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(Stroke. 1997;28:2315-2320.)
© 1997 American Heart Association, Inc.

Articles

Vascular Effects of Statins in Stroke

Norman Delanty, MD; Carl J. Vaughan, MD

From the Departments of Neurology (N.D.) and Medicine (C.J.V.), New York Hospital, Cornell Medical Center, New York, NY.

Correspondence to Carl J. Vaughan, MD, Department of Medicine, New York Hospital–Cornell Medical Center, 525 E 68th St, New York, NY 10021. E-mail cvaughan{at}nyhs.med.cornell.edu

	Abstract

Top Abstract Introduction Trials of Statins and... Statins, Lipids, and... Statins and Endothelium Statins, Platelets, and... Summary Conclusion References

 
Background Recent clinical trials and meta-analyses of ß-hydroxy-ß-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) have demonstrated a reduction in ischemic stroke in patients with a history of coronary artery disease both with and without elevations of serum cholesterol. This review summarizes clinical trials of these compounds and their recent impact on stroke and explores the underlying vascular mechanisms of their actions.

Summary of Review Use of statins in patients with vascular disease has been shown to lower the incidence of stroke by approximately 30%. Statins exhibit a number of antiatherosclerotic and antithrombotic properties that likely underlie the recently observed reductions in cerebrovascular disease. Statins reduce inflammatory, proliferative, and thrombogenic processes in plaque, making it less likely to rupture. Additionally, they reverse the endothelial dysfunction and platelet activation accompanying hypercholesterolemia and may reduce the tendency to thrombosis.

Conclusions Hypercholesterolemia has reemerged as a risk factor for ischemic stroke. Statins protect against thromboembolic stroke through multiple beneficial effects within the vascular milieu. Further data are awaited to support the growing importance of cholesterol as a risk factor for ischemic stroke and the benefits of statin therapy in patients with cerebrovascular disease.

Key Words: cholesterol • HMG-CoA reductase inhibitors • hypercholesterolemia

	Introduction

Top Abstract Introduction Trials of Statins and... Statins, Lipids, and... Statins and Endothelium Statins, Platelets, and... Summary Conclusion References

 
Despite its established role in the pathogenesis of coronary artery disease,^1,2 the evidence that hypercholesterolemia is an important risk factor in the development of cerebrovascular disease has been equivocal.^3–7 Recent clinical trial and surrogate end point data strongly suggest that therapy with the cholesterol-lowering agents ß-hydroxy-ß-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) protect against stroke and carotid atherosclerosis. This report outlines the beneficial effects of statin therapy in cerebrovascular disease and highlights mechanisms by which statins may be protective beyond their effects on lowering cholesterol.

Classically the risk factors for vascular disease have had different significance in different vascular beds. Hypercholesterolemia has been considered a major determinant of coronary disease and of little significance in terms of stroke. In contrast, hypertension has been considered a major risk factor for stroke and of much lesser importance in terms of its impact on coronary atherosclerosis. Hypercholesterolemia and hypertension are not categorical risk factors for both coronary disease and stroke, respectively, but rather have different relative importance in both the coronary and cerebral systems (Fig 1).

View larger version (23K): [in this window] [in a new window]   Figure 1. Risk factors for coronary artery disease and stroke. Hypothetical representation of relative importance of hypercholesterolemia and hypertension as risk factors for coronary artery disease and stroke.

Prior epidemiological data from the Multiple Risk Factor Intervention Trial (MRFIT) suggest that hypercholesterolemia is a risk factor for nonhemorrhagic or ischemic stroke⁸; this is supported by two previous trials in which hemorrhagic and ischemic stroke were examined separately.^9,10 The majority of nonlacunar ischemic strokes are caused by thromboemboli arising from atheromatous disease outside the brain, either from the carotid artery,^11,12 the aortic arch,^13–15 or the heart,¹⁶ where hypercholesterolemia is an important risk factor for the development of atherosclerosis. Furthermore, coronary artery disease causes ischemic left ventricular dysfunction,¹⁷ postinfarction wall motion abnormalities, and atrial fibrillation, all of which significantly increase stroke risk. Thus, the reduction of coronary artery disease with cholesterol-lowering therapy should itself lead to reductions in the incidence of ischemic stroke.

Although it is likely that statins reduce precerebral and large-vessel cerebral atherosclerosis, direct evidence is not available to assess differential effects of statin therapy on various subtypes of ischemic stroke. It is unknown whether statin therapy reduces small-vessel lipohyalinosis and thus prevents lacunar stroke. Many clinical "lacunes" are not due to lipohyalinosis but to artery-to-artery embolization. Furthermore, since hypertension and diabetes mellitus are frequently associated with hypercholesterolemia, statin therapy may ameliorate the small-vessel atherosclerotic effects of these potent risk factors for lacunar infarction. Prospective data are needed to determine these questions.

	Trials of Statins and Stroke

Top Abstract Introduction Trials of Statins and... Statins, Lipids, and... Statins and Endothelium Statins, Platelets, and... Summary Conclusion References

 
The reemergence of hypercholesterolemia as an important risk factor for stroke has been supported by recent prospective placebo-controlled clinical trials with various statins. These compounds significantly reduce the risk of myocardial infarction by 30% in patients with a prior history of coronary heart disease and hypercholesterolemia,¹⁸ in patients with hypercholesterolemia without a history of clinical heart disease,¹⁹ and in patients with heart disease with average serum cholesterol levels.²⁰ These recent studies also suggest that statins have beneficial effects that extend beyond the coronary vascular bed. Stroke was a specified end point in the Cholesterol and Recurrent Events (CARE) trial of 40 mg of pravastatin daily versus placebo in 4159 patients with a history of myocardial infarction but with average cholesterol levels.²⁰ Pravastatin significantly reduced stroke incidence by 31%, without an increase in risk of hemorrhagic stroke. Post hoc analysis of the Scandinavian Simvastatin Survival Study (4S),¹⁸ which examined the effects of 20 to 40 mg daily of simvastatin in patients with known coronary artery disease, also showed a similar significant reduction in stroke incidence in the treatment group without hemorrhagic complications. In the West of Scotland primary prevention trial in middle-aged men with hypercholesterolemia, there was a nonsignificant 11% reduction in stroke noted during 5 years of follow-up.¹⁹ The clinical benefit of statins in preventing ischemic stroke in secondary prevention trials is corroborated by two recent meta-analyses that reported that statin therapy significantly lowers stroke risk by approximately 30%^21,22 (Table). These meta-analyses suggest that statin therapy can reduce stroke risk in patients with evidence of vascular disease by an extent comparable to that of aspirin. Clinical benefit of statins is also supported by the observation that both pravastatin and lovastatin reverse progression of ultrasonically assessed carotid intimal-medial thickening. The Asymptomatic Carotid Artery Progression Study (ACAPS)²³ demonstrated reversal or slowing of the typical progression of intimal-medial thickening in the carotid artery using B-mode ultrasound in men and women with moderately elevated cholesterol treated for 3 years with lovastatin. Similarly, the Pravastatin, Lipids, and Atherosclerosis in the Carotids II (PLAC-II) study²⁴ demonstrated a significant 35% reduction in carotid intimal-medial thickness using B-mode ultrasound.

View this table: [in this window] [in a new window]   Table 1. Summary of Major Clinical Intervention Trials and Meta-analyses of the Effects of Statins on Stroke

	Statins, Lipids, and Atherosclerosis

Top Abstract Introduction Trials of Statins and... Statins, Lipids, and... Statins and Endothelium Statins, Platelets, and... Summary Conclusion References

 
Statins inhibit HMG-CoA reductase, the rate-limiting enzyme in cholesterol synthesis, leading to a depletion of intracellular cholesterol in hepatocytes. This in turn induces an upregulation of hepatic LDL receptors, which promotes a lowering of LDL levels. The drugs generally lower LDL in a dose-dependent manner, the optimum doses reducing LDL by 25% to 35%. Although many cholesterol-lowering drugs were available before the discovery of statins, none were as potent as the statins or as free of untoward side effects. Prior intervention studies with other classes of compounds used to lower serum cholesterol have shown equivocal effects on the incidence of stroke. However, this may have been due to unrecognized adverse actions of some of the agents used. In contrast, statins appear to have many beneficial effects on vascular physiology that may be independent of their effects on cholesterol reduction.²⁵ These adjunctive effects of statins may help to explain the significant recent reduction in both coronary and cerebrovascular events. It is likely that these favorable modulations in the vascular milieu occur not only in the coronary bed (where they have been most extensively studied) but also in the aorta, carotids, and intracranial vasculature.

The reduction in clinical events secondary to lipid lowering has traditionally been attributed to depletion of both the lipid and foam cell content of plaque by reducing cholesterol deposition and by promoting cholesterol efflux from plaque. It has been hypothesized that this alteration of plaque architecture makes it less prone to fissuring, disruption, and acute thrombosis. In coronary arteries, lowering LDL has yielded significant clinical benefits in a number of trials, whereas the magnitude of the accompanying anatomic plaque regression demonstrated by coronary angiography has been relatively small. This discrepancy between angiographic and clinical data in the coronary artery suggests that plaque regression is not the only beneficial mechanism of action of statins in the vasculature. Whereas changes in plaque composition and development are likely to contribute significantly to the reduction in clinical end points in the long term, concurrent changes in other constituents of plaque or vessel wall may contribute to and explain the early benefits of statin therapy in the prevention of acute vascular events.

Atherosclerosis is a chronic inflammatory disorder characterized by the presence of monocytes or macrophages and T-lymphocytes in the atherosclerotic plaque as well as the proliferation of smooth muscle cells (SMC), elaboration of extracellular matrix, and neovascularization. Evidence is accumulating that statin therapy favorably modulates a number of constituents of atherosclerotic plaque, which confers stability on the plaque and makes rupture and thrombosis less likely. Pravastatin has been shown to directly influence cholesterol synthesis in macrophages in vivo and in vitro, potentially reducing cholesterol accumulation within these cells.²⁶ Reducing macrophage activity in plaque likely attenuates macrophage activation, which has been shown to be associated with plaque instability.²⁷ Recently macrophages have been implicated in the pathophysiology of acute vascular syndromes by producing enzymes, including members of the metalloproteinase family (interstitial collagenase, gelatinase, and stromelysin) that digest and weaken the plaque cap, making disruption more likely. ²⁸ Among the many other products elaborated by macrophages is tissue factor, a membrane-bound glycoprotein that plays an integral role in the extrinsic pathway of blood coagulation. Recently therapy with fluvastatin has been shown to inhibit tissue factor expression by cultured human macrophages, suggesting that this may be a mechanism by which these compounds reduce thrombotic events.²⁹ Statins can also reduce SMC replication within plaque, and this inhibition of SMC proliferation by statins can be overcome by mevalonate, an intermediate in cholesterol biosynthesis.³⁰ It appears that statins have direct antiatherosclerotic effects on the arterial wall, probably through a reduction in the synthesis of intermediates in cholesterol metabolism, such as isoprenoids, compounds that have been implicated in the control of cell proliferation.³¹ Additionally, statins have been shown to modulate immunologic function and to alter regulation of DNA transcription, regulate natural-killer-cell cytotoxicity, and inhibit antibody-dependent cellular cytotoxicity.³² Statin therapy appears to modulate immune cell activation within plaque and may attenuate cellular recruitment and reduce the inflammatory responses that lead to plaque instability.

	Statins and Endothelium

Top Abstract Introduction Trials of Statins and... Statins, Lipids, and... Statins and Endothelium Statins, Platelets, and... Summary Conclusion References

 
Vasoactive factors produced by the endothelium exert a powerful influence on vascular tone in the cerebral circulation. Endothelium-derived relaxing factor or nitric oxide (NO) is produced under basal conditions and mediates endothelium-dependent relaxation in response to a number of stimuli such as platelet activation, shear stress, and concentrations of thrombin, serotonin, and catecholamines. Endothelium-dependent relaxation is reduced in atherosclerosis and hypercholesterolemia,³³ and it appears that LDL is the major determinant of this phenomenon.

LDL is oxidized in vascular endothelial cells to oxidized LDL, which is injurious to the endothelial cell. Oxidized LDL appears to cause endothelial dysfunction through a number of mechanisms, including inactivation of NO by oxygen-derived free radicals and reduced transcription and destabilization of NO synthase mRNA.³⁴ The dysfunctional endothelial cell accordingly promotes platelet adhesion, macrophage migration, vasoconstriction, leukocyte adhesion, and thrombosis. Huang et al³⁵ recently demonstrated larger infarcts in endothelial NO synthase knockout mice than in controls, thus highlighting the important protective effect of the cerebral endothelial NO system.

A number of studies in humans have demonstrated that the endothelial dysfunction accompanying hypercholesterolemia is reversible with statin therapy. In a study of the epicardial coronary arteries,³⁶ pravastatin caused an 80% reduction in constrictor response to acetylcholine in conjunction with a 60% increase in coronary blood flow after 6 months of therapy. In a similar study lovastatin produced comparable improvements in endothelial vasomotor function compared with baseline.³⁷ Paralleling the findings in the coronary vasculature, forearm blood flow abnormalities also seen in hypercholesterolemic subjects have been normalized by statin therapy. Recently, a study examining the effects of cholesterol-lowering therapy with simvastatin on the endothelial function of patients with moderate hypercholesterolemia demonstrated significant improvement in the vasodilator response to acetylcholine after only 4 weeks of treatment.³⁸ In this study improvement in endothelial function increased with continued administration of simvastatin despite the absence of further reduction in serum cholesterol levels. Although the studies to date have primarily focused on improvements in both coronary and forearm blood flow, circulatory systems that are easily amenable to investigation, it is very likely that similar improvements occur in the carotid and cerebral circulations since elevations of serum cholesterol appear to cause global derangement of arterial function. In support of this, Walzl and colleagues³⁹ demonstrated increased cerebral blood flow after acute LDL and fibrinogen reduction with heparin-induced extracorporeal LDL precipitation in 15 patients with diffuse cerebrovascular disease. More recently, single-session LDL apheresis has been shown to improve forearm endothelial function in subjects with hypercholesterolemia.⁴⁰ Taken together, these studies suggest that the endothelial dysfunction accompanying hypercholesterolemia is rapidly reversed by lowering LDL. Statin therapy therefore may reduce the risk of ischemic stroke by improving cerebral endothelial function and vascular tone as well as by reducing the hemorheologic stresses that give rise to atherosclerotic plaque disruption and thrombosis.

	Statins, Platelets, and Thrombosis

Top Abstract Introduction Trials of Statins and... Statins, Lipids, and... Statins and Endothelium Statins, Platelets, and... Summary Conclusion References

 
Platelets contribute to both atherosclerosis and thrombosis and play a pivotal role in the pathophysiology of thromboembolic cerebrovascular disease. A number of platelet abnormalities have been associated with stroke. Enhanced platelet aggregation has been demonstrated in stroke,⁴¹ and increases in mean platelet volume and a reduction in platelet count⁴² have been documented in both the acute and nonacute phases of cerebral ischemia and appear to precede and contribute to the acute event. Moreover, increased thromboxane biosynthesis has been characterized in patients with acute coronary⁴³ and cerebral ischemic syndromes,⁴⁴ indicating platelet activation in these conditions. In platelets, hypercholesterolemia is accompanied by hypersensitivity to various aggregating agents⁴⁵ and an increased platelet cell membrane cholesterol content.⁴⁶ It is becoming increasingly evident that lowering cholesterol reduces the tendency of platelets to aggregate. In subjects with type-IIa hypercholesterolemia, therapy with lovastatin significantly reduces ADP-induced platelet aggregation.⁴⁷ Additionally, in a study of subjects with coronary artery disease, platelet thrombus formation in an ex vivo system was significantly higher in hypercholesterolemic subjects than in normocholesterolemic subjects at baseline, and platelet aggregation decreased at both low and high shear rates in the hypercholesterolemic subjects after 2 to 3 months of therapy with pravastatin.⁴⁸ The mechanism underlying the effect of statin therapy on platelet function is unclear but may be through decreased platelet thromboxane production.⁴⁹ Interestingly, the plasma membrane and cytosolic calcium level of platelets appear altered in hypercholesterolemic states, perhaps increasing platelet reactivity.⁵⁰ Recently, Nofer and colleagues⁵¹ have demonstrated a novel mechanism that increases human platelet activation in hypercholesterolemia through inhibition of platelet Na⁺/H⁺ antiport by LDL.

In addition to an effect on platelets, hypercholesterolemia is also associated with an enhanced thrombotic and a reduced fibrinolytic state that can be reversed by lowering LDL. The impact of cholesterol lowering on thrombotic tendency is highlighted in a study by Wada et al⁵² of subjects with hypercholesterolemia treated with pravastatin, in whom previously elevated levels of thrombin-antithrombin III complex, fibrinopeptide A, thrombomodulin, and plasminogen activator inhibitor-1 were significantly reduced after statin therapy. Acute ischemic stroke has also been shown to be associated with elevation of prothrombotic markers such as fibrinogen,⁵³ plasminogen activator inhibitor-1 activity,⁵⁴ and increased levels of thrombin-antithrombin III complex.⁵⁵ These data suggest that the link between hypercholesterolemia, thrombosis, and ischemic stroke may be more important than previously realized and that this aberrant thrombotic-fibrinolytic balance can be normalized with cholesterol-lowering statin therapy.

	Summary

Top Abstract Introduction Trials of Statins and... Statins, Lipids, and... Statins and Endothelium Statins, Platelets, and... Summary Conclusion References

 
Statins inhibit HMG-CoA reductase, the rate-limiting enzyme in cholesterol synthesis. This leads to a depletion of intracellular cholesterol in hepatocytes, which induces an upregulation of hepatic LDL receptors, which in turn promotes a lowering of LDL levels. Statins appear to stabilize atherosclerotic plaque through a number of mechanisms, including reduced macrophage cholesterol metabolism and activation, attenuated foam cell formation, a reduction in tissue factor expression, and reduced cytokine and immune activation (Fig 2). Statins also inhibit SMC proliferation and activation. The antiproliferative actions of these agents may be due to the reduced levels of oxidized LDL and reduced synthesis of intermediates in cholesterol metabolism, such as isoprenoids, compounds that have been implicated in the control of cell proliferation.

View larger version (28K): [in this window] [in a new window]   Figure 2. Vascular actions of statins. Uptake and endogenous synthesis of cholesterol by macrophages lead to foam cell formation. Release of metalloproteinases by macrophages leads to weakening of the plaque cap and thrombosis. Macrophages elaborate cytokines, which stimulate smooth muscle cell and lymphocyte proliferation, as well as elaboration of tissue factor (TF) expression. In plaque statins appear to attenuate macrophage activation, smooth muscle replication, and TF expression and render plaque more stable and less likely to undergo thrombotic disruption. Statins also ameliorate the endothelial dysfunction that accompanies hypercholesterolemia.

Endothelium-dependent relaxation is reduced in atherosclerosis and hypercholesterolemia, and oxidized LDL may be a major determinant of this phenomenon. In a number of studies statin therapy has been shown to reverse the endothelial dysfunction accompanying the hypercholesterolemic state. Improvements in endothelial function conceivably lead to a normalization of vascular tone, a reduction in hemorheologic stress, and a restoration of the thrombotic-fibrinolytic balance. Statins also reduce enhanced platelet reactivity and the humoral thrombogenic state associated with hypercholesterolemia.

	Conclusion

Top Abstract Introduction Trials of Statins and... Statins, Lipids, and... Statins and Endothelium Statins, Platelets, and... Summary Conclusion References

 
Cholesterol has reemerged as a risk factor for stroke. Recent trials employing statin therapy in patients with coronary artery disease have yielded significant reductions in stroke. This reduction is supported by imaging studies that have demonstrated attenuation of carotid atherosclerosis by statin therapy in tandem with a reduced rate of clinical events. The biological plausibility of a reduced stroke rate as a consequence of cholesterol-lowering therapy is strong since hypercholesterolemia is a potent reversible risk factor for precerebral atherosclerosis and thus artery-to-artery embolic stroke. Moreover, evidence is accumulating that statin therapy favorably modulates a number of abnormalities in the vasculature that accompany the hypercholesterolemic state. Statins appear to render plaque more stable and less likely to undergo thrombotic disruption. Statins also ameliorate the endothelial dysfunction that accompanies hypercholesterolemia and reduce the associated hemorheologic stress. Finally, statin therapy has a beneficial impact on both platelet and coagulation abnormalities that are associated with hypercholesterolemia and that appear to be important in the pathophysiology of thromboembolic stroke.

Specific evidence that statins reduce stroke risk in patients with cerebrovascular disease may become available after the completion of the ongoing Medical Research Council/British Heart Foundation Heart Protection Study using simvastatin in patients with transient ischemic attack or minor ischemic stroke.⁵⁶ At present, clinical trial and basic science evidence supports the role of statin therapy in preventing ischemic stroke. Further work is required to address the specific effects of statins within the cerebral vasculature and to define patient subgroups with or at risk of cerebrovascular disease who may benefit from statin therapy.

Received June 2, 1997; revision received August 6, 1997; accepted August 25, 1997.

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