Thomas A. B. Sanders

BACKGROUND: Recent meta-analyses of randomized controlled trials have raised concerns that treatment with omega-3 fatty acids may increase the risk of atrial fibrillation (AF). However, these meta-analyses included at most 8 trials. The aim of this current meta-analysis was to expand the search by including other eligible omega-3 randomized controlled trials with AF incidence data, incorporating both published and unpublished data. METHODS: Eligible studies were randomized controlled trials investigating daily doses of ≥500 mg/d of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). Additional inclusion criteria included ≥12 months of treatment with EPA/DHA, participants ≥50 years of age, and, where possible, the absence of known AF/atrial flutter at baseline. The primary outcome was the occurrence of new-onset AF. Our primary hypothesis was that risk for AF would simultaneously depend on both omega-3 dose (above or below 1500 mg/d) and background cardiovascular disease risk status, and that their combined impact on AF risk would be synergistic. RESULTS: A total of 35 randomized controlled trials (37 data sets; n=114 592) were included in this meta-analysis. Only studies including patients at high-risk for cardiovascular disease who were treated with high-doses of EPA/DHA (>1500 mg/d) showed a statistically significant increase in AF risk with a pooled odds ratio (OR) of 1.43 (95% CI, 1.14–1.79) and an absolute risk difference of 0.8% (0.40%–1.1%). None of the other 3 groups showed statistically significant levels of AF risk (odds ratios, 1.07 [high risk–low dose], 1.06 [low risk–low dose], and 1.03 [low risk–high dose]). CONCLUSIONS: This meta-analysis suggests that high-dose EPA/DHA treatment is associated with an increased risk of AF in patients at high cardiovascular disease risk, whereas low-dose EPA/DHA does not appear to increase AF risk, even in high-risk populations. Further prospective studies are needed to evaluate any potential increased risk of higher doses balanced against potential benefits.

Background: Recent meta-analyses of randomized controlled trials (RCTs) have raised concerns that treatment with omega-3 fatty acids may increase risk of atrial fibrillation (AF). However, these meta-analyses included at most eight trials. The aim of this current meta-analysis was to expand the search by including other eligible omega-3 RCTs with AF incidence data, incorporating both published and unpublished data. Methods: Eligible studies were RCTs investigating daily doses of ≥500 mg/d of docosahexaenoic acid (DHA) and/or eicosapentaenoic acid (EPA). Additional inclusion criteria included ≥12 months treatment with EPA/DHA, participants ≥ 50 years of age, and where possible, the absence of known AF/atrial flutter at baseline. The primary outcome was occurrence of new-onset AF. Our primary hypothesis was that risk for AF would simultaneously depend on both omega-3 dose (above or below 1500 mg/d) and background cardiovascular disease (CVD) risk status, and that their combined impact on AF risk would be synergistic. Results: A total of 34 RCTs (36 datasets; n=114,326) were included in this meta-analysis. Only studies including patients at high-risk for CVD who were treated with high-doses of EPA/DHA (>1500 mg/day) showed a statistically significant increase in AF risk with a pooled odds ratio (OR) of 1.48 (95% CI, 1.21-1.81) and an absolute risk difference of 0.8% (0.40-1.1%). None of the other three groups showed statistically significant levels of AF risk (ORs 1.07 (high risk, low dose), 1.06 (low risk, low dose) and 0.95 (low risk, high dose). Conclusion: This meta-analysis suggests that treatment with EPA/DHA is most likely to increase risk for AF in patients at high-risk for CVD who are treated with high doses of EPA/DHA. The risk for AF should be balanced against the benefits of EPA/DHA in making treatment decisions.

Fatty acids are important as structural components, energy sources, and signaling mediators. While studies have extensively explored genetic regulation of fatty acids in serum and other bodily fluids, their regulation within adipose tissue, a crucial regulator of cardiovascular and metabolic health remains unclear. Here, we investigated the genetic regulation of 18 fatty acids in subcutaneous adipose tissue from 569 female twins from TwinsUK. Using twin models, the heritability of fatty acids ranged from 5% to 59%, indicating a substantial genetic regulation of fatty acid levels within adipose tissue, which was also tissue-specific in many cases. Genome-wide association studies identified ten significant loci, in SCD, ADAMTSL1, ZBTB41, SNTB1, EXOC6B, ACSL3, LINC02055, MKRN2/TSEN2, FADS1 and HAPLN across 13 fatty acids or fatty acid product-to-precursor ratios. Using adipose gene expression and methylation, which were concurrently measured in these samples, we detected five fatty acid-associated signals that colocalized with eQTL and meQTL signals, highlighting fatty acids that are regulated by molecular processes within adipose tissue. We identified strong associations of adipose fatty acids-associated loci with type 2 diabetes, body fat percentage, and cardiovascular disease. We explored links between polygenic scores of common metabolic traits and adipose fatty acid levels, and identified associations between polygenic scores of BMI, body-fat distribution and triglycerides and several fatty acids, indicating these risk scores impact local adipose tissue content. Overall, our results identified local genetic regulation of fatty acids within adipose tissue and highlighted their links with renal and cardio-metabolic health.

Objective: Errors in blood pressure (BP) measurement account for a large proportion of misclassified hypertension diagnoses. Ambulatory blood pressure monitoring (ABPM) is often considered to be the gold standard for measurement of BP, but uncertainty remains regarding the degree of measurement error. The aim of this study was to determine reproducibility of sequential ABPM in a population of normotensive and well controlled hypertensive individuals. Methods: Individual participant data from three randomized controlled trials, which had recorded ABPM and carotid-femoral pulse wave velocity (PWV) at least twice were combined (n = 501). We calculated within-individual variability of daytime and night-time BP and compared the variability between normotensive (n = 324) and hypertensive (n = 177) individuals. As a secondary analysis, variability of PWV measurements was also calculated, and multivariable linear regression was used to assess characteristics associated with blood pressure variability (BPV). Results: Within-individual coefficient of variation (CoV) for systolic BP was 5.4% (day) and 7.0% (night). Equivalent values for diastolic BP were 6.1% and 8.4%, respectively. No statistically significant difference in CoV was demonstrated between measurements for normotensive and hypertensive individuals. Within-individual CoV for PWV exceeded that of BP measurements (10.7%). BPV was associated with mean pressures, and BMI for night-time measurements. PWV was not independently associated with BPV. Conclusion: The variability of single ABPM measurements will still yield considerable uncertainty regarding true average pressures, potentially resulting in misclassification of hypertensive status and incorrect treatment regimes. Repeated ABPM may be necessary to refine antihypertensive therapy.

The gastrointestinal tract (GIT) plays a key role in regulating nutrient metabolism and appetite responses. This study aimed to identify changes in the GIT that are important in the development of diet related obesity and diabetes. GIT samples were obtained from C57BL/6J male mice chronically fed a control diet or a high sucrose diet (HSD) and analysed for changes in gene, protein and metabolite levels. In HSD mice, GIT expression levels of fat oxidation genes were reduced, and increased de novo lipogenesis was evident in ileum. Gene expression levels of the putative sugar sensor, slc5a4a and slc5a4b, and fat sensor, cd36, were downregulated in the small intestines of HSD mice. In HSD mice, there was also evidence of bacterial overgrowth and a lipopolysaccharide activated inflammatory pathway involving inducible nitric oxide synthase (iNOS). In Caco-2 cells, sucrose significantly increased the expression levels of the nos2, iNOS and nitric oxide (NO) gas levels. In conclusion, sucrose fed induced obesity/diabetes is associated with changes in GI macronutrient sensing, appetite regulation and nutrient metabolism and intestinal microflora. These may be important drivers, and thus therapeutic targets, of diet-related metabolic disease.

There may be differences in hematological parameters between meat-eaters and vegetarians. The aim of this study was to perform cross-sectional analyses of hematological parameters by diet group in a large cohort in the United Kingdom. A complete blood count was carried out in all UK Biobank participants at recruitment (2006–2010). We examined hemoglobin, red and white blood cell counts, and platelet counts and volume in regular meat eaters (>3 times/wk of red/processed meat consumption, n = 212,831), low meat eaters (n = 213,092), poultry eaters (n = 4815), fish eaters (n = 10,042), vegetarians (n = 6548), and vegans (n = 398) of white ethnicity and meat eaters (n = 3875) and vegetarians (n = 1362) of British Indian ethnicity. In both white and British Indian populations, compared with regular meat eaters (or meat eaters in Indians), the other diet groups had up to 3.7% lower age-adjusted hemoglobin concentrations (difference not significant in white vegan women) and were generally more likely to have anemia (e.g., 8.7% of regular meat eaters compared with 12.8% of vegetarians in white premenopausal women; P < 0.05 after Bonferroni correction). In the white population, compared with regular meat eaters, all other diet groups had lower age- and sex-adjusted total white cells, neutrophils, lymphocytes, monocytes, and eosinophils (P-heterogeneity < 0.001 for all), but basophil counts were similar across diet groups; in British Indians, there was no significant difference in any of the white blood cell counts by diet group. Compared with white regular meat eaters, the low meat eaters, poultry eaters, fish eaters, and vegans had significantly lower platelet counts and higher platelet volume, whereas vegetarians had higher counts and lower volume. Compared with British Indian meat eaters, vegetarians had higher platelet count and lower volume. In the UK Biobank, people with low or no red meat intake generally had lower hemoglobin concentrations and were slightly more likely to be anemic. The lower white blood cell counts observed in low and non-meat eaters, and differences in mean platelet counts and volume between diet groups, warrant further investigation. This observational study was registered at http://www.isrctn.com/ as ISRCTN10125697.

Adherence to dietary guidelines (DG) may result in higher intake of polyphenols via increased consumption of fruits, vegetables and whole grains. We compared polyphenol dietary intake and urinary excretion between two intervention groups in the Cardiovascular risk REduction Study: Supported by an Integrated Dietary Approach study: a 12-week parallel-arm, randomised controlled trial (n161; sixty-four males, ninety-seven females; aged 40–70 years). One group adhered to UK DG, whereas the other group consumed a representative UK diet (control). We estimated polyphenol dietary intake, using a 4-d food diary (4-DFD) and FFQ, and analysed 24-h polyphenol urinary excretion by liquid chromatography-tandem MS on a subset of participants (n46 control;n45 DG). A polyphenol food composition database for 4-DFD analysis was generated using Phenol-Explorer and USDA databases. Total polyphenol intake by 4-DFD at endpoint (geometric means with 95 % CI, adjusted for baseline and sex) was significantly higher in the DG group (1279 mg/d per 10 MJ; 1158, 1412) compared with the control group (1084 mg/d per 10 MJ; 980, 1197). The greater total polyphenol intake in the DG group was attributed to higher intake of anthocyanins, proanthocyanidins and hydroxycinnamic acids, with the primary food sources being fruits, cereal products, nuts and seeds. FFQ estimates of flavonoid intake also detected greater intake in DG compared with the control group. 24-h urinary excretion showed consistency with 4-DFD in their ability to discriminate between dietary intervention groups for six out of ten selected, individual polyphenols. In conclusion, following UK DG increased total polyphenol intake by approximately 20 %, but not all polyphenol subclasses corresponded with this finding.

Study design Multicentre, double-blind, placebo-controlled randomised clinical trial. Objectives To compare the effectiveness of long chain omega-3 polyunsaturated fatty acids (PUFAs) as part of the management for people diagnosed with rotator cuff related shoulder pain (RCRSP). Summary of background Although there is no robust evidence to support their use, omega-3 PUFAs have been recommended for those with tendinopathy due to their potential to moderate inflammation. Methods Participants with RCRSP (n=73) were randomised to take either nine MaxEPA capsules providing 1.53 g eicosapentaenoic acid, 1.04 g docosahexaenoic acid or nine matching placebo capsules containing oleic acid per day for 8 weeks. In addition, participants attended an exercise/education programme for 8 weeks. Participants were assessed at prerandomisation, 8 weeks (primary outcome point), 3 months, 6 months and 12 months (secondary outcome point). Primary outcome was the Oxford Shoulder Score (OSS). Secondary outcomes included the Shoulder Pain and Disability Index (SPADI), Patient Specific Functional Score, Euro Qol 5D-3L, Short Form 36, global rating of change and impairment measurements. Analysis was by intention to treat. Results Difference in the change in the OSS between the two groups at 2 months was –0.1 (95% CI −2.6 to 2.5, p=0.95). The change in SPADI scores was −8.3 (95% CI −15.6 to −0.94, p=0.03, analysed by analysis of covariance adjusted for baseline) at 3 months. Conclusion Omega-3 PUFA supplementation may have a modest effect on disability and pain outcomes in RCRSP.