(Circulation. 2001;103:919.)
© 2001 American Heart Association, Inc.
Clinical Investigation and Reports |
Effects of Ramipril and Vitamin E on Atherosclerosis
The Study to Evaluate Carotid Ultrasound Changes in Patients Treated With Ramipril and Vitamin E (SECURE)
From the Departments of Medicine (E.M.L., S.Y., Q.Y., S.S., A.M.-C., J.B., K.K.T.) and Radiology (C.I.D.), McMaster University, Hamilton, Ontario, Canada; The University of Alberta Hospitals, Edmonton, Alberta, Canada (V.D., K.K.T.); the Canadian Cardiovascular Collaboration (E.M.L., S.Y., V.D., C.I.D., Q.Y., S.S., A.M.-C., J.B., K.K.T.); and the Bowman Gray School of Medicine, Department of Neurology, Winston-Salem, NC (W.A.R.).
Correspondence to Eva Lonn, MD, Hamilton Health Sciences Corporation, General Site, 237 Barton Street East, Hamilton, Ontario, Canada L8L 2X2. E-mail hope{at}ccc.mcmaster.ca
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Abstract |
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Background—Activation of the renin-angiotensin-aldosterone system and oxidative modification of LDL cholesterol play important roles in atherosclerosis. The Study to Evaluate Carotid Ultrasound changes in patients treated with Ramipril and vitamin E (SECURE), a substudy of the Heart Outcomes Prevention Evaluation (HOPE) trial, was a prospective, double-blind, 3x2 factorial design trial that evaluated the effects of long-term treatment with the angiotensin-converting enzyme inhibitor ramipril and vitamin E on atherosclerosis progression in high-risk patients.
Methods and Results—A
total of 732 patients 
55 years of age who had vascular disease or
diabetes and at least one other risk factor and who did not have heart
failure or a low left ventricular ejection fraction were randomly
assigned to receive ramipril 2.5 mg/d or 10 mg/d and vitamin E
(RRR-
-tocopheryl acetate) 400 IU/d or their matching
placebos. Average follow-up was 4.5 years. Atherosclerosis progression
was evaluated by B-mode carotid ultrasound. The progression slope of
the mean maximum carotid intimal medial thickness was 0.0217 mm/year in
the placebo group, 0.0180 mm/year in the ramipril 2.5 mg/d group, and
0.0137 mm/year in the ramipril 10 mg/d group
(P=0.033). There were no
differences in atherosclerosis progression rates between patients on
vitamin E and those on placebo.
Conclusions—Long-term treatment with ramipril had a beneficial effect on atherosclerosis progression. Vitamin E had a neutral effect on atherosclerosis progression.
Key Words: atherosclerosis • angiotensin • carotid arteries • ultrasonics
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Experimental and epidemiological data suggest that activation of the renin-angiotensin-aldosterone system and oxidative modification of LDL cholesterol play important roles in atherogenesis and that prolonged angiotensin-converting enzyme (ACE) inhibition and antioxidant vitamin E therapy may be beneficial.1 2 To date, only limited data exist from randomized clinical trials evaluating the impact of these interventions on human atherosclerosis. Therefore, we conducted a prospective, randomized, clinical trial that assessed the effects of ramipril and of vitamin E on atherosclerosis. The Study to Evaluate Carotid Ultrasound changes in patients treated with Ramipril and vitamin E (SECURE) is a substudy of the Heart Outcomes Prevention Evaluation (HOPE) trial, which included 9541 patients and evaluated the impact of these interventions on clinical outcomes.3 4
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Methods |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The study design and baseline characteristics have been described in detail previously.5 A brief summary follows.
Patients
HOPE and its substudy SECURE enrolled subjects
at a high risk for cardiovascular
events.3 4 5
Patients were recruited between December 1993 and August 1995 from 6
Canadian centers that were selected based on expertise in B-mode
carotid ultrasound (CUS) at 2 centers or proximity to these 2 centers,
which performed all CUS examinations in all study patients. Patients
were eligible if they were 55 years old, had vascular disease or
diabetes and at least one additional cardiovascular risk factor, and
adequate baseline CUS examinations. Adequate CUS examinations were
defined throughout the study as those allowing reliable measurements
from a minimum of 4 predefined carotid arterial segments. Exclusion
criteria included heart failure, known low left ventricular ejection
fraction (<0.40%), myocardial infarction, unstable angina or stroke
within 1 month before study enrollment, use of an ACE inhibitor or
vitamin E, uncontrolled hypertension (defined as a blood pressure
[BP] >160/90 mm Hg), overt nephropathy, or major illness expected
to affect trial participation. All patients provided written, informed
consent, and the study protocol was approved by the Research Ethics
Board of each participating center.
Study Design, Randomization, Interventions,
and Follow-up
SECURE is a randomized, double-blind trial with
parallel groups and a 3x2 factorial design. Initial assessment,
including first baseline CUS examination, was performed at the
eligibility and run-in visit
(Figure
).
Eligible patients entered a run-in period on active ramipril 2.5 mg/d
(single-blind) for 7 to 10 days. This was followed by a serum
creatinine and potassium measurement and by 10 to 14 days of ramipril
placebo. Of the 818 patients who entered the run-in period, 86 patients
were excluded from the trial within 3 weeks, and the remaining 732
patients were randomly assigned to ramipril 10 mg/d or ramipril 2.5
mg/d and to natural-source vitamin E (RRR--tocopheryl acetate) 400
IU/d or their matching placebos and had a second baseline CUS
examination. For the ramipril 10 mg/d arm of the study, forced
titration to the target dose or highest tolerated dose or matching
placebo was performed over a 1-month period.
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Follow-up visits occurred 1 month after randomization and
every 6 months thereafter. All study-end visits and CUS examinations
were completed by July 1, 1999. Systolic and diastolic BP were measured
by experienced study nurses at randomization, 1 month, 2 years, and at
study end using a standard sphygmomanometer and a standardized protocol
(all study visits occurred during morning hours while study drug was
taken in the evening, use of appropriate cuff size was ensured, and
patients were supine for 5 minutes, thereafter 2 exact readings
avoiding rounding were obtained from each arm, and the lowest readings
from the right and the left arms were averaged).
B-mode CUS
Duplicate CUS examinations (maximum, 3 weeks apart)
were performed at baseline and at study end 4 to 5 years (median, 4.5
years) after randomization, and a single follow-up CUS examination was
obtained 1.5 to 2.2 years after randomization. The CUS methods have
been reviewed in detail.5
High-frequency CUS imaging was performed by 3 trained and certified
sonographers. Standardized CUS scanning and reading protocols were
used.6 7 A
circumferential longitudinal scan was performed to record the maximum
intimal medial thickness (IMT) in each of 12 carotid artery segments
(1-cm long), which were defined relative to the carotid flow divider as
the near and far walls of the internal, bifurcation, and common left
and right carotid arteries. All CUS measurements were performed by 2
certified readers who were unaware of treatment assignment. For each
patient, the mean maximum IMT was computed as the average of the
segment maximum IMTs across the 12 carotid arterial segments. The
difference in the mean maximum IMT between the 732 paired baseline CUS
examinations was 0.014±0.17 mm, the mean absolute difference was
0.12±0.11 mm, Pearson’s correlation coefficient
(r) was 0.87, and the
intraclass correlation coefficient was 0.87. At study end, the mean
difference in the mean maximum IMT between 641 paired CUS examinations
was 0.004±0.09 mm, the mean absolute difference was 0.06±0.06 mm,
r was 0.97, and the intraclass
correlation coefficient was 0.97. Detailed between- and
within-sonographer and reader reproducibility assessments showed high
reproducibility and absence of temporal drifts in
reading.
Study Outcomes
The primary study outcome was the annualized
progression slope of the mean maximum IMT. The secondary outcome was
the annualized progression slope of the single maximum IMT among any of
the 12 carotid segments. Clinical outcomes were recorded and analyzed
as part of the HOPE study, which was adequately powered to evaluate the
effect of the study interventions on clinical
events.
Statistical Analysis
All analyses were by intention-to-treat and were done
in SAS 6.12. There was no significant interaction between the study
treatments for the primary or secondary CUS outcomes
(P=0.90 and
P=0.61, respectively, for
interaction terms in the ANOVA models). Therefore, analyses were done
to compare differences between ramipril overall and at each of the 2
doses versus ramipril placebo and between vitamin E versus vitamin E
placebo. Baseline characteristics were compared by 1-way ANOVA and
2 tests as appropriate. The slopes of the
mean maximum IMT and the single maximum IMT were computed for each
patient from all serial CUS data by least-squares regression (after
verifying the absence of significant deviations from linearity). The
overall effect of ramipril, the effect of each dose of ramipril (2.5
and 10 mg/d), and the effect of vitamin E were analyzed by ANOVA, with
the slope of the mean maximum IMT as the dependent variable and
treatment assignment as the independent variables. Analyses adjusted
for systolic and diastolic BP changes and with multivariate adjustment
for variables found to influence the slope of the mean maximum IMT on
univariate analysis, for imbalances in baseline variables, and for
important design variables were performed by ANCOVA. Dunnett’s test
for comparison of multiple treatments against one control was used to
adjust the level of statistical significance in the comparisons of the
2 doses of ramipril versus ramipril
placebo.8 The prespecified
primary analysis included all patients with an evaluable slope, ie,
those who had completed the duplicate baseline CUS examinations and at
least one subsequent
examination.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Baseline Characteristics, Follow-up, and Compliance
There were no differences in the baseline characteristics between the active treatment groups and their respective placebos, with the exception of smoking history, which was more common in the active vitamin E group (Table 1
). The baseline characteristics of the 693
patients in the final primary analysis were similar.
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Clinical follow-up was complete in all study patients. An
adequate follow-up CUS examination was obtained in 690 patients 1.5 to
2.2 years after randomization. Of the initial 732 patients, 17 had
died, 15 missed the follow-up CUS examination due to illness, and 10
moved, refused repeat CUS, or did not have a technically adequate
examination. Three additional patients who did not complete the
follow-up CUS examination had adequate study-end CUS studies.
Therefore, the primary study analysis included 693 patients (95% of
all randomized patients and 97% of randomized patients alive at the
time of the first follow-up CUS assessment). Of these, 637 had
completed all 5 scheduled CUS examinations (87% of all randomized
patients and 95% of those alive at study end;
Figure
).
Compliance with study treatments is shown in
Table 2. Only cough was a more common cause of permanent
discontinuation of study drug in the active ramipril groups than in the
placebo group (1.6% in the ramipril placebo, 9.0% in the ramipril 2.5
mg/d, and 9.8% in the ramipril 10 mg/d groups). Vitamin E caused no
significant side effects.
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BP Changes
The mean BP at study entry was 132/76 mm Hg in all
study groups. Both active ramipril groups reduced systolic and
diastolic BP versus ramipril placebo, but there were no significant
differences in BP changes between the ramipril 2.5 mg/d and 10 mg/d
groups
(Table 3). Vitamin E had no significant effect on
BP.
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Changes in Ultrasonographically Determined
Carotid Atherosclerosis Progression
Among all baseline variables and relevant interaction
terms, those found to influence the mean maximum IMT slope on
univariate analysis were the baseline mean maximum IMT
(P=0.0002), a history of high
total cholesterol (P=0.0002) or
of low HDL cholesterol
(P=0.008), total and LDL
cholesterol concentrations
(P=0.03 and
P=0.01, respectively), and
treatment assignment to ramipril 10 mg/d
(P=0.028). In the multivariate
model, only baseline mean maximum IMT
(P<0.001), history of
dyslipidemia (P=0.005), and
treatment assignment to ramipril 10 mg/d
(P=0.046) were independent
predictors of the mean maximum IMT slope.
The main study results are summarized in
Table 4. Because the number of nonquantifiable
carotid artery segments was low (average 5%), the primary study
analysis was performed without imputation for missing CUS data. There
was an overall effect of ramipril, which reduced the annualized slope
of the mean maximum IMT versus ramipril placebo
(P=0.033), and there was a
strong trend for benefit in the ramipril 10 mg/d group versus ramipril
placebo (P=0.028; Dunnett’s
correction for multiple comparisons results in an adjustment in the
level of statistical significance to
P=0.027).
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We tested the robustness of our findings by additional analyses. In the analysis of 711 patients, including those in the primary analysis and an additional 18 with early death, debilitating myocardial infarction, or stroke who did not have a follow-up CUS and for whom rapid atherosclerosis progression (defined as the highest 10th percentile of the mean maximum IMT of the entire SECURE study population) was assumed, there was a reduced atherosclerosis progression rate for ramipril overall versus ramipril placebo (P=0.019, P=0.027 when controlling for BP changes, and P=0.027 after multivariate adjustment) and for the ramipril 10 mg/d group versus ramipril placebo (P=0.015, P=0.022 when controlling for BP changes, and P=0.031 after multivariate adjustment). Similar trends were noted in the analyses of the 637 study patients who completed all 5 CUS examinations (P=0.068 for the overall effect of ramipril versus ramipril placebo and P=0.055 for ramipril 10 mg/d versus ramipril placebo) and for the secondary CUS outcome measurement, the progression slope of the single maximum IMT. The absolute difference for this outcome between the ramipril 10 mg/d and the placebo groups was greater than that observed for the mean maximum IMT slope, but it did not reach statistical significance due to the greater variability of this measurement. In the analysis of the 637 patients who completed all 5 CUS examinations, ramipril had a highly significant effect on the single maximum IMT slope (P=0.003 for the overall effect of ramipril versus placebo and P=0.008 for ramipril 10 mg/d versus placebo).
Vitamin E had a neutral effect on the primary and secondary CUS outcome measurements.
Clinical Outcomes
As expected in this relatively small substudy,
there were no significant differences in the primary clinical outcome
(the composite of cardiovascular death, myocardial infarction, and
stroke), which occurred in 41 patients (16.8%) in the ramipril
placebo, 34 (13.9%) in the ramipril 2.5 mg/d, and 31 (12.7%) in the
ramipril 10 mg/d groups and in 55 patients (15.1%) in the vitamin E
placebo and 51 (13.9%) in the active vitamin E groups. Reliable data
on clinical outcomes are provided by the adequately powered parent HOPE
study.3 4
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The SECURE trial shows that long-term ACE inhibitor therapy retards the progression of human atherosclerosis, whereas vitamin E has a neutral effect.
The method used to evaluate treatment effects on atherosclerosis, B-mode CUS, is well-validated and has been increasingly used in clinical trials. It is a highly reproducible technique, which correlates with risk factors for coronary artery disease and with prevalent and incident coronary disease and stroke.9 Previous studies used various ultrasound instrumentation, scanning and reading procedures, and outcome measurements. We selected the change in the aggregate mean maximum IMT from 12 carotid arterial segments as the primary outcome in SECURE, because this aggregate measurement was shown to correlate best with angiographic coronary artery disease10 and to be sensitive to the detection of changes related to treatment effects.11 We used measurements of segment maximum rather than segment mean IMT, because this approach minimizes missing data, focuses on the most diseased regions, and results in very stable measurements when averaged across the 12 arterial segments.7 11 The CUS scanning and reading protocols have been extensively validated,6 7 and we achieved high measurement reproducibility.
Treatment with ramipril resulted in reduced atherosclerosis progression rates. This effect was noted in high-risk patients, the majority of whom were already on effective therapies, including aspirin (84%), lipid-lowering agents (34%), ß-blockers (43%), diuretics (9%), nitrates (32%), and calcium-channel blockers (43%). Although the absolute differences in atherosclerosis progression rates between ramipril- and placebo-treated patients are small, the relative reduction in mean maximum IMT was 37% for ramipril 10 mg/d versus placebo, which is similar to the 32% reduction in the risk of stroke in HOPE. Similar magnitudes of change on atherosclerosis progression have been demonstrated in trials of cholesterol lowering, and they were associated with impressive reductions in clinical events, suggesting a stabilizing effect on the underlying disease process. The study was not powered to compare the 2 doses of ramipril. However, there was a trend suggesting a dose-dependent effect, with highest benefit in the ramipril 10 mg/d study group. Ramipril 10 mg/d is also the dose used in the large parent HOPE trial, where it had very clear benefits on a range of clinical end points.3
Ramipril had only a modest BP lowering effect in our study, because most study patients did not have a history of hypertension or had well-controlled BP; other antihypertensive and antianginal drugs were frequently used (>75% of patients). The beneficial effect of ramipril on atherosclerosis remained statistically significant after adjusting for a history of hypertension and for BP changes, suggesting the benefit is not fully explained by BP lowering and may be related to a direct vascular protective effect.
Increased tissue ACE activity has been demonstrated in human coronary artery lesions,12 and long-term ACE inhibition has been shown to reduce atherosclerotic lesion area in the aorta, carotid, and coronary arteries in normotensive animal models of atherosclerosis.13 14 These antiatherogenic properties may be related both to the inhibition of tissue and circulating angiotensin II formation and to bradykinin potentiation, resulting in decreased proliferation and migration of smooth muscle cells, decreased accumulation and activation of inflammatory cells, decreased oxidative stress, and increased endothelial nitric oxide formation, leading to improved endothelial function.1
Previous randomized clinical trials evaluating the effects of ACE inhibition on human atherosclerosis include the angiographic substudy of the Quinapril Ischemic Event Trial (QUIET), the Simvastatin/Enalapril Coronary Atherosclerosis (SCAT) study, and the Prevention of Atherosclerosis with Ramipril Trial (PART-2).15 16 17 Two of these studies, QUIET and SCAT, used coronary angiography and reported no overall benefit with quinapril and enalapril, respectively, although in a subgroup analysis of QUIET, quinapril-treated patients with elevated LDL cholesterol had a reduced progression of coronary atherosclerosis. Differences in the results of SECURE and these studies may be related to the specific ACE inhibitor used, the ACE inhibitor dose, the study design, and the methods used for the assessment of atherosclerosis progression. The CUS measurements used in SECURE focus on the arterial wall and may be more sensitive than angiography. In PART-2, ramipril 5 to 10 mg/d had no effect on CUS IMT measurements; however, this study only evaluated changes in the mean far wall IMT of the common carotid arteries. The use of the aggregate IMT measurement in SECURE, which is derived from common, bifurcation, and internal carotid artery segments, may be more sensitive to change11 and may account for the apparent differences in the results of these 2 trials.
Natural-source vitamin E 400 IU/d had a neutral effect on atherosclerosis progression. Compliance with vitamin E was high, the use of other nonstudy antioxidant vitamins was low, and the study was adequately powered to demonstrate a moderate treatment effect (80% power to detect a 48% reduction and 50% power to detect a 33% reduction in the primary outcome). Our original sample size calculation assumed a higher IMT progression rate based on the data available at the time of the study design. Therefore, a smaller treatment effect with vitamin E cannot be fully excluded.
We did not measure vitamin E levels or the effects of
vitamin E on LDL oxidation in the SECURE trial. Previous studies have
demonstrated, however, that natural-source vitamin E 400 IU/d leads to
significant elevations in plasma and tissue levels of -tocopherol
and that similar or lower doses can increase LDL resistance to
oxidation18 19 ;
similar findings on LDL oxidation were observed in a separate substudy
of HOPE (R. Hoeschen, MD, personal communication, 2000).
Furthermore, the main aim of our study was to evaluate the effects of
vitamin E supplementation, a therapy used by millions worldwide without
knowledge of oxidative status.
Experimental data suggest an important role for the oxidation of LDL cholesterol in atherogenesis, and vitamin E is an efficient antioxidant that has been shown to reduce atherosclerosis in animal models,2 20 although these data are not fully consistent.21 An observational study reported reduced coronary atherosclerosis progression in individuals taking vitamin E supplements,22 and large epidemiological studies also suggest a cardioprotective effect of vitamin E. The Cambridge Heart Antioxidant Study showed a reduction in nonfatal events in patients treated with vitamin E after myocardial infarction,23 but there was a trend toward increased mortality, and several larger, randomized clinical trials of longer duration failed to confirm benefits.4 24 To date, there are only limited data from randomized trials on the effects of vitamin E on atherosclerosis. A small study in 15 individuals with homozygous familial hypercholesterolemia found rapid progression of carotid IMT in vitamin E–treated subjects but regression of disease with statins.25 Preliminary reports from the Antioxidant Supplementation in Atherosclerosis Prevention (ASAP) study indicate no beneficial effect on carotid IMT changes with vitamin E alone or combined vitamin E and C supplementation in women, but a beneficial effect of combined therapy in hypercholesterolemic men who smoke.26
The results of the SECURE trial on atherosclerosis are concordant with the results of the HOPE trial on clinical events. In conjunction, these studies demonstrate that ramipril reduces atherosclerosis progression and prevents major vascular events. By contrast, vitamin E administered for 4 to 6 years does not have a significant impact on atherosclerosis or on clinical events. The role of vitamin E alone or in combination with other antioxidants in various patient groups requires further investigation.
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Acknowledgments |
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Supported in part by the Medical Research Council of Canada (grant UI-12363) and Hoechst-Marion Roussel.
Received August 9, 2000; revision received October 19, 2000; accepted October 19, 2000.
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 E. M. Lonn, H. C. Gerstein, P. Sheridan, S. Smith, R. Diaz, V. Mohan, J. Bosch, S. Yusuf, G. R. Dagenais, and DREAM (Diabetes REduction Assessment with ramipril Effect of Ramipril and of Rosiglitazone on Carotid Intima-Media Thickness in People With Impaired Glucose Tolerance or Impaired Fasting Glucose STARR (STudy of Atherosclerosis with Ramipril and Rosiglitazone). J. Am. Coll. Cardiol., June 2, 2009; 53(22): 2028 - 2035. [Abstract] [Full Text] [PDF]
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 S. E. Kjeldsen, T. A. Aksnes, R. H. Fagard, and G. Mancia CHAPTER 13 Hypertension ESC Textbook of Cardiovascular Medicine, January 1, 2009; 2(1): med-9780199566990-chapter - med-9780199566990-chapter. [Abstract] [Full Text] [PDF]
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C. Held, G. Sumner, P. Sheridan, M. McQueen, S. Smith, G. Dagenais, S. Yusuf, and E. Lonn Correlations between plasma homocysteine and folate concentrations and carotid atherosclerosis in high-risk individuals: baseline data from the Homocysteine and Atherosclerosis Reduction Trial (HART) Vascular Medicine, November 1, 2008; 13(4): 245 - 253. [Abstract] [PDF]
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L. A. Calo, M. Puato, S. Schiavo, M. Zanardo, C. Tirrito, E. Pagnin, G. Balbi, P. A. Davis, P. Palatini, and P. Pauletto Absence of vascular remodelling in a high angiotensin-II state (Bartter's and Gitelman's syndromes): implications for angiotensin II signalling pathways Nephrol. Dial. Transplant., September 1, 2008; 23(9): 2804 - 2809. [Abstract] [Full Text] [PDF]
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 L. R. Caplan A 70-Year-Old Man With a Transient Ischemic Attack: Review of Internal Carotid Artery Stenosis JAMA, July 2, 2008; 300(1): 81 - 90. [Abstract] [Full Text] [PDF]
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A. J. Flammer, I. Sudano, F. Hermann, S. Gay, A. Forster, M. Neidhart, P. Kunzler, F. Enseleit, D. Periat, M. Hermann, et al. Angiotensin-Converting Enzyme Inhibition Improves Vascular Function in Rheumatoid Arthritis Circulation, April 29, 2008; 117(17): 2262 - 2269. [Abstract] [Full Text] [PDF]
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B. V. Howard, M. J. Roman, R. B. Devereux, J. L. Fleg, J. M. Galloway, J. A. Henderson, Wm. J. Howard, E. T. Lee, M. Mete, B. Poolaw, et al. Effect of Lower Targets for Blood Pressure and LDL Cholesterol on Atherosclerosis in Diabetes: The SANDS Randomized Trial JAMA, April 9, 2008; 299(14): 1678 - 1689. [Abstract] [Full Text] [PDF]
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G. A. Knoll, M. Cantarovitch, E. Cole, J. Gill, S. Gourishankar, D. Holland, B. Kiberd, N. Muirhead, R. Prasad, L. A. Tibbles, et al. The Canadian ACE-inhibitor trial to improve renal outcomes and patient survival in kidney transplantation study design Nephrol. Dial. Transplant., January 1, 2008; 23(1): 354 - 358. [Abstract] [Full Text] [PDF]
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 R. Siekmeier, C. Steffen, and W. Marz Role of Oxidants and Antioxidants in Atherosclerosis: Results of In Vitro and In Vivo Investigations Journal of Cardiovascular Pharmacology and Therapeutics, December 1, 2007; 12(4): 265 - 282. [Abstract] [PDF]
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 C. Kojima, A. Kawakami, T. Takei, K. Nitta, and M. Yoshida Angiotensin-Converting Enzyme Inhibitor Attenuates Monocyte Adhesion to Vascular Endothelium through Modulation of Intracellular Zinc J. Pharmacol. Exp. Ther., December 1, 2007; 323(3): 855 - 860. [Abstract] [Full Text] [PDF]
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 S. Devaraj, R. Tang, B. Adams-Huet, A. Harris, T. Seenivasan, J. A de Lemos, and I. Jialal Effect of high-dose {alpha}-tocopherol supplementation on biomarkers of oxidative stress and inflammation and carotid atherosclerosis in patients with coronary artery disease Am. J. Clinical Nutrition, November 1, 2007; 86(5): 1392 - 1398. [Abstract] [Full Text] [PDF]
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 E. Suganuma, V. R. Babaev, M. Motojima, Y. Zuo, N. Ayabe, A. B. Fogo, I. Ichikawa, M. F. Linton, S. Fazio, and V. Kon Angiotensin Inhibition Decreases Progression of Advanced Atherosclerosis and Stabilizes Established Atherosclerotic Plaques J. Am. Soc. Nephrol., August 1, 2007; 18(8): 2311 - 2319. [Abstract] [Full Text] [PDF]
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 Authors/Task Force Members:, G. Mancia, G. De Backer, A. Dominiczak, R. Cifkova, R. Fagard, G. Germano, G. Grassi, A. M. Heagerty, S. E. Kjeldsen, et al. 2007 Guidelines for the Management of Arterial Hypertension: The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC) Eur. Heart J., June 11, 2007; (2007) ehm236v1. [Full Text] [PDF]
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M. Gianni, J. Bosch, J. Pogue, J. Probstfield, G. Dagenais, S. Yusuf, and E. Lonn Effect of long-term ACE-inhibitor therapy in elderly vascular disease patients Eur. Heart J., June 1, 2007; 28(11): 1382 - 1388. [Abstract] [Full Text] [PDF]
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J. Bleys, E. R Miller III, L. J Appel, and E. Guallar Reply to J Hathcock Am. J. Clinical Nutrition, May 1, 2007; 85(5): 1435 - 1436. [Full Text] [PDF]
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I. J. Kullo and A. R. Malik Arterial Ultrasonography and Tonometry as Adjuncts to Cardiovascular Risk Stratification J. Am. Coll. Cardiol., April 3, 2007; 49(13): 1413 - 1426. [Abstract] [Full Text] [PDF]
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J. R. Crouse III, J. S. Raichlen, W. A. Riley, G. W. Evans, M. K. Palmer, D. H. O'Leary, D. E. Grobbee, M. L. Bots, and for the METEOR Study Group Effect of Rosuvastatin on Progression of Carotid Intima-Media Thickness in Low-Risk Individuals With Subclinical Atherosclerosis: The METEOR Trial JAMA, March 28, 2007; 297(12): 1344 - 1353. [Abstract] [Full Text] [PDF]
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E. R. Bates, C. J. D. Babb, D. E. Casey, C. U. Cates, G. R. Duckwiler, T. E. Feldman, W. A. Gray, K. Ouriel, E. D. Peterson, K. Rosenfield, et al. ACCF/SCAI/SVMB/SIR/ASITN 2007 Clinical Expert Consensus Document on Carotid Stenting: A Report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents (ACCF/SCAI/SVMB/SIR/ASITN Clinical Expert Consensus Document Committee on Carotid Stenting) Vascular Medicine, February 1, 2007; 12(1): 35 - 83. [PDF]
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J. Bleys, E. R Miller III, R. Pastor-Barriuso, L. J Appel, and E. Guallar Vitamin-mineral supplementation and the progression of atherosclerosis: a meta-analysis of randomized controlled trials. Am. J. Clinical Nutrition, October 1, 2006; 84(4): 880 - 887. [Abstract] [Full Text] [PDF]
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 T. W. Rice and A. B. Lumsden Optimal Medical Management of Peripheral Arterial Disease Vascular and Endovascular Surgery, August 1, 2006; 40(4): 312 - 327. [Abstract] [PDF]
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 J. R. Crouse III Thematic review series: Patient-Oriented Research. Imaging atherosclerosis: state of the art J. Lipid Res., August 1, 2006; 47(8): 1677 - 1699. [Abstract] [Full Text] [PDF]
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J.-G. Wang, J. A. Staessen, Y. Li, L. M. Van Bortel, T. Nawrot, R. Fagard, F. H. Messerli, and M. Safar Carotid Intima-Media Thickness and Antihypertensive Treatment: A Meta-Analysis of Randomized Controlled Trials Stroke, July 1, 2006; 37(7): 1933 - 1940. [Abstract] [Full Text] [PDF]
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 A.-I. Tropeano, P. Boutouyrie, B. Pannier, R. Joannides, E. Balkestein, S. Katsahian, B. Laloux, C. Thuillez, H. Struijker-Boudier, and S. Laurent Brachial Pressure-Independent Reduction in Carotid Stiffness After Long-Term Angiotensin-Converting Enzyme Inhibition in Diabetic Hypertensives Hypertension, July 1, 2006; 48(1): 80 - 86. [Abstract] [Full Text] [PDF]
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L. M Yunker, J. S Parboosingh, H. E Conradson, P. Faris, P. J Bridge, J. Buithieu, L. M Title, F. Charbonneau, S. Verma, E. M Lonn, et al. The effect of iron status on vascular health Vascular Medicine, May 1, 2006; 11(2): 85 - 91. [Abstract] [PDF]
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I. Fleming Signaling by the Angiotensin-Converting Enzyme Circ. Res., April 14, 2006; 98(7): 887 - 896. [Abstract] [Full Text] [PDF]
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 N. Danchin, M. Cucherat, C. Thuillez, E. Durand, Z. Kadri, and P. G. Steg Angiotensin-Converting Enzyme Inhibitors in Patients With Coronary Artery Disease and Absence of Heart Failure or Left Ventricular Systolic Dysfunction: An Overview of Long-term Randomized Controlled Trials. Arch Intern Med, April 10, 2006; 166(7): 787 - 796. [Abstract] [Full Text] [PDF]
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S. Ashfaq, J. L. Abramson, D. P. Jones, S. D. Rhodes, W. S. Weintraub, W. C. Hooper, V. Vaccarino, D. G. Harrison, and A. A. Quyyumi The Relationship Between Plasma Levels of Oxidized and Reduced Thiols and Early Atherosclerosis in Healthy Adults J. Am. Coll. Cardiol., March 7, 2006; 47(5): 1005 - 1011. [Abstract] [Full Text] [PDF]
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D. Versari, E. Daghini, M. Rodriguez-Porcel, K. Sattler, O. Galili, K. Pilarczyk, C. Napoli, L. O. Lerman, and A. Lerman Chronic Antioxidant Supplementation Impairs Coronary Endothelial Function and Myocardial Perfusion in Normal Pigs Hypertension, March 1, 2006; 47(3): 475 - 481. [Abstract] [Full Text] [PDF]
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R. L. Armentano, J. G. Barra, D. B. Santana, F. M. Pessana, S. Graf, D. Craiem, L. M. Brandani, H. P. Baglivo, and R. A. Sanchez Smart Damping Modulation of Carotid Wall Energetics in Human Hypertension: Effects of Angiotensin-Converting Enzyme Inhibition Hypertension, March 1, 2006; 47(3): 384 - 390. [Abstract] [Full Text] [PDF]
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E. Suganuma, Y. Zuo, N. Ayabe, J. Ma, V. R. Babaev, M. F. Linton, S. Fazio, I. Ichikawa, A. B. Fogo, and V. Kon Antiatherogenic Effects of Angiotensin Receptor Antagonism in Mild Renal Dysfunction J. Am. Soc. Nephrol., February 1, 2006; 17(2): 433 - 441. [Abstract] [Full Text] [PDF]
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 G. H. Werstuck, M. I. Khan, G. Femia, A. J. Kim, V. Tedesco, B. Trigatti, and Y. Shi Glucosamine-Induced Endoplasmic Reticulum Dysfunction Is Associated With Accelerated Atherosclerosis in a Hyperglycemic Mouse Model Diabetes, January 1, 2006; 55(1): 93 - 101. [Abstract] [Full Text] [PDF]
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 J.-P. Baguet, L. Hammer, P. Levy, H. Pierre, S. Launois, J.-M. Mallion, and J.-L. Pepin The Severity of Oxygen Desaturation Is Predictive of Carotid Wall Thickening and Plaque Occurrence Chest, November 1, 2005; 128(5): 3407 - 3412. [Abstract] [Full Text] [PDF]
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E. R. Miller III, L. J. Appel, E. Guallar, and R. Pastor-Barriuso High-Dosage Vitamin E Supplementation and All-Cause Mortality Ann Intern Med, July 19, 2005; 143(2): 156 - 158. [Full Text] [PDF]
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R. T. Yan, T. J. Anderson, F. Charbonneau, L. Title, S. Verma, E. Lonn, and on behalf of the FATE Investigators Relationship Between Carotid Artery Intima-Media Thickness and Brachial Artery Flow-Mediated Dilation in Middle-Aged Healthy Men J. Am. Coll. Cardiol., June 21, 2005; 45(12): 1980 - 1986. [Abstract] [Full Text] [PDF]
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E. Shinoda, Y. Yui, K. Kodama, A. Hirayama, H. Nonogi, K. Haze, T. Sumiyoshi, S. Hosoda, C. Kawai, and for the Japan Multicenter Investigation for Cardio Quantitative Coronary Angiogram Analysis: Nifedipine Retard Versus Angiotensin-Converting Enzyme Inhibitors (JMIC-B Side Arm Study) Hypertension, June 1, 2005; 45(6): 1153 - 1158. [Abstract] [Full Text] [PDF]
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M.R. Langenfeld, T. Forst, C. Hohberg, P. Kann, G. Lubben, T. Konrad, S.D. Fullert, C. Sachara, and A. Pfutzner Pioglitazone Decreases Carotid Intima-Media Thickness Independently of Glycemic Control in Patients With Type 2 Diabetes Mellitus: Results From a Controlled Randomized Study Circulation, May 17, 2005; 111(19): 2525 - 2531. [Abstract] [Full Text] [PDF]
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J. N Hathcock, A. Azzi, J. Blumberg, T. Bray, A. Dickinson, B. Frei, I. Jialal, C. S Johnston, F. J Kelly, K. Kraemer, et al. Vitamins E and C are safe across a broad range of intakes Am. J. Clinical Nutrition, April 1, 2005; 81(4): 736 - 745. [Abstract] [Full Text] [PDF]
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 S. Yusuf, J. Pogue, M. G. Myers, C. McCullough, M. A. Pfeffer, M. J. Domanski, and E. Braunwald ACE Inhibition in Stable Coronary Artery Disease N. Engl. J. Med., March 3, 2005; 352(9): 937 - 939. [Full Text] [PDF]
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F. W. Asselbergs, A. M. van Roon, H. L. Hillege, P. E. de Jong, R. O.B. Gans, A. J. Smit, W. H. van Gilst, and on behalf of the PREVEND IT Investigators Effects of Fosinopril and Pravastatin on Carotid Intima-Media Thickness in Subjects With Increased Albuminuria Stroke, March 1, 2005; 36(3): 649 - 653. [Abstract] [Full Text] [PDF]
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A. Zanchetti, G. Crepaldi, M. G. Bond, G. Gallus, F. Veglia, G. Mancia, A. Ventura, G. Baggio, L. Sampieri, P. Rubba, et al. Different Effects of Antihypertensive Regimens Based on Fosinopril or Hydrochlorothiazide With or Without Lipid Lowering by Pravastatin on Progression of Asymptomatic Carotid Atherosclerosis: Principal Results of PHYLLIS--A Randomized Double-Blind Trial Stroke, December 1, 2004; 35(12): 2807 - 2812. [Abstract] [Full Text] [PDF]
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K. D. Flemming and R. D. Brown Jr Secondary Prevention Strategies in Ischemic Stroke: Identification and Optimal Management of Modifiable Risk Factors Mayo Clin. Proc., October 1, 2004; 79(10): 1330 - 1340. [Abstract] [PDF]
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Task Force Members, J. Lopez-Sendon, K. Swedberg, J. McMurray, J. Tamargo, A. P. Maggioni, H. Dargie, M. Tendera, F. Waagstein, J. Kjekshus, et al. Expert consensus document on angiotensin converting enzyme inhibitors in cardiovascular disease: The Task Force on ACE-inhibitors of the European Society of Cardiology Eur. Heart J., August 2, 2004; 25(16): 1454 - 1470. [Full Text] [PDF]
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 M. Rema, V. Mohan, R. Deepa, and R. Ravikumar Association of Carotid Intima-Media Thickness and Arterial Stiffness With Diabetic Retinopathy: The Chennai Urban Rural Epidemiology Study (CURES-2) Diabetes Care, August 1, 2004; 27(8): 1962 - 1967. [Abstract] [Full Text] [PDF]
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 T. A. Henriques, J. Huang, S. S. D'Souza, A. Daugherty, and L. A. Cassis Orchidectomy, But Not Ovariectomy, Regulates Angiotensin II-Induced Vascular Diseases in Apolipoprotein E-Deficient Mice Endocrinology, August 1, 2004; 145(8): 3866 - 3872. [Abstract] [Full Text] [PDF]
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 M. Zureik, P. Galan, S. Bertrais, L. Mennen, S. Czernichow, J. Blacher, P. Ducimetiere, and S. Hercberg Effects of Long-Term Daily Low-Dose Supplementation With Antioxidant Vitamins and Minerals on Structure and Function of Large Arteries Arterioscler Thromb Vasc Biol, August 1, 2004; 24(8): 1485 - 1491. [Abstract] [Full Text] [PDF]
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 S. I. Sokol, E. L. Portnay, J. P. Curtis, M. A. Nelson, P. R. Hebert, J. F. Setaro, and J. M. Foody Modulation of the renin-angiotensin-aldosterone system for the secondary prevention of stroke Neurology, July 27, 2004; 63(2): 208 - 213. [Abstract] [Full Text] [PDF]
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Z. T. Bloomgarden Consequences of Diabetes: Cardiovascular disease Diabetes Care, July 1, 2004; 27(7): 1825 - 1831. [Full Text] [PDF]
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G. B. J. Mancini, B. Dahlof, and J. Diez Surrogate Markers for Cardiovascular Disease: Structural Markers Circulation, June 29, 2004; 109(25_suppl_1): IV-22 - IV-30. [Full Text] [PDF]
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 B. Jiang, S. Xu, X. Hou, D. R. Pimentel, and R. A. Cohen Angiotensin II Differentially Regulates Interleukin-1-{beta}-inducible NO Synthase (iNOS) and Vascular Cell Adhesion Molecule-1 (VCAM-1) Expression: ROLE OF p38 MAPK J. Biol. Chem., May 7, 2004; 279(19): 20363 - 20368. [Abstract] [Full Text] [PDF]
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M. Hanefeld, J. L. Chiasson, C. Koehler, E. Henkel, F. Schaper, and T. Temelkova-Kurktschiev Acarbose Slows Progression of Intima-Media Thickness of the Carotid Arteries in Subjects With Impaired Glucose Tolerance Stroke, May 1, 2004; 35(5): 1073 - 1078. [Abstract] [Full Text] [PDF]
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A. Scuteri, S. S. Najjar, D. C. Muller, R. Andres, H. Hougaku, E. J. Metter, and E. G. Lakatta Metabolic syndrome amplifies the age-associated increases in vascular thickness and stiffness J. Am. Coll. Cardiol., April 21, 2004; 43(8): 1388 - 1395. [Abstract] [Full Text] [PDF]
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 M. Marre, M. Lievre, G. Chatellier, J. F E Mann, P. Passa, and J. Menard Effects of low dose ramipril on cardiovascular and renal outcomes in patients with type 2 diabetes and raised excretion of urinary albumin: randomised, double blind, placebo controlled trial (the DIABHYCAR study) BMJ, February 28, 2004; 328(7438): 495. [Abstract] [Full Text] [PDF]
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P. Poredos Intima-media thickness: indicator of cardiovascular risk and measure of the extent of atherosclerosis Vascular Medicine, February 1, 2004; 9(1): 46 - 54. [Abstract] [PDF]
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K. Kohlstedt, R. P. Brandes, W. Muller-Esterl, R. Busse, and I. Fleming Angiotensin-Converting Enzyme Is Involved in Outside-In Signaling in Endothelial Cells Circ. Res., January 9, 2004; 94(1): 60 - 67. [Abstract] [Full Text] [PDF]
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J. Ostergren, P. Sleight, G. Dagenais, K. Danisa, J. Bosch, Y. Qilong, S. Yusuf, and for the HOPE study investigators Impact of ramipril in patients with evidence of clinical or subclinical peripheral arterial disease Eur. Heart J., January 1, 2004; 25(1): 17 - 24. [Abstract] [Full Text] [PDF]
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T. J. Rabelink Cardiovascular risk in patients with renal disease: treating the risk or treating the risk factor? Nephrol. Dial. Transplant., January 1, 2004; 19(1): 23 - 26. [Full Text] [PDF]
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G. D. Laverman, G. Remuzzi, and P. Ruggenenti ACE Inhibition versus Angiotensin Receptor Blockade: Which Is Better for Renal and Cardiovascular Protection? J. Am. Soc. Nephrol., January 1, 2004; 15(90010): S64 - 70. [Abstract] [Full Text]
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M. L. Bots, G. W. Evans, W. A. Riley, and D. E. Grobbee Carotid Intima-Media Thickness Measurements in Intervention Studies: Design Options, Progression Rates, and Sample Size Considerations: A Point of View Stroke, December 1, 2003; 34(12): 2985 - 2994. [Abstract] [Full Text] [PDF]
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R. Arroyo-Espliguero, N. Mollichelli, P. Avanzas, E. Zouridakis, V. R Newey, D. K Nassiri, and J. C. Kaski Chronic inflammation and increased arterial stiffness in patients with cardiac syndrome X Eur. Heart J., November 2, 2003; 24(22): 2006 - 2011. [Abstract] [Full Text] [PDF]
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A. T Hirsch and D. Duprez The potential role of angiotensin-converting enzyme inhibition in peripheral arterial disease Vascular Medicine, November 1, 2003; 8(4): 273 - 278. [Abstract] [PDF]
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J. Galle and S. Seibold Has the time come to use antioxidant therapy in uraemic patients? Nephrol. Dial. Transplant., August 1, 2003; 18(8): 1452 - 1455. [Full Text] [PDF]
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G. Jennings New definitions in cardiovascular risk management: is it time for angiotensin II receptor blockers to become first-line medication? Eur. Heart J. Suppl., August 1, 2003; 5(suppl_F): F3 - F11. [Abstract] [PDF]
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S. S. Anand, Q. Yi, H. Gerstein, E. Lonn, R. Jacobs, V. Vuksan, K. Teo, B. Davis, P. Montague, and S. Yusuf Relationship of Metabolic Syndrome and Fibrinolytic Dysfunction to Cardiovascular Disease Circulation, July 29, 2003; 108(4): 420 - 425. [Abstract] [Full Text] [PDF]
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B. M. Singh and J. L. Mehta Interactions Between the Renin-Angiotensin System and Dyslipidemia: Relevance in the Therapy of Hypertension and Coronary Heart Disease Arch Intern Med, June 9, 2003; 163(11): 1296 - 1304. [Abstract] [Full Text] [PDF]
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L. E. Wagenknecht, D. Zaccaro, M. A. Espeland, A. J. Karter, D. H. O'Leary, and S. M. Haffner Diabetes and Progression of Carotid Atherosclerosis: The Insulin Resistance Atherosclerosis Study Arterioscler Thromb Vasc Biol, June 1, 2003; 23(6): 1035 - 1041. [Abstract] [Full Text] [PDF]
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D. S. Jacoby and D. J. Rader Renin-Angiotensin System and Atherothrombotic Disease: From Genes to Treatment Arch Intern Med, May 26, 2003; 163(10): 1155 - 1164. [Abstract] [Full Text] [PDF]
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C. Anderson Blood Pressure-Lowering for Secondary Prevention of Stroke: ACE Inhibition Is the Key Stroke, May 1, 2003; 34(5): 1333 - 1334. [Full Text] [PDF]
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S. Dhein, A. Kabat, A. Olbrich, P. Rosen, H. Schroder, and F.-W. Mohr Effect of Chronic Treatment with Vitamin E on Endothelial Dysfunction in a Type I in Vivo Diabetes Mellitus Model and in Vitro J. Pharmacol. Exp. Ther., April 1, 2003; 305(1): 114 - 122. [Abstract] [Full Text]
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J. V. Linseman and M. R. Bristow Drug Therapy and Heart Failure Prevention Circulation, March 11, 2003; 107(9): 1234 - 1236. [Full Text] [PDF]
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J. M. O. Arnold, S. Yusuf, J. Young, J. Mathew, D. Johnstone, A. Avezum, E. Lonn, J. Pogue, J. Bosch, and on behalf of the HOPE Investigators Prevention of Heart Failure in Patients in the Heart Outcomes Prevention Evaluation (HOPE) Study Circulation, March 11, 2003; 107(9): 1284 - 1290. [Abstract] [Full Text] [PDF]
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K. Fukuyama, T. Ichiki, K. Takeda, T. Tokunou, N. Iino, S. Masuda, M. Ishibashi, K. Egashira, H. Shimokawa, K. Hirano, et al. Downregulation of Vascular Angiotensin II Type 1 Receptor by Thyroid Hormone Hypertension, March 1, 2003; 41(3): 598 - 603. [Abstract] [Full Text] [PDF]
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R. M. Salonen, K. Nyyssonen, J. Kaikkonen, E. Porkkala-Sarataho, S. Voutilainen, T. H. Rissanen, T.-P. Tuomainen, V.-P. Valkonen, U. Ristonmaa, H.-M. Lakka, et al. Six-Year Effect of Combined Vitamin C and E Supplementation on Atherosclerotic Progression: The Antioxidant Supplementation in Atherosclerosis Prevention (ASAP) Study Circulation, February 25, 2003; 107(7): 947 - 953. [Abstract] [Full Text] [PDF]
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V. S. Monroe, R. A. Kerensky, E. Rivera, K. M. Smith, and C. J. Pepine Pharmacologic plaque passivation for the reduction of recurrent cardiac events in acute coronary syndromes J. Am. Coll. Cardiol., February 19, 2003; 41(4_Suppl_S): 23S - 30S. [Abstract] [Full Text] [PDF]
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E. G. Lakatta and D. Levy Arterial and Cardiac Aging: Major Shareholders in Cardiovascular Disease Enterprises: Part I: Aging Arteries: A "Set Up" for Vascular Disease Circulation, January 7, 2003; 107(1): 139 - 146. [Full Text] [PDF]
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H. C. Gerstein, S. Anand, Q. L. Yi, V. Vuksan, E. Lonn, K. Teo, K. Malmberg, M. McQueen, and S. Yusuf The Relationship Between Dysglycemia and Atherosclerosis in South Asian, Chinese, and European Individuals in Canada: A randomly sampled cross-sectional study Diabetes Care, January 1, 2003; 26(1): 144 - 149. [Abstract] [Full Text] [PDF]
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U. Landmesser and H. Drexler Oxidative stress, the renin-angiotensin system, and atherosclerosis Eur. Heart J. Suppl., January 1, 2003; 5(suppl_A): A3 - A7. [Abstract] [PDF]
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E. Lonn, H.C. Gerstein, M. Smieja, J.F.E. Mann, and S. Yusuf Mechanisms of cardiovascular risk reduction with ramipril: insights from HOPE and HOPE substudies Eur. Heart J. Suppl., January 1, 2003; 5(suppl_A): A43 - A48. [Abstract] [PDF]
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