Cross-sectional study of the associations between circulating vitamin D concentrations and insulin resistance in children aged 9-10 years of South Asian, black African Caribbean and white European origins.

BACKGROUND: Lower circulating vitamin D 25-hydroxyvitamin D (25(OH)D) concentrations are associated with higher type 2 diabetes risk in adults, although causality remains uncertain. However, associations between 25(OH)D and type 2 diabetes risk markers in children have been little studied, particularly in ethnic minority populations. We examined whether 25(OH)D concentrations were associated with insulin resistance in children and whether lower 25(OH)D concentrations in South Asians and black African Caribbeans could contribute to their higher insulin resistance. METHODS: Cross-sectional study of 4650 UK primary school children aged 9-10 years of predominantly South Asian, black African Caribbean and white European ethnicity. Children had fasting blood measurements of circulating 25(OH)D metabolite concentrations, insulin and glucose. RESULTS: Lower 25(OH)D concentrations were observed in girls, South Asians and black African Caribbeans. In analyses adjusted for age, sex, month, ethnic group and school, circulating 25(OH)D was inversely associated with fasting insulin (-0.38%, 95% CI -0.49% to -0.27%), homoeostasis model assessment (HOMA) insulin resistance (-0.39%, 95% CI -0.50% to -0.28%) and fasting glucose (-0.03%, 95% CI -0.05% to -0.02%) per nmol/L increase in 25(OH)D; associations did not differ between ethnic groups. Ethnic differences in fasting insulin and HOMA insulin resistance (higher among South Asian and black African Caribbeans) were reduced by >40% after adjustment for circulating 25(OH)D concentrations. CONCLUSION: Circulating vitamin D was inversely associated with insulin resistance in all ethnic groups; higher insulin resistance in South Asian and black African children were partly explained by their lower vitamin D levels. Whether vitamin D supplementation can reduce emerging type 2 diabetes risk needs further evaluation.

Network Meta-Analysis of Randomized Trials Evaluating the Comparative Efficacy of Lipid-Lowering Therapies Added to Maximally Tolerated Statins for the Reduction of Low-Density Lipoprotein Cholesterol.

Background Lowering low-density lipoprotein cholesterol (LDL-C) levels decreases major cardiovascular events and is recommended for patients at elevated cardiovascular risk. However, appropriate doses of statin therapy are often insufficient to reduce LDL-C in accordance with current guidelines. In such cases, treatment could be supplemented with nonstatin lipid-lowering therapy. Methods and Results A systematic literature review and network meta-analysis were conducted on randomized controlled trials of nonstatin lipid-lowering therapy added to maximally tolerated statins, including statin-intolerant patients. The primary objective was to assess relative efficacy of nonstatin lipid-lowering therapy in reducing LDL-C levels at week 12. Secondary objectives included the following: LDL-C level reduction at week 24 and change in non-high-density lipoprotein cholesterol and apolipoprotein B at week 12. There were 48 randomized controlled trials included in the primary network meta-analysis. All nonstatin agents significantly reduced LDL-C from baseline versus placebo, regardless of background therapy. At week 12, evolocumab, 140 mg every 2 weeks (Q2W)/420 mg once a month, and alirocumab, 150 mg Q2W, were the most efficacious regimens, followed by alirocumab, 75 mg Q2W, alirocumab, 300 mg once a month, inclisiran, bempedoic acid/ezetimibe fixed-dose combination, and ezetimibe and bempedoic acid used as monotherapies. Primary end point results were generally consistent at week 24, and for other lipid end points at week 12. Conclusions Evolocumab, 140 mg Q2W/420 mg once a month, and alirocumab, 150 mg Q2W, were consistently the most efficacious nonstatin regimens when added to maximally tolerated statins to lower LDL-C, non-high-density lipoprotein cholesterol, and apolipoprotein B levels and facilitate attainment of guideline-recommended risk-stratified lipoprotein levels.

Impact of nutraceuticals on markers of systemic inflammation: Potential relevance to cardiovascular diseases - A position paper from the International Lipid Expert Panel (ILEP).

Inflammation is a marker of arterial disease stemming from cholesterol-dependent to -independent molecular mechanisms. In recent years, the role of inflammation in atherogenesis has been underpinned by pharmacological approaches targeting systemic inflammation that have led to a significant reduction in cardiovascular disease (CVD) risk. Although the use of nutraceuticals to prevent CVD has largely focused on lipid-lowering (e.g, red-yeast rice and omega-3 fatty acids), there is growing interest and need, especially now in the time of coronavirus pandemic, in the use of nutraceuticals to reduce inflammatory markers, and potentially the inflammatory CVD burden, however, there is still not enough evidence to confirm this. Indeed, diet is an important lifestyle determinant of health and can influence both systemic and vascular inflammation, to varying extents, according to the individual nutraceutical constituents. Thus, the aim of this Position Paper is to provide the first attempt at recommendations on the use of nutraceuticals with effective anti-inflammatory properties.

Do nuclear magnetic resonance (NMR)-based metabolomics improve the prediction of pregnancy-related disorders? Findings from a UK birth cohort with independent validation.

BACKGROUND: Prediction of pregnancy-related disorders is usually done based on established and easily measured risk factors. Recent advances in metabolomics may provide earlier and more accurate prediction of women at risk of pregnancy-related disorders. METHODS: We used data collected from women in the Born in Bradford (BiB; n = 8212) and UK Pregnancies Better Eating and Activity Trial (UPBEAT; n = 859) studies to create and validate prediction models for pregnancy-related disorders. These were gestational diabetes mellitus (GDM), hypertensive disorders of pregnancy (HDP), small for gestational age (SGA), large for gestational age (LGA) and preterm birth (PTB). We used ten-fold cross-validation and penalised regression to create prediction models. We compared the predictive performance of (1) risk factors (maternal age, pregnancy smoking, body mass index (BMI), ethnicity and parity) to (2) nuclear magnetic resonance-derived metabolites (N = 156 quantified metabolites, collected at 24-28 weeks gestation) and (3) combined risk factors and metabolites. The multi-ethnic BiB cohort was used for training and testing the models, with independent validation conducted in UPBEAT, a multi-ethnic study of obese pregnant women. RESULTS: Maternal age, pregnancy smoking, BMI, ethnicity and parity were retained in the combined risk factor and metabolite models for all outcomes apart from PTB, which did not include maternal age. In addition, 147, 33, 96, 51 and 14 of the 156 metabolite traits were retained in the combined risk factor and metabolite model for GDM, HDP, SGA, LGA and PTB, respectively. These include cholesterol and triglycerides in very low-density lipoproteins (VLDL) in the models predicting GDM, HDP, SGA and LGA, and monounsaturated fatty acids (MUFA), ratios of MUFA to omega 3 fatty acids and total fatty acids, and a ratio of apolipoprotein B to apolipoprotein A-1 (APOA:APOB1) were retained predictors for GDM and LGA. In BiB, discrimination for GDM, HDP, LGA and SGA was improved in the combined risk factors and metabolites models. Risk factor area under the curve (AUC 95% confidence interval (CI)): GDM (0.69 (0.64, 0.73)), HDP (0.74 (0.70, 0.78)) and LGA (0.71 (0.66, 0.75)), and SGA (0.59 (0.56, 0.63)). Combined risk factor and metabolite models AUC 95% (CI): GDM (0.78 (0.74, 0.81)), HDP (0.76 (0.73, 0.79)) and LGA (0.75 (0.70, 0.79)), and SGA (0.66 (0.63, 0.70)). For GDM, HDP and LGA, but not SGA, calibration was good for a combined risk factor and metabolite model. Prediction of PTB was poor for all models. Independent validation in UPBEAT at 24-28 weeks and 15-18 weeks gestation confirmed similar patterns of results, but AUCs were attenuated. CONCLUSIONS: Our results suggest a combined risk factor and metabolite model improves prediction of GDM, HDP and LGA, and SGA, when compared to risk factors alone. They also highlight the difficulty of predicting PTB, with all models performing poorly.

Metabolic Age Based on the BBMRI-NL 1H-NMR Metabolomics Repository as Biomarker of Age-related Disease.

BACKGROUND: The blood metabolome incorporates cues from the environment and the host's genetic background, potentially offering a holistic view of an individual's health status. METHODS: We have compiled a vast resource of proton nuclear magnetic resonance metabolomics and phenotypic data encompassing over 25 000 samples derived from 26 community and hospital-based cohorts. RESULTS: Using this resource, we constructed a metabolomics-based age predictor (metaboAge) to calculate an individual's biological age. Exploration in independent cohorts demonstrates that being judged older by one's metabolome, as compared with one's chronological age, confers an increased risk on future cardiovascular disease, mortality, and functionality in older individuals. A web-based tool for calculating metaboAge (metaboage.researchlumc.nl) allows easy incorporation in other epidemiological studies. Access to data can be requested at bbmri.nl/samples-images-data. CONCLUSIONS: In summary, we present a vast resource of metabolomics data and illustrate its merit by constructing a metabolomics-based score for biological age that captures aspects of current and future cardiometabolic health.

Risk factors for COVID-19-related mortality in people with type 1 and type 2 diabetes in England: a population-based cohort study.

BACKGROUND: Diabetes has been associated with increased COVID-19-related mortality, but the association between modifiable risk factors, including hyperglycaemia and obesity, and COVID-19-related mortality among people with diabetes is unclear. We assessed associations between risk factors and COVID-19-related mortality in people with type 1 and type 2 diabetes. METHODS: We did a population-based cohort study of people with diagnosed diabetes who were registered with a general practice in England. National population data on people with type 1 and type 2 diabetes collated by the National Diabetes Audit were linked to mortality records collated by the Office for National Statistics from Jan 2, 2017, to May 11, 2020. We identified the weekly number of deaths in people with type 1 and type 2 diabetes during the first 19 weeks of 2020 and calculated the percentage change from the mean number of deaths for the corresponding weeks in 2017, 2018, and 2019. The associations between risk factors (including sex, age, ethnicity, socioeconomic deprivation, HbA1c, renal impairment [from estimated glomerular filtration rate (eGFR)], BMI, tobacco smoking status, and cardiovascular comorbidities) and COVID-19-related mortality (defined as International Classification of Diseases, version 10, code U07.1 or U07.2 as a primary or secondary cause of death) between Feb 16 and May 11, 2020, were investigated by use of Cox proportional hazards models. FINDINGS: Weekly death registrations in the first 19 weeks of 2020 exceeded the corresponding 3-year weekly averages for 2017-19 by 672 (50·9%) in people with type 1 diabetes and 16 071 (64·3%) in people with type 2 diabetes. Between Feb 16 and May 11, 2020, among 264 390 people with type 1 diabetes and 2 874 020 people with type 2 diabetes, 1604 people with type 1 diabetes and 36 291 people with type 2 diabetes died from all causes. Of these total deaths, 464 in people with type 1 diabetes and 10 525 in people with type 2 diabetes were defined as COVID-19 related, of which 289 (62·3%) and 5833 (55·4%), respectively, occurred in people with a history of cardiovascular disease or with renal impairment (eGFR <60 mL/min per 1·73 m2). Male sex, older age, renal impairment, non-white ethnicity, socioeconomic deprivation, and previous stroke and heart failure were associated with increased COVID-19-related mortality in both type 1 and type 2 diabetes. Compared with people with an HbA1c of 48-53 mmol/mol (6·5-7·0%), people with an HbA1c of 86 mmol/mol (10·0%) or higher had increased COVID-19-related mortality (hazard ratio [HR] 2·23 [95% CI 1·50-3·30, p<0·0001] in type 1 diabetes and 1·61 [1·47-1·77, p<0·0001] in type 2 diabetes). In addition, in people with type 2 diabetes, COVID-19-related mortality was significantly higher in those with an HbA1c of 59 mmol/mol (7·6%) or higher than in those with an HbA1c of 48-53 mmol/mol (HR 1·22 [95% CI 1·15-1·30, p<0·0001] for 59-74 mmol/mol [7·6-8·9%] and 1·36 [1·24-1·50, p<0·0001] for 75-85 mmol/mol [9·0-9·9%]). The association between BMI and COVID-19-related mortality was U-shaped: in type 1 diabetes, compared with a BMI of 25·0-29·9 kg/m2, a BMI of less than 20·0 kg/m2 had an HR of 2·45 (95% CI 1·60-3·75, p<0·0001) and a BMI of 40·0 kg/m2 or higher had an HR of 2·33 (1·53-3·56, p<0·0001); the corresponding HRs for type 2 diabetes were 2·33 (2·11-2·56, p<0·0001) and 1·60 (1·47-1·75, p<0·0001). INTERPRETATION: Deaths in people with type 1 and type 2 diabetes rose sharply during the initial COVID-19 pandemic in England. Increased COVID-19-related mortality was associated not only with cardiovascular and renal complications of diabetes but, independently, also with glycaemic control and BMI. FUNDING: None.

Prescribing Paradigm Shift? Applying the 2019 European Society of Cardiology-Led Guidelines on Diabetes, Prediabetes, and Cardiovascular Disease to Assess Eligibility for Sodium-Glucose Cotransporter 2 Inhibitors or Glucagon-Like Peptide 1 Receptor Agonists as First-Line Monotherapy (or Add-on to Metformin Monotherapy) in Type 2 Diabetes in Scotland.

OBJECTIVE: In 2019, the European Society of Cardiology led and released new guidelines for diabetes cardiovascular risk management, reflecting recent evidence of cardiovascular disease (CVD) reduction with sodium-glucose cotransporter 2 inhibitors (SGLT-2is) and some glucagon-like peptide 1 receptor agonists (GLP-1RAs) in type 2 diabetes (T2D). A key recommendation is that all those with T2D who are (antihyperglycemic) drug naïve or on metformin monotherapy should be CVD risk stratified and an SGLT-2i or a GLP-1RA initiated in all those at high or very high risk, irrespective of glycated hemoglobin. We assessed the impact of these guidelines in Scotland were they introduced as is. RESEARCH DESIGN AND METHODS: Using a nationwide diabetes register in Scotland, we did a cross-sectional analysis, using variables in our register for risk stratification at 1 January 2019. We were conservative in our definitions, assuming the absence of a risk factor where data were not available. The risk classifications were applied to people who were drug naïve or on metformin monotherapy and the anticipated prescribing change calculated. RESULTS: Of the 265,774 people with T2D in Scotland, 53,194 (20.0% of those with T2D) were drug naïve, and 56,906 (21.4%) were on metformin monotherapy. Of these, 74.5% and 72.4%, respectively, were estimated as at least high risk given the guideline risk definitions. CONCLUSIONS: Thus, 80,830 (30.4%) of all those with T2D (n = 265,774) would start one of these drug classes according to table 7 and figure 3 of the guideline. The sizeable impact on drug budgets, enhanced clinical monitoring, and the trade-off with reduced CVD-related health care costs will need careful consideration.

Plasma fatty acids and the risk of vascular disease and mortality outcomes in individuals with type 2 diabetes: results from the ADVANCE study.

AIMS/HYPOTHESIS: This biomarker study aimed to quantify the association of essential and other plasma fatty acid biomarkers with macrovascular disease, microvascular disease and death in individuals with type 2 diabetes. METHODS: A case-cohort study (N = 3576), including 654 macrovascular events, 341 microvascular events and 631 deaths during 5 years of (median) follow-up, was undertaken as a secondary analysis of the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified-Release Controlled Evaluation (ADVANCE) study (full details of the study design and primary endpoints of the ADVANCE trial and its case-cohort have been published previously). This current study considers new data: fatty acids measured from baseline plasma samples by proton NMR analysis. The fatty acids measured were n-3, docosahexaenoic acid (DHA), n-6, linoleic acid, and polyunsaturated, monounsaturated and saturated fatty acids. HRs were modelled per SD higher (percentage) fatty acid. C statistics and continuous net reclassification improvement were used to test the added value of fatty acids compared with traditional cardiovascular risk factors. RESULTS: After adjustment for traditional cardiovascular risk factors, an inverse association was observed for n-3 fatty acids and DHA with the risk of macrovascular events (HR [95% CI]: 0.87 [0.80, 0.95] and 0.88 [0.81, 0.96], respectively, per 1 SD higher percentage), and for n-3 fatty acids with the risk of death (HR 0.91 [95% CI 0.84, 0.99] per 1 SD higher percentage). Such associations were also evident when investigating absolute levels of fatty acids. There were no statistically significant associations between any fatty acids and microvascular disease after adjustment. However, there was limited improvement in the predictive ability of models when any fatty acid was added. CONCLUSIONS/INTERPRETATION: Plasma n-3 fatty acids and DHA were found to be inversely associated with macrovascular disease, while n-3 fatty acids were also inversely associated with death. These results support the cardioprotective effects of n-3 fatty acids and DHA and further merit testing the role of high-dose supplementation with n-3 fatty acids in individuals with type 2 diabetes. TRIAL REGISTRATION: ClinicalTrials.gov NCT00145925. Graphical abstract.

Association of types of dietary fats and all-cause and cause-specific mortality: A prospective cohort study and meta-analysis of prospective studies with 1,164,029 participants.

BACKGROUND: Associations between dietary fats and mortality are unclear. METHODS: We evaluated the relationship between quartiles of total fat, mono-unsaturated (MUFA), polyunsaturated (PUFA) and saturated fatty acid (SFA) consumption, and all-cause, coronary heart disease (CHD), stroke, and type 2 diabetes (T2D)-associated mortality in 24,144 participants from the National Health and Nutrition Examination Surveys (NHANES) 1999-2010. We added our results to a meta-analysis based on searches until November 2018. RESULTS: In fully adjusted Cox-proportional hazard models in our prospective study, there was an inverse association between total fat (HR: 0.90, 95% confidence interval 0.82, 0.99, Q4 vs Q1) and PUFA (0.81, 0.78-0.84) consumption and all-cause mortality, whereas SFA were associated with the increased mortality (1.08, 1.04-1.11). In the meta-analysis of 29 prospective cohorts (n = 1,164,029) we found a significant inverse association between total fat (0.89, 0.82-0.97), MUFA (0.94, 0.89-0.99) and PUFA (0.89, 0.84-0.94) consumption and all-cause mortality. No association was observed between total fat and CVD (0.93, 0.80-1.08) or CHD mortality (1.03 0.99-1.09). A significant association between SFA intake and CHD mortality (1.10, 1.01-1.21) was observed. Neither MUFA nor PUFA were associated with CVD or CHD mortality. Inverse associations were observed between MUFA (0.80, 0.67-0.96) and PUFA (0.84, 0.80-0.90) intakes and stroke mortality. CONCLUSIONS: We showed differential associations of total fat, MUFA and PUFA with all-cause mortality, but not CVD or CHD mortalities. SFA was associated with higher all-cause mortality in NHANES and with CHD mortality in our meta-analysis. The type of fat intake appears to be associated with important health outcomes.

Improving prevention strategies for cardiometabolic disease.

There is a growing burden of cardiometabolic disease in many parts of the world. Despite some progress in its prevention, more can be done to tackle risks of its development in the community and in different specialty clinics. Currently, the identification and management of those at elevated risk of developing cardiovascular disease or diabetes or with conditions such as fatty liver disease remains fragmented and is not linked to constructive lifestyle advice. In this Perspective, we argue for a more consistent weight-management approach, alongside a holistic assessment of the risk for developing cardiometabolic diseases, offering patients a range of simple or more-intensive evidence-based lifestyle options in an empathetic manner, with encouragement for repeated attempts and a willingness to embrace failure.

Yoga and Cardiovascular Health Trial (YACHT): a UK-based randomised mechanistic study of a yoga intervention plus usual care versus usual care alone following an acute coronary event.

OBJECTIVE: To determine the effects of yoga practice on subclinical cardiovascular measures, risk factors and neuro-endocrine pathways in patients undergoing cardiac rehabilitation (CR) following acute coronary events. DESIGN: 3-month, two-arm (yoga +usual care vs usual care alone) parallel randomised mechanistic study. SETTING: One general hospital and two primary care CR centres in London. Assessments were conducted at Imperial College London. PARTICIPANTS: 80 participants, aged 35-80 years (68% men, 60% South Asian) referred to CR programmes 2012-2014. INTERVENTION: A certified yoga teacher conducted yoga classes which included exercises in stretching, breathing, healing imagery and deep relaxation. It was pre-specified that at least 18 yoga classes were attended for inclusion in analysis. Participants and partners in both groups were invited to attend weekly a 6- to 12-week local standard UK National Health Service CR programme. MAIN OUTCOME MEASURES: (i) Estimated left ventricular filling pressure (E/e'), (ii) distance walked, fatigue and breathlessness in a 6 min walk test, (iii) blood pressure, heart rate and estimated peak VO2 following a 3 min step-test. Effects on the hypothalamus-pituitary-adrenal axis, autonomic function, body fat, blood lipids and glucose, stress and general health were also explored. RESULTS: 25 participants in the yoga + usual care group and 35 participants in the usual care group completed the study. Following the 3-month intervention period, E/e' was not improved by yoga (E/e': between-group difference: yoga minus usual care:-0.40 (-1.38, 0.58). Exercise testing and secondary outcomes also showed no benefits of yoga. CONCLUSIONS: In this small UK-based randomised mechanistic study, with 60 completing participants (of whom 25 were in the yoga + usual care group), we found no discernible improvement associated with the addition of a structured 3-month yoga intervention to usual CR care in key cardiovascular and neuroendocrine measures shown to be responsive to yoga in previous mechanistic studies. TRIAL REGISTRATION NUMBER: NCT01597960; Pre-results.

Effect of non-surgical weight management on weight and glycaemic control in people with type 2 diabetes: A comparison of interventional and non-interventional outcomes at 3 years.

AIMS: To examine the long-term effectiveness of lifestyle weight management interventions, recommended in clinical guidelines for patients with type 2 diabetes mellitus (T2DM) and obesity. MATERIALS AND METHODS: Electronic health records were used to follow 23 208 patients with T2DM and obesity in Glasgow, UK, for up to 3 years between 2005 and 2014. Patients were stratified by referral to and attendance at a lifestyle weight management intervention, and by attainment of a target weight loss of ≥5 kg over 7 to 9 sessions ("successful completers"). Outcomes were change in weight, glycated haemoglobin (HbA1c) and diabetes medications. RESULTS: A total of 3471 potentially eligible patients were referred to the service, and fewer than half of these attended (n = 1537). Of those who attended 7 to 9 sessions, >40% successfully completed and achieved 5-kg weight loss (334/808). Successful completers maintained greater weight loss (change at 3 years -8.03 kg; 95% confidence interval [CI] -9.44 to -6.62) than the non-completers (-3.26 kg; 95% CI -4.01 to -2.51; P < .001) and those not referred to the service (-1.00 kg; 95% CI -1.15 to -0.85; P < .001). Successful completers were the only patient group who did not increase their use of diabetes medication and insulin over 3 years. In adjusted models, successful completers had a clinically significant reduction in HbA1c (-3.7 mmol/mol; 95% CI -5.82 to -1.51) after 3 years; P ≤ .001) compared with non-completers and unsuccessful completers. CONCLUSIONS: A real-life structured weight management intervention in patients with diabetes can reduce weight in the medium term, result in improved glycaemic control with fewer medications, and may be more effective than pharmacological alternatives. Challenges include getting a higher proportion of patients referred to and engaged with interventions.

Effects of a beverage rich in (poly)phenols on established and novel risk markers for vascular disease in medically uncomplicated overweight or obese subjects: A four week randomized placebo-controlled trial.

OBJECTIVE: To determine if (poly)phenols alter cardiovascular risk factors, we assessed the potential of a high (poly)phenol beverage drink, rich in hydroxycinnamates and flavonoids, to modify vascular function in middle aged, overweight or obese subjects without medical co-morbidity in a randomized placebo controlled pilot study. METHODS: Randomly assigned active 250 ml beverages containing 361 mg of (poly)phenols and 120 mg of vitamin C or placebo (no polyphenol/vitamin C) were taken twice daily for 4 weeks. Both beverages contained 40 kcals/250 ml. The primary end-points were pulse wave velocity (PWV) and cutaneous microvascular responses to sodium nitroprusside (SNP) and acetyl choline (ACh) laser doppler iontophoresis. A range of established and novel plasma markers were also measured. RESULTS: Twenty subjects received active beverage and 19 placebo; all completed the study. There was no difference in cutaneous vascular response to either SNP or ACh with mean group differences (logΔ area under perfusion curve) of 0.30 (-0.65, 1.26) and 0.35 (-0.11, 0.81) respectively. Nor was there evidence of a change in log PWV with a mean group difference of 0.029 m/s (-0.042, 0.10). No significant differences were seen in plasma leptin, apolipoproteins, cystatin C, insulin, adiponectin, CRP, ICAM-1, E-Selectin or t-PA, but IL-6 increased in active versus placebo recipients (0.32 vs - 0.18 pg/ml; p=0.010). CONCLUSION: There was no evidence for a short-term beneficial effect of (poly)phenol intervention on microcutaneous vascular response or pulse wave velocity, and no evidence for a benefit on established or novel risk factors in overweight or obese subjects. Our results do not support a short-term benefit of (poly)phenol supplementation on cardiometabolic risk. REGISTRATION: Clinical Trials.gov (NCT00795834).

N-terminal pro-brain-type natriuretic peptide (NT-pro-BNP) and mortality risk in early inflammatory polyarthritis: results from the Norfolk Arthritis Registry (NOAR).

BACKGROUND: We measured N-terminal pro-brain natriuretic peptide (NT-pro-BNP), a marker of cardiac dysfunction, in an inception cohort with early inflammatory polyarthritis (IP) and assessed its association with disease phenotype, cardiovascular disease (CVD), all-cause and CVD related mortality. METHODS: Subjects with early IP were recruited to the Norfolk Arthritis Register from January 2000 to December 2008 and followed up to death or until March 2010 including any data from the national death register. The associations of baseline NT-pro-BNP with IP related factors and CVD were assessed by linear regression. Cox proportional hazards models examined the independent association of baseline NT-pro-BNP with all-cause and CVD mortality. RESULTS: We studied 960 early IP subjects; 163 (17%) had prior CVD. 373 (39%) patients had a baseline NT-pro-BNP levels ≥ 100 pg/ml. NT-pro-BNP was associated with age, female gender, HAQ score, CRP, current smoking, history of hypertension, prior CVD and the presence of carotid plaque. 92 (10%) IP subjects died including 31 (3%) from CVD. In an age and gender adjusted analysis, having a raised NT-pro-BNP level (≥ 100 pg/ml) was associated with both all-cause and CVD mortality (adjusted HR (95% CI) 2.36 (1.42 to 3.94) and 3.40 (1.28 to 9.03), respectively). These findings were robust to adjustment for conventional CVD risk factors and prevalent CVD. CONCLUSIONS: In early IP patients, elevated NT-pro-BNP is related to HAQ and CRP and predicts all-cause and CVD mortality independently of conventional CVD risk factors. Further study is required to identify whether NT-pro-BNP may be clinically useful in targeting intensive interventions to IP patients at greatest risk of CVD.

Circulating 25OHD, dietary vitamin D, PTH, and calcium associations with incident cardiovascular disease and mortality: the MIDSPAN Family Study.

CONTEXT: Observational studies relating circulating 25-hydroxyvitamin D (25OHD) and dietary vitamin D intake to cardiovascular disease (CVD) have reported conflicting results. OBJECTIVE: Our objective was to investigate the association of 25OHD, dietary vitamin D, PTH, and adjusted calcium with CVD and mortality in a Scottish cohort. DESIGN AND SETTING: The MIDSPAN Family Study is a prospective study of 1040 men and 1298 women from the West of Scotland recruited in 1996 and followed up for a median 14.4 yr. PARTICIPANTS: Locally resident adult offspring of a general population cohort were recruited from 1972-1976. MAIN OUTCOME MEASURES: CVD events (n = 416) and all-cause mortality (n = 100) were evaluated. RESULTS: 25OHD was measured using liquid chromatography-tandem mass spectrometry in available plasma (n = 2081). Median plasma 25OHD was 18.6 ng/ml, and median vitamin D intake was 3.2 µg/d (128 IU/d). Vitamin D deficiency (25OHD <15 ng/ml) was present in 689 participants (33.1%). There was no evidence that dietary vitamin D intake, PTH, or adjusted calcium were associated with CVD events or with mortality. Vitamin D deficiency was not associated with CVD (fully adjusted hazard ratio = 1.00; 95% confidence interval = 0.77-1.31). Results were similar after excluding patients who reported an activity-limiting longstanding illness at baseline (18.8%) and those taking any vitamin supplements (21.7%). However, there was some evidence vitamin D deficiency was associated with all-cause mortality (fully adjusted hazard ratio = 2.02; 95% confidence interval = 1.17-3.51). CONCLUSION: Vitamin D deficiency was not associated with risk of CVD in this cohort with very low 25OHD. Future trials of vitamin D supplementation in middle-aged cohorts should be powered to detect differences in mortality outcomes as well as CVD.

Which circulating antioxidant vitamins are confounded by socioeconomic deprivation? The MIDSPAN family study.

BACKGROUND: Antioxidant vitamins are often described as having "independent" associations with risk of cancer, cardiovascular disease (CVD) and mortality. We aimed to compare to what extent a range of antioxidant vitamins and carotenoids are associated with adulthood and childhood markers of socioeconomic deprivation and to adverse lifestyle factors. METHODS AND FINDINGS: Socioeconomic and lifestyle measures were available in 1040 men and 1298 women from the MIDSPAN Family Study (30-59 years at baseline) together with circulating levels of vitamins A, C, E, and carotenoids (alpha-carotene, beta-carotene, lutein and lycopene). Markers of socioeconomic deprivation in adulthood were consistently as strongly associated with lower vitamin C and carotenoid levels as markers of adverse lifestyle; the inverse association with overcrowding was particularly consistent (vitamin C and carotenoids range from 19.1% [95% CI 30.3-6.0] to 38.8% [49.9-25.3] lower among those in overcrowded residencies). These associations were consistent after adjusting for month, classical CVD risk factors, body mass index, physical activity, vitamin supplements, dietary fat and fibre intake. Similar, but weaker, associations were seen for childhood markers of deprivation. The association of vitamin A or E were strikingly different; several adult adverse lifestyle factors associated with higher levels of vitamin A and E, including high alcohol intake for vitamin A (9.5% [5.7-13.5]) and waist hip ratio for vitamin E (9.5% [4.8-14.4]), with the latter associations partially explained by classical risk factors, particularly cholesterol levels. CONCLUSIONS: Plasma vitamin C and carotenoids have strong inverse associations with adulthood markers of social deprivation, whereas vitamin A and E appear positively related to specific adverse lifestyle factors. These findings should help researchers better contextualize blood antioxidant vitamin levels by illustrating the potential limitations associated with making causal inferences without consideration of social deprivation.

More knocks to the oxidation hypothesis for vascular disease?

The oxidation hypothesis for CHD (coronary heart disease) is attractive; however, the almost universal failure of antioxidant vitamin supplementation as a CVD (cardiovascular disease) risk modifier challenges the oxidation hypothesis, at least as a concept that easily 'translates' into clinical benefit for the population. At the same time, quality prospective data on lipid or protein oxidation markers as predictors of vascular events are sparse. In the present issue of Clinical Science, Woodward and co-workers provide much needed prospective data examining the relationship between markers of oxidative damage and CHD outcome in a general population. Despite noting the expected associations between several established CHD risk factors and CHD events, no significant link was observed between measured oxidation markers and CHD risk, a finding which further challenges the oxidation hypothesis for CHD.