他汀类药物非调脂作用机制的研究进展

他汀类药物除了其调脂主导作用外，近期研究发现还具有不依赖于其降血脂特性的非调脂抗动脉粥样硬化作用如抑制血管平滑肌细胞增殖与迁移，改善内皮功能，抗炎症反应和稳定斑块等多向性效应，本文对他汀类药物非调脂作用机制的最新研究进展作一综述。     

他汀药非调脂作用及在心血管疾病中的应用

大量基础和临床试验证明,他汀类药物不仅可以明显改善血脂水平,而且具有多向、多效的非调脂作用,早期应用他汀药可以抗心律失常、改善心功能,降低心血管事件的发生率和死亡率,因此更加广泛的应用于临床。本文即对他汀药非调脂作用及在心血管疾病中临床应用作如下综述。     

非他汀类调脂药物的研究进展

近年来国内外对于非他汀类药物的研究取得了重大的成果。综述胆固醇吸收抑制剂、贝特类、前蛋白转化酶枯草溶菌素9(PCSK9)抑制剂、胆固醇酯转运蛋白(CETP)抑制剂等非他汀类调脂药物的作用机制、安全性和有效性等的研究进展,以期为调脂治疗方案提供更多的选择。     

他汀类药物的非调脂作用研究进展

他汀类药物 (statins)即戊二酰辅酶A(HMG -CoA)还原酶抑制剂 ,是一类强有力的调脂药 ,主要包括辛伐他汀、普伐他汀、洛伐他汀、阿伐他汀、氟伐他汀、美伐他汀及西伐他汀等。国际上已有多项大规模随机双盲的临床试验证实 ,他汀类药物能显著降低心脑血管病的发病率和死亡率[1～ 3 ] 。近期的研究表明 ,他汀类药物对心脑血管病的益处已远远超过其调脂作用所带来的效应。本文即对他汀类药物的非调脂作用综述如下。1　抑制动脉平滑肌细胞的增殖HMG -CoA还原酶是胆固醇合成途径中的限速酶 ,是体内催化乙酰辅酶A合成甲羟戊酸代谢途径的关键酶 …     

他汀类药物非调脂作用及其对围手术期心肌损伤保护作用的研究进展

临床研究表明,他汀类药物可以降低胆固醇特别是低密度脂蛋白胆固醇水平,通过多种途径防治动脉粥样硬化的形成,预防和减少心血管事件的发生并显著提高冠心病患者血清肌酐清除率^[1]等。这一效果除得益于他汀类药物的调脂效果外,还和其非调脂作用密切相关^[2]。本文着重分析他汀类药物非调脂疗效研究的最新进展及其对围手术期心肌损伤的保护作用。     

老年人调脂治疗研究进展

他汀类药物治疗可以降低动脉粥样硬化性心血管疾病(ASCVD)的病死率,减少心血管事件。由于老年人心血管疾病患病率高,发生心血管事件的危险更大,他汀治疗带来的绝对获益更大。目前,缺乏专为高龄老年人设计的前瞻、随机、对照、大规模临床试验,缺乏大剂量他汀类药物治疗使老年人获益的临床证据。低密度脂蛋白水平是老年人血脂异常管理的首要目标,非高密度脂蛋白水平是次要目标。健康的饮食结构和生活方式是治疗老年人血脂异常的基本措施,他汀类药物是首选的调脂药物。建议根据患者心血管疾病的危险分层及个体特点,充分评估调脂治疗的利弊,合理地选择调脂药物,以达到改善生活质量、减少心血管事件和降低病死率的目的。     

他汀类药物调脂外的抗动脉粥样硬化作用机制

他汀类药物是一类应用广泛的调脂药物，越来越多的研究表明它在抗动脉粥样硬化的形成和发展方面也发挥重要作用，而这一作用与他汀类药物的调脂作用无关。他汀类药物除调脂外的抗动脉粥样硬化机制主要包括改善血管内皮功能，抗炎，抑制平滑肌细胞的迁移和聚集，诱导平滑肌细胞凋亡以及稳定斑块。     

冠心病二级预防中的调脂治疗

本文回顾了调脂治疗在冠心病二级预防中的意义及应用并对他汀类的非降脂定义作了简介。     

调脂治疗面临的挑战

国际上里程碑性的大规模、多中心的随机临床研究 ,已充分显示调脂治疗对于动脉粥样硬化性疾病和冠心病的益处 ,降低血清总胆固醇 (ＴＣ)水平 ,尤其是低密度脂蛋白胆固醇 (ＬＤＬ Ｃ)水平 ,可显著降低冠心病患病率、死亡率、心血管事件发生率及总死亡率。基础研究也显示 ,他汀类调脂药物除有调脂作用外 ,还有调脂以外的抗动脉粥样硬化作用。因此 ,调脂治疗与动脉粥样硬化性疾病已成为当今医学研究中一个非常活跃的领域。1　调脂治疗注重于升高高密度脂蛋白胆固醇　　流行病学研究已充分证实高密度脂蛋白胆固醇 (ＨＤＬ Ｃ)是冠状动脉性疾病的…     

他汀类调脂药的附加作用

汀类药物因其调脂作用明显，已被广泛用于临床。实践证明，他汀类药物能使已经形成的动脉粥样硬化斑块发展减缓，甚至减退，从而打破了冠心病不可逆转的传统观念，由此引发了一场“血脂革命”。临床发现，他汀类药物除调脂作用外还有许多其他作用，如减缓动脉粥样硬化进程和管腔狭窄、减轻左室肥厚、降低心血管意外和脑卒中风险、     

Direct vascular effects of HMG-CoA reductase inhibitors

The 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors, or statins, are potent inhibitors of cholesterol synthesis and large clinical trials have demonstrated that these agents reduce cholesterol and the incidence of cardiovascular diseases. Recent evidence, however, suggests 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 vascular wall cells. In particular, the small GTP-binding protein, Rho, whose membrane localization and activity are affected by post-translational isoprenylation, may play an important role in mediating the direct vascular effects of statins.     

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.     

Effect of statins on cholesterol crystallization and atherosclerotic plaque stabilization

Pleiotropic effects of statins have not been fully elucidated. Recently we demonstrated that cholesterol expands when crystallizing and may trigger plaque rupture. The present study evaluated the potential direct effects of statins in altering cholesterol crystallization as a possible mechanism for plaque stabilization independent of cholesterol lowering. Cholesterol powder was dissolved in oil with and without pravastatin, simvastatin, or atorvastatin (10 to 90 mg) and then allowed to crystallize to measure peak volume expansion (ΔVE) in graduated cylinders. Effect of ΔVE on fibrous membrane damage was also evaluated. Human coronary, carotid, and peripheral arterial plaques (65 plaques from 55 patients) were incubated with statin or saline solution using matched plaque segments to evaluate direct effects of statins on preformed crystals. Also, the effect of in vivo use of oral statins on crystal structure was examined by scanning electron microscopy and crystal content in plaques scored from 0 to +3. For all statins, ΔVE decreased significantly in a dose-dependent fashion (0.76 ± 0.1 vs 0 ml at 60 mg, p <0.001). By scanning electron microscopy crystal structure with statins had loss of pointed tip geometries, averting fibrous membrane damage. Cholesterol crystal density was markedly decreased and appeared dissolved in human plaques incubated with statins (+2.1 ± 1.1 vs +1.3 ± 1.0, p = 0.0001). Also, plaques from patients taking oral statins compared to controls had significantly more dissolving crystals (p = 0.03). In conclusion, statins decreased ΔVE by altering cholesterol crystallization and blunting sharp-tipped crystal structure and dissolving cholesterol crystals in human arteries in vivo and in vitro, providing plaque stabilization.     

Are statins effective for simultaneously treating dyslipidemias and hypertension?

3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) are unequivocally useful for lowering cholesterol levels in patients with dyslipidemias characterized by elevations in total and/or low-density lipoprotein cholesterol. The beneficial effects of statins to lower serum cholesterol translate into significant reductions in cardiovascular morbidity and mortality. In addition to lowering cholesterol levels, statins have other biological effects relevant to cardiovascular homeostasis including anti-inflammatory actions and downregulation of angiotensin type 1 receptor expression that contribute to improvements in endothelial function and arterial compliance. Since endothelial dysfunction and reduced arterial compliance are important pathophysiological determinants of essential hypertension, these actions of statins raise the possibility that statin therapy may be useful for simultaneously treating dyslipidemias and hypertension. However, it has been unclear whether statins are effective in lowering blood pressure. This controversy stems from a variety of methodological limitations including inadequate sample size, confounding effects of antihypertensive drugs, differences in blood pressure measurement techniques, and differences in patient populations. However, based on published results from both small clinical studies and large randomized clinical trials, statins modestly lower blood pressure in patients with high, but not normal, blood pressure, regardless of cholesterol level.     

他汀类药物多效性的临床研究进展

近年来数个大规模临床研究相继证实,应用他汀类药物可明显降低血清总胆固醇和低密度脂蛋白胆固醇水平,显著降低冠心病发病率、心血管病死亡率乃至全因死亡率,从而奠定了他汀在冠心病一级、二级预防中的基石地位。然而,随着基础与临床研究的深入,越来越多的证据表明,他汀类药物具有独立于调脂作用外的多种疗效,即他汀的多效性。现将着重从循证医学的角度对他汀类药物的多效性进行综述。     

The intestinal absorption of biliary and dietary cholesterol as a drug target for lowering the plasma cholesterol level

Elevated plasma low-density lipoprotein cholesterol levels constitute a major risk factor for coronary heart disease. The plasma low-density lipoprotein cholesterol concentration is dictated partly by the efficiency of intestinal cholesterol absorption. The efficacy of treatments designed to block cholesterol absorption is partially offset to the extent that the liver compensates for the interruption to the enterohepatic movement of cholesterol by increasing the rate at which it synthesizes cholesterol. Currently, the most widely-used treatment for hypercholesterolemia is based on a class of agents (statins) that partially inhibit cholesterol synthesis within the body. Recent clinical trials with a unique, potent, and selective cholesterol absorption inhibitor (ezetimibe) used in combination with lower doses of various statins showed an additive reduction in plasma low-density lipoprotein cholesterol levels which equaled the reduction achieved with maximal doses of statins given alone. Combination therapy using a statin and this novel cholesterol absorption inhibitor represents an efficacious new approach to the treatment of hypercholesterolemia in the general population.     

Conceptual foundations of the UCSD Statin Study: a randomized controlled trial assessing the impact of statins on cognition, behavior, and biochemistry

BACKGROUND: Statin cholesterol-lowering drugs are among the most prescribed drugs in the United States. Their cardiac benefits are substantial and well supported. However, there has been persistent controversy regarding possible favorable or adverse effects of statins or of cholesterol reduction on cognition, mood, and behavior (including aggressive or violent behavior). METHODS: The literature pertaining to the relationship of cholesterol or statins to several noncardiac domains was reviewed, including the link between statins (or cholesterol) and cognition, aggression, and serotonin. RESULTS: There are reasons to think both favorable and adverse effects of statins and low cholesterol on cognition may pertain; the balance of these factors requires further elucidation. A substantial body of literature links low cholesterol level to aggressive behavior; statin randomized trials have not supported a connection, but they have not been designed to address this issue. A limited number of reports suggest a connection between reduced cholesterol level and reduced serotonin level, but more information is needed with serotonin measures that are practical for clinical use. Whether lipophilic and hydrophilic statins differ in their impact should be assessed. CONCLUSION: There is a strong need for randomized controlled trial data to more clearly establish the impact of hydrophilic and lipophilic statins on cognition, aggression, and serotonin, as well as on other measures relevant to risks and quality-of-life impact in noncardiac domains.     

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新型胆固醇吸收抑制剂依哲麦布(ezetimihe,EZ)可显著降低患者的低密度脂蛋白胆固醇(LDL-C),升高高密度脂蛋白胆固醇(HDL-C)水平,不良反应较少.EZ与他汀类药物联合应用,有良好的药物协同效应,可避免大剂量他汀潜在的不良反应.如果患者在单用最佳剂量他汀类治疗的情况下没有达标,那么EZ联合他汀类可以是一种合理的治疗.     

Statins effect on smooth muscle cell proliferation

Clinical trials have firmly established that 3-hydroxy-3-methylglutaryl-coenzyme-A reductase inhibitors (statins) can induce regression of vascular atherosclerosis as well as reduction of cardiovascular-related morbidity and death in patients with and without coronary artery disease. These beneficial effects of statins are usually assumed to result from their ability to reduce cholesterol synthesis. However, because mevalonic acid is the precursor not only of cholesterol but also of many nonsteroidal isoprenoid compounds, inhibition of 3-hydroxy-3-methylglutaryl-coenzyme-A reductase may result in pleiotropic effects. Indeed, statins can interfere with major events involved in the formation and the evolution of atherosclerotic lesions, such as arterial myocyte migration and proliferation and cholesterol accumulation, independent of their hypolipidemic properties. The aim of this article is to focus on clinical and experimental data that show that statins possess effects beyond cholesterol lowering, particularly on arterial smooth muscle cell proliferation. The contribution of these direct vascular effects to the reduction of cardiovascular events observed in clinical trials with statins represents one of the major challenges for future studies to understand the antiatherosclerotic benefits of these agents.     

Isoprenoid metabolism and the pleiotropic effects of statins

Convincing evidence from basic research and animal studies shows that 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors (ie, statins) exert cardiovascular protective effects beyond cholesterol lowering. Because of the central role of low-density lipoprotein (LDL) cholesterol in mediating vascular pathology and the efficacy of statins for lowering LDL cholesterol, the clinical importance of these additional nonlipid effects remains to be determined. Nevertheless, there is growing evidence from recent clinical trials that suggests that some of the beneficial effects of statins may be unrelated to changes in LDL cholesterol. Indeed, in animal studies many of the cholesterol-independent or pleiotropic effects of statins are due predominantly to inhibition of isoprenoid, but not cholesterol, synthesis. Thus, with the recent findings of the Heart Protection Study and Anglo-Scandinavian Cardiac Outcomes Trial—Lipid Lowering Arm, the potential cholesterol-independent effects of statins have shifted the treatment strategy from numerical lipid parameters to the global assessment of cardiovascular risks.