operation group12. Ligation of abdominal aorta established heart failure rat model, modeling success of rats were randomly divided into4groups, respectively, hairy holly low dose group, high dose group of hair holly, captopril group and control group.②The hairy holly low dose group gavage hairy holly10g/kg/D; hairy holly high dose group gavage hairy holly20g/kg/D; western medicine control group fed with captopril in100mg/kg/D; blank control group and sham operation group gavage ns2ml/d.③The groups were gavage for2weeks after transthoracic ultrasound heartbeat graph, line detection, the rat arterial blood centrifuge serum, using Elisa enzyme immunoassay kit for determination of serum interleukin lbeta (beta IL-1), nuclear factor kB target and carries on the comparison, the observation of hair holly on the SD rats with CHF inflammatory status and effect of heart function.Results1. Clinical research:①Of heart failure in patients with serum hs-CRP, TNF A, IL-1, NF Beta Kappa B and plasma BNP levels were significantly higher than those in healthy population (P<0.05), and with the severity of heart failure the index rises further.②Two groups of patients after treatment, serum hs-CRP, TNF-A, IL-1, NF Beta Kappa B and inflammatory factor level, plasma BNP levels were significantly decreased, compared with before treatment, the changes were statistically significant (P<0.05), the two groups before and after treatment of every index value comparison, the difference has statistical significance (P<0.05). Before and after treatment in two groups of patients with different types of serum hs-CRP, TNF-A, IL-1, NF Beta Kappa B and plasma BNP level comparison shows, the treatment group two syndromes after each treatment index lower than those before therapy, the changes were statistically significant (P<0.05).③The conventional treatment of Western medicine are added on the basis of Chinese holly and red hair, can improve heart function, significantly reduce the efficacy of Chinese medicine symptom integral, the Minnesota heart failure score of life quality, compared with the control group had statistical significance (P<0.05).2.Clinical research:Chinese traditional medicine by gavage hairy holly CHF rats serum IL-lbeta, NF kappa B levels were significantly lower than those in the control group, the difference has statistical significance (P<0.05). The heart color surpasses the related indicators, gavage of hair holly CHF rat left ventricular diastolic diameter (LVDd), left ventricular systolic diameter (LVDs), ejection fraction (EF), fractional shortening (FS) and other groups than between groups, the difference was significant (P<0.05).Conclusion1. CHF process in the presence of immune and inflammatory system activation in patients with CHF, serum inflammatory factor hs-CRP, TNF-A, IL-1, NF kappa B levels were significantly higher than normal group.2.CHF patients serum inflammatory factor hs-CRP, TNF-A, IL-1, NF kappa B levels with the severity of HF (elevated plasma BNP level) and elevated during CHF, indicating systemic inflammatory activity.3. Hairy holly and red ginseng can improve the different syndrome type of CHF in patients with cardiac function and TCM syndromes, alleviate the clinical symptoms, the animal experimental verification of hair Holly can relieve the inflammatory status in patients with CHF.4.Detoxicating and activating blood method can improve CHF inflammatory state, improve clinical symptoms and prognosis of CHF.更多还原