The effect of aggressive versus conventional lipid-lowering therapy on markers of inflammatory and oxidative stress.

PURPOSE: Recent trial results are in favor of aggressive lipid lowering using high dose statins in patients needing secondary prevention. It is unclear whether these effects are solely due to more extensive lipid lowering or the result of the potentially anti-inflammatory properties of statins. We aimed to determine whether aggressive compared with conventional statin therapy is more effective in reducing systemic markers of inflammation and oxidative stress. MATERIALS AND METHODS: This was a multi-centre, double-blind, placebo-controlled trial. Patients with previous cardiovascular disease, who did not achieve low density lipoprotein (LDL) cholesterol levels <2.6 mmol/l on conventional statin therapy (simvastatin 40 mg) were randomized to continue with simvastatin 40 mg or to receive atorvastatin 40 mg for 8 weeks and thereafter atorvastatin 80 mg for the final 8 weeks (aggressive treatment). Lipids, C-reactive protein, soluble cellular adhesion molecules, neopterin, von Willebrand Factor, and antibodies against oxidized LDL were measured at baseline and after 16 weeks. RESULTS: Lipid levels decreased significantly in the aggressive treatment group (LDL-C reduction 20.8%; P < 0.001), whereas a slight increase was observed in the conventional group (LDL-C increase 3.7%; P = 0.037). A significant reduction in antibodies against oxidized LDL was seen in the aggressive (13.4%; P < 0.001) and the conventional (26.8%; P < 0.001) group, but there was no difference between groups (P = 0.25). Furthermore, no significant differences in change in other biomarkers was observed between both groups. CONCLUSIONS: This study does not support the hypothesis that a more profound reduction in inflammatory and oxidative stress contributes to the benefits of aggressive statin therapy.

Long-term effects of nutritional group education for persons at high cardiovascular risk.

BACKGROUND: Treatment of persons at high risk for coronary heart disease (CHD) should include nutritional counselling, but little is known about the effects of different types of education. METHODS: In a quasi-experimental study design the effects of a nutritional education programme (1st year: three group sessions by a dietitian; 2nd year: one group session; 3rd year: additional focus on saturated fat; reinforcement by written nutritional messages annually) (intervention group; n=103) are compared with the effects of a posted leaflet containing standard dietary guidelines (control group; n=163). Participants had hypercholesterolemia (6-8 mmol/l) and at least two other CHD risk factors. RESULTS: After 3 years, no significant differences existed in established CHD risk factors between intervention and control groups (adjusted mean net differences: total cholesterol (0 mmol/l), diastolic blood pressure (-1.1 mm Hg; NS), and body weight (+0.3 kg, NS)). Regarding dietary intake, the intervention group had a lower intake of total (net difference -2.0% of energy, SEM 0.9) and saturated fat (-1.2% of energy, SEM 0.4) and a higher fish (+11 g/day, SEM 4) and vegetables consumption (+21 g/day, SEM 10) during the study period (p<0.05 for all). CONCLUSION: A nutritional education programme with group sessions changed dietary intake more effectively than a posted leaflet, but no additional positive effects were observed on established CHD risk factors after three years of follow-up.

Effects of amlodipine and lisinopril on intima-media thickness in previously untreated, elderly hypertensive patients (the ELVERA trial).

OBJECTIVE: To compare the effects of the calcium channel blocker amlodipine and the angiotensin-converting enzyme inhibitor lisinopril on intima-media thickness (IMT) in elderly, previously untreated hypertensive individuals. DESIGN: A double-blind randomized parallel-group trial (the ELVERA trial). PATIENTS: The study population comprised 166 newly diagnosed hypertensive individuals (aged 60-75 years) with diastolic blood pressure between 95 and 115 mmHg or systolic blood pressure between 160 and 220 mmHg, or both. INTERVENTION: Patients were allocated randomly to groups to receive amlodipine 5-10 mg or lisinopril 10-20 mg for 2 years. MAIN OUTCOME MEASURES: Before and after 1 and 2 years of treatment, IMT was measured in three carotid and two femoral arterial sites by B-mode ultrasound. The primary endpoint was the change from baseline of the combined mean maximum far wall IMT of carotid and femoral arteries, evaluated by repeated measurement analysis of the treatment effect in an intention-to-treat analysis. RESULTS: After 2 years of treatment, amlodipine decreased IMT by 0.089 mm [95% confidence interval (CI) 0.144 to 0.037]. Lisinopril decreased IMT by 0.065 mm (95% CI 0.124 to 0.010). No differences between the two drugs were found (P = 0.18). Both treatment regimens achieved the greatest reduction of IMT after 1 year, with a slight increase after the second year, whereas the reduction in blood pressure was maintained. Comparing the carotid and femoral arteries, a significant treatment difference in the change from baseline in favour of amlodipine was observed in the IMT of the elastic common carotid artery (P < 0.05). The effects of the two drugs on the muscular common femoral artery were not different. CONCLUSION: In a long-term study, amlodipine and lisinopril reduce IMT to a similar extent in newly diagnosed elderly hypertensive patients. It is suggested that the two drugs have different effects on arteries that are not prone to atherosclerosis.

Effects of nifedipine on carotid and femoral arterial wall thickness in previously untreated hypertensive patients.

BACKGROUND: Experimental and clinical evidence suggests that calcium-channel blockers may retard the atherosclerotic process after long-term treatment. Whether these effects exist after intermediate-term treatment in hypertensive patients is mainly unknown. OBJECTIVE: To determine the 26-week effects of the long-acting calcium-channel blocker nifedipine on intima media thickness (IMT) in newly found hypertensive patients. DESIGN: Open-label study with blinded end-point analysis. METHODS: From a population survey, 131 previously untreated mild hypertensives (4 x systolic blood pressure between 160 and 220 mmHg and/or diastolic blood pressure between 95 and 115 mmHg) were included. Patients were treated with long-acting nifedipine 30-60 mg targeted to reach a predetermined drop in blood pressure. Prior to and after 26 weeks of treatment, IMT was measured by ultrasonography in the carotid and femoral artery. The combined mean maximal far wall IMT was used as primary endpoint. Change from baseline was evaluated by paired t-test in an intention-to-treat analysis. RESULTS: The mean maximal far wall IMT at baseline was 1.03 +/- 0.23 mm, and decreased by 0.078 mm (95% confidence interval, CI 0.044-0.111) after treatment. Regression analysis, including baseline IMT and changes of blood pressure, showed that reduction of IMT was mostly influenced by baseline IMT (p < 0.001; model R2 = 0.1). CONCLUSION: Our observations show that 26 weeks of nifedipine treatment inhibits IMT progression in these newly found hypertensive patients. This effect was mostly seen in arterial walls with highest IMT before treatment, suggesting that patients with highest cardiovascular risk benefit most of antihypertensive treatment.

Correlates of endothelial function and their relationship with inflammation in patients with familial hypercholesterolaemia.

Atherosclerosis is characterized by a low-grade systemic inflammatory response and endothelial dysfunction. The aim of the present study was to investigate a possible relationship between systemic markers of inflammation, serum markers of endothelial activation and endothelium-dependent vasodilatation in a group of high-risk patients, and to evaluate the effects of intervention with high doses of simvastatin on these parameters. In patients with heterozygous familial hypercholesterolaemia, without atherosclerotic events, flow-mediated vasodilatation (FMD) of the brachial artery was measured after a wash-out period for lipid-lowering drugs (baseline) and after 6 weeks of treatment with simvastatin 80 mg daily. Levels of C-reactive protein (CRP), soluble intercellular cell-adhesion molecule (s-ICAM) and soluble E-selectin (s-E-selectin) were determined at baseline and again after 6 weeks and 12 months of therapy. A total of 35 subjects participated in the study (mean age 42 years; 60% male). When divided into tertiles according to FMD (<3.9%, 3.9-9.0% and >9.0%), no differences in levels of CRP, s-ICAM-1 and/or s-E-selectin were detected between the groups. Moreover, no changes in FMD, levels of CRP or levels of s-ICAM-1 and/or s-E-selectin were found during treatment with simvastatin. We conclude that endothelial function, as reflected by FMD, does not seem to be related to markers of inflammation in familial hypercholesterolaemia subjects at high risk of, but without clinically overt signs of, atherosclerosis. Moreover, aggressive lipid-lowering therapy with simvastatin does not result in improved endothelial function or in a reduction of markers of inflammation in these patients.

Change in saturated fat intake is associated with progression of carotid and femoral intima-media thickness, and with levels of soluble intercellular adhesion molecule-1.

BACKGROUND: A high saturated fat (SFA) intake may stimulate progression of atherosclerosis, and may be positively associated with expression of adhesion molecules. METHODS: In moderately hypercholesterolaemic participants of a dietary intervention study (n=103; 55+/-10 years), we examined associations between reported changes in SFA intake and changes in carotid and femoral intima-media thickness (IMT) and soluble intercellular adhesion molecule-1 (sICAM-1) levels after 2 years. The carotid and femoral IMT was assessed by high-resolution B-mode ultrasound images. RESULTS: After 2 years, dietary intake of SFA decreased with 1.8+/-2.6% of energy (P<0.01). In the lowest quintile of change in SFA intake (-5.9+/-1.4% of energy), changes in carotid and femoral IMT were +0.03 mm (SEM 0.03) and -0.09 mm (SEM 0.07), respectively, versus +0.10 mm (SEM 0.03), +0.17 mm (SEM 0.07) in the top quintile (+1.6+/-0.7% of energy) (P linear trend 0.07 (carotis), 0.02 (femoralis)). Changes in sICAM-1 were -19.0 ng/nl (SEM 5.6) in the lowest quintile, versus +8.6 ng/ml (SEM 5.3) in the top quintile (P linear trend <0.001), adjusted for baseline level, SFA intake, body mass index, age, changes in intake of fruit, polyunsaturated fat, and dietary cholesterol. Adjustments for changes in established risk factors did not alter these results. CONCLUSIONS: Decreased SFA intake may reduce progression of atherosclerosis, as assessed by IMT, and is associated with reduced levels of sICAM-1 after 2 years. Further research using randomised placebo-controlled trials is necessary to exclude potential confounding variables and to confirm causality.

Effect of an increased intake of alpha-linolenic acid and group nutritional education on cardiovascular risk factors: the Mediterranean Alpha-linolenic Enriched Groningen Dietary Intervention (MARGARIN) study.

BACKGROUND: The effect of long-term increased intakes of alpha-linolenic acid (ALA; 18:3n-3) on cardiovascular risk factors is unknown. OBJECTIVES: Our objectives were to assess the effect of increased ALA intakes on cardiovascular risk factors and the estimated risk of ischemic heart disease (IHD) at 2 y and the effect of nutritional education on dietary habits. DESIGN: Subjects with multiple cardiovascular risk factors (124 men and 158 women) were randomly assigned in a double-blind fashion to consume a margarine rich in either ALA [46% linoleic acid (LA; 18:2n-6) and 15% ALA; n = 114] or LA (58% LA and 0.3% ALA; n = 168). An intervention group (n = 110; 50% ALA) obtained group nutritional education, and a control group (n = 172; 34% ALA) received a posted leaflet containing the standard Dutch dietary guidelines. RESULTS: Average ALA intakes were 6.3 and 1.0 g/d in the ALA and LA groups, respectively. After 2 y, the ALA group had a higher ratio of total to HDL cholesterol (+0.34; 95% CI: 0.12, 0.56), lower HDL cholesterol (-0.05 mmol/L; -0.10, 0), higher serum triacylglycerol (+0.24 mmol/L; 0.02, 0.46), and lower plasma fibrinogen (-0.18 g/L; -0.31, -0.04; after 1 y) than did the LA group (adjusted for baseline values, sex, and lipid-lowering drugs). No significant difference existed in 10-y estimated IHD risk. After 2 y, the intervention group had lower saturated fat intakes and higher fish intakes than did the control group. CONCLUSIONS: Increased ALA intakes decrease the estimated IHD risk to an extent similar to that found with increased LA intakes. Group nutritional education can effectively increase fish intake.