OBJECTIVES
The purpose of this study was to determine whether lowering homocysteine levels with folic acid, with or without antioxidants, will improve endothelial dysfunction in patients with ...coronary artery disease (CAD).
BACKGROUND
Elevated plasma homocysteine levels are a risk factor for atherosclerosis. Homocysteine may promote atherogenesis through endothelial dysfunction and oxidative stress.
METHODS
In a double-blind, placebo-controlled, randomized trial, we used vascular ultrasound to assess the effect of folic acid alone or with antioxidants on brachial artery endothelium-dependent flow-mediated dilation (FMD). Seventy-five patients with CAD (screening homocysteine level ≥9 μmol/liter) were randomized equally to one of three groups: placebo, folic acid alone or folic acid plus antioxidant vitamins C and E. Patients were treated for four months. Plasma folate, homocysteine, FMD and nitroglycerin-mediated dilation were measured before and after four months of treatment.
RESULTS
Plasma folate, homocysteine and FMD were unchanged in the placebo group. Compared with placebo, folic acid alone increased plasma folate by 475% (p < 0.001), reduced plasma homocysteine by 11% (p = 0.23) and significantly improved FMD from 3.2 ± 3.6% to 5.2 ± 3.9% (p = 0.04). The improvement in FMD correlated with the reduction in homocysteine (r = 0.5, p = 0.01). Folic acid plus antioxidants increased plasma folate by 438% (p < 0.001), reduced plasma homocysteine by 9% (p = 0.56) and insignificantly improved FMD from 2.6 ± 2.4% to 4.0 ± 3.7% (p = 0.45), as compared with placebo. Nitroglycerin-mediated dilation did not change significantly in any group.
CONCLUSIONS
Folic acid supplementation significantly improved endothelial dysfunction in patients with coronary atherosclerosis. Further clinical trials are required to determine whether folic acid supplementation may reduce cardiovascular events.
Diabetes is associated with endothelial dysfunction, which in part may be related to uncoupling of the endothelial nitric oxide (NO) synthase enzyme, thus reducing the availability of NO. As folates ...may potentially reverse the uncoupling of NO synthase, we wanted to determine whether folic acid supplementation could modulate endothelial function and markers of inflammation in patients with type 2 diabetes without vascular disease. Nineteen patients with type 2 diabetes were treated with folic acid (10 mg/day for 2 weeks) versus placebo in a randomized, placebo-controlled, cross-over study with an 8-week washout period between treatments. Fasting endothelium-dependent flow-mediated dilatation (FMD) of the brachial artery, endothelium-independent nitroglycerin-mediated dilatation (NMD), plasma homocysteine, serum lipids, folate, and inflammatory markers (high-sensitivity C-reactive protein, soluble intercellular adhesion molecule-1 and vascular cell adhesion molecule-1, interleukin-18, tumor necrosis factor-alpha) were assessed after each 2-week treatment period. Folic acid supplementation significantly increased folate levels and lowered plasma homocysteine levels. Folic acid significantly improved FMD compared to placebo (5.8 4.8% vs 3.2 2.7%, p 0.02). There were no significant effects of folic acid supplementation on lipids, NMD, or the inflammatory markers. There was no relationship between the change in homocysteine and the improvement in FMD. Thus, 2 weeks of folic acid supplementation can improve endothelial dysfunction in type 2 diabetics independent of homocysteine-lowering, but does not modulate markers of inflammation.
Abstract Objectives To assess the efficacy and safety of rosiglitazone on saphenous vein graft (SVG) atherosclerosis prevention and on modification of the global cardiometabolic risk profile. Methods ...and results This was a double-blind, randomized, placebo-controlled, multicenter trial which enrolled 193 post-CABG patients with type 2 diabetes. Atherosclerosis changes in one SVG were assessed with intravascular ultrasound at baseline and at 12 months. Serial cardiometabolic assessments were performed. At baseline, both groups had mean HbA1C < 7%, LDL-cholesterol (LDL-C) < 2.3 mmol/l, HDL-cholesterol (HDL-C) > 1.0 mmol/l and blood pressure < 130/75 mmHg. After 12 months, plaque volume in SVG had increased (median interquartile range) by 7.7 mm3 (−17.2 to 37.9) in the placebo group and decreased by 0.3 mm3 (−19.1 to 22.3) in the rosiglitazone group ( P = 0.22). Compared to placebo, rosiglitazone treated patients had a higher (mean ± SD) body weight (89 ± 15 kg vs. 84 ± 15 kg, P = 0.02) at the end of the study, mostly related to an increment in subcutaneous adipose tissue. Rosiglitazone treated patients also displayed further improvements in glycemic control compared to placebo (HbA1C : 6.4 ± 0.7% vs. 7.0 ± 0.9%, P < 0.001) as well as in several cardiometabolic parameters such as lipids (HDL-C: 1.16 ± 0.28 mmol/l vs. 1.06 ± 0.23 mmol/l, P = 0.003), inflammatory profile (C-reactive protein: 0.92 mg/l 0.51–1.56 vs. 1.37 mg/l 0.79–3.08, P = 0.02), and adiponectin levels (11.1 μg/ml 8.19–17.9 vs. 4.65 μg/ml 3.27–7.15, P < 0.001). There was no significant difference in the incidence of serious adverse cardiovascular events. However, more patients in the rosiglitazone group had peripheral oedema (33% vs. 18%, P = 0.0019). Conclusion After a 12-month follow-up, we found no evidence for a statistically significant effect of rosiglitazone on SVG atherosclerosis whereas significant effects on glycemic control and on the cardiometabolic risk profile appeared to be modulated in part by changes in subcutaneous adiposity.
Abstract
Metabolic syndrome (MetSyn) may predispose to cardiovascular disease (CVD) by causing vascular dysfunction. This study aimed to determine the association of MetSyn with vascular function, as ...assessed by brachial artery flow-mediated dilatation (FMD) and hyperemic shear stress (HSS). A total of 1,417 male firefighters without established diabetes and CVD were classified for MetSyn, according to the National Cholesterol Education Program Adult Treatment Panel III (NCEP) definition. MetSyn was present in 267 individuals (19%). Although FMD was lower in those with versus without MetSyn (8.1 ± 4.1 vs 8.7 ± 4.0%; p = 0.02), this was not significant after adjusting for baseline differences (age, smoking, and brachial artery diameter) (p = 0.2). However, HSS was significantly lower in those with versus without MetSyn (72.0 ± 27.8 vs 80.9 ± 24.8 dyne/cm2; p < 0.001), and there was a significant inverse graded relationship with the number of NCEP criteria present (mean HSS for those with 0, 1, 2, 3, 4, and 5 criteria: 83.2 ± 22.5, 82.2 ± 24.7, 76.5 ± 27.2, 74.3 ± 27.4, 66.5 ± 28.4, 67.1 ± 27.6 dyne/cm2; p < 0.001 for trend). The individual NCEP criteria of abdominal obesity, systolic hypertension, and impaired fasting glucose were independent predictors for HSS. In conclusion, MetSyn was not associated with impaired FMD. Alternatively, HSS, a measure of microvascular function, was significantly lower in those with MetSyn. Thus, MetSyn may contribute to CVD by causing microvascular dysfunction.
Aims The present study was designed to (a) examine the interrelationship between endothelial function and CRP in healthy individuals and (b) evaluate the relationship of each biomarker towards global ...Framingham risk scores. Methods and results Brachial artery flow-mediated vasodilatation (FMD), CRP, and traditional cardiovascular risk factors were measured in the Firefighters and Their Endothelium (FATE) study, which recruited 1154 male participants (mean age 47.4±9.8 years) with no known history of cardiovascular disease. No relationship was observed between FMD and CRP (p=0.96). FMD and the Framingham risk score tended to correlate but not significantly (p=0.07). A lower FMD was related to a higher systolic and diastolic blood pressure (p<0.001 and p=0.002, respectively) in the univariate analysis, and higher systolic blood pressure (p=0.001) in the multivariate analysis. Elevated CRP levels independently correlated most closely with overall Framingham risk score (r=0.36, p<0.001) and a weaker although statistically significant relationship was seen with individual traditional cardiovascular risk factors (p<0.005). Conclusions The current study provided evidence that brachial artery FMD had no relationship to CRP in a large cohort of healthy subjects. These observations suggest that the predictive value of CRP may be largely independent of abnormalities in endothelial function. The additive prognostic value of endothelial vasodilator testing remains to be established.
The aim of this study was to determine whether selective cyclooxygenase-2 (COX-2) inhibition with rofecoxib can modulate endothelial dysfunction and levels of circulating inflammatory markers in ...patients with established coronary artery disease (CAD).
Expression of COX-2 is upregulated in atherosclerosis. Thus, it has been hypothesized that COX-2 may contribute to atherogenesis by producing eicosanoids, which mediate vascular inflammation and endothelial dysfunction.
In a randomized, double-blind, placebo-controlled, parallel-design trial, we studied the vascular effects of rofecoxib on brachial artery vasoreactivity and inflammatory markers in 60 patients with angiographically proven CAD who were taking concomitant low-dose aspirin. Patients were randomly assigned to receive either rofecoxib (25 mg/day; n = 30) or placebo (n = 30) for eight weeks. Brachial artery endothelium-dependent flow-mediated dilation (FMD), endothelium-independent nitroglycerin-mediated dilation (NMD), and inflammatory markers (i.e., high-sensitivity C-reactive protein CRP, soluble intercellular adhesion molecule-1 sICAM-1, and soluble interleukin-6 receptor sIL-6r) were measured at baseline and after eight-week follow-up.
Baseline clinical characteristics were similar in the two groups. After eight weeks of treatment, FMD did not significantly change in either the rofecoxib or placebo group (4.0 ± 3.0% to 4.0 ± 3.8% vs. 2.7 ± 2.7% to 3.1 ± 2.7%, respectively; p = 0.6 by two-way analysis of variance). Similarly, NMD remained unchanged in both groups. Levels of CRP, sICAM-1, and sIL-6r were not significantly altered in either the rofecoxib or placebo group.
The addition of selective COX-2 inhibition with rofecoxib did not appear to have any favorable or adverse effects on endothelial dysfunction or vascular inflammation in patients with CAD using concomitant low-dose aspirin.
Background The Total Occlusion Study of Canada (TOSCA) is a multicenter, randomized trial evaluating the effect of stenting with ≥1 heparin-coated stent on long-term patency after percutaneous ...coronary intervention by balloon angioplasty of occluded coronary arteries. The purpose of the current study was to compare the effect of stenting and balloon angioplasty on global left ventricular ejection fraction (LVEF) and regional wall motion and to examine what clinical and angiographic factors may have an effect on left ventricular function in this setting. Methods and Results Analysis at the core angiographic laboratory of paired baseline and follow-up left ventricular angiograms, as well as target vessel patency, was possible in 244 of 410 cases. An improvement in LVEF was observed in the entire group (59.4% ± 11% to 61.0% ± 11%, P =.003). The LVEF change was +1.84 ± 7.54 in the stent group (P =.009) and 1.28 ± 8.16 in the percutaneous transluminal coronary angioplasty group (P =.085). There was no significant intergroup difference. Patients with duration of occlusion ≤6 weeks had an improvement in LVEF (+2.98 ± 8.68, P =.0006), whereas those with an occlusion duration of >6 weeks had no improvement (+0.48 ± 7.01, P not significant). Multivariate analysis revealed baseline LVEF <60%, duration of occlusion ≤6 weeks, and Canadian Cardiology Society angina class I or II to be independent predictors of improvement in LVEF. Conclusions The restoration of coronary patency of nonacute occluded coronary arteries is associated with a small but significant improvement in regional and global left ventricular function, especially in patients with recent occlusions and depressed left ventricular function. In spite of significant effect on long-term patency, stenting of nonacute coronary occlusions does not result in significantly better left ventricular function compared with balloon angioplasty in this setting. (Am Heart J 2001;142:301-8.)
The time course and differential effects of statin regimens on endothelial function after acute coronary syndromes (ACSs) are unknown and could contribute to the superiority of a more intense ...strategy. A subset of subjects who were enrolled in the PROVE IT-TIMI 22 trial (n = 50) underwent evaluation of vascular reactivity by high-resolution brachial ultrasound. Endothelium-dependent flow-mediated dilation (FMD) and endothelium-independent sublingual nitroglycerin-mediated dilation (NMD) were measured at baseline and at 48 hours, 1 month, and 4 months after the initiation of 40 mg of pravastatin (n = 26) or 80 mg of atorvastatin (n = 24). After 4 months, low-density lipoprotein cholesterol was decreased by 32% in the atorvastatin group but was not different from baseline after ACS in the pravastatin group. C-reactive protein decreased similarly in the 2 groups. Brachial artery diameters at rest were similar in the 2 groups and at each time point of the trial. FMD and NMD increased significantly after 4 months by 27% and 24%, respectively (p <0.05), with no difference between groups. There was no correlation between the change in FMD and the change in lipids or C-reactive protein. In subjects who had received previous statin therapy (n = 15), there was no significant variation in FMD (p = 0.140) and NMD (p = 0.129). In conclusion, initiation of statin therapy soon after ACS is associated with improvements in endothelium-dependent and independent vascular reactivities after 4 months.
Objectives This paper describes the medical therapy used in the COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation) trial and its effect on risk factors. Background ...Most cardiovascular clinical trials test a single intervention. The COURAGE trial tested multiple lifestyle and pharmacologic interventions (optimal medical therapy) with or without percutaneous coronary intervention in patients with stable coronary disease. Methods All patients, regardless of treatment assignment, received equivalent lifestyle and pharmacologic interventions for secondary prevention. Most medications were provided at no cost. Therapy was administered by nurse case managers according to protocols designed to achieve predefined lifestyle and risk factor goals. Results The patients (n = 2,287) were followed for 4.6 years. There were no significant differences between treatment groups in proportion of patients achieving therapeutic goals. The proportion of smokers decreased from 23% to 19% (p = 0.025), those who reported <7% of calories from saturated fat increased from 46% to 80% (p < 0.001), and those who walked ≥150 min/week increased from 58% to 66% (p < 0.001). Body mass index increased from 28.8 ± 0.13 kg/m2 to 29.3 ± 0.23 kg/m2 (p < 0.001). Appropriate medication use increased from pre-randomization to 5 years as follows: antiplatelets 87% to 96%; beta-blockers 69% to 85%; renin-angiotensin-aldosterone system inhibitors 46% to 72%; and statins 64% to 93%. Systolic blood pressure decreased from a median of 131 ± 0.49 mm Hg to 123 ± 0.88 mm Hg. Low-density lipoprotein cholesterol decreased from a median of 101 ± 0.83 mg/dl to 72 ± 0.88 mg/dl. Conclusions Secondary prevention was applied equally and intensively to both treatment groups in the COURAGE trial by nurse case managers with treatment protocols and resulted in significant improvement in risk factors. Optimal medical therapy in the COURAGE trial provides an effective model for secondary prevention among patients with chronic coronary disease. (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation; NCT00007657 )
Background The Glu298Asp polymorphism of endothelial nitric oxide synthase (eNOS) gene has been associated with coronary artery disease (CAD) in some but not all studies. To determine the impact of ...the mutant Asp298 eNOS allele on the development of premature CAD, we examined the prevalence of this mutation in patients with early-onset CAD compared with those manifesting CAD later in life. If this mutation confers an increased risk of premature CAD, we hypothesized that the frequency of the homozygous mutation (Asp298Asp298) would be greater among the younger patient group. Methods A total of 299 patients with a history of myocardial infarction (MI) or angina pectoris plus angiographically documented CAD were studied. Patients were divided into 2 groups: group 1 (149 patients) included patients with CAD before the age of 50 years and group 2 (150 patients) included patients with a first presentation of CAD at >65 years old. Prevalence of eNOS Glu298 and Asp298 alleles was assessed by molecular analysis and compared for the 2 groups. Results There was no significant difference in the frequency of the mutant Asp298 allele between the 2 groups (G1: 42% vs G2: 42.7%, P =.79). The frequencies of the Glu298Glu298, Glu298Asp298, and Asp298Asp298 genotypes were similar in both groups (34.9%, 46.3%, and 18.8% for G1 and 29.3%, 56%, and 14.7% for G2, respectively, P =.29). Conclusions Our study does not support the conclusion that the eNOS Asp298 allele contributes to the development of premature CAD. (Am Heart J 2001;142:586-9.)
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