内皮功能、炎症因子在动脉粥样硬化中的变化及阿司匹林的预防作用
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摘要
目的:1、高脂血症及早期AS内皮功能及炎症因子的变化。2、阿司匹林对内皮功能、炎症因子C-反应蛋白(CRP)及早期AS病变的影响。3、冠心病病人CRP的影响因素及对主要不良心脏事件(MACE)的预测。
材料与方法:1、将36头小型猪随机分成4组:(1)对照组(n=6),喂正常猪饲料;(2)1.5%胆固醇组(n-12),1.5%胆固醇高脂饮食;(3)3%胆固醇组(n=12),3.0%胆固醇高脂饮食;(4)阿司匹林组(n=6),3.0%胆固醇高脂饮食+阿司匹林150mg/天。高脂饮食4个月。2、每月测定血脂(TG、TC、HDL-C、LDL-C)及血糖(GLU),每2个月测定内皮功能指标(TXA_2、PGI_2、ET)和CRP,分析高脂血症内皮功能和CRP变化及阿司匹林的作用。3、高脂饮食4个月后,处死部分动物,研究早期AS病变特征及阿司匹林对其影响.4、临床部分对177例冠心病病人,研究CRP升高的影响因素,随访分析CRP对MACE的预测价值。
结果:1、高脂饮食4个月,TC、LDL-C和HDL-C分别从基线时1.68～1.95mmol/L、0.72～1.03mmol/L和0.64～0.77mmol/L上升至15.5～17.7mmol/L、11.6～13.0mmol/L和4.45～5.76mmol/L,TG及GLU没有升高,形成高胆固醇血症,阿司匹林对血脂无明显影响。2、高脂饮食后TXA_2和TXA_2/PGI_2升高,而ET呈下降趋势;阿司匹林组与3%胆固醇组相比,TXA_2、TXA_2/PGI_2水平明显降低(P<0.01),ET下降趋势明显(P<0.01),PGI_2无明显变化。3、高脂饮食使血清CRP明显上升;阿司匹林组CRP在高脂饮食2个月时没有升高,但4个月时也明显升高,与3%胆固醇组相比无显著差异,说明阿司匹林在AS初期有一定的抑制CRP的作用,但随后没有明显的抑制CRP作用。4、高脂饮食4个月,小型猪形成了AS脂纹和纤维斑块早期病变,早期AS病变突出表现为内膜剥脱不完整、斑块内的细胞以泡沫细胞(巨噬细胞吞噬脂质后形成)为主;阿司匹林组的冠状动脉AS内膜最大厚度、斑块截面积与3%胆固醇组相比稍低,但无显著性差异。5、临床研究显示,冠心病病人CRP
Objective 1. Changes of endothelial function and C-reaction protein (CRP) in hyperlipidemia and early atherosclerosis (AS). 2. The effects of aspirin on endothelial dysfunction, CRP and AS. 3. The relative factors of CRP and prediction of major adverse cardiac events (MACE) for coronary disease (CHD).Methods 1. Thirty-six 4-month-old miniature pigs were randomly assigned into four groups: (1) control (n=6) which were feeded on normal chow;(2) 1.5% cholesterol group (n=12) which were feeded on atherogenic diet containing 1.5% cholesterol, 10.0% beef tallow, 6.0% peanut oil, and 0.5% bile;(3) 3% cholesterol group (n=12) which was replaced with 3% cholesterol in 1.5% cholesterol group atherogenic diet;(4) aspirin group (n=6) which was added aspirin 150mg/d in 3% cholesterol group atherogenic diet. The atherogenic diet was continued for 4 months. 2. Total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and glucose were measured monthly. Thromboxane A_2 (TXA2), prostacyclin I_2 (PGI_2), endothelin (ET) and CRP were measured bimonthly. The changes of endothelial function, CRP and effects of aspirin were analyzed. 3. Three pigs for each group were killed to determine the extent of AS and the effects of aspirin. Morphometric analysis of sections (6 μm) of the left anterior descending, left circumflex and right coronary artery was performed using image J system. 4. In the clinical trial, the related factors of CRP were analyzed in 177 CHD patients. In the follow-up study, the predicted role of CRP and LDL-C for MACE was analyzed.Results 1. Serum TC, LDL-C and HDL-C of three atherogenic diet groups increased steadily over the 4 months. From very low level in baseline, TC, LDL-C and HDL-C was reached 15.5-17.7 mmol/L, 11.6-13.0 mmol/L and 4.45-5.76 mmol/L by 4 months, repectively. TG and glucose was not increased. Aspirin had
no impact on lipids. 2. Plasma TXA2 and TXA2/PGI2 went up and ET reduced with atherogenic diet. TXA2, TXA2/PGI2 and ET makedly reduced (P<0.01), and PGI2 remained no changes in aspirin group compared with 3% cholesterol group. 3. Serum CRP increased makedly with atherogenic diet. The level of CRP in aspirin group had no statistic decline compared with 3% cholesterol group. 4. Cholesterol feeding induced significant peripheral and coronary artery plaque by 4 months. Early AS plaque presented endothelial cells un-integrity and the predominant cell was macrophage. Morphometric analysis showed the maximal intima thickness, intima area had no statistic decline in aspirin group compared with 3% cholesterol group. 5. Clinical study showed CRP was correlated with erythrocyte sedimentation rate and eccentric lesion. The correlation between CRP and serum lipids was modest. Survival analysis indicated CRP level played an important role in the prediction of MACE in CHD patients (Log-rank =12.0;P<0.01). However, LDL-C had not obvious predicted value for MACE. Multivariate COX regression showed that abnormal CRP (OR=3.16, P<0.05) was independent risk factors for MACE.Conclusion 1. Hyperlipidemia pig model was induced by feed on containing 1.5-3.0 % cholesterol atherogenic diet. Aspirin had no impact on lipids. 2. Plasma TXA2 and TXA2/PGI2 went up and ET reduced with atherogenic diet, which suggested damage and anti-damage procedure. Aspirin improved endothelial dysfunction in hyperlipidemia. 3. Hyperlipidemia and early AS were associated with inflammation. Aspirin had no obvious reduction for CRP in hyperlipidemia. Thus, anti-thrombotic properties of low dose of aspirin achieved by a decline of TXA2 concentrations, but not CRP. 4. Aspirin did not remarkably attenuated AS plaque. 5. CRP was correlated with erythrocyte sedimentation rate and eccentric lesion. The correlation between CRP and serum lipids was modest. CRP played an important role in the prediction of MACE for CHD.
材料与方法:1、将36头小型猪随机分成4组:(1)对照组(n=6),喂正常猪饲料;(2)1.5%胆固醇组(n-12),1.5%胆固醇高脂饮食;(3)3%胆固醇组(n=12),3.0%胆固醇高脂饮食;(4)阿司匹林组(n=6),3.0%胆固醇高脂饮食+阿司匹林150mg/天。高脂饮食4个月。2、每月测定血脂(TG、TC、HDL-C、LDL-C)及血糖(GLU),每2个月测定内皮功能指标(TXA_2、PGI_2、ET)和CRP,分析高脂血症内皮功能和CRP变化及阿司匹林的作用。3、高脂饮食4个月后,处死部分动物,研究早期AS病变特征及阿司匹林对其影响.4、临床部分对177例冠心病病人,研究CRP升高的影响因素,随访分析CRP对MACE的预测价值。
结果:1、高脂饮食4个月,TC、LDL-C和HDL-C分别从基线时1.68～1.95mmol/L、0.72～1.03mmol/L和0.64～0.77mmol/L上升至15.5～17.7mmol/L、11.6～13.0mmol/L和4.45～5.76mmol/L,TG及GLU没有升高,形成高胆固醇血症,阿司匹林对血脂无明显影响。2、高脂饮食后TXA_2和TXA_2/PGI_2升高,而ET呈下降趋势;阿司匹林组与3%胆固醇组相比,TXA_2、TXA_2/PGI_2水平明显降低(P<0.01),ET下降趋势明显(P<0.01),PGI_2无明显变化。3、高脂饮食使血清CRP明显上升;阿司匹林组CRP在高脂饮食2个月时没有升高,但4个月时也明显升高,与3%胆固醇组相比无显著差异,说明阿司匹林在AS初期有一定的抑制CRP的作用,但随后没有明显的抑制CRP作用。4、高脂饮食4个月,小型猪形成了AS脂纹和纤维斑块早期病变,早期AS病变突出表现为内膜剥脱不完整、斑块内的细胞以泡沫细胞(巨噬细胞吞噬脂质后形成)为主;阿司匹林组的冠状动脉AS内膜最大厚度、斑块截面积与3%胆固醇组相比稍低,但无显著性差异。5、临床研究显示,冠心病病人CRP
Objective 1. Changes of endothelial function and C-reaction protein (CRP) in hyperlipidemia and early atherosclerosis (AS). 2. The effects of aspirin on endothelial dysfunction, CRP and AS. 3. The relative factors of CRP and prediction of major adverse cardiac events (MACE) for coronary disease (CHD).Methods 1. Thirty-six 4-month-old miniature pigs were randomly assigned into four groups: (1) control (n=6) which were feeded on normal chow;(2) 1.5% cholesterol group (n=12) which were feeded on atherogenic diet containing 1.5% cholesterol, 10.0% beef tallow, 6.0% peanut oil, and 0.5% bile;(3) 3% cholesterol group (n=12) which was replaced with 3% cholesterol in 1.5% cholesterol group atherogenic diet;(4) aspirin group (n=6) which was added aspirin 150mg/d in 3% cholesterol group atherogenic diet. The atherogenic diet was continued for 4 months. 2. Total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and glucose were measured monthly. Thromboxane A_2 (TXA2), prostacyclin I_2 (PGI_2), endothelin (ET) and CRP were measured bimonthly. The changes of endothelial function, CRP and effects of aspirin were analyzed. 3. Three pigs for each group were killed to determine the extent of AS and the effects of aspirin. Morphometric analysis of sections (6 μm) of the left anterior descending, left circumflex and right coronary artery was performed using image J system. 4. In the clinical trial, the related factors of CRP were analyzed in 177 CHD patients. In the follow-up study, the predicted role of CRP and LDL-C for MACE was analyzed.Results 1. Serum TC, LDL-C and HDL-C of three atherogenic diet groups increased steadily over the 4 months. From very low level in baseline, TC, LDL-C and HDL-C was reached 15.5-17.7 mmol/L, 11.6-13.0 mmol/L and 4.45-5.76 mmol/L by 4 months, repectively. TG and glucose was not increased. Aspirin had
no impact on lipids. 2. Plasma TXA2 and TXA2/PGI2 went up and ET reduced with atherogenic diet. TXA2, TXA2/PGI2 and ET makedly reduced (P<0.01), and PGI2 remained no changes in aspirin group compared with 3% cholesterol group. 3. Serum CRP increased makedly with atherogenic diet. The level of CRP in aspirin group had no statistic decline compared with 3% cholesterol group. 4. Cholesterol feeding induced significant peripheral and coronary artery plaque by 4 months. Early AS plaque presented endothelial cells un-integrity and the predominant cell was macrophage. Morphometric analysis showed the maximal intima thickness, intima area had no statistic decline in aspirin group compared with 3% cholesterol group. 5. Clinical study showed CRP was correlated with erythrocyte sedimentation rate and eccentric lesion. The correlation between CRP and serum lipids was modest. Survival analysis indicated CRP level played an important role in the prediction of MACE in CHD patients (Log-rank =12.0;P<0.01). However, LDL-C had not obvious predicted value for MACE. Multivariate COX regression showed that abnormal CRP (OR=3.16, P<0.05) was independent risk factors for MACE.Conclusion 1. Hyperlipidemia pig model was induced by feed on containing 1.5-3.0 % cholesterol atherogenic diet. Aspirin had no impact on lipids. 2. Plasma TXA2 and TXA2/PGI2 went up and ET reduced with atherogenic diet, which suggested damage and anti-damage procedure. Aspirin improved endothelial dysfunction in hyperlipidemia. 3. Hyperlipidemia and early AS were associated with inflammation. Aspirin had no obvious reduction for CRP in hyperlipidemia. Thus, anti-thrombotic properties of low dose of aspirin achieved by a decline of TXA2 concentrations, but not CRP. 4. Aspirin did not remarkably attenuated AS plaque. 5. CRP was correlated with erythrocyte sedimentation rate and eccentric lesion. The correlation between CRP and serum lipids was modest. CRP played an important role in the prediction of MACE for CHD.
引文
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2. Libby P, Ridker PM, Maseri A. Inflammation and Atherosclerosis. Circulation, 2002, 105 (9): 1135-1143.
3. Lusis AJ. Atherosclerosis. Nature, 2000, 407: 233-241.
4. Danesh J, Wheeler J, Hirschfield GM, et al. C-reaction protein and other circulating markers of inflammation in the prediction of coronary heart disease. New Engl J Med, 2004, 350 (14): 1387-1397.
5. Ridker PM, Buring JE, Cook NR, et al. C-Reactive Protein, the Metabolic Syndrome, and Risk of Incident Cardiovascular Events: An 8-Year Follow-Up of 14 719 Initially Healthy American Women. Circulation, 2003, 107: 391-397.
6. Lerman A, Zeiher AM. Endothelial function: Cardiac events. Circulation, 2005;111: 363-368.
7. Bonetti PO, Lerman LO, Lerman A. Endothelial dysfunction: a marker of atherosclerotic risk. Arterioscler thromb vasc boil, 2003, 23: 168-175.
8. Ridker PM, Cannon CP, Morrow D, et al. C-reaction protein levels and outcomes after statin therapy. New Engl J Med, 2005, 352: 20-28.
9. Folsom AR, Pankow JS, Tracy RP, et al. Association of C-reactive protein with markers of prevalent atherosclerotic disease. Am J Cardiol. 2001;88: 112-117.
10. Jialal I, Devaraj S, Venugopal SK. C-Reactive Protein: Risk Marker or Mediator in Atherothrombosis? Hypertension, 2004, 44 (1): 6-11.
11. Ridker PM, Cannon CP, Morrow D, et al. C-reaction protein levels and outcomes after statin therapy. New Engl J Med, 2005, 352: 20-28.
12. Bailey DB, Mitchell JA, Warner TD. COX-2 in Cardiovascular Disease. Arterioscler Thromb Vasc Biol, 2006, 26: 956-958.
13.魏泓主编.医学实验动物学,第2版,成都:四川科学技术出版社,2001: 286-292.
14. Swindle MM and Smith AC. Information Resources on Swine in Biomedical Research 1990-2000.
15. Holvoet P, Theilmeier G, Shivalkar B, et al. LDL hypercholesterolemia is associated with accumulation of oxidized LDL, atherosclerotic plaque growth, and compensatory vessel enlargement in coronary arteries of miniature pigs.
16. Post MJ, de Smet BJ, van der Helm Y, et al. Arterial remodeling after balloon angioplasty or stenting in an atherosclerotic experimental model. Circulation, 1997, 96 (3): 996-1003.
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