溶栓前使用他汀类药物对缺血性卒中静脉溶栓疗效的系统评价

目的系统评价缺血性卒中急性期静脉溶栓前使用他汀类药物对患者的疗效和安全性。方法计算机检索Pub Med、EMbase、Web of Science和Cochrane Library等数据库,并辅以手工和其他检索,收集关于静脉溶栓前他汀类药物使用对缺血性卒中急性期静脉溶栓患者的疗效和安全性的研究,检索时间截至2016年4月。由两名研究者按照纳入与排除标准独立筛选文献、提取资料和评价纳入研究的方法学质量后,采用Rev Man 5.3软件进行统计学分析。结果共纳入12个队列研究,包括9 237例患者。他汀类药物使用对缺血性卒中静脉溶栓与近期预后无关(3个月改良Rankin量表评分≤2分:OR=1.05,95%CI:0.93~1.18,P=0.47)或呈负相关(3个月改良Rankin量表评分≤1分:OR=0.82,95%CI:0.73~0.92,P0.01);与症状性颅内出血呈正相关(OR=1.46,95%CI:1.17~1.82,P0.01);与病死率无关(OR=1.16,95%CI:0.79~1.71,P=0.44)。结论溶栓前使用他汀类药物可能导致急性缺血性卒中患者溶栓后出血等不良反应,并且可能导致卒中患者溶栓后3个月预后不良。     

An International Atherosclerosis Society Position Paper: Global recommendations for the management of dyslipidemia-Full report

An international panel of the International Atherosclerosis Society has developed a new set of recommendations for the management of dyslipidemia. The panel identifies non-high-density lipoprotein cholesterol as the major atherogenic lipoprotein. Primary and secondary prevention are considered separately. Optimal levels for atherogenic lipoproteins are derived for the two forms of prevention. For primary prevention, the recommendations emphasize lifestyle therapies to reduce atherogenic lipoproteins; drug therapy is reserved for subjects at greater risk. Risk assessment is based on estimation of lifetime risk according to differences in baseline population risk in different nations or regions. Secondary prevention emphasizes use of cholesterol-lowering drugs to attain optimal levels of atherogenic lipoproteins.     

The effects of systemic treatment with aminobisphosphonates and statins on circulating Vγ9Vδ2-T cells in patients with advanced cancer

Aminobisphosphonates (NBP) are used for treatment of metastatic bone disease. Frequently, patients undergoing NBP-treatment experience side-effects, known as acute phase response (APR), resulting from cytokine production by Vγ9Vδ2-T cells. As opposed to NBP, statins reduce intracellular phosphoantigen levels and prevent NBP-induced Vγ9Vδ2-T cell activation in vitro. We conducted a pilot study in patients with (bone-)metastasized malignancies receiving NBP-treatment and evaluated the phenotype and function of circulating Vγ9Vδ2-T cells in vivo and the effects of statins on Vγ9Vδ2-T cell responses and the associated APR. We observed reduced expression of perforin, granzyme B and HLA-DR on Vγ9Vδ2-T cells in patients treated with NBP and statins. However, statins could not prevent NBP-induced changes in circulating Vγ9Vδ2-T cell numbers or production of IFNγ and TNFα. Consistent with this, simvastatin could not prevent the occurrence of APR upon NBP-infusion. These observations call for the exploration of alternative strategies to prevent collateral APR upon NBP treatment.     

JCL roundtable: Managing lipid disorders in young women

The roundtable discussion in this issue will focus on the problems faced by young women with lipid disorders. This is often the source of confusion for the patient and physician because the myth continues that young women do not have complications of atherosclerosis as a result of elevated blood cholesterol. The essential role of women in bearing children during the early years of adulthood also produces difficult decisions because the mother and fetus are usually experiencing similar exposure to therapeutic regimens. We are joined in this discussion by Drs. Pamela Morris of the Medical University of South Carolina and Robert Wild of the University of Oklahoma Health Sciences Center. Dr Morris is an Internist, and Dr Wild is an Obstetrician and Gynecologist. Both are board certified in clinical lipidology and are actively publishing in this field. We have recorded this roundtable discussion during the National Lipid Association Scientific Sessions held in New Orleans during May 2016.     

Association of blood lipids,atherosclerosis and statin use with dementia and cognitive impairment after stroke: A systematic review and meta-analysis

BackgroundTrial and observational evidence is conflicting in terms of the association of blood lipids, atherosclerosis and statin use with dementia and cognitive impairment in the general population. It is uncertain whether the associations occur in stroke patients, who are at known higher risk of cognitive decline. This systematic review was to synthesize the evidence for these associations among stroke patients.MethodsMEDLINE, EMBASE, the Cochrane Library and trial registries were searched. We included randomized controlled trials (RCTs) or observational cohort studies conducted among patients with stroke and reported on the association of blood lipids, atherosclerosis or statin use with dementia or cognitive impairment. Meta-analysis was conducted separately for crude and maximally adjusted odds ratios (ORs) and hazard ratios (HRs).ResultsOf 18,026 records retrieved, 56 studies (one RCT and 55 cohort studies) comprising 38,423 stroke patients were included. For coronary heart disease, the pooled OR of dementia and cognitive impairment was 1.32 (95%CI 1.10–1.58, n = 15 studies, I² = 0%) and 1.23 (95%CI 0.99–1.54, n = 14, I² = 26.9%), respectively. Peripheral artery disease was associated with dementia (OR 3.59, 95%CI 1.47–8.76, n = 2, I² = 0%) and cognitive impairment (OR 2.70, 95%CI 1.09–6.69, n = 1). For carotid stenosis, the pooled OR of dementia and cognitive impairment was 2.67 (95%CI 0.83–8.62, n = 3, I² = 77.9%) and 3.34 (95%CI 0.79–14.1, n = 4, I² = 96.6%), respectively. For post-stroke statin use, the pooled OR of dementia and cognitive impairment was 0.89 (95%CI 0.65–1.21, n = 1) and 0.56 (95%CI 0.46-0.69, n = 3, I² = 0%), respectively. No association was observed for hypercholesterolemia. These results were mostly consistent with adjusted ORs or HRs, which were reported from limited evidence.ConclusionAtherosclerosis was associated with an increased risk of post-stroke dementia. Post-stroke statin use was associated with decreased risk of cognitive impairment. To confirm whether or not statins confer advantages in the post-stroke population in terms of preventing cognitive decline over and above their known effectiveness in reducing risk of further vascular events, further stroke trials including cognitive assessment and observational analyses adjusted for key confounders, focusing on key subgroups or statin use patterns are required.     

阿托伐他汀通过抑制PKC的激活对抗高糖诱导的人脐静脉内皮细胞氧化应激反应

目的:探讨阿托伐他汀对高糖诱导的人脐静脉血管内皮细胞(HUVECs)产生氧化应激的影响及其作用机制。方法:体外培养HUVECs,以25 mmol/L葡萄糖干预,模拟糖尿病患者体内环境,通过流式细胞术和共聚焦显微镜检测细胞内的活性氧(ROS)水平,采用Lucigenin分析方法测定还原型烟酰胺腺嘌呤二核苷酸磷酸(NADPH)氧化酶活性,分别应用实时荧光定量PCR和免疫印迹杂交的方法检测 NADPH氧化酶亚基Nox4和Nox2/gp91^phox的表达水平,用免疫印迹杂交方法检测蛋白激酶C(PKC)蛋白的磷酸化水平。结果:(1)在高糖环境(终浓度为25 mmol/L)下,HUVECs内ROS生成显著增加,NADPH氧化酶的活性显著增强,NADPH 氧化酶Nox4和Nox2/gp91^phox亚基的mRNA和蛋白表达水平显著上调;(2)阿托伐他汀可显著抑制高糖诱导的ROS 生成、NADPH氧化酶活性的增强及NADPH 氧化酶Nox4和Nox2/gp91^phox亚基表达水平的增加幅度,且具有浓度依赖性;(3)PKC抑制剂(PKC inhibitor peptide, 20 μmol/L)可显著抑制高糖环境下ROS的生成、NADPH氧化酶活性的增强及NADPH 氧化酶Nox4和Nox2/gp91^phox亚基表达水平的增加幅度;(4)阿托伐他汀可抑制高糖诱导的PKC蛋白的磷酸化。结论:PKC的活化参与了高糖诱导的HUVECs产生的氧化应激反应。阿托伐他汀通过抑制PKC蛋白的活化对抗高糖诱导的内皮细胞产生的氧化应激反应。     

An Association of Prior Statin Use with Decreased Perihematomal Edema

Objective  To investigate the impact of statins on perihematomal edema following spontaneous supratentorial intracerebral hemorrhage (ICH). Background  Hematoma expansion and evolution of perihematomal edema are most commonly responsible for neurological deterioration following ICH. A possible role of statins in reducing perihematomal edema has been suggested based on studies in animal models. Methods  Records of consecutive ICH patients admitted to The Johns Hopkins Hospital from 1999 to 2006 were reviewed. Patients with ICH related to trauma or underlying lesions (e.g., brain tumors, aneurysms, and arterio-venous malformations) and of infratentorial location were excluded. Absolute and relative perihematomal edema were assessed on initial head CT. Using regression analysis, the impact of prior statin use on absolute and relative edema at presentation was assessed correcting for other factors possibly impacting perihematomal edema, such as age, coagulopathy, aspirin use, admission mean arterial pressure (MAP), and blood glucose. Results  A total of 125 consecutive ICH patients were studied. Patients with prior statin exposure had a mean edema volume of 13.2 ± 9.2 cc compared to 22.3 ± 18.3 cc in patients who were not using statins at the time of ICH. Following multiple linear regression analysis, we have identified a statistically significant association between prior statin use with reduced early absolute perihematomal edema (P = 0.035). Mean relative perihematomal edema was significantly lower in patients on statins at presentation (0.44) as opposed to 0.81 in patients with no prior statin use. This difference remained statistically significant (P = 0.021) after correcting for other variables. Conclusions  We report the association between statin use prior to ICH and decreased absolute and relative perihematomal edema. A prospective study analyzing the role of statins in perihematomal edema reduction and the resultant effect on mortality and functional outcomes following ICH is warranted.     

Prestroke Statins,Progression of White Matter Hyperintensities,and Cognitive Decline in Stroke Patients with Confluent White Matter Hyperintensities

Cerebral white matter hyperintensities (WMH) are a consequence of cerebral small vessel disease. Statins have been shown to reduce recurrent stroke among patients with various stroke subtypes, including lacunar stroke, which also arises from small vessel disease. In this study, we investigated the hypothesis that prestroke statin use would reduce the progression of WMH and/or cognitive decline among stroke patients with confluent WMH. Patients (n = 100) were participants of the VITAmins To Prevent Stroke magnetic resonance imaging substudy. All patients had confluent WMH on magnetic resonance imaging at baseline. Eighty-one patients completed the 2-year follow-up. We assessed general cognition and executive function using the mini-mental state examination and Mattis dementia rating scale–initiation/perseveration subscale, respectively. We compared the change in volume of WMH and cognition between prestroke statin use and prestroke nonstatin use groups. We also evaluated the effects of prestroke statin use on incident lacunes and microbleeds. The prestroke statin use group (n = 51) had less WMH volume progression (1.54 ± 4.52 cm³vs 5.01 ± 6.00 cm³, p = 0.02) compared with the prestroke nonstatin use group (n = 30). Multivariate linear regression modeling identified prestroke statin use as an independent predictor of WMH progression (β = –0.31, p = 0.008). Prestroke statin use was also associated with less decline (Mattis dementia rating scale–initiation/perseveration subscale; β = 0.47, p = 0.001). No association was observed with changes in mini-mental state examination scores. There were no between group differences on incident lacunes or incident microbleeds. Prestroke statin use may reduce WMH progression and decline in executive function in stroke patients with confluent WMH.

Electronic supplementary material

The online version of this article (doi:10.1007/s13311-014-0270-5) contains supplementary material, which is available to authorized users.     

抗骨质疏松治疗的最佳他汀类药物及剂量选择的动物实验研究

目的探索具有最佳抗骨质疏松作用的他汀药物种类和药物剂量,为进一步研究他汀药物同时发挥抗骨质疏松和调脂作用提供基础。方法 40只12月龄新西兰白兔通过双侧卵巢切除和泼尼松龙诱导8周建立骨质疏松症模型,随机分为四组:生理盐水(normal saline,NS)组,瑞舒伐他汀(rosuvastatin,RSV)组,辛伐他汀(simvastatin,Sim)组,阿仑膦酸钠片(Alendronate,ALN)组。RSV组和Sim组按药物浓度梯度分为五个小组。定期测量白兔股骨骨密度(bone mineral desity,BMD)和骨钙素(bone gamma-carboxyglutamic-acid-containing proteins,BGP)、抗酒石酸酸性磷酸酶5b(tartrateresistant acid phosphatase 5b,TRACP-5b)值。结果8周末BMD较0周时明显降低(P<0.05)。12、24和36周末,RSV组、Sim组和ALN组比NS组BMD、BGP水平明显升高,TRACP-5b水平显著降低(P<0.01),并且RSV组与ALN组指标接近(P>0.05)。RSV组内中以60 mg/(kg·d)喂养时,BMD、BGP较其他组明显升高。结论他汀类药物具有抗骨质疏松的作用,效果接近唑来膦酸;亲水性瑞舒伐他汀比疏水性他汀药物作用更佳;并且剂量在60 mg/(kg·d)时效果更好。