Hypolipemic agents for stroke prevention

An important issue for stroke prevention is identification and treatment of risk factors such as hypercholesterolemia. The four reasons to test hypolipidemic agents in stroke prevention are: (i) a statistical link between elevated low-density lipoprotein cholesterol (LDL-c) or decreased high-density lipoprotein cholesterol (HDL-c) and ischemic stroke; (ii) a reduction in vascular risk in randomized trials in patients with coronary heart disease; (iii) evidence of a decreased plaque progression under statins, (iv) pooled analyses of primary and secondary prevention trials showing that reduction of total serum cholesterol reduces the incidence of stroke, especially with the highest rate of cholesterol reduction, and in patients with the highest risk of stroke (i.e., with statins in secondary prevention trials), and (v) prophylactic neuroprotection induced by hypolipidemic agents in animal models of cerebral ischemia. Data provided by trials conducted in subjects with coronary heart disease and in asymptomatic individuals should now be confirmed in stroke patient.     

HYPOLIPEMIC AGENTS FOR STROKE PREVENTION

An important issue for stroke prevention is identification and treatment of risk factors such as hypercholesterolemia. The four reasons to test hypolipidemic agents in stroke prevention are: (i) a statistical link between elevated low-density lipoprotein cholesterol (LDL-c) or decreased high-density lipoprotein cholesterol (HDL-c) and ischemic stroke; (ii) a reduction in vascular risk in randomized trials in patients with coronary heart disease; (iii) evidence of a decreased plaque progression under statins, (iv) pooled analyses of primary and secondary prevention trials showing that reduction of total serum cholesterol reduces the incidence of stroke, especially with the highest rate of cholesterol reduction, and in patients with the highest risk of stroke (i.e., with statins in secondary prevention trials), and (v) prophylactic neuroprotection induced by hypolipidemic agents in animal models of cerebral ischemia. Data provided by trials conducted in subjects with coronary heart disease and in asymptomatic individuals should now be confirmed in stroke patient.     

Statins for stroke prevention

Unlike coronary heart disease, epidemiologic studies find a weak and inconsistent relationship between cholesterol levels and overall stroke risk. There does, however, appear to be a positive relationship between total and low-density lipoprotein cholesterol levels and the risk of ischemic stroke, with an inverse relationship between cholesterol levels and hemorrhagic stroke. Treatment with statins is associated with the reduction in the risk of a first stroke in various populations of patients at increased risk of cardiovascular events. Treatment of patients with prior cerebrovascular disease is associated with a reduction in major cardiovascular events and, in a single study, with a reduction in fatal and nonfatal stroke in patients with prior stroke or transient ischemic attack and no known coronary heart disease. Whether the benefit of statins in reducing the risk of stroke is due to their potent lipid-lowering effects, pleiotropic effects, or a combination of the two cannot be determined based on data available from clinical trials.     

Statins and ischemic stroke

The 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors or statins are potent inhibitors of cholesterol synthesis. Several large clinical trials have demonstrated that these agents reduce serum cholesterol levels and the incidence of cardiovascular diseases. However, overlap and meta-analyses of these clinical trials suggest that the beneficial effects of statins may extend beyond their effects on serum cholesterol levels. Because statins also inhibit the synthesis of isoprenoid intermediates in the cholesterol biosynthetic pathway, they may have pleiotropic effects on the vascular wall. In particular, the ability of statins to decrease the incidence of ischemic stroke highlights some of their non-cholesterol effects since serum cholesterol levels are poorly correlated with the risk for ischemic stroke.     

Statin therapy to prevent stroke in the elderly

The incidence of stroke increases with advanced age, and improved strategies for preventing both first and second stroke in the elderly are needed. Recent trials prove that low-density lipoprotein reduction by statins in high-risk patients, including the elderly, reduces the risk of ischemic stroke. Patients with any history of cerebrovascular disease who are treated with statins have a reduced risk of coronary ischemic events and of all major vascular ischemic events, independent of patient age. Patients with recent transient ischemic attack or ischemic stroke show significantly reduced risks of both recurrent stroke and coronary events when they are treated with high-dose statin therapy. The vast majority of patients with ischemic cerebrovascular disease, most of whom are elderly, should be placed on statin drugs. However, the majority of stroke patients are not currently treated to recommended levels, and the elderly are particularly undertreated. No valid reasons exist for avoiding statins in elderly patients at risk for stroke.     

Hypercholesterolemia. The evidence supports use of statins

Using statins to treat older men and women with coronary artery disease (CAD) and hypercholesterolemia reduces the risk of all-cause mortality, cardiovascular mortality, coronary events, coronary revascularization, stroke, Intermittent claudication, and congestive heart failure. The target serum low-density lipoprotein (LDL) cholesterol level is < 100 mg in older patients with CAD, prior stroke, peripheral arterial disease, extracranial carotid arterial disease, abdominal aortic aneurysm, diabetes meilitus, and the metabolic syndrome. Statins are also effective in reducing cardiovascular events in older persons with hypercholesterolemia without cardiovascular disease. Consider using statins in older persons without cardiovascular disease but with a serum LDL cholesterol > or = 130 mg/dL, or a serum high-density lipoprotein cholesterol < 50 mg/dL. Data from the Heart Protection Study favor treating patients at high risk for vascular events with statins regardless of age or initial serum lipids.     

Statins and stroke prevention

Data from studies on the benefits of statins in coronary artery disease patients in preventing recurrent primary and secondary cardiac endpoints, as well as ischemic strokes, imply the potential value of statins in recurrent ischemic stroke prevention without coronary artery disease symptoms or, by extension, primary ischemic stroke prevention. However, data on the latter are lacking, although the ongoing Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) study is designed to answer that question. Until these data become available, clinicians are justified in using statins to avert recurrent ischemic strokes due to atherosclerosis, especially if elevated total cholesterol, increased low-density lipoprotein cholesterol, and/or reduced high-density lipoprotein cholesterol, as specified in the National Cholesterol Education Program Third Adult Treatment Panel, are present. This article reviews the pathophysiology of atherosclerosis, particularly the major components of atheromas of cholesterol, smooth muscle cells, inflammation, “foam cells,” and connective tissue elements. Emphasis is placed on the first three and the results of statin trials in coronary artery disease, as well as the beneficial pleiotrophic effects of statins in ischemic strokes.     

The effects of statins on high-density lipoproteins

Statins inhibit cholesterol synthesis and are effective in lowering total cholesterol levels in plasma or serum due to reductions in low-density lipoprotein and very low-density lipoproteins, as well as reducing progression of coronary atherosclerosis, coronary heart disease, and stroke morbidity and mortality. These agents also modestly raise levels of high-density lipoprotein (HDL) cholesterol and its major protein, apolipoprotein (apo) A-I. The more effective statins can also raise the levels of large α-I HDL particles as assessed by two-dimensional gel electrophoresis. High levels of these particles promote reverse cholesterol transport and protect against coronary heart disease and progression of coronary atherosclerosis. The mechanism whereby statins alter HDL and its subspecies appears to be due to reduction of triglyceride-rich lipoproteins, with a secondary decrease in cholesteryl ester transfer protein activity, and less transfer of HDL cholesterol to triglyceride-rich lipoprotein acceptor particles. Increasingly, statins will be combined with other agents such as ezetimibe, fibrates, niacin, and cholesteryl ester transfer protein inhibitors to optimize the entire lipoprotein profile to alter not only low-density lipoprotein, but also HDL, triglycerides, lipoprotein(a), and C-reactive protein, and also to reduce cardiovascular morbidity and mortality.     

Cholesterol, stroke risk, and stroke prevention

Serum cholesterol traditionally has been considered a poor predictor of total stroke risk; however, it is associated positively with ischemic stroke risk and associated negatively with hemorrhagic stroke risk. Although studies failed to demonstrate stroke reduction using older cholesterol-lowering medications, recent study of the statin class of medications shows both consistent stroke and other cardiovascular benefits. Ischemic stroke and coronary heart disease share similar underlying mechanisms, likely explaining much of the therapeutic benefit from statins. Current research is directed at further determining groups of patients most likely to benefit from lipid reduction in stroke prevention. In the interim, patients with established atherosclerosis should be treated with a statin to achieve a low-density lipoprotein cholesterol level less than 100 mg/dL.     

血清超敏C反应蛋白水平与急性脑梗死的相关性分析

目的探讨血清超敏C反应蛋白（hs-CRP）水平与急性脑梗死的相关性。方法100例72小时内的急性脑梗死病人分为A组（分脑血栓形成、脑栓塞、腔隙性脑梗死三个亚组），80例健康对照组为B组，分别测入院当天、1月后的hs-CRP水平，进行神经功能缺损评分（NIHSS）并两者比较，测A组病人入院当天的血糖、血脂、血压、D-二聚体水平，计算梗塞面积，并与hs-CRP水平进行相关性分析。结果（1）急性期脑梗死组的hs-CRP水平高于对照组（P〈0.0001）；急性期三亚组之间差异也有统计学意义（P〈0.0001），其中脑栓塞组hs-CRP水平最高，1月后仅栓寒组与腔梗组hs-CRP水平之间的差异具有统计学意义（P=0.028）；（2）脑梗死急性期hs-CRP水平与急性期NIHSS评分、梗塞面积、血糖、甘油三脂、低密度脂蛋白、D-二聚体、收缩压水平呈正相关，与高密度脂蛋白水平、1月后NIHSS评分下降百分比呈负相关（P〈0.0001）。其中NIHSS评分、D-二聚体、血糖三项可进入回归方程。结论麻清hs-CRP水平与急性脑梗死的发生、发展相关，与血糖、甘油三脂、高密度脂蛋白、低密度脂蛋白、收缩压等血管性危险因子及D-二聚体密切相关。     

血清非高密度脂蛋白胆固醇对缺血性脑卒中患者急性期神经功能损害的影响

目的探讨血清非高密度脂蛋白胆固醇(non-HDLC)对缺血性脑卒中急性期神经功能损害的影响及其在风险评估中的临床价值。方法选择符合入组条件的急性缺血性卒中患者共611例,应用美国国立卫生研究院卒中量表(NIHSS)、中国脑卒中患者临床神经功能缺损程度评分量表(1995)(CSS)、欧洲版神经功能缺损评分(ESS)以及日常生活能力评定量表Barthel指数(BI)评价神经功能。同时测定空腹血糖、糖化血红蛋白(HbA1c)、血清高敏C反应蛋白(hs-CRP)、同型半胱氨酸(Hcy)、总胆固醇(TC)、甘油三酯(TG)、高密度脂蛋白胆固醇(HDLC)和低密度脂蛋白胆固醇(LDLC)等生化指标,并计算出non-HDLC的含量,比较non-HDLC高水平组与理想水平组患者NIHSS、CSS、ESS、BI分值,以探讨高non-HDLC水平与急性缺血性卒中神经功能损害的关系。结果与non-HDLC理想水平组患者相比,高non-HDLC水平组患者体质指数高、NIHSS、CSS评分高(P0.05),ESS和BI分值低(P0.05)。血清TC、TG、LDLC、Hcy、空腹血糖和HbA1c水平高,HDLC水平低(P0.05)。相关分析发现,随着non-HDLC水平升高,急性缺血性卒中神经功能损害的危险性明显增加。结论 Non-HDLC水平增高是缺血性脑卒中患者急性期神经功能损害的危险因素,可作为缺血性脑卒中神经功能损害危险评估的有效靶点。     

The evolving role of statins in the management of atherosclerosis

Significant advances in the management of cardiovascular disease have been made possible by the development of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors--"statins." Initial studies explored the impact of statin therapy on coronary artery disease (CAD) progression and regression. Although the angiographic changes were small, associated clinical responses appeared significant. Subsequent large prospective placebo-controlled clinical trials with statins demonstrated benefit in the secondary and primary prevention of CAD in subjects with elevated cholesterol levels. More recently, the efficacy of statins has been extended to the primary prevention of CAD in subjects with average cholesterol levels. Recent studies also suggest that statins have benefits beyond the coronary vascular bed and are capable of reducing ischemic stroke risk by approximately one-third in patients with evidence of vascular disease. In addition to lowering low-density lipoprotein (LDL) cholesterol, statin therapy appears to exhibit pleiotropic effects on many components of atherosclerosis including plaque thrombogenicity, cellular migration, endothelial function and thrombotic tendency. Growing clinical and experimental evidence indicates that the beneficial actions of statins occur rapidly and yield potentially clinically important anti-ischemic effects as early as one month after commencement of therapy. Future investigations are warranted to determine threshold LDL values in primary prevention studies, and to elucidate effects of statins other than LDL lowering. Finally, given the rapid and protean effects of statins on determinants of platelet reactivity, coagulation, and endothelial function, further research may establish a role for statin therapy in acute coronary syndromes.     

HDL-C and LDL-C: Their role in stroke pathogenesis and implications for treatment

Elevated serum low-density lipoprotein cholesterol (LDL-C) and low serum high-density lipoprotein cholesterol (HDL-C) are risk factors for atherosclerotic ischemic stroke. The National Cholesterol Education Panel and the American Heart Association have released guidelines for the treatment of dyslipidemia that stress LDL-C reduction using HMG CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase inhibitors (statins) and are applicable to individuals who have had or are at a high risk of having a stroke. Treatment of low HDL-C is a secondary goal of these guidelines and can be best achieved by using extended-release niacin (alone or in combination with statins) and fibrates. Early and aggressive treatment of dyslipidemia is an important component of a multimodality approach to stroke prevention.     

Progress in HDL-Based Therapies for Atherosclerosis

Atherosclerosis is a chronic inflammatory disease affecting medium and large arteries resulting from a complex interaction between genetic and environmental risk factors that include dyslipidemia, hypertension, diabetes mellitus, and smoking. The most serious manifestations of atherosclerotic vascular disease, such as unstable angina, myocardial infarction, ischemic stroke, and sudden death, largely result from thrombosis superimposed on a disrupted (ruptured or eroded) atherosclerotic plaque. Adoption and maintenance of a healthy lifestyle coupled with management of modifiable risk factors significantly reduce the adverse clinical consequences of athero-thrombosis. Reducing low-density lipoprotein cholesterol levels using statins and other agents serves as the primary pharmacologic approach to stabilize atherosclerotic vascular disease. However, a large residual risk remains, prompting the search for additional therapies for atherosclerosis management, such as raising atheroprotective high-density lipoprotein (HDL) and/or improving HDL function. This review focuses on new and emerging HDL-based therapeutic strategies targeting atherosclerosis.     

他汀类与非酒精性脂肪肝病患者的卒中预防

非酒精性脂肪肝病(non-alcoholic fatty liver disease,NAFLD)是慢性肝病中的一个重要类型,其发病率日益增高,是代谢综合征的肝脏表现,与心脑血管病的发生关系密切.对NAFLD患者的卒中预防十分重要.他汀类药物是最重要的一类降胆固醇药物,通过抑制羟甲基戊二酰辅酶A(hydroxy-methyl-glutaryl coenzyme A HMG-CoA)还原酶,减少胆固醇合成,上调肝脏低密度脂蛋白(low-density lipoprotein,LDL)受体,降低循环低密度脂蛋白胆固醇(low-density lipoprotein cholesterol,LDL-C)水平,有效降低卒中风险.此外,他汀类的多效性以及对胆同醇相关细胞信号通路的影响,能减缓或防止NAFLD的进展.由于他汀类药物对肝脏有一定的不良作用,是否能应用于慢性肝病患者存在较大争议.现有证据显示,他汀类药物可在NAFLD患者中安全使用,通常无需监测肝酶,过分关注他汀类药物的肝毒性反而可能采取不恰当的停药,导致心血管事件风险的增高.为此,他汀类对NAFLD患者的有效性及安全性尚需进一步评估.     

Cholesterol 2001. Rationale for lipid-lowering in older patients with or without CAD

Statin treatment of men and women age > or = 50 with coronary artery disease (CAD) and hypercholesterolemia reduces the risk of all-cause mortality, cardiovascular mortality, coronary events, coronary revascularization, stroke, and intermittent claudication. The target serum low-density lipoprotein (LDL) cholesterol level is < 100 mg/dL in older patients with CAD, prior stroke, peripheral arterial disease, or extracranial carotid arterial disease and serum LDL cholesterol > 125 mg/dL despite diet therapy. Statins are also effective in reducing cardiovascular events in older persons with hypercholesterolemia but without cardiovascular disease. Consider using statins in patients age 50 to 80 without cardiovascular disease, serum LDL cholesterol > 130 mg/dL, and serum high-density lipoprotein (HDL) cholesterol < 50 mg/dL.     

Sekundärprophylaxe des Schlaganfalls aus neurologischer Perspektive

Patients who have suffered ischemic stroke or transient ischemic attack (TIA) are at high risk of recurrent stroke, myocardial infarction or vascular death. Early pathophysiological based diagnostics and resulting secondary prevention are critical for reduction of stroke risk. Optimization of lifestyle factors, treatment of hypertension, cholesterol reduction with statins and use of antiplatelet agents in non-cardiogenic or anticoagulation in cardiogenic ischemia as well as internal carotid revascularization, in cases of more than 50% diameter stenosis of the internal carotid artery, are proven strategies for reduction of ischemic stroke risk.     

Statin Effects on Both Low-Density Lipoproteins and High-Density Lipoproteins: Is There a Dual Benefit?

Considerable evidence has demonstrated that use of statins has a beneficial impact on both progression of atherosclerosis and cardiovascular events. Accordingly, statins have been increasingly used in preventive strategies to reduce cardiovascular risk. More recent reports have demonstrated an incremental benefit with use of higher doses of statins and when used early in the setting of acute ischemic syndromes. Although lowering levels of low-density lipoprotein cholesterol is likely to underscore the majority of the clinical benefit, emerging evidence suggests that additional properties may also be important. In particular, a number of reports have demonstrated that modest elevations in levels of high-density lipoprotein cholesterol are likely to contribute to the benefit of statins. As a result, a favorable influence on the ratio of atherogenic and protective lipid species is likely to have the most profound impact on cardiovascular risk in statin-treated individuals.     

急性缺血性卒中患者早期神经功能恶化的预测因素

目的 探讨急性缺血性卒中患者早期神经功能恶化(early neurologic deterioration,END)的危险因素.方法 回顾性纳入急性缺血性卒中患者,收集患者的临床资料和实验室检查结果.根据发病后7d内美国国立卫生研究院卒中量表(National Institutes of Health Stroke Scale,NIHSS)评分变化分为END组与非END组,END定义为NIHSS评分较基线水平增加≥3分.采用多变量logistic回归分析确定急性缺血性卒中患者END的独立危险因素.结果 共纳入328例急性缺血性卒中患者,其中74例(22.6％)发生END,254例(77.4％)未发生END.END组男性、高血压、既往卒中或短暂性脑缺血发作史、脑干或小脑梗死、入院前使用抗高血压药的患者构成比以及入院前收缩压均显著高于非END组(P均＜0.05),白细胞计数、中性粒细胞百分比、低密度脂蛋白胆固醇、空腹血糖、高半胱氨酸、C反应蛋白和纤维蛋白原水平均显著高于非END组(P均＜0.05).多变量logistic回归分析显示,白细胞计数[优势比(odds ratio,OR)2.126,95％可信区间(confidence interval,CI)1.240 ～4.325);P=0.028]、低密度脂蛋白胆固醇(OR 2.486,95％ CI 1.932 ～6.021;P=0.036)、高半胱氨酸(OR 2.787,95％ CI 1.194 ～6.902;P=0.036)和C反应蛋白(OR 3.416,95％ CI 1.552～10.650;P =0.032)较高是急性缺血性卒中患者发生END的独立预测因素.结论 白细胞计数、低密度脂蛋白胆固醇、高半胱氨酸和C反应蛋白较高是急性缺血性卒中患者END的独立预测因素.     

The benefit of fibrates in the treatment of 'bad HDL-C responders to statins'

BACKGROUND: Lowering high levels of low-density lipoprotein cholesterol (LDL-C) is the primary aim in the prevention of cardiac events. However, low levels of high-density lipoprotein cholesterol (HDL-C) are also associated with an increased risk of ischemic heart disease. Some patients have lower HDL-C during statin treatment than before the treatment. These patients were first described in 2002 as 'bad HDL-C responders to statins'. The aim of this study was to describe the benefit of fibrates in monotherapy for these patients. METHODS: A cross-sectional survey of lipid levels, cardiovascular disease and risk factors in outpatients treated for dyslipidemia. For this study we analyzed the lipid levels, drug treatment and medical history for 14 patients with low HDL-C (<40 mg/dl) during statin treatment and ever treated with fibrates. RESULTS: Total cholesterol (TC) and LDL-C were respectively 8% and 6% higher with fibrates compared to statins. Mean HDL-C was 49% higher during fibrate treatment and TC to HDL-C and LDL-C to HDL-C were respectively 26% and 27% lower with fibrates. CONCLUSIONS: Patients with low levels of HDL-C during statin treatment had far better levels for HDL-C, TC to HDL-C and LDL-C to HDL-C with fibrates in monotherapy. For bad HDL-C responders to statins with low or normal LDL-C treatment with fibrates instead of statins should be considered. For those with high LDL-C fibrates should be added to statins. A randomized double-blind crossover trial with simvastatin and fenofibrate has been initiated to corroborate these findings.