他汀类药物治疗慢性心力衰竭的非降脂作用

他汀类药物是冠状动脉粥样硬化性心脏病的一级和二级预防的有效药物。目前的研究发现他汀类药物还具有许多非降脂作用,如稳定动脉粥样硬化中的不稳定斑块,促进新生血管的形成,增强血管的舒张功能等。在慢性心力衰竭中,他汀类药物还可以通过抑制炎症反应,调节免疫功能,抗氧化,改善内皮功能,调节神经体液反射,抗心室重构等作用,从而有益于患者的治疗。     

他汀类药物的多效性在心血管疾病中的应用进展

他汀类药物不仅作为羟甲基戊二酰辅酶A还原酶抑制剂降低血清胆固醇水平,还通过改善血管内皮功能、抑制炎症及氧化反应、抗血小板聚集和抑制血栓形成、稳定粥样硬化斑块、抑制心肌重塑及心肌细胞凋亡、抑制心脏电生理重塑及调节心脏植物神经功能等其它多效性在冠状动脉粥样硬化性心脏病、心功能衰竭、心律失常等心血管损伤中发挥其作用。     

他汀类药物的抗炎作用

近年有人提出冠状动脉粥样硬化应称为动脉粥样硬化性炎症更为确切。他汀类药物除具有明显的降脂作用 ,一些研究提示他汀类药物还具有明显的抗炎作用 ,包括抑制炎性细胞向病变处的迁移以及大量炎症因子的释放 ,抑制平滑肌细胞增殖 ,进而促进斑块稳定 ,改善血管内皮的功能 ,抑制细胞凋亡 ,降低病人急性相反应蛋白CRP的水平等作用。进而达到稳定粥样斑块 ,预防急性冠脉综合征的发生。     

他汀类药物在急性冠状动脉综合征的应用

他汀类药物用于冠心病一级预防 (WOSCOPS)和二级预防 (如 4S ,CARE ,LIPID等 )大规模临床试验显示其可明显降低冠心病事件的发生率 ,即使在平均胆固醇水平的冠心病患者也可收到显著裨益。临床研究结果显示 ,他汀类药物治疗时低密度脂蛋白胆固醇 (LDL C)基线水平及治疗后水平如何 ,对心脑血管事件的发生只产生很少影响。他汀类药物的非降脂作用如稳定斑块 ,改善内皮功能 ,减少炎症反应和抑制血栓形成等作用 ,显然也与心脑血管事件的降低相联系。急性冠状动脉综合征 (ACS)的病理生理基础是冠状动脉粥样硬化斑块破裂和血栓形成 ,各种…     

从循征医学看老年心血管病药物治疗进展（下）

三、老年冠状动脉粥样硬化性心脏病（冠心病）的药物治疗 1．他汀类药物：对这类药物的药理研究发现它除了良好的降胆固醇、甘油三酯的作用外,还具有重要的非调脂作用,如抑制炎症、稳定斑块,改善内皮功能,抗血小板聚集、改善血流状态,抑制平滑肌细胞增殖等作用。因而他汀类药物在临床得到广泛的应用。甚至有人认为它所带来的贡献可以与20世纪40年代青霉素所带来的贡献相媲美。因此,他汀类药物成为目前研究的热点和重点。     

从循征医学看老年心血管病药物治疗进展(下)

三、老年冠状动脉粥样硬化性心脏病(冠心病)的药物治疗 1.他汀类药物:对这类药物的药理研究发现它除了良好的降胆固醇、甘油三酯的作用外,还具有重要的非调脂作用,如抑制炎症、稳定斑块,改善内皮功能,抗血小板聚集、改善血流状态,抑制平滑肌细胞增殖等作用.因而他汀类药物在临床得到广泛的应用.甚至有人认为它所带来的贡献可以与20世纪40年代青霉素所带来的贡献相媲美.因此,他汀类药物成为目前研究的热点和重点.     

经皮冠状动脉介入治疗围手术期强化他汀药物治疗机制的初步探讨

ARMYDA和NAPLES系列研究提示,经皮冠状动脉介入治疗(PCI)术前给予大剂量他汀药物治疗,可以显著降低围手术期心肌梗死和30天主要心脏不良事件的发生率。PCI可导致血管内皮损伤,加重炎症反应。围手术期强化他汀治疗带来的获益主要来自于他汀药物的生物学多效性,可能机制包括抗炎症反应、改善血管内皮功能,抗栓作用,扩张冠状动脉微血管等调脂以外的作用。强化他汀治疗还可以降低对比剂肾病的发生率,对于改善患者的远期预后起到积极的作用。     

瑞舒伐他汀的研究进展

许多大规模临床试验已证实他汀类药物明显降低冠状动脉性心脏病的发病率和心血管事件的发生,强化调脂治疗在极高危患者中的地位日益受到重视。与其他他汀类药物相比,瑞舒伐他汀具有一些有利的药理特性,一系列临床研究也显示,此药对各类血脂异常患者的低密度脂蛋白胆固醇降低效果均显著优于同类其他药物,而且还有改善血管内皮功能和稳定斑块、抗氧化、抗炎等非调脂作用。现综述瑞舒伐他汀目前的研究进展。     

他汀类药物对室性心律失常的作用及机制研究

心脏性猝死是冠状动脉粥样硬化性心脏病患者的常见死因,而心脏性猝死大部分与致死性室性心律失常有关。大量研究表明他汀类药物可降低心血管疾病的发病率和病死率。令人注目的是大量的证据显示他汀类药物有抗室性心律失常的作用。他汀类药物可能通过增加副交感神经活性、改变跨膜离子通道的性质、修复粥样硬化斑块、稳定血小板、抗炎和抗增生作用、抗氧化作用、改善血管内皮功能、激活损害心肌、减轻因缺血导致的心肌细胞肥大等机制而有一定的抗室性心律失常的作用。     

他汀类药物在急性冠状动脉综合征中的抗炎地位

临床试验证实，羟甲基戊二酰辅酶A(HMG CoA)还原酶抑制剂，即他汀类药物，可减少心血管事件的发生，这种结果是不能完全用降低基线低密度脂蛋白(LDL)胆固醇水平来解释的。国际大规模研究显示，他汀类药物对临床事件的有益作用涉及非调脂机制，这些机制包括改善内皮功能、抗炎症反应、稳定斑块和抑制血栓形成等。     

Current questions regarding the use of statins in patients with coronary heart disease

The discovery of statins caused a revolution in the field of lipid intervention. Statins are drugs with a good safety profile. Their clinical benefit has been extensively documented in primary and secondary prevention of coronary heart disease. There is substantial evidence that the clinical outcome can be improved with aggressive statin treatment both in patients with unstable as well as with stable coronary heart disease. Also, early administration of statins in acute coronary syndromes is accompanied by rapid clinical benefits, mainly through their "pleiotropic" action (anti-inflammatory, anti-thrombotic, improvement of endothelial function, etc) which is probably a lipid-independent effect. Moreover, emerging data indicate that statins can achieve additional benefit when low density lipoprotein (LDL) cholesterol reduction is coupled with C-reactive protein reduction (<2 mg/L). The prevailing message from the recent statin trials is that intensive LDL cholesterol lowering treatment with statins achieves further clinical benefit beyond that achieved with standard statin therapy. This should encourage the medical community to consider prescribing statins in every coronary patient, aiming at LDL cholesterol levels <100 mg/dL, preferably in the range of 70-80 mg/dL in stable coronary patients, while in coronary patients at very high risk, the optional target for LDL cholesterol levels should be in the range of 50-70 mg/dL.     

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.     

他汀类药物对缺血再灌注心肌的保护作用及机制

他汀类药物是目前临床上广泛使用的调脂药,近年来他汀类药物的非调脂作用日益引起人们的重视。动物实验发现,他汀类药物对缺血再灌注心肌有保护作用。大规模的临床试验也证实他汀类药物能有效减少冠脉事件的发生,并可以减少短期内冠脉事件再发的危险性,且长期应用受益更大。目前研究认为他汀类药物对缺血再灌注心肌的保护作用主要是通过改善内皮功能和抗炎作用实现的,也可通过动员内皮祖细胞、抗血栓、提高心肌能量及抗氧化损伤等机制有效的减轻缺血再灌注损伤。     

Statins and blood pressure regulation

Hypertension and high serum cholesterol levels are two of the most relevant risk factors for cardiovascular diseases. A combined increase in both risk factors has been reported in a significant proportion of patients with coronary artery disease. Statins are the most widely used drugs to treat hypercholesterolemia, and they interact with blood pressure control in different populations of hypertensive patients. A significant reduction in blood pressure associated with the use of statins has been described in patients with untreated hypertension and in patients treated with antihypertensive drugs, particularly angiotensin converting enzyme inhibitors and calcium channel blockers. The effect of statins on blood pressure control has also been reported in diabetic patients. The mechanisms responsible for the hypotensive effect seem to be largely independent of the effect of statins on lipid profile, and are probably related to their interaction with endothelial function or angiotensin II receptors. The capacity of statins to improve blood pressure control could be a useful consideration for an integrated approach to better prevention of cardiovascular diseases.     

Early use of statins in acute coronary syndromes

This review examines the use of HMG-CoA reductase inhibitor (statin) medications early in the clinical course of acute coronary syndrome. Available data demonstrate that there are clear clinical benefits to this practice. Numerous previous studies have documented the primary and secondary benefits of statins in the prevention of coronary events. Recent trials show that when statins are used during hospital admissions for acute coronary syndrome (ACS), patients experience decreased recurrent myocardial infarction, lower death rates, and fewer repeat hospitalizations for ischemia or revascularization. Several studies suggest that the positive effects of statins on plaque stabilization, inflammation, thrombosis, and endothelial function may be independent of lipid levels. There is also an emerging view that beneficial lipid-lowering with statins in high-risk patients has no lower limit. This information suggests that all patients admitted for ACS should be treated with statins, regardless of cholesterol levels.     

HDL-C: role as a risk modifier

Evidence that low-density lipoprotein-cholesterol (LDL-C) causes cardiovascular disease (CVD) is overwhelming. It has also been proven beyond all doubt that lowering the level of LDL-C using statins reduces CV risk. However, many people remain at high risk even when their level of LDL-C has been reduced by aggressive treatment with statins. One reason for this residual risk can be a low level of high-density lipoprotein-cholesterol (HDL-C). The concentration of HDL-C is an independent, inverse predictor for CVD. This relationship is apparent even when treatment with statins has reduced the level of LDL-C to below 1.8 mmol/L (70 mg/dL). It has therefore been suggested that raising the level of HDL-C should be considered as a therapeutic strategy for reducing the residual CV risk that persists in some people, despite aggressive LDL-C lowering with statins. HDL particles have several functions with the potential to protect against arterial disease, the best known of which relates to their ability to promote cholesterol efflux from macrophages in the artery wall. However, HDLs have several additional protective properties that are independent of their involvement in cholesterol metabolism. For example, they have properties that reduce oxidation, vascular inflammation and thrombosis, improve endothelial function, promote endothelial repair, enhance insulin sensitivity and promote insulin secretion by pancreatic beta islet cells. There is also a large and compelling body of evidence in animal models showing that interventions that increase HDL levels are profoundly anti-atherogenic. Major causes of low HDL are abdominal obesity and type 2 diabetes, the worldwide incidences of which are increasing at alarming rates. Strategies to increase the concentration of HDL should begin with lifestyle changes such as weight reduction, increased physical activity and smoking cessation. However, compliance with such measures is frequently poor and pharmacological intervention may be required. Currently available HDL-raising medications include fibrates, niacin and statins. There is indisputable evidence that lowering LDL-C levels using statins translates into a large reduction in CV risk. There is also mounting evidence that increasing the level of HDL-C using statins contributes to an additional reduction in CV risk. For example, the increase in HDL-C levels that was associated with simvastatin treatment in the 4S study was a significant predictor for the reduction in CV events. Moreover, a meta-analysis of 1,455 patients in 4 coronary intravascular ultrasound imaging trials showed that both the achieved level of LDL-C and the increase in HDL-C concentration during statin treatment were significant independent predictors for coronary atheroma progression as assessed by coronary intravascular ultrasound. In conclusion, evidence suggests that low levels of HDL-C are associated with an increased CV risk even when LDL-C is reduced to below 1.7 mmol/L (70 mg/dL) with a statin. Moreover, there is mounting evidence that increasing the level of HDL-C has the capacity to reduce CV risk. Thus, there is a compelling case for targeting both the LDL and HDL fractions to reduce CV risk in people with dyslipidemia, high CV risk and low levels of HDL-C.     

Effects of statins on vascular structure and function: a systematic review

PURPOSE: Statins reduce cardiovascular events by more than can be explained by their effects on lipids. We conducted a systematic review of how statins affect vascular structure and function, differences among statins, and correlations between the effects of statins on vascular outcomes and either lipid levels or cardiovascular outcomes. METHODS: We primarily searched MEDLINE (1980 to March 2004) to identify all studies with at least 10 subjects that reported the effects of currently available statins on coronary artery stenosis, carotid intima-media thickness, and endothelial function (excluding studies of drug combinations and subjects with organ transplants). Meta-analyses were performed when feasible. RESULTS: Statins decrease the progression and increase the regression of coronary artery lesions and luminal narrowing. Compared with placebo, statins decrease the likelihood of coronary artery restenosis (summary risk ratio = 0.85; 95% confidence interval: 0.77 to 0.95). Statins appear to slow the progression of carotid artery intima-media thickness. Although the effect of statins on coronary endothelial function is uncertain, statins appear to improve peripheral endothelial function. There is no conclusive evidence to suggest that individual statins differ in their effects on these outcomes. Studies generally found weak or no correlation between the effects of statins on vascular outcomes and lipid levels. No study showed a correlation between vascular effect and clinical outcome. CONCLUSION: Statins slow the progression of, and may reverse, atherosclerosis. The magnitude of these effects, however, is small compared with the effects of statins on cardiovascular events. Statins also improve measures of vascular function, which may contribute to their clinical benefits. There is insufficient evidence to suggest that individual statins differ in their vascular effects.     

Early use of statins in acute coronary syndromes

This review examines the use of statin medications early in the clinical course of acute coronary syndrome (ACS). Available data demonstrate that there are clear clinical benefits to this practice. Numerous previous studies have documented the primary and secondary benefits of statins in the prevention of coronary events. Recent trials show that when statins are used during hospital admissions for ACS, patients experience decreased recurrent myocardial infarction, lower death rates, and fewer repeat hospitalizations for ischemia or revascularization. Several studies suggest that the positive effects of statins on plaque stabilization, inflammation, thrombosis, and endothelial function may be independent of lipid levels. There is also an emerging view that beneficial lipid-lowering with statins in high-risk patients has no lower limit. This information suggests that all patients admitted for ACS should be treated with statins, regardless of cholesterol levels.     

Adjunctive interventions in myocardial infarction: The role of statin therapy

Statin therapy has reduced cardiovascular morbidity and mortality across the spectrum of atherosclerosis. The administration of statins has been demonstrated to be effective in primary and secondary prevention clinical trials evaluating patients with high and low risk-factor profiles. The presumed mechanism of benefit of hypolipidemic therapy in the prevention of atherosclerotic disease was a reduction in the deposition of atherogenic lipoproteins in vulnerable areas of the coronary vasculature. Subsequent experimental studies with statins demonstrated a variety of potentially beneficial effects that would extend clinical benefit beyond lipid-lowering per se. Statin therapy beneficially alters inflammation, coagulation and fibrinolytic parameters, endothelial function, vasoreactivity, and platelet function. The demonstration of the non-lipid or pleiotropic effects provided the theoretical basis for a possible role as an adjunctive therapy in acute coronary syndromes. Retrospective analysis of a variety of early trials indicated a potential benefit of statins during acute ischemic syndromes. Recent clinical trials have addressed this important clinical question in a prospective controlled manner. The Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) and the Thrombolysis In Myocardial Infarction (TIMI)-22 studies present strong clinical evidence in favor of the administration of statins as adjunctive therapy in acute ischemic syndromes.     

Effects of statins on endothelium and endothelial progenitor cell recruitment

Statins appear to be potent drugs with a variety of pleiotropic effects with vasculoprotective and cardioprotective activity. The beneficial effects of statins on endothelial cells as well as on endothelial cell function appear to be related to improved nitric oxide bioavailability. Mechanistically, statins induce endothelial nitric oxide synthase mRNA stability in endothelial cells and promote endothelial nitric oxide synthase activity through a PI3K/Akt dependent pathway, which is a common signal transduction pathway shared by growth factors such as vascular endothelial growth factors or fibroblast growth factors (FGFs), estrogens, or statins. Furthermore, statins have potent antiinflammatory capacities by potently interfering with the generation of reactive oxygen species or activating scavenging systems for free radicals such as the thioredoxin system. These mechanisms might all contribute to improved NO bioavailability and confer the beneficial actions of statins. The proangiogenic properties of statins and their effects on reendothelialization following vessel injury include novel actions such as the mobilization, differentiation, and improved survival of endothelial progenitor cells. Statin therapy might reverse the impaired functional regeneration capacities seen in patients with risk factors for coronary artery disease or documented active coronary artery disease by specifically interacting with progenitor cell function. Accordingly, augmentation of functionally active endothelial progenitor cells with improved homing capacity will be a critical step in advancing therapeutic neovascularization as well as reendothelialization in patients with coronary artery disease.