hyperlipidemia is a major risk factor for atherosclerosis , and several large scale trials demonstrate that cholesterol lowering therapy with 3-hydroxy-3-methyl coenzyme a ( hmgcoa ) reductase inhibitors reduces coronary event rates in both primary and secondary prevention . paradoxes revealed by these trials , however , raise the possibility that statins may have effects that go beyond simple lipid reduction . despite large reductions in cardiac event rates , second , several trials suggest that the observed clinical benefit of statin therapy is greater than that expected on the basis of low density lipoprotein ( ldl ) reduction alone . for instance , when the framingham coronary heart disease model was applied to the west of scotland coronary prevention study ( woscops ) population , the model accurately predicted risk in the placebo group but underestimated the risk reduction in the pravastatin group . the benefits of ldl reduction with statins also appear to occur earlier than is observed with other cholesterol lowering therapies such as cholestyramine and ileal bypass surgery , even among patients with similar levels of cholesterol after therapy . finally , statins reduce the risk of stroke , but ldl is not an important risk factor for stroke . one additional mechanism by which statins may reduce vascular event rates relates to potential anti - inflammatory effects of these agents . inflammatory processes , in this regard , play a pivotal role in the pathogenesis of atherosclerosis , and elevated plasma levels of markers of inflammation such as high sensitivity c - reactive protein ( hs - crp ) , serum amyloid a , il-6 and soluble intercellular adhesion molecule-1 have been shown to predict cardiovascular events . unstable plaques are characterized by active inflammation that overwhelms the plaque 's capacity for repair . macrophages and t cells are abundant in the regions of plaque rupture , while smooth muscle cells are few . stable plaques , conversely , contain few inflammatory cells and abundant smooth muscle cells . macrophages are capable of degrading the extracellular matrix and , by secreting matrix metalloproteinase ( mmp ) , may weaken the fibrous cap and thus predispose an atheromatous plaque to rupture . fluvastatin and simvastatin have recently been shown to inhibit mmp-9 ( gelatinase b ) activity and secretion by macrophages . this effect is reversed by the addition of mevalonate , suggesting that it is mediated by hmgcoa reductase inhibition . mmp-1 , or interstitial collagenase , is also thought to play a role in atherosclerotic plaque rupture . fluvastatin appears to decrease mmp-1 expression in human vascular endothelial cells in a time- and dose - dependent manner . this effect is also seen with lovastatin and again is completely blocked by coincubation with mevalonate . the concentration of fluvastatin required to reduce mmp-1 expression is similar to that seen in clinical practice . pravastatin has been shown to cause changes in the composition of atheromatous plaque independent of its cholesterol lowering effect . pravastatin - treated monkeys have better vasodilator function and favorable changes in the composition of atheromatous plaque compared with control animals with similar changes in lipid profile caused by diet alone . the pravastatin - treated monkeys had fewer macrophages in the intima and media , less calcification and less neovascularization in the intima . pravastatin may thus serve to stabilize vulnerable plaques by promoting regression of fragile , rupture prone microvessels in the intima . oxidized ldl causes monocyte tissue factor expression , and the proliferation and apoptosis of smooth muscle cells . oxidized ldl also inhibits nitric oxide synthase activity and hence impairs endothelium - dependent vasodilation . statins reduce the cholesterol content of lipoproteins through their hypocholesterolemic effects , and thus lower the amount of substrate available for oxidation . simvastatin has been shown to reduce macrophage superoxide formation , thereby decreasing cell oxygen production . fluvastatin and lovastatin bind to phospholipid on the surface of ldl and thus prevent diffusion into the lipoprotein core of free radicals generated under oxidative stress . statins can directly upregulate endothelial nitric oxide synthase ( enos ) expression in vitro under cholesterol clamped conditions . both simvastatin and lovastatin upregulate enos expression almost fourfold , and completely prevent its downregulation by oxidized ldl . a significant increase in endothelium - dependent vasodilation in patients with moderate hypercholesterolemia has been observed after 4 weeks of treatment with simvastatin . the neuroprotective effect of statins is absent in enos deficient mice , suggesting that enhanced enos activity by statins is a main mechanism by which hmgcoa reductase inhibitors protect against cerebral injury . hypercholesterolemic rats treated with fluvastatin have attenuated leukocyte adherence responses to platelet activation factor and leukotriene b4 . statins inhibit the expression of cd-11b on the cell surface , thus reducing the adhesiveness of macrophages to the vascular endothelium . this decrease in monocyte chemoattractant protein-1 is related to a reduction in nuclear factor b activation , a transcription factor involved in the induction of monocyte chemoattractant protein-1 and other proinflammatory cytokines such as il-1 and tumor necrosis factor- ( tnf- ) . statins also cause decreased macrophage expression of soluble intercellular adhesion molecule-1 and lipopolysaccharide - induced secretion of il-6 and tnf- by monocytes and macrophages . recent data show that simvastatin therapy for 8 weeks reduces monocyte expression of tnf- and il-1 by 49 and 35% , respectively ; this is intriguing data because elevated plasma levels of both soluble intercellular adhesion molecule-1 and il-6 have been shown to predict risk for myocardial infarction . a recent analysis from the cholesterol and recurrent events ( care ) trial showed that plasma concentrations of tnf- are also persistently elevated among postmyocardial infarction patients at increased risk for coronary events . these findings provide supportive evidence that anti - inflammatory effects of statins may make an important contribution to their clinical efficacy . in addition to reducing synthesis of cholesterol , hmgcoa reductase inhibitors lower levels of isoprenoids , which are derived from intermediates in the cholesterol biosynthetic pathway . isoprenoids prenylate a number of cellular proteins that play key roles in cell growth and signal transduction pathways such as g proteins , which have been shown to modulate mitogenic pathways . statins have been reported to induce apoptosis in cultured vascular smooth muscle cells , and both atorvastatin and fluvastatin increase apoptosis in injured carotid arteries in rabbits . both simvastatin and fluvastatin inhibit smooth muscle cell proliferation , while pravastatin is devoid of such an effect . lipophilic statins ( simvastatin and fluvastatin ) have been shown to decrease tissue factor expression and activity in cultured human monocyte derived macrophages . statins also increase tissue plasminogen activator levels and cause a concomitant fall in plasminogen activating inhibitor-1 activity . other in vivo effects common to statins include a reduction of platelet aggregation ex vivo and in vitro . pravastatin therapy is associated with a reduction in the number of episodes of rejection following cardiac transplantation . the inhibition of natural killer t cell activity by pravastatin may explain , in part , this beneficial effect . although transplant vasculopathy is an entity distinct from atherosclerotic disease , similar inflammatory mediators may contribute to plaque instability . clinical data regarding the anti - inflammatory role of statins has until recently been limited . intriguing data from the care trial suggests that pravastatin may directly attenuate the adverse effects of inflammation in a process independent of ldl lowering . the care trial specifically randomized patients with a prior history of myocardial infarction to receive either 40 mg pravastatin daily or placebo . patients with evidence of persistent inflammation ( as evidenced by elevation of both hs - crp and serum amyloid a ) were at increased risk for recurrent cardiovascular events . the study group with the highest risk of recurrent events was that of patients with persistent evidence of inflammation who were assigned to placebo ( relative risk=2.81 , p = 0.007 ) . in a stratified analysis , however , the association between inflammation and risk was significant among those randomized to placebo ( relative risk=2.11 , p = 0.048 ) but was attenuated and not significant among those randomized to pravastatin ( relative risk=1.29 , p = 0.5 ) . the proportion of recurrent cardiac events prevented by pravastatin was 54% among those patients with persistent evidence of inflammation compared with 25% among those without inflammation ( fig . this difference in benefit was observed despite identical baseline ldl levels in these two groups . compared with placebo , moreover , pravastatin therapy resulted in a 22% reduction in median hs - crp levels over a 5 year period ( fig . 2 ) , an effect that was independent of statin - induced changes in ldl . taken together , these data suggest that , in addition to lowering ldl cholesterol , pravastatin may have clinically important anti - inflammatory properties . relative risks of recurrent coronary events among postmyocardial infarction patients according to the presence or absence of ongoing inflammation and according to placebo or pravastatin therapy . median ( solid lines ) and mean ( dotted lines ) levels of hs - crp at baseline and at 5 years among participants in the care trial , according to placebo or pravastatin assignment . atorvastatin and simvastatin have also been shown to reduce crp levels in a small study of 66 hyperlipidemic patients with coronary artery disease . simvastatin has been found to reduce crp levels in type ii diabetic patients with hyperlipidemia . the observed change in crp did not correlate with changes in total cholesterol or high density lipoprotein . the relative importance of hs - crp reduction compared with ldl reduction is currently uncertain , and several ongoing studies are directly addressing this issue . what is clear , however , is that markers of inflammation such as hs - crp appear to add to the predictive value of lipid screening in terms of predicting cardiovascular risk ( fig . it is also clear , at least in secondary prevention , that statins lower hs - crp levels even in the absence of hyperlipidemia . it has thus been hypothesized that screening for inflammatory markers may provide an improved method to target statin therapy in primary prevention . relative risk of first cardiovascular events in apparently healthy men and women according to baseline levels of the total cholesterol : high density lipoprotein cholesterol ( tc : hdlc ) ratio and by baseline level of hs - crp . it is not currently known if all statins have clinically relevant anti - inflammatory effects or whether any one agent is more powerful than another is in this regard . furthermore , the time course of the anti - inflammatory effects of statins is not known . clinical trials with head to head comparison of statins ( such as the prove - it study ) and studies designed to examine the time - course of statin therapy on hs - crp levels ( such as the prince trial ) will help to resolve these remaining questions .
large scale clinical trials demonstrate significant reductions in cardiovascular event rates with statin therapy . the observed benefit of statin therapy , however , may be larger in these trials than that expected on the basis of lipid lowering alone . 
 emerging evidence from both clinical trials and basic science studies suggest that statins have anti - inflammatory properties , which may additionally lead to clinical efficacy . 
 measurement of markers of inflammation such as high sensitivity c - reactive protein in addition to lipid parameters may help identify those patients who will benefit most from statin therapy .