Beneficial Cardiovascular Pleiotropic Effects of Statins

Jean Davignon, MD

Abstract—Pleiotropic effects of a drug are actions other than those for which the agent was specifically developed. These
effects may be related or unrelated to the primary mechanism of action of the drug, and they are usually unanticipated.
Pleiotropic effects may be undesirable (such as side effects or toxicity), neutral, or, as is especially the case with
HMG-CoA reductase inhibitors (statins), beneficial. Pleiotropic effects of statins include improvement of endothelial
dysfunction, increased nitric oxide bioavailability, antioxidant properties, inhibition of inflammatory responses, and
stabilization of atherosclerotic plaques. These and several other emergent properties could act in concert with the potent
low-density lipoprotein cholesterol-lowering effects of statins to exert early as well as lasting cardiovascular protective
effects. Understanding the pleiotropic effects of statins is important to optimize their use in treatment and prevention
of cardiovascular disease.(Circulation. 2004;109[suppl III]:III-39 –III-43.)
Key Words: endothelial dysfunction 䡲 inflammation 䡲 oxidation 䡲 pleiotropic effects 䡲 statins

A s HMG-CoA reductase inhibitors (statins) became more

widely used in greater numbers of patients, their effects
beyond lipid lowering began to emerge. Such pleiotropic
effects include improvement of endothelial dysfunction, in-
creased nitric oxide bioavailability, antioxidant effects, anti-
inflammatory properties, and stabilization of atherosclerotic
plaques. Additional effects of growing interest include the
ability to recruit endothelial progenitor cells (EPCs), a puta-
tive immunosuppressive activity, and inhibition of cardiac
Downloaded from http://ahajournals.org by on September 25, 2019
Normalized Vasomotion
Short-term treatment with statins has been shown to improve
endothelial dysfunction and increase myocardial perfusion. In
hypercholesterolemic patients with perfusion abnormalities,
for instance, treatment with fluvastatin (40 to 80 mg/d) for 6
to 12 weeks significantly increased myocardial perfusion in
ischemic segments (30%; P⬍0.001), and the change from
baseline was significantly greater than that observed in
normal segments (5%; P⬍0.005).3 In subjects with moder-

hypertrophy. Research indicates that some of the pleiotropic
effects of statins may be unrelated to the cholesterol-lowering
properties of the drugs. Others may even be fully dissociated
from inhibition of HMG-CoA reductase, and many take place
at very low drug concentrations. This review focuses on
effects that have special cardiovascular relevance. Under-
standing the full spectrum of benefits associated with statin
therapy may allow better therapeutic application and foster
the early use of statins in acute coronary syndromes.
Improvement of Endothelial Dysfunction
Endothelial injury contributes to the initiation of the athero-
genic process. Endothelial dysfunction, an early manifesta-
tion of such injury, is associated with a paradoxical vasocon-
striction to acetylcholine due to impaired synthesis, release,
and activity of endothelium-derived nitric oxide (NO). Ab-
normal endothelium-dependent vasomotor responses predict
the long-term progression of atherosclerosis and associated
coronary events, as well as events shortly after vascular
surgery.1,2 It is therefore not surprising that the well-
established ability of statins to improve endothelial dysfunc-
tion, a class effect, has received much attention in recent
years.
ately elevated cholesterol levels (6.2 to 7.5 mmol/L), treat-
ment with simvastatin 20 mg/d, compared with placebo,
significantly (P⬍0.0005) increased the vasodilatory response
to acetylcholine as determined by forearm blood flow as early
as 4 weeks after initiation of therapy.4 After an additional 3
months of treatment, improvement in the simvastatin group
was significantly (P⬍0.005) greater than that observed at 4
weeks.
A recent study5 compared atorvastatin 10 mg/d plus dietary
therapy with dietary therapy alone in postmenopausal women
with hypercholesterolemia. Significant improvement in bra-
chial artery vasoreactivity was observed as early as 2 weeks
after beginning atorvastatin compared with dietary therapy
alone (P⬍0.001), as well as at 4 and 8 weeks.5 Only a weak
correlation was observed between level of cholesterol reduc-
tion with atorvastatin and the improvement in vasoreactivity.5
In fact, a small study in healthy normocholesterolemic young
men indicated improved endothelial function within 24 hours
of treatment with atorvastatin 80 mg and rapid impairment on
statin withdrawal after 30 days.6 The effect occurred before
levels of serum cholesterol and high sensitivity C-reactive
protein (hsCRP) were decreased after 2 days of treatment.
These findings support the view that statins may exert

From the Hyperlipidemia and Atherosclerosis Research Group, Clinical Research Institute of Montreal, Montreal, Québec, Canada.
Correspondence to Jean Davignon, MD, IRCM, 110 Pine Ave W, Montreal, QC Canada H2W 1R7. E-mail davignj@ircm.qc.ca
© 2004 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org DOI: 10.1161/01.CIR.0000131517.20177.5a

III-39
 III-40 Circulation June 15, 2004
beneficial effects on endothelial dysfunction that are indepen-
dent of the degree of plasma cholesterol lowering.
Long-term statin therapy also improves endothelial func-
tion in patients with atherosclerosis. Diet alone, a low-density
lipoprotein (LDL)-lowering regimen (lovastatin and cho-
lestyramine), and an LDL-lowering plus antioxidant regimen
(lovastatin and probucol) were tested for 1 year on
acetylcholine-induced vasoconstriction in epicardial coronary
arteries.7 The greatest improvement in the vasoconstrictor
response was seen in the LDL-lowering antioxidant group
(P⫽0.01).
Whether statin therapy has a similar beneficial effect on
endothelium-dependent vasodilatation in diabetes mellitus is
under investigation. Recent studies with simvastatin and
atorvastatin have shown no impact of statin therapy on
endothelium-dependent vasodilatation in type 2 diabetes.8,9
However, another study with atorvastatin in type 2 diabetes
demonstrated a significant improvement in endothelium-
dependent vasodilatation.10 A similar finding was reported
with atorvastatin in young patients with type 1 diabetes and
normal cholesterol levels.11 The conflicting results obtained
in these studies may have been due to differences in the statin
dosage, study design, patient selection, concomitant medica-
tion, and technology used to measure endothelial function.
Increased Bioavailability of Nitric Oxide
Statins improve endothelial dysfunction in part by lowering
LDL-cholesterol; more specifically, they have been shown to
prevent downregulation of endothelial nitric oxide synthase
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(eNOS), the enzyme that catalyzes the formation of NO from
L-arginine, by native LDL.12 Downregulation of eNOS may
be mediated by the ability of LDL to increase levels of
caveolin-1, a major inhibitor of eNOS activity.13
Statins also directly enhance constitutive eNOS activity,
thereby increasing the bioavailability of NO.14 Several mech-
anisms may be involved, including a reduction of caveolin-1
abundance and an increase in Hsp90, which acts as a
molecular chaperone to facilitate long-term activation of
eNOS.13 Other mechanisms include stabilization of eNOS
messenger RNA15 and decreased production of reactive
oxygen species that inactivate NO.16 Statins also interfere
with the prenylation of Rho GTPase by geranylgeranyl
pyrophosphate (GGPP), preventing its translocation to the
cell membrane where it negatively regulates eNOS activity.17
The PI3-kinase/Akt pathway is also involved in NO regu-
lation. Statins were found to activate the serine/threonine
kinase Akt (protein kinase B) in endothelial cells, thereby
enhancing the phosphorylation of the endogenous Akt sub-
strate eNOS and producing an increase in NO.18
Antioxidant Effects
The failure of antioxidants to prevent coronary artery disease
in recent trials19 does not invalidate the oxidation theory of
atherosclerosis. The lack of benefit may have been due to
inadequate dosing, treatment length, or type of antioxidant.20
In addition, emphasis may need to be shifted toward acute
events and early effects or more consideration given to the
interplay of oxidative stress and inflammation in atherogen-
esis. In view of the central role played by oxidized LDL in
atherogenesis, the established antioxidant effect of statin
therapy is of major interest.
In addition to reversing the inhibitory effect of oxidized
LDL on eNOS, statins also have direct antioxidant effects on
LDL in vitro and ex vivo.21,22 Hydroxy metabolites of
atorvastatin, but not the parent compound, inhibit oxidation
of both LDL and very-low-density lipoprotein as well as
high-density lipoprotein.23 In addition, the hydroxy metabo-
lites, representing 70% of active atorvastatin in plasma,
demonstrate free radical-scavenging abilities that may con-
tribute to inhibition of lipoprotein oxidation. Statins may also
indirectly affect normal oxidative mechanisms by curbing the
ability of macrophages to oxidize lipoproteins.24 Statins have
also been shown to decrease the activity of macrophage
CD36, a recognized receptor for oxidized LDL.25 The mech-
anism of this effect is under investigation.
Oxidized LDL particles are negatively charged. Possible
causes of electronegative LDL include glycation and abnor-
mal sialic acid content.26 Regardless of the source, electro-
negative LDL is likely to be cytotoxic. In patients with
familial hypercholesterolemia, treatment with simvastatin 40
mg/d significantly decreased the proportion of electronega-
tive LDL at 3 months (29%, P⬍0.0002) and 6 months (21%,
P⬍0.0001). During 6 months of simvastatin therapy, the
amount of cholesterol transported in electronegative LDL
continually declined, achieving an overall reduction of 60%.
Changes in the lipid parameters, however, were evident much
earlier, at 1 month.26 These findings suggest that long-term
statin therapy in humans may lead to a progressive reduction
in the atherogenic potential associated with electronegative
LDL.
Antiinflammatory Effects
Over the past decade, the importance of inflammation in the
development of atherosclerosis has become clear. Elevated
levels of markers for inflammation such as CRP,
interleukin-6, intercellular adhesion molecule-1 (ICAM-1),
and serum amyloid A (SAA) have been associated with
increased risk for first and recurrent cardiovascular
events.27,28 CRP levels, especially, appear to be among the
most powerful predictors of future events.
Reduction of Serum CRP
There is now compelling evidence that statin therapy may
attenuate the effect of inflammation on risk of cardiovascular
events. Among 708 postinfarction patients in the Cholesterol
and Recurrent Events (CARE) trial,27 subjects with elevated
levels of CRP and SAA (⬎90th percentile) had a higher risk
and benefited more from therapy with pravastatin 40 mg/d
than those without elevated levels of these inflammatory
markers.27 The relative risk of a recurrent coronary event was
reduced by 54% and 25% in the 2 groups, respectively,
compared with placebo.27 At baseline, both subsets had
nearly identical plasma lipid and lipoprotein profiles.
Long-term therapy with pravastatin in the CARE trial also
reduced levels of CRP in postinfarction patients.29 Although
baseline median CRP levels for active treatment and placebo
were similar, the median level after 5 years was 21.6% lower
in the pravastatin group than in the placebo group (P⫽0.007).

Effect of statin therapy on levels of high-sensitivity C-reactive
protein (hs-CRP). Data are presented as 25th percentile,
median, and 75th percentile. *P⬍0.025 compared with baseline.
Adapted with permission from Jialal I et al. Circulation.
2001;103:1933–1935.
The change in CRP levels associated with pravastatin treat-
ment was not correlated with the reduction in LDL-choles-
terol levels. The latter finding has been confirmed in the
recent 24-week prospective Pravastatin Inflammation/CRP
Evaluation (PRINCE) trial.30
A 6-week triple crossover trial compared the effect of
pravastatin, simvastatin, and atorvastatin therapy on hs-CRP
levels in patients with combined hyperlipidemia.31 All 3
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drugs, at doses reported to have equivalent effects on LDL-
cholesterol, significantly reduced median hs-CRP levels (pra-
vastatin by 20%, simvastatin by 23%, and atorvastatin by
28%; Figure), and these reductions were not correlated with
reductions in LDL-cholesterol. This study is in contrast to the
negative result of a similar comparison using a parallel design
and a 3-month exposure with a smaller number of subjects in
each subset.32 In the Atorvastatin versus Simvastatin on
Atherosclerosis Progression (ASAP) study, aggressive statin
therapy (atorvastatin 80 mg) reduced CRP levels to a greater
extent than conventional therapy (simvastatin 40 mg).33
Moreover, a significant correlation was found in univariate
analysis between the decrease in CRP and the reduction of
intima media thickness (IMT) of carotid artery segments.
A recent study showed that simvastatin lowered CRP
within 14 days,34 independently of LDL-cholesterol reduc-
tion. Rapid reductions in CRP levels with statins could
explain in part the early beneficial effects of these drugs in
acute coronary syndromes.35
Reduction of Adhesion Molecules
Adhesion molecules and chemoattractants play an important
role in the inflammatory process.36 They mediate adhesion
and transmigration of leukocytes to the subendothelium as
part of the atherogenic process. One may measure soluble
forms of adhesion molecules in plasma or study their inter-
action in vitro with inflammatory cell surface integrins.
Statins appear to reduce adhesion and chemotactic mole-
cules and to inhibit integrin activity. However, studies have
yielded inconsistent results. Aggressive lipid-lowering ther-
Davignon Statin Pleiotropic Effects III-41
apy with simvastatin and atorvastatin was associated with a
decrease in soluble E-selectin but not soluble vascular cell
adhesion molecule (VCAM) or soluble ICAM in an early
uncontrolled study.37 Recently, atorvastatin and simvastatin
were found to lower significantly soluble E-selectin,
P-selectin, and ICAM-1, but simvastatin increased soluble
VCAM-1.38 Another recent comparison of atorvastatin and
simvastatin at high doses, however, showed only small and
inconsistent effects of both drugs on ICAM-1 levels.39 Flu-
vastatin therapy in patients with hypercholesterolemia re-
duced circulating levels of P-selectin and ICAM-1; this effect
appeared to be independent of the lipid-lowering effect.14 An
important recent study demonstrated that a modified statin
with no inhibitory effect on HMG-CoA reductase could have
a potent and selective direct antiinflammatory effect.40 This
finding proves that a statin pleiotropic effect may be fully
dissociated from the inhibition of cholesterol synthesis.
Plaque Stabilization
Several mechanisms could account for the plaque-stabilizing
effect of statins that was elegantly demonstrated in animal
models.41 Reduction of LDL-cholesterol may contribute to
the downsizing of the lipid core.42 Statins inhibit uptake of
oxidized LDL by CD36,43 scavenger receptor A,44 and
lectin-like oxidized LDL (LOX-1) receptor45 and inhibit
macrophage oxidative properties.24 These effects of statins
could theoretically contribute to reduced foam cell formation.
Elevated plasma levels of several markers of the inflam-
matory cascade have been shown to predict future risk of
plaque rupture. These markers include P-selectin,
interleukin-6, tumor necrosis factor-␣, soluble ICAM-1, and
CRP.36 The beneficial effect of statins on the inflammatory
process has been discussed above. Weakening of the fibrous
cap in unstable plaques is associated with increased produc-
tion of matrix metalloproteinases (MMPs) by macrophages.
In cultured macrophage, fluvastatin decreased the activity of
MMP-9 by 20% to 40%.46 In a study in humans,47 pravastatin
treatment changed the composition of carotid artery plaques
in a manner that favored stabilization. Patients with carotid
artery stenosis received either pravastatin 40 mg/d or no
therapy for 3 months before carotid endarterectomy. Plaques
removed from the statin-treated group were composed of
significantly less lipid and oxidized LDL, fewer macro-
phages, and fewer T cells. They had higher collagen content
and demonstrated less MMP-2 immunoreactivity than control
plaques. In addition, apoptosis was significantly reduced and
immunoreactivity to tissue inhibitor of metalloproteinase-1 (a
potent inhibitor of MMP-1 and MMP-9) was significantly
increased in the pravastatin group compared with controls.47
Additional Effects
Stimulation of Endothelial Progenitor Cell Recruitment
Endothelial progenitor cells play an important role in the
repair of ischemic injury.48 Data from in vitro and in vivo
studies indicate that statins are at least as effective as vascular
endothelial growth factor, a key cytokine in the regulation of
neovascularization, in augmenting EPC differentiation.48 Ev-
idence suggests that statins enhance the level of circulating
EPCs and promote their mobilization to ischemic areas.49 In
 III-42 Circulation June 15, 2004
patients with documented stable coronary artery disease,
treatment with atorvastatin 40 mg/d for 4 weeks was associ-
ated with a 1.5-fold increase in the number of circulating
EPCs at week 1, which increased to 3-fold over the 4-week
period.49 Atorvastatin treatment stimulated the differentiation
of a subset of endothelial precursor cells into EPCs rather
than augmenting the total number of circulating hematopoi-
etic stem cells.49 In addition, atorvastatin significantly en-
hanced the migration of EPCs in response to vascular
endothelial growth factor.
The practical significance of these observations may seem
remote at this time but appear promising when taken in the
context of a recent study50 in a mouse model of myocardial
infarction. Investigators found that EPCs mobilized by stem
cell factor and by granulocyte colony stimulating factor
homed to and partly repaired the infarcted heart, reducing
mortality by 68% and improving myocardial function.
Immunomodulation
Immune mechanisms are important in atherogenesis. Increas-
ing evidence suggests that statins may act as immunomodu-
lators and that use of statins may have applicability in organ
transplantation and other conditions requiring immunosup-
pression. Pravastatin treatment, added to standard antirejec-
tion medications (cyclosporine, prednisone, and azathioprine)
after cardiac transplant, has been reported to significantly
decrease the frequency of rejection (3 versus 14; P⫽0.005)
and increase survival (94% versus 78%; P⫽0.025) at 12
months compared with controls.51 In cardiac transplant pa-
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tients, simvastatin treatment in combination with antirejection
medications and a lipid-lowering diet significantly increased
survival and decreased the incidence of accelerated graft
disease (a serious late complication of cardiac transplanta-
tion) compared with diet alone over a 4-year period.52 The
possibility of intrinsic immunosuppressive activity of statins
has also been raised. Recently, atorvastatin and lovastatin
(10 ␮mol/L) and, to a lesser extent, pravastatin (20 ␮mol/L)
were found to decrease interferon-␥–induced major histo-
compatibility complex-II (MHC-II) in human endothelial
cells and macrophages.53 This effect was reversed by meva-
lonate and was attributed to the inhibitory effect of statins on
promoter IV of MHC-II transactivating factor, leading to
suppression of T-lymphocyte activation. This finding could
explain in part the improved survival observed with statins in
heart transplant recipients if T helper cell-1 immune re-
sponses were suppressed in the process.54
Inhibition of Myocardial Hypertrophy
Left ventricular hypertrophy is a risk factor for coronary
artery disease and congestive heart failure. Rat cardiomyo-
cyte hypertrophy induced in vitro by angiotensin II was
abolished by simvastatin. Cardiac hypertrophy in vivo, in-
duced in rats either by angiotensin II infusion (presence of
hypertension) or by transaortic constriction (absence of hy-
pertension), was also inhibited by simvastatin (2 mg/kg/d for
4 weeks).55 These findings add to the evidence that statins
exert a protective effect on organs, including the kidney56 and
pancreas,57,58 in addition to the vascular wall and the heart.
Conclusions
Although the possibility that statins might have pleiotropic
effects was met at first with a healthy skepticism, the vast
amount of knowledge accrued over the past few years has
moved these effects into the spotlight. Many of the statin
pleiotropic effects operate independently of LDL-cholesterol
reduction, correlate poorly or not at all with LDL-cholesterol
changes, take place rapidly, and are rapidly reversible on
discontinuation of the drug. Direct effects in the absence of
LDL or total cholesterol modification have been shown both
in vitro and in vivo. The pleiotropic effects of statins and
other drugs are under continued investigation to fully estab-
lish their role in the prevention of cardiovascular events. The
results of several ongoing clinical trials aimed more specifi-
cally at pleiotropic effects should enlighten us on their
relative clinical relevance and importance.
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