Time And Dose Related Relationship Of Simvastatin On Protecting Endothelial Function In Patients With Acute Coronary Syndrome

Background and Objective Blood vessel endothelium (BVE) is an important endocrine and paracrine organ that can produce and secrete many biological activators, and has special protection on blood vessel function. When it is damaged, endothelin (ET), a vasoconstriction factor, is released abnomaly and excessively, on the contrast, as a vasorelaxation factor, the synthesis, excretion and activity of nitric oxide (NO)will be impaired. As a result, the dynamic balance of NO and ET-1 will be deranged. Some researchers have shown that the unstable plaque of the patients with acute coronary syndrome (ACS) is relevant to blood vessel endothelium dysfunction. Others researchers have shown that statins have pleiotropic effects, in particular, the improvement of blood vessel endothelium function, which is responsible for clinical benefits of statins. Recent clinical trials have demonstrated that intensive lipid lowering in high risk patients with coronary heart disease(CHD) provides significant clinical benefit beyond moderate lipid lowering, However, taking the costs and safety into account, internal physicians are accustomed to adopting moderate or low dose statin. Consequently, the purpose of this study is to observe time-related and dose- related relationship of simvastatin on lowering lipid and protecting endothelial function, and to assess the efficacy of moderate or low dose statin.Methods 85 patients with ACS(ACS group) were consecutively enrolled to the study and divided randomly into four groups. The control group (n=20) was treated by routine treatment, simvastatin 20mg/day, 40mg/day, 80mg/day were devided to 20mg group (n=23), 40mg group (n=21), 80mg group (n=21), respectively. Total-cholesterol (TC) and low density lipoprotein-cholesterol (LDL-C) were measured at admission and 2, 4, 8, 10 weeks after treatment. ET-1, NO, endothelium-dependent vasodilation and non-endothelium-dependent vasodilation function in brachial artery were measured with high resolution ultrasound at admission and 4,8, 10weeks after treatment. At the same time, 17 healthy persons were enrolled to the study also, and all the indices were examined on admission, but they did not accept any treatment.Results Demography and clinical medication of every group were similar (P >0. 05) . There were an increase on TC,LDL-C,ET-1 levels and a decrease on FMD,NMD,NO levels in ACS patients than the healthy (P >0. 05) . Among the four treatment groups, no difference was observed before treatment (P >0. 05) . Post treatment, comparison with pre-treatment, TC,LDL-C,ET-1 levels were found to be reduced and NO, FMD raised significantly in every statin group(P <0.05 ), particularly, in 40mg and 80mg group, the efficacy were marked at 4 weeks(P <0.05), and furthered at 8 weeks(P <0. 001). Comparison between groups, the best outcome was in 80mg group, followed by 40mg and 20mg group,the control being the worst, but the difference among the 20mg , 40mg and 80mg group was weakened more significantly at 8 weeks than at 4 weeks. Following drug withdrawl after 2 weeks, All indices were restored, however, TC,LDL-C and ET-1 levels were slightly decreased in 80mg group than pre-treatment, NO and FMD were elevated in each statin group compared to pre-treatment (P≤0. 05). In the control group, plasma NO at 4,8,10 weeks and FMD at 8,10weeks was significantly raised after treatment than before treatment(P <0.05). There was no difference on NMD among statin groups and between pretherapy and post-therapy(P >0.05). The average days of follow-up was 68±5, 10 patients had experienced cardiovascular events, of which one in the control group and one in the 20mg group due to dying of cardiogenic sudden death within 1 month after AMI, One with AMI in the control group had experienced the second revascularization, 2, 2, 2 and 1 patients with angina pectoris recurrenced in the control, 20mg, 40mg and 80mg, respectively. Twelve patients developed adverse effect (2 in the control, 2 in 20mg, 3 in 40mg and 5 in 80mg, respectively), among which, one developed muscle pain, seven had increased liver enzymes, the others gastrointestinal tract discomfort. Two of the 80mg group were included from the study(one for the increase in liver enzymes increase, another for muscle pain).Conclusion Among ACS patients, TC, LDL-C ,ET-1 levels are increased and FMD,NMD, NO levels are decreased. Different doses of simvastatin has favourable lowering lipid and protecting endothelial function, However, these effects were time-dependent and dose-dependent relationship during short period, but the relationships becoming weaker following the prolongation of treatment. Simvastatin can decease the morbidity and mortalify of cardiovascular event, and this can be observed within 1 month of treatment. During follow-up, the higher dose of simvastatin prescribed was found to have increase in adverse effect.