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Short-term withdrawal of simvastatin induces endothelial dysfunction in patients with coronary artery disease: A dose-response effect dependent on endothelial nitric oxide synthase
Chen, Hong1,2; Ren, Jing-Yi1,2; Xing, Yan1,2; Zhang, Wan-Lei3; Liu, Xin1,2; Wu, Pei1,2; Wang, Ruo-Jie1,2; Luo, Yu1,2
关键词Simvastatin Endothelial Function Nitric Oxide Coronary Artery Disease
刊名INTERNATIONAL JOURNAL OF CARDIOLOGY
2009-01-24
DOI10.1016/j.ijcard.2007.10.044
131期:3页:313-320
收录类别SCI
文章类型Article
WOS标题词Science & Technology
类目[WOS]Cardiac & Cardiovascular Systems
研究领域[WOS]Cardiovascular System & Cardiology
关键词[WOS]LOW-DENSITY-LIPOPROTEIN ; SMOOTH-MUSCLE-CELLS ; STATIN TREATMENT ; DISCONTINUATION ; ATORVASTATIN ; EXPRESSION ; THERAPY ; RATES
英文摘要

Background: Patients with coronary artery disease (CAD) have impaired endothelial function. Simvastatin therapy has been demonstrated to significantly improve endothelial function in these patients. Although withdrawal of statins is a frequent problem in clinical practice, the effects after discontinuation of statins treatment on endothelial function in patients with CAD are largely unknown.

Objective: This study investigated the effects after withdrawal of simvastatin on brachial artery endothelial function in patients with CAD and the underlying mechanisms.

Methods: We recruited 30 patients with established CAD. They were treated with 20 mg simvastatin for 4 weeks. Endothelial dependent flow-mediated vasodilation (FMD) was assessed in the brachial artery using high-resolution ultrasound at baseline, 4 weeks during simvastatin treatment, and 1 week after termination of therapy. 20 healthy subjects were also studied as a control group. Furthermore, we investigated underlying mechanisms on human umbilical vein endothelial cells (HUVECs) confluent monolayers at passages 2-3. HUVECs were exposed to simvastatin. After 24 h cells were repeatedly washed to remove the drugs, and the conditioned mediums were collected at the indicated time points. The nitric oxide (NO) production and levels of eNOS mRNA after 24 h of withdrawal of statins were examined.

Results: (1) Abrupt discontinuation of simvastatin treatment leads to a rebound of serum total cholesterol (21.3%) and LDL cholesterol (18.2%) in patients within 1 week, but they were still lower than the baseline values (P<0.05 for each parameter). (2) A significant decreased of FMD (-59.3%) was observed in patients after discontinuation of simvastatin in 1 week, and furthermore, the FMD was even lower than the baseline levels (4.6% vs. 5.6%, P<0.05). The reduction of FMD was not correlated with the change of LDL cholesterol (r=-0.343, P=0.081). In contrast to the unchanged LDL cholesterol level, abrupt discontinuation of therapy caused a rapid and significant decrease in FMD from 10.6% to 5.2% in healthy subjects at day 1, but it returned to baseline levels within 1 week. (3) In HUVECs, a maximum decrease of nitrite levels (-80%) was observed at 6 h after stopping simvastatin treatment, which was below the control levels. 24 h after stopping 10(-5) mmol/L and 10(-6) mmol/L simvastatin treatment, eNOS mRNA expression decreased to - 71% and - 42% (P<0.05), respectively.

Conclusions: Abrupt withdrawal of simvastatin treatment not only acutely and completely abrogates its beneficial effects on endothelial function in patients with CAD, but also induced further vascular injury compared with pretreatment status, independent of cholesterol levels. The underlying mechanism of these negative effects may be related to the suppression of endothelial NO production, which are dose-dependent. (C) 2008 Published by Elsevier Ireland Ltd.

语种英语
WOS记录号WOS:000262328700004
项目编号NSFC30240036
资助机构National Natural Science Foundation of China
引用统计
被引频次:41[WOS]   [WOS记录]     [WOS相关记录]
文献类型期刊论文
条目标识符http://ir.bjmu.edu.cn/handle/400002259/58168
专题北京大学第三临床医学院_儿科
北京大学第二临床医学院_心血管内科
北京大学第二临床医学院_超声影像科
作者单位1.Natl Nat Sci Fdn China, Beijing, Peoples R China
2.Peking Univ, Peoples Hosp, Dept Cardiol, Beijing 100871, Peoples R China
3.Peking Univ, Peoples Hosp, Dept Ultrasonog, Beijing 100871, Peoples R China
推荐引用方式
GB/T 7714
Chen, Hong,Ren, Jing-Yi,Xing, Yan,et al. Short-term withdrawal of simvastatin induces endothelial dysfunction in patients with coronary artery disease: A dose-response effect dependent on endothelial nitric oxide synthase[J]. INTERNATIONAL JOURNAL OF CARDIOLOGY,2009,131(3):313-320.
APA Chen, Hong.,Ren, Jing-Yi.,Xing, Yan.,Zhang, Wan-Lei.,Liu, Xin.,...&Luo, Yu.(2009).Short-term withdrawal of simvastatin induces endothelial dysfunction in patients with coronary artery disease: A dose-response effect dependent on endothelial nitric oxide synthase.INTERNATIONAL JOURNAL OF CARDIOLOGY,131(3),313-320.
MLA Chen, Hong,et al."Short-term withdrawal of simvastatin induces endothelial dysfunction in patients with coronary artery disease: A dose-response effect dependent on endothelial nitric oxide synthase".INTERNATIONAL JOURNAL OF CARDIOLOGY 131.3(2009):313-320.
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