Clinical trials of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase
inhibitors or statin therapy have demonstrated that baseline or treated low-density
lipoprotein (LDL) cholesterol levels are only weakly associated with net coronary
angiographic change or cardiovascular events. The beneficial effects of statins
on clinical events may involve nonlipid mechanisms that modify endothelial
function, inflammatory responses, plaque stability, and thrombus formation.
Experimental animal models suggest that statins may foster stability through
a reduction in macrophages and cholesterol ester content and an increase in
volume of collagen and smooth muscle cells. The thrombotic sequelae caused
by plaque disruption is mitigated by statins through inhibition of platelet
aggregation and maintenance of a favorable balance between prothrombotic and
fibrinolytic mechanisms. These nonlipid properties of statins may help to
explain the early and significant cardiovascular event reduction reported
in several clinical trials of statin therapy.
CLINICAL TRIALS of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase
inhibitors or statin therapy demonstrate an improvement in cardiovascular
end points and coronary stenosis that is incompletely explained by the baseline
or treated low-density lipoprotein (LDL) cholesterol level.1-5
The beneficial effects of statins on clinical events may involve nonlipid
mechanisms that modify endothelial function, inflammatory responses, plaque
stability, and thrombus formation (Table
1, Figure 1). This article
discusses several nonlipid mechanisms that may contribute to the cardiovascular
event reduction observed in clinical trials of statin therapy.
Ldl and cardiovascular events
The LDL cholesterol levels serve as the focus of cholesterol treatment
guidelines that were established to prevent coronary heart disease (CHD) in
patients with hypercholesterolemia who are initially free of CHD and for those
with established CHD.6-9
Treatment guidelines target LDL cholesterol levels on the basis of epidemiological
associations rather than clinical trial outcomes and, thus, promulgate the
concept that the magnitude of LDL cholesterol reduction equates directly with
a proportionate reduction in atherosclerotic burden and clinical cardiovascular
events. The LDL cholesterol level is an important target of cardiovascular
prevention; however, elevated LDL cholesterol levels identify less than one
half of individuals who will die from CHD.10,11
The LDL cholesterol concentrations had a sensitivity of 47% in predicting
10-year CHD death rates in the Lipid Research Clinics Prevalence Study.12 Similar data are available from the Finnish cohort
(n=444) of the Seven Countries Study for which only a modest correlation between
serum cholesterol and 30-year CHD mortality was observed (r=0.42).11 The revised National Cholesterol
Education Program (NCEP II) guidelines7 that
stratify risk by LDL cholesterol levels and conventional risk factors are
no better in predicting risk.12 The importance
of LDL cholesterol levels on the prediction of CHD can be improved by concomitant
measurements of high-density lipoprotein cholesterol levels,13
fibrinogen,14,15 plasma viscosity,16 and C-reactive protein.15
Clinical trials with statin therapy are accompanied by comparable changes
in LDL cholesterol levels, but varying reductions in cardiovascular events3-5,17-30
(Table 2). The relationship between
baseline and treated LDL cholesterol levels and cardiovascular end points
has been evaluated in several clinical trials.3-5
The Regression Growth Evaluation Statin Study (REGRESS) demonstrated that
the effect of pravastatin on change in mean coronary artery segment diameter,
minimum obstruction diameter, and clinical events was not influenced by baseline
LDL cholesterol level.3 Similarly, the Scandinavian
Simvastatin Survival Study reported that major coronary events were reduced
by a similar amount regardless of the baseline LDL cholesterol level.4 The West of Scotland Coronary Prevention Study (WOSCOPS)
evaluated the relationship between on-treatment LDL cholesterol levels or
total cholesterol change and CHD risk5 using
the Framingham CHD-risk model.31 The CHD event
rate in pravastatin-treated patients was not related to the magnitude of LDL
cholesterol level lowering when the LDL cholesterol level reduction ranged
from 19% to 54%.5 The Framingham model accurately
predicted the CHD event risk rate in the placebo group but underestimated
the CHD risk reduction in the pravastatin therapy group by 35%. These analyses
suggest that nonlipid mechanisms32,33
may contribute to the cardiovascular event reduction in WOSCOPS21
and explain the early clinical benefit in this trial and several others.3,17,18,20,21,34
The vulnerable plaque and acute coronary syndromes
Coronary plaque rupture and erosions are recognized precipitants of
thrombosis in acute myocardial infarction, unstable angina pectoris, and sudden
death.35-40
The vast majority of acute myocardial infarctions arise from atherosclerotic
lesions that are minimal to moderate in severity as quantified by arteriography.38,41 The rapid progression of subclinical
coronary stenosis has led to an appreciation of the vulnerable plaque.35,36
The characteristics of the typical vulnerable plaque include increased
numbers of inflammatory cells, such as macrophages and T lymphocytes at the
shoulder region of the plaque, a large lipid pool, few smooth muscle cells
and collagen fibers, and a thin fibrous cap37-39,42-44
(Figure 1). The content of macrophages
and T lymphocytes within the plaque is an important determinant of plaque
disruption. The macrophages release proteolytic enzymes that weaken a thin
overlying fibrous cap and accelerate collagen degradation. T lymphocytes release
interferon gamma (IFN-γ) at sites of human plaque disruption.43 Interferon gamma inhibits smooth muscle cells from
expressing interstitial collagen genes and provides a molecular basis for
impaired collagen synthesis and inhibition of smooth muscle cell proliferation.45-47 In addition to impaired
synthesis of structural proteins, catabolism of the extracellular matrix by
metalloproteinases (interstitial collagenase, gelatinases, stromelysins) can
weaken the fibrous cap.37 These matrix-degrading
proteinases are expressed by macrophage-derived foam cells and smooth muscle
cells that are exposed to inflammatory cytokines (interleukin 1 or tumor necrosis
factor). Plaque erosion is characterized by endothelial cell loss, sparsely
distributed inflammatory cells, clusters of smooth muscle cells, and proteoglycans
at the luminal surface.40
Experimental animal models demonstrate that statin therapy can stabilize
atherosclerotic plaques.48,49
These compositional changes include a reduction in extracellular lipid deposits
and the area of macrophages in the intima and media, increase in collagen
area and the ratio of collagen area to the area of extracellular lipid deposits,
increase in smooth muscle cells, and less calcification and neovascularization
in the intima. Lipid-lowering therapies may reduce cardiovascular risk not
only through altering the arterial wall (endothelial dysfunction, atherogenesis,
plaque stability), but also through their thrombogenic effects and effects
on blood flow properties(Table 3).
Elevated LDL cholesterol levels are a major predisposing factor to atherosclerosis.
Oxidized LDL impairs endothelial-dependent vasodilation, induces apoptosis
of human endothelial cells via activation of a CPP32-like protease, a member
of the interleukin 1β–converting enzyme-like protease family,50 and generates an inflammatory response. Oxidized
LDL modifies the functional response of vascular smooth muscle cells to angiotensin
II stimulation.51
Oxidized LDL inhibits nitric oxide synthase activity of platelets,52,53 which promotes thrombus formation
through an enhancement of fibrinogen binding to platelets.54
Oxidized LDL binds to platelet activation factor, which is an intracellular
proinflammatory regulator.55 Modified LDL promotes
tissue factor expression by monocytes, but LDL inhibits activation of the
extrinsic coagulation pathway through binding to the tissue factor pathway
inhibitor (TEPI).56,57 The LDL
levels correlate with vitamin K–dependent coagulation factors (and inhibitors)
and fibrinogen levels58; however, the significance
of these relationships is unresolved.59 In
subjects with hypobetalipoproteinemia (LDL cholesterol level, <1.81 mmol/L
[69.99 mg/dL]), levels of fibrinogen and fibrinolytic markers (plasminogen
activator inhibitor 1 [PAI-1] antigen), tissue plasminogen activator inhibitor
1 antigen) are low and this association further supports the relationship
between LDL and these hemostatic factors.60
In addition, LDL contributes to atherothrombogenesis through an increase in
plasma and blood viscosity as shown in in vitro experiments and supported
by epidemiological studies.59
Endothelial-mediated vasodilatation is impaired in hypercholesterolemia
and atherosclerosis.61,62 In coronary
arteries of patients with atherosclerosis, cholesterol lowering with pravastatin
and lovastatin improves endothelial function as evidenced by limiting acetylcholine-induced
vasoconstriction (Table 3). 63-65 While this improvement
in endothelial function was not seen with simvastatin,66
the LDL cholesterol–lowering therapy with simvastatin improves peripheral
nitric oxide–mediated vascular relaxation.67-70
The improved coronary blood flow and vasodilatory response with statin therapy
alleviates transient ischemia in patients with stable angina pectoris71,72 and improves myocardial perfusion.73,74 In patients with mild hypertension,
cardiovascular reactivity to angiotensin II and norepinephrine is diminished
after 3 weeks of therapy with pravastatin.75
Statin therapy can ameliorate endothelial dysfunction and contribute to the
observed clinical benefits of those agents, and this improvement may be ascribed
to LDL cholesterol lowering and antioxidant properties of statins.
An early step in atherogenesis involves monocyte adhesion to the endothelium
and penetration into the subendothelial space. Oxidized LDL binds to the scavenger
cell receptor on monocyte-derived macrophages and contributes to foam cell
formation. Inflammatory cytokines secreted by macrophages and T lymphocytes
can modify endothelial function, smooth muscle cell proliferation, collagen
degradation, and thrombosis.46,47,76-78
Cholesterol level lowering in experimental models is accompanied by a reduction
of inflammatory cells within atherosclerotic plaque.48,49,79-81
Subjects with hypercholesterolemia have increased adhesiveness of isolated
monocytes to fixed endothelial cells in vitro, and this response is diminished
with lovastatin and simvastatin.81 Hypercholesterolemic
rats treated with fluvastatin have significantly attenuated leukocyte-adherence
responses to platelet activation factor and leukotriene B4.81
In patients with cardiac transplants, pravastatin may suppress the inflammatory
response and inhibit natural killer cell activity in cyclosporin-treated patients.82 Although transplant vasculopathy is a distinct pathological
entity from atherosclerotic vascular disease, the same inflammatory mediators
may determine plaque vulnerability.
Effect of Lipid Composition on Plaque Stability
The relative content of cholesterol esters in plaque is an important
factor influencing plaque stability. The pools of lipid-laden macrophage foam
cells are nondistensible and do not absorb transmitted energy. Circumferential
shear stress is concentrated on the fibrous cap that separates blood from
the thrombogenic lipid core,83,84
and plaque disruption exposes the underlying plaque components to blood components
that initiate thrombogenesis.85,86
Statins inhibit cholesterol ester accumulation in monocyte-derived macrophages
either by reducing the availability of free cholesterol toward the enzyme
acyl-coenzyme A cholesterol acyltransferase by trapping it in phospholipid-containing
pools, or by inhibiting LDL endocytosis related to reduced synthesis of mevalonate
or mevalonate by-products required for cholesterol esterification.87 Kempen et al88 reported
a dose-dependent inhibition of cholesterol accumulation in macrophages that
was greater with lovastatin and simvastatin than with pravastatin (Table 3). Lowering blood LDL cholesterol
levels may facilitate plaque stability either through a reduction in size89,90 or by an alteration of the physiochemical
properties of lipid cores.91,92
Hydrolysis of liquid cholesterol esters to solid cholesterol crystals can
yield firmer plaques.
Another factor obscuring the relationship between LDL cholesterol levels
and clinical events is the distribution of LDL subspecies within the plaque
and the susceptibility of select LDL particles to oxidative modification.
Small, dense LDL particles are more atherogenic than larger, buoyant particles,
in part, because of enhanced oxidative susceptibility93
and reduced total antioxidant defense.94 The
small LDL particle diameter is an independent predictor of myocardial infarction,95,96 and a predominance of dense LDL particles
(density, >1.0378 g/mL) predicted coronary arteriographic benefit in the Stanford
Coronary Risk Intervention Project.97
In the Kuopio Atherosclerosis Prevention Study (KAPS),26
3 years of pravastatin therapy prolonged the lag time of LDL lipoproteins
(a measure of oxidation resistance), increased plasma and LDL vitamin E levels,
and improved overall LDL antioxidant capacity (Table 3). 98 Lovastatin and simvastatin
have been shown to inhibit LDL oxidation and uptake by macrophages in studies
of shorter duration.99-105
Simvastatin treatment for 6 months maintains total antioxidant capacity of
LDL particles; however, measurements of plasma antioxidants (ubiquinone, dolichol, α-tocopherol, β-carotene,
and lycopene) were either reduced103,104
or unchanged.105 Tissue concentrations of ubiquinone
may be reduced with certain statins as reported in animal studies.106,107 In contrast, plasma ubiquinone
levels fall with simvastatin therapy, whereas the concentration of ubiquinone
in skeletal muscle biopsy specimens remains unchanged.105
Overall, these data suggest that statin therapy does not alter tissue antioxidant
balance but increases total antioxidant capacity of plasma.
Smooth Muscle Cell Proliferation and Collagen Synthesis
Smooth muscle cells foster plaque stabilization39,108
through synthesis of macromolecules that strengthen the fibrous cap37 and absorption of energy transmitted to the vessel
wall, which reduces circumferential shear stress along the endothelial surface.83,84 Mechanical stress serves as a stimulus
for smooth muscle cell synthesis.109 The smooth
muscle cell also is involved in the normal healing process.39,108
After a plaque ulcerates, the normal reparative process requires proliferation
of vascular smooth muscle cells. Vascular smooth muscle cells regulate synthesis
of interstitial collagens that are stimulated by transforming growth factor β
and platelet-derived growth factor and inhibited by IFN-γ.47
The influence of statins on smooth muscle cell proliferation has been
evaluated in cell cultures of human femoral and rat myocytes and carotid arteries
of rabbits.110-114
Balloon-mediated injury of rabbit carotid arteries caused intimal proliferation
that was not inhibited in placebo- and pravastatin-treated rabbits, whereas
this process was inhibited by treatment with all other statins.110,112
In cell culture experiments, most statins (atorvastatin, cerivastatin, fluvastatin,
simvastatin) except pravastatin inhibit smooth muscle cell proliferation and
migration induced by the platelet-derived growth factor and fibrinogen.111,112 The permissive action of pravastatin
on smooth muscle cell proliferation may be an advantage for the reparative
process that follows plaque ulceration.108
The concentration of statin needed to inhibit smooth muscle cell proliferation
in vivo is comparable to plasma levels observed in humans administered conventional
doses of these agents.114
Whether plaque disruption leads to an acute ischemic event depends,
in part, on the propensity for thrombus to form on the damaged vessel wall.
The thrombogenic response may be influenced by the thrombogenicity of the
vessel wall components,86 interaction of blood
components with the lipid pool or smooth muscle cell and proteoglycan complexes,
local blood flow properties, and circulating hemostatic factors. The prothrombotic
factors that have been evaluated with the statins include tissue factor expression,
platelet aggregation, fibrinogen, plasma viscosity, and fibrinolytic factors
(Table 3).
Tissue factor and corresponding messenger RNA have been localized in
macrophages of human atherosclerotic plaque.85
Tissue factor serves as a cofactor for plasma factor VII and cellular receptor
for factor VIIa and, thus, plays a central role as the initiator of the extrinsic
coagulation pathway.115 Lipophilic statins
(fluvastatin, simvastatin) suppress tissue factor expression by cultured human
macrophages through inhibition of a geranylgeranylated protein involved in
tissue factor biosynthesis.116 This effect
on tissue factor was not observed with pravastatin.
The extrinsic coagulation activation pathway is counterbalanced by a
serine protease inhibitor known as TEPI. TEPI binds to factor Xa, and this
complex inhibits tissue factor–mediated coagulation through binding
to the tissue factor—factor VIIa complex.56,57
Circulating TEPI is transported by dense subspecies of LDL, lipoprotein(a)
(Lp[a]), and high-density lipoprotein.117 TEPI
activity is increased in subjects with heterozygous familial hypercholesterolemia,118,119 and types IIa (by 70%, P<.001) and IIb (by 36%, P<.001) hyperlipoproteinemias.120 Cholesterol level lowering with simvastatin reduces
LDL and TEPI without a significant change in factor VIIc.118
Platelets from patients with elevated LDL levels are more sensitive
to aggregating agents than are platelets of normocholesterolemic subjects.121 The LDL causes intracellular acidification through
inhibition of Na+/H+ antiport in human platelets, which
mobilizes intracellular calcium in the resting state and after stimulation
with agonists.122 The adenosine diphosphate–induced
fibrinogen binding to platelets is increased in a dose-dependent manner by
LDL (0.5-2.0 g of protein per liter).123 Simvastatin
reduces platelet aggregation and thromboxane production after 4 to 24 weeks
of therapy, whereas lipid lowering was observed by 2 weeks of treatment.124,125 Lovastatin therapy has been accompanied
by both an increase and a decrease in platelet count and adenosine diphosphate–induced
platelet aggregation.126,127 Pravastatin
normalizes platelet-dependent thrombin generation in hypercholesterolemic
subjects, but this effect is unaccompanied by a change in prostaglandin production.128 Pravastatin also has been shown to reduce cytosolic
calcium and platelet aggregation.129
Statins may reduce platelet aggregation by changing the cholesterol
content of platelet membranes, which alters membrane fluidity.129
In an experimental model that simulates primary hemostasis, hypercholesterolemic
patients treated with aspirin (325 mg/d) deposit more platelet aggregates
on damaged porcine aorta than normocholesterolemic subjects, and this response
was reduced by pravastatin therapy.130 In hypercholesterolemic
subjects treated with aspirin (325 mg/d) and randomized to either pravastatin
or simvastatin at equivalent LDL cholesterol-lowering doses, pravastatin inhibited
platelet-thrombus formation on an injured artery. This was not observed in
simvastatin-treated patients.131 These latter
studies suggest a differential effect of statins on tissue-dependent platelet
aggregation.
Fibrinogen levels and plasma viscosity may be used to stratify cardiovascular
risk in hypercholesterolemic patients with and without established CHD.14-16 Elevated plasma viscosity
may contribute to atherothrombosis through impaired microcirculatory flow,
shear stress damage at the blood-endothelial interface, facilitation of plasma
protein interaction with the endothelium in poststenotic recirculation zones,
and increased propensity for thrombosis.132
Several studies examining the influence of statins on fibrinogen levels
in hypercholesterolemic patients have shown mixed results.133
Lovastatin has been accompanied by 19% to 24% increases in fibrinogen levels
in two 6-month studies of 26 and 49 patients, respectively,126,134
and by 5% in a 12-month study of 260 patients.135
Two other small, short-term studies of 15 and 35 patients reported no change
in fibrinogen concentration.136,137
In contrast, Mayer et al127 found a significant
10% reduction in fibrinogen levels in 20 hypercholesterolemic patients treated
with lovastatin after 16 weeks of therapy, with further reductions throughout
the 12-month interval of the study. This study was limited by fibrinogen measurements
made at monthly intervals without adjustment for multiple observations and
selection of a second fibrinogen value at baseline that was 4% higher than
the initial value.133
Lovastatin has been accompanied by an increase in whole blood viscosity,126 while plasma viscosity is either reduced136 or does not change.126,137
Pravastatin has been accompanied by a 7% to 9% lowering of fibrinogen levels
in 3 studies of 16 to 24 patients treated from 10 to 24 weeks.138-140
Three studies reported no change in fibrinogen concentration with pravastatin.26,141,142 However, KAPS reported
a nonsignificant 7% elevation in fibrinogen in patients treated with either
pravastatin and placebo for 3 years, but the increase in fibrinogen was 20%
lower in the pravastatin group than in the placebo group.26
Unlike the Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial,143 KAPS did not age adjust fibrinogen levels.26 In addition, 2 pravastatin studies reported a reduction
in whole blood viscosity at shear rates ranging from 75 to 375 seconds−1, corrected blood viscosity at 112.5 seconds−1
and 225 seconds−1, and plasma viscosity.138,140
Simvastatin does not change fibrinogen as shown in 4 studies of 12 to 111
subjects followed up for 10 weeks to 2 years.140,142,144,145
Additionally, blood, plasma and serum viscosity measurements were unchanged
with simvastatin therapy.144 Two comparative
studies that randomized subjects to either pravastatin or simvastatin reported
a favorable or neutral change in fibrinogen with pravastatin and a neutral
change with simvastatin.140,142
No published studies have evaluated the effect of fluvastatin on fibrinogen
levels. Atorvastatin (80 mg daily) was accompanied by a 46% increase in fibrinogen
levels in 22 heterozygous familial hypercholesterolemic subjects treated for
6 weeks.146 The fibrinogen elevation was greater
in subjects randomized to atorvastatin administered as a twice-daily dose
compared to a single dose (P<.05). In 789 subjects,
a lower dose of atorvastatin (10 mg daily) was accompanied by a smaller (4%)
elevation in plasma fibrinogen levels.135 Other
investigators evaluated multiple dosages of atorvastatin (10-80 mg daily)
on fibrinogen levels in 95 subjects and reported an increase in fibrinogen
levels that ranged from 19% to 24%.147
The variable effect of statins on fibrinogen may result from different
actions on fibrinogen-regulating cytokines,78
study populations with genetic variation at the fibrinogen gene locus,148 or measurement variability.149
Another factor to consider is age adjustment of fibrinogen levels in long-term
studies.143
Fibrinolytic mechanisms evaluated with statins include measurements
of Lp(a) and PAI-1, the principal inhibitor of the fibrinolytic system. Impaired
fibrinolysis as measured by an elevation in PAI-1 is predictive of ischemic
heart disease in free-living subjects150 and
survivors of myocardial infarction.150-152
Pravastatin reduces PAI-1 antigen levels by 26% to 56%,139,141
and this appears to facilitate fibrinolysis. Lovastatin has been shown to
both decrease PAI-1 by 22%134 and elevate PAI-1
by 34% in 260 subjects.135 Atorvastatin therapy
increased PAI-1 by 36% after 12 months.135
Simvastatin increased PAI-1 by 18% in 111 patients treated for 2 years.145 Fluvastatin has a neutral effect on PAI-1 antigen.153
Lipoprotein(a) interferes with fibrinolysis by competing with plasminogen
binding to plasminogen receptors, fibrinogen, and fibrin.154
The net effect is impaired plasminogen activation and plasmin generation at
the thrombus surface.155 The Lp(a) levels can
increase by as much as 34% with statin therapy156-160
and potentially impair clot lysis. Since the importance of Lp(a) on cardiovascular
risk diminishes with LDL cholesterol–lowering therapy,155
the importance of this modest evaluation in Lp(a) levels on overall cardiovascular
risk is unclear. The opposing effects of statins on the different mediators
of fibrinolysis may offset each other.
Statins influence critical pathways that regulate plaque stability and
thrombosis, and these properties extend beyond LDL lowering. The spectrum
of direct antiatherogenic properties of statins includes maintenance of endothelial
function, anti-inflammatory actions, and a permissive action on smooth muscle
cell proliferation that allows for synthesis of extracellular matrix proteins
involved in the reparative response. Following plaque disruption, statins
influence thrombosis through variable inhibitory actions on platelet deposition
and aggregation, coagulation factors, rheology, and fibrinolysis. The qualitative
differences among statins may influence the effectiveness in the prevention
of cardiovascular events and atherosclerosis disease progression.
Knowledge about the intricacies of atherosclerosis and thrombosis continues
to expand rapidly, and these mechanisms should be used to support the evidence
from randomized clinical trials. Since the nonlipid properties of statins
differ despite comparable LDL cholesterol level lowering, the net clinical
efficacy of these agents requires validation by randomized clinical trials.
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