(Circulation. 2000;102:846.)
© 2000 American Heart Association, Inc.
Clinical Investigation and Reports |
Effect of Cholesterol-Lowering Therapy on Coronary Endothelial Vasomotor Function in Patients With Coronary Artery Disease
From the Boston University School of Medicine (J.A.V.), Boston, Mass; Stanford University Medical Center (A.C.Y.), Palo Alto, Calif; University of Iowa Hospitals and Clinics (M.W.), Iowa City; University Hospitals of Cleveland (J.M.H.), Cleveland, Ohio; Emory University School of Medicine (C.B.T., J.L.K.), Atlanta, Ga; The University of Michigan Medical Center (S.W.), Ann Arbor; St Louis University Hospital (M.K.), St Louis, Mo; Merck Research Laboratories (D.P., W.J.S., Y.M.), Rahway, NJ; and Brigham and Women’s Hospital (P.G.), Boston, Mass.
Correspondence to Joseph A. Vita, MD, Section of Cardiology, Boston Medical Center, 88 East Newton Street, Boston, MA 02118. E-mail jvita{at}bu.edu
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Abstract |
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Background—Improved endothelial function may contribute to the beneficial effects of cholesterol-lowering therapy.
Methods and Results—In this randomized, double-blind study, we compared the effect of 6 months of simvastatin (40 mg/d) treatment with that of placebo on coronary endothelial vasomotor function in 60 patients with coronary artery disease. Simvastatin lowered LDL-cholesterol by 40±12% from 130±28 mg/dL (P<0.001). Peak intracoronary acetylcholine infusion produced epicardial coronary constriction at baseline in both the simvastatin (-17±13%) and placebo (-24±16%) groups. After treatment, acetylcholine produced less constriction in both groups (-12±19% and -15±14%, respectively, P=0.97). The increase in coronary blood flow during infusion of the peak dose of substance P was blunted at baseline in both the simvastatin (42±50%) and placebo (55±71%) groups, reflecting impaired endothelium-dependent dilation of coronary microvessels. After treatment, the flow increase was 82±81% in the simvastatin group and 63±53% in the placebo group (P=0.16).
Conclusions—Six months of cholesterol-lowering therapy has no significant effect on coronary endothelial vasomotor function in the study population of patients with coronary artery disease and mildly elevated cholesterol levels. These findings suggest that the effects of cholesterol lowering on endothelial function are more complex than previously thought.
Key Words: endothelium • lipids • coronary disease
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Introduction |
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The endothelium controls vascular homeostasis through the elaboration of paracrine factors, including nitric oxide. Endothelium-dependent vasodilation is impaired in epicardial coronary arteries1 and in the coronary microcirculation2 of patients with coronary artery disease (CAD). The loss of endothelium-derived nitric oxide (EDNO) promotes vasospasm, platelet aggregation, and inflammation in atherosclerotic coronary arteries and thus contributes to the clinical expression of CAD.3 4
Recent studies have conclusively shown that cholesterol-lowering therapy reduces cardiovascular events5 6 7 and total mortality rates5 in patients with CAD, but the exact mechanisms of benefit remain unknown. Although statistically significant reductions in lesion severity have been demonstrated, the extent of improvement is modest, suggesting that alternative mechanisms are operative, including plaque stabilization and improved endothelial function.3
Several prior studies8 9 10 11 examined the effect of cholesterol-lowering therapy on coronary endothelial function in patients with hypercholesterolemia, CAD, or both. In those studies, cholesterol-lowering therapy reduced coronary artery constriction8 9 10 11 and increased coronary blood flow responses during intracoronary acetylcholine infusion,9 reflecting improved EDNO action in conduit coronary arteries and coronary microvessels, respectively. Improved endothelium-dependent dilation after cholesterol-lowering therapy has also been shown in the forearm circulation.12 13 Some of those prior coronary studies were not well controlled,8 9 and a relatively small number of subjects were enrolled. The study that examined the coronary microvasculature9 was not randomized. Therefore, the purpose of the present study was to examine the effect of cholesterol-lowering therapy on coronary conduit and microvascular endothelial function in a well-controlled manner.
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Methods |
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Patients
The Coronary Artery Reactivity After Treatment with Simvastatin (CARATS) Study was a randomized, double-blind study that compared the effect of simvastatin with that of placebo on coronary endothelial vasomotor function. Entry criteria were age of 25 to 80 years, total serum cholesterol level of 180 to 300 mg/dL, angiographically documented CAD (diffuse luminal irregularities or
1 vessel with
>50% stenosis), and an index vessel for study of >2.0
mm in diameter with no stenosis of >30% that supplied
normally contracting myocardium. Exclusion criteria
included hypertension (blood pressure of >140/90 mm Hg or
antihypertensive treatment), cigarette smoking within 1 month, diabetes
mellitus (random glucose level of >200 mg/dL or hypoglycemic
treatment), and hypertriglyceridemia (>350
mg/dL). Patients were also excluded if they had left main or 3-vessel
disease, CABG within 6 months, coronary angioplasty within 2
weeks, mean pulmonary capillary wedge pressure of >25
mm Hg, or left ventricular ejection fraction of <0.40.
Other exclusion criteria included cholesterol-lowering
medication within 6 weeks, creatinine level of >1.8 mg/dL,
creatine kinase level of >50% above the upper limit of normal,
transaminase of >20% above the upper limit of normal, and a history
of liver disease within 6 months. All site institutional review boards
approved the study, and patients provided informed consent.
Coronary Vasomotor Studies
Coronary vasomotor function was assessed after
diagnostic catheterization or before
coronary angioplasty.1 10 11 Nitrates, calcium
channel blockers, ß-adrenergic blockers, and ACE
inhibitors were withheld for >18 hours. Additional heparin
was administered (total dose 10 000 U), and a 3F infusion catheter and
an 0.018-inch Doppler flow wire (Cardiometrics Inc) were positioned
in the index vessel via a 7F or an 8F guiding catheter. Serial
infusions (0.8 mL/min) were made as follows: (1) 2-minute vehicle
infusion of 5% dextrose with 1 U/mL heparin, (2) three 2-minute
infusions of acetylcholine (Miochol; CIBA Vision) at 0.14, 1.4, and 14
µg/min, yielding estimated intracoronary concentrations of
10-8, 10-7, and
10-6 mol/L with the assumption of a flow rate of
80 mL/min), (3) 5-minute vehicle infusion, (4) three 2-minute infusions
of substance P (Sigma Chemical Co) at 5, 20, and 40 pmol/min), (5)
5-minute vehicle infusion, and (6) 2-minute adenosine infusion
(Sigma Chemical Co) at 2.2 mg/min. The order of acetylcholine and
substance P administration was randomized. At the end of each infusion,
arterial blood pressure and blood flow velocity were
recorded, and angiography was performed with nonionic contrast
medium and a power injector.
Both acetylcholine and substance P dilate epicardial and microvessels
via EDNO-dependent mechanisms.14 Substance P at 20
pmol/min increases coronary flow 
150% in normal
subjects.15 Adenosine-induced vasodilation is
largely independent of EDNO synthesis.16
Treatment and Follow-Up
On the day after catheterization, patients
started the American Heart Association cholesterol-lowering
Phase I diet and study medication (40 mg/d simvastatin or
placebo). They returned after 8, 16, and 26 weeks for a reassessment of
lipid profile and safety markers. At the final visit, patients
underwent repeat research catheterization. Care was
taken to replicate time when medications were held, angiographic views,
tube height, catheter and flow wire positions, and order of infusions
used in the baseline study. Lipid profiles were measured at a Centers
for Disease Control and Prevention/National Heart, Lung, and Blood
Institute–certified core laboratory (Medical Research Laboratories).
LDL-cholesterol was calculated according to the Friedewald
formula.
Assessment of Coronary Artery Diameter and Flow
Quantitative angiography was performed at a core laboratory
(Emory University). An end-diastolic frame from each
infusion was digitized (10 pixels/mm), and the diameter of the index
vessel was measured with CAAS II software (PIE Medical).
Analysis was begun at a proximal landmark and continued
distally for a maximum of 5 cm. Films from the baseline and follow-up
studies were examined in parallel (blinded to chronological sequence)
to ensure analysis of the identical portion of the vessel. The
analysis software divided the vessel into contiguous 5-mm
segments and determined the diameter of each segment.
Epicardial responses were expressed as percent change in diameter compared with those for the preceding dextrose infusion. We examined both the mean response for all measured segments and the response of the single 5-mm segment that was the site of maximal abnormal vasoactivity (SMAV). For acetylcholine, the SMAV was defined as the segment that demonstrated the most severe constriction, and for substance P, the SMAV was the segment that demonstrated the least vasodilation. The SMAV of the baseline study was identified, and the same segment was reexamined at follow-up, even if that segment no longer showed the most abnormal response.
Coronary blood flow velocity was determined by averaging the mean velocity for 8 consecutive beats at the end of each infusion. Flow was estimated as the product of velocity and the cross-sectional area of a 2-mm segment centered 5 mm distal to the flow wire tip.17 Flow responses were expressed as percent change relative to the preceding dextrose infusion.
Statistical Analysis
The primary end point was the effect of treatment
(simvastatin or placebo) on the change in the diameter
response of the SMAV to the maximal dose of acetylcholine. The study
was planned to have 80% power to detect a difference of 14 percentage
points for this end point with a sample size of 80 patients (
=0.05,
2-tailed), with an assumed within-group SD of change in diameter
response of 22%. The key secondary end point was the effect of
treatment on change in the coronary blood flow response to the
maximal dose of substance P. The study was planned to have 80% power
to detect a difference of 22 percentage points for the key secondary
end point with a sample size of 80 patients (=0.05 2-tailed), with
an assumed within-group SD of change in blood flow of 35%.
Other end points included (1) coronary blood flow responses to the maximal doses of acetylcholine and adenosine, (2) diameter responses to the maximal doses of substance P and adenosine, (3) diameter responses to the maximal doses of all 3 agonists with the average of all analyzed segments used for the analysis, rather than the SMAV, and (4) dose response for substance P–mediated changes in coronary blood flow. The dose responses to acetylcholine could not be examined because some patients did not receive all 3 doses due to severe constriction at a submaximum dose.
ANOVA was used to compare the treatment groups for the primary, key secondary, and first 3 other end points. The model included terms for treatment group, investigator, and response to the agonist at the baseline visit. The effect of treatment on the dose response to substance P at the follow-up visit was examined with an analysis of repeated measures with use of the mixed model that included dose of substance P, the treatment, and the interaction of dose and treatment. The effect of treatment on lipid profile was compared by ANOVA with treatment group and investigator in the model. The analysis was performed with SAS statistical software. A 2-tailed P value of <0.05 was considered to be statistically significant. All data are expressed as mean±SD unless otherwise indicated.
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Results |
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Clinical Characteristics and Adverse Events
A total of 83 patients were enrolled. Twenty-three patients were withdrawn (simvastatin group n=11, placebo group n=12). Two patients in the simvastatin group had an adverse drug experience (muscle cramps n=1, urticaria n=1). The remaining patients were withdrawn due to unwillingness to undergo the second catheterization (simvastatin n=6, placebo n=4); protocol violation (placebo n=1); non–medication-related adverse experience, including the development of unstable angina (simvastatin n=2, placebo n=3); or other reasons, including the exacerbation of preexisting non-CAD conditions (simvastatin n=1, placebo n=4). In 1 subject, the follow-up catheterization was complicated by acute myocardial infarction (peak creatine kinase 1300 U/L) due to failure to administer heparin before instrumentation and thrombus formation on the infusion catheter. The subject was treated with heparin and intracoronary urokinase and was discharged in stable condition with a mild hypokinesis in the involved territory (lateroinferior wall) on echocardiography. Thus, a total of 60 patients were available for analysis. The demographic and clinical characteristics of the evaluable patients are given in Table 1
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Lipid Effects
Lipid results are shown in Table 2.
The effect of simvastatin treatment was significantly
different from that for placebo for total cholesterol
(P<0.001) and LDL-cholesterol
(P<0.001) levels. At follow-up, LDL-cholesterol
was <100 mg/dL in 30 of 34 patients in the simvastatin
group and 4 of 25 patients in the placebo group.
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Epicardial Vasomotor Function
As shown in Table 3, blood pressure,
heart rate, and baseline coronary diameter were similar in both
groups and were unaffected by either treatment. Coronary
diameter and flow returned to baseline during the vehicle infusion
before the next agonist.
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The effect of acetylcholine infusion on coronary diameter is
shown in Figure 1. The
10-6 mol/L dose of acetylcholine was omitted in
6 patients in the simvastatin group and 8 patients in the
placebo group due to excessive vasoconstriction at
10-7 mol/L. The maximal dose of acetylcholine
produced coronary constriction at the SMAV at baseline in both
groups (-17±13% and -24±16%, respectively). After 6 months,
acetylcholine produced less severe constriction in both groups
(-12±19% and -15±14%, respectively). Because the baseline
constrictor responses for the 2 groups were different, the change was
adjusted for baseline response with ANCOVA. The adjusted changes in the
response to acetylcholine were 6±15 percentage points for the
simvastatin group and 6±15 percentage points for the
placebo group (P=0.97). Adjustment for investigator site,
age, extent of atherosclerosis, and baseline LDL level
did not alter the findings.
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When epicardial function was assessed with the average response of all analyzed segments rather than the 5-mm segment with maximal constriction (SMAV), the extent of coronary constriction was still greater in the placebo group than in the simvastatin group at baseline (-11% versus -5%, respectively) and at follow-up (-12% versus -9%, respectively). The adjusted changes in acetylcholine response between baseline and follow-up were equivalent for the simvastatin group (-3±14 percentage points) and the placebo group (-3±14 percentage points, P=0.95).
The maximal dose of substance P produced modest vasodilation at the SMAV at baseline in both the simvastatin (1±10%) and placebo (1±10%) groups. After 6 months, the dilator response to substance P was increased in both groups (11±11% and 13±13%, respectively). The changes in substance P–induced dilation were equivalent in the 2 groups (P=0.53). The findings were similar when the average response of all segments was used for the analysis rather than the SMAV (data not shown).
Intracoronary adenosine induced coronary dilation at baseline for the simvastatin (4±12%, n=27) and placebo (5±10%, n=19) groups. After 6 months, the dilator response was greater in both groups (20±19% and 16±23%, respectively). The changes in adenosine-induced dilation were equivalent in the 2 groups (P=0.45).
Microvessel Vasomotor Function
Coronary blood flow responses to substance P infusion are
displayed in Figure 2. The maximal dose
of substance P increased coronary blood flow at baseline in
both the simvastatin (42±50%) and placebo (55±71%)
groups. After 6 months, the response was greater in both groups
(82±81% and 63±53%, respectively). The unadjusted improvement was
greater in the simvastatin group (39±79 percentage points)
than the placebo group (8±79 percentage points). Blood flow responses
differed according to participating center, and after adjustment for
investigator site and baseline response, the change was 57±70
percentage points for the simvastatin group and 33±67
percentage points for the placebo group (P=0.16). Adjustment
for age, extent of atherosclerosis, and baseline LDL
level did not alter the findings.
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When the entire dose response to substance P was considered, the flow
response to substance P improved significantly in the
simvastatin group (P=0.03 by analysis of
repeated measures) but not in the placebo group (P>0.69)
(see Figure
2). However, there was no
significant difference between groups in the degree of improvement for
all 3 doses of substance P (P=0.21).
The maximal dose of acetylcholine increased coronary blood flow at baseline in both the simvastatin (63±100%) and placebo (33±76%) groups. After 6 months, acetylcholine increased coronary blood flow by 49±87% in the simvastatin group and 35±85% in the placebo group. The change in acetylcholine response was equivalent in the 2 groups (-14±105 and 1±118 percentage points, respectively, P=0.49).
The intracoronary infusion of adenosine increased coronary blood flow at baseline in both the simvastatin (327±183%) and placebo (387±296%) groups. After 6 months, the increase was 388±269% and 353±223%, respectively. Thus, the change in adenosine-induced increase in coronary blood flow was 61±246 percentage points for the simvastatin group and -33±334 percentage points for the placebo group (P=0.36).
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Discussion |
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In these patients with mild CAD and mildly elevated cholesterol levels, acetylcholine infusion produced epicardial coronary vasoconstriction, and there was a blunted blood flow response to substance P. Adenosine, which primarily acts on vascular smooth muscle in the coronary vasculature, produced epicardial dilation and expected increases in coronary blood flow. These findings suggest the presence of endothelial vasomotor dysfunction at baseline. Six-month treatment with simvastatin markedly improved the lipid profile, whereas placebo had no effect. At follow-up, the severity of acetylcholine-induced vasoconstriction was less in both treatment groups, but there was no difference in the extent of improvement. There also was no significant difference between groups in the degree of improvement in the coronary blood flow response to peak substance P dose (P=0.16), although the analysis of all 3 doses of substance P raised the possibility of a beneficial effect in the simvastatin group (P=0.03). Overall, cholesterol-lowering treatment for 6 months failed to improve coronary endothelial vasomotor function in this patient population.
The present study has a number of strengths. More patients were enrolled than in any prior study of this issue. The investigators were experienced, and the study was rigorously controlled with centralized blinding and core laboratories. In this study, patients with isolated hypercholesterolemia were examined, and thus, the potentially confounding effects of other risk factors were avoided. In addition to acetylcholine, substance P was also used, which permitted an examination of microvascular endothelial function without the simultaneous constriction of epicardial arteries. These features all suggest that the findings are reliable.
Prior Studies
Four previous studies examined the effects of
cholesterol-lowering therapy on coronary
endothelial vasomotor function (Table 4). In an uncontrolled study, Leung et
al8 reported that cholestyramine lowered total
cholesterol by 29% and converted acetylcholine-induced
constriction to vasodilation in hypercholesterolemic
men with normal coronary arteries. In an open-label study,
Egashira et al9 reported improved epicardial and
microvascular responses to acetylcholine after pravastatin
treatment in patients with 1-vessel CAD and no change in a
nonrandomized control group. In a randomized, double-blind
placebo-controlled study, Treasure et al10 examined the
epicardial coronary responses to acetylcholine in patients with
1-vessel CAD. Lovastatin plus diet reduced total
cholesterol by 31% and improved acetylcholine-induced
coronary constriction (-16% to 0%), whereas placebo plus
diet had no effect (-19 to -18%). Like in the present study,
Treasure et al10 examined the SMAV and used the same
quantitative angiography core laboratory. Finally, Anderson et
al11 randomized patients with CAD to treatment with diet
alone, lovastatin plus cholestyramine, or
lovastatin plus the
antioxidant/cholesterol-lowering agent probucol.
Lovastatin plus cholestyramine reduced total
cholesterol by 23%, and there was a trend for a reduction
in the constrictor response to acetylcholine (P=0.08).
Notably, the combination of cholesterol-lowering and
antioxidant therapy produced a significant improvement in
endothelial vasomotor function.
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In contrast to those prior studies, the present study demonstrated
no effect of cholesterol-lowering therapy on the response
to acetylcholine. Several factors might explain these apparently
discrepant findings. One possibility is a difference in the study
population, and it is notable that baseline total and
LDL-cholesterol levels were higher in all 3
studies8 9 10 that showed a beneficial effect with
cholesterol-lowering therapy alone (Table
4). The finding in the present study that there
was no relation between baseline LDL-cholesterol and the
response to therapy, at least within the limited range of
cholesterol values in the study, argues somewhat against
this potential explanation. Likely related to the modest LDL elevation
is the relatively mild degree of endothelial
dysfunction at baseline in the present study (average 5%
constriction), which may also be attributable to the exclusion of
patients with other coronary risk factors. Furthermore, the
extent of atherosclerosis was relatively mild in the
present study (half had no stenosis of >50%), whereas in
the previous controlled studies,9 10 11 nearly all patients
had at least 1-vessel coronary disease. The duration of therapy
might also be a factor. Although baseline lipid levels in the study by
Anderson et al11 were similar to those of the present
study, the duration of therapy was twice as long. Thus, it is possible
that more prolonged treatment is required to demonstrate improved
coronary endothelial function in patients with
lower baseline cholesterol levels.
The present study has certain limitations. First, despite the randomized design, there were significant group differences in baseline vasomotor function. For example, the constrictor response to acetylcholine was more severe in the placebo group than in the simvastatin group. It also is unclear whether the basal tone was equivalent in the initial and follow-up studies, because the adenosine-induced vasodilation of epicardial arteries was higher during the follow-up study for both groups. Second, the use of the Doppler flow wire to assess coronary flow was relatively new at the time of the study. It is possible that there were unplanned methodological differences among sites. Third, the placebo group demonstrated sizable improvement in the epicardial response to acetylcholine, a finding that likely represents "regression to the mean." This phenomenon was not observed when the vasomotor response of the entire segment was considered, indicating a limitation of the SMAV analysis for intervention studies. However, the overall findings of the study were the same by either approach to analysis. Finally, the study may have lacked sufficient power to demonstrate an effect of therapy on the microvascular response to substance P given that fewer than the planned number of patients were enrolled and the variability was greater than expected. If the planned number of subjects had been studied, the observed changes in microvascular function might have reached statistical significance.
Clinical Implications and Conclusions
It has been suggested that improvement of coronary
endothelial function contributes to the reduction in
CAD events associated with long-term cholesterol-lowering
therapy.3 In the CARE6 and
LIPID7 studies, which involved patients with CAD and lipid
levels comparable to those of the patients in the present study,
there were no reductions in cardiovascular disease
events during the first 2 to 3 years of treatment. The finding in the
present study that endothelial function remained
unimproved after only 6 months of treatment is consistent with
the results of those clinical trials. It is possible that more
prolonged treatment is associated with an improvement in
coronary endothelial function that might
contribute to the observed reduction in events.
In the present study, there was a suggestion that
cholesterol-lowering therapy improved microvascular
endothelial function (Figure 2),
although the group difference did not reach statistical significance.
Recent studies have shown that short-term
cholesterol-lowering therapy (3 to 5 months) reduces
ambulatory18 and stress-induced 19
ischemia in patients with CAD and higher total
cholesterol levels than those in the present study (238
to 297 mg/dL). Because endothelial vasomotor function
in coronary microvessels is relevant to metabolic
regulation of coronary blood flow,20 it is
possible that improved microvascular endothelial
function contributes to the reduction in myocardial ischemia in
these patients. However, the present study does not provide
conclusive evidence to support this speculation.
In summary, this relatively large, well-controlled study demonstrated that 6 months of cholesterol-lowering therapy has no significant effect on coronary endothelial function in a group of patients with mildly elevated cholesterol levels, no concomitant coronary risk factors, and mild CAD. These findings suggest that the effects of cholesterol lowering on endothelial function are more complex than previously thought.
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Acknowledgments |
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The authors thank Francois Charbonneau, MD; J. Jeffery Marshall, MD; Tai-Tien Lim, MD; Richard Bach, MD; Ravi Nair, MD; and John F. Keaney, Jr, MD, who assisted in the completion of study protocols.
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Footnotes |
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D. Plotkin, W.J. Shih, and Y. Mitchel are employed by Merck Research Laboratories, which manufactures simvastatin.
Received December 14, 1999; revision received March 7, 2000; accepted March 27, 2000.
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References |
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G. I. Boger, T. K. Rudolph, R. Maas, E. Schwedhelm, E. Dumbadze, A. Bierend, R. A. Benndorf, and R. H. Boger Asymmetric Dimethylarginine Determines the Improvement of Endothelium-Dependent Vasodilation by Simvastatin: Effect of Combination With Oral L-Arginine J. Am. Coll. Cardiol., June 12, 2007; 49(23): 2274 - 2282. [Abstract] [Full Text] [PDF]
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S. Fichtlscherer, C. Schmidt-Lucke, S. Bojunga, L. Rossig, C. Heeschen, S. Dimmeler, and A. M. Zeiher Differential effects of short-term lipid lowering with ezetimibe and statins on endothelial function in patients with CAD: clinical evidence for 'pleiotropic' functions of statin therapy Eur. Heart J., May 2, 2006; 27(10): 1182 - 1190. [Abstract] [Full Text] [PDF]
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F. Tomai, F. Ribichini, A. S. Ghini, V. Ferrero, G. Ando, C. Vassanelli, F. Romeo, F. Crea, and L. Chiariello Elevated C-reactive protein levels and coronary microvascular dysfunction in patients with coronary artery disease Eur. Heart J., October 2, 2005; 26(20): 2099 - 2105. [Abstract] [Full Text] [PDF]
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P. H. Stone, D. M. Lloyd-Jones, S. Kinlay, B. Frei, W. Carlson, J. Rubenstein, T. C. Andrews, M. Johnstone, G. Sopko, H. Cole, et al. Effect of Intensive Lipid Lowering, With or Without Antioxidant Vitamins, Compared With Moderate Lipid Lowering on Myocardial Ischemia in Patients With Stable Coronary Artery Disease: The Vascular Basis for the Treatment of Myocardial Ischemia Study Circulation, April 12, 2005; 111(14): 1747 - 1755. [Abstract] [Full Text] [PDF]
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 J.-H. Bae, E. Bassenge, K.-Y. Kim, Y.-C. Synn, k.-R. Park, and M. Schwemmer Effects of Low-Dose Atorvastatin on Vascular Responses in Patients Undergoing Percutaneous Coronary Intervention With Stenting Journal of Cardiovascular Pharmacology and Therapeutics, July 1, 2004; 9(3): 185 - 192. [Abstract] [PDF]
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J. Davignon and P. Ganz Role of Endothelial Dysfunction in Atherosclerosis Circulation, June 15, 2004; 109(23_suppl_1): III-27 - III-32. [Abstract] [Full Text]
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M. E. Widlansky, N. Gokce, J. F. Keaney Jr, and J. A. Vita The clinical implications of endothelial dysfunction J. Am. Coll. Cardiol., October 1, 2003; 42(7): 1149 - 1160. [Abstract] [Full Text] [PDF]
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J. T. Kuvin and R. H. Karas Clinical Utility of Endothelial Function Testing: Ready for Prime Time? Circulation, July 1, 2003; 107(25): 3243 - 3247. [Full Text] [PDF]
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The ENCORE Investigators* Effect of Nifedipine and Cerivastatin on Coronary Endothelial Function in Patients With Coronary Artery Disease: The ENCORE I Study (Evaluation of Nifedipine and Cerivastatin On Recovery of coronary Endothelial function) Circulation, January 28, 2003; 107(3): 422 - 428. [Abstract] [Full Text] [PDF]
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 C. Staniloae, A. J. Schwab, A. Simard, R. Gallo, I. Dyrda, G. Gosselin, J. Lesperance, J. W. Ryan, and J. Dupuis In vivo measurement of coronary circulation angiotensin-converting enzyme activity in humans Am J Physiol Heart Circ Physiol, January 1, 2003; 284(1): H17 - H22. [Abstract] [Full Text] [PDF]
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S. de Jongh, M. R. Lilien, J. op't Roodt, E. S. G. Stroes, H. D. Bakker, and J. J. P. Kastelein Early statin therapy restores endothelial function in children with familial hypercholesterolemia J. Am. Coll. Cardiol., December 18, 2002; 40(12): 2117 - 2121. [Abstract] [Full Text] [PDF]
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D. H. Walter, K. Rittig, F. H. Bahlmann, R. Kirchmair, M. Silver, T. Murayama, H. Nishimura, D. W. Losordo, T. Asahara, and J. M. Isner Statin Therapy Accelerates Reendothelialization: A Novel Effect Involving Mobilization and Incorporation of Bone Marrow-Derived Endothelial Progenitor Cells Circulation, June 25, 2002; 105(25): 3017 - 3024. [Abstract] [Full Text] [PDF]
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J. H. Stein, C. M. Carlsson, K. Papcke-Benson, S. E. Aeschlimann, A. Bodemer, M. Carnes, and P. E. McBride The effects of lipid-lowering and antioxidant vitamin therapies on flow-mediated vasodilation of the brachial artery in older adults with hypercholesterolemia J. Am. Coll. Cardiol., December 1, 2001; 38(7): 1806 - 1813. [Abstract] [Full Text] [PDF]
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R. G. Bach Heterogeneity of response to lipid-lowering therapy J. Am. Coll. Cardiol., December 1, 2001; 38(7): 2136 - 2137. [Full Text] [PDF]
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J. L. Houghton Effect of Cholesterol-Lowering Therapy on Endothelial Function Circulation, July 10, 2001; 104 (2): e6 - e6. [Full Text] [PDF]
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C. H. Bolton, L. G. Downs, J. G.G. Victory, J. F. Dwight, C. R.V. Tomson, M. I. Mackness, and J. H. Pinkney Endothelial dysfunction in chronic renal failure: roles of lipoprotein oxidation and pro-inflammatory cytokines Nephrol. Dial. Transplant., June 1, 2001; 16(6): 1189 - 1197. [Abstract] [Full Text] [PDF]
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C. P. Tiefenbacher Tetrahydrobiopterin: a critical cofactor for eNOS and a strategy in the treatment of endothelial dysfunction? Am J Physiol Heart Circ Physiol, June 1, 2001; 280(6): H2484 - H2488. [Full Text] [PDF]
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S. John, C. Delles, J. Jacobi, M. P. Schlaich, M. Schneider, G. Schmitz, and R. E. Schmieder Rapid improvement of nitric oxide bioavailability after lipid-lowering therapy with cerivastatin within two weeks J. Am. Coll. Cardiol., April 1, 2001; 37(5): 1351 - 1358. [Abstract] [Full Text] [PDF]
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