【作者】 谢昌联；

【导师】 孟素荣；

【作者基本信息】 南方医科大学 ， 内科学， 2008， 硕士

【摘要】 心力衰竭（CHF）是指由于各种原因导致心脏功能受损,特别是心室肌收缩和或舒张功能受损,心脏不能维持足够的心输出量以满足身体对代谢的需要和静脉血流受阻的状态,是各种心脏疾病发展的终末阶段并导致心功能不全而表现的一组临床综合征,主要表现是呼吸困难和疲乏,在人群中高发病率和死亡率。CHF的病理生理学表现主要在于心室重构和神经-内分泌-细胞因子系统的激活。这些被激活的神经-内分泌-细胞因子系统主要包括:肾上腺素能系统、肾素-血管紧张素-醛固酮系统（RASS）、细胞因子系统以及肽类信号系统中的具收缩血管作用的内皮素系统和扩张血管功能的钠利尿肽系统,是CHF发生后的一系列维持循环功能的代偿活动,但同样也导致了心室重构和CHF症状加重,使病情恶化。脑利钠肽（brain natriuretic peptide,BNP）和心房利钠肽（atrialnatriuretic peptide,ANP）是钠利尿肽系统的主要成员。BNP是由心室分泌,半衰期为18 min,随CHF的加重而分泌增加,代偿性拮抗肾上腺素能、肾素-血管紧张素-醛固酮和内皮素系统的活性,松弛血管平滑肌细胞而扩张外周动静脉血管,增加钠的排泄而利钠利尿,减轻心脏的前后负荷,有益于CHF病情的缓解。重组人脑利钠肽（recombinant human brain natriuretiC peptide,rhBNP）是利用DNA重组技术产生的高纯度冻干粉针剂,与内源性BNP具有相同的32个氨基酸序列和空间立体结构,因此具有相同的生物活性和作用机制,它通过与利钠肽受体结合,激活结合型鸟苷酸环化酶,升高细胞内环一磷酸鸟苷（cyclicguanosine monophosphate,cGMP）浓度,是一类具有血管扩张特性的新药物,它没有强心作用,不抑制磷酸二酯酶,不依赖β肾上腺素能受体,通过增加cGMP发挥作用,具有排钠利尿,降低肺毛细血管压、全身血管阻力和肺动脉压,增加心脏指数和射血分数,减少血浆醛固酮水平。另外,在严重心力衰竭阶段存在内源性BNP相对不足或BNP抵抗。因此,补充外源性BNP可用于失代偿性心力衰竭（decompensated heart failure,DHF）的治疗。rhBNP首先在美国研制成功并已成为新一代静脉注射用治疗失代偿性CHF的药物。目的比较重组人脑利钠肽（rhBNP）和硝酸甘油对失代偿性心力衰竭的临床疗效。方法我院50例失代偿性心力衰竭住院患者随机分为硝酸甘油组和rhBNP组,分别记录两组患者给药前及给药后30min、6h及24h的呼吸困难程度以及整体临床情况,以及用药24h后液体的出入量和血流动力学参数和72h后室性心律失常情况。其中硝酸甘油组使用硝酸甘油开始剂量为5μg/min,每3～5分钟增加5μg/min,根据个体的血流动力学参数来调整用量;rhBNP组使用rhBNP,首先以1.5μg/kg弹丸式静脉冲击,随后以0.0075μg·kg^-1·min^-1连续静脉滴注72h。应用SPSS15.0软件进行统计分析,显著性水平设为0.05（双侧）。计量资料比较采用独立样本t检验,计数资料比较采用Pearson卡方检验,等级资料采用Wilcoxon W检验或Kruskal Wallis检验等统计方法。结果rhBNP组患者静脉给药后30min和6h的呼吸困难好转程度（P值分别为0.042和0.019）和整体临床状况好转程度（P值分别是0.018和0.044）均显著优于硝酸甘油组,24h后两组未有明显差异（P值分别是0.192和0.179）;用药24h后的尿量rhBNP组（1513.8±242.9）ml显著多于硝酸甘油组（1341.2±239.7）ml（P=0.015）:用药24h时rhBNP组患者射血分数的增加以及肺动脉压和收缩压的降低均显著多于硝酸甘油组（P值分别是0.001、0.000及0.002）,用药72h后rhBNP组室性期前收缩、成对期前收缩和阵发性室性心动过速等室性心律失常发作的次数显著减少（P值分别是0.000、0.001和0.002）。结论rhBNP通过促进尿量的排泄、降低肺动脉压及增加左室射血分数等途径明显改善失代偿性心力衰竭患者呼吸困难和整体临床状况,以及显著减少室性心律失常的发作。更多还原

【Abstract】 Congestive heart failure (CHF) refers to a variety of causes impaired heart function, particularly ventricular systolic and diastolic function damaged, heart can not maintain an adequate cardiac output to meet the needs of the body metabolism and venous blood flow obstruction state, CHF is a group of clinical syndrome of the end stage of heart disease, and the main complaints are dyspnea and fatigue, and CHF is high morbidity and mortality. The main pathophysiology of CHF is the ventricular remodeling and nerve-endocrine-cytokine activation system. Activation of these neurons - endocrine - cytokines system include: adrenergic system, renin-angiotensin-aldosterone system(RASS), cytokines and signal peptide systems which include endothelin system and natriuretic peptide system, endothelin is a shrinking role of the vascular system and natriuretic peptide is expansion of the vascular function, neurons - endocrine - cytokines system are a series of compensatory activities of circulatory function after CHF, but these also led to the left ventricular remodeling and CHF symptoms increase, and the condition worsened. Brain natriuretic peptide (BNP) and atrial natriuretic peptide (ANP) are the principal members of natriuretic peptide system. BNP is secreted by ventricular, half-life is 18 min, with the CHF increased secretion increased, and it compensatory antagonism the activity of adrenergic antagonist, renin - angiotensin - aldosterone and endothelin system, and it relaxates the vascular smooth muscle cells and expansese the peripheral arteriovenous, and increasese sodium excretion and natriuretic, these reduce the preload and afterload of heart, so BNP can release CHF conditions.RhBNP that using recombinant DNA technologies to produce is high-purity freeze-dried powder, and it with the same 32 amino acid sequence and three-dimensional structure of the endogenous BNP ,and therefore they have the same biological activity and mechanisms. BNP binding natriuretic peptide receptor to activate the combination guanylate cyclase, and increasing guanosine monophosphate (cGMP) concentration inner the cell,it is a class new drug of blood vessel dilation , it does not have strong hearts, not inhibit phosphodiesterase, do not rely onβ-adrenergic receptors, BNP increasing cGMP plays roles of natriuretic and reducing pulmonary capillary pressure and systemic vascular resistance and pulmonary artery pressure,increasing cardiac index and ejection fraction, but also does not affect synthesis of renin-- angiotensin-aldosterone system of reducing plasma aldosterone levels. RhBNP first produced in the United States and has developed a new generation of intravenous treatment of decompensated CHF drugs. In more severe stages of heart failure, there may be a relative shortage of endogenous BNP or BNP resistance. Therefore, the exogenous BNP may be the treatment of decompensated heart failure (DHF).Objective To compare the clinical efficacy of recombinant human brain natriuretic peptide (rhBNP) and nitroglycerin on acute decompensated heart failure (ADHF). Methods 50 cases of ADHF patients were randomly divided into rhBNP group and the nitroglycerin groups. In all patients, dyspnea and global clinical status were assessed at 30 minutes, 6 hours and 24 hours after the use of study drug, and the input liquid and urine and hemodynamic parameters were recorded after administration 24 hours. First the nitroglycerin group used the dose of nitroglycerin 5μg / min, and then every three to five minutes increased 5μg / min, according to the hemodynamic parameters of the individual to adjust the dosage; and the rhBNP group use rhBNP (first 1.5μg per kilogram of body weight bolus intravenous followed by a infusion of 0.0075μg per kilogram of body weight per minute for 72 hours). Application SPSS15.0 software for statistical analysis, as a significant level of 0.05 (bilateral). Comparison of measurement data using independent samples t-test, compared with the count data using Pearson Chi-square test, grading information using Wilcoxon W test or Kruskal Wallis test . Results The improved level of dyspnea and global clinical status of the rhBNP group were significantly better than those of the nitroglycerin group at 30 minutes and 6 hours after the start of study drug (the P value is 0.042 and 0.019 for dyspnea ,and it is 0.018 and 0.044 for global clinical status, respectively); after 24 hours those were no significant difference in the two groups (P values were 0.192 and 0.179); After 24 hours ,the urine of rhBNP group (1513.8±242.9) ml were significantly more than that of the nitroglycerin group (1341.2±239.7) ml (the P value is 0.015) , and the increase in ejection fraction and the decrease in pulmonary arterial pressure and systolic blood pressure of the rhBNP group were significantly more than those of the nitroglycerin group (P values were 0.001,0.000 and 0.002, respectively); After 72 hours the number of premature ventricular contraction and couplets premature beats and paroxysmal ventricular tachycardia of the rhBNP group were significantly lower than those of the nitroglycerin group (P values were 0, 0.001 and 0.002). Conclusion RhBNP promote the excretion of urine, decrease pulmonary artery pressure and increase left ventricular ejection fraction, so rhBNP can significantly improved dyspnea and global clinical status for the patients of decompensated heart failure, and significantly reduce the onset of ventricular arrhythmias.更多还原