螺内酯和雷米普利在慢性心力衰竭中的作用
摘要
慢性心力衰竭是临床上常见的综合症，各种类型心脏病发展到一定阶段均可出现心力衰竭，过去认为心力衰竭发生机制主要是血液动力学障碍，故临床上采用强心、利尿、扩血管。但经过大量的循证医学证明，这样虽然使患者临床症状改善。但是不能改善患者的预后，降低死亡率。为此，近年来针对心力衰竭发生发展的机制做了大量的临床研究，研究结果表明心力衰竭的发生发展的机制是心室重塑。那么导致心室重塑的根本因素就是：神经内分泌细胞因子激活等。这里最重要的是肾素-血管紧张素-醛固酮系统的激活，ACE抑制剂正是对抗该系统的有效药物，但长期应用临床上出现“醛固酮逃逸现象”，有效地阻断醛固酮作用显得十分重要，本研究在ACE抑制剂雷米普利基础上加用醛固酮受体拮抗剂螺内酯观察二者在慢性心力衰竭中的作用。
本研究选择2002年10月至2003年10月期间在我院住院的慢性心力衰竭患者60例，其中男性38例，女性22例。年龄36-72岁（平均58.8±13.1岁）。60例患者符合：符合：①Framingham(美国)诊断标准：病史6个月以上，入选前未使用过ACEI类药物及螺内酯者；②心功能（NYHA）分级Ⅲ-Ⅳ级
者；③左心室射血分数（LVEF）≤0.45者（超声心动图）。将60例心力衰竭患者随机分为常规治疗组30例（对照组）和螺内酯、雷米普利组30例（治疗组），在常规治疗相同的条件下（利尿剂、强心、血管扩张药等），治疗组每日给予螺内酯20mg, 雷米普利每日2.5～5mg，连续服用8周。
二组病人分别于治疗前和治疗后8周使用美国GE VIVID FIVE彩色心脏超声仪测量左室收缩末容积（LVESV），左室舒张末容积（LVEDV），射血分数（EF）。治疗组通过24小时动态心电图监测治疗前和治疗8周后室性心律失常情况，同时治疗组测定治疗前及治疗后血钾情况。
治疗前二组临床相关资料应用构成比的χ2检验，由超声心动图直接获得的计数资料以及NYHA心功能分级都以均数±标准差（±S）表示。应用组间方差分析和配对t检验。P<0.05为有显著性差异。
结果如下：
一、对左室重塑的影响
治疗组在常规治疗基础上给予螺内酯和雷米普利观察8周后左室收缩末容积，左室舒张末容积明显降低，与对照组相比有显著差异（p<0.05）；射血分数明显升高，与对照组相比有显著差异（p<0.05），对照组改善不明显。
二、心功能和射血分数的影响
治疗组治疗8周后与治疗前相比，射血分数明显增加，心功能NYHA分级改善，差异有显著性（p<0.05）。治疗组与对照组在治疗8周后比较：射血分数增加，差异有显著性（p<0.05），心功能NYHA分级无明显统计学差异（p>.05）。对照组治疗后与治疗前比较：心功能NYHA分级改善（p<0.05）。
三、对室性心律失常和血钾影响
治疗组治疗前后对比室性心律失常明显减少，有显著性差异（p<0.05），血钾在治疗前后仍在正常范围
在初始的心肌损伤以后，有多种内源的神经内分泌激活，细胞因子激活，包括去甲肾上腺素、血管紧张素Ⅱ（AngⅡ）醛固酮，其他如内皮素、肿瘤坏死因子等。心力衰竭时心肌ACE活性增加，血管紧张素原mRNA水平上升，AngⅡ受体密度增加。实验研究更表明AngⅡ引起心肌细胞和 成纤维细胞DNA和蛋白质合成。肾素—血管紧张素—醛固酮系统在心室重塑中起关键作用。ACE抑制剂有益于慢性心力衰竭治疗主要通过以下2个机制：1、抑制肾素—血管紧张素—醛固酮系统，不仅抑制循环系统的肾素—血管紧张素—醛固酮系统，而且也抑制组织的肾素—血管紧张素—醛固酮系统，并且组织的肾素—血管紧张素—醛固酮系统在心力衰竭的病理生理机制心室重塑中
起重要作用。2、作用于激肽酶Ⅱ，抑制缓激肽降解，提高缓激肽水平，缓激肽降解减少可引起扩血管的前列腺素生成增多和抗增生的效果。临床上目前发现心力衰竭患者短期应用ACE抑制剂时，可降低血中醛固酮水平，但长期应用时，血中醛固酮水平却不能保持稳定、持续的降低，即所谓“醛固酮逃逸现象” 。故在临床上完全阻断醛固酮有着重要意义。心肌细胞、心脏成纤维细胞、内皮细胞具有高亲和力醛固酮受体，醛固酮与之结合促进心脏细胞的Ⅰ型和Ⅲ型胶原基因表达，使胶原合成增多[10]，对心脏肌小节的数量，排列及心肌细胞直径大小等产生影响，心肌间质和部分血管周围胶原聚集，促使心肌间质纤维化，造成心室重塑和动脉内膜、中膜组织增厚，平滑肌纤维增生 。使心脏舒张和收缩功能进行性恶化，大动脉顺应性降低，压力反射减弱，引起心脏组织的传导不均一，增加心律失常和猝死危险。另外，醛固酮可阻断心肌对儿茶酚胺的摄取，从而使细胞外儿茶酚胺增多，有致心律失常和促心肌缺血作用。醛固酮有降低副交感神经作用。故在临床上阻断醛固酮有着重要意义。本研究应用醛固酮受体拮抗剂螺内酯和ACE抑制剂雷米普利从慢性心力衰竭的发生发展机制方面抑制神经内分泌细胞因子活化，抑制心室重塑，改善患者的预后，归因于二者阻断血管紧张素Ⅱ、醛固酮作用。螺内酯具有抗心律失
常作用与其促进心肌对儿茶酚胺的摄取，从而使细胞外儿茶酚胺减少，增加副交感神经作用，保钾保镁有关。雷米普利轻度升高血钾，二者合用减少室性心律失常发生，减少猝死的发生，慢性
The chronic heart failure is a common clinical syndrome. Various heart diseases may develop to heart failure. We regarded heart failure mechanism as hemodynamic abnormal in the past time, so we took treatmeat of correcting hemodynamic abnormal. This kind of traditional treatment of correcting hemodynamic abnormal can’t improve prognosys and reduce death rate. Now many tests show the basic mechanism of heart failure is myocardial remodeling, which is a central feature in the process of my cardial failure. This process, which is related to renin-angiotensin-aldosterone system (RAAS).
The angiotensin-converting enzyme inhibitors can resist the RAAS. But the escape of aldosterone sterone produced in patients with left ventricular dysfunction treated with an angiotensin – converting enzyme inhibitor. It is very importmant for us to take addition of aldosterone inhibitor to angiotensin–converting enzyme inhibitor in heart failure. The objective of the study is to compare the effect the inhibitory of angiotensin–converting enzyme Ramipril and aldosterone antagonist–Spironolactone on left vertricular remodeling and ventricular arrhythmia .
We slected 60 patients with heart failure , in which 38 cases are male and 22 cases are female, from the patients in department of
candiovasology of our hospital. The dignosis was lined with the Framingham (American) criterion and heart failure was graded by the NYHA, arrhythmia was assessed by twenty four hours electrocardiography.
A total of 60 patients with heart failure were entered into study, 30 patients were randomized to conventional treatment group, 30 patients gived Ramipril and Spironolactone treatment group. The patients in Ramipril and Spironolactone were preseribed Ramipril 2.5~5mg and Spiromolactone 20mg everyday besides the rountine treatment. The treatment continued until the end of the 8th week. The LVEDV、LVESV and LVEF were measured by VIVID FIVE echocardiogram at the 1th day and the end of week of the 8th treatment. The ventricular arrhythmia was assessed by twenty four hours electrocardiography.
The results were showed by mean±standard deviation. T test was used to compare the differences of parameters between two groups and analysis of variance was used to compare the differences among groups. P<0.05 shows there are significant differences among groups . The results in the studies are showed as follows : changes of LVEDV/LVESV and LVEF in pre-therapy and post-therapy. LVEDV、LVESV obviously decrease and LVEF increases compared the 8th weekend with the 1th day in heart failure patients after rountine treatment. The cardiac function and
LVEF obviously improve in the two groups compared the 8th weekend with the 1th day. There is no obvious difference on cardiac function between rountine group and therapy group after the end of the 8 th week treatment. The ventricular arrhythmia obviously decreases on therapy group in pre-therapy and post–therapy.
Now many studies show that the essence of heart failure was the changes of structure of the ventricle, which was caused by some biochemical factors, nerve endocrine system was activated，such as renin-angintensin-aldosterone system、 norepinephrine, consist of a variety of molecular and cellule events that can lead to important changes in myocardial remodeling. The central feature of myocardial remodeling is an increase in myocardial mass associated with a change in the shape of the ventricle and an increase in ventricular volume.
Renin-angiotensin-aldosterone system (RAAS) has the potential to act directly on cardiac cells, independently of its vascular and metabolic actions, thereby affecting myocardial remodeling. Angiotensin increases protein synthesis in cardiac myocytes and DNA synthesis in cardiac fibroblasts. In addition, angiotensin can cause apoptosis in cardiac myocytes in culture. Many scientists think RAAS is a central feature in the process of myocardial remodeling in heart failure .
In this study we take ACEI-Ramipril countact RAAS、SAS. Ramipril can eff
本研究选择2002年10月至2003年10月期间在我院住院的慢性心力衰竭患者60例，其中男性38例，女性22例。年龄36-72岁（平均58.8±13.1岁）。60例患者符合：符合：①Framingham(美国)诊断标准：病史6个月以上，入选前未使用过ACEI类药物及螺内酯者；②心功能（NYHA）分级Ⅲ-Ⅳ级
者；③左心室射血分数（LVEF）≤0.45者（超声心动图）。将60例心力衰竭患者随机分为常规治疗组30例（对照组）和螺内酯、雷米普利组30例（治疗组），在常规治疗相同的条件下（利尿剂、强心、血管扩张药等），治疗组每日给予螺内酯20mg, 雷米普利每日2.5～5mg，连续服用8周。
二组病人分别于治疗前和治疗后8周使用美国GE VIVID FIVE彩色心脏超声仪测量左室收缩末容积（LVESV），左室舒张末容积（LVEDV），射血分数（EF）。治疗组通过24小时动态心电图监测治疗前和治疗8周后室性心律失常情况，同时治疗组测定治疗前及治疗后血钾情况。
治疗前二组临床相关资料应用构成比的χ2检验，由超声心动图直接获得的计数资料以及NYHA心功能分级都以均数±标准差（±S）表示。应用组间方差分析和配对t检验。P<0.05为有显著性差异。
结果如下：
一、对左室重塑的影响
治疗组在常规治疗基础上给予螺内酯和雷米普利观察8周后左室收缩末容积，左室舒张末容积明显降低，与对照组相比有显著差异（p<0.05）；射血分数明显升高，与对照组相比有显著差异（p<0.05），对照组改善不明显。
二、心功能和射血分数的影响
治疗组治疗8周后与治疗前相比，射血分数明显增加，心功能NYHA分级改善，差异有显著性（p<0.05）。治疗组与对照组在治疗8周后比较：射血分数增加，差异有显著性（p<0.05），心功能NYHA分级无明显统计学差异（p>.05）。对照组治疗后与治疗前比较：心功能NYHA分级改善（p<0.05）。
三、对室性心律失常和血钾影响
治疗组治疗前后对比室性心律失常明显减少，有显著性差异（p<0.05），血钾在治疗前后仍在正常范围
在初始的心肌损伤以后，有多种内源的神经内分泌激活，细胞因子激活，包括去甲肾上腺素、血管紧张素Ⅱ（AngⅡ）醛固酮，其他如内皮素、肿瘤坏死因子等。心力衰竭时心肌ACE活性增加，血管紧张素原mRNA水平上升，AngⅡ受体密度增加。实验研究更表明AngⅡ引起心肌细胞和 成纤维细胞DNA和蛋白质合成。肾素—血管紧张素—醛固酮系统在心室重塑中起关键作用。ACE抑制剂有益于慢性心力衰竭治疗主要通过以下2个机制：1、抑制肾素—血管紧张素—醛固酮系统，不仅抑制循环系统的肾素—血管紧张素—醛固酮系统，而且也抑制组织的肾素—血管紧张素—醛固酮系统，并且组织的肾素—血管紧张素—醛固酮系统在心力衰竭的病理生理机制心室重塑中
起重要作用。2、作用于激肽酶Ⅱ，抑制缓激肽降解，提高缓激肽水平，缓激肽降解减少可引起扩血管的前列腺素生成增多和抗增生的效果。临床上目前发现心力衰竭患者短期应用ACE抑制剂时，可降低血中醛固酮水平，但长期应用时，血中醛固酮水平却不能保持稳定、持续的降低，即所谓“醛固酮逃逸现象” 。故在临床上完全阻断醛固酮有着重要意义。心肌细胞、心脏成纤维细胞、内皮细胞具有高亲和力醛固酮受体，醛固酮与之结合促进心脏细胞的Ⅰ型和Ⅲ型胶原基因表达，使胶原合成增多[10]，对心脏肌小节的数量，排列及心肌细胞直径大小等产生影响，心肌间质和部分血管周围胶原聚集，促使心肌间质纤维化，造成心室重塑和动脉内膜、中膜组织增厚，平滑肌纤维增生 。使心脏舒张和收缩功能进行性恶化，大动脉顺应性降低，压力反射减弱，引起心脏组织的传导不均一，增加心律失常和猝死危险。另外，醛固酮可阻断心肌对儿茶酚胺的摄取，从而使细胞外儿茶酚胺增多，有致心律失常和促心肌缺血作用。醛固酮有降低副交感神经作用。故在临床上阻断醛固酮有着重要意义。本研究应用醛固酮受体拮抗剂螺内酯和ACE抑制剂雷米普利从慢性心力衰竭的发生发展机制方面抑制神经内分泌细胞因子活化，抑制心室重塑，改善患者的预后，归因于二者阻断血管紧张素Ⅱ、醛固酮作用。螺内酯具有抗心律失
常作用与其促进心肌对儿茶酚胺的摄取，从而使细胞外儿茶酚胺减少，增加副交感神经作用，保钾保镁有关。雷米普利轻度升高血钾，二者合用减少室性心律失常发生，减少猝死的发生，慢性
The chronic heart failure is a common clinical syndrome. Various heart diseases may develop to heart failure. We regarded heart failure mechanism as hemodynamic abnormal in the past time, so we took treatmeat of correcting hemodynamic abnormal. This kind of traditional treatment of correcting hemodynamic abnormal can’t improve prognosys and reduce death rate. Now many tests show the basic mechanism of heart failure is myocardial remodeling, which is a central feature in the process of my cardial failure. This process, which is related to renin-angiotensin-aldosterone system (RAAS).
The angiotensin-converting enzyme inhibitors can resist the RAAS. But the escape of aldosterone sterone produced in patients with left ventricular dysfunction treated with an angiotensin – converting enzyme inhibitor. It is very importmant for us to take addition of aldosterone inhibitor to angiotensin–converting enzyme inhibitor in heart failure. The objective of the study is to compare the effect the inhibitory of angiotensin–converting enzyme Ramipril and aldosterone antagonist–Spironolactone on left vertricular remodeling and ventricular arrhythmia .
We slected 60 patients with heart failure , in which 38 cases are male and 22 cases are female, from the patients in department of
candiovasology of our hospital. The dignosis was lined with the Framingham (American) criterion and heart failure was graded by the NYHA, arrhythmia was assessed by twenty four hours electrocardiography.
A total of 60 patients with heart failure were entered into study, 30 patients were randomized to conventional treatment group, 30 patients gived Ramipril and Spironolactone treatment group. The patients in Ramipril and Spironolactone were preseribed Ramipril 2.5~5mg and Spiromolactone 20mg everyday besides the rountine treatment. The treatment continued until the end of the 8th week. The LVEDV、LVESV and LVEF were measured by VIVID FIVE echocardiogram at the 1th day and the end of week of the 8th treatment. The ventricular arrhythmia was assessed by twenty four hours electrocardiography.
The results were showed by mean±standard deviation. T test was used to compare the differences of parameters between two groups and analysis of variance was used to compare the differences among groups. P<0.05 shows there are significant differences among groups . The results in the studies are showed as follows : changes of LVEDV/LVESV and LVEF in pre-therapy and post-therapy. LVEDV、LVESV obviously decrease and LVEF increases compared the 8th weekend with the 1th day in heart failure patients after rountine treatment. The cardiac function and
LVEF obviously improve in the two groups compared the 8th weekend with the 1th day. There is no obvious difference on cardiac function between rountine group and therapy group after the end of the 8 th week treatment. The ventricular arrhythmia obviously decreases on therapy group in pre-therapy and post–therapy.
Now many studies show that the essence of heart failure was the changes of structure of the ventricle, which was caused by some biochemical factors, nerve endocrine system was activated，such as renin-angintensin-aldosterone system、 norepinephrine, consist of a variety of molecular and cellule events that can lead to important changes in myocardial remodeling. The central feature of myocardial remodeling is an increase in myocardial mass associated with a change in the shape of the ventricle and an increase in ventricular volume.
Renin-angiotensin-aldosterone system (RAAS) has the potential to act directly on cardiac cells, independently of its vascular and metabolic actions, thereby affecting myocardial remodeling. Angiotensin increases protein synthesis in cardiac myocytes and DNA synthesis in cardiac fibroblasts. In addition, angiotensin can cause apoptosis in cardiac myocytes in culture. Many scientists think RAAS is a central feature in the process of myocardial remodeling in heart failure .
In this study we take ACEI-Ramipril countact RAAS、SAS. Ramipril can eff
引文
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[18]Ditty D. ACE inhibitor co-therapy in patients with heart failure: rational for the randomized Aldactone Evaluation study(RALFS) Eur heart J, 1995,16(SupplN):107.
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[21]Pitt B. “Escape” of aldosterone sterone production in patients with left ventricular dysfunction treated with an angiotension converting enzyme inhibitor: implications for therapy Cardiovase Drugs Ther, 1995,9:145-149.
[22]Struthers AD. Aldosterone sterone escape during angiotension-converting enzyme inhibitor therapy in chronic heart failure J card fail, 1996,2:47-54.
[23]郭家旺，崔卫华，何振山.慢性心力衰竭的生物学治疗.国外医学心血管疾病分册，2002，5：160-162.
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[25]Urata H, Strobel F, Ganteu D, et al, widespread tppsure distribution of human chymase , J hypertens suppl, 1994,12(9):17.
[26]戴闺柱. 慢性心力衰竭治疗的现代概念[J] 中华心血管病杂志，2000，28:75-78.
[27]程远植 . 醛固酮拮抗体螺内酯在慢性心力衰竭治疗中的作用机制和应用进展.中华心血管病杂志，2003，30（1）: 69-70.
[28]Pitt B,Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failue:Randomized Aldactone Evaluation Study Investigators. N Engl J Med, 1999,341:709-717.
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