(Circulation. 1999;99:3227-3233.)
© 1999 American Heart Association, Inc.
Clinical Investigation and Reports |
Cholesterol Reduction Rapidly Improves Endothelial Function After Acute Coronary Syndromes
The RECIFE (Reduction of Cholesterol in Ischemia and Function of the Endothelium) Trial
From the Department of Medicine and Research Centre, Montreal Heart Institute, Montreal, Quebec, Canada.
Correspondence to Dr Jocelyn Dupuis, Research Centre, Montreal Heart Institute, 5000 Bélanger Street East, Montreal, Quebec H1T 1C8, Canada. E-mail dupuisj{at}icm.umontreal.ca
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Abstract |
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Background—Cholesterol lowering reduces coronary events. One mechanism could be improvement of endothelial function. In line with this hypothesis, this study investigates whether cholesterol reduction can result in rapid improvement of endothelial function after acute coronary syndromes.
Methods and Results—Patients with acute myocardial infarction or
unstable angina and total cholesterol levels at admission
5.2 mmol/L or LDL 3.4 mmol/L were randomized to placebo
(n=30) or pravastatin 40 mg daily (n=30) for 6 weeks.
Brachial ultrasound was used to measure
endothelium-dependent flow-mediated dilatation (FMD)
and response to endothelium-independent
nitroglycerin. Changes in the levels of markers of
platelet activation, coagulation factors, and plasma endothelin
levels were also assessed. Total and LDL cholesterol levels
were similar at admission and before randomization in both groups. With
pravastatin, but not with placebo, they decreased by 23%
(P<0.05) and 33% (P<0.01),
respectively. FMD was unchanged with placebo, 5.43±0.74% (mean±SEM)
to 5.84±0.81%, but increased with pravastatin,
4.93±0.81% to 7.0±0.79% (P=0.02),
representing a 42% relative increase. Responses to
nitroglycerin were similar during the time
course of the study in the 2 groups. Markers of platelet activity,
coagulation factors, and endothelin levels were not affected by
pravastatin.
Conclusions—Cholesterol reduction with pravastatin initiated early after acute coronary syndromes rapidly improves endothelial function after 6 weeks of therapy.
Key Words: coronary disease • cholesterol • endothelium • risk factors
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Cholesterol-lowering agents reduce the risks of mortality and myocardial infarction.1 Although cholesterol lowering effectively induces regression and delays the progression of coronary atherosclerosis,2 these beneficial morphological modifications are of a small magnitude that contrast with the marked clinical benefits of therapy observed in large cholesterol reduction trials.3 Other mechanisms, of which plaque regression may represent an epiphenomenon, have therefore been postulated to explain these findings. Thus, cholesterol lowering may stabilize the vulnerable plaque by modifying its content, mostly through a reduction of the oxidized lipids in its core, which renders it susceptible to rupture.4 Cholesterol reduction also improves both coronary5 and systemic6 endothelial functions. This effect can be rapid as recently demonstrated in hypercholesterolemic patients with no coronary artery disease by improved forearm endothelial function after 4 weeks of oral pharmacologic therapy,7 and within minutes after LDL apheresis.8 Another potential benefit of cholesterol reduction could be thrombus reduction through an effect on hemostatic factors.9 10
Despite these considerations, pharmacological cholesterol reduction is often delayed after acute coronary syndromes11 because of concerns about the significance of cholesterol values obtained in the acute phase12 and the desire to initially test dietary therapy. Moreover, there is presently no evidence that rapid cholesterol reduction after acute coronary syndromes will reduce recurrent ischemic events. Because patients with acute coronary syndromes have plaque instability, more rapid improvement in both endothelial function and platelet-endothelium interactions may be desirable.
The REduction of Cholesterol in Ischemia and Function of the Endothelium (RECIFE) trial was designed to test this mechanistic hypothesis. The effect of rapid cholesterol reduction on vascular endothelial reactivity after acute myocardial infarction and unstable angina was evaluated. Patients were randomized to placebo or pravastatin for a period of 6 weeks and vascular endothelial cell function was measured using flow-mediated dilatation of the brachial artery. The effect of therapy on hemostatic factors and platelet function was also evaluated.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Study Objectives
The primary objective was to evaluate the effect of therapy on noninvasively measured endothelial function as assessed by brachial artery flow-mediated dilatation using high-resolution ultrasonography. Secondary objectives included evaluation of the variations of hemostatic factors, platelet activity, and plasma immunoreactive endothelin-1 (ET-1) concentrations. Because this study is based on the use of admission cholesterol as an entry criterion, a tertiary objective was to confirm the reliability of the admission lipid profile and compare the effects of dietary and combined dietary plus pharmacological cholesterol reductions on plasma lipids after only 6 weeks of therapy.
Study Population
Subjects were randomized in a double-blind fashion to placebo
(n=30) or pravastatin (40 mg daily at bedtime; n=30) for a
duration of 6 weeks. Patients admitted to the coronary care
unit of the Montreal Heart Institute with a diagnosis of acute
myocardial infarction or unstable angina were eligible if they had
admission total serum cholesterol 5.2 mmol/L or LDL
cholesterol 3.4 mmol/L and serum
triglycerides 4.5 mmol/L. Exclusion criteria were
the presence of heart failure with an ejection fraction of <40%,
administration of lipid lowering agents in the preceding 8 weeks, renal
failure with serum creatinine level >200 mmol/L, and
patients requiring coronary artery bypass surgery.
Premenopausal women were also excluded as well as postmenopausal women
on hormone replacement therapy. All patients received and were taught
American Heart Association step 2 diet. Vitamin supplements were not
permitted. All medications were held constant throughout the entire
study. None of the smokers quit during the duration of the study.
Coronary angiography was performed for 21 patients in the
placebo group and 18 patients in the pravastatin group
(P=NS), with angioplasty in 16 patients from each group.
Randomization in the study was done at the end of the in-hospital investigation (time 0) and was continued for a period of 6 weeks. Noninvasive evaluation of endothelial function as well as lipid profiles, hemostatic factors, and ET-1 levels were obtained in the fasting state at time 0 and after 6 weeks of therapy. The study protocol has been approved by the Research and Ethics committees of the Montreal Heart Institute and written informed consent was obtained before inclusion in the study.
Endothelial Function
The examinations were performed early in the morning at the
noninvasive imaging laboratory of the Montreal Heart Institute in a
quiet, dimly lit room. Patients were in a fasting state, did not use
tobacco on the morning of the evaluation, and rested in a supine
position for a minimum of 10 minutes before study. All drugs, with the
exception of salicylates, were withheld on the morning of the study.
High resolution ultrasound examination of the brachial artery was
performed with a 7.5-MHz transducer connected to a Hewlett Packard
Sonos 1000 echocardiographic machine. Images were
recorded on a S-VHS tape. A nontortuous segment of the brachial
artery on the arm, above the antecubital fossa, was identified. The
distance between the tip of the third finger and the transducer was
recorded to serve as an index of transducer position for repeated
examinations. Baseline imaging was performed by scanning the brachial
artery in a longitudinal fashion. After optimization of depth and gain
settings, images were magnified in a 20-mmx20-mm viewing window. A
pneumatic blood pressure cuff positioned on the arm was inflated to
60 mm Hg above the systolic pressure for 5 minutes. The
cuff was then released and the artery continuously imaged for 5
minutes. After an additional 5 minutes of recuperation, a new baseline
imaging was obtained followed by the administration of 0.4 mg
sublingual nitroglycerin spray and continuous imaging
for an additional 5 minutes. Percent flow-mediated dilatation (FMD),
measured 1 minute after cuff deflation, was used as an index of
endothelium-dependent dilatation; percent dilatation
obtained 3 minutes after the administration of
nitroglycerin represented
endothelium-independent dilatation.
The mean diameter of the 20-mm brachial artery segment was quantified through the use of a proprietary software by 2 independent technicians blinded to treatment allocation. Frames from 3 consecutive cardiac cycles were taken at the peak of the R wave and the results were averaged. Using this methodology and analysis, the intra- and inter-observer variability in our laboratory for brachial artery diameter determinations are 0.056±0.024 and 0.073±0.031 mm, respectively, and the variability for FMD performed on 2 separate days is 1.05±0.35%.
Thrombostatic Factors and Endothelin Levels
Immunoreactive ET-1 levels were measured as previously described
in detail.13 Commercially available enzyme immunoassay
kits were used to determine the concentrations of thrombin-antithrombin
III complex (Enzygnost R TAT micro, Behring Diagnostics),
plasminogen activator inhibitor 1
(ASSERACHROM R PAI-1, Diagnostica Stago), von
Willebrand factor (ASSERACHROM R vWF, Diagnostica
Stago), tissue factor (IMUBIND R TF, American Diagnostica)
and total tissue factor pathway inhibitor (IMUBIND R TFPI,
American Diagnostica). These tests were performed on a
Dynatech MR 300 microplate reader (Dynatech Laboratories Inc).
Chromogenic assays were used for the quantitative determination of fibrinogen (IL Test TM Fibrinogen-C, Instrumentation Laboratory), factor VIII:C (ACTICHROM R Factor VIII:C, American Diagnostica) and for factor VII activity (Coaset R FVII, Chromogenix). These assays were performed on an ACL TM1 3000 PLUS instrument (Instrumentation Laboratory).
Flow cytometry served for the quantitative assessment of the glycoprotein IIb/IIIa complex in its activated state using PAC-1 FITC (Becton Dickinson, San Jose, CA) and nonactivated state with anti-CD41 PE (Serotec, Oxford, England) and for P-selectin expression using anti-CD 62P FITC (Serotec). The samples were analyzed in an EPICS R XL flow cytometer (Coulter Corporation).
Statistical Analysis
Five patients withdrew from the trial and did not come to the
second visit. Consequently, 27 patients in the placebo group and 28 in
the pravastatin group completed the trial and were included
in the analysis. Differences between baseline clinical
characteristics of the 2 groups were compared using
2 tests for noncontinuous variables and
by 2-tailed independent t tests for continuous
variables. Variations in serum lipids measured at admission, at
time 0, and after 6 weeks were evaluated by mixed-model ANOVA followed
by multiple comparisons with t tests where appropriate.
Differences in all other parameters measured at time 0 and
after 6 weeks were evaluated by 2-tailed paired t tests
(within group comparisons) and independent group t tests
(between group comparisons) where appropriate. Correlation between the
absolute changes in total cholesterol, LDL
cholesterol, and apo B values and absolute changes in
percent FMD were done by linear regression analysis. All values
are reported as mean±SEM and P<0.05 was considered
significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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A few more women, smokers, and patients with previous hypertension were present in the placebo group, but the differences were not statistically significant (Table 1
). Admission diagnosis was the same:
44% Q wave myocardial infarction in the placebo patients and 39% in
the pravastatin patients, and non-Q wave myocardial
infarction/unstable angina in 56% and 61%, respectively. Ejection
fraction was within the normal range in both groups. Total and LDL
cholesterol were similarly elevated in the 2 treatment arms
both at admission and before randomization.
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Lipids
The mean delay between admission and randomization into the study
was 10.4±0.69 days. During this period, there was a significant and
similar fall in total cholesterol of 12% in the placebo
group and 9% in the pravastatin group (Figure 1). After 6 weeks of therapy, total
cholesterol increased to return to baseline value in the
placebo group, while a further decrease occurred in the
pravastatin group for an overall of 23% reduction compared
with admission values. LDL cholesterol levels also
decreased between admission and the time of randomization by 7% in
both groups. After 6 weeks, LDL had increased back to near admission
values in the placebo group while there was a further decrease in the
pravastatin group, which resulted in a 33% total reduction
compared with admission. HDL cholesterol mildly but
significantly decreased in both groups during the hospital phase and
remained at that level in the placebo group while it significantly
increased after 6 weeks with pravastatin therapy.
Triglyceride levels were not significantly modified
throughout the course of the study.
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P<0.01 vs
placebo; and 
P<0.01 vs time 0.
Endothelial Function
Analyzable brachial artery ultrasound examinations were obtained
from all patients in the pravastatin group. In the placebo
group, 3 examinations could not be analyzed because of poor
image quality. At randomization, the brachial artery diameter was
similar in the placebo group, 3.9±0.11 mm, and the
pravastatin group, 4.0±0.09 mm; this remained similar
at 6 weeks, 3.9±0.12 and 4.1±0.09 mm, respectively.
Endothelium-dependent dilatation measured from percent
flow-mediated dilatation of the brachial artery was similar in both
groups at randomization (Figure 2). In
the placebo group, percent FMD did not significantly vary from
5.43±0.74% at randomization to 5.84±0.81% at 6 weeks. It, however,
increased in the pravastatin-treated group from 4.93±
0.81% to 7.0±0.79% (P=0.02, Figure 2),
representing a 42% relative increase. Similar results were
obtained when brachial artery diameters or absolute variations in
brachial artery diameters were analyzed instead of percent
increase. In the pravastatin group, no correlations were
detected between the improvement in percent FMD and the fall in total
cholesterol (r2=0.05,
P=0.25) and in LDL cholesterol
(r2=0.04, P=0.39).
Endothelium-independent responses tested by sublingual
nitroglycerin were similar in both groups at all time
points of the study (Figure 2).
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Other Analysis
Variations in other lipid fractions, thrombostatic factors,
platelet function tests, and ET-1 concentrations are shown in Table 2. There were no differences and no
variations in LP(a) levels. Apo B concentrations significantly
decreased by 20% in the pravastatin group, but the change
did not correlate with the improvement in percent FMD
(r2=0.02, P=0.48). Thrombin
antithrombin complex, fibrinogen and factor VIII-c levels were
mildly elevated at time 0 and similarly decreased after 6 weeks of
pravastatin therapy or placebo. At baseline, platelets
were clearly hyperresponsive to stimulation with a low concentration of
adenosine diphosphate, as demonstrated by an important
expression of P-selectin at the membrane surface. This hyperresponse
was not present at 6 weeks in all patients. Plasminogen
activator inhibitor, von Willebrand
factor, tissue factor, and factor VII-c levels did not show any
consistent changes throughout the study. Tissue factor pathway
inhibitor levels were reduced by pravastatin
therapy. ET-1 levels were mildly elevated in both groups throughout the
duration of the study with no effect of therapy.
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Clinical Evolution
The 5 patients who did not complete the study did not present
any adverse events. During the 6 weeks of the study, there were 3
adverse events in the placebo group: one non-Q wave myocardial
infarction, one unstable angina caused by early restenosis
after angioplasty, and one hospitalization for dyspnea attributed to
heart failure. In the pravastatin-treated group, there were
2 rehospitalizations for chest pain: one patient did not demonstrate
restenosis of the previously dilated artery and the other had
no evidence of myocardial ischemia on dypiridamole stress
testing. None of the patients presenting those clinical
complications stopped study medications.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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This study documents that pravastatin therapy rapidly initiated after myocardial infarction or unstable angina prevents the increase in cholesterol levels observed in the following weeks and is associated with an early improvement in endothelial function. It also provides new insights into the evolution of acute phase reactants, thrombogenic and endothelial markers, and platelet activation in the weeks following an acute coronary syndrome.
Blood Lipids
As in previous studies,14 15 blood lipid values in
the placebo group decreased in the days following the acute phase but
subsequently increased to levels observed at admission in the following
weeks. This study also showed that early treatment with an HMG-CoA
reductase inhibitor not only prevented this increase but
also further decreased blood lipids. Thus, in the placebo group, LDL
cholesterol decreased by 7% between admission and the time
of randomization and subsequently increased to admission levels. With
pravastatin, the levels decreased by an additional 26%,
resulting in a total 33% reduction compared with admission levels.
These findings give support to the recommendation of the ACC/AHA task
force on risk reduction16 that cholesterol
values measured immediately on hospital admission provide a reasonable
estimate of baseline cholesterol and can be used to select
potential candidates for cholesterol lowering drugs.
Cholesterol Reduction Rapidly Improves Endothelial
Function
Our study further supports the validity of the current
recommendations by demonstrating, for the first time, an early
improvement in endothelium-dependent dilatation with
treatment started soon after the acute phase of coronary
syndromes. This extends the previous observations that
cholesterol lowering improves
endothelium-dependent dilatation in the
coronary arteries5 17 as well as in
peripheral vessels.6 7 8 Flow-mediated
dilatation of the brachial artery correlates well with coronary
response to the endothelium-dependent dilator
acetylcholine.18 Such an improvement may be particularly
important soon after acute coronary syndromes when the risk of
recurrence is high. The RECIFE trial has addressed this issue
in a population composed of hypercholesterolemic
coronary patients with other risk factors and with standard
cardiovascular therapy for their condition. We have
thus demonstrated, for the first time, that cholesterol
reduction can also rapidly improve
endothelium-dependant vasodilation in a high-risk group
of patients with proven active coronary lesions and that
brachial artery ultrasonography is a useful noninvasive method for
evaluating endothelial function after acute
coronary syndromes. It becomes particularly relevant to
evaluate the rapidity of onset of action of cholesterol
lowering drugs in a population that may profit from rapid stabilization
of their active lesions.
Improved endothelial function has been postulated as one of the mechanisms by which cholesterol lowering induces plaque stabilization and reduces myocardial infarctions as well as coronary deaths.19 In patients with obstructive coronary artery disease, lipid lowering reduces myocardial ischemia detected by ambulatory ECG monitoring done 4 to 6 months after initiating therapy.20 The present mechanistic study was not designed to evaluate the incidence of recurrent ischemic episodes but raises the hypothesis that early improvement in endothelial function could translate into earlier plaque stabilization and, perhaps, earlier and greater events reduction in these higher risk patients. Larger scale trials will be necessary to confirm this hypothesis.
This study evaluated only one aspect of endothelial function: endothelium-dependant dilation mediated by NO. Although cholesterol and oxidized LDL in particular are clearly associated with endothelial cell dysfunction21 22 and reduced bioavailability of NO, pravastatin therapy may improve endothelial function through other mechanisms, some of which could be independent of its cholesterol lowering effects.23 24 The improvement in endothelial reactivity found in the RECIFE trial did not correlate with the reductions in various lipid fractions. Possible explanations for this finding include an insufficient sample size and the presence of associated risk factors for endothelial dysfunction in our population that could limit the magnitude of the isolated impact of lipid reduction found in previous trials. We consequently cannot convincingly conclude that cholesterol-independent effects of pravastatin may have contributed to our findings.
Hemostatic Factors, Platelets Activity, and Endothelin
Levels
It was previously suggested that pravastatin
therapy could reduce platelet thrombus formation by studies in ex
vivo chambers superfused with blood from stable
hypercholesterolemic coronary
patients10 and improve hemostatic parameters
in hypercholesterolemic patients.9 In our
study, thrombin-antithrombin, fibrinogen, and factor VIII-c were
elevated at the time of randomization, probably as part of the acute
phase reaction response. Platelets were also hyperresponsive,
suggesting a thrombogenic state. These abnormalities were almost
completely reversed after 6 weeks with no specific effect of
pravastatin. A benefit of therapy on these
parameters cannot, however, be excluded because the
analyses were performed relatively late past the acute phase.
Thus, we cannot exclude that serial determinations could have shown a
more rapid improvement with treatment.
Endothelin levels were only mildly elevated at randomization, with no effect of treatment. Previous studies have shown an elevation that resolved early within days after the acute phase.25 Although activation of the endothelin system may contribute to the abnormal vascular reactivity brought on by hypercholesterolemia, our results do not support a role for this endothelial function in the short-term improvement found in endothelial reactivity with pravastatin therapy.
Total tissue factor pathway inhibitor (TFPI) levels were decreased by pravastatin therapy. This natural anticoagulant is mostly bound to LDL cholesterol.26 For the 2 groups combined, changes in TFPI were directly correlated with changes in LDL cholesterol (r=0.46, P<0.01); there was a tendency for the pravastatin group alone (r=0.38, P=0.11) but no correlation for the placebo group alone (r=0.06, P=0.84). It is unlikely that the reduction in TFPI would represent an adverse effect of therapy because others have shown that neither the carrier-free TFPI nor the magnitude of the vascular pool of TFPI, with its anticoagulant potency, were affected by therapeutic lowering of LDL by lovastatin therapy.26
Study Limitations
Patients in the RECIFE trial presented other
conditions known to cause endothelial dysfunction, such
as smoking, high blood pressure, and diabetes. Some baseline clinical
characteristics were differently distributed and although
nonstatistically significant, these differences and their combination
could have influenced the results. Also, many other factors not
measured in this study could have influenced the results: for example,
plasma homocysteine concentrations, also known to affect
endothelial function, were not measured. However,
because there were no differences in percent FMD at randomization and
none of the patients took vitamins or folate supplements, it is
unlikely that variations in homocysteine levels or the effect of
nonstudy medications could explain our findings. Antioxidant vitamins
such as vitamins E and C were also prohibited during the study to
eliminate potential effects on endothelial reactivity.
Therapy with the tissue specific angiotensin-converting
enzyme inhibitor quinapril improves coronary
vasodilation to acetlylcholine after 6 months of
therapy.27 In the present study, the tendency for a
greater use of angiotensin-converting enzyme
inhibitors in the placebo group, however, was not
associated with significant modifications of percent FMD after 6
weeks.
Conclusion and Clinical Implications
Despite the highly publicized efficacy of lipid lowering
therapy in secondary prevention,
hypercholesterolemia is still underdetected and
undertreated after acute coronary syndromes.11 Why
some physicians are still poorly compliant with The National
Cholesterol Education Program guidelines is unclear but may
result from concern with the validity of in-hospital
cholesterol values and the lack of demonstrated short-term
benefit of therapy.
In the present study, we have shown that cholesterol reduction with pravastatin initiated early after acute coronary syndromes rapidly improves endothelial function after 6 weeks of therapy. We confirm that the admission cholesterol levels adequately reflect homeostasis and should be used to avoid delays in initiating therapy. Larger scale trials are required to determine whether the rapid improvement of endothelial function in the acute and early recovery phase is associated with a reduction in cardiovascular events. Such a trial is presently underway: the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) trial evaluates the effect of pharmacological cholesterol lowering, started 1 to 4 days after unstable angina and non-Q-wave myocardial infarction, on early recurrent ischemic events.28
RECIFE is a French acronym that translates in English as reef. The vascular endothelium, not unlike a reef, is a delicate structure whose equilibrium is essential to the maintenance of surrounding life. Any disruption of this equilibrium may carry immediate and longer term consequences; we believe that, conversely, any signs of improvement must be considered seriously for their potential immediate and long-term impacts.
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Acknowledgments |
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Dr Dupuis and Dr Tardif are scholars from the Fonds de la Recherche en Santé du Québec. This work was supported in part by an unrestricted grant from Bristol-Myers Squibb, Canada. The authors would like to thank Suzanne Bujold, Johanne Marquis, Marie Gagnon, Ginette Grenier, Johanne Vincent, Marta Ghitescu, Jacynthe Rivard, Charles Dupont, and Micheline De Belder.
Received December 31, 1998; revision received March 24, 1999; accepted April 9, 1999.
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G. G. Schwartz, A. G. Olsson, M. D. Ezekowitz, P. Ganz, M. F. Oliver, D. Waters, A. Zeiher, B. R. Chaitman, S. Leslie, T. Stern, et al. Effects of Atorvastatin on Early Recurrent Ischemic Events in Acute Coronary Syndromes: The MIRACL Study: A Randomized Controlled Trial JAMA, April 4, 2001; 285(13): 1711 - 1718. [Abstract] [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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J. C. Chambers, L. Fusi, I. S. Malik, D. O. Haskard, M. De Swiet, and J. S. Kooner Association of Maternal Endothelial Dysfunction With Preeclampsia JAMA, March 28, 2001; 285(12): 1607 - 1612. [Abstract] [Full Text] [PDF]
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U. Stenestrand, L. Wallentin, and for the Swedish Register of Cardiac Intensive Care Early Statin Treatment Following Acute Myocardial Infarction and 1-Year Survival JAMA, January 24, 2001; 285(4): 430 - 436. [Abstract] [Full Text] [PDF]
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S. Vehkavaara, T. Hakala-Ala-Pietila, A. Virkamaki, R. Bergholm, C. Ehnholm, O. Hovatta, M.-R. Taskinen, and H. Yki-Jarvinen Differential Effects of Oral and Transdermal Estrogen Replacement Therapy on Endothelial Function in Postmenopausal Women Circulation, November 28, 2000; 102(22): 2687 - 2693. [Abstract] [Full Text] [PDF]
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M. Shechter, M. Sharir, M. J. P. Labrador, J. Forrester, B. Silver, and C. N. Bairey Merz Oral Magnesium Therapy Improves Endothelial Function in Patients With Coronary Artery Disease Circulation, November 7, 2000; 102(19): 2353 - 2358. [Abstract] [Full Text] [PDF]
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L. M. Title, P. M. Cummings, K. Giddens, J. J. Genest Jr, and B. A. Nassar Effect of folic acid and antioxidant vitamins on endothelial dysfunction in patients with coronary artery disease J. Am. Coll. Cardiol., September 1, 2000; 36(3): 758 - 765. [Abstract] [Full Text] [PDF]
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J. A. Vita, A. C. Yeung, M. Winniford, J. M. Hodgson, C. B. Treasure, J. L. Klein, S. Werns, M. Kern, D. Plotkin, W. J. Shih, et al. Effect of Cholesterol-Lowering Therapy on Coronary Endothelial Vasomotor Function in Patients With Coronary Artery Disease Circulation, August 22, 2000; 102(8): 846 - 851. [Abstract] [Full Text] [PDF]
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D. Waters Cholesterol Lowering : Should It Continue to Be the Last Thing We Do? Circulation, June 29, 1999; 99(25): 3215 - 3217. [Full Text] [PDF]
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A. W. Chan, D. L. Bhatt, D. P. Chew, M. J. Quinn, D. J. Moliterno, E. J. Topol, and S. G. Ellis Early and Sustained Survival Benefit Associated With Statin Therapy at the Time of Percutaneous Coronary Intervention Circulation, February 12, 2002; 105(6): 691 - 696. [Abstract] [Full Text] [PDF]
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K. Yokoyama, T. Ishibashi, H. Ohkawara, J. Kimura, I. Matsuoka, T. Sakamoto, K. Nagata, K. Sugimoto, S. Sakurada, and Y. Maruyama HMG-CoA Reductase Inhibitors Suppress Intracellular Calcium Mobilization and Membrane Current Induced by Lysophosphatidylcholine in Endothelial Cells Circulation, February 26, 2002; 105(8): 962 - 967. [Abstract] [Full Text] [PDF]
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