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This study evaluated the association between systemic arterial blood pressure and cerebral perfusion in 740 participants of the UK's largest tri-ethnic study with measurements of cerebral blood flow (CBF) performed using arterial spin labelling MRI. A significant negative correlation between blood pressure, age and CBF was observed across the patient cohort. The lowest CBF values were recorded in the group of patients with hypertension that were prescribed with anti-hypertensive drugs, but uncontrolled on medication. These findings confirm that hypertension is associated with reduced cerebral perfusion and highlight the importance of blood pressure control for the benefit of maintaining brain blood flow.

Ethnic differences in non-communicable disease risk have been described between individuals of South Asian and European ethnicity that are only partially explained by genetics and other known risk factors. DNA methylation is one underexplored mechanism that may explain differences in disease risk. Currently, there is little knowledge of how DNA methylation varies between South Asian and European ethnicities. This study characterised differences in blood DNA methylation between individuals of self-reported European and South Asian ethnicity from two UK-based cohorts: Southall and Brent Revisited and Born in Bradford. DNA methylation differences between ethnicities were widespread throughout the genome (n = 16,433 CpG sites, 3.4% sites tested). Specifically, 76% of associations were attributable to ethnic differences in cell composition with fewer effects attributable to smoking and genetic variation. Ethnicity-associated CpG sites were enriched for EWAS Catalog phenotypes including metabolites. This work highlights the need to consider ethnic diversity in epigenetic research., (© 2022. The Author(s).)

We propose a novel approach to the estimation of multiple Graphical Models to analyse temporal patterns of association among a set of metabolites over different groups of patients. Our motivating application is the Southall And Brent REvisited (SABRE) study, a tri-ethnic cohort study conducted in the UK. We are interested in identifying potential ethnic differences in metabolite levels and associations as well as their evolution over time, with the aim of gaining a better understanding of different risk of cardio-metabolic disorders across ethnicities. Within a Bayesian framework, we employ a nodewise regression approach to infer the structure of the graphs, borrowing information across time as well as across ethnicities. The response variables of interest are metabolite levels measured at two time points and for two ethnic groups, Europeans and South-Asians. We use nodewise regression to estimate the high-dimensional precision matrices of the metabolites, imposing sparsity on the regression coefficients through the dynamic horseshoe prior, thus favouring sparser graphs. We provide the code to fit the proposed model using the software Stan, which performs posterior inference using Hamiltonian Monte Carlo sampling, as well as a detailed description of a block Gibbs sampling scheme., Competing Interests: No potential conflict of interest was reported by the author(s)., (© 2022 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

Background: An exaggerated blood pressure (BP) response to exercise and low exercise capacity are risk factors for cardiovascular disease (CVD). The effect of pharmacological antihypertensive treatment on exercise BP in older adults is largely unknown. This study investigates these effects accounting for differences in exercise capacity., Methods: Participants enrolled in the Southall and Brent Revisited (SABRE) study undertook a 6-min stepper test with expired gas analysis and BP measured throughout exercise. Participants were stratified by antihypertensive treatment status and resting BP control. Exercise systolic and diastolic BP (exSBP and exDBP) were compared between groups using potential outcome means [95% confidence intervals (CIs)] adjusted for exercise capacity. Exercise capacity was also compared by group., Results: In total, 659 participants were included (mean age ± SD: 73 ± 6.6 years, 57% male). 31% of normotensive and 23% of hypertensive older adults with controlled resting BP had an exaggerated exercise BP. ExSBP was similar between normotensive and treated/controlled individuals [mean (95%CI): 180 (176 184) mmHg vs. 177 (173 181) mmHg, respectively] but was higher in treated/uncontrolled and untreated/uncontrolled individuals [mean (95% CI): 194 (190 197) mmHg, P  < 0.001 and 199 (194 204) mmHg, P  < 0.001, respectively]; these differences persisted after adjustment for exercise capacity and other confounders. Exercise capacity was lower in treated vs. normotensive individuals [mean (95% CI) normotensive: 16.7 (16.0,17.4) ml/kg/min]; treated/controlled: 15.5 (14.8,16.1) ml/kg/min, P  = 0.009; treated/uncontrolled: [15.1 (14.5,15.7) ml/kg per min, P  = 0.001] but was not reduced in untreated/uncontrolled individuals [mean (95% CI): 17.0 (16.1,17.8) ml/kg per min, P  = 0.621]., Conclusion: Irrespective of resting BP control and despite performing less exercise, antihypertensive treatment does not fully mitigate an exaggerated BP response to exercise suggesting residual CVD risk in older adults., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background and Aims: Risk of stroke and dementia is markedly higher in people of South Asian and African Caribbean descent than white Europeans in the UK. This is unexplained by cardiovascular risk factors (CVRF). We hypothesized this might indicate accelerated early vascular aging (EVA) and that EVA might account for stronger associations between cerebral large artery characteristics and markers of small vessel disease., Methods: 360 participants in a tri-ethnic population-based study (120 per ethnic group) underwent cerebral and vertebral MRI. Length and median diameter of the basilar artery (BA) were derived from Time of Flight images, while white matter hyperintensities (WMH) volumes were obtained from T1 and FLAIR images. Associations between BA characteristics and CVRF were assessed using multivariable linear regression. Partial correlation coefficients between WMH load and BA characteristics were calculated after adjustment for CVRF and other potential confounders., Results: BA diameter was strongly associated with age in South Asians (+11.3 μm/year 95% CI = [3.05; 19.62]; p = 0.008), with unconvincing relationships in African Caribbeans (3.4 μm/year [-5.26, 12.12]; p = 0.436) or Europeans (2.6 μm/year [-5.75, 10.87]; p = 0.543). BA length was associated with age in South Asians (+0.34 mm/year [0.02; 0.65]; p = 0.037) and African Caribbeans (+0.39 mm/year [0.12; 0.65]; p = 0.005) but not Europeans (+0.08 mm/year [-0.26; 0.41]; p = 0.653). BA diameter (rho = 0.210; p = 0.022) and length (rho = 0.261; p = 0.004) were associated with frontal WMH load in South Asians (persisting after multivariable adjustment for CVRF)., Conclusions: Compared with Europeans, the basilar artery undergoes more accelerated EVA in South Asians and in African Caribbeans, albeit to a lesser extent. Such EVA may contribute to the higher burden of CSVD observed in South Asians and excess risk of stroke, vascular cognitive impairment and dementia observed in these ethnic groups., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer JC declared a shared affiliation with some of the authors, CS, SM, SO, and MC, to the handling editor at time of review., (Copyright © 2022 Sudre, Moriconi, Rehwald, Smith, Tillin, Barnes, Atkinson, Ourselin, Chaturvedi, Hughes, Jäger and Cardoso.)

Measuring local haemodynamics in skeletal muscle has the potential to provide valuable insight into the oxygen delivery to tissue, especially during high demand situations such as exercise. The aim of this study was to compare the skeletal muscle microvascular response during post-occlusive reactive hyperaemia (PORH) with the response to exercise, each measured using near-infrared spectroscopy (NIRS) and to establish if associations exist between muscle measures and exercise capacity or sex. Participants were from a population-based cohort study, the Southall and Brent Revisited (SABRE) study. Skeletal muscle measures included changes in tissue saturation index at the onset of exercise (∆TSI BL-INC ) and across the whole of exercise (∆TSI BL-EE ), time to 50%, 95% and 100% PORH, rate of PORH recovery, area under the curve (AUC) and total oxygenated Haemoglobin (oxy-Hb) change during PORH. Exercise capacity was measured using a 6-min stepper test (6MST). Analysis was by multiple linear regression. In total, 558 participants completed the 6MST with NIRS measures of TSI (mean age±SD: 73 ± 7years, 59% male). A sub-set of 149 participants also undertook the arterial occlusion. Time to 100% PORH, recovery rate, AUC and ∆oxy-Hb were all associated with ∆TSI BL-EE (β-coefficient (95%CI): 0.05 (0.01, 0.09), p = 0.012; -47 (-85, -9.9), p = 0.014; 1.7 (0.62, 2.8), p = 0.002; 0.04 (0.002.0.108), p = 0.041, respectively). Time to 95% & 100% PORH, AUC and ∆oxy-Hb were all associated with ∆TSI BL-INC (β-coefficient (95%CI): -0.07 (-0.12,-0.02), p = 0.02; -0.03 (-0.05, -0.003), p = 0.028; 0.85 (0.18, 1.5), p = 0.013 & 0.05 (0.02, 0.09), p = 0.001, respectively). AUC and ∆Oxy-Hb were associated with steps achieved (β-coefficient (95%CI): 18.0 (2.3, 33.7), p = 0.025; 0.86 (0.10, 1.6), p = 0.027). ∆TSI BL-EE was associated with steps and highest VO 2 (1.7 (0.49, 2.9), p = 0.006; 7.7 (3.2, 12.3), p = 0.001). ∆TSI BL-INC was associated with steps and VO 2 but this difference was attenuated towards the null after adjustment for age, sex and ethnicity. ∆TSI BL-EE was greater in women (3.4 (0.4, 8.9) versus 2.1 (0.3, 7.4), p = 0.017) and ∆TSI BL-INC was lower in women versus men (2.4 (0.2, 10.2) versus 3.2 (0.2, 18.2), p = 0.016). These Local microvascular NIRS-measures are associated with exercise capacity in older adults and several measures can detect differences in microvascular reactivity between a community-based sample of men and women., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Jones, Tillin, Williams, Rapala, Chaturvedi and Hughes.)

Background: Observational findings for high-density lipoprotein (HDL)-mediated cholesterol efflux capacity (HDL-CEC) and coronary heart disease (CHD) appear inconsistent, and knowledge of the genetic architecture of HDL-CEC is limited., Objectives: A large-scale observational study on the associations of HDL-CEC and other HDL-related measures with CHD and the largest genome-wide association study (GWAS) of HDL-CEC., Participants/methods: Six independent cohorts were included with follow-up data for 14,438 participants to investigate the associations of HDL-related measures with incident CHD (1,570 events). The GWAS of HDL-CEC was carried out in 20,372 participants., Results: HDL-CEC did not associate with CHD when adjusted for traditional risk factors and HDL cholesterol (HDL-C). In contradiction, almost all HDL-related concentration measures associated consistently with CHD after corresponding adjustments. There were no genetic loci associated with HDL-CEC independent of HDL-C and triglycerides., Conclusion: HDL-CEC is not unequivocally associated with CHD in contrast to HDL-C, apolipoprotein A-I, and most of the HDL subclass particle concentrations., (© 2022 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.)

Background Image-quality (IQ) compromises left ventricle assessment by 3-dimensional echocardiography (3DE). Sicker/frailer patients often have suboptimal IQ, and therefore observed associations may be biased by IQ. We investigated its effect in an observational study of older people and when IQ was modified experimentally in healthy volunteers. Methods and Results 3DE feasibility by IQ was assessed in 1294 individuals who attended the second wave of the Southall and Brent Revisited study and was compared with 2-dimensional (2D)-echocardiography feasibility in 147 individuals. Upon successful analysis, means of ejection fraction (3D-EF) and global longitudinal strain (3D-GLS) (plus 2D-EF) were compared in individuals with poor versus good IQ. In 2 studies of healthy participants, 3DE-IQ was impaired by (1) intentionally poor echocardiographic technique, and (2) use of a sheet of ultrasound-attenuating material (neoprene rubber; 2-4 mm). The feasibility was 41% (529/1294) for 3DE versus 61% (89/147) for 2D-EF, P <0.0001. Among acceptable images (n=529), good IQ by the 2015 American Society of Echocardiography/European Association of Cardiovascular Imaging criteria was 33.6% (178/529) and 71.3% (377/529) for 3D-EF and 3D-GLS, respectively. Individuals with poor IQ had lower 3D-EF and 3D-GLS (absolute) than those with good IQ (3D-EF: 52.8±6.0% versus 55.7±5.7%, Mean-Δ -2.9 [-3.9, 1.8]; 3D-GLS: 18.6±3.2% versus 19.2±2.9%, Mean-Δ -0.6 [-1.1, 0.0]). In 2 experimental models of poor IQ (n=36 for both), mean differences were (-2.6 to -3.2) for 3D-EF and (-1.2 to -2.0) for 3D-GLS. Similar findings were found for other 3DE left ventricle volumes and strain parameters. Conclusions 3DE parameters have low feasibility and values are systematically lower in individuals with poor IQ. Although 3D-EF and 3D-GLS have potential advantages over conventional echocardiography, further technical improvements are required to improve the utility of 3DE in clinical practice.

Ethnic differences in bone mineral density (BMD) and fracture risk are well-described; the aim of this study was to investigate whether central adiposity or inflammatory status contribute to these ethnic differences in BMD in later life. The Southall and Brent Revisited study (SABRE) is a UK-based tri-ethnic cohort of men and women of European, South Asian or African Caribbean origin. At the most recent SABRE follow-up (2014-2018), in addition to measures of cardiometabolic phenotype, participants had dual-energy X-ray absorptiometry (DXA) bone and body composition scans. Multiple linear regression was used to determine whether markers of body composition, central adiposity or inflammatory status contributed to ethnic differences in BMD. In men and women, age- and height-adjusted BMD at all sites was higher in African Caribbeans compared to Europeans (femoral neck: standardised β (95% confidence interval): men: 1.00SD (0.75, 1.25); women: 0.77SD (0.56, 0.99)). South Asian men had higher BMD than European men at the hip (femoral neck: 0.34SD (95%CI: 0.15, 0.54)). Although adjustment for body mass index (BMI) or lean mass index (LMI) at the lumbar spine reduced the size of the difference in BMD between African Caribbean and European men (age and height adjusted difference: 0.35SD (0.08, 0.62); age and BMI adjusted difference: 0.25SD (-0.02, 0.51)), in both men and women ethnic differences remained after adjustment for measures of central adiposity (estimated visceral adipose tissue mass (VAT mass) and android to gynoid ratio) and inflammation (interleukin-6 (logIL-6) and C-reactive protein (logCRP)). Furthermore, in women, we observed ethnic differences in the relationship between BMI (overall interaction: p = 0.04), LMI (p = 0.04) or VAT mass (p = 0.009) and standardised lumbar spine BMD. In this tri-ethnic cohort, ethnic differences in BMD at the femoral neck, total hip or lumbar spine were not explained by BMI, central adiposity or inflammatory status. Given ethnic differences in fracture incidence, it is important to further investigate why ethnic differences in BMD exist., (Copyright © 2021. Published by Elsevier Inc.)

Objectives: We characterised differences in BP control and use of antihypertensive medications in European (EA), South Asian (SA) and African-Caribbean (AC) people with hypertension and investigated the potential role of type 2 diabetes (T2DM), reduced arterial compliance (C a ), and antihypertensive medication use in any differences., Methods: Analysis was restricted to individuals with hypertension [age range 59-85 years; N = 852 (EA = 328, SA = 356, and AC =168)]. Questionnaires, anthropometry, BP measurements, echocardiography, and fasting blood assays were performed. BP control was classified according to UK guidelines operating at the time of the study. Data were analysed using generalised structural equation models, multivariable regression and treatment effect models., Results: SA and AC people were more likely to receive treatment for high BP and received a greater average number of antihypertensive agents, but despite this a smaller proportion of SA and AC achieved control of BP to target [age and sex adjusted odds ratio (95% confidence interval) = 0.52 (0.38, 0.72) and 0.64 (0.43, 0.96), respectively]. Differences in BP control were partially attenuated by controlling for the higher prevalence of T2DM and reduced C a in SA and AC. There was little difference in choice of antihypertensive agent by ethnicity and no evidence that differences in efficacy of antihypertensive regimens contributed to ethnic differences in BP control., Conclusions: T2DM and more adverse arterial stiffness are important factors in the poorer BP control in SA and AC people. More effort is required to achieve better control of BP, particularly in UK ethnic minorities., Competing Interests: NC receives funding from AstraZeneca to serve on data safety and monitoring committees for clinical trials. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Hughes, Eastwood, Tillin and Chaturvedi.)

Objective: The coexistence of wild-type transthyretin cardiac amyloidosis (ATTR) is common in patients with severe aortic stenosis (AS) undergoing transcatheter aortic valve implantation (TAVI). However, the impact of ATTR and AS on the resultant AS-ATTR is unclear and poses diagnostic and management challenges. We therefore used a multicohort approach to evaluate myocardial structure, function, stress and damage by assessing age-related, afterload-related and amyloid-related remodelling on the resultant AS-ATTR phenotype., Methods: We compared four samples (n=583): 359 patients with AS, 107 with ATTR (97% Perugini grade 2), 36 with AS-ATTR (92% Perugini grade 2) and 81 age-matched and ethnicity-matched controls. 99m Tc-3,3-diphosphono-1,2-propanodicarboxylic acid (DPD) scintigraphy was used to diagnose amyloidosis (Perugini grade 1 was excluded). The primary end-point was NT-pro Brain Natriuretic Peptide (BNP) and secondary end-points related to myocardial structure, function and damage., Results: Compared with older age controls, the three disease cohorts had greater cardiac remodelling, worse function and elevated NT-proBNP/high-sensitivity Troponin-T (hsTnT). NT-proBNP was higher in AS-ATTR (2844 (1745, 4635) ng/dL) compared with AS (1294 (1077, 1554)ng/dL; p=0.002) and not significantly different to ATTR (3272 (2552, 4197) ng/dL; p=0.63). Diastology, hsTnT and prevalence of carpal tunnel syndrome were statistically similar between AS-ATTR and ATTR and higher than AS. The left ventricular mass indexed in AS-ATTR was lower than ATTR (139 (112, 167) vs 180 (167, 194) g; p=0.013) and non-significantly different to AS (120 (109, 130) g; p=0.179)., Conclusions: The AS-ATTR phenotype likely reflects an early stage of amyloid infiltration, but the combined insult resembles ATTR. Even after treatment of AS, ATTR-specific therapy is therefore likely to be beneficial., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The risk of developing type 2 diabetes associated with poor sleep quality is comparable to other lifestyle factors (eg, overweight, physical inactivity). In the UK, these risk factors could not explain the two to three-fold excess risks in South-Asian and African-Caribbean men compared with Europeans. This study investigates (1) the association between mid-life sleep quality and later-life type 2 diabetes risk and (2) the potential modifying effect of ethnicity., Methods: The Southall and Brent REvisited cohort is composed of Europeans, South-Asians and African-Caribbeans (median follow-up 19 years). Complete-case analysis was performed on 2189 participants without diabetes at baseline (age=51.7±7 SD). Competing risks regressions were used to estimate the HRs of developing diabetes associated with self-reported baseline sleep (difficulty falling asleep, early morning waking, waking up tired, snoring and a composite sleep score), adjusting for confounders. Modifying effects of ethnicity were analysed by conducting interaction tests and ethnicity-stratified analyses., Results: There were 484 occurrences of incident type 2 diabetes (22%). Overall, there were no associations between sleep exposures and diabetes risk. Interaction tests suggested a possible modifying effect for South-Asians compared with Europeans for snoring only (p=0.056). The ethnicity-stratified analysis found an association with snoring among South-Asians (HR 1.41, 95% CI 1.08 to 1.85), comparing those who snored often/always versus occasionally/never. There were no elevated risks for the other sleep exposures., Conclusion: The association between snoring and type 2 diabetes appeared to be modified by ethnicity, and was strongest in South-Asians., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

Characterizing genetic influences on DNA methylation (DNAm) provides an opportunity to understand mechanisms underpinning gene regulation and disease. In the present study, we describe results of DNAm quantitative trait locus (mQTL) analyses on 32,851 participants, identifying genetic variants associated with DNAm at 420,509 DNAm sites in blood. We present a database of >270,000 independent mQTLs, of which 8.5% comprise long-range (trans) associations. Identified mQTL associations explain 15-17% of the additive genetic variance of DNAm. We show that the genetic architecture of DNAm levels is highly polygenic. Using shared genetic control between distal DNAm sites, we constructed networks, identifying 405 discrete genomic communities enriched for genomic annotations and complex traits. Shared genetic variants are associated with both DNAm levels and complex diseases, but only in a minority of cases do these associations reflect causal relationships from DNAm to trait or vice versa, indicating a more complex genotype-phenotype map than previously anticipated., (© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)

We examined the association between plasma metabolites and abnormal sleep patterns using data from the Southall and Brent REvisited (SABRE) cohort. Nuclear magnetic resonance spectroscopy provided 146 circulating plasma metabolites. Sleep questionnaires identified the presence or absence of: difficulty falling asleep, early morning waking, waking up tired, and snoring. Metabolites were compared between the sleep quality categories using the t test, and then filtered using a false discovery rate of 0.05. Generalised linear models with logit-link assessed the associations between filtered metabolites and sleep phenotypes. Adjustment was made for important demographic and health-related covariates. In all, 2,718 participants were included in the analysis. After correcting for multiple testing, three metabolites remained for difficulty falling asleep, 59 for snoring, and none for early morning waking and waking up tired. After adjusting for sex, age, ethnicity and years of education, 1 standard deviation increase in serum histidine and valine associated with lower odds of difficulty falling asleep by 0.89-0.90 (95% confidence intervals [CIs] 0.80-0.99). Branched-chain and aromatic amino acids (odds ratios [ORs] 1.19-1.25, 95% CIs 1.09-1.36) were positively associated with snoring. Total cholesterol in low-density lipoprotein (OR 0.90, 95% CI 0.83-0.97) and high-density lipoprotein (OR 0.88, 95% CI 0.81-0.95) associated with lower odds of snoring. In the fully adjusted model, most associations persisted. To conclude, histidine and valine associated with lower odds of difficulty falling asleep, while docosahexaenoic acid and cholesterol in low-density lipoprotein and high-density lipoprotein subfractions associated with lower odds of snoring. Identified metabolites could provide guidance on the metabolic pathways associated with adverse sleep quality., (© 2020 The Authors. Journal of Sleep Research published by John Wiley & Sons Ltd on behalf of European Sleep Research Society.)

Background: Low socio-economic position (SEP) is a risk factor for multiple health outcomes, but its molecular imprints in the body remain unclear., Methods: We examined SEP as a determinant of serum nuclear magnetic resonance metabolic profiles in ∼30 000 adults and 4000 children across 10 UK and Finnish cohort studies., Results: In risk-factor-adjusted analysis of 233 metabolic measures, low educational attainment was associated with 37 measures including higher levels of triglycerides in small high-density lipoproteins (HDL) and lower levels of docosahexaenoic acid (DHA), omega-3 fatty acids, apolipoprotein A1, large and very large HDL particles (including levels of their respective lipid constituents) and cholesterol measures across different density lipoproteins. Among adults whose father worked in manual occupations, associations with apolipoprotein A1, large and very large HDL particles and HDL-2 cholesterol remained after adjustment for SEP in later life. Among manual workers, levels of glutamine were higher compared with non-manual workers. All three indicators of low SEP were associated with lower DHA, omega-3 fatty acids and HDL diameter. At all ages, children of manual workers had lower levels of DHA as a proportion of total fatty acids., Conclusions: Our work indicates that social and economic factors have a measurable impact on human physiology. Lower SEP was independently associated with a generally unfavourable metabolic profile, consistent across ages and cohorts. The metabolites we found to be associated with SEP, including DHA, are known to predict cardiovascular disease and cognitive decline in later life and may contribute to health inequalities., (© The Author(s) 2020. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Background: Biological aging estimators derived from DNA methylation data are heritable and correlate with morbidity and mortality. Consequently, identification of genetic and environmental contributors to the variation in these measures in populations has become a major goal in the field., Results: Leveraging DNA methylation and SNP data from more than 40,000 individuals, we identify 137 genome-wide significant loci, of which 113 are novel, from genome-wide association study (GWAS) meta-analyses of four epigenetic clocks and epigenetic surrogate markers for granulocyte proportions and plasminogen activator inhibitor 1 levels, respectively. We find evidence for shared genetic loci associated with the Horvath clock and expression of transcripts encoding genes linked to lipid metabolism and immune function. Notably, these loci are independent of those reported to regulate DNA methylation levels at constituent clock CpGs. A polygenic score for GrimAge acceleration showed strong associations with adiposity-related traits, educational attainment, parental longevity, and C-reactive protein levels., Conclusion: This study illuminates the genetic architecture underlying epigenetic aging and its shared genetic contributions with lifestyle factors and longevity.

Aim: To determine whether metformin's effects on carotid artery intima-media thickness (cIMT) in type 1 diabetes differ according to smoking status., Methods: Regression model effect estimates for the effect of metformin versus placebo (double-blind) on carotid IMT were calculated as a subgroup analysis of the REMOVAL trial., Results: In 428 randomized participants (227 never-smokers, 201 ever-smokers), averaged mean carotid IMT progression (per year) was reduced by metformin versus placebo in never-smokers (-0.012 mm, 95% CI -0.021 to -0.002; p = .0137) but not in ever-smokers (0.003 mm, 95% CI -0.008 to 0.014; p = .5767); and similarly in non-current smokers (-0.008 mm, 95% CI -0.015 to -0.00001; p = .0497) but not in current smokers (0.013 mm, 95% CI -0.007 to 0.032; p = .1887). Three-way interaction terms (treatment*time*smoking status) were significant for never versus ever smoking (p = .0373, prespecified) and non-current versus current smoking (p = .0496, exploratory). Averaged maximal carotid IMT progression (per year) was reduced by metformin versus placebo in never-smokers (-0.020 mm, 95% CI -0.034 to -0.006; p = .0067) but not in ever-smokers (-0.006 mm, 95% CI -0.020 to 0.008; p = .4067), although this analysis was not supported by a significant three-way interaction term., Conclusions: This subgroup analysis of the REMOVAL trial provides additional support for a potentially wider role of adjunct metformin therapy in cardiovascular risk management in type 1 diabetes, particularly for individuals who have never smoked cigarettes., (© 2021 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Objective: Ethnic differences in cardiovascular disease incidence, but not cardiovascular disease recurrence, are reported. We characterised long-term risk of major adverse cardiovascular event (MACE) and mortality following a non-fatal cardiovascular event in a British cohort of South Asians, African Caribbeans and Europeans., Methods: We identified index and recurrent cardiovascular events and mortality between 1988 and 2017 using hospital records and death registry. Using multivariable hazards models, we separately calculated the adjusted HR of MACE and death following index event, adjusting for demographics, vascular and lifestyle risk factors. Using interaction terms, we evaluated if decade of index event modified the association between ethnicity and outcomes., Results: South Asians were younger at the index event (median age 66 years, n=396) than Europeans (69 years, n=335) and African Caribbeans (70 years, n=70). During 4228 person-years, of the 801 patients, 537 developed MACE and 338 died, with the highest crude rate of MACE in South Asians. On adjustment of baseline factors, compared with the Europeans, the higher risk of MACE (HR 0.97, 95% CI 0.77 to 1.21) and the lower risk of mortality (HR 0.95, 95% CI 0.72 to 1.26) in South Asians was eliminated. African Caribbeans had similar outcomes to Europeans (HR MACE 1.04, 95% CI 0.74 to 1.47; and HR death 1.07, 95% CI 0.70 to 1.64). Long-term survival following an index event improved in South Asians (p trend 0.02) and African Caribbeans (p trend 0.07) compared with Europeans., Conclusions: Baseline vascular risk factors explained the observed ethnic variation in cardiovascular disease recurrence and long-term mortality, with a relative improvement in survival of minority ethnic groups over time., Competing Interests: Competing interests: NC receives funds from AstraZeneca for work on a trial data safety and monitoring committee. MVV holds a Fellowship Award from the Canadian Institutes of Health Research and the Prince Mahidol Marmot Fellowship Award., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

Human protein glycosylation is a complex process, and its in vivo regulation is poorly understood. Changes in glycosylation patterns are associated with many human diseases and conditions. Understanding the biological determinants of protein glycome provides a basis for future diagnostic and therapeutic applications. Genome-wide association studies (GWAS) allow to study biology via a hypothesis-free search of loci and genetic variants associated with a trait of interest. Sixteen loci were identified by three previous GWAS of human plasma proteome N-glycosylation. However, the possibility that some of these loci are false positives needs to be eliminated by replication studies, which have been limited so far. Here, we use the largest set of samples so far (4802 individuals) to replicate the previously identified loci. For all but one locus, the expected replication power exceeded 95%. Of the 16 loci reported previously, 15 were replicated in our study. For the remaining locus (near the KREMEN1 gene), the replication power was low, and hence, replication results were inconclusive. The very high replication rate highlights the general robustness of the GWAS findings as well as the high standards adopted by the community that studies genetic regulation of protein glycosylation. The 15 replicated loci present a good target for further functional studies. Among these, eight loci contain genes encoding glycosyltransferases: MGAT5, B3GAT1, FUT8, FUT6, ST6GAL1, B4GALT1, ST3GAL4 and MGAT3. The remaining seven loci offer starting points for further functional follow-up investigation into molecules and mechanisms that regulate human protein N-glycosylation in vivo., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Having the physical function to undertake activities of daily living (ADLs) is essential in order to maintain independence. The aim of this study is to investigate factors associated with physical function in older adults and determine if these associations differ in men versus women. In total, 726 participants (57% men; 73±7 years old) from a population-based cohort, the Southall and Brent Revisited (SABRE) study, completed questionnaires permitting a physical function score (PFS) to be calculated. Detailed phenotyping was performed including cardiovascular (echocardiography and macrovascular and microvascular functions), skeletal muscle (grip strength and oxidative capacity) and lung (pulmonary) function measurements. In a sub-group, maximal aerobic capacity was estimated from a sub-maximal exercise test. In women versus men, the association between grip strength and PFS was nearly 3 times stronger, and the association between microvascular dysfunction and PFS was over 5 times stronger (standardized β-coefficient (95% CI) 0.34 (0.22, 0.45) versus 0.11 (0.01,0.22) and -0.27 (-0.37, -0.17) versus -0.05 (-0.14, 0.04), respectively). In men, the association between cardiorespiratory fitness and PFS was 3 times greater than that in women (standardized β-coefficient (95% CI) 0.33 (0.22, 0.45) versus 0.10 (-0.04, 0.25). Cardiovascular, skeletal muscle and pulmonary factors all contribute to self-reported physical function, but the relative pattern of contribution differs by sex. Grip strength and microvascular function are most strongly associated with physical function in women while cardiorespiratory fitness is most strongly associated with physical function in men. This is relevant to the design of effective interventions that target maintenance of physical function in old age.

Background: Nuclear magnetic resonance (NMR) spectroscopy allows triglycerides to be subclassified into 14 different classes based on particle size and lipid content. We recently showed that these subfractions have differential associations with cardiovascular disease events. Here we report the distributions and define reference interval ranges for 14 triglyceride-containing lipoprotein subfraction metabolites., Methods: Lipoprotein subfractions using the Nightingale NMR platform were measured in 9073 participants from four cohort studies contributing to the UCL-Edinburgh-Bristol consortium. The distribution of each metabolite was assessed, and reference interval ranges were calculated for a disease-free population, by sex and age group (<55, 55-65, >65 years), and in a subgroup population of participants with cardiovascular disease or type 2 diabetes. We also determined the distribution across body mass index and smoking status., Results: The largest reference interval range was observed in the medium very-low density lipoprotein subclass (2.5th 97.5th percentile; 0.08 to 0.68 mmol/L). The reference intervals were comparable among male and female participants, with the exception of triglyceride in high-density lipoprotein. Triglyceride subfraction concentrations in very-low density lipoprotein, intermediate-density lipoprotein, low-density lipoprotein and high-density lipoprotein subclasses increased with increasing age and increasing body mass index. Triglyceride subfraction concentrations were significantly higher in ever smokers compared to never smokers, among those with clinical chemistry measured total triglyceride greater than 1.7 mmol/L, and in those with cardiovascular disease, and type 2 diabetes as compared to disease-free subjects., Conclusion: This is the first study to establish reference interval ranges for 14 triglyceride-containing lipoprotein subfractions in samples from the general population measured using the nuclear magnetic resonance platform. The utility of nuclear magnetic resonance lipid measures may lead to greater insights for the role of triglyceride in cardiovascular disease, emphasizing the importance of appropriate reference interval ranges for future clinical decision making.

Background: People of South Asian and African Caribbean ethnicities living in UK have a high risk of cardiometabolic disease. Limited data exist regarding detailed cardiometabolic phenotyping in this population. Methods enabling this are widely available, but the practical aspects of undertaking such studies in large and diverse samples are seldom reported. Methods: The Southall and Brent Revisited (SABRE) study is the UK's largest tri-ethnic longitudinal cohort. Over 1,400 surviving participants (58-85 years) attended the 2nd study visit (2008-2011); during which, comprehensive cardiovascular phenotyping, including 3D-echocardiography [3D-speckle-tracking (3D-STE)], computed tomography, coronary artery calcium scoring, pulse wave velocity, central blood pressure, carotid artery ultrasound, and retinal imaging, were performed. We describe the methods used with the aim of providing a guide to their feasibility and reproducibility in a large tri-ethnic population-based study of older people. Results: Conventional echocardiography and all vascular measurements showed high feasibility (>90% analyzable of clinic attendees), but 3D-echocardiography (3DE) and 3D-STE were less feasible (76% 3DE acquisition feasibility and 38% 3D-STE feasibility of clinic attendees). 3D-STE feasibility differed by ethnicity, being lowest in South Asian participants and highest in African Caribbean participants ( p < 0.0001). Similar trends were observed in men ( P < 0.0001) and women ( P = 0.005); however, in South Asians, there were more women with unreadable 3D-images compared to men (67 vs. 58%). Intra- and inter-observer variabilities were excellent for most of conventional and advanced echocardiographic measures. The test-retest reproducibility was good-excellent and fair-good for conventional and advanced echocardiographic measures, respectively, but lower than when re-reading the same images. All vascular measures demonstrated excellent or fair-good reproducibility. Conclusions: We describe the feasibility and reproducibility of detailed cardiovascular phenotyping in an ethnically diverse population. The data collected will lead to a better understanding of why people of South Asian and African Caribbean ancestry are at elevated risk of cardiometabolic diseases., (Copyright © 2020 Al Saikhan, Alobaida, Bhuva, Chaturvedi, Heasman, Hughes, Jones, Eastwood, Manisty, March, Ghosh, Mayet, Oguntade, Tillin, Williams, Wright and Park.)

Background and Aims: Mechanisms underlying the association between cardiovascular disease (CVD) and depression are unknown, and sex differences understudied. We investigated associations between a comprehensive set of measures of macro and microvascular disease and depressive symptoms in older men and women., Methods: We performed cross-sectional analyses of the SABRE (Southall And Brent REvisited) population-based study. Participants (1396) attended clinic between 2008 and 2011 for assessment of subclinical macrovascular (carotid ultrasound, echocardiography, cerebral magnetic resonance imaging) and microvascular (retinopathy, nephropathy) disease, and depression., Results: Mean age of 1396 participants was 69.5 years, and 76.2% were male. The median (interquartile range) of depression score was 1 [0, 2] for men and 1 [0, 3] for women. All measures of subclinical macro and microvascular disease were adversely associated with depressive symptoms, even when known CVD was excluded. Physical activity partly explained some of these relationships. The association between left atrial dimension index (LADI), a measure of chronic elevated left ventricular filling pressure, and depressive symptoms was stronger in women (regression coefficient 0.23 [95% CI 0.11, 0.35]) than men (0.07 [-0.01, 0.15]), p for interaction 0.06, on multivariable adjustment., Conclusions: Subclinical macro and microvascular disease is associated with depressive symptoms, even in the absence of established CVD. These were in part accounted for by physical activity. We observed stronger association between LADI and depressive symptoms in women than in men. The beneficial role of physical activity in abrogating the association between subclinical CVD and depression warrants further investigation., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Aims: Elevated low-density lipoprotein cholesterol (LDL-C) is a risk factor for cardiovascular disease; however, there is uncertainty about the role of total triglycerides and the individual triglyceride-containing lipoprotein sub-fractions. We measured 14 triglyceride-containing lipoprotein sub-fractions using nuclear magnetic resonance and examined associations with coronary heart disease and stroke., Methods: Triglyceride-containing sub-fraction measures were available in 11,560 participants from the three UK cohorts free of coronary heart disease and stroke at baseline. Multivariable logistic regression was used to estimate the association of each sub-fraction with coronary heart disease and stroke expressed as the odds ratio per standard deviation increment in the corresponding measure., Results: The 14 triglyceride-containing sub-fractions were positively correlated with one another and with total triglycerides, and inversely correlated with high-density lipoprotein cholesterol (HDL-C). Thirteen sub-fractions were positively associated with coronary heart disease (odds ratio in the range 1.12 to 1.22), with the effect estimates for coronary heart disease being comparable in subgroup analysis of participants with and without type 2 diabetes, and were attenuated after adjustment for HDL-C and LDL-C. There was no evidence for a clear association of any triglyceride lipoprotein sub-fraction with stroke., Conclusions: Triglyceride sub-fractions are associated with increased risk of coronary heart disease but not stroke, with attenuation of effects on adjustment for HDL-C and LDL-C.

We analyse data from the Southall And Brent REvisited (SABRE) tri-ethnic study, where measurements of metabolic and anthropometric variables have been recorded. In particular, we focus on modelling the distribution of insulin resistance which is strongly associated with the development of type 2 diabetes. We propose the use of a Bayesian nonparametric prior to model the distribution of Homeostasis Model Assessment insulin resistance, as it allows for data-driven clustering of the observations. Anthropometric variables and metabolites concentrations are included as covariates in a regression framework. This strategy highlights the presence of sub-populations in the data, characterised by different levels of risk of developing type 2 diabetes across ethnicities. Posterior inference is performed through Markov Chains Monte Carlo (MCMC) methods., (© 2020 Walter de Gruyter GmbH, Berlin/Boston.)

Immunoglobulin G (IgG) is the most abundant serum antibody which structural characteristics and effector functions are modulated through the attachment of various sugar moieties called glycans. Composition of the IgG N-glycome changes with age of an individual and in different diseases. Variability of IgG glycosylation within a population is well studied and is known to be affected by both genetic and environmental factors. However, global inter-population differences in IgG glycosylation have never been properly addressed. Here we present population-specific N-glycosylation patterns of IgG, analyzed in 5 different populations totaling 10,482 IgG glycomes, and of IgG's fragment crystallizable region (Fc), analyzed in 2,579 samples from 27 populations sampled across the world. Country of residence associated with many N-glycan features and the strongest association was with monogalactosylation where it explained 38% of variability. IgG monogalactosylation strongly correlated with the development level of a country, defined by United Nations health and socioeconomic development indicators, and with the expected lifespan. Subjects from developing countries had low levels of IgG galactosylation, characteristic for inflammation and ageing. Our results suggest that citizens of developing countries may be exposed to environmental factors that can cause low-grade chronic inflammation and the apparent increase in biological age.

The Dementias Platform UK Data Portal is a data repository facilitating access to data for 3 370 929 individuals in 42 cohorts. The Data Portal is an end-to-end data management solution providing a secure, fully auditable, remote access environment for the analysis of cohort data. All projects utilising the data are by default collaborations with the cohort research teams generating the data. The Data Portal uses UK Secure eResearch Platform infrastructure to provide three core utilities: data discovery, access, and analysis. These are delivered using a 7 layered architecture comprising: data ingestion, data curation, platform interoperability, data discovery, access brokerage, data analysis and knowledge preservation. Automated, streamlined, and standardised procedures reduce the administrative burden for all stakeholders, particularly for requests involving multiple independent datasets, where a single request may be forwarded to multiple data controllers. Researchers are provided with their own secure 'lab' using VMware which is accessed using two factor authentication. Over the last 2 years, 160 project proposals involving 579 individual cohort data access requests were received. These were received from 268 applicants spanning 72 institutions (56 academic, 13 commercial, 3 government) in 16 countries with 84 requests involving multiple cohorts. Projects are varied including multi-modal, machine learning, and Mendelian randomisation analyses. Data access is usually free at point of use although a small number of cohorts require a data access fee.

Background We aimed at investigating the association of circulating fatty acids with coronary heart disease (CHD) and stroke risk. Methods and Results We conducted an individual-participant data meta-analysis of 5 UK-based cohorts and 1 matched case-control study. Fatty acids (ie, omega-3 docosahexaenoic acid, omega-6 linoleic acid, monounsaturated and saturated fatty acids) were measured at baseline using an automated high-throughput serum nuclear magnetic resonance metabolomics platform. Data from 3022 incident CHD cases (13 104 controls) and 1606 incident stroke cases (13 369 controls) were included. Logistic regression was used to model the relation between fatty acids and odds of CHD and stroke, adjusting for demographic and lifestyle variables only (ie, minimally adjusted model) or with further adjustment for other fatty acids (ie, fully adjusted model). Although circulating docosahexaenoic acid, but not linoleic acid, was related to lower CHD risk in the fully adjusted model (odds ratio, 0.85; 95% CI, 0.76-0.95 per standard unit of docosahexaenoic acid), there was evidence of high between-study heterogeneity and effect modification by study design. Stroke risk was consistently lower with increasing circulating linoleic acid (odds ratio for fully adjusted model, 0.82; 95% CI, 0.75-0.90). Circulating monounsaturated fatty acids were associated with higher CHD risk across all models and with stroke risk in the fully adjusted model (odds ratio, 1.22; 95% CI, 1.03-1.44). Saturated fatty acids were not related to increased CHD risk in the fully adjusted model (odds ratio, 0.94; 95% CI, 0.82-1.09), or stroke risk. Conclusions We found consistent evidence that linoleic acid was associated with decreased risk of stroke and that monounsaturated fatty acids were associated with increased risk of CHD. The different pattern between CHD and stroke in terms of fatty acids risk profile suggests future studies should be cautious about using composite events. Different study designs are needed to assess which, if any, of the associations observed is causal.

Aims/hypothesis: The aim of this study was to compare exercise capacity, strength and skeletal muscle perfusion during exercise, and oxidative capacity between South Asians, African Caribbeans and Europeans, and determine what effect ethnic differences in the prevalence of type 2 diabetes has on these functional outcomes., Methods: In total, 708 participants (aged [mean±SD] 73 ± 7 years, 56% male) were recruited from the Southall and Brent Revisited (SABRE) study, a UK population-based cohort comprised of Europeans (n = 311) and South Asian (n = 232) and African Caribbean (n = 165) migrants. Measurements of exercise capacity using a 6 min stepper test (6MST), including measurement of oxygen consumption ([Formula: see text]) and grip strength, were performed. Skeletal muscle was assessed using near infrared spectroscopy (NIRS); measures included changes in tissue saturation index (∆TSI%) with exercise and oxidative capacity (muscle oxygen consumption recovery, represented by a time constant [τ]). Analysis was by multiple linear regression., Results: When adjusted for age and sex, in South Asians and African Caribbeans, exercise capacity was reduced compared with Europeans ([Formula: see text] [ml min -1  kg -1 ]: β = -1.2 [95% CI -1.9, -0.4], p = 0.002, and β -1.7 [95% CI -2.5, -0.8], p < 0.001, respectively). South Asians had lower and African Caribbeans had higher strength compared with Europeans (strength [kPa]: β = -9 [95% CI -12, -6), p < 0.001, and β = 6 [95% CI 3, 9], p < 0.001, respectively). South Asians had greater decreases in TSI% and longer τ compared with Europeans (∆TSI% [%]: β = -0.9 [95% CI -1.7, -0.1), p = 0.024; τ [s]: β = 11 [95% CI 3, 18], p = 0.006). Ethnic differences in [Formula: see text] and grip strength remained despite adjustment for type 2 diabetes or HbA 1c (and fat-free mass for grip strength). However, the differences between Europeans and South Asians were no longer statistically significant after adjustment for other possible mediators or confounders (including physical activity, waist-to-hip ratio, cardiovascular disease or hypertension, smoking, haemoglobin levels or β-blocker use). The difference in ∆TSI% between Europeans and South Asians was marginally attenuated after adjustment for type 2 diabetes or HbA 1c and was also no longer statistically significant after adjusting for other confounders; however, τ remained significantly longer in South Asians vs Europeans despite adjustment for all confounders., Conclusions/interpretation: Reduced exercise capacity in South Asians and African Caribbeans is unexplained by higher rates of type 2 diabetes. Poorer exercise tolerance in these populations, and impaired muscle function and perfusion in South Asians, may contribute to the higher morbidity burden of UK ethnic minority groups in older age.

Background: The role of family history in determining excess risk of coronary heart disease (CHD) in South Asians compared with Europeans is unclear. We hypothesized that family history would be more strongly associated with CHD in South Asians., Methods: We performed cross-sectional analyses of 20-year follow-up data from SABRE (Southall And Brent Revisited) population-based study. Initial recruitment (1988-1991) was by random selection from general practitioners' lists in north-west London. 974 Europeans and 734 South Asians completed follow-up questionnaire (2008-2011) and had complete CHD and family history data. 831 participants without cardiovascular disease had complete coronary artery calcium (CAC) data., Results: South Asians with family history of CHD were more likely to have diagnosed CHD (odds ratio 1.71 [95% CI 1.21, 2.42]; p = 0.002) and more previous CHD events (regression coefficient 0.44 [0.16, 0.72]; p = 0.002) than those without family history, independent of biological and sociodemographic risk factors. Family history associations with diagnosed CHD/number of events were weaker in Europeans (odds ratio 1.11 [0.78, 1.57]; p = 0.562/regression coefficient 0.02 [-0.25, 0.30]; p = 0.878), largely explained by biological risk factors. South Asians with family history had modestly increased CAC burden compared with Europeans., Conclusions: There were markedly stronger associations between family history and clinical CHD in South Asians, and a similar trend for subclinical CHD. Early preventive and therapeutic interventions are particularly important in South Asians with a family history of CHD., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: High blood pressure is a major risk factor for cardiovascular disease and is influenced by both environmental and genetic factors. Epigenetic processes including DNA methylation potentially mediate the relationship between genetic factors, the environment and cardiovascular disease. Despite an increased risk of hypertension and cardiovascular disease in individuals of South Asians compared to Europeans, it is not clear whether associations between blood pressure and DNA methylation differ between these groups., Methods: We performed an epigenome-wide association study and differentially methylated region (DMR) analysis to identify DNA methylation sites and regions that were associated with systolic blood pressure, diastolic blood pressure and hypertension. We analyzed samples from 364 European and 348 South Asian men (first generation migrants to the UK) from the Southall And Brent REvisited cohort, measuring DNA methylation from blood using the Illumina Infinium® HumanMethylation450 BeadChip., Results: One CpG site was found to be associated with DBP in trans-ancestry analyses (i.e. both ethnic groups combined), while in Europeans alone seven CpG sites were associated with DBP. No associations were identified between DNA methylation and either SBP or hypertension. Comparison of effect sizes between South Asian and European EWAS for DBP, SBP and hypertension revealed little concordance between analyses. DMR analysis identified several regions with known relationships with CVD and its risk factors., Conclusion: This study identified differentially methylated sites and regions associated with blood pressure and revealed ethnic differences in these associations. These findings may point to molecular pathways which may explain the elevated cardiovascular disease risk experienced by those of South Asian ancestry when compared to Europeans., Competing Interests: TRG receives funding from GlaxoSmithKline, Biogen and Sanofi for research unrelated to the work presented here. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Cholesteryl ester transfer protein (CETP) inhibition reduces vascular event risk, but confusion surrounds its effects on low-density lipoprotein (LDL) cholesterol. Here, we clarify associations of genetic inhibition of CETP on detailed lipoprotein measures and compare those to genetic inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR). We used an allele associated with lower CETP expression (rs247617) to mimic CETP inhibition and an allele associated with lower HMGCR expression (rs12916) to mimic the well-known effects of statins for comparison. The study consists of 65,427 participants of European ancestries with detailed lipoprotein subclass profiling from nuclear magnetic resonance spectroscopy. Genetic associations were scaled to 10% reduction in relative risk of coronary heart disease (CHD). We also examined observational associations of the lipoprotein subclass measures with risk of incident CHD in 3 population-based cohorts totalling 616 incident cases and 13,564 controls during 8-year follow-up. Genetic inhibition of CETP and HMGCR resulted in near-identical associations with LDL cholesterol concentration estimated by the Friedewald equation. Inhibition of HMGCR had relatively consistent associations on lower cholesterol concentrations across all apolipoprotein B-containing lipoproteins. In contrast, the associations of the inhibition of CETP were stronger on lower remnant and very-low-density lipoprotein (VLDL) cholesterol, but there were no associations on cholesterol concentrations in LDL defined by particle size (diameter 18-26 nm) (-0.02 SD LDL defined by particle size; 95% CI: -0.10 to 0.05 for CETP versus -0.24 SD, 95% CI -0.30 to -0.18 for HMGCR). Inhibition of CETP was strongly associated with lower proportion of triglycerides in all high-density lipoprotein (HDL) particles. In observational analyses, a higher triglyceride composition within HDL subclasses was associated with higher risk of CHD, independently of total cholesterol and triglycerides (strongest hazard ratio per 1 SD higher triglyceride composition in very large HDL 1.35; 95% CI: 1.18-1.54). In conclusion, CETP inhibition does not appear to affect size-specific LDL cholesterol but is likely to lower CHD risk by lowering concentrations of other atherogenic, apolipoprotein B-containing lipoproteins (such as remnant and VLDLs). Inhibition of CETP also lowers triglyceride composition in HDL particles, a phenomenon reflecting combined effects of circulating HDL, triglycerides, and apolipoprotein B-containing particles and is associated with a lower CHD risk in observational analyses. Our results reveal that conventional composite lipid assays may mask heterogeneous effects of emerging lipid-altering therapies., Competing Interests: The authors have declared that no competing interests exist.

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 VO 2 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., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. Published by BMJ.)

Aims/hypothesis: Type 2 diabetes, hyperglycaemia and insulin resistance are associated with cognitive impairment and dementia, but causal inference studies using Mendelian randomisation do not confirm this. We hypothesised that early-life cognition and social/educational advantage may confound the relationship., Methods: From the population-based British 1946 birth cohort, a maximum number of 1780 participants had metabolic variables (type 2 diabetes, insulin resistance [HOMA2-IR] and HbA 1c ) assessed at age 60-64 years, and cognitive state (Addenbrooke's Cognitive Examination III [ACE-III]) and verbal memory assessed at age 69 years. Earlier-life measures included socioeconomic position (SEP), cognition at age 8 years and educational attainment. Polygenic risk scores (PRSs) for type 2 diabetes were calculated. We first used a PRS approach with multivariable linear regression to estimate associations between PRSs and metabolic traits and later-life cognitive state. Second, using a path model approach, we estimated the interrelationships between earlier-life measures, features of mid-life type 2 diabetes and cognitive state at age 69 years. All models were adjusted for sex., Results: The externally weighted PRS for type 2 diabetes was associated with mid-life metabolic traits (e.g. HOMA2-IR β = 0.08 [95% CI 0.02, 0.16]), but not with ACE-III (β = 0.04 [-0.02, 0.90]) or other cognitive outcomes. While there was an association between HOMA2-IR and subsequent ACE-III (β = -0.09 [-0.15, -0.03]), path modelling showed no direct effect (β = -0.01 [-0.06, 0.03]) after accounting for the association between childhood SEP and education with HOMA2-IR. The same pattern was observed for later-life verbal memory., Conclusions/interpretation: Associations between type 2 diabetes and mid-life metabolic traits with subsequent cognitive state do not appear causal, and instead they may be explained by SEP in early life, childhood cognition and educational attainment. Therefore, glucose-lowering medication may be unlikely to combat cognitive impairment in older age.

Objectives: Cerebral blood flow (CBF) estimates from arterial spin labelling (ASL) show unexplained variability in older populations. We studied the impact of variation of haematocrit (Hct) on CBF estimates in a tri-ethnic elderly population., Materials and Methods: Approval for the study was obtained from the Fulham Research Ethics Committee and participants gave written informed consent. Pseudo-continuous arterial spin labelling was performed on 493 subjects (age 55-90) from a tri-ethnic community-based cohort recruited in London. CBF was estimated using a simplified Buxton equation, with and without correction for Hct measured from blood samples. Differences in perfusion were compared, stratified by sex, ethnicity and diabetes. Results of Student's t tests were reported with effect size., Results: Hct adjustment decreased CBF estimates in all categories except white European men. The decrease for women was 2.7 (3.0, 2.4) mL/100 g/min) (mean (95% confidence interval (CI)), p < 0.001 d = 0.38. The effect size differed by ethnicity with estimated mean perfusion in South Asian and African Caribbean women found to be lower by 3.0 (3.6, 2.5) mL/100 g/min, p < 0.001 d = 0.56 and 3.1 (3.6, 2.5) mL/100 g/min), p < 0.001 d = 0.48, respectively. Estimates of perfusion in subjects with diabetes decreased by 1.8 (2.3, 1.4) mL/100 g/min, p < 0.001 d = 0.23) following Hct correction. Correction for individual Hct altered sample frequency distributions of CBF values, especially in women of non-European ethnicity., Conclusion: ASL-derived CBF values in women, non-European ethnicities and individuals with diabetes are overestimated if calculations are not appropriately adjusted for individual Hct., Key Points: • CBF quantification from ASL using a fixed Hct of 43.5%, as recommended in the ISMRM white paper, may lead to erroneous CBF estimations particularly in non-European and female subjects. • Individually measured Hct values improve the accuracy of CBF estimation and, if these are not available, an adjusted value according to gender, ethnicity or diabetes status should be considered. • Hct-corrected ASL could be potentially important for CBF threshold decision making in the fields of neurodegenerative disease and neuro-oncology.

Background: Both long and short sleep duration increase risk of mortality. Most previous studies have been performed in Europeans and have focused on sleep duration. Thus, we aimed to investigate the association between sleep quality and mortality across three different ethnic groups., Methods: We used data from the Southall and Brent REvisited Study (SABRE) cohort, which comprises first generation migrant South Asian and African Caribbean men and women, aged 40-69 years, recruited between 1988 and 1991. In sum, 4399 participants provided complete data at baseline and follow-up. Of those, 1656 died by December 2017. Our exposures (eg, difficulty falling asleep, early morning waking and waking up tired in the morning) were self-reported and our primary outcome was mortality. We used Cox proportional hazards models to analyse our data, adjusting for baseline-measured confounders., Results: None of the sleep measures were strongly associated with all-cause mortality in Europeans or African Caribbeans, whilst in South Asians difficulty falling asleep was related to an increased risk of all-cause mortality (HR = 1.28, 95%CI = 1.01; 1.61). In Europeans, early morning waking was associated with a moderately increased risk of cardiovascular death (HR = 1.31, 95%CI = 1.05; 1.63); alternately, this association was not as strong in the other groups., Conclusion: Our findings suggest that the relationship between sleep quality and mortality may differ by ethnic group, but formal heterogeneity tests indicated that the strongest difference in HRs was observed for early morning waking and cardiovascular disease (CVD) mortality across the three groups (Cochran's Q test p = 0.036). As such, these results are novel and provide support for ethnic differences in sleep quality and mortality, and may have implications for precision medicine., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The Consortium of Metabolomics Studies (COMETS) was established in 2014 to facilitate large-scale collaborative research on the human metabolome and its relationship with disease etiology, diagnosis, and prognosis. COMETS comprises 47 cohorts from Asia, Europe, North America, and South America that together include more than 136,000 participants with blood metabolomics data on samples collected from 1985 to 2017. Metabolomics data were provided by 17 different platforms, with the most frequently used labs being Metabolon, Inc. (14 cohorts), the Broad Institute (15 cohorts), and Nightingale Health (11 cohorts). Participants have been followed for a median of 23 years for health outcomes including death, cancer, cardiovascular disease, diabetes, and others; many of the studies are ongoing. Available exposure-related data include common clinical measurements and behavioral factors, as well as genome-wide genotype data. Two feasibility studies were conducted to evaluate the comparability of metabolomics platforms used by COMETS cohorts. The first study showed that the overlap between any 2 different laboratories ranged from 6 to 121 metabolites at 5 leading laboratories. The second study showed that the median Spearman correlation comparing 111 overlapping metabolites captured by Metabolon and the Broad Institute was 0.79 (interquartile range, 0.56-0.89)., (Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health 2019.)

Cardiac rehabilitation (CR) after myocardial infarction is highly effective. It is unavailable in public hospitals in India due to limited resources. Our objective was to develop a scalable model of CR for India based on yoga, which could also appeal to some groups with low uptake of CR (e.g., ethnic minorities, women, and older people) globally. The intervention was developed using a structured process. A literature review and consultations with yoga experts, CR experts, and postmyocardial infarction patients were conducted to systematically identify and shortlist appropriate yoga exercises and postures, breathing exercises, meditation and relaxation practices, and lifestyle changes, which were incorporated into a conventional CR framework. The draft intervention was further refined based on the feedback from an internal stakeholder group and an external panel of international experts, before being piloted with yoga instructors and patients with myocardial infarction. A four-phase yoga-based CR (Yoga-CaRe) programme was developed for delivery by a single yoga instructor with basic training. The programme consists of a total of 13 instructor-led sessions (2 individual and 11 group) over a 3-month period. Group sessions include guided practice of yoga exercises and postures, breathing exercises, and meditation and relaxation practices, and support for the lifestyle change and coping through a moderated discussion. Patients are encouraged to self-practice daily at home and continue long-term with the help of a booklet and digital video disc (DVD). Family members/carers are encouraged to join throughout. In conclusion, a novel yoga-based CR programme has been developed, which promises to provide a scalable CR solution for India and an alternative choice for CR globally. It is currently being evaluated in a large multicentre randomised controlled trial across India.

Dietary inorganic nitrate in beetroot can act as a source of nitric oxide and has been reported to lower brachial blood pressure (BP). This study examined the effect of inorganic nitrate in beetroot juice on aortic (central) BP acutely and over the subsequent 24-h period. A double blind, randomized, placebo-controlled crossover trial was performed in fifteen healthy, normotensive men and women (age 22-40 years). Participants were randomized to receive beetroot juice containing nitrate (6.5-7.3 mmol) or placebo beetroot juice from which nitrate had been removed (<0.06 mmol nitrate). Effects on aortic systolic BP were measured at 30 min (primary endpoint), 60 min and over a subsequent 24 h period using an ambulatory BP monitor. Carotid-femoral pulse wave velocity (cfPWV) was also measured at 30 min. Following a washout period, the procedure was repeated within 7 days with crossover to the opposite arm of the trial. Compared with placebo, ingestion of beetroot juice containing nitrate lowered aortic systolic BP at 30 min by 5.2 (1.9-8.5) mmHg [mean (95% confidence interval); p < 0.01]. A smaller effect on aortic systolic BP was observed at 60 min. There were minimal effects on brachial BP or cfPWV. Effects on aortic systolic BP were not sustained over the subsequent 24 h and there were no effects on other hemodynamic parameters during ambulatory monitoring. A single dose of beetroot juice containing nitrate lowers aortic BP more effectively than brachial BP in the short term, but the effects are comparatively short-lived and do not persist over the course of the same day.

Background: Evidence is limited on ethnic differences in associations between kidney function markers and mortality or cardiovascular disease (CVD)., Methods: Baseline cross-sectional analysis and longitudinal follow-up study of a UK population-based cohort of 1,116 Europeans and 1,104 South Asians of predominantly Indian descent, age 52 ± 7 years at baseline (1988-1991). Kidney function was estimated using Cystatin C and creatinine-based chronic kidney disease (CKD) Epidemiology Collaboration estimated glomerular filtration rate (eGFR) equations, and urinary albumin-creatinine ratio (ACR). Mortality was captured at 27 years, and incident CVD at 22 years, from death certification, medical records and participant report. Longitudinal associations between eGFR/ACR and mortality/incident CVD were examined using Cox models., Results: eGFRcys was lower and ACR higher in South Asians than Europeans. eGFRcys and -eGFRcreat were more strongly associated with outcomes in Europeans than South Asians. Conversely, associations between ACR and outcomes were greater in South Asians than Europeans, for example, for CVD mortality: HRs (95% CI) adjusted for CVD risk factors and ACR/eGFRcys as appropriate, p for ethnicity interaction: eGFRcys: Europeans: 0.76 (0.62-0.92), South Asians: 0.92 (0.78-1.07), p = 0.05, eGFRcreat: Europeans 0.81 (0.67-0.99), South Asians 1.18 (0.97-1.41), p = 0.002, ACR: -Europeans: 1.24 (1.08-1.42), South Asians: 1.39 (1.25-1.57), p= 0.23. Addition of all CKD measures to a standard CVD risk factor model modestly improved prediction capability in -Europeans; in South Asians only ACR contributed to improvement., Conclusions: Strong associations between ACR and outcomes in South Asians of predominantly Indian origin, and null associations for eGFRcys and eGFRcreat, suggest that ACR may have greater utility in CVD risk prediction in South Asians. Further work is needed to validate these -findings., (The Author(s). Published by S. Karger AG, Basel.)

Background: Cigarette smoking is associated with earlier menopause, but the impact of being a former smoker and any dose-response relationships on the degree of smoking and age at menopause have been less clear. If the toxic impact of cigarette smoking on ovarian function is irreversible, we hypothesized that even former smokers might experience earlier menopause, and variations in intensity, duration, cumulative dose, and age at start/quit of smoking might have varying impacts on the risk of experiencing earlier menopause., Methods and Findings: A total of 207,231 and 27,580 postmenopausal women were included in the cross-sectional and prospective analyses, respectively. They were from 17 studies in 7 countries (Australia, Denmark, France, Japan, Sweden, United Kingdom, United States) that contributed data to the International collaboration for a Life course Approach to reproductive health and Chronic disease Events (InterLACE). Information on smoking status, cigarettes smoked per day (intensity), smoking duration, pack-years (cumulative dose), age started, and years since quitting smoking was collected at baseline. We used multinomial logistic regression models to estimate multivariable relative risk ratios (RRRs) and 95% confidence intervals (CIs) for the associations between each smoking measure and categorised age at menopause (<40 (premature), 40-44 (early), 45-49, 50-51 (reference), and ≥52 years). The association with current and former smokers was analysed separately. Sensitivity analyses and two-step meta-analyses were also conducted to test the results. The Bayesian information criterion (BIC) was used to compare the fit of the models of smoking measures. Overall, 1.9% and 7.3% of women experienced premature and early menopause, respectively. Compared with never smokers, current smokers had around twice the risk of experiencing premature (RRR 2.05; 95% CI 1.73-2.44) (p < 0.001) and early menopause (1.80; 1.66-1.95) (p < 0.001). The corresponding RRRs in former smokers were attenuated to 1.13 (1.04-1.23; p = 0.006) and 1.15 (1.05-1.27; p = 0.005). In both current and former smokers, dose-response relationships were observed, i.e., higher intensity, longer duration, higher cumulative dose, earlier age at start smoking, and shorter time since quitting smoking were significantly associated with higher risk of premature and early menopause, as well as earlier menopause at 45-49 years. Duration of smoking was a strong predictor of age at natural menopause. Among current smokers with duration of 15-20 years, the risk was markedly higher for premature (15.58; 11.29-19.86; p < 0.001) and early (6.55; 5.04-8.52; p < 0.001) menopause. Also, current smokers with 11-15 pack-years had over 4-fold (4.35; 2.78-5.92; p < 0.001) and 3-fold (3.01; 2.15-4.21; p < 0.001) risk of premature and early menopause, respectively. Smokers who had quit smoking for more than 10 years had similar risk as never smokers (1.04; 0.98-1.10; p = 0.176). A limitation of the study is the measurement errors that may have arisen due to recall bias., Conclusions: The probability of earlier menopause is positively associated with intensity, duration, cumulative dose, and earlier initiation of smoking. Smoking duration is a much stronger predictor of premature and early menopause than others. Our findings highlight the clear benefits for women of early smoking cessation to lower their excess risk of earlier menopause., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: JEC is a director of Dietary Assessment Ltd, a University of Leeds spin out company to support measurement of dietary intake. All other authors have declared that no competing interests exist.

Introduction: Lower cerebral blood flow (CBF) is associated with cardiovascular disease and vascular risk factors, and is increasingly acknowledged as an important contributor to cognitive decline and dementia. In this cross-sectional study, we examined the association between CBF and cognitive functioning in a community-based, multi-ethnic cohort. Methods: From the SABRE (Southall and Brent Revisited) study, we included 214 European, 151 South Asian and 87 African Caribbean participants (71 ± 5 years; 39%F). We used 3T pseudo-continuous arterial spin labeling to estimate whole-brain, hematocrit corrected CBF. We measured global cognition and three cognitive domains (memory, executive functioning/attention and language) with a neuropsychological test battery. Associations were investigated using linear regression analyses, adjusted for demographic variables, vascular risk factors and MRI measures. Results: Across groups, we found an association between higher CBF and better performance on executive functioning/attention (standardized ß [stß] = 0.11, p < 0.05). Stratification for ethnicity showed associations between higher CBF and better performance on memory and executive functioning/attention in the white European group (stß = 0.14; p < 0.05 and stß = 0.18; p < 0.01 respectively), associations were weaker in the South Asian and African Caribbean groups. Conclusions: In a multi-ethnic community-based cohort we showed modest associations between CBF and cognitive functioning. In particular, we found an association between higher CBF and better performance on executive functioning/attention and memory in the white European group. The observations are consistent with the proposed role of cerebral hemodynamics in cognitive decline.

Background: Metformin might reduce insulin requirement and improve glycaemia in patients with type 1 diabetes, but whether it has cardiovascular benefits is unknown. We aimed to investigate whether metformin treatment (added to titrated insulin therapy) reduced atherosclerosis, as measured by progression of common carotid artery intima-media thickness (cIMT), in adults with type 1 diabetes at increased risk for cardiovascular disease., Methods: REMOVAL was a double-blind, placebo-controlled trial undertaken at 23 hospital diabetes clinics in five countries (Australia, Canada, Denmark, the Netherlands, and the UK). Adults aged 40 years and older with type 1 diabetes of at least 5 years' duration and at least three of ten specific cardiovascular risk factors were randomly assigned (via an interactive voice response system) to oral metformin 1000 mg twice daily or placebo. Participants and site staff were masked to treatment allocation. The primary outcome was averaged mean far-wall cIMT, quantified annually for 3 years, analysed in a modified intention-to-treat population (all randomly assigned participants with post-randomisation data available for the outcome of interest at any given timepoint, irrespective of subsequent adherence or study participation), using repeated measures regression. Secondary outcomes were HbA 1c , LDL cholesterol, estimated glomerular filtration rate (eGFR), incident microalbuminuria (not reported), incident retinopathy, bodyweight, insulin dose, and endothelial function, also analysed in all participants with post-randomisation data available for the outcome of interest at any given timepoint. This trial is registered with ClinicalTrials.gov, number NCT01483560., Findings: Between Dec 14, 2011, and June 24, 2014, 493 participants entered a 3 month run-in to optimise risk factor and glycaemic control (single-blind placebo in the final month). Of 428 randomly assigned patients, 219 were allocated to metformin and 209 to placebo. Progression of mean cIMT was not significantly reduced with metformin (-0·005 mm per year, 95% CI -0·012 to 0·002; p=0·1664), although maximal cIMT (a prespecified tertiary outcome) was significantly reduced (-0·013 mm per year, -0·024 to -0·003; p=0·0093). HbA 1c (mean 8·1% [SD 0·9] for metformin and 8·0% [0·8] for placebo at baseline) was reduced on average over 3 years by metformin (-0·13%, 95% CI -0·22 to -0·037; p=0·0060), but this was accounted for by a reduction at the 3-month timepoint (-0·24%, -0·34 to -0·13; p<0·0001) that was not sustained thereafter (p=0·0163 for visit-by-treatment interaction). Bodyweight (-1·17 kg, 95% CI -1·66 to -0·69; p<0·0001) and LDL cholesterol (-0·13 mmol/L, -0·24 to -0·03; p=0·0117) were reduced with metformin over 3 years of treatment, and eGFR was increased (4·0 mL/min per 1·73m 2 , 2·19 to 5·82; p<0·0001). Insulin requirement was not reduced on average over 3 years (-0·005 units per kg, 95% CI -0·022 to 0·012; p=0·545), but there was a significant visit-by-treatment interaction (p=0·0018). There was no effect on endothelial function as measured by reactive hyperaemia index, or on retinopathy. Discontinuation of treatment in 59 (27%) participants on metformin versus 26 (12%) on placebo (p=0·0002) was mainly due to an excess of gastrointestinal adverse effects, and there was no increase in hypoglycaemia with metformin. Five deaths occurred among patients allocated to metformin and two occurred among those allocated to placebo; none were judged by site principal investigators to be related to study medication., Interpretation: These data do not support use of metformin to improve glycaemic control in adults with long-standing type 1 diabetes as suggested by current guidelines, but suggest that it might have a wider role in cardiovascular risk management., Funding: JDRF., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

It is often necessary to assess physical function in older adults to monitor disease progression, rehabilitation or decline in function with age. However, increasing frailty and poor balance that accompany aging are common barriers to exercise testing protocols. We investigated whether a 6-min stepper test (6MST) was acceptable to older adults and provided a measure of exercise capacity and a predicted value for peak aerobic capacity (VO 2max ). 635 older adults from a tri-ethnic UK population-based cohort were screened to undertake a self-paced 6MST. Expired gas analysis, heart rate and blood pressure monitoring were carried out. A sub-set of 20 participants performed a second 6MST for assessment of reproducibility and a further sub-set of 10 performed the 6-min walk test as verification against a well-recognized and accepted self-paced exercise test. 518 (82%) participants met inclusion criteria and undertook the 6MST (299 men, mean age 71.2 ± 6.4). Step rate showed a strong positive correlation with measured VO 2 ( r = 0.75, p < 0.001) and VO 2 was lower in women (male-female difference in VO 2 = 2.61 (95% confidence interval -3.6, -1.7) ml/min/kg; p < 0.001). 20 participants repeated a 6MST, step rate was higher in the second test but the predicted VO 2max showed good agreement (mean difference = 0.1 [3.72, 3.95] ml/min/kg). In 10 participants who completed a 6MST and a 6-min walk test there was a strong positive correlation between walking rate and step rate ( r = 0.77; p < 0.009) and weaker positive correlations between the tests for measured VO 2 and peak heart rate. In conclusion, the 6MST is a convenient, acceptable method of assessing exercise capacity in older adults that allows VO 2max to be predicted reproducibly. The test shows good correlation between performance and measured physiological markers of performance and can detect the expected gender differences in measured VO 2 . Furthermore, the 6MST results correlate with a previously verified and established self-paced exercise test.

Background: Subclinical left ventricular (LV) dysfunction has been inconsistently associated with early cognitive impairment, and mechanistic pathways have been poorly considered. We investigated the cross-sectional relationship between LV dysfunction and structural/functional measures of the brain and explored the role of potential mechanisms., Method and Results: A total of 1338 individuals (69±6 years) from the Southall and Brent Revisited study underwent echocardiography for systolic (tissue Doppler imaging peak systolic wave) and diastolic (left atrial diameter) assessment. Cognitive function was assessed and total and hippocampal brain volumes were measured by magnetic resonance imaging. Global LV function was assessed by circulating N-terminal pro-brain natriuretic peptide. The role of potential mechanistic pathways of arterial stiffness, atherosclerosis, microvascular disease, and inflammation were explored. After adjusting for age, sex, and ethnicity, lower systolic function was associated with lower total brain (beta±standard error, 14.9±3.2 cm 3 ; P <0.0001) and hippocampal volumes (0.05±0.02 cm 3 , P =0.01). Reduced diastolic function was associated with poorer working memory (-0.21±0.07, P =0.004) and fluency scores (-0.18±0.08, P =0.02). Reduced global LV function was associated with smaller hippocampal volume (-0.10±0.03 cm 3 , P =0.004) and adverse visual memory (-0.076±0.03, P =0.02) and processing speed (0.063±0.02, P =0.006) scores. Separate adjustment for concomitant cardiovascular risk factors attenuated associations with hippocampal volume and fluency only. Further adjustment for the alternative pathways of microvascular disease or arterial stiffness attenuated the relationship between global LV function and visual memory., Conclusions: In a community-based sample of older people, measures of LV function were associated with structural/functional measures of the brain. These associations were not wholly explained by concomitant risk factors or potential mechanistic pathways., (© 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

Background: Adverse effects of air pollution on cardiovascular disease (CVD) mortality are well established. There are comparatively fewer studies in Europe, and in the UK particularly, than in North America. We examined associations in two British cohorts with >25years of follow-up., Methods: Annual average NO 2 , SO 2 and black smoke (BS) air pollution exposure estimates for 1991 were obtained from land use regression models using contemporaneous monitoring data. From the European Study of Cohorts and Air Pollution (ESCAPE), air pollution estimates in 2010-11 were obtained for NO 2 , NO x , PM 10 , PM coarse and PM 2.5 . The exposure estimates were assigned to place of residence 1989 for participants in a national birth cohort born in 1946, the MRC National Study of Health and Development (NSHD), and an adult multi-ethnic London cohort, Southall and Brent Revisited (SABRE) recruited 1988-91. The combined median follow-up was 26years. Single-pollutant competing risk models were employed, adjusting for individual risk factors., Results: Elevated non-significant hazard ratios for CVD mortality were seen with 1991 BS and SO 2 and with ESCAPE PM 10 and PM 2.5 in fully adjusted linear models. Per 10μg/m 3 increase HRs were 1.11 [95% CI: 0.76-1.61] for BS, 1.05 [95% CI: 0.91-1.22] for SO 2 , 1.16 [95% CI: 0.70-1.92] for PM 10 and 1.30 [95% CI: 0.39-4.34] for PM 2.5 , with largest effects seen in the fourth quartile of BS and PM 2.5 compared to the first with HR 1.24 [95% CI: 0.91-1.61] and 1.21 [95% CI: 0.88-1.66] respectively. There were no consistent associations with other ESCAPE pollutants, or with 1991 NO 2 . Modelling using Cox regression led to similar results., Conclusion: Our results support a detrimental long-term effect for air pollutants on cardiovascular mortality., (Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.)