Johanna M. Geleijnse

Influence of Weight Reduction on Blood Pressure A Meta-Analysis of Randomized Controlled Trials

Abstract—Increased body weight is a strong risk factor for hypertension. A meta-analysis of randomized controlled trials was performed to estimate the effect of weight reduction on blood pressure overall and in population subgroups. Twenty-five randomized, controlled trials (comprising 34 strata) published between 1966 and 2002 with a total of 4874 participants were included. A random-effects model was used to account for heterogeneity among trials. A net weight reduction of −5.1 kg (95% confidence interval [CI], −6.03 to −4.25) by means of energy restriction, increased physical activity, or both reduced systolic blood pressure by −4.44 mm Hg (95% CI, −5.93 to −2.95) and diastolic blood pressure by −3.57 mm Hg (95% CI, −4.88 to −2.25). Blood pressure reductions were −1.05 mm Hg (95% CI, −1.43 to −0.66) systolic and −0.92 mm Hg (95% CI, −1.28 to −0.55) diastolic when expressed per kilogram of weight loss. As expected, significantly larger blood pressure reductions were observed in populations with an average weight loss >5 kg than in populations with less weight loss, both for systolic (−6.63 mm Hg [95% CI, −8.43 to −4.82] vs −2.70 mm Hg [95% CI, −4.59 to −0.81]) and diastolic (−5.12 mm Hg [95% CI, −6.48 to −3.75] vs −2.01 mm Hg [95% CI, −3.47 to −0.54]) blood pressure. The effect on diastolic blood pressure was significantly larger in populations taking antihypertensive drugs than in untreated populations (−5.31 mm Hg [95% CI, −6.64 to −3.99] vs −2.91 mm Hg [95% CI, −3.66 to −2.16]). This meta-analysis clearly shows that weight loss is important for the prevention and treatment of hypertension.

n–3 Fatty Acids and Cardiovascular Events after Myocardial Infarction

BACKGROUND Results from prospective cohort studies and randomized, controlled trials have provided evidence of a protective effect of n-3 fatty acids against cardiovascular diseases. We examined the effect of the marine n-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and of the plant-derived alpha-linolenic acid (ALA) on the rate of cardiovascular events among patients who have had a myocardial infarction. METHODS In a multicenter, double-blind, placebo-controlled trial, we randomly assigned 4837 patients, 60 through 80 years of age (78% men), who had had a myocardial infarction and were receiving state-of-the-art antihypertensive, antithrombotic, and lipid-modifying therapy to receive for 40 months one of four trial margarines: a margarine supplemented with a combination of EPA and DHA (with a targeted additional daily intake of 400 mg of EPA-DHA), a margarine supplemented with ALA (with a targeted additional daily intake of 2 g of ALA), a margarine supplemented with EPA-DHA and ALA, or a placebo margarine. The primary end point was the rate of major cardiovascular events, which comprised fatal and nonfatal cardiovascular events and cardiac interventions. Data were analyzed according to the intention-to-treat principle, with the use of Cox proportional-hazards models. RESULTS The patients consumed, on average, 18.8 g of margarine per day, which resulted in additional intakes of 226 mg of EPA combined with 150 mg of DHA, 1.9 g of ALA, or both, in the active-treatment groups. During the follow-up period, a major cardiovascular event occurred in 671 patients (13.9%). Neither EPA-DHA nor ALA reduced this primary end point (hazard ratio with EPA-DHA, 1.01; 95% confidence interval [CI], 0.87 to 1.17; P=0.93; hazard ratio with ALA, 0.91; 95% CI, 0.78 to 1.05; P=0.20). In the prespecified subgroup of women, ALA, as compared with placebo and EPA-DHA alone, was associated with a reduction in the rate of major cardiovascular events that approached significance (hazard ratio, 0.73; 95% CI, 0.51 to 1.03; P=0.07). The rate of adverse events did not differ significantly among the study groups. CONCLUSIONS Low-dose supplementation with EPA-DHA or ALA did not significantly reduce the rate of major cardiovascular events among patients who had had a myocardial infarction and who were receiving state-of-the-art antihypertensive, antithrombotic, and lipid-modifying therapy. (Funded by the Netherlands Heart Foundation and others; ClinicalTrials.gov number, NCT00127452.).

Blood pressure response to fish oil supplementation: metaregression analysis of randomized trials

Objective The antihypertensive effect of fish oil was estimated from randomized trials using metaregression analysis. Modification of the blood pressure (BP) effect by age, gender, blood pressure, and body mass index was examined. Methods A total of 90 randomized trials of fish oil and BP were identified through MEDLINE (1966–March 2001). Trials with co-interventions, patient populations, non-placebo controls, or duration of < 2 weeks were excluded. A total of 36 trials (50 strata) were included, 22 of which had a double-blind design. Original reports were retrieved for data collection on sample size, study design, duration, fish oil dose, BP changes and baseline characteristics of trial populations. Pooled BP estimates were obtained by metaregression analysis, weighted for trial sample sizes. Stratified analyses according to population characteristics were performed. Results Intake of fish oil was high in most trials (median dose: 3.7 g/day). Fish oil reduced systolic BP by 2.1 mmHg [95% confidence interval (CI): 1.0, 3.2;P < 0.01] and diastolic BP by 1.6 mmHg (95% CI: 1.0. 2.2;P < 0.01). Restricting the analysis to double-blind trials yielded BP reductions of 1.7 mmHg (95% CI: 0.3, 3.1) and 1.5 mmHg (95% CI: 0.6, 2.3), respectively. BP effects tended to be larger in populations that were older (> 45 years) and in hypertensive populations (BP ⩾ 140/90 mmHg). Conclusions High intake of fish oil may lower BP, especially in older and hypertensive subjects. The antihypertensive effect of lower doses of fish oil (< 0.5 g/day) however, remains to be established.

Continuous Dose-Response Relationship of the LDL-Cholesterol–Lowering Effect of Phytosterol Intake

Phytosterols (plant sterols and stanols) are well known for their LDL-cholesterol (LDL-C)-lowering effect. A meta-analysis of randomized controlled trials in adults was performed to establish a continuous dose-response relationship that would allow predicting the LDL-C-lowering efficacy of different phytosterol doses. Eighty-four trials including 141 trial arms were included. A nonlinear equation comprising 2 parameters (the maximal LDL-C lowering and an incremental dose step) was used to describe the dose-response curve. The overall pooled absolute (mmol/L) and relative (%) LDL-C-lowering effects of phytosterols were also assessed with a random effects model. The pooled LDL-C reduction was 0.34 mmol/L (95% CI: -0.36, -0.31) or 8.8% (95% CI: -9.4, -8.3) for a mean daily dose of 2.15 g phytosterols. The impacts of subject baseline characteristics, food formats, type of phytosterols, and study quality on the continuous dose-response curve were determined by regression or subgroup analyses. Higher baseline LDL-C concentrations resulted in greater absolute LDL-C reductions. No significant differences were found between dose-response curves established for plant sterols vs. stanols, fat-based vs. non fat-based food formats and dairy vs. nondairy foods. A larger effect was observed with solid foods than with liquid foods only at high phytosterol doses (>2 g/d). There was a strong tendency (P = 0.054) towards a slightly lower efficacy of single vs. multiple daily intakes of phytosterols. In conclusion, the dose-dependent LDL-C-lowering efficacy of phytosterols incorporated in various food formats was confirmed and equations of the continuous relationship were established to predict the effect of a given phytosterol dose. Further investigations are warranted to investigate the impact of solid vs. liquid food formats and frequency of intake on phytosterol efficacy.

Blood pressure response to changes in sodium and potassium intake: a metaregression analysis of randomised trials

The objective of the study was to assess the blood pressure response to changes in sodium and potassium intake and examine effect modification by age, gender, blood pressure, body weight and habitual sodium and potassium intake. Randomised trials of sodium reduction or potassium supplementation and blood pressure were identified through reference lists of systematic reviews and an additional MEDLINE search (January 1995–March 2001). A total of 40 sodium trials and 27 potassium trials in adults with a minimum duration of 2 weeks were selected for analysis. Data on changes in electrolyte intake and blood pressure during intervention were collected, as well as data on mean age, gender, body weight, initial electrolyte intake and initial blood pressure of the trial populations. Blood pressure effects of changes in electrolyte intake were assessed by weighted metaregression analysis, overall and in strata of trial population characteristics. Analyses were repeated with adjustment for potential confounders. Sodium reduction (median: −77 mmol/24 h) was associated with a change of −2.54 mmHg (95% CI: −3.16, −1.92) in systolic blood pressure and −1.96 mmHg (−2.41, −1.51) in diastolic blood pressure. Corresponding values for increased potassium intake (median: 44 mmol/24 h) were −2.42 mmHg (−3.75, −1.08) and −1.57 mmHg (–2.65, –0.50). Blood pressure response was larger in hypertensives than normotensives, both for sodium (systolic: −5.24 vs −1.26 mmHg, P<0.001; diastolic: −3.69 vs −1.14 mmHg, P<0.001) and potassium (systolic: −3.51 vs −0.97 mmHg, P=0.089; diastolic: −2.51 vs −0.34 mmHg, P=0.074). In conclusion, reduced intake of sodium and increased intake of potassium could make an important contribution to the prevention of hypertension, especially in populations with elevated blood pressure.

Milk and dairy consumption and incidence of cardiovascular diseases and all-cause mortality: dose-response meta-analysis of prospective cohort studies

BACKGROUND The consumption of dairy products may influence the risk of cardiovascular disease (CVD) and total mortality, but conflicting findings have been reported. OBJECTIVE The objective was to examine the associations of milk, total dairy products, and high- and low-fat dairy intakes with the risk of CVD [including coronary heart disease (CHD) and stroke] and total mortality. DESIGN PubMed, EMBASE, and SCOPUS were searched for articles published up to February 2010. Of > 5000 titles evaluated, 17 met the inclusion criteria, all of which were original prospective cohort studies. Random-effects meta-analyses were performed with summarized dose-response data. Milk as the main dairy product was pooled in these analyses. RESULTS In 17 prospective studies, there were 2283 CVD, 4391 CHD, 15,554 stroke, and 23,949 mortality cases. A modest inverse association was found between milk intake and risk of overall CVD [4 studies; relative risk (RR): 0.94 per 200 mL/d; 95% CI: 0.89, 0.99]. Milk intake was not associated with risk of CHD (6 studies; RR: 1.00; 95% CI: 0.96, 1.04), stroke (6 studies; RR: 0.87; 95% CI: 0.72, 1.05), or total mortality (8 studies; RR per 200 mL/d: 0.99; 95% CI: 0.95, 1.03). Limited studies of the association of total dairy products and of total high-fat and total low-fat dairy products (per 200 g/d) with CHD showed no significant associations. CONCLUSION This dose-response meta-analysis of prospective studies indicates that milk intake is not associated with total mortality but may be inversely associated with overall CVD risk; however, these findings are based on limited numbers.

Blood pressure response to chronic intake of coffee and caffeine: a meta-analysis of randomized controlled trials

Purpose Coffee is a widely consumed beverage and small health effects of substances in coffee may have large public health consequences. It has been suggested that caffeine in coffee increases the risk of hypertension. We performed a meta-analysis of randomized controlled trials of coffee or caffeine and blood pressure (BP). Data identification BP trials of coffee or caffeine published between January 1966 and January 2003 were identified through literature databases and manual serach. Study selection A total of 16 studies with a randomized, controlled design and at least 7 days of intervention was selected, comprising 25 strata and 1010 subjects. Data extraction Two persons independently obtained data on sample size, type and duration of intervention, changes in BP and heart rate (HR), and subjects’ characteristics for each trial. Meta-analysis was performed using a random-effects model. Results A significant rise of 2.04 mmHg [95% confidence interval (CI), 1.10–2.99] in systolic BP and 0.73 mmHg (95% CI, 0.14–1.31) in diastolic BP was found after pooling of coffee and caffeine trials. When coffee trials (n = 18, median intake: 725 ml/day) and caffeine trials (n = 7, median dose: 410 mg/day) were analysed separately, BP elevations appeared to be larger for caffeine [systolic: 4.16 mmHg (2.13–6.20); diastolic: 2.41 mmHg (0.98–3.84)] than for coffee [systolic: 1.22 mmHg (0.52–1.92) and diastolic: 0.49 mmHg (−0.06–1.04)]. Effects on HR were negligible. Conclusions Regular caffeine intake increases BP. When ingested through coffee, however, the blood pressure effect of caffeine is small.

Effect of fish oil on cognitive performance in older subjects A randomized, controlled trial

Background: High intake of n-3 polyunsaturated fatty acids may protect against age-related cognitive decline. However, results from epidemiologic studies are inconclusive, and results from randomized trials in elderly subjects without dementia are lacking. Objective: To investigate the effect of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) supplementation on cognitive performance. Methods: Double-blind, placebo-controlled trial involving 302 cognitively healthy (Mini-Mental State Examination score > 21) individuals aged 65 years or older. Participants were randomly assigned to 1,800 mg/d EPA–DHA, 400 mg/d EPA–DHA, or placebo capsules for 26 weeks. Cognitive performance was assessed using an extensive neuropsychological test battery that included the cognitive domains of attention, sensorimotor speed, memory, and executive function. Results: The mean age of the participants was 70 years, and 55% were male. Plasma concentrations of EPA–DHA increased by 238% in the high-dose and 51% in the low-dose fish oil group compared with placebo, reflecting excellent compliance. Baseline scores on the cognitive tests were comparable in the three groups. Overall, there were no significant differential changes in any of the cognitive domains for either low-dose or high-dose fish oil supplementation compared with placebo. Conclusions: In this randomized, double-blind, placebo-controlled trial, we observed no overall effect of 26 weeks of eicosapentaenoic acid and docosahexaenoic acid supplementation on cognitive performance.

Dietary assessment in the elderly : validation of a semiquantitative food frequency questionnaire

Objective: The study was conducted to assess the relative validity of a 170-item semiquantitative food frequency questionnaire (SFFQ) adapted for use in the elderly.Design and subjects: The study was carried out in a sample of 80 men and women aged 55–75 y participating in a community based prospective cohort study in Rotterdam, The Netherlands. The two-step dietary assessment comprised a simple self-administered questionnaire (20 min) followed by a structured interview with trained dietitians (20 min) based on the completed questionnaire. Multiple food records (FR) collected over a one year period served as reference method. 24 h urine urea was used as indirect marker for protein intake.Results: Compared with FR, the SFFQ generally overestimated nutrient intake as reflected by difference in means and the ratio of SFFQ to FR. Energy adjustment reduced the observed overestimation. Pearson’s correlation coefficients varied from close to 0.5 to about 0.9 for crude data, and after adjustment for age, sex, total energy intake, and for within-person variability in daily intake for 0.4–0.8. Cross-classification into quintiles resulted in correct classification into the same or adjacent quintile of 75.8% for crude and 76.8% for energy-adjusted data. Validation of protein intake estimated by SFFQ with protein excretion from 24 h urine urea indicated overestimation of protein intake by SFFQ. Spearman correlation coefficient between protein intake estimated from urea excretion and SFFQ was 0.67.Conclusions: Adaptation of a SFFQ for use in the elderly resulted in a valid and time-efficient dietary assessment instrument. Its ability to adequately rank study subjects according to their dietary intake support its application in epidemiological studies in the elderly.Sponsorship: ROMERES and Akzo Nobel, the Netherlands; K. Klipstein-Grobusch was supported by the Ministry of Research, Culture, and Science of the Federal State of Brandenburg, Germany.

Fish-oil supplementation induces antiinflammatory gene expression profiles in human blood mononuclear cells

BACKGROUND Polyunsaturated fatty acids can have beneficial effects on human immune cells, such as peripheral blood mononuclear cells (PBMCs). However, the mechanisms of action of polyunsaturated fatty acids on immune cells are still largely unknown. OBJECTIVE The objective was to examine the effects of supplementation with the polyunsaturated fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on whole-genome PBMC gene expression profiles, in healthy Dutch elderly subjects participating in a double-blind trial, by using whole-genome transcriptomics analysis. DESIGN The subjects were randomly allocated to 1 of 3 groups: 1) consumption of 1.8 g EPA+DHA/d (n = 36), 2) consumption of 0.4 g EPA+DHA/d (n = 37), or 3) consumption of 4.0 g high-oleic acid sunflower oil (HOSF)/d (n = 38). All supplements were given in capsules. Before and after 26 wk of intervention, blood samples were collected. Microarray analysis was performed on PBMC RNA from 23 subjects who received 1.8 g EPA+DHA/d and 25 subjects who received HOSF capsules. Quantitative real-time polymerase chain reaction was performed in all 111 subjects. RESULTS A high EPA+DHA intake changed the expression of 1040 genes, whereas HOSF intake changed the expression of only 298 genes. EPA+DHA intake resulted in a decreased expression of genes involved in inflammatory- and atherogenic-related pathways, such as nuclear transcription factor kappaB signaling, eicosanoid synthesis, scavenger receptor activity, adipogenesis, and hypoxia signaling. CONCLUSION These results are the first to show that intake of EPA+DHA for 26 wk can alter the gene expression profiles of PBMCs to a more antiinflammatory and antiatherogenic status. This trial was registered at clinicaltrials.gov as NCT00124852.