比索洛尔对实验性兔急性心肌梗死后左室功能和左室重构的作用研究
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摘要
研究背景 心梗后左室重构是指急性心肌梗死（AMI）后整个左心室形态、
大小和功能的改变，目前心梗后左室重构的概念还包括心肌细胞和间质结构
的改变。大量临床和实验研究表明，左室重构是AMI后发生左室功能障碍
和心力衰竭的重要原因，也是远期心源性死亡最重要的危险因素。因此，研
究心梗后左室重构的病理机制和探索合理的治疗措施是近年来冠心病研究
的热点问题之一。
梗塞相关动脉早期再通可挽救部分濒死心肌，防止梗死区伸展，是防治
左室重构的有效方法。然而，即使AMI早期实施了成功再灌注，也有部分
患者发生左心室扩张。硝酸酯类、抗炎药物和钙离子通道阻滞剂对心梗后左
室重构的作用尚存在一定争议。血管紧张素转换酶抑制剂（ACEI）可减小
心梗面积，防止心梗后左室扩张，降低心梗后死亡率，但目前对AMI后ACEI
起始治疗时间尚无统一认识，ACEI起始治疗时间的不同，对心梗后左室重
构的作用也不同。β受体阻滞剂是另一类在心梗治疗中显示有益作用的药
物，但β受体阻滞剂对心梗后左室重构作用的研究甚少，动物实验和临床研
究结果存在很大矛盾，可能与β受体阻滞剂类型和剂量、心梗面积大小以及
治疗时间窗的选择等原因有关。因此，进一步研究药物治疗左室重构的有效
性和可行性具有重要的临床意义。
本研究的目的是建立实验性兔急性心梗后左室重构和功能障碍模型，在
心梗后不同时间段服用β受体阻滞剂—比索洛尔（bisoprolol），观察比索洛
尔长期应用对左室功能和左室重构的影响，探讨β受体阻滞剂治疗心梗后左
室重构的临床意义。
第四军医大学硕士研究生论文
实验方法 采用结扎健康新西兰兔冠状动脉左室支的方法制备急性心梗以
及 AMI后左室重构和功能障碍模型。实验兔随机分为伪手术组门组）10
只，心梗组（MI组）8只，心梗后48小时之内用比索洛尔组＊arly—B组）
9只和心梗后 14天用比索洛尔组门ate—B组）10只。术前和术后 4周分别
记录各实验兔心率，于术后4周经颈动脉插管记录左室舒张末压（LVEDP）
和左室压力微分门p用t人取左心室血，高效液相色谱电化学法测定血浆去
甲肾上腺素（NE）的浓度，放兔分析法测定血浆血管紧张素＊（Aug 11）和
内皮素（ET）的浓度。取出心脏，10％甲醛溶液固定，石蜡包埋切片行H－E
染色和胶原纤维染色，经计算机图像分析测定梗死癫痕长度、左室内膜层和
外膜层平均周长，计算心梗面积比，测定胶原密度。
实验结果（l）血流动力学指标：术前各组实验兔基础心率无显著差异。
术后 4周，MI组较S组心率有升高趋势，但无显著差异，early8组和 late
—B组两组间心率无显著差异，但较 S组和 MI组显著减慢。与 S组相比，
MI组的 LVEDP显著升高，士 LVdp川t max显著降低，心梗后比索洛尔早期
禾晚期治疗均能降低 LVEDP，升高＋LVdp／dt max，但对一LVdp／dt max无明
显作用。Q）血清学指标：术后 4周，i组血浆 NE、Aug 11和 ET水平较
S组显著升高，early一B和 late一B组 NE、Aug 11和 ET水平较 MI组显著
降低，但高于 S组，earlg—B组 NE、Aug 11和 ET水平降低趋势较 late一
B组明显。（3）光镜下心肌组织改变：梗死区正常心肌组织结构消失，弥漫
性成纤维细胞及胶原组织增生，可见少量淋巴细胞和脂肪细胞浸润及毛细血
管再生。K）计算机图像分析测定结果：MI组、early—B组和late—B组
心梗面积无显著差异，earlr—B组和late—B组心内膜周长、心外膜周长
较 S组和 MI组显著增加，其中 early—B组较 late—B组增加更明显。MI
组胶原密度较伪手术组胶原密度显著增加，early—B组和 late—B组胶原
密度较M组和 S组均明显增加。（显著性界值 P＜0．05）
结论（1）本实验制备的动物模型，符合AMI后左室重构和功能障碍的病理
特征，是研究删I后左室重构的病理机制和治疗措施的良好实验动物模型。
（2）心梗后比索洛尔早期和晚期用药均显著降低心率，降低实验兔 AMI后
血浆 NE、Aug 11和 ET水平，早期应用效果更明显。但不管是早期应用（AMI
－3－
第四军医大学硕土研究生论文
后 48 ／J’时之内）还是晚期应用（AMI后 2周）均不能使血浆 NE、Aug 11和
ET水平降至伪手术组水平。（3）心梗后比索洛尔早期或晚期用药均促进实
验兔删I后非梗死区胶原沉积。（4）比索洛尔能有效改善地I后左室功能障
碍。但不管是早期用药还是晚期用药，比索洛尔均促进实验兔AMI后左室扩
张。值得注意的是晚期用药较早期用药左室扩张程度减轻，其机制尚待进一
步研究。
Backgroud The general process by which the left ventricular experiences changes in structure, shape and function after acute myocardial infarction is often referred as "left ventricular remodeling". Recently, it also involves the changes in myocardial cells and in both the quantity and quality of the extracellular matrix. A great deal of clinical and experimental studies indicate that left ventricular remodeling is the main reason of progressing left ventricular dysfunction and congestive heart failure after myocardial infarction and it is also the most important risk factor of late cardiac death. Therefore, the pathophysiologic process of left ventricular remodeling and to find better treatment have been better appreciated recently.
Both experimental and clinical studies indicated that early reperfusion of infarct-related artery may salvage the endocardial tissue and restore stuned myocardium in the infarct border zone, reduce infarct size and prevent infarct expansion. It is an efficient treatment in acute phase to prevent left ventricular remodeling after myocardial infarction. But patients with a patent infarct-artery also may undergo left ventricular remodeling. Other experiments and clinical trials have studied the effects of nitrate-based vasodilating agents,
antiimflammation drugs and Ca2+ channel blockers on the left ventricular remodeling, but the results were controversial. The efficacy of ACE inhibitors in reducing infarct size, attenuating left ventricular dilation after infarction was associated with improved survival. But with the different time of treatment after infarction, the effects of ACE inhibitors on left ventricular remodeling are different and when to use ACE inhibitors in AMI need to be further studied.
Treatment with J3 -blockers reduces mortality among patients with myocardial infarction, but studies on the effect of ?-blockers on remodeling after myocardial infarction have been sparse and some experimental observations were in conflict with the beneficial effects of & -blockers reported in clinical studies. Various factors may have influenced the experimental studied available so far: |3 -blocker type, size of infarction and time to start treatment after myocardial infarction. In addition, detailed hemodynamic studies have not been performed to determine the long-term effect of P -blockers after myocardial infarction. Therefore, the present study aimed to develope a rabbit model with left ventricular dysfunction after myocardial infarction, abserve the effects of early and late use of ?-blocker bisoprolol on hemodynamic function and left ventricular remodeling and discuss effects of P -blocker clinical use on left ventricular remodeling after myocardial infarction.
Methods Rabbit left ventricular myocardial infarction was produced by ligation of the left coronary artery. 4 weeks later, LV dysfunction and left ventricular remodeling developed. 48 rabbits weight from 1.8 to 2.5kg were used and 11 rabbits died during and after the operation. 10 of the rabbits randomized to sham-operated group (S group), 8 to myocardial infarction group (MI group), 9 to bisoprolol used within 48 hours after myocardial infarction group (early-B group) and 10 to bisoprolol used about 14 days after myocardial infarction group (late-B group). Before operation and 4 weeks after operation heart rates were determined from the electrocardiographic records. Hemodynamic measurements 4 weeks after operation were obtained under 3%
pentobarbital anesthesia. A micro-tip pressure transducer catheter was inserted successfully into the right carotid artery. Left ventricular end-diastolic pressure (LVEDP) and LV pressure with first positive and negative derivates of pressure (i dp/dt max ) obtained. Plasma noraurenalme (NE) was measured by a simplified liquid chromatography and electrochemical detection method and plasma angiotensin II (Ang II ) and endothelin (ET) were measured by radioimmunoassay. Then the heart was rapidly excised and immersed in 10% buffered formalin, dehydrated in 95?ethanol and
大小和功能的改变，目前心梗后左室重构的概念还包括心肌细胞和间质结构
的改变。大量临床和实验研究表明，左室重构是AMI后发生左室功能障碍
和心力衰竭的重要原因，也是远期心源性死亡最重要的危险因素。因此，研
究心梗后左室重构的病理机制和探索合理的治疗措施是近年来冠心病研究
的热点问题之一。
梗塞相关动脉早期再通可挽救部分濒死心肌，防止梗死区伸展，是防治
左室重构的有效方法。然而，即使AMI早期实施了成功再灌注，也有部分
患者发生左心室扩张。硝酸酯类、抗炎药物和钙离子通道阻滞剂对心梗后左
室重构的作用尚存在一定争议。血管紧张素转换酶抑制剂（ACEI）可减小
心梗面积，防止心梗后左室扩张，降低心梗后死亡率，但目前对AMI后ACEI
起始治疗时间尚无统一认识，ACEI起始治疗时间的不同，对心梗后左室重
构的作用也不同。β受体阻滞剂是另一类在心梗治疗中显示有益作用的药
物，但β受体阻滞剂对心梗后左室重构作用的研究甚少，动物实验和临床研
究结果存在很大矛盾，可能与β受体阻滞剂类型和剂量、心梗面积大小以及
治疗时间窗的选择等原因有关。因此，进一步研究药物治疗左室重构的有效
性和可行性具有重要的临床意义。
本研究的目的是建立实验性兔急性心梗后左室重构和功能障碍模型，在
心梗后不同时间段服用β受体阻滞剂—比索洛尔（bisoprolol），观察比索洛
尔长期应用对左室功能和左室重构的影响，探讨β受体阻滞剂治疗心梗后左
室重构的临床意义。
第四军医大学硕士研究生论文
实验方法 采用结扎健康新西兰兔冠状动脉左室支的方法制备急性心梗以
及 AMI后左室重构和功能障碍模型。实验兔随机分为伪手术组门组）10
只，心梗组（MI组）8只，心梗后48小时之内用比索洛尔组＊arly—B组）
9只和心梗后 14天用比索洛尔组门ate—B组）10只。术前和术后 4周分别
记录各实验兔心率，于术后4周经颈动脉插管记录左室舒张末压（LVEDP）
和左室压力微分门p用t人取左心室血，高效液相色谱电化学法测定血浆去
甲肾上腺素（NE）的浓度，放兔分析法测定血浆血管紧张素＊（Aug 11）和
内皮素（ET）的浓度。取出心脏，10％甲醛溶液固定，石蜡包埋切片行H－E
染色和胶原纤维染色，经计算机图像分析测定梗死癫痕长度、左室内膜层和
外膜层平均周长，计算心梗面积比，测定胶原密度。
实验结果（l）血流动力学指标：术前各组实验兔基础心率无显著差异。
术后 4周，MI组较S组心率有升高趋势，但无显著差异，early8组和 late
—B组两组间心率无显著差异，但较 S组和 MI组显著减慢。与 S组相比，
MI组的 LVEDP显著升高，士 LVdp川t max显著降低，心梗后比索洛尔早期
禾晚期治疗均能降低 LVEDP，升高＋LVdp／dt max，但对一LVdp／dt max无明
显作用。Q）血清学指标：术后 4周，i组血浆 NE、Aug 11和 ET水平较
S组显著升高，early一B和 late一B组 NE、Aug 11和 ET水平较 MI组显著
降低，但高于 S组，earlg—B组 NE、Aug 11和 ET水平降低趋势较 late一
B组明显。（3）光镜下心肌组织改变：梗死区正常心肌组织结构消失，弥漫
性成纤维细胞及胶原组织增生，可见少量淋巴细胞和脂肪细胞浸润及毛细血
管再生。K）计算机图像分析测定结果：MI组、early—B组和late—B组
心梗面积无显著差异，earlr—B组和late—B组心内膜周长、心外膜周长
较 S组和 MI组显著增加，其中 early—B组较 late—B组增加更明显。MI
组胶原密度较伪手术组胶原密度显著增加，early—B组和 late—B组胶原
密度较M组和 S组均明显增加。（显著性界值 P＜0．05）
结论（1）本实验制备的动物模型，符合AMI后左室重构和功能障碍的病理
特征，是研究删I后左室重构的病理机制和治疗措施的良好实验动物模型。
（2）心梗后比索洛尔早期和晚期用药均显著降低心率，降低实验兔 AMI后
血浆 NE、Aug 11和 ET水平，早期应用效果更明显。但不管是早期应用（AMI
－3－
第四军医大学硕土研究生论文
后 48 ／J’时之内）还是晚期应用（AMI后 2周）均不能使血浆 NE、Aug 11和
ET水平降至伪手术组水平。（3）心梗后比索洛尔早期或晚期用药均促进实
验兔删I后非梗死区胶原沉积。（4）比索洛尔能有效改善地I后左室功能障
碍。但不管是早期用药还是晚期用药，比索洛尔均促进实验兔AMI后左室扩
张。值得注意的是晚期用药较早期用药左室扩张程度减轻，其机制尚待进一
步研究。
Backgroud The general process by which the left ventricular experiences changes in structure, shape and function after acute myocardial infarction is often referred as "left ventricular remodeling". Recently, it also involves the changes in myocardial cells and in both the quantity and quality of the extracellular matrix. A great deal of clinical and experimental studies indicate that left ventricular remodeling is the main reason of progressing left ventricular dysfunction and congestive heart failure after myocardial infarction and it is also the most important risk factor of late cardiac death. Therefore, the pathophysiologic process of left ventricular remodeling and to find better treatment have been better appreciated recently.
Both experimental and clinical studies indicated that early reperfusion of infarct-related artery may salvage the endocardial tissue and restore stuned myocardium in the infarct border zone, reduce infarct size and prevent infarct expansion. It is an efficient treatment in acute phase to prevent left ventricular remodeling after myocardial infarction. But patients with a patent infarct-artery also may undergo left ventricular remodeling. Other experiments and clinical trials have studied the effects of nitrate-based vasodilating agents,
antiimflammation drugs and Ca2+ channel blockers on the left ventricular remodeling, but the results were controversial. The efficacy of ACE inhibitors in reducing infarct size, attenuating left ventricular dilation after infarction was associated with improved survival. But with the different time of treatment after infarction, the effects of ACE inhibitors on left ventricular remodeling are different and when to use ACE inhibitors in AMI need to be further studied.
Treatment with J3 -blockers reduces mortality among patients with myocardial infarction, but studies on the effect of ?-blockers on remodeling after myocardial infarction have been sparse and some experimental observations were in conflict with the beneficial effects of & -blockers reported in clinical studies. Various factors may have influenced the experimental studied available so far: |3 -blocker type, size of infarction and time to start treatment after myocardial infarction. In addition, detailed hemodynamic studies have not been performed to determine the long-term effect of P -blockers after myocardial infarction. Therefore, the present study aimed to develope a rabbit model with left ventricular dysfunction after myocardial infarction, abserve the effects of early and late use of ?-blocker bisoprolol on hemodynamic function and left ventricular remodeling and discuss effects of P -blocker clinical use on left ventricular remodeling after myocardial infarction.
Methods Rabbit left ventricular myocardial infarction was produced by ligation of the left coronary artery. 4 weeks later, LV dysfunction and left ventricular remodeling developed. 48 rabbits weight from 1.8 to 2.5kg were used and 11 rabbits died during and after the operation. 10 of the rabbits randomized to sham-operated group (S group), 8 to myocardial infarction group (MI group), 9 to bisoprolol used within 48 hours after myocardial infarction group (early-B group) and 10 to bisoprolol used about 14 days after myocardial infarction group (late-B group). Before operation and 4 weeks after operation heart rates were determined from the electrocardiographic records. Hemodynamic measurements 4 weeks after operation were obtained under 3%
pentobarbital anesthesia. A micro-tip pressure transducer catheter was inserted successfully into the right carotid artery. Left ventricular end-diastolic pressure (LVEDP) and LV pressure with first positive and negative derivates of pressure (i dp/dt max ) obtained. Plasma noraurenalme (NE) was measured by a simplified liquid chromatography and electrochemical detection method and plasma angiotensin II (Ang II ) and endothelin (ET) were measured by radioimmunoassay. Then the heart was rapidly excised and immersed in 10% buffered formalin, dehydrated in 95?ethanol and
引文
1 Pfeffer MA et al. Ventricular remodeling after myocardial infarction: experimental observations and clinical implication. Circulation, 1990;81(4) :1161-1172
2． Erlebacher JA, Weisfeldt ML, et al. Early dilation of the infracted segment in acute transmural myocardial infarction: role of infarct expansion in acute left ventricular enlargement. J Am Coll Cardiol. 1984;4:201-208．
3． Weisman HF et al. Cellular mechanisms of myocardial infarct expansion. Circulation, 19S8;78(1) -186-201．
4． Anversa P et al. Ischemic cardiomyopathy: pathophysiologic mechanisms. Prog Cardiovasc Dis, 1990;33(1) .49-70．
5． Olivetti G et al. Side-to-side slippage of myocytes participates in ventricular wall remodeling acutely after myocardial infarction in rats. Circulation Res, 1990;67(1) -23-34．
6． White HD, Norris RM, Brown MA, et al. Left ventricular end-systolic volume as the major determinant of survival after recovery from myocardial infarction. Circulation. 1987,76:44-51．
7． Hochman JS, Choo H. Limitation of myocardial infarct expansion by reperfusion independent of myocardial salvage. Circulation 1987;75:299-306．
8． Jeremy RW, Hackworthy RA, Bautovich G, et al. Infarct artery perfusion and changes in left ventricular volume in the month after acute myocardial infarction. J Am Coll Cardiol 1987;9． 989-95
9． Horie H, Takahashi M, Minai K, et al. Long-term beneficial effect of late reperfusion for acute anterior myocardial infarction with percutaneous transluminal coronary angioplasty. Circulation 1998,98-2377-82．
10． Anversa P, Olivetti G, Meggs LG, et al. Cardiac anatomy and ventricular loading after myocardial infarction. Circulation 1993;87(suppl Ⅶ):Ⅶ-22-7
11 Olivetti G, Capasso JM, Meggs LG, et al Cellular basis of chronic ventricular remodeling after myocardial infarction m rats. Circ Res 1991:68:856-69．
12． Pirolo JS, Hutchins GM, Moore GW. Infarct expansion, pathologic analysis of 204 patients with a single myocardial infarction. J Am Coll Cardiol 1989,14-1149-58．
13． Brown EJ Jr, Swinford RD, Gadde P, et al. Acute effects of delayed reperfusion on infarct shape and left ventricular volume: a potential menchanism of additional benefits from thrombolytic therapy J Am Coll Cardiol 1991;17:1641-50．
14． Bolognese L, Cerisano G, Buonamici P, et al. Timing and magnitude of left ventricular dilation following direct angioplasty in acute myocardial infarction[abstract]. J Am Coll Cardiol 1999;33(suppl).343A.
15． Marino P, Zonolla L, Zardini P. Effect of streptokinase on left ventricular remodeling and function after myocardial infarction:GISSI trial. J Am Coll Cardiol. 1989;14:1149．
16． Jugdatt BI, Basualdo CA. Myocardial mfact wxpansion during indomethacin or ibuprofen therapy for
other pharmacologic agents during remodeling. Can J Cardiol 1989;5:211．
17． Boden WE, Krone RJ, Oades D, et al. Electrocardiographic subset analysis of diltiazem administration on longterm outcome after acute myocardial infarction. Am J Cardiol 1991;67(5) :335．
18． Ertl G, Kloner RA, Alexander RW, Braunwald E. Limitation of experimental infarct size by an angiotensin-converting enzyme inhibitor. Circulation 1982;65:40-8．
19． Tobe TJ, de Langen CD, Tio RA, Bel KJ, Mook PH, Wesseling H. In vivo effect of bradykinin during ischemia and reperfusion: improved electrical stability two weeks after myocardial infarction in the pig. J Cardiovasc Pharmacol 1991;17:600-607．
20． 中国CEI-AMI临床研究协作组。卡托普利对前壁和下壁心肌梗塞作用差异的临床实验。中华心血管病杂志 1995: 23 (3) : 165．
21． Fishbein MC, Lei LQ, Rubin SA. Long-term propranolol administration alters myocyte and ventricular geometry in rat hearts with and without infarction. Circulation. 1988 Aug;78(2) :369-75．
22． Hochman JS, Wong SC. Effect of atenolol on myocardial infarct expansion in a nonreperfused rat model. Am Heart J 1991;122:689-694．
23． Sadoshima J-I, Jahn L, Takahashi T, Kulik TJ, Izumo S. Melecular characterizations of the stretch-induced adaptation of cultures cardiac cells. An in vitro model of load-induced cardiac hypertrophy. J Biol Chem 1992;267:10551-10560．
24． Sugden PH. Signalling in myocardial hypertrophy-life after calcineurin? Circ Res 1999;84:33-46．
25． Simpson PC. Role of proto-oncogenes in myocardial hypertrophy. Am J Cardiol 1988;62(suppl):13-19G.
26． Iwaki K, Sukhatme VP, Shubeita HE, et al. α-and β-adrenergic stimulation induces distinct patterns of immediate gene expression in neonatal rat myocardial cells. J Biol Chem 1990;265:13809-17．
27． Chien KR, Zhu H, Knowlton KU, Miller-Hance W, van-Bilsen M, O' Brien TX, Evans SM. Transcriptional regulation during cardiac growth and development. Annu Rev Physiol, 1993;55:77-95．
28． Gerdes AM, Capasso JM. Structural remodeling and mechanical dysfunction of cardiac myocytes in heart failure. J Mol Cell Cardiol, 1995;27:849-56．
29． Arai M, Alpert NR, MacLennan DH, Barton P, Periasamy M. Alterations in sarcoplasmic reticulum gene expression in human heart failure. Circ Res 1993;72:463-469．
30． Saraste A, Pulkki K, Kallajoki M, Henriksen K, Parvinen M, Voipio-Pulkki L-M. Apoptosis in human acute myocardial infarction. Circulation 1997;95:320-323．
31． Gottlieb RA, Burleson KO, Kloner RA, Babior BM, Engler RL. Reperfusion injury induces apoptosis in rabbit cardiomyocytes. J Clin Invest 1994;94:1621-1628．
32． Kajstura J, Cheng W, Reiss K, Clark WA, Sonnenblick EH, Krajewski S, Reed JC, Olivetti G, Anversa P. Apoptotic and necrotic myocyte cell death are independent contributing variable of
infarct size in rats. Lab Invest 1996;74:86-107．
33． Liu Y, Cigola E, Cheng W, Kajstura J, Olivetti G, Hintze TH, Anversa P. Myocyte nuclear mitotic division and programmed myocyte death chracterize the cardiac myopathy induced by rapid ventricular pacing in dogs. Lab Invest 1995;73:771-787．
34． Cheng W, Li B, Kajstura J, Li P, Wolin MS, Sonnenblick EH, Hintze TH, Olivetti G, Anversa P. Stretch-induced programmed myocyte cell death. J Clin Invest 1995;96:2247-2259．
35． Teiger E, Dam T-V, Richard L, Wisnewsky C, Tea B-S. Gaboury L, Tremblay J, Schwartz K, Hamet P. Apoptosis in pressure overload-induced heart hypertrophy in the rat. J Clin Invest 1996;97:2891-2897．
36． Weber KT, Brilla CG. Pathological hypertrophy and cardiac interstitium. Fibrosis and renin-angiotensin-aldosterone system. Circulation 1991;83:184 9-1865．
37． Conrad CH, Brooks WW, Hayes JA, Sen S, Robinson KG, Bing OHL. Myocardial fibrosis and stiffness with hypertrophy and heart failure in the spontaneously hypertensive rat. Circulation 1995;91:161-170．
38． Calderone A, Takahashi N, Izzo NJ, Thaik CM, Colucci WS. Pressure-and volume-induced left ventricular hypertrophies are associated with distinct myocyte phenotypes and dfferential induction of peptide growth factor mRNAs. Circulation 1995;92:2385-2390．
39． Guarda E, KatwaLC, Myers PR, Tyagi SC, Weber Kt. Effects of endothelins on collagen turnover in cardiac fibroblasts. Cardiovasc Res 1993;27:2130-2134．
40． Pfeffer MA, Pfeffer JM, Fishbein MC, Fletcher PJ, Spadaro J, Kloner RA, Braunwald E: Myocardial infarct size and ventricular function in rats. Circ Res 1979;44:503-512．
41． Pitcher PJ, Pfeffer JM, Pfeffer MA, Braunwald E. Left ventricular diastolic pressure-volume relation in rats with healed myocardial infarction: Effects on systolic function. Circ Res 1981;49:618-626．
42． Hodsman GP, Kohzuki M, Howes LG, Sumithran E, Tsunoda K, Johnston CI. Neurohumoral responses to chronic myocardial infarction in rats. Circulation 1988;78:376-391．
43． Earon LW et al. Regional cardiac dilatation after acute myocardial infarction. N Engl J Med, 1979,300:57-62．
44． Vannan MA et al. Ventricular remodeling after myocardial infarction. Br Heart J, 1992,68:257-259．
45． Mitchell GF et al. Left ventricular remodeling in the year after first anterior myocardial infarction: a quantitative analysis of contractile segment lengths and ventricular shape. J Am Coll Cardiol, 19:1136-1144．
46． Shape N. Ventricular remodeling following myocardial infarction. Am J Cardiol, 1992,70:20c-26c.
47． Mckay RG, Pfeffer MA et al. Left ventricular remodeling following myocardial infarction: a corollary to infarct expansion. Circulation, 1986, 74:693-702．
48． Gerdes AM, Kellerman SE, Moore JA, Muffly KE, Clark LC, Reaves PY, Make KB, McKeown PP, Schocken DD. Structural remodeling of cardiac myocytes in patients with ischemic cardiomyopathy. Circulation, 1992; 86(2) :426-430．
49． 郑兴、章同华、秦永文等。心肌梗死大鼠梗死区和非梗死区间质胶原重构。第二军医大学学报1999 Sept: 20 (9) : 662-665．
50． Molinari R et al. Changes in serum levels of N-terminal procollagen type Ⅲ propeptide as an idex of postinfarction ventricular remodeling. Cardiologia, 1997;42(6) :627-633．
51． Weber KT, Sun Y, Katwa LC, Cleutjens JP. Connective tissue: a metabolic entity? J Mol Cell Cardiol,1995;27:107-20．
52． Weber KT, Sun Y, Campbell SE. Structural remodeling of the heart by fibrous tissue: role of ciculating hormones and locally produced peptides. Eur Heart J, 1995;16(suppl N): 12-18．
53． McAlpine HM, Morton JJ, Leckie B, et al. Neuroendocrine activation after acute myocardial infarction. Br Heart J 1988;60:117-24．
54． Packer M. The neurohormonal hypothesis: a theory to explain the mechanism of disease progression in heart failure. J Am Coll Cardiol 1992;20:248-54．
55． Francis GS, Benedict C, Johnstone DE, Kirlin PC, Nicklas J, Liang CS, et al. Comparison of neuroendocrine activation in patients with left ventricular dysfunction with and without congestive heart failure:substudy of the Studies of Left Ventricular Dysfunction(SOLVD). Circulation 1990;82:1724-1729．
56． Benedict CR, Shelton B, Johnstone DE, Francis G, Greenberg B, Konstam M, et al. Prognostic significance of plasma norepinephrine in patients with asymptomatic left ventricular dysfunction. Circulation 1996;94:690-697．
57． Fraccarollo D, Hu K, Galuppo P, Gaudron P, Ertl G. Chronic endothelin receptor blockade attenuates progressive ventricular dilation and improve cardiac function in rats with myocardial infarction. Possible involvement of myocardial endothelin system in ventricular remodeling. Circulation 1997;96:3963-3973．
58． Howes LG, Hodsman GP, Mccarone C, Kohzuki M, Johnston CI. Cardiac 3,4-dihydroxyphenylethylene glycol(DHPG) and catecholamine levels in a rat model of left ventricular failure. J Cardiovasc Pharmacol 1989;13:348-352．
59． Simpson P, McGrath A. Norepinephrine-stimulated hypertrophy of cultured rat myocardial cells is an alphal adrenergic response. J Clin Invest 1983;72:732-738．
60． Knowlton KU, Michel MC, Itani M, Shubeita HE, Ishihara K, Brown JH, Chien KR. The a 1A adrenergic receptor subtype mediates biochemical, molecular, and morphologic features of cultured myocardial cell hypertrophy. J Biol Chem 1993;268:15374-15380．
61． Clark WA, Rudnick SJ, LaPress JJ, Andersen LC, LaPointe MC. Regulation of hypertrophy and atrophy in cultures adult heart cells. Circ Res 1993;73:1163-1176．
62． Mann DL, Kent RL, Parsons B, Cooper G. Adrenergic effects on the biology of the adult mammalian cardiocyte. Circulation 1992;85:790-804．
63． Calderone A, Thaik CM, Takahashi N, Colucci WS. Norepinephrine-stimulated DNA and protein synthesis in cardiac fibroblasts are inhibited by nitic oxide and atrial naturetic factor. Circulation
1995;92(suppl Ⅰ):Ⅰ-382.
64．盖晓波，郑卫星，杜日映。心梗梗塞早期左室重构和血中儿茶酚胺和血管紧张素Ⅱ变化的关系。中国实用内科杂志1997：17：2．
65. Markedly different effects on ventricular remodeling result in a decrease in inducibility of ventricular arrhythimias. J Am Coll Cardiol 1994;23:505-13.
66. Zanchetti, Stella A. Neural control of rennin release. Clin Sci Mol Med 1975,48:s215-s233.
67. Danser JAH, van Kesteren CAM, Willem A, et al. Prorenin, renin, angiotensinogen and angiotensin-converting enzyme in normal and failing human hearts. Circulation 1997;96:220-226.
68. Asano K, Dutcher DL, Port JD, et al. Selective downregulation of the angiotensin Ⅱ AT1-recepter subtype in failing human ventricular myocardium. 1997;95:1193-1200.
69. Sadoshima J-I, Xu Y, Slayter HS, Izumo S. Autocrine release of angiotensin Ⅱ mediates stretch-induced hypertrophy of cardiac myocytes in vitro. Cell 1993;75:977-984.
70. Shubeita HE, McDonough PM, Harris AN, Knowlton KU, Glembotski CC, Brown JH, Chien KR. Endothelin induction of inositol phospholipid hydrolysis, sarcomere assembly, and cardiac gene expression in ventricular myocytes. A paracrine mechanism for myocardial cell hypertrophy. J Biol Chem 1990;256:20555-20562.
71. Levin ER. Endothelins. N Engl J Med 1995;333:356-63.
72. Watanabe T, Suzuki N, Shimamoto N, et al. Endothelin in myocardial infarction. Nature 1990;344:114.
73. Mulder P, Richard V, Derumeaux G, et al. Role of endogenous endothlin in chronic heart failure: effect of long-term treatment with an endothelin antagonist on survival, hemodynamics and cardiac remodeling. Circulation 1997;96:1976-82.
74. Gaudron P, Eilles C, Kugler I, et al. Progressive left ventricular dysfunction and remodeling after myocardial infarction:potential mechanisms and early predictios. Circulation 1993;87:755-63.
75. Lamas GA, Pfeffer MA. Increased left ventricular volume following myocardial infarction in man. Am Heart J 1986;111:30-5.
76. Hayashida WH, Van Eyll C, Rousseau MF, et al. Regional remodeling and nonuniform changes in diastolic function in patients with left ventricular dysfunction: modification by long-term enalapril treatment. J Am Coll Cardiol 1993;22:1403-10.
77. Anand IS, Liu D, Chugh SS, et al. Isolated myocyte contractile function is normal in postinfarct remodeled rat heart with systolic dysfunction. Circulation 1997;96:3974-84.
78. Bolognese L, Cerisano G, Buonamici P, et al. Timing and magnitude of left ventricular dilation following direct angioplasty in acute myocardial infarction[abstract]. J Am Coll Cardiol 1999;33(suppl):343A.
79. Lamas GA, St John Sutton M, Flaker G, et al. Infarct artery patency does not prevent LV remodeling. J Am Coll Cardiol 1995;25:104A.
80. Bonow RO. Regional left ventricular nonuniformity: effects on left ventricular diastolic function in
2． Erlebacher JA, Weisfeldt ML, et al. Early dilation of the infracted segment in acute transmural myocardial infarction: role of infarct expansion in acute left ventricular enlargement. J Am Coll Cardiol. 1984;4:201-208．
3． Weisman HF et al. Cellular mechanisms of myocardial infarct expansion. Circulation, 19S8;78(1) -186-201．
4． Anversa P et al. Ischemic cardiomyopathy: pathophysiologic mechanisms. Prog Cardiovasc Dis, 1990;33(1) .49-70．
5． Olivetti G et al. Side-to-side slippage of myocytes participates in ventricular wall remodeling acutely after myocardial infarction in rats. Circulation Res, 1990;67(1) -23-34．
6． White HD, Norris RM, Brown MA, et al. Left ventricular end-systolic volume as the major determinant of survival after recovery from myocardial infarction. Circulation. 1987,76:44-51．
7． Hochman JS, Choo H. Limitation of myocardial infarct expansion by reperfusion independent of myocardial salvage. Circulation 1987;75:299-306．
8． Jeremy RW, Hackworthy RA, Bautovich G, et al. Infarct artery perfusion and changes in left ventricular volume in the month after acute myocardial infarction. J Am Coll Cardiol 1987;9． 989-95
9． Horie H, Takahashi M, Minai K, et al. Long-term beneficial effect of late reperfusion for acute anterior myocardial infarction with percutaneous transluminal coronary angioplasty. Circulation 1998,98-2377-82．
10． Anversa P, Olivetti G, Meggs LG, et al. Cardiac anatomy and ventricular loading after myocardial infarction. Circulation 1993;87(suppl Ⅶ):Ⅶ-22-7
11 Olivetti G, Capasso JM, Meggs LG, et al Cellular basis of chronic ventricular remodeling after myocardial infarction m rats. Circ Res 1991:68:856-69．
12． Pirolo JS, Hutchins GM, Moore GW. Infarct expansion, pathologic analysis of 204 patients with a single myocardial infarction. J Am Coll Cardiol 1989,14-1149-58．
13． Brown EJ Jr, Swinford RD, Gadde P, et al. Acute effects of delayed reperfusion on infarct shape and left ventricular volume: a potential menchanism of additional benefits from thrombolytic therapy J Am Coll Cardiol 1991;17:1641-50．
14． Bolognese L, Cerisano G, Buonamici P, et al. Timing and magnitude of left ventricular dilation following direct angioplasty in acute myocardial infarction[abstract]. J Am Coll Cardiol 1999;33(suppl).343A.
15． Marino P, Zonolla L, Zardini P. Effect of streptokinase on left ventricular remodeling and function after myocardial infarction:GISSI trial. J Am Coll Cardiol. 1989;14:1149．
16． Jugdatt BI, Basualdo CA. Myocardial mfact wxpansion during indomethacin or ibuprofen therapy for
other pharmacologic agents during remodeling. Can J Cardiol 1989;5:211．
17． Boden WE, Krone RJ, Oades D, et al. Electrocardiographic subset analysis of diltiazem administration on longterm outcome after acute myocardial infarction. Am J Cardiol 1991;67(5) :335．
18． Ertl G, Kloner RA, Alexander RW, Braunwald E. Limitation of experimental infarct size by an angiotensin-converting enzyme inhibitor. Circulation 1982;65:40-8．
19． Tobe TJ, de Langen CD, Tio RA, Bel KJ, Mook PH, Wesseling H. In vivo effect of bradykinin during ischemia and reperfusion: improved electrical stability two weeks after myocardial infarction in the pig. J Cardiovasc Pharmacol 1991;17:600-607．
20． 中国CEI-AMI临床研究协作组。卡托普利对前壁和下壁心肌梗塞作用差异的临床实验。中华心血管病杂志 1995: 23 (3) : 165．
21． Fishbein MC, Lei LQ, Rubin SA. Long-term propranolol administration alters myocyte and ventricular geometry in rat hearts with and without infarction. Circulation. 1988 Aug;78(2) :369-75．
22． Hochman JS, Wong SC. Effect of atenolol on myocardial infarct expansion in a nonreperfused rat model. Am Heart J 1991;122:689-694．
23． Sadoshima J-I, Jahn L, Takahashi T, Kulik TJ, Izumo S. Melecular characterizations of the stretch-induced adaptation of cultures cardiac cells. An in vitro model of load-induced cardiac hypertrophy. J Biol Chem 1992;267:10551-10560．
24． Sugden PH. Signalling in myocardial hypertrophy-life after calcineurin? Circ Res 1999;84:33-46．
25． Simpson PC. Role of proto-oncogenes in myocardial hypertrophy. Am J Cardiol 1988;62(suppl):13-19G.
26． Iwaki K, Sukhatme VP, Shubeita HE, et al. α-and β-adrenergic stimulation induces distinct patterns of immediate gene expression in neonatal rat myocardial cells. J Biol Chem 1990;265:13809-17．
27． Chien KR, Zhu H, Knowlton KU, Miller-Hance W, van-Bilsen M, O' Brien TX, Evans SM. Transcriptional regulation during cardiac growth and development. Annu Rev Physiol, 1993;55:77-95．
28． Gerdes AM, Capasso JM. Structural remodeling and mechanical dysfunction of cardiac myocytes in heart failure. J Mol Cell Cardiol, 1995;27:849-56．
29． Arai M, Alpert NR, MacLennan DH, Barton P, Periasamy M. Alterations in sarcoplasmic reticulum gene expression in human heart failure. Circ Res 1993;72:463-469．
30． Saraste A, Pulkki K, Kallajoki M, Henriksen K, Parvinen M, Voipio-Pulkki L-M. Apoptosis in human acute myocardial infarction. Circulation 1997;95:320-323．
31． Gottlieb RA, Burleson KO, Kloner RA, Babior BM, Engler RL. Reperfusion injury induces apoptosis in rabbit cardiomyocytes. J Clin Invest 1994;94:1621-1628．
32． Kajstura J, Cheng W, Reiss K, Clark WA, Sonnenblick EH, Krajewski S, Reed JC, Olivetti G, Anversa P. Apoptotic and necrotic myocyte cell death are independent contributing variable of
infarct size in rats. Lab Invest 1996;74:86-107．
33． Liu Y, Cigola E, Cheng W, Kajstura J, Olivetti G, Hintze TH, Anversa P. Myocyte nuclear mitotic division and programmed myocyte death chracterize the cardiac myopathy induced by rapid ventricular pacing in dogs. Lab Invest 1995;73:771-787．
34． Cheng W, Li B, Kajstura J, Li P, Wolin MS, Sonnenblick EH, Hintze TH, Olivetti G, Anversa P. Stretch-induced programmed myocyte cell death. J Clin Invest 1995;96:2247-2259．
35． Teiger E, Dam T-V, Richard L, Wisnewsky C, Tea B-S. Gaboury L, Tremblay J, Schwartz K, Hamet P. Apoptosis in pressure overload-induced heart hypertrophy in the rat. J Clin Invest 1996;97:2891-2897．
36． Weber KT, Brilla CG. Pathological hypertrophy and cardiac interstitium. Fibrosis and renin-angiotensin-aldosterone system. Circulation 1991;83:184 9-1865．
37． Conrad CH, Brooks WW, Hayes JA, Sen S, Robinson KG, Bing OHL. Myocardial fibrosis and stiffness with hypertrophy and heart failure in the spontaneously hypertensive rat. Circulation 1995;91:161-170．
38． Calderone A, Takahashi N, Izzo NJ, Thaik CM, Colucci WS. Pressure-and volume-induced left ventricular hypertrophies are associated with distinct myocyte phenotypes and dfferential induction of peptide growth factor mRNAs. Circulation 1995;92:2385-2390．
39． Guarda E, KatwaLC, Myers PR, Tyagi SC, Weber Kt. Effects of endothelins on collagen turnover in cardiac fibroblasts. Cardiovasc Res 1993;27:2130-2134．
40． Pfeffer MA, Pfeffer JM, Fishbein MC, Fletcher PJ, Spadaro J, Kloner RA, Braunwald E: Myocardial infarct size and ventricular function in rats. Circ Res 1979;44:503-512．
41． Pitcher PJ, Pfeffer JM, Pfeffer MA, Braunwald E. Left ventricular diastolic pressure-volume relation in rats with healed myocardial infarction: Effects on systolic function. Circ Res 1981;49:618-626．
42． Hodsman GP, Kohzuki M, Howes LG, Sumithran E, Tsunoda K, Johnston CI. Neurohumoral responses to chronic myocardial infarction in rats. Circulation 1988;78:376-391．
43． Earon LW et al. Regional cardiac dilatation after acute myocardial infarction. N Engl J Med, 1979,300:57-62．
44． Vannan MA et al. Ventricular remodeling after myocardial infarction. Br Heart J, 1992,68:257-259．
45． Mitchell GF et al. Left ventricular remodeling in the year after first anterior myocardial infarction: a quantitative analysis of contractile segment lengths and ventricular shape. J Am Coll Cardiol, 19:1136-1144．
46． Shape N. Ventricular remodeling following myocardial infarction. Am J Cardiol, 1992,70:20c-26c.
47． Mckay RG, Pfeffer MA et al. Left ventricular remodeling following myocardial infarction: a corollary to infarct expansion. Circulation, 1986, 74:693-702．
48． Gerdes AM, Kellerman SE, Moore JA, Muffly KE, Clark LC, Reaves PY, Make KB, McKeown PP, Schocken DD. Structural remodeling of cardiac myocytes in patients with ischemic cardiomyopathy. Circulation, 1992; 86(2) :426-430．
49． 郑兴、章同华、秦永文等。心肌梗死大鼠梗死区和非梗死区间质胶原重构。第二军医大学学报1999 Sept: 20 (9) : 662-665．
50． Molinari R et al. Changes in serum levels of N-terminal procollagen type Ⅲ propeptide as an idex of postinfarction ventricular remodeling. Cardiologia, 1997;42(6) :627-633．
51． Weber KT, Sun Y, Katwa LC, Cleutjens JP. Connective tissue: a metabolic entity? J Mol Cell Cardiol,1995;27:107-20．
52． Weber KT, Sun Y, Campbell SE. Structural remodeling of the heart by fibrous tissue: role of ciculating hormones and locally produced peptides. Eur Heart J, 1995;16(suppl N): 12-18．
53． McAlpine HM, Morton JJ, Leckie B, et al. Neuroendocrine activation after acute myocardial infarction. Br Heart J 1988;60:117-24．
54． Packer M. The neurohormonal hypothesis: a theory to explain the mechanism of disease progression in heart failure. J Am Coll Cardiol 1992;20:248-54．
55． Francis GS, Benedict C, Johnstone DE, Kirlin PC, Nicklas J, Liang CS, et al. Comparison of neuroendocrine activation in patients with left ventricular dysfunction with and without congestive heart failure:substudy of the Studies of Left Ventricular Dysfunction(SOLVD). Circulation 1990;82:1724-1729．
56． Benedict CR, Shelton B, Johnstone DE, Francis G, Greenberg B, Konstam M, et al. Prognostic significance of plasma norepinephrine in patients with asymptomatic left ventricular dysfunction. Circulation 1996;94:690-697．
57． Fraccarollo D, Hu K, Galuppo P, Gaudron P, Ertl G. Chronic endothelin receptor blockade attenuates progressive ventricular dilation and improve cardiac function in rats with myocardial infarction. Possible involvement of myocardial endothelin system in ventricular remodeling. Circulation 1997;96:3963-3973．
58． Howes LG, Hodsman GP, Mccarone C, Kohzuki M, Johnston CI. Cardiac 3,4-dihydroxyphenylethylene glycol(DHPG) and catecholamine levels in a rat model of left ventricular failure. J Cardiovasc Pharmacol 1989;13:348-352．
59． Simpson P, McGrath A. Norepinephrine-stimulated hypertrophy of cultured rat myocardial cells is an alphal adrenergic response. J Clin Invest 1983;72:732-738．
60． Knowlton KU, Michel MC, Itani M, Shubeita HE, Ishihara K, Brown JH, Chien KR. The a 1A adrenergic receptor subtype mediates biochemical, molecular, and morphologic features of cultured myocardial cell hypertrophy. J Biol Chem 1993;268:15374-15380．
61． Clark WA, Rudnick SJ, LaPress JJ, Andersen LC, LaPointe MC. Regulation of hypertrophy and atrophy in cultures adult heart cells. Circ Res 1993;73:1163-1176．
62． Mann DL, Kent RL, Parsons B, Cooper G. Adrenergic effects on the biology of the adult mammalian cardiocyte. Circulation 1992;85:790-804．
63． Calderone A, Thaik CM, Takahashi N, Colucci WS. Norepinephrine-stimulated DNA and protein synthesis in cardiac fibroblasts are inhibited by nitic oxide and atrial naturetic factor. Circulation
1995;92(suppl Ⅰ):Ⅰ-382.
64．盖晓波，郑卫星，杜日映。心梗梗塞早期左室重构和血中儿茶酚胺和血管紧张素Ⅱ变化的关系。中国实用内科杂志1997：17：2．
65. Markedly different effects on ventricular remodeling result in a decrease in inducibility of ventricular arrhythimias. J Am Coll Cardiol 1994;23:505-13.
66. Zanchetti, Stella A. Neural control of rennin release. Clin Sci Mol Med 1975,48:s215-s233.
67. Danser JAH, van Kesteren CAM, Willem A, et al. Prorenin, renin, angiotensinogen and angiotensin-converting enzyme in normal and failing human hearts. Circulation 1997;96:220-226.
68. Asano K, Dutcher DL, Port JD, et al. Selective downregulation of the angiotensin Ⅱ AT1-recepter subtype in failing human ventricular myocardium. 1997;95:1193-1200.
69. Sadoshima J-I, Xu Y, Slayter HS, Izumo S. Autocrine release of angiotensin Ⅱ mediates stretch-induced hypertrophy of cardiac myocytes in vitro. Cell 1993;75:977-984.
70. Shubeita HE, McDonough PM, Harris AN, Knowlton KU, Glembotski CC, Brown JH, Chien KR. Endothelin induction of inositol phospholipid hydrolysis, sarcomere assembly, and cardiac gene expression in ventricular myocytes. A paracrine mechanism for myocardial cell hypertrophy. J Biol Chem 1990;256:20555-20562.
71. Levin ER. Endothelins. N Engl J Med 1995;333:356-63.
72. Watanabe T, Suzuki N, Shimamoto N, et al. Endothelin in myocardial infarction. Nature 1990;344:114.
73. Mulder P, Richard V, Derumeaux G, et al. Role of endogenous endothlin in chronic heart failure: effect of long-term treatment with an endothelin antagonist on survival, hemodynamics and cardiac remodeling. Circulation 1997;96:1976-82.
74. Gaudron P, Eilles C, Kugler I, et al. Progressive left ventricular dysfunction and remodeling after myocardial infarction:potential mechanisms and early predictios. Circulation 1993;87:755-63.
75. Lamas GA, Pfeffer MA. Increased left ventricular volume following myocardial infarction in man. Am Heart J 1986;111:30-5.
76. Hayashida WH, Van Eyll C, Rousseau MF, et al. Regional remodeling and nonuniform changes in diastolic function in patients with left ventricular dysfunction: modification by long-term enalapril treatment. J Am Coll Cardiol 1993;22:1403-10.
77. Anand IS, Liu D, Chugh SS, et al. Isolated myocyte contractile function is normal in postinfarct remodeled rat heart with systolic dysfunction. Circulation 1997;96:3974-84.
78. Bolognese L, Cerisano G, Buonamici P, et al. Timing and magnitude of left ventricular dilation following direct angioplasty in acute myocardial infarction[abstract]. J Am Coll Cardiol 1999;33(suppl):343A.
79. Lamas GA, St John Sutton M, Flaker G, et al. Infarct artery patency does not prevent LV remodeling. J Am Coll Cardiol 1995;25:104A.
80. Bonow RO. Regional left ventricular nonuniformity: effects on left ventricular diastolic function in