Chen Hong, Ren Jing-Yi, Xing Yan, Zhang Wan-Lei, Liu Xin, Wu Pei, Wang Ruo-Jie, Luo Yu
Department of Cardiology, Peking University People's Hospital, Beijing, China.
Int J Cardiol. 2009 Jan 24;131(3):313-20. doi: 10.1016/j.ijcard.2007.10.044. Epub 2008 Jan 24.
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.
This study investigated the effects after withdrawal of simvastatin on brachial artery endothelial function in patients with CAD and the underlying mechanisms.
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.
(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.
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.
冠心病（CAD）患者存在内皮功能受损。已证实辛伐他汀治疗可显著改善这些患者的内皮功能。尽管在临床实践中停用他汀类药物是一个常见问题，但CAD患者停用他汀类药物治疗后对内皮功能的影响在很大程度上尚不清楚。
本研究调查了停用辛伐他汀后对CAD患者肱动脉内皮功能的影响及其潜在机制。
我们招募了30例确诊为CAD的患者。他们接受20mg辛伐他汀治疗4周。在基线、辛伐他汀治疗4周期间以及治疗终止后1周，使用高分辨率超声评估肱动脉的内皮依赖性血流介导的血管舒张（FMD）。还研究了20名健康受试者作为对照组。此外，我们在第2 - 3代人脐静脉内皮细胞（HUVECs）融合单层上研究了潜在机制。将HUVECs暴露于辛伐他汀。24小时后，反复冲洗细胞以去除药物，并在指定时间点收集条件培养基。检查停用他汀类药物24小时后的一氧化氮（NO）产生和eNOS mRNA水平。
（1）辛伐他汀治疗突然中断导致患者在1周内血清总胆固醇（21.3%）和低密度脂蛋白胆固醇（18.2%）反弹，但仍低于基线值（每个参数P<0.05）。（2）停用辛伐他汀1周后，患者的FMD显著降低（-59.3%），此外，FMD甚至低于基线水平（4.6%对5.6%，P<0.05）。FMD的降低与低密度脂蛋白胆固醇的变化无关（r = -0.343，P = 0.081）。与低密度脂蛋白胆固醇水平不变相反，治疗突然中断导致健康受试者在第1天FMD从10.6%迅速显著下降至5.2%，但在1周内恢复到基线水平。（3）在HUVECs中，停用辛伐他汀治疗后6小时观察到亚硝酸盐水平最大降低（-80%），低于对照水平。停用10(-5)mmol/L和10(-6)mmol/L辛伐他汀治疗24小时后，eNOS mRNA表达分别降至-71%和-42%（P<0.05）。
突然停用辛伐他汀治疗不仅急性且完全消除了其对CAD患者内皮功能的有益作用，而且与治疗前状态相比还导致了进一步的血管损伤，与胆固醇水平无关。这些负面影响的潜在机制可能与内皮NO产生的抑制有关，且呈剂量依赖性。
