Changes Of Endothelial Function And Inflammatory Factor In Atherosclerosis And The Effects Of Aspirin

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 A₂ (TXA2), prostacyclin I₂ (PGI₂), 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 hadno 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.