Microcirculation as a target for the anti-inflammatory properties of statins

Statins are inhibitors of the 3-hydroxy-3-methylglutaryl coenzyme A reductase, a ubiquitous enzyme critical for the biosynthesis of cholesterol. Because of their cholesterol-lowering properties, statins are extensively used in medical practice, and large clinical trials have shown that statins effectively reduce cardiovascular related morbidity and mortality. In the past 5 years, an important, new concept suggesting that the cardioprotective effects of statins are not necessarily related to cholesterol-lowering actions has emerged. Indeed, in vivo findings have clearly shown that statins exert anti-inflammatory and immunomodulatory effects and that they modulate vascular remodeling under normocholesterolemic conditions. These pleiotropic properties of statins affect important molecules in vascular biology and help preserve endothelial function in acute and chronic inflammatory states of the cardiovascular system, including coronary and cerebral artery diseases, diabetes, and atherosclerosis. Emerging evidence indicates that the microcirculation is a crucial target for the pleiotropic actions of statins because of its important role in regulating blood flow, leukocyte-endothelium interactions, and vascular remodeling. Accordingly, this review focuses on the role that the microcirculation plays in the vascular protective action of statins.     

Prognostic effects of combined treatment with calcium channel blockers and statins in patients with coronary narrowing: from the Japanese Coronary Artery Disease study

Calcium channel blockers (CCB) and statins are frequently prescribed for patients with coronary artery disease (CAD) complicated by hypertension and/or hypercholesterolemia. CCB have pleiotropic actions beyond their blood pressure-lowering effect, while statins have pleiotropic actions beyond their cholesterol-lowering effect. We assessed the hypothesis that combined treatment with CCB and statins has additional prognostic benefits resulting from potential additive or synergistic pleiotropic actions of both classes of drugs in the Japanese CAD (JCAD) study population. The JCAD study consisted of 13,812 patients with angiographically demonstrable significant coronary narrowing in at least 1 of 3 major coronary arteries who were followed-up for a mean of 2.7 years (follow-up rate, 88.4%). The primary endpoint of the present study was all cardiovascular events. We compared the event rate between patients receiving neither CCB nor statins and those receiving each drug alone or as a combination treatment using propensity score matching analysis. The rate of all events was 62.8 per 1,000 patient-years in the JCAD study. Kaplan-Meier analysis with the log-rank test showed no statistically significant difference in the event rate in each comparison. In conclusion, there may be no additional prognostic benefit beyond the blood-pressure-lowering and cholesterol-lowering effects in the combined treatment with CCB and statins for angiographically documented CAD patients.     

他汀类药物治疗高胆固醇血症外的作用

他汀类药物是羟甲基戊二酰辅酶A（HMG—CoA）还原酶的竞争性抑制剂,可抑制内源性胆固醇的合成和刺激低密度脂蛋白（LDL）受体的合成,临床上被广泛用来治疗高胆固醇血症。大量的研究发现,他汀类药物除了显著地降低胆固醇、抗动脉粥样硬化和心血管保护作用之外,还具有独立于此之外的其它作用,如肺、肾保护作用、延缓肾衰竭进展、抑制动脉瘤的形成和扩张作用、抗肿瘤作用、促进骨形成作用、促进伤口愈合作用、以及降低感染性休克的死亡风险等多方面的作用。     

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.     

Is targeting eNOS a key mechanistic insight of cardiovascular defensive potentials of statins?

Statins are widely used in the treatment of dyslipidemia and associated cardiovascular abnormalities including atherosclerosis, hypertension and coronary heart disease. Needless to mention, statins have cholesterol-lowering effects by means of inhibiting 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase, a rate-limiting enzyme of cholesterol biosynthesis. Besides cholesterol-lowering effects, statins possess pleiotropic anti-inflammatory, anti-oxidant, anti-platelet and anti-fibrotic properties, which may additionally play imperative roles in statins-mediated cardiovascular protection. However, the precise mechanisms involved in the cardiovascular defensive potential of statins have not completely been elucidated. Intriguingly, a considerable number of studies demonstrated the potential modulatory role of statins on endothelial nitric oxide synthase (eNOS), a key enzyme involved in the regulation of cardiovascular function by generating endothelium-derived relaxing factor (often represented 'nitric oxide'). Worthy of note is that vascular generation of nitric oxide has beneficial anti-inflammatory, anti-platelet and vasodilatory actions. The upregulation of eNOS by statins is mediated through inhibition of synthesis of isoprenoids and subsequent prevention of isoprenylation of small GTPase Rho, whereas statin-induced activation of eNOS is mediated through activation of phosphotidylinositol-3-kinase (PI3K)/protein kinase B (PKB/Akt) signals. Additionally, statins enhance eNOS activation by abrogating caveolin-1 expression in vascular endothelium. In light of this view-point, we suggest in this review that eNOS upregulation and activation, in part, could play a fundamental role in the cardiovascular defensive potential of statins. The eNOS modulatory role of statins may have an imperative influence on the functional regulation of cardiovascular system and may offer new perspectives for the better use of statins in ameliorating cardiovascular disorders.     

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.     

Statins: potential new indications in inflammatory conditions

Hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) are potent cholesterol-lowering drugs. In addition to their cholesterol-lowering properties, statins exert a number of so-called 'pleiotropic', vasculoprotective actions that include improvement of endothelial function, increased nitric oxide (NO) bioavailability, antioxidant properties, stabilisation of atherosclerotic plaques, regulation of progenitor cells, inhibition of inflammatory responses and immunomodulatory actions. Pleiotropic actions of statins may have potential clinical impact in vascular disease beyond cholesterol lowering. The ongoing Justification for the Use of statins in Primary prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER), for example, tests the effects of statins in the primary prevention of cardiovascular disease among patients with low levels of low-density lipoprotein cholesterol (LDL-C) and elevated high-sensitivity C-reactive protein (hs-CRP). Additionally, previous studies have shown that although cholesterol is not an established stroke risk factor, statin therapy is associated with a reduction in the incidence of strokes. It is known that sudden withdrawal of statin treatment may acutely impair vascular function and increase morbidity and mortality in patients with vascular disease. Furthermore, the anti-inflammatory effects of statins may have clinical impact in a number of non-vascular conditions including multiple sclerosis and rheumatoid arthritis.     

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.     

Management of hyperlipidemia with statins in the older patient

Numerous randomized, double-blind, placebo-controlled studies and observational studies have demonstrated that statins decrease mortality and major cardiovascular events in older high-risk persons with hypercholesterolemia. The Heart Protection Study found that statins decreased mortality and major cardiovascular events in high-risk persons regardless of the initial level of serum lipids, age, or gender. The updated National Cholesterol Education Program (NCEP) III guidelines state that in very high-risk patients, a serum low-density lipoprotein (LDL) cholesterol level of <70 mg/dl is a reasonable clinical strategy, regardless of age. When a high-risk person has hypertriglyceridemia or low serum high-density lipoprotein cholesterol, consideration can be given to combining a fibrate or nicotinic acid with an LDL cholesterol-lowering drug. For moderately high-risk persons (2 or more risk factors and a 10-year risk for coronary heart disease of 10% to 20%), the serum LDL cholesterol should be decreased to <100 mg/dl. When LDL cholesterol-lowering drug therapy is used to treat high-risk persons or moderately high-risk persons, the serum LDL cholesterol should be decreased at least 30% to 40%.     

The pleiotropic effects of statins

PURPOSE OF REVIEW: 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) are the most widely prescribed drugs worldwide for lowering cholesterol levels. In use for more than 15 years, they have demonstrated efficacy, safety, and tolerability across a broad range of patients. This class of drugs has been designed to lower the cholesterol level by competitively inhibiting the enzyme responsible for its biosynthesis and thereby to play a major role in reducing cardiovascular risk. However, both basic evidence and clinical evidence also supports the idea that reductions in cardiovascular risk are dependent on mechanisms beyond cholesterol reduction alone, such as the reduction of endothelial dysfunction, inhibition of inflammatory responses, stabilization of atherosclerotic plaques, and modulation of procoagulant activity and platelet function. RECENT FINDINGS: In fact, as shown in several clinical trials, the beneficial effects of statin treatment begin earlier than its cholesterol-lowering effect. These other mechanisms could act in concert with the potent low-density lipoprotein cholesterol-lowering effects of this class of drugs to exert early and lasting cardiovascular protective effects. Recently, several studies have shown that an intensive lipid-lowering regimen with a statin provides greater protection against death or major cardiovascular events than does a standard regimen. SUMMARY: This review summarizes the new findings in these pleiotropic effects and describes their impact on vascular processes.     

PCI术前强化他汀治疗的新进展

他汀类药物可减少围手术期心肌损伤、弥漫性心肌坏死、心肌梗死和无复流现象发生,可能与其降低炎症反应、改善内皮功能、抑制血栓形成等多效性作用有关。此外,强化他汀治疗可减少经皮冠状动脉介入（percutaneous coronary intervention,PCI）术后发生对比剂肾病(contrast-induced nephropathy,CIN)的风险,可能是全因死亡率及心血管死亡率减低的非心源性机制。目前PCI术前强化他汀治疗成为临床医生关注的热点,本文将对PCI术前强化他汀的获益、作用机制以及安全性的相关研究新进展做一综述。     

他汀类药物治疗慢性心力衰竭的进展

他汀类药被广泛用于降低胆固醇,但近来的实验室及临床研究发现,他汀类药物用于慢性心力衰竭治疗,可延缓慢性心力衰竭进展,改善心功能,降低慢性心力衰竭致残率、死亡率。他汀类药物治疗慢性心力衰竭的机制与改善血管内皮功能、抗氧化应激、抗炎、改善心肌重构、调节神经及内分泌的“多重效应”有关。     

Aktuelle Lipidtherapie bei Diabetes mellitus

Background

Patients with type 2 diabetes are at increased risk of developing cardiovascular diseases and have been shown to greatly benefit from tight control not only of the blood glucose but also of LDL (low density lipoprotein) cholesterol levels.

Cardiovascular risk reduction

So far an aggressive treatment regimen with potent statins has been recommended. The IMPROVE IT study caused a paradigm shift in that it showed additional cardiovascular risk reduction if LDL cholesterol was reduced below target levels independent of the pleiotropic statin actions. These effects were even more significant in patients with type 2 diabetes.

Conclusions

Therefore even though statins are still first choice, a combination with ezetimibe or the novel PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors is warranted to further reduce cardiovascular risk. As secondary targets, non-HDL (high density lipoprotein) cholesterol or ApoB (apolipoprotein B) levels serve as surrogate markers for atherogenic lipid particles. Depending on the individual lipid levels, combination therapy with fibrates or ω?3 fatty acids might be of benefit.

     

Pleiotropic effects and cholesterol-lowering therapy

HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase inhibitors, or 'statins', have revolutionized the management of patients with atherosclerotic vascular disease. Following 2 large acute coronary syndrome trials, additional clinical benefit outside their effect of low-density lipoprotein (LDL) lowering was proposed. This concept was introduced following the observation of cardiovascular event rate reduction, only weeks after initiation of treatment and supposedly before the effect of LDL lowering could have influenced atheroma volume burden. Furthermore, there has been a substantial compilation of experimental data demonstrating beneficial effects of statins on inflammation, thrombosis, platelet aggregation, immunomodulation and endothelial function. These are hypothesized to occur via the interruption of the mevalonate pathway. However, the absolute benefit of these non-lipid-lowering effects, often referred to as 'pleiotropic effects', has been challenged by meta-analysis data. Anti-inflammatory actions have also been proposed to occur by the process of LDL lowering alone rather than due to a unique property of statins. Furthermore, some experimental data reports have shown evidence of pleiotropic effects in non-statin lipid-modifying agents. In this review article, we consolidate what is known so far and critically analyse the literature in order to highlight the outstanding issues.     

他汀获益机制——抗动脉粥样硬化是关键

他汀治疗对改善心血管病人预后方面,取得了令人瞩目的成就。除了公认的降胆固醇作用外,研究证据亦表明,他汀具有明确的保护血管内皮细胞、抑制平滑肌细胞增生、抗炎、抗氧化、抑制血小板聚集和稳定斑块等作用。虽然临床中他汀降脂的同时均伴有心血管事件的减少,但仍有部分预后终点改善不能用低密度脂蛋白一胆固醇水平下降所解释,而刚好与他汀调脂外机制的作用吻合。显然,他汀治疗与预后终点改善间存在重要的干预机制,那就是包括他汀调脂在内的抗动脉粥样硬化作用。     

Do the pleiotropic effects of statins have a clinical significance?

The effectiveness of statins in the treatment of hypercholesterolaemia and the reduction in cardiovascular risk have now been clearly demonstrated. While their beneficial effects on the reduction of atherosclerosis and its clinical manifestations occur mainly due to the reduction in LDL-cholesterol, some pleiotropic actions which are independent of LDL-cholesterol have frequently been put forward in recent years. In effect, an improvement in endothelial function (increased vasodilatation in particular), an in vitro reduction in smooth muscle cell proliferation, a reduction in thrombosis, promotion of fibrinolysis and positive effects on atheromatous plaque stabilisation have been observed. Elsewhere, some anti-oxidant and anti-inflammatory properties have been attributed to statins. However, many of the described 'pleiotropic' effects are not due to the direct action of statins, but occur with the reduction in LDL-cholesterol. Furthermore, certain in vitro effects only occur at much higher than therapeutic doses. These considerations have therefore caused doubt about the clinical significance of the statins' pleiotropic effects. Finally, analysis of the results of human clinical trials on statins have proved that their effectiveness relies on the reduction in LDL-cholesterol and that the pleiotropic effects do not actually have a clinical implication.     

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.     

Comparison of cardiovascular events in patients with angiographically documented coronary narrowing with combined renin-angiotensin system inhibitor plus statin versus renin-angiotensin system inhibitor alone versus statin alone (from the Japanese Coronary Artery Disease Study)

Statins and renin-angiotensin system (RAS) inhibitors are 2 classes of drugs prescribed frequently in clinical practice that may have pleiotropic effects in addition to cholesterol-lowering and blood pressure-lowering effects, respectively. Combined treatment with statins and RAS inhibitors may have additional benefits beyond each monotherapy. We assessed the usefulness of the combined treatment in the Japanese Coronary Artery Disease (JCAD) Study population. In the JCAD Study, 13,812 patients with angiographically shown narrowing in > or =1 of 3 major coronary arteries were followed up for a mean of 2.7 years. The primary end point of the study was all cardiovascular events. In the present study, baseline covariates possibly influencing the event rate were adjusted between the control and treatment groups. Although there were no statistically significant differences in event rates between patients receiving neither statins nor RAS inhibitors and those receiving either drug, Kaplan-Meier analysis showed a 22% decrease (p = 0.0286) in the event rate with combined treatment. In conclusion, statins combined with RAS inhibitors may decrease cardiovascular events in patients with coronary artery disease.     

Cross-talk between statins and PPARalpha in cardiovascular diseases: clinical evidence and basic mechanisms

Although a change in lifestyle is the first choice in controlling cardiovascular risk, lipid-lowering drugs are effective in normalizing different forms of atherogenic dyslipidemia. Although statins are a class of drugs which primarily lower low-density lipoprotein cholesterol, fibrates decrease triglycerides, normalize the low-density lipoprotein cholesterol profile, and increase high-density lipoprotein cholesterol. As lipids are important determinants for cardiovascular diseases, these drugs reduce cardiovascular morbidity. However, a number of recent studies indicate that, in addition to their lipid-normalizing activities, statins and fibrates exhibit pleiotropic actions, such as inhibit inflammation, improve endothelial function, suppress the production of reactive oxygen species, etc. Statins are competitive inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase, the rate-limiting enzyme of cholesterol synthesis, whereas fibrates are activators of the nuclear receptor peroxisome proliferator-activated receptor alpha (PPARalpha). The similarity between the pleiotropic effects of statins and fibrates is remarkable and suggests a mechanistic link between these two classes of drugs. Here we discuss recent data on the cross-talk between statins and PPARalpha agonists and the mechanisms behind these actions.     

Multiorgan-protective actions of blockers of the renin-angiotensin system, statins and erythropoietin: common pleiotropic effects in reno-, cardio- and neuroprotection

Renal diseases induce nephroprotective measures that may affect the heart, brain and other organs. In addition, many cardiovascular and neurological diseases are accompanied by renal lesions. For these reasons, multiorgan-protective measures, including cardio-, reno- and neuro-protective measures, are necessary to treat these diseases. The drugs used in nephrology are often pleiotropic. Although they usually address a single organ or tissue, many of them have complex actions that may provide multiorgan-protection. The present paper aims to review 3 classes of drugs that are commonly prescribed in nephrological practice: statins, RAS blockers (such as ACEIs and ARBs) and erythropoietin (EPO). This paper highlights the renoprotective actions, as well as those that are protective of the heart, brain and other organs, of these drugs at the cellular and molecular level. Their protective actions are attributable to their main effects and pleiotropic effects. The protective pleiotropic actions of these drugs may be exerted on multiple organs, making them multiorgan-protective. Another objective is to analyse the shared multiorgan-protective pleiotropic effects of RAS blockers (ACEIs and ARBs), statins and erythropoietin. This will allow for the practical association of the main renoprotective drugs with multiorgan protection.