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.     

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.     

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.     

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.     

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.     

The role of statins in the prevention of ischemic stroke

Statin treatment has been demonstrated to diminish the risk for stroke in patients with coronary heart disease, hypercholesterolemia, normocholesterolemia, in the elderly, and among hypertensive and diabetic patients. Stroke incidence in patients on statin treatment has been reduced in all these clinical settings involving both primary and secondary prevention but not in patients with previous stroke. Two recent meta-analyses confirm this conclusion. The mechanism by which statins provide benefit against stroke is likely multifactorial, involving both the low-density lipoprotein cholesterol-lowering effect with stabilization of vulnerable plaques, and pleiotropic effects such as improvement of endothelial function, increased nitric oxide bioavailability, antioxidant properties, inhibition of inflammatory responses, immunomodulatory actions, and regulation of progenitor cells.     

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.     

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.     

Beyond Lipid Lowering: The Anti-Hypertensive Role of Statins

INTRODUCTION: The management of the hypercholesterolemic patient has evolved tremendously with the introduction of the HMG-CoA Reductase inhibitors, a class of drugs better known as the statins. Statins modify cholesterol metabolism by inhibiting the rate-limiting enzyme of cholesterol biosynthesis, producing greater decreases in plasma cholesterol levels than previously realized with hypolipidemic therapy. With the advent of the classic statin-megatrials such as the Scandinavian Simvastatin Survival Study (4S), WOSCOPS, CARE, and the more recent Heart Protection Study (HPS), the role of statins in both the primary and secondary prevention and ultimate risk reduction of patients with coronary disease has been firmly established. DISCUSSION: With an increase in use and popularity, a number of beneficial actions of the statins unrelated to their cholesterol-lowering ability have been reported. These effects have generated greater interest in the possible additional roles and indications for the use of these drugs. Of central focus in this paper is the cholesterol-independent benefit of this group of agents on the cardiovascular system, particularly on the lowering of systemic blood pressure. A number of hypotheses have been proposed for this action and these shall be reviewed within this paper. CONCLUSION: We explore recent data that suggests that statins may provide substantial reduction of blood pressure in the hypertensive, hypercholesterolemic patient independent of their lipid-lowering effect. In addition, we review several notable publications that postulate unique mechanisms for this action and benefit. We also present plausible explanations as to why some of the larger statin trials did not report similar such findings.     

Do Statins Cause Diabetes?

A wealth of evidence has established that cholesterol-lowering statin drugs, widely used for the prevention of cardiovascular disease, do increase the risk of new-onset diabetes, possibly by impairing pancreatic beta cell function and decreasing peripheral insulin sensitivity. Groups at particular risk include the elderly, women, and Asians. The diabetogenic effect of statins appear directly related to statin dose and the degree of attained cholesterol lowering. Statins can cause hyperinsulinemia even in the absence of hyperglycemia and the potential mitogenic effects and implications of prolonged hyperinsulinemia are discussed. Suggestions are made as to how physicians might avert the hyperinsulinemic and diabetogenic effects of statin therapy in clinical practice, and modulate the detrimental effects of these drugs on exercise performance. Finally, long-term studies are needed to determine if the deleterious hyperinsulinemic and diabetogenic effects of statin therapy undermine the beneficial cardiovascular disease risk outcomes in various segments of the population.     

The lower the better? Reviewing the evidence for more aggressive cholesterol reduction and goal attainment

There is considerable evidence that more aggressive lowering of low-density lipoprotein (LDL) cholesterol is associated with increased benefits in reducing atherosclerotic disease burden, supporting the notion of 'the lower, the better.' However, achievement of currently recommended goals has proven difficult with lipid-lowering agents at the commonly used doses. Current options for achieving greater LDL cholesterol reductions include use of high doses of the most effective of the available statins and use of high or moderate statin doses in combination with agents that work in a complementary manner (e.g. bile acid sequestrants or niacin). Near-term options may include statins with increased LDL cholesterol-lowering effectiveness and better-tolerated secondary agents that can be combined with statin therapy. Rosuvastatin (Crestor, AstraZeneca) is a new statin that may prove to be of considerable utility in achieving greater LDL cholesterol reductions than are currently possible with existing statins. Recent phase III clinical trials have shown that this agent produces significantly greater LDL cholesterol reductions than atorvastatin, simvastatin, or pravastatin in patients with primary hypercholesterolemia and significantly greater reductions than the maximal dose of atorvastatin in patients with familial hypercholesterolemia.     

Do statins prevent heart failure in patients after myocardial infarction?

3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, or statins, reduce morbidity and mortality in patients with coronary artery disease (CAD). Because CAD is the major cause of heart failure (HF) in developed countries, prevention of CAD may result in reduced HF. Evidence from randomized trials on lipid reduction (Cholesterol and Recurrent Events and the Scandinavian Simvastatin Survival Study) has shown statins to decrease progression to HF. Recently, many beneficial effects of statins have been demonstrated beyond cholesterol lowering. These agents improve endothelial function, exhibit anti-inflammatory properties, and prevent cardiac hypertrophy. Experimental studies have shown attenuation of left ventricular remodeling after myocardial infarction, possibly through reduced oxidative stress. However, no clinical evidence exists to support an effect on ventricular remodeling. Small, short-lasting clinical studies have also suggested that statin therapy might be associated with improved survival in ischemic and nonischemic HF.     

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.     

The role of cholesterol and statins in stroke

Flawed observational studies find weak associations between high cholesterol and ischemic stroke, and low cholesterol and hemorrhagic stroke. Low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides each appear to have individual effects on stroke risk and type. Statins decrease the risk of cerebral infarction in patients with coronary disease, diabetes, hypertension, and hypercholesterolemia. They also significantly decrease the risk of ischemic stroke in patients with recent cerebrovascular disease, while potentially increasing the risk of intracerebral hemorrhage. Lower achieved cholesterol values are associated with greater reductions in stroke risk. Besides their cholesterol-lowering properties, statins are also pleiotropic agents with various neuroprotective mechanisms. Neurologic disability and infarct size are decreased in patients administered statins during stroke. Mortality and neurologic deterioration are higher in patients with statin cessation during acute ischemic stroke. Cholesterol is a modifiable risk factor for stroke, and statins are excellent agents for prophylaxis and acute therapy.     

Beyond lipid lowering: the role of statins in vascular protection

The introduction of the hydroxy methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) in 1987 was a major advance in the prevention and treatment of cardiovascular disease. Several landmark clinical trials have demonstrated the benefit of lipid lowering with statins for the primary and secondary prevention of coronary heart disease (CHD), namely The Scandinavian Simvastatin Survival Study (4S), Cholesterol And Recurrent Events (CARE), Long-term Intervention with Pravastatin in Ischemic Disease (LIPID), West of Scotland Coronary Prevention Study (WOSCOPS) and Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS). Although it is widely accepted that the majority of clinical benefit obtained with statins is a direct result of their lipid-lowering properties, these agents appear to display additional cholesterol-independent or pleiotropic effects on various aspects of cardiovascular disease, including improving endothelial function, decreasing vascular inflammation and enhancing plaque stability. Although the full impact of statin therapy on each of these processes is not fully understood, ongoing studies with current and new statins are likely to shed further light on the potential cholesterol-independent benefits of these agents.     

Pathological Changes in Acute Coronary Syndromes: The Role of Statin Therapy in the Modulation of Inflammation,Endothelial Function and Coagulation

Considerable progress has been made in our understanding of the pathophysiology of coronary artery disease (CAD), their acute presentations as acute coronary syndromes (ACS) and the role of LDL cholesterol. In particular there is clear evidence that atherosclerosis is far from being a process that leads to an amorphous flow limiting lesion on an angiogram, but rather involves a complex interplay between the endothelium, inflammatory cells and the coagulation cascade occurring throughout the coronary vascular bed. While a culprit flow limiting lesion may be effectively treated by a drug eluting stent or coronary bypass surgery, this will have little impact on the global molecular processes that determine recurrent plaque instability at non-culprit sites. The search for systemic long term therapy, which is safe and effective and reduces the changes in inflammation, endothelial function and thrombosis that are the hallmark of ACS, has pushed statins to the forefront. A number of recent clinical trials have shown the benefits of early statin therapy in the treatment of ACS. In addition to their effects on LDL cholesterol, statins have a number of properties collectively referred to as pleiotropic effects, which enable them to modulate the adverse biological changes that are associated with ACS. The purpose of this review is to acquaint the reader with the biological changes that accompany ACS, highlight how these pathways may be modulated for clinical benefit by statins and identify potential novel targets for future therapy.Abbreviated abstract. Acute coronary syndromes are associated with pathological changes in inflammation, endothelial function, and coagulation, and many of these are attenuate by statins in a lipid independent manner. In light of recent clinical trials showing the early benefit of statin therapy in ACS, this review discusses how the pleiotropic effects of statins may result in early clinical benefit.     

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.     

Nonlipid-lowering effects of statins

Optional statement Statins have been shown to effectively reduce cardiovascular events in patients with hypercholesterolemia, diabetes, and coronary disease, and after an acute coronary syndrome in several large-scale clinical trials. Interestingly, numerous studies have suggested that statins exert potentially important effects independent of lipid lowering (ie, improve endothelial function, reduce oxidant stress), and have direct antiinflammatory, antithrombotic, and plaque-stabilizing effects. These beneficial effects may contribute to cardiovascular protection by statin therapy beyond low-density lipoprotein (LDL) cholesterol lowering. Therefore, it remains unclear at present to what extent the beneficial cardiovascular effects of statin treatment are dependent on LDL cholesterol lowering (ie, whether the same effect would be achieved by other modes of lipid lowering). Consequently, statins should be used as a first-line therapy for lipid lowering. Importantly, the observation of LDL cholesterol-independent effects of statins has stimulated clinical studies testing a wider use of statin treatment for diseases that are not thought to be related to increased LDL cholesterol levels, such as in patients with chronic heart failure (in particular dilated cardiomyopathy) and even in inflammatory diseases such as rheumatoid arthritis and multiple sclerosis.     

Clinically relevant pleiotropic effects of statins: drug properties or effects of profound cholesterol reduction?

Clinical trials have firmly established that 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) can induce the regression of vascular atherosclerosis and reduce cardiovascular-related morbidity and death in patients with and without coronary artery disease. It is usually assumed that these beneficial effects are due to the ability of statins to reduce cholesterol synthesis. However, because mevalonic acid is not only the precursor of cholesterol but also of many non-steroidal isoprenoid compounds, the inhibition of HMG-CoA reductase may lead to pleiotropic effects. As shown by the data reported in this review, some statins can interfere with major events involved in the formation of atherosclerotic lesions, regardless of their hypolipidemic properties. The relevance of these effects in humans remains to be established (particularly in view of the high statin doses required to produce a direct vascular action), thus their contribution to the reduction in cardiovascular events observed in clinical trials has become one of the major challenges for future studies aimed at clarifying the anti-atherosclerotic benefits of statins.     

Long-term statin use and psychological well-being

OBJECTIVES: We sought to study the effect of long-term statin use on psychometric measures in an adult population with underlying coronary artery disease (CAD). BACKGROUND: Previous studies have suggested associations between cholesterol lowering and psychological well-being. METHODS: Study subjects were recruited from an outpatient cardiology clinic. Psychological well-being was assessed at baseline and annually during follow-up. The exposure of interest was long-term statin use and the outcomes of interest were depression, anxiety, and hostility. We estimated the odds ratios (ORs) and 95% confidence intervals (CI) that represented the strength of association between statin use (vs. no use of any cholesterol-lowering drug) and the risk of having abnormal depression, anxiety, and hostility scores. RESULTS: Study subjects had an average follow-up of four years and maximum of seven years. Comparing the 140 patients who had continuous use of statins with the 231 patients who did not use any cholesterol-lowering drugs, statin use was associated with lower risk of abnormal depression scores (OR 0.63, 95% CI 0.43 to 0.93), anxiety (OR 0.69, 95% CI 0.47 to 0.99), and hostility (OR 0.77, 95% CI 0.58 to 0.93) after adjustment for the propensity for statin use and potential confounders. The beneficial psychological effects of the statins appeared to be independent of the drugs' cholesterol-lowering effects. CONCLUSIONS: Long-term use of statins among patients with CAD appeared to be associated with reduced risk of anxiety, depression, and hostility.