Fluvastatin inhibits raft dependent Fcgamma receptor signalling in human monocytes

Statins inhibit HMG-CoA reductase and thus block cholesterol and isoprenoid biosynthesis. Since statins also have anti-inflammatory effects, we investigated the effect of fluvastatin on monocyte Fcgamma receptor function. Fluvastatin (0.5-20 microM) inhibited Fcgamma receptor signal transduction at the level of tyrosine kinase activation, in a time and dose dependent manner. Initiation of tyrosine phosphorylation is not thought to involve prenylated proteins; thus, we hypothesised that fluvastatin might disrupt cholesterol and sphingolipid membrane rafts to impair signalling. Consistent with this hypothesis, fluvastatin decreased (and mevalonate rescued) signalling molecules within membrane rafts in parallel with effects on tyrosine phosphorylation events. Raft integrity was unaffected by prenyl transferase inhibitors. In addition, Fcgamma receptor mediated immune complex trafficking, activation of MAP kinases (ERK and p38), and downstream inflammatory mediator release (MMP-1 and IL-6) were blocked by fluvastatin. Thus, HMG-CoA reductase inhibition alters immune receptor signalling by disrupting membrane rafts essential for the initiation of signal transduction. Inhibition of Fcgamma receptor function may limit development and progression of atherosclerosis by decreasing monocyte/macrophage inflammatory mediator release. Since many receptors utilise cholesterol rich rafts this mechanism may have broader significance given the pleiotropic effects of statins.     

Statins in the treatment of chronic heart failure: biological and clinical considerations

Patients with increased cholesterol levels are at increased risk to experience cardiovascular events and to die from vascular disease. Statins have been proven to effectively reduce cholesterol levels and subsequently reduce cardiovascular events in patients with coronary artery disease or at increased risk to develop coronary artery disease. However, in patients with chronic heart failure (CHF), not high, but low levels of cholesterol are related to increased mortality. This phenomenon of reverse epidemiology is not unique to CHF, but also exists in other critical diseases and in the elderly in general as well. An important rationale has been provided by the endotoxin hypothesis, which suggests that cholesterol has an important scavenger function regarding harmful endotoxins. Indeed, these lines of evidence predict a harmful effect of statin treatment in patients with CHF. However, statins not only lower cholesterol, but also have been reported to exhibit a plethora of pleiotropic effects, including reduction of inflammation and improvement of endothelial function. In order to reconcile these contradictory lines of evidence, it is necessary to examine the pharmacological mechanisms of effects of statin treatment. Understanding the pharmacology of statin intervention in CHF models and patients may facilitate the development of therapeutic strategies. In this review, we provide an overview of the known associations between serum cholesterol and CHF in human subjects. In addition, we review the available lines of evidence in animal models and humans predicting both harmful and beneficial effects of statin treatment in CHF. We emphasize the importance of additional research specifically in CHF models and patients.     

Drug insight: statins for nonischemic heart failure--evidence and potential mechanisms

While 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, also known as statins, have a well-established in role in the treatment and prevention of ischemic coronary artery disease, their utility in the setting of heart failure (HF) and left ventricular (LV) dysfunction remains under investigation. Although a reduction in LDL is the major effect of statin therapy, pleiotropic effects have been demonstrated, which could be responsible for the reduction in morbidity and mortality seen with statin use in patients with HF. Patients with both ischemic and nonischemic HF have been shown to have improved survival with statin therapy, and patients receiving statin therapy are less likely to develop HF. Studies have demonstrated that statins reduce inflammation, improve endothelial function, decrease thrombogenicity, and improve LV and autonomic function. In this Review, we present the literature supporting the pleiotropic effects of statin therapy in patients with HF or LV dysfunction, and discuss the mechanisms by which statins might elicit the improvements in morbidity and mortality seen in these patients.     

Models for describing relations among the various statin drugs, low-density lipoprotein cholesterol lowering, pleiotropic effects, and cardiovascular risk

Five models are proposed to describe the relations among statins, pleiotropic effects, low-density lipoprotein (LDL) cholesterol lowering, and cardiovascular risk reduction. On the basis of the evidence available, the pleiotropic effects of statins do not appear to reduce cardiovascular risk more than would be predicted from LDL cholesterol lowering alone, which suggests that model 1 is not a valid model. Although most attention has focused on models 2 through 4, most data to date support model 3 for describing the relation between statins, inflammation, and cardiovascular risk. Stronger consideration should also be given to model 5, in which pleiotropic effects are the result of cardiovascular risk reduction in and of itself. It may be that other models are operative for nonatherosclerotic inflammatory disorders. However, beneficial effects of statins on rheumatologic or other noncardiovascular may still be due to effects of cholesterol reduction on the immune system, as in model 3. More high-quality research is needed to determine the role of statin pleiotropic effects in cardiovascular risk reduction. Well-designed animal studies can help elucidate potential mechanisms, which will then require confirmation in human studies with cardiovascular event outcomes. Substudies of cardiovascular end point trials and mechanistic studies should be methodologically sound and designed to test specific models. To sort out the independence of pleiotropic effects from LDL cholesterol lowering, studies will need to achieve similar LDL cholesterol reductions in each treatment group. It may be that the biologic impact of a specific pleiotropic effect is mediated by >1 model. Ultimately, once a predominant model has been identified for a given pleiotropic effect, long-term studies would be needed to evaluate the relative contributions of various pleiotropic effects to cardiovascular risk reduction. These findings may reveal new targets for the development of new agents that will prove effective for reducing cardiovascular events when added to LDL cholesterol lowering. To date, little evidence supports consideration of statin pleiotropic effects in clinical decision making. In conclusion, LDL cholesterol is currently the only reliable marker for statin effects on cardiovascular risk reduction. The focus should remain on closing the treatment gap and improving adherence to therapies directed at lowering LDL cholesterol and non-high-density lipoprotein cholesterol to reduce the burden of cardiovascular disease.     

All hydrophobic HMG-CoA reductase inhibitors induce apoptotic death in rat pulmonary vein endothelial cells

3-Hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase inhibitors (statins) are effective in patients with hypercholesterolemia to reduce risk of cardiovascular diseases, because of not only their lowering cholesterol effects but also their pleiotropic effects, such as improvement of endothelial cell dysfunction. On the other hand, statins prevent cell proliferation of various cells, including endothelial cells. We examined effects of all statins available at present on the viability of cultured rat pulmonary vein endothelial cells. Lovastatin, simvastatin, atorvastatin, fluvastatin and cerivastatin, which are hydrophobic statins, markedly reduced cell viability associated with DNA fragmentation, DNA laddering and activation of caspase-3, suggesting apoptotic cell death. Pravastatin, which is a hydrophilic statin, however, did not induce cell apoptosis. Apoptosis induced by hydrophobic statins was associated with activation of apoptosis-related intracellular signal transduction systems; attenuation of localization of RhoA to the membrane, induction of Rac1, and increase in phosphorylation of c-Jun N-terminal kinase and c-Jun. Endothelial cell apoptosis is underlying the improvement of the endothelial dysfunction with hydrophobic statins.     

Statins and autoimmune diseases

Inhibitors of 3‐hydroxy‐3methylglutaryl coenzyme A (HMG‐CoA) reductase or statins are effective lipid lowering drugs. The lipid lowering activity is mainly achieved through reduction of cholesterol synthesis and up‐regulation of low density lipoprotein receptors that in turn clear low density lipoproteins and low density lipoprotein precursors from the blood. HMG‐CoA reductase competitively blocks mevalonate, the enzyme reaction product that is the precursor not only of cholesterol but also of several non‐steroidal isoprenoid compounds. Isoprenoids allow the attachment to the cell membrane of signalling proteins involved in various cell functions; their inhibition explains the so‐called pleiotropic effects of statins, which include anti‐inflammatory, anticoagulant and immunomodulatory properties. Such pleiotropic activities have been suggested to justify the benefits of statin therapy besides the simple reduction in plasma cholesterol levels. Accelerated atherosclerosis has been reported in several autoimmune rheumatic diseases. Non‐traditional risk factors for atherosclerosis, such as inflammation, immune‐mediated responses and thrombophilia, have been suggested to play a major role in sustaining premature atherosclerosis in autoimmune rheumatic diseases. This review focuses on the potential use of statins as a new therapeutical tool for treating autoimmune rheumatic diseases based on their antiatherosclerotic activity and on their pleiotropic effect on inflammation, haemostasis and the immune responses.     

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.     

Statins and biomarkers of inflammation

Clinical and epidemiologic studies convincingly demonstrate that increased levels of low-density lipoprotein cholesterol promote premature atherosclerosis. Several large clinical trials have demonstrated that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) decrease cardiovascular events. The beneficial effects of statins may extend to mechanisms beyond cholesterol reduction. Evidence for the pleiotropic effects of statins is provided by recent clinical trials in which the benefit of statin drugs is manifest early in the course of lipid-lowering therapy, well before plaque regression could occur. Inflammation is pivotal in all stages of atherosclerosis, and C-reactive protein (CRP), the prototypic marker of inflammation, has emerged as a cardiovascular risk marker. Statins reduce CRP levels, and this reduction in most studies does not correlate to reduction in cholesterol. In addition, statins have beneficial effects on endothelial function, monocytemacrophages, and platelets. In this review we discuss the role of inflammation in atherosclerosis, the role of CRP as a risk marker, the clinical evidence implicating the anti-inflammatory effects of statins, and the cellular and molecular basis underlying the anti-inflammatory effects of statins.     

Statins in heart failure. Beyond the lipid lowering effect

Statins, the most widely prescribed medications in patients with hyperlipidemia and coronary heart disease, have a number of pleiotropic actions beyond cholesterol lowering. They improve endothelial function, they have antioxidant and anti-inflammatory effects, they regulate neovascularization and have immunomodulatory activities. Experimental evidence suggests that statins may be beneficial in heart failure as they can inhibit myocardial hypertrophy, reduce cardiomyocyte loss by apoptosis, reduce oxidative stress and restore neurohormonal imbalance. Furthermore small randomised clinical trials showed that short term statin administration may improve key pathophysiological aspects of this syndrome. Finally retrospective analyses of large statin trials imply a long term profit on clinical outcome in this group of patients. These results however need to be reviewed with caution as certain studies have demonstrated that low serum cholesterol is associated with worse prognosis in HF and that ubiquinone levels, a micronutrient with antioxidant actions, reduces significantly following statin administration. Large prospective randomised controlled trials are needed to confirm the beneficial effect of statins on cardiovascular outcome in HF patients and further elucidate the contributing mechanisms. Finally the statin dose and the interaction with co-administered drugs need to be studied.     

Cholesterol-independent effects of statins and new therapeutic targets: ischemic stroke and dementia

The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, or "statins", are used as cholesterol-lowering agents worldwide. Statins inhibit cholesterol biosynthesis, leading to enhanced uptake of low-density lipoprotein (LDL) from the circulation via LDL receptors. This strong cholesterol-lowering action contributes to the beneficial effects of statins. For example, large clinical trials have demonstrated that statins significantly reduce cardiovascular risk. Recent research has shown that statins have other multiple actions involved in endothelial function, cell proliferation, inflammatory response, immunological reactions, platelet function, and lipid oxidation. These "pleiotropic actions" of statins probably provide a significant contribution to the reduction of cardiovascular events. This review summarizes the pleiotropic actions of statins in both basic and clinical studies. It also considers the potential for statin therapy in the treatment of stroke and dementia.     

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 role of statins in clinical medicine--LDL--cholesterol lowering and beyond

In the past years, statins have emerged as the most important class of lipid lowering agents. Through inhibition of HMG-CoA reductase, they restrict the rate-limiting step of cholesterol synthesis, which leads to upregulation of LDL receptors on the cell membrane and thus reduction of atherogenic LDLs. This effect translates into clinical benefit by reducing cardiovascular events both in primary and secondary prevention settings. As an approximate rule, statin therapy leads to a relative risk reduction of 25-30% in most of the large randomised controlled trials. Stroke risk is reduced to a similar degree. Despite initial concerns, the currently available statins have a favourable safety profile; however, potential interactions with other drugs must be considered. Recently, characteristics unrelated to LDL lowering have been intensively studied. These pleiotropic statin effects result from decreased levels of isoprenoid intermediates of cholesterol synthesis. They include--among others--anti-inflammatory, anti-proliferative, and immunomodulatory actions. Pleiotropic effects favourably influence pathomechanisms of plaque formation. Furthermore, they may prove beneficial in the prevention or treatment of diseases unrelated to atherosclerosis, eg rheumatoid arthritis, multiple sclerosis, or cancer.     

Pleiotropic effects of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors: candidate mechanisms for anti-lipid deposition in blood vessels

The 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) are considered first-line therapeutic agents for the prevention of coronary heart disease and atherosclerotic disorders related to hypercholesterolemia. Statins inhibit lipid deposition in the aortic endothelium. Although it has been accepted that the statins are potent inhibitors of cholesterol biosynthesis in the liver and that they lower circulating cholesterol levels, several cholesterol-independent (pleiotropic) effects have been reported. The cholesterol-independent effects of statins involve normalization of the nitric oxide (NO)-NO synthase system, anti-inflammatory effects through the inhibition of cytokine/chemokine production, inhibition of vascular smooth muscle cell proliferation and migration, and inhibition of platelet thrombus formation/reduction of the thrombotic response. Some pleiotropic effects of statins may depend on the inhibition of the biosynthesis of farnesyl- and geranylgeranyl-nonsterol compounds from mevalonate in the cells. The Rho/Rho kinase pathway and the phospatidylinositol-3 kinase/Akt pathway mediate the pleiotropic effects of statins. As variations occur in absorption, metabolism, and excretion mechanisms due to the characteristics of specific statins including their hydrophilicity and lipophilicity, there are differences in the transfer mechanisms of statins into tissues. However, the pleiotropic effects occur regardless of statin hydrophilicity and lipophilicity. This review summarizes the pleiotropic effects of statins on lipid deposition in blood vessels.     

他汀预处理对行冠状动脉分流移植术或经皮冠状动脉介入治疗手术主要心脑血管事件影响研究进展

他汀类药不仅具有调节血脂的作用,而且有明显的抗炎,抑制血栓形成等多种效能,在抗动脉粥样硬化的过程中发挥着重要作用,但国内有关他汀预处理对冠状动脉分流移植术及经皮冠状动脉介入治疗手术患者主要心脑血管事件发生的影响研究相对较少,而且国外近年文献报道的研究结果也不一致,目前尚缺乏大规模的临床随机对照实验,现综述他汀预处理对行或经皮冠状动脉介入治疗手术患者主要心脑血管事件影响的最新治疗进展。     

Statin Therapy for Vascular Failure

There is increasing evidence that statins reduce cardiovascular events such as coronary artery disease or stroke in hypercholesterolemic patients in both primary and secondary prevention. The striking benefit achieved with statin treatments in patients with a wide range of cholesterol levels cannot be attributed to their cholesterol lowering effect alone. Substantial data has recently accumulated showing that statins exert various effects on multiple targets, namely pleiotropic effects, especially targeting the concept of ‘vascular failure’, including the improvement of vascular endothelial function, inhibition of vascular smooth muscle cell proliferation and migration, anti-inflammatory actions, anti-oxidative effects or stabilization of vulnerable plaques. These effects have potential in the treatments of coronary artery disease in various settings, such as prevention of its onset as well as its progression, or plaque rupture. Statin therapy should be more extensively applied even in normolipidemic patients if there are additional risk factors such as hypertension, diabetes mellitus, or others. Furthermore, statins may be used to intervene in earlier stage risk conditions such as postprandial hyperlipidemia or hyperglycemia, insulin resistant state, masked hypertension, or metabolic syndrome to further reduce mortality or morbidity of coronary artery disease and heart failure.     

Statin therapy reduces contrast-induced nephropathy: an analysis of contemporary percutaneous interventions

PURPOSE: We sought to examine whether statin therapy before percutaneous coronary intervention results in reduction in contrast-induced nephropathy (CIN). Intravascular administration of contrast media can have nephrotoxic effects, particularly in patients with baseline renal insufficiency. Along with lowering serum cholesterol, statins have pleiotropic effects in the vasculature. The effect of statin use on CIN is unknown. SUBJECTS AND METHODS: We studied 29409 patients who had both baseline preprocedure and peak postprocedure serum creatinine measured at the time of their percutaneous coronary intervention (PCI). Baseline demographics and creatinine profile before and after the procedure were compared between patients who received preprocedure statins and those who did not. CIN was defined as an increase in serum creatinine of < or =0.5 mg/dL. RESULTS: Baseline serum creatinine was similar between the two groups. When compared with patients who did not receive preprocedure statins, patients on preprocedure statins had a lower incidence of CIN (4.37 vs 5.93, P <0.0001) and nephropathy requiring dialysis (0.32 vs 0.49, P = 0.03). After adjustments for comorbidities, preprocedure statin use was associated with a significant reduction in CIN (odds ration [OR] 0.87, 95% confidence interval [CI] 0.77-0.99, P = 0.03). CONCLUSIONS: Preprocedure statin use is associated with significant reduction in CIN after contemporary PCI. This reinforces the need to initiate statin therapy before percutaneous coronary interventions.     

Statin therapy in heart failure: prognostic effects and potential mechanisms

The use of statins as therapy for heart failure remains controversial. Nevertheless, many of the pleiotropic effects of statins are potentially applicable in heart failure. Although early statin trials excluded patients with heart failure because of concerns that lowering serum cholesterol could worsen an already poor prognosis, statin treatment has not been shown to have adverse effects on either cardiovascular events or mortality, and recent experimental and clinical studies have shown promise of benefit. Two large, ongoing trials should provide definitive evidence of the value of statin therapy for patients with heart failure. Pending those results, it is reasonable to follow current National Cholesterol Education Program guidelines in this high-risk population.     

Pleiotropic effects of statins

The advent of statin therapy has revolutionized the ability of the clinician to manage patients at risk for the development of an ischemic event due to dyslipidemia. Large-scale clinical trials involving thousands of patients in both primary and secondary prevention have clearly demonstrated that statin therapy will reduce cardiovascular mortality across a broad spectrum of patient subgroups. Additionally, in adequately powered trials, total mortality has been successfully decreased by the use of statin therapy. However, the precise mechanism underlying the benefit of statin therapy has been controversial due to the multiplicity of potential benefits that statins have demonstrated in addition to pure lipid lowering. The causal theory of pharmacologic benefit reiterates the lipid hypothesis, which states that dyslipidemia is central to the process of atherosclerosis and the clinical benefit which accrues from statin therapy is a function of the degree of lipid lowering. The noncausal theory supports the premise that clinical benefits are related primarily to pleiotropic effects of statins (endothelial function, inflammation, coagulation and plaque vulnerability) as being the major modulators of clinical benefit. This review will focus on the potential beneficial effects of statin therapy on a number of the pleiotropic effects of statins and the potential role that these activities play in the reduction of risk for ischemic events.     

Should a statin be prescribed to every patient with heart failure?

Chronic heart failure (HF) represents an emerging epidemic since its prevalence is continuously increasing despite advances in treatment. Many recent clinical studies have clearly demonstrated that statin therapy is associated with improved outcomes in HF irrespective of aetiology (ischaemic or not) or baseline cholesterol levels. Indeed, most of the conducted large statin trials and trials in HF have demonstrated a positive effect of statins in HF patients. Furthermore, the use of statins in HF seems to be safe as none of the recent trials has resulted in worse outcomes for HF patients treated with statins. Potential mechanisms through which statins could benefit the failing myocardium include non-sterol effects of statins, as well as effects on nitric oxide and endothelial function, inflammation and adhesion molecules, apoptosis and myocardial remodelling and neurohormonal activation. This review discusses the pathophysiological basis of statin effects on HF and focuses on clinical data for the benefit from statin use in this setting. Until today there are no official recommendations in both the American and the European guidelines regarding the use of statins in HF patients, as the available data come from small observational or larger but retrospective, non-randomised studies. Therefore, HF patients should be treated according to current lipid guidelines. Large randomised clinical trials are underway and will further delineate the role of statin therapy in HF patients. Until more data are available, we could not recommend statin use to every patient with HF irrespective of HF aetiology and baseline cholesterol levels.     

Statins: therapeutic cascade of their effects

Concept of sequence and time of appearance of various effects of statins is presented. Apart from hypolipidemic action due to inhibition of HMG CoA reductase activity statins exert multiple pleiotropic effects. Combination of these effects makes statins a unique instrument for solution of global tasks of prevention and treatment of atherosclerosis and its consequences (ischemic heart disease etc.). Manifestations of various pleiotropic effects of statins appear after different time intervals and in most cases are not related to suppression of cholesterol synthesis in the body. First 3-4 months (first level of the statin cascade) are characterized mainly by activity of pleiotropic properties aimed at restoration of endothelial function. These properties are responsible for enhanced eNOS expression, antiischemic, antithrombotic and antiatherogenic effects. During same period of time stabilization of unstable atheromas takes place. Manifestations of second level of the cascade of statin action appear after 2 years of treatment. They are represented by retardation of progression and even partial regression of atheromatosis of coronary and peripheral arteries. Third level is signified by achievement of strategic aims of therapy with statins (in 4-5 years) -- lowering of total and cardiac mortality, reduction of number of cardiac complications. Forth level of the cascade is represented by beneficial influences on nonatherogenic cardiological phenomena and comprise hypotensive, antiarrhythmic and cardiotonic effects. And finally some other important properties of statins constitute the fifth level of the therapeutic cascade. These properties are responsible for effects directed at noncardiac pathology (prevention of diabetes, dementia, including dementia associated with Alzheimer's disease, fractures). Immunodepression, ability to reduce saturation of bile with cholesterol belong to this group of effects.