REVIEW ARTICLE
The evolving role of statins in the management of atherosclerosis
Carl J. Vaughan, MD, MRCPIa,
Antonio M. Gotto, Jr., MD, DPhil, FACCa and
Craig T. Basson, MD, PhD, FACCa
a Division of Cardiology, Department of Medicine, Weill Medical College of Cornell University, The New York Presbyterian Hospital, Starr 4, 525 East 68th Street, New York, New York 10021.USA
Manuscript received February 23, 1999;
revised manuscript received August 3, 1999,
accepted October 5, 1999.
Reprint requests and correspondence: Dr. Craig T. Basson, Director, Molecular Cardiology, Cardiology Division, Department of Medicine, Weill Medical College of Cornell University, Starr 4, 525 East 68th Street, New York, New York 10021.
ctbasson{at}mail.med.cornell.edu
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Abstract
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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.
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Abbreviations and Acronyms
| | AFCAPS/TexCAPS | = Air Force/Texas Coronary Atherosclerosis Prevention Study | | CAD | = coronary artery disease | | CARE | = Cholesterol and Recurrent Events trial | | HDL | = high-density lipoprotein cholesterol | | HMG CoA | = 3-hydroxy-3-methylglutaryl coenzyme A | | LDL | = low-density lipoprotein cholesterol | | LIPID | = Long-term Intervention with Pravastatin in Ischemic Disease study | | MI | = myocardial infarction | | NCEP | = National Cholesterol Education Program | | 4S | = Scandinavian Simvastatin Survival Study | | WOSCOPS | = West of Scotland Coronary Prevention Study |
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Recent advances in the management of hypercholesterolemia are primarily due to the development of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors or "statins." The discovery of statins led to important improvements in the primary and secondary prevention of coronary artery disease (CAD). Initial studies explored the impact of statin therapy on CAD progression and regression. Although angiographic changes in response to therapy were modest, accompanying clinical benefit appeared significant. Subsequent large prospective clinical trials have provided unequivocal evidence that cholesterol-lowering therapy with this class of compounds not only reduces the major coronary event rate in primary and secondary prevention, but also reduces all-cause mortality in secondary prevention. This review describes the evolving impact of this class of compounds from their debut in angiographic trials to their subsequent prominence in large primary and secondary prevention studies. Additionally, we explore the pleiotropic actions of statins in reducing atherosclerosis and its complications.
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Mechanism of action and pharmacology of statins
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HMG CoA reductase is the rate-limiting enzyme for cholesterol formation in the liver and other tissues; HMG CoA reductase responds to negative feedback regulation by both sterol and nonsterol products of mevalonate metabolism through decreased reductase gene expression (1). By inhibiting HMG CoA reductase, statins reduce the hepatocyte cholesterol content and increase expression of low-density lipoprotein (LDL) receptors, responsible for LDL cholesterol uptake via receptor-mediated endocytosis (Fig. 1). Additionally, a second mechanism of LDL reduction may relate to LDL and very-low-density lipoprotein (VLDL) interactions. However, increases in HMG CoA reductase synthesis shortly after statin therapy restore cellular VLDL levels, and the ultimate effect of reductase inhibition is enhanced LDL receptor expression and lower plasma LDL in the setting of normal cellular cholesterol content.
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Figure 1 Regulation of cholesterol synthesis. Inhibition of HMG CoA reductase reduces intracellular cholesterol levels, thus activating a protease, which in turn cleaves sterol regulatory element-binding proteins (SREBPs) from the endoplasmic reticulum. The SREBPs translocate to the nucleus where they upregulate expression of the LDL receptor gene. Enhanced LDL receptor expression increases receptor-mediated endocytosis of LDL and thus lowers serum LDL. Inhibition of HMG CoA reductase also reduces intracellular levels of isoprenoids, which are intermediates in cholesterol biosynthesis.
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Statins differ in absorption, plasma protein binding, excretion and solubility (Table 1) and exhibit variable dose-related efficacy in reducing LDL. In addition to lowering LDL, statins cause relatively small reductions in triglyceride levels (5% to 10%) in conjunction with minor increases in high-density lipoprotein (HDL) cholesterol (5% to 10%), and statin therapy does not reduce lipoprotein (a) (2). Most common adverse effects associated with statin therapy are mild, transient, reversible, and include dyspepsia, abdominal pain and flatulence. However, the most important adverse reactions are elevations in serum transaminases and the development of myositis. The risk of myositis increases in patients receiving statins in conjunction with gemfibrozil, nicotinic acid or macrolides, and there is an appreciable risk of myositis in patients also receiving cyclosporine (3). Administration of drugs that inhibit cytochrome P450, such as azole antifungals, cimetidine and methotrexate, also increases the likelihood of adverse effects.
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Regression of atherosclerosis
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Although vascular remodeling occurs naturally in the evolution of atherosclerosis (4), it was hypothesized that the introduction of cholesterol-lowering therapy would promote regression and/or retard the progression of atheroma. Trials with nonstatin compounds such as the Lipid Research Clinics Coronary Primary Prevention Trial using cholestyramine (5), and the Helsinki Heart Study (6) using gemfibrozil, supported this hypothesis and demonstrated significant reductions in coronary events. Thus, a number of trials (7–14) were conceived to explore the impact of statin therapy on the progression of coronary atherosclerosis using both quantitative and nonquantitative coronary angiography (Table 2). Although these angiographic trials were not powered to examine clinical outcomes, the relatively small angiographic changes reported were accompanied by an unexpected clinical benefit. More recently, the beneficial effects of statin treatment on vein graft atherosclerosis were addressed in the Post Coronary Artery Bypass Graft (Post CABG) Trial (15); aggressive LDL reduction to a mean of 95 mg/dl led to a 31% reduction in the likelihood of progression of graft atherosclerosis and a 29% reduction in the rate of revascularization.
Although these angiographic studies used different patient-selection criteria, different baseline cholesterol levels and variable doses and duration of therapy, they demonstrated that plaque progression is common without therapy (40% to 50% of patients) and is reduced by more than one-third with statin therapy. Although clear plaque regression is uncommon (
10% of patients) without therapy, the frequency of regression more than doubles with statins. Because these trials were designed to explore the anatomic impact of statin therapy they were not powered to assess clinical outcome. Nonetheless, small anatomic changes were accompanied by a greater reduction in clinical events than expected based on the angiographic measures, suggesting that statin therapy may cause regression of lipid-rich lesions prone to rupture (16) and/or that statin therapy modulates atherosclerosis through mechanisms independent of anatomic regression (17). These trials provided an important foundation for subsequent large outcome studies.
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Statins and cardiovascular events
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Landmark clinical trials have demonstrated that HMG CoA reductase inhibitors not only reduce CAD morbidity and mortality but also increase survival in the setting of both hypercholesterolemia or normocholesterolemia (Table 3). The Scandinavian Simvastatin Survival Study (4S) provided the first evidence that cholesterol-lowering therapy can reduce all-cause mortality in subjects with a history of angina pectoris or myocardial infarction (MI) (18). This study of 4,444 men and women with total cholesterol levels of 212 to 310 mg/dl (5.5 to 8.0 mmol/liter) initially used simvastatin at 20 mg/day and then titrated the drug to 10 or 40 mg/day. At five years, all-cause mortality was reduced by 30%, major coronary event rate by 34% and the coronary death rate by 42%. The dramatic results of the 4S study were extended in the West of Scotland Coronary Prevention Study (WOSCOPS), which was a primary-prevention trial of pravastatin 40 mg daily in 6,595 men with mean total cholesterol levels of 272 mg/dl (7.0 mmol/liter) but without documented CAD (19). After an average of 4.9 years of follow-up, all-cause mortality was nonsignificantly reduced by 22% (p = 0.051), but nonfatal MI or death from CAD was significantly reduced by 31% and the CAD death rate reduced by 28%. The need for coronary angiography and revascularization was also significantly lower in the treated group. The Cholesterol and Recurrent Events (CARE) trial was a secondary prevention trial of pravastatin 40 mg daily in 4,159 men and women who had an acute MI between 3 and 20 months before randomization and in whom the total cholesterol level was <240 mg/dl (6.2 mmol/liter) with an LDL level of 115 to 174 mg/dl (3.0 to 4.5 mmol/liter) (20). The primary end point of fatal coronary event or nonfatal MI was reduced by 24%, and the need for coronary artery bypass surgery was reduced by 26%. Finally, the CARE study also demonstrated that women experienced a major reduction in risk for coronary events and stroke, with benefit evident beginning at one year (21). It is noteworthy that statins not only reduce overall cardiovascular mortality but also reduce sudden death by a similar order of magnitude as other cardiovascular events (18). The observed reduction in sudden death may be due to reduced plaque rupture and reduced acute ischemia.
Recent studies have confirmed and extended these results. The Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) (22) investigated 6,605 men and women without clinical evidence of CAD, with an average LDL level (130 to 190 mg/dl) with below average HDL cholesterol level (<50 mg/dl), and who were treated with placebo or lovastatin titrated up to 40 mg daily to achieve an LDL level less than 110 mg/dl. After 4.8 years of follow-up, the incidence of first major acute coronary event was reduced by 37% in the treated group. The Long-term Intervention with Pravastatin in Ischemic Disease study (LIPID) (23) was a secondary prevention study to compare pravastatin 40 mg daily to placebo in 9,014 men and women with prior MI or unstable angina and total cholesterol levels between 155 and 271 mg/dl. After a mean follow-up of 6.1 years, all-cause mortality was reduced by 22%, mortality due to CAD by 24%, and stroke by 19%.
These trials have unequivocally shown that lowering LDL increases survival by both secondary and primary prevention of CAD not only in individuals with elevated LDL levels, but also in those with average LDL levels. The evidence to date suggests that statin therapy should reduce the clinical consequences of atherosclerosis in a large proportion of the population at risk. These studies have raised questions regarding the relative appropriate pretreatment LDL levels in both primary and secondary CAD prevention and the degree to which LDL should be lowered. The relative reduction in LDL achieved in these trials is depicted in Figure 2.
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Figure 2 LDL lowering in primary and secondary prevention trials of statin therapy. The mean LDL enrollment levels are depicted for major trials testing statin utility in primary prevention (WOSCOPS, AFCAPS) and secondary prevention (4S, CARE, LIPID) of coronary artery disease. Mean LDL levels achieved after statin therapy in each trial are also depicted. The NCEP-recommended goals for LDL lowering are depicted for both primary and secondary CAD prevention. Note that mean LDL levels achieved with statins in the AFCAPS primary prevention trial to determine drug efficacy are lower than the NCEP goals. (*Absolute value extrapolated from a reported 25% reduction in LDL [23]).
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The results of 4S, CARE and LIPID indicate that statin therapy is highly beneficial in CAD secondary prevention for patients with both elevated and average LDL levels. Thus, most patients with CAD will benefit from statin therapy. Although CARE suggested that no further risk reduction occurs by lowering LDL below 125 mg/dl, this lower threshold remains controversial. The Post CABG trial demonstrated reduced saphenous vein graft atherosclerosis and reduced need for revascularization in patients in whom LDL was aggressively lowered to a mean of 95 mg/dl (15). The National Cholesterol Education Program (NCEP) has established guidelines for cholesterol management (24) in patients with CAD or peripheral atherosclerotic disease; the recommended goal is an LDL of 
100 mg/dl. Recently published subgroup analyses from 4S and CARE indicate that these NCEP guidelines for secondary prevention of CAD are generally appropriate (25,26). It will be important to determine whether further aggressive LDL lowering will yield additional benefit, especially in subgroups of patients with advanced atherosclerosis.
The WOSCOPS trial (19,27) provides strong evidence that cholesterol-lowering therapy is effective in primary prevention in patients with high LDL. However, WOSCOPS did not give a clear indication of the optimal LDL cholesterol for the initiation of statin therapy in this setting. The AFCAPS/TexCAPS study revealed that men and women with average LDL and without evidence of vascular disease also derived benefit from statin therapy. Although the NCEP recommends for primary prevention a minimal goal of LDL <160 mg/dl, and in patients with a high burden of risk factors a goal <130 mg/dl, AFCAPS/TexCAPS data support benefit of statin therapy at LDL levels below those currently targeted by the NCEP guidelines. Based on these findings, it would now seem, at minimum, prudent to apply aggressively the NCEP guidelines in the primary prevention of vascular disease. However, given the absence of reduction in overall mortality with statin therapy in AFCAPS/TexCAPS, further studies are warranted to explore the benefit of achieving target cholesterol levels as outlined by the NCEP. It is possible that in high-risk patients it may be appropriate to lower LDL even further. Aggressive LDL lowering may be achieved through combination therapy of statins with other lipid-lowering drugs. Additional studies are warranted to address these important questions.
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Statins and cerebrovascular disease
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Despite the established role of cholesterol in the pathogenesis of CAD, current evidence does not demonstrate a clear relationship between the risk of stroke and plasma cholesterol level (28,29). Despite a paucity of clear epidemiologic evidence of a relationship between plasma cholesterol and stroke risk, recent studies indicate that statins have beneficial effects that extend beyond the coronary vascular bed (30,31). Clinical benefit of statins is also supported by imaging studies showing reversal of carotid intimal-medial thickening by statins (32–34). In the CARE study, pravastatin significantly reduced the specified end point stroke by 31%, without increased hemorrhagic stroke (20). Post hoc analysis of the 4S trial (18) showed a similarly significant reduction in stroke. In the WOSCOPS primary prevention trial, a nonsignificant 11% reduction in stroke was noted during five-year follow-up (19). Furthermore, two meta-analyses indicate that statin therapy lowers stroke risk by about 30%, an extent comparable to aspirin (31,35).
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Anti-ischemic properties of statins
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In addition to angiographic and clinical outcome studies, several investigators have explored the impact of statin therapy on the endothelial control of vasomotor tone in hypercholesterolemic patients (36–38). Improvement in coronary vasomotor function may be seen after as little as six months of therapy (36). Decreased vasospasm is also suggested by improved forearm blood flow in hypercholesterolemic patients treated with statins for only four weeks (39). The relationship between LDL reduction and amelioration of endothelial dysfunction in hypercholesterolemia is supported by the observation that single-session LDL apheresis improves forearm blood flow (40). Improvement in myocardial perfusion, reported to occur after only three months of statin therapy, may relate to decreased vasospasm (41,42). Electron-beam–computed tomography has recently shown that statins reduce the volume of calcified plaque in coronary arteries in 12 months (43). This radiographic surrogate suggests that statins may alter the constituents and behavior of plaque, rendering it more stable. Ultimately, the anti-ischemic effect of statin therapy can also be directly shown with quantitative ST-segment monitoring during 24-h ambulatory electrocardiography (44,45).
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Plaque stabilization
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Atherogenesis is initiated by accumulation of LDL in the subendothelial space, where it becomes oxidized to minimally modified LDL (46), which induces local production of monocyte chemotactic protein 1 (MCP1) as well as other chemotactic factors that recruit additional leukocytes to the arterial wall (47). Oxidized LDL attracts macrophages directly (48) and stimulates their binding to the endothelium through induction of adhesion molecules such as P-selectin (49) and vascular cell adhesion molecule 1 (VCAM-1) (50). The HMG-CoA reductase inhibitors prevent the oxidation of LDL (51) possibly through preservation of the activity of the endogenous antioxidant system, superoxide dismutase (52). Statins also alter macrophage handling and uptake of LDL. Lovastatin not only inhibits oxidation of LDL, but also reduces the avidity with which macrophages ingest oxidized LDL (51). Reduced LDL oxidation and uptake by macrophages may be due to direct effects of statins on LDL, which change its propensity for oxidization (51). Statins also reduce vascular expression of adhesion molecules (53,54). In humans, both simvastatin and lovastatin reduce monocyte CD11b expression and ex vivo CD11b-dependent monocyte adhesion to endothelium in patients with hypercholesterolemia (55).
The monocyte/macrophage is not only a promiscuous initiator of atherosclerosis but also a central orchestrator of plaque rupture, the event which heralds most acute coronary syndromes (56). Modified LDL induces macrophage transformation into foam cells and also promotes macrophage activation, which leads to plaque instability (57). Macrophages have been implicated in the pathophysiology of acute coronary 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 (58,59). In addition, macrophages elaborate tissue factor, a membrane-bound glycoprotein that plays an integral role in blood coagulation, and is an important determinant of plaque thrombogenicity (60). Statin therapy inhibits tissue factor expression by cultured human macrophages, and this may reduce thrombotic events (61). In addition to effects on LDL, macrophage activation, and adhesion molecule expression, statins may also attenuate atherogenesis through the inhibition of vascular smooth muscle cell proliferation and migration (62,63) and thus attenuate plaque growth and new lesion formation. Interestingly, pravastatin, a hydrophilic statin, may not share this antiproliferative effect (64), and yet it shows clinical benefit in angiographic and event trials. Experimental/clinical disparities such as this raise questions about the clinical applicability of isolated in vitro studies of statins.
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Statins and endothelial dysfunction
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Several lines of evidence indicate that statins biochemically "modify" the paracrine functions of endothelium in hypercholesterolemia, and transform the endothelium from predominantly prothrombotic and vasospastic to thromboresistant and vasodilatory. The mechanisms underlying the benefit of statin therapy on endothelial dysfunction induced by hypercholesterolemia remain unclear, but hypotheses center on nitric oxide (NO)-dependent mechanisms. Direct upregulation of endothelial nitric oxide synthase (eNOS) by HMG CoA reductase inhibitors has recently been reported, and this may represent an important mechanism by which these compounds preserve endothelial NO synthesis (65). Nitric oxide regulates the paracrine antiatherosclerotic functions of the endothelium, which include inhibition of leukocyte and platelet adhesion, control of vascular tone and growth and maintenance of a thromboresistant interface between the bloodstream and the vessel wall. There is a growing body of evidence suggesting that impaired NO synthesis or activity accompanies hypercholesterolemia (66). Increased concentrations of oxidized LDL may directly inhibit NO by excess production of oxygen-derived free radicals and reduced transcription or increased posttranslational destabilization of eNOS mRNA (66). Hypercholesterolemia also reduces eNOS activity through cytokine production (67), or increases in dimethyl arginine, an endogenous inhibitor of eNOS (68).
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Inhibition of isoprenoid biosynthesis
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In addition to lowering intracellular levels of sterols, HMG CoA reductase inhibitors reduce levels of isoprenoids, which are derived from intermediates of the cholesterol biosynthetic pathway (Fig. 1). Isoprenoids posttranslationally prenylate a variety of cellular proteins that play central roles in both cell growth and in signal transduction pathways such as low-molecular weight guanine nucleotide binding proteins (G-proteins), which have been shown to modulate signal transduction and mitogenic pathways (69). Finally, the putative antioxidant effects attributed to statins (52) may be due to attenuated isoprenylation of NADPH oxidase, which in its isoprenylated state generates superoxide anion (70).
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Anti-thrombotic actions of statins
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Platelets play a fundamental role in atherogenesis and in the pathophysiology of acute coronary syndromes (71,72). Hypercholesterolemia is associated with both hypercoagulability as well as enhanced platelet activation (73). High LDL levels increase platelet reactivity in association with enhanced thromboxane A2 (TXA2) biosynthesis, and enhanced TXA2 production has been demonstrated in the majority of patients with type IIa hypercholesterolemia (74). Hypercholesterolemia has also been associated with increased platelet alpha2 adrenergic receptor density (75), changes in the composition of platelet membrane phospholipids and cholesterol (76) and increases in platelet cytosolic calcium (77).
Several studies demonstrate reductions in platelet reactivity with statin treatment (74,78,79). Although the precise mechanism responsible for the effects of statins on platelet function is unclear, one mechanism may involve decreased platelet TXA2 production. The finding that the membrane cholesterol content of both erythrocytes and platelets is reduced in patients treated with pravastatin (80) suggests that certain properties of these membranes are altered in a manner that renders them less prone to participation in thrombosis. Moreover, Nofer and colleagues (81) have recently elucidated a novel mechanism that increases platelet activation in hypercholesterolemia through inhibition of platelet Na+/H+ antiport by LDL. Statin therapy also ameliorates the enhanced thrombotic and reduced fibrinolytic state that accompanies hypercholesterolemia (82). Although statins do not directly reduce lipoprotein (a) [Lp(a)] levels and may even increase levels of this lipoprotein (2), statins may still modify prothrombotic states related to simultaneously elevated LDL and Lp(a) (83–85). Additionally, platelet-dependent thrombin generation is increased in subjects with hypercholesterolemia, and treatment with pravastatin normalizes thrombin production (86).
These observations add to the growing body of evidence linking hypercholesterolemia and thrombosis and suggest that statins reverse the thrombotic-fibrinolytic imbalance that accompanies hypercholesterolemia. Given that thrombotic disruption of plaque precipitates most acute coronary syndromes, the impact of statin therapy in reducing both the thrombotic tendency of blood, in addition to the thrombogenicity of plaque, may be particularly important in the overall reduction of clinical events.
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Summary
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Recent advances in the management of hypercholesterolemia are largely due to the development of HMG CoA reductase inhibitors. Initial studies explored the impact of statin therapy on CAD progression and regression, and although the angiographic changes were unimpressive, the accompanying clinical benefit appeared significant. Subsequent large prospective clinical trials gave clear evidence that statin therapy not only reduces major coronary event rate but also reduces all-cause mortality. For lipid lowering, the NCEP-defined goals provide targets for statin therapy. For patients with CAD or other atherosclerotic disease, the NCEP goal is an LDL of 100 mg/dl. The NCEP recommends a minimal goal of LDL <160 mg/dl in primary prevention, and in patients with a high burden of risk factors, the recommended goal is LDL <130 mg/dl. The anatomic/clinical disparity manifest in clinical trials may best be explained by effects of statins over and above lipid lowering: promotion of plaque stability, improvement of endothelial dysfunction and reversal of coagulation and platelet abnormalities that accompany hypercholesterolemia. Recent studies also suggest that statins have beneficial effects extending beyond the coronary vascular bed and are capable of reducing ischemic stroke risk by approximately one-third in patients with evidence of vascular disease. Burgeoning clinical and experimental evidence indicates that the beneficial action of statins occurs rapidly and may yield clinically important anti-ischemic effects as early as one month after commencement of therapy. Statins exhibit pleiotropic effects on many components of atherosclerosis, including plaque thrombogenicity, cellular migration, endothelial function and thrombotic tendency (Fig. 3). Clinical benefits of these effects in vivo remains to be determined.
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Figure 3 Statins and determinants of acute coronary syndromes. Statins exhibit pleiotropic effects on many components of atherosclerosis that accompany hypercholesterolemia, including platelet coagulation abnormalities, abnormal endothelial function, and determinants of plaque thrombogenicity such as plaque inflammation and proliferation.
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Future directions
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Although statin therapy is established as an integral component in the management of CAD, many questions concerning such therapy remain unanswered. The issue of how far LDL should be lowered is still controversial. The management of patients with CAD and baseline LDL of 100 to 129 mg/dl needs to be addressed in a specific clinical trial as well as a study exploring threshold LDL values in primary prevention. The role of hypertriglyceridemia and its treatment in patients already receiving statin therapy also needs prospective evaluation. Several promising small studies (87,88) should prompt large-scale clinical trials and meta-analyses of current databases to test utility of other lipid-lowering drugs in combination with statins in patients with a spectrum of dyslipidemias. Further data are also awaited to support the growing importance of cholesterol as a risk factor for ischemic stroke and the benefit of statin therapy in patients with cerebrovascular disease. Elucidation of statin effects other than LDL lowering will undoubtedly provide an increasing number of therapeutic goals for statin therapy. In addition, the role of immediate statin therapy in patients presenting with acute coronary syndromes is unknown. Given the rapid and protean effects of statins on determinants of platelet reactivity, coagulation and endothelial function, future investigation may address a role for statin therapy in acute coronary syndromes.
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Footnotes
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Dr. Vaughan is supported by an American College of Cardiology/Merck research fellowship; Dr. Basson is supported by NIH 5K08 HL03468 and NIH 1R01 HL61785 grants.
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Mechanism of action and...
