强化调脂治疗及其安全性问题

血脂水平异常是心脑血管疾病的主要危险因素,也是临床医师尤其是心脑血管疾病专业医师需要特别关注的问题.2007年,我国公布了<中国成人血脂异常防治指南>[1],对提高我国血脂水平异常的防治、降低心脑血管疾病的发生率具有十分重要的临床意义.     

SPARCL研究是强化调脂治疗的循证基石

冠心病和脑卒中的共同病理学基础是脂质代谢异常和动脉粥样硬化,后者在心脑血管疾病的发病机制中起着极为关键的作用.以他汀类药物为代表的调脂治疗已经成为心脑血管疾病的临床常规治疗方法,且其应用于心脏科远早于神经科.一些关于冠心病一级和二级预防的大型临床试验结果表明,他汀类药物在减少心肌梗死发生率的同时,也使缺血性卒中的发生率显著降低.     

他汀类调脂药神经肌肉系统不良反应

正他汀类调脂药是目前应用最广泛的调脂药物,通过抑制内源性胆固醇合成过程中的3-羟基-3-甲基戊二酰辅酶A还原酶(HMGCR)而发挥药理学作用。他汀类调脂药可以减少心脑血管疾病的风险,目前全球每年约30×106例患者服用他汀类调脂药,其中约10%因神经肌肉系统不良反应而停药~([1])。本文拟对他汀类调脂药的神经肌肉系统不良反应,如肌肉毒性、神经毒性、重症肌无力(MG)等进行简要概述。     

积极调脂有效防治缺血性心脑血管病

为了更为恰当地反映血脂水平异常对国人的潜在危害,国内学者提出:采用缺血性心脑血管病发病危险反映血脂水平异常及其他心脑血管疾病主要危险因素的综合性致病危险[1].与仅应用冠心病发病危险相比,这一指标使得血清胆固醇水平升高对国人心脑血管疾病发病的绝对危险约上升至原来的3～5倍,从而更恰当地反映了血脂水平异常对国人的潜在危害[2].     

他汀类药物在心脑血管疾病防治中的临床循证医学证据

据流行病学资料显示,血清总胆固醇(TC)水平升高与动脉粥样硬化性心脑血管事件显著相关,随着血清总胆固醇水平的升高,心脑血管事件的发生率和死亡率也逐渐升高,降低总胆固醇水平可以显著改善患者的长期预后,尤其是危险分层越高的患者,其调脂治疗获益越明显,调脂幅度与心脑血管事件风险的降低程度呈显著正相关.     

血脂水平正常的颈动脉粥样硬化患者是否应进行调脂治疗?

大动脉内膜中层厚度(IMT)异常反映了脂质在血管内皮的聚集和动脉粥样硬化斑块的形成,提示血管内皮、内皮下结缔组织和血管平滑肌功能异常.颈动脉内膜中层厚度增加已被公认为是早期动脉粥样硬化的标志[1],常见于有高血压、糖尿病、肥胖、吸烟等心脑血管性危险因素患者及心脑血管疾病患者.众多临床研究表明,中老年人颈动脉内膜中层厚度增加与心肌梗死和脑卒中明显相关[2,3];脑卒中患者常合并颈动脉粥样硬化斑块形成[4].临床研究业已证实,他汀类药物在降低血清低密度脂蛋白-胆固醇(LDL-C)水平的同时,可以延缓甚至逆转颈动脉粥样硬化斑块的进展[5],具有显著的预防心肌梗死和脑卒中的作用.     

他汀类药物对内皮祖细胞的相关作用

背景：他汀类药物作为临床上广泛应用的降脂类药物,其不同剂量与疗程对于内皮祖细胞有着不同的近期及远期作用。 目的：综述国内外他汀类药物对内皮祖细胞作用的现状和进展。 方法：应用计算机检索CNKI和Pubmed数据库中1995-01/2009-11关于内皮祖细胞和他汀类药物的文章,在标题中以“内皮祖细胞,他汀类药物”或“endothelial progenitor cells,statins”为检索词进行检索。选择文章内容与内皮祖细胞及他汀类药物有关者,同一领域文献则选择近期发表或发表在权威杂志文章。初检得到843篇文献,根据纳入标准选择关于内皮祖细胞及他汀类药物的19篇文献进行综述。 结果与结论：他汀类药物对于内皮祖细胞有多重的作用。在短期治疗和低剂量的情况下,对心血管疾病有保护作用,增强内皮祖细胞各方面功能;在长期、大剂量应用他汀类药物后,造成其数量减少,抑制了血管生成,这对于抑制肿瘤血管发生有一定的研究价值。     

动态观察他汀类药物对脑梗死患者颈动脉内膜-中层厚度的影响

目的 评价他汀类药物对脑梗死患者颈动脉内膜-中层厚度(IMT)的影响.方法 选择186例脑梗死患者,采用彩色多普勒对颈动脉IMT进行测定,依据是否服用他汀类药物分为服药组和非服药组,12个月后再次进行检测.结果 服药组脑梗死患者12个月后颈动脉IMT较服药前明显减少,比较差异有统计学意义(P<0.01).非服药组脑梗死患者12个月后颈动脉IMT较发病时差异无统计学意义(P>0.05).结论 长期服用他汀类药物有改善脑梗死患者颈动脉粥样硬化的作用,可作为治疗急性脑梗死患者的联合药物.     

缺血性卒中急性期他汀类药物治疗对血清超敏C-反应蛋白影响及预后评价

对他汀类药物治疗组(他汀治疗组)或非他汀类药物治疗组(对照组)患者入院时和发病30 d时临床资料进行分析,并比较两组血清超敏C-反应蛋白水平的变化。结果显示,他汀治疗组患者发病30 d时血清超敏C-反应蛋白低于对照组(t=9.925,P=0.015),发病后3个月预后优于对照组(χ2=4.762,P=0.029);经逐步Logistic回归分析,入院时美国国立卫生研究院卒中量表评分(OR=1.383,95%CI:1.062~1.800;P=0.028)和发病48 h血清超敏C-反应蛋白水平(OR=1.472,95%CI:0.500~4.370;P=0.001)对患者发病3个月时的预后具有独立预测作用。提示他汀类药物可以降低急性缺血性卒中患者血清超敏C-反应蛋白水平,对发病3个月时的预后具有预测作用。     

匹伐他汀与阿托伐他汀对缺血性卒中患者疗效及安全性的对比研究

目的评价匹伐他汀与阿托伐他汀对缺血性脑卒中(IS)患者血脂调控的疗效,对比其改善IS患者颈动脉粥样硬化效力的差异。方法 2012年3月至2013年2月在北京大学人民医院选择急性脑梗死患者70例随机分为2组,匹伐他汀组40例,接受匹伐他汀治疗,每晚2 mg,其中前循环梗死23例,后循环梗死14例,分水岭梗死3例;阿托伐他汀组30例,接受阿托伐他汀治疗,每晚10 mg,其中前循环梗死16例,后循环梗死14例。从入组开始治疗共6个月。分别于治疗前、治疗后2周、1个月、3个月及6个月末随访,记录疗效观察指标(血脂水平、双侧颈动脉内中膜厚度),安全性观察指标(血、尿常规,肝肾功能,空腹血糖,肌酸激酶,心电图),神经功能观察指标(NIHSS和m RS评分)。采用SPSS 19.0统计软件进行检验,P<0.05为差异有统计学意义。结果治疗6个月后,匹伐他汀组LDL-C显著下降(t=4.01,P<0.01),下降幅度为18.5%,阿托伐他汀组下降幅度为21.0%(t=4.56,P<0.01),两组间无显著差异(t=1.92,P=0.059)。匹伐他汀组右颈总动脉内膜中层厚度(IMT)有所减少(t=1.92,P=0.063),并且软斑数量有所减少(χ2=0.33,P=0.85),但与治疗前比较,差异均无统计学意义(P<0.05)。两组患者心电图、尿蛋白、空腹血糖、血肌酸激酶、丙氨酸转氨酶、转肽酶以及肌酐水平治疗前后均无显著变化(P<0.05)。结论匹伐他汀降低LDL-C的作用和治疗颈动脉粥样硬化的远期作用可能与阿托伐他汀相当,不良反应较轻微,可用于IS患者高胆固醇血症和动脉粥样硬化的治疗。     

Effects of statins on microglia

High serum cholesterol level has been shown as one of the risk factors for Alzheimer's disease (AD), and epidemiological studies indicate that treatment with cholesterol-lowering substances, statins, may provide protection against AD. An acute-phase reaction and inflammation, with increased levels of proinflammatory cytokines, are well known in the AD brain. Notably, there is evidence for antiinflammatory activities of statins, such as reduction in proinflammatory cytokines. Consequently, it is of interest to analyze the effects of statins on microglia, the main source of inflammatory factors in the brain, such as in AD. The aims of this study were to determine the effects of statins (atorvastatin and simvastatin) on microglial cells with regard to the secretion of the inflammatory cytokine interleukin-6 (IL-6) and cell viability after activation of the cells with bacterial lipopolysaccharides (LPS) or beta-amyloid1-40 (Abeta1-40) and in unstimulated cells. Cells of the human microglial cell line CHME-3 and primary cultures of rat neonatal cortical microglia were used. Incubation with LPS or Abeta1-40 induced secretion of IL-6, and Abeta1-40, but not LPS, reduced cell viability. Both atorvastatin and simvastatin reduced the basal secretion of IL-6 and the cell viability of the microglia, but only atorvastatin reduced LPS- and Abeta1-40-induced IL-6 secretion. Both statins potentiated the Abeta1-40-induced reduction in cell viability. The data indicate the importance of also considering the microglial responses to statins in evaluation of their effects in AD and other neurodegenerative disorders with an inflammatory component.     

Meta-analysis of the cardiovascular benefits of intensive lipid lowering with statins

Chan DKY, O’Rourke F, Shen Q, Mak JCS, Hung WT. Meta‐analysis of the cardiovascular benefits of intensive lipid lowering with statins.
Acta Neurol Scand: 2011: 124: 188–195.
© 2010 John Wiley & Sons A/S. Objective – To evaluate the efficacy of intensive lipid lowering with higher‐dose statins. Methods – Meta‐analysis of seven randomized controlled trials comprising 50,972 participants. Results – Mean follow‐up was 3.1 years with mean age 63 years. Final LDL‐C levels in intensive lipid‐lowering group were 1.42–2.07 mmol/l compared to 2.1–3.5 mmol/l in the less intensive or control group. The intensive arm had significantly lower risks for stroke OR 0.80 (95% CI 0.71–0.89); major coronary events OR 0.74 (95% CI 0.65–0.83); cardiovascular disease (CVD) or coronary heart disease (CHD) deaths OR 0.84 (95% CI 0.74–0.95). Significantly higher liver enzyme abnormalities occurred in intensive group* (OR 3.96; 95% CI 2.08–7.53), but it was not associated with drug discontinuations (OR 1.20; 95% CI 0.88–1.64). Conclusion – In those at high risk of cardiovascular events, intensive lipid lowering with statins to LDL‐C level <2.1 mmol/l significantly reduces risk of stroke, major coronary events and CVD or CHD deaths compared to LDL‐C level ≥2.1 mmol/l. [*Correction added on 11 January 2011 after first online publication on 27 October 2010. The phrase, “Significantly higher liver enzyme abnormalities occurred in less intensive group”, was amended to “Significantly higher liver enzyme abnormalities occurred in intensive group”.]     

The risk of dementia in relation to statins and other lipid lowering agents

Recent epidemiological reports suggest that statins, and possibly other lipid lowering agents, might be protective for Alzheimer disease, and for other types of dementia. Importantly, however, epidemiological reports of this type are susceptible to indication bias, i.e. people who elect to take lipid-lowering agents might be healthier than those who do not, so that it may be these other health factors which explain their lower risk of dementia. Limited clinical trials data support the notion that statins, in particular, have important effects on cerebral cholesterol metabolism, but the link to clinical effects in dementia has yet to be established, and the mechanisms by which lipid lowering agents might confer protective effects is unclear. Dedicated clinical trials are now under way, and their results are awaited with great interest.     

Metabotropic glutamate receptors: beyond the regulation of synaptic transmission

Metabotropic glutamate (mGlu) receptors are G-protein coupled receptors activated by glutamate, the major excitatory neurotransmitter of the CNS. A growing body of evidence suggests that the function of mGlu receptors is not restricted to the regulation of synaptic transmission. mGlu receptors are expressed in a variety of peripheral cells, including inter alia hepatocytes, pancreatic cells, osteoblasts and immune cells. Within the immunological synapses, mGlu receptors expressed by T cells might contribute to the vast array of signals generated by the antigen-presenting cells. mGlu receptors are also found in embryonic and neural stem cells. This suggests their involvement in the pathophysiology of brain tumors, which likely originates from cancer stem cells similar to neural stem cells. Ligands of mGlu3 and mGlu4 receptors are potential candidates for the experimental treatment of malignant gliomas and medulloblastomas, respectively.     

Effects of statins on the progression of cerebral white matter lesion

Arteriosclerotic related cerebral white matter lesion (WML) is associated with increased risk of death, stroke, dementia, depression, gait disturbance, and urinary incontinence. We investigated the effects of statins on WML progression by performing a post hoc analysis on the ROCAS (Regression of Cerebral Artery Stenosis) study, which is a randomized, double-blind, placebo-controlled study evaluating the effects of statins upon asymptomatic middle cerebral artery stenosis progression among stroke-free individuals. Two hundreds and eight randomized subjects were assigned to either placebo (n = 102) or simvastatin 20 mg daily (n = 106) for 2 years. Baseline severity of WML was graded visually into none, mild, and severe. Volume (cm³) of WML was determined quantitatively at baseline and at end of study using a semi-automated method based on MRI. Primary outcome was the change in WML volume over 2 years. After 2 years of follow-up, there was no significant change in WML volume between the active and the placebo group as a whole. However, stratified analysis showed that for those with severe WML at baseline, the median volume increase in the active group (1.9 cm³) was less compared with that in the placebo group (3.0 cm³; P = 0.047). Linear multivariate regression analysis identified that baseline WML volume (β = 0.63, P < 0.001) and simvastatin treatment (β = −0.214, P = 0.043) independently predicted change in WML volume. Our findings suggest that statins may delay the progression of cerebral WML only among those who already have severe WML at baseline.     

Dendritic cells in atherosclerosis: functions in immune regulation and beyond

Chronic inflammation drives the development of atherosclerosis. Dendritic cells (DCs) are known as central mediators of adaptive immune responses and the development of immunological memory and tolerance. DCs are present in non-diseased arteries, and accumulate within atherosclerotic lesions where they can be localised in close vicinity to T cells. Recent work has revealed important functions of DCs in regulating immune mechanisms in atherogenesis, and vaccination strategies using DCs have been explored for treatment of disease. However, in line with a phenotypical and functional overlap with plaque macrophages vascular DCs were also identified to engulf lipids, thus contributing to lipid burden in the vessel wall and initiation of lesion growth. Furthermore, a function of DCs in regulating cholesterol homeostasis has been revealed. Finally, phenotypically distinct plasmacytoid dendritic cells (pDCs) have been identified within atherosclerotic lesions. This review will dissect the multifaceted contribution of DCs and pDCs to the initiation and progression of atherosclerosis and the experimental approaches utilising DCs in therapeutic vaccination strategies.     

An examination of the incremental contribution of emotion regulation difficulties to health anxiety beyond specific emotion regulation strategies

Given the potential transdiagnostic importance of emotion dysregulation, as well as a lack of research examining emotion dysregulation in relation to health anxiety, the present study sought to examine associations among specific emotion regulation strategies (cognitive reappraisal and expressive suppression), emotion regulation difficulties, and health anxiety in a physically healthy sample of adults (N = 482). As hypothesized, results of a series of hierarchical multiple regression analyses showed that emotion regulation difficulties provided a significant incremental contribution, beyond the specific emotion regulation strategies, in predicting each of the three health anxiety variables. Among the six dimensions of emotion regulation difficulties, the dimension representing perceived access to effective emotion regulation strategies was the only emotion regulation difficulty dimension that predicted all three health anxiety variables beyond the effects of the specific emotion regulation strategies. Results indicate that emotion regulation difficulties, and particularly one's subjective appraisal of his/her ability to effectively regulate emotions, may be of importance to health anxiety. Clinical implications are discussed.