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BackgroundThree-dimensional echocardiography (3DE) measures of the left ventricle (LV) predict outcomes in high risk individuals, but their prognostic value in the general population is unknown. We aimed to establish whether 3DE was associated with mortality and morbidity in a multi-ethnic community-based sample, if associations differed by sex, and explored potential mechanisms explaining sex differences.Methods922 individuals (69.7 ± 6.2 years; 717 men) from the SABRE study underwent a health examination including echocardiography. Associations between 3DE LV measures (ejection fraction (EF), end-diastolic volume (EDV), end-systolic volume (ESV), LV remodeling index (LVRI) and LV sphericity index (LVSI), and all-cause mortality and a composite cardiovascular endpoint [comprising new onset (non)fatal coronary heart disease, heart failure hospitalization, new-onset arrhythmias and cardiovascular mortality] were determined using multivariable Cox regression over a median follow-up of 8 years (all-cause mortality) and 7 years (composite cardiovascular endpoint).ResultsThere were 123 deaths and 151 composite cardiovascular endpoints. Lower EF, higher LV volumes and LVSI were associated with increased all-cause mortality, and higher LV volumes were associated with the composite cardiovascular endpoint independent of potential confounders. Associations between LV volumes, LVRI, LVSI, and mortality differed by sex (p interaction

3D-speckle tracking echocardiography(3D-STE) allows simultaneous assessment of ejection fraction(EF) and multidirectional strains, but its prognostic utility in the general population is unknown. We investigated if 3D-STE strains predicted a composite of major cardiac endpoints(MACE) beyond cardiovascular risk factors(CVDRF), and whether they were superior to 3D-EF. 529 participants in SABRE, a UK-based tri-ethnic general population cohort (69±6y; 76.6% male) with acceptable 3D-STE imaging were studied. Associations between 3D-EF or multidirectional myocardial strains and MACE(coronary heart disease(fatal/non-fatal), heart failure hospitalization, new-onset arrhythmia and cardiovascular mortality) were determined using Cox regression including adjustment for CVDRF and 2D-EF. Whether 3D-EF, global longitudinal strain(3D-GLS) and principle tangential strain(3D-PTS/3D-strain) improved cardiovascular risk stratification over CVDRF was investigated using a likelihood ratio test on a series of nested Cox proportional hazards models and Harrell's C statistics. During follow-up(median, 12y), there were 92 events. 3D-EF, 3D-GLS and 3D-PTS and 3D-RS were associated with MACE in unadjusted and models adjusted for CVDRF but not CVDRF+2D-EF. Compared to 3D-EF, both 3D-GLS and 3D-PTS slightly improved the predictive value over CVDRF for MACE, but the improvement was modest(C statistic increased from 0.698(0.647, 0.749) to 0.715(0.663, 0.766) comparing CVDRF with CVDRF +3D-GLS). 3D-STE-derived LV myocardial strains predicted MACE in a multi-ethnic general population sample of elderly individuals from the UK; however the added prognostic value of 3D-STE myocardial strains was small.

BackgroundAtherosclerotic cardiovascular disease (ASCVD) risk differs by ethnicity. In comparison with Europeans (EA) South Asian (SA) people in UK experience higher risk of coronary heart disease (CHD) and stroke, while African Caribbean people have a lower risk of CHD but a higher risk of stroke.AimTo compare carotid atherosclerosis in EA, SA, and AC participants in the Southall and Brent Revisited (SABRE) study and establish if any differences were explained by ASCVD risk factors.MethodsCardiovascular risk factors were measured, and carotid ultrasound was performed in 985 individuals (438 EA, 325 SA, 228 AC). Carotid artery plaques and intima-media thickness (cIMT) were measured. Associations of carotid atherosclerosis with ethnicity were investigated using generalised linear models (GLMs), with and without adjustment for non-modifiable (age, sex) and modifiable risk factors (education, diabetes, hypertension, total cholesterol, HDL-C, alcohol consumption, current smoking).ResultsPrevalence of any plaque was similar in EA and SA, but lower in AC (16, 16, and 6%, respectively; p < 0.001). In those with plaque, total plaque area, numbers of plaques, plaque class, or greyscale median did not differ by ethnicity; adjustment for risk factors had minimal effects. cIMT was higher in AC than the other ethnic groups after adjustment for age and sex, adjustment for risk factors attenuated this difference.ConclusionPrevalence of carotid artery atherosclerotic plaques varies by ethnicity, independent of risk factors. Lower plaque prevalence in in AC is consistent with their lower risk of CHD but not their higher risk of stroke. Higher cIMT in AC may be explained by risk factors. The similarity of plaque burden in SA and EA despite established differences in ASCVD risk casts some doubt on the utility of carotid ultrasound as a means of assessing risk across these ethnic groups.

Abstract 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.

Background and aimsRisk 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.Methods360 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.ResultsBA 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).ConclusionsCompared 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.

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 (∆TSIBL-INC) and across the whole of exercise (∆TSIBL-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 ∆TSIBL-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 ∆TSIBL-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). ∆TSIBL-EE was associated with steps and highest VO2 (1.7 (0.49, 2.9), p = 0.006; 7.7 (3.2, 12.3), p = 0.001). ∆TSIBL-INC was associated with steps and VO2 but this difference was attenuated towards the null after adjustment for age, sex and ethnicity. ∆TSIBL-EE was greater in women (3.4 (0.4, 8.9) versus 2.1 (0.3, 7.4), p = 0.017) and ∆TSIBL-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.

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

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 (Ca), 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 Ca 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.

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 (71% 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.

[This corrects the article DOI: 10.1371/journal.pbio.3000572.].

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.

Background: Functional capacity declines with age leading to disability and increased cost of health and social care. In older adults, factors that influence the ability to sustain sub-maximal exercise (a marker of functional capacity) are not well defined. We aimed to determine the contribution of cardiac function, skeletal muscle oxygen desaturation, extraction and oxidative capacity to sub-maximal exercise performance in a population-based sample of older adults. Methods: Participants in the SABRE study undertook a 6-minute stepper test (6MST). Sub-maximal exercise performance was assessed as the highest achieved whole-body oxygen uptake (VO2) during the 6MST. Near Infrared Spectroscopy (NIRS) was used to locally assess skeletal muscle oxygen extraction, desaturation and maximum oxidative capacity. Echocardiography was used to measure cardiac function. Analysis was by multiple linear regression adjusted for confounders: age, sex, ethnicity, diabetes and obesity. Results: 395 participants (73.0 ± 6.3 years old, male; n = 229) undertook the 6MST, skeletal muscle desaturation measurements and echocardiography. Skeletal muscle desaturation and cardiac output were independently associated with whole-body VO2 (standardized β: −0.20, p < 0.001 & 0.47, p < 0.001, respectively). Local skeletal muscle oxygen extraction was independently associated with whole-body VO2 (standardized β adjusted for confounders & cardiac output: 0.32, p < 0.001). Maximum oxidative capacity was not associated with VO2 (β (95% CI: 0.02 (−0.01, 0.04), p = 0.152). Conclusion: Local oxygen extraction and desaturation in skeletal muscle are independent predictors of sub-maximal exercise performance in older adults. These associations persist with adjustment for cardiac output suggesting local capacity to extract oxygen could be a major limiting factor functional capacity in older adults.

Background: We have previously shown that 3D echocardiography-derived (3DE) indices of left ventricular (LV) structure predict all-cause mortality differently in men and women [1]. However, the mechanism behind these sex differences remains unknown. We therefore examined the role of macro- and micro-vascular disease in explaining these sex differences. Methods: 910 individuals (age, 69.7 ± 6.2 years; 77.7% male) from the SABRE study, a UK-largest tri-ethnic longitudinal cohort, underwent a health examination. Associations between 3DE-derived LV measures (end-diastolic volume (EDV), end-systolic volume (ESV) and LV remodeling index (LVRI)) and all-cause mortality were determined using multivariable Cox regression. Total arterial compliance (TAC), augmentation index (AI), eGFR and microalbuminuria were added to these models. Results: 103 (14.5%) men and 17 (8.4%) women died over median follow-up of 8 years. After multivariable adjustment, lower LVRI, and higher volumes were independently associated with increased risk of mortality in men; however, associations were reversed in women (Table 1; p (interaction: LVRI = 0.034, EDV = 0.051, and ESV = 0.009)). TAC was lower in women (0.73 ± 0.24 vs 0.83 ± 0.27, p < 0.0001) and AI higher (156.1 ± 22.3 vs 145.4 ± 21, p < 0.0001; adjustment for TAC and AI attenuated the associations in women, but not in men (Table 1), resulting in smaller sex differences in associations. Adjustment for measures of microvascular disease had negligible effect on associations in men or women. Table 1Associations between 3DE-derived indices of LV structure and all-cause mortality Men, HR (95% CI), p Women, HR (95% CI), p 3D LVRI† (N = 689; 99 deaths, SD = 0.37 g/ml) (N = 190; 16 deaths, SD = 0.34 g/ml) Model 1 0.77 (0.63, 0.94), 0.012 1.5 (0.95, 2.5), 0.082 + TAC 0.82 (0.66, 1.0), 0.071 1.25 (0.72, 2.1), 0.426 + Central AI 0.82 (0.67, 1.0), 0.072 (N = 629; 89 deaths) 1.23 (0.67, 2.2), 0.504 (N = 170; 13 deaths) + TAC + Central AI 0.87 (0.70, 1.1), 0.260 (N = 629; 89 deaths) 1.1 (0.58, 2.0), 0.801 (N = 170; 13 deaths) + eGFR 0.79 (0.64, 0.96), 0.021 1.5 (0.95, 2.4), 0.083 + Microalbuminuria 0.78 (0.64, 0.95), 0.015 1.6 (0.99, 2.8), 0.053 + eGFR + Microalbuminuria 0.79 (0.65, 0.97), 0.023 1.6 (0.98, 2.7), 0.061 3D EDV (N = 707; 103 deaths, SD = 9.9 ml/m2) (N = 203; 17 deaths, SD = 7.3 ml/m2) Model 1 1.26 (1.1, 1.5), 0.007 0.51 (0.25, 1.1), 0.076 + TAC 1.23 (0.99, 1.5), 0.060 0.78 (0.29, 2.0), 0.613 + Central AI 1.25 (1.04, 1.5), 0.013 (N = 646; 92 deaths) 0.75 (0.31, 1.8), 0.519 (N = 183; 14 deaths) + TAC + Central AI 1.22 (0.98, 1.5), 0.078 (N = 646; 92 deaths) 1.0 (0.38, 3.1), 0.871 (N = 183; 14 deaths) + eGFR 1.23(1.0, 1.45), 0.014 0.51 (0.25, 1.0), 0.071 + Microalbuminuria 1.25 (1.0, 1.5), 0.010 0.60 (0.28, 1.3), 0.189 + eGFR + Microalbuminuria 1.23 (1.0, 1.45), 0.016 0.57 (0.27, 1.2), 0.144 3D ESV (N = 707; 103 deaths, SD = 6.1 ml/m2) (N = 203; 17 deaths, SD = 3.7 ml/m2) Model 1 1.37 (1.14, 1.66), 0.001 0.56 (0.31, 1.0), 0.048 + TAC 1.34 (1.1, 1.6), 0.004 0.68 (0.36, 1.3), 0.221 + Central AI 1.38 (1.13, 1.7), 0.001 (N = 646; 92 deaths) 0.72 (0.36, 1.4), 0.347 (N = 183; 14 deaths) + TAC + Central AI 1.35 (1.1, 1.7), 0.004 (N = 646; 92 deaths) 0.82 (0.40, 1.7), 0.598 (N = 183; 14 deaths) 3D ESV (N = 707; 103 deaths, SD = 6.1 ml/m2) (N = 203; 17 deaths, SD = 3.7 ml/m2) + eGFR 1.34 (1.1, 1.6), 0.002 0.58 (0.32,1.0), 0.059 + Microalbuminuria 1.37 (1.1, 1.6), 0.001 0.58 (0.31, 1.1), 0.079 + eGFR + Microalbuminuria 1.33 (1.1, 1.6), 0.002 0.61 (0.33, 1.1), 0.104 Model 1: adjusted for age, ethnicity, SBP, antihypertensive medication, cholesterol: HDL ratio, BMI, DM, smoking. †LV remodelling index (LVRI) defined as LV mass to end-diastolic volumes (EDV) ratio (the lower numbers for LVRI due to lower available numbers of LV mass (N= 879)). 3D ESV is log transformed. AI, augmentation index (%); EDV, end-diastolic volumes (ml/m2); eGFR, estimated glomerular filtration rate (ml/min/1.73 m2); ESV, end-systolic volumes (ml/m2); HR, hazard ratio; LVRI, left ventricular remodelling index (g/ml); TAC, total arterial compliance (ml/mmHg); SD, standard deviation. Conclusion: In a large tri-ethnic sample of the UK general population, sex differences in associations between 3DE LV structural measures and mortality seem to be partially explained by arterial stiffness and wave reflection.

BackgroundHigh 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.MethodsWe 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.ResultsOne 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.ConclusionThis 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.

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.

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 >25 years of follow-up. Methods: Annual average NO2, SO2 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 NO2, NOx, PM10, PMcoarse and PM2.5. 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 26 years. 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 SO2 and with ESCAPE PM10 and PM2.5 in fully adjusted linear models. Per 10 μg/m3 increase HRs were 1.11 [95% CI: 0.76–1.61] for BS, 1.05 [95% CI: 0.91–1.22] for SO2, 1.16 [95% CI: 0.70–1.92] for PM10 and 1.30 [95% CI: 0.39–4.34] for PM2.5, with largest effects seen in the fourth quartile of BS and PM2.5 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 NO2. Modelling using Cox regression led to similar results. Conclusion: Our results support a detrimental long-term effect for air pollutants on cardiovascular mortality. Keywords: Follow-up studies, Environmental epidemiology, Particulate matter, Particles, Long-term exposure

Summary: Background: Early menopause is linked to an increased risk of cardiovascular disease mortality; however, the association between early menopause and incidence and timing of cardiovascular disease is unclear. We aimed to assess the associations between age at natural menopause and incidence and timing of cardiovascular disease. Methods: We harmonised and pooled individual-level data from 15 observational studies done across five countries and regions (Australia, Scandinavia, the USA, Japan, and the UK) between 1946 and 2013. Women who had reported their menopause status, age at natural menopause (if postmenopausal), and cardiovascular disease status (including coronary heart disease and stroke) were included. We excluded women who had hysterectomy or oophorectomy and women who did not report their age at menopause. The primary endpoint of this study was the occurrence of first non-fatal cardiovascular disease, defined as a composite outcome of incident coronary heart disease (including heart attack and angina) or stroke (including ischaemic stroke or haemorrhagic stroke). We used Cox proportional hazards models to estimate multivariate hazard ratios (HRs) and 95% CIs for the associations between age at menopause and incident cardiovascular disease event. We also adjusted the model to account for smoking status, menopausal hormone therapy status, body-mass index, and education levels. Age at natural menopause was categorised as premenopausal or perimenopausal, younger than 40 years (premature menopause), 40–44 years (early menopause), 45–49 years (relatively early), 50–51 years (reference category), 52–54 years (relatively late), and 55 years or older (late menopause). Findings: Overall, 301 438 women were included in our analysis. Of these 301 438 women, 12 962 (4·3%) had a first non-fatal cardiovascular disease event after menopause, of whom 9369 (3·1%) had coronary heart disease and 4338 (1·4%) had strokes. Compared with women who had menopause at age 50–51 years, the risk of cardiovascular disease was higher in women who had premature menopause (age

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 (

Background: Mean arterial pressure (MAP) is required for many hemodynamic calculations. Most automated devices do not report MAP and a form factor (FF) is used to estimate it from systolic and diastolic blood pressure (BP). The appropriate choice of FF in the brachial artery is controversial: 0.33 is the traditional value, but invasive measurements report a value of 0.4. [1] Non-invasive studies have provided some support for FF = 0.4 but have usually not measured MAP directly, nor used brachial blood pressure waveforms, or accounted for BP measurement errors. We addressed these issues in a sample of white Europeans drawn from the Southall and Brent Revisited study. Methods: BP was measured using a Pulsecor device (USCOM). Form factors (FFosc and FFwave) were calculated as (MAP-diastolic BP)/(systolic BP-diastolic BP) using MAPosc calculated by oscillometry and MAPwave calculated as the waveform mean respectively. Results: Data are mean ± SD of 527 observations (Table 1). FFosc was lower than FFwave and use of FF = 0.4 (MAP0.4) overestimated MAPosc. Allowing for measurement errors based on [2–3] gave estimates of MAPwave that were more similar to MAPosc. Conclusions: Measurement errors confound estimation of MAP using FF. Measurement errors vary substantially between devices [4] precluding a single FF for all studies. Non-invasive MAP should be estimated by oscillometric methods.

Background: Oscillometric mean arterial pressure (MAP) agrees closely with invasive MAP, [1] but most devices do not report MAP and it is usually estimated by a form factor (FF). However, blood pressure (BP) measurement errors will affect FF, its correlations with exposures, and introduce errors into MAP estimated from the BP waveform. Methods: Brachial BP was measured using a Pulsecor device in 1,112 participants in the Southall and Brent Revisited study (68.8 ± 6.1 y; 78.2% male; 47.4% White-European; 38.3% South-Asian; 14.3% African-Caribbean). Form factors (FFosc and FFwave) were calculated as (MAP-diastolic BP)/(systolic BP-diastolic BP) by oscillometry (MAPosc) or from the BP waveform (MAPwave). Results: FFosc and FFwave differed (0.28 (SD = 0.02) vs. 0.36 (SD = 0.04); p

BackgroundCigarette 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 findingsA 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 (ConclusionsThe 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.

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: Arterial stiffness is blood pressure (BP) dependent. Using 24-hour ambulatory BP monitoring (24hABPM) pulse pressure (PP) can be split into an ‘elastic’ part (elPP: ‘diastolic stiffness’), and a ‘stiffening’ part (stPP: ‘stiffness change during systole’). We investigated associations of elPP, stPP and PP with brain MRI measures. Methods: A community-based sample of 542 individuals (59±6y) with 24hABPM and brain MRI, including hippocampal volume (HPCMV), severity of White Matter Hyperintensities (WMH_SVR), and number of brain infarcts (N_INFRCT). ‘High’/’low’ (HI/LO) marked variables status (by medians). Results: elPP and stPP were weakly correlated (r = 0.15); stPP-to-PP ratio was 0.21±0.08. Adjusted HPCMV calculated at age quartiles for the HI_PP cohort correlated better with values from HI_stPP than from HI_elPP. For HI_PP and HP_stPP HPCMV reduction between age quartiles 1&4 was similar, but 20% larger than for HI_elPP. In hypertensives at highest age quartile HPCMV correlated negatively with stPP (P < 0.05: adjusted for age, sex and diabetes), but not with PP and elPP. Adjusted WMH_SVR was greater in HI_elPP, HI_PP and HI_elPP comparing diabetics with non-diabetics by 0.38(P = 0.001), 0.29(P = 0.008) and 0.13 (P = 0.25), respectively. In hypertensives N_INFRCT was greater in past-stroke than no-stroke cohorts in HI&LO elPP, stPP and PP subgroups by 1.96&0.63, 1.48&1.26, and 1.53&1.18 (P < 0.0001 for all). Conclusion: The association of elastic and stiffening components calculated from ambulatory PP differ for different MRI brain measures and may provide a practical tool for associating arterial properties with brain-related pathological changes. Associations with PP may be mainly explained by its relatively-small stiffening component during systole.

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 (VO2max). 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 VO2 (r = 0.75, p < 0.001) and VO2 was lower in women (male-female difference in VO2 = 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 VO2max 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 VO2 and peak heart rate. In conclusion, the 6MST is a convenient, acceptable method of assessing exercise capacity in older adults that allows VO2max 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 VO2. Furthermore, the 6MST results correlate with a previously verified and established self-paced exercise test.

BackgroundSubclinical 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 ResultsA 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 cm3; P

BackgroundHigher circulating levels of the branched-chain amino acids (BCAAs; i.e., isoleucine, leucine, and valine) are strongly associated with higher type 2 diabetes risk, but it is not known whether this association is causal. We undertook large-scale human genetic analyses to address this question.Methods and findingsGenome-wide studies of BCAA levels in 16,596 individuals revealed five genomic regions associated at genome-wide levels of significance (p < 5 × 10-8). The strongest signal was 21 kb upstream of the PPM1K gene (beta in standard deviations [SDs] of leucine per allele = 0.08, p = 3.9 × 10-25), encoding an activator of the mitochondrial branched-chain alpha-ketoacid dehydrogenase (BCKD) responsible for the rate-limiting step in BCAA catabolism. In another analysis, in up to 47,877 cases of type 2 diabetes and 267,694 controls, a genetically predicted difference of 1 SD in amino acid level was associated with an odds ratio for type 2 diabetes of 1.44 (95% CI 1.26-1.65, p = 9.5 × 10-8) for isoleucine, 1.85 (95% CI 1.41-2.42, p = 7.3 × 10-6) for leucine, and 1.54 (95% CI 1.28-1.84, p = 4.2 × 10-6) for valine. Estimates were highly consistent with those from prospective observational studies of the association between BCAA levels and incident type 2 diabetes in a meta-analysis of 1,992 cases and 4,319 non-cases. Metabolome-wide association analyses of BCAA-raising alleles revealed high specificity to the BCAA pathway and an accumulation of metabolites upstream of branched-chain alpha-ketoacid oxidation, consistent with reduced BCKD activity. Limitations of this study are that, while the association of genetic variants appeared highly specific, the possibility of pleiotropic associations cannot be entirely excluded. Similar to other complex phenotypes, genetic scores used in the study captured a limited proportion of the heritability in BCAA levels. Therefore, it is possible that only some of the mechanisms that increase BCAA levels or affect BCAA metabolism are implicated in type 2 diabetes.ConclusionsEvidence from this large-scale human genetic and metabolomic study is consistent with a causal role of BCAA metabolism in the aetiology of type 2 diabetes.

Background: Mid-life cardiovascular risk factors may be detrimental to cognitive function in later life; however results are inconsistent. We investigated the impact of mid-life blood pressure, glucose, cholesterol and obesity on cognitive function. Methods: In a community based sample aged 49.6±6years: waist-to-hip ratio (WHR), fasting blood glucose, HDL cholesterol and blood pressure were measured. 20 years later 1284 of these individuals underwent cognitive function testing to assess global function, executive function, memory and attention. Data are β±SE, *p

Background: Vascular risk factors have been associated with brain aging. We aimed to determine the associations between blood pressure (BP), atherosclerosis, arterial stiffness and microvascular damage with both structural and functional measures of the brain. Methods: A community-based sample of 1287 individuals (69 ± 6 yrs) underwent cognitive function testing and MRI to measure hippocampal brain volumes. Brachial and central systolic BP (SBP, cSBP) and pulse pressure (PP, cPP), diastolic BP (DBP), arterial stiffness (cfPWV), atherosclerosis (cIMT) and microvascular disease (composite from retinopathy, ACR and eGFR measures) were measured. Results: After adjusting for age, sex and ethnicity hippocampal volume was significantly associated with SBP (β ± SE: −0.004 ± 0.002; p = 0.01), PP (β ± SE: −0.008 ± 0.002; p < 0.0001), cPP(β ± SE: −0.01 ± 0.003; p < 0.0001) and cfPWV (β ± SE: −0.02 ± 0.01; p = 0.04). Cognitive function (z-score) was significantly associated with PP (β ± SE: −0.004 ± 0.002; p = 0.003) and cPP (β ± SE: −0.005 ± 0.002; p = 0.02). After further adjustment for concomitant risk factors (heart-rate, diabetes, hypertension, previous stroke, coronary artery disease, waist-to-hip ratio, years of education and smoking) only the associations with PP (Hippocampal volume β ± SE: −0.005 ± 0.002; p = 0.02, cognitive function β ± SE: −0.004 ± 0.001; p = 0.01) and cPP (Hippocampal volume β ± SE: −0.008 ± 0.003; p = 0.004, cognitive function β ± SE: −0.004 ± 0.002; p = 0.048) remained significant. Conclusion: In this community based sample brachial and central PP were significantly associated with measures of brain structure and function, not explained by concomitant risk factors.

There is consistent evidence on the impact of health behaviours on risk of cardiovascular disease (CVD) in European populations. As South Asians in the UK have an excess risk of CVD and coronary heart disease (CHD) compared to Europeans, we investigated whether a similar association between combined health behaviours and risk of CVD and CHD among this high-risk group exists, and estimated the population impact.In a prospective cohort of 1090 Europeans and 1006 South Asians (40-69 y) without prevalent CVD at baseline (1988-1990), followed up for 21 years to 2011, there were 601 incident CVD events [Europeans n = 255; South Asians n = 346] of which 520 were CHD events [n = 207 and 313 respectively]. Participants scored between 0 to 4 points for a composite score including four baseline healthy behaviours (non-smoker, moderate alcohol intake, physically active, frequent fruit/vegetable intake). Adjusted hazard ratios (95% confidence intervals) for incident CHD in Europeans who had three, two, one, and zero compared to four health behaviours were 1.33 (0.78-2.29), 1.96 (1.15-3.33), 1.36 (0.74-2.48) and 2.45 (1.18-5.10), respectively, p-trend = 0.025. In South Asians, corresponding HRs were 2.88 (1.33-6.24), 2.28 (1.06-4.91), 3.36 (1.53-7.39) and 3.48 (1.38-8.81), p-trend = 0.022. The results were similar for incident CVD; Europeans HR 2.12 (1.14-3.94), p-trend = 0.014; South Asians HR 2.73 (1.20-6.21), p-trend = 0.018. The population attributable fraction in Europeans was 43% for CHD and 28% for CVD. In South Asians it was 63% and 51% respectively.Lack of adherence to four combined health behaviours was associated with 2 to 3-fold increased risk of incident CVD in Europeans and South Asians. A substantial population impact in the South Asian group indicates important potential for disease prevention in this high-risk group by adherence to healthy behaviours.

BackgroundChanges in ventricular rotation measured by two-dimensional speckle tracking echocardiography (2DSTE) are early indicators of cardiac disease. Data on the clinical feasibility of this important measure are scarce and there is no information on the comparability of different software versions. We assessed the feasibility, reproducibility and within patient temporal variability of 2DSTE in a large community based sample of older adults. We additionally compared 2DSTE results to those generated by 3DSTE.Methods and results1408 participants underwent transthoracic echocardiography. Using Philips Qlab 8.1 peak LV rotation at either the base or the apex was analysable in 432 (31%) participants. Peak twist measurements were achieved in 274 (20%) participants. 66 participants were randomly selected for the reproducibility study. 20 additional participants had scans 4-6 weeks apart for temporal variability and 3D echocardiography to assess the agreement between 2DSTE and 3DSTE. Reproducibility was evaluated using the intraclass coefficient of correlation (ICC). Better reproducibility for rotation and twist were obtained when measured at the endocardium, and when using more recent software versions, Peak twist and rotation were significantly different using two versions of the same software. Agreement with 3DSTE was better using newer software.ConclusionFeasibility of 2DSTE is low in this cohort of elderly individuals severely limiting its utility in clinical settings. However if high quality images can be acquired assessment of ventricular rotation by 2DSTE is reproducible. Caution should be taken when comparing measurements of ventricular rotation by software from different vendors or different versions of software from the same vendor.

People of South Asian descent have an increased risk of cardiovascular disease (CVD) and diabetes, but little is known about the microcirculation in South Asian people despite evidence that this plays an important role in the aetiology of CVD. We compared the retinal microcirculation in a population-based sample of 287 middle-aged adults (144 European 143 South Asian) matched for age and sex. Retinal photographs were taken and analysed using a validated semi-automated program and microvascular measures were compared. Blood pressure, anthropometry and fasting bloods were also measured. South Asians had significantly fewer arteriolar and venular vessels and bifurcations. Arterioles and venules were longer and venules were also more tortuous in South Asians. These differences were not explained by adjustment for traditional risk factors including blood pressure, body mass index, diabetes or measures of insulin resistance. People of South Asian descent have rarefaction of the retinal microcirculation compared to age-sex matched individuals of European descent. Reduced microvascular density could contribute to the elevated risk of CVD and impaired glucose tolerance in South Asian people.

BACKGROUND:South Asians and African Caribbeans experience more cardiometabolic disease than Europeans. Risk factors include visceral (VAT) and subcutaneous abdominal (SAT) adipose tissue, which vary with ethnicity and are difficult to quantify using anthropometry. OBJECTIVE:We developed and cross-validated ethnicity and gender-specific equations using anthropometrics to predict VAT and SAT. DESIGN:669 Europeans, 514 South Asians and 227 African Caribbeans (70 ± 7 years) underwent anthropometric measurement and abdominal CT scanning. South Asian and African Caribbean participants were first-generation migrants living in London. Prediction equations were derived for CT-measured VAT and SAT using stepwise regression, then cross-validated by comparing actual and predicted means. RESULTS:South Asians had more and African Caribbeans less VAT than Europeans. For basic VAT prediction equations (age and waist circumference), model fit was better in men (R(2) range 0.59-0.71) than women (range 0.35-0.59). Expanded equations (+ weight, height, hip and thigh circumference) improved fit for South Asian and African Caribbean women (R(2) 0.35 to 0.55, and 0.43 to 0.56 respectively). For basic SAT equations, R(2) was 0.69-0.77, and for expanded equations it was 0.72-0.86. Cross-validation showed differences between actual and estimated VAT of

BACKGROUND:To compare disability prevalence rates in the major ethnic groups in the UK and understand the risk factors contributing to differences identified. It was hypothesised that Indian Asian and African Caribbean people would experience higher rates of disability compared with Europeans. METHODS:Data was collected from 888 European, 636 Indian Asian and 265 African Caribbean men and women, aged 58-88 years at 20-year follow-up of community-based cohort study, based in West London. Disability was measured using a performance-based locomotor function test and self-reported questionnaires on functional limitation, and instrumental (IADL) and basic activities of daily living (ADL). RESULTS:The mean (SD) age of participants at follow-up was 69.6 (6.2) years. Compared with Europeans, Indian Asian people were significantly more likely to experience all of the disability outcomes than Europeans; this persisted after adjustment for socioeconomic, behavioural, adiposity and chronic disease risk factors measured at baseline (locomotor dysfunction: adjusted odds ratio (OR) 2.20, 95% CI 1.56-3.11; functional limitation: OR 2.77, 2.01-3.81; IADL impairment: OR 3.12, 2.20-4.41; ADL impairment: OR 1.58, 1.11-2.24). In contrast, a modest excess risk of disability was observed in African Caribbeans, which was abolished after adjustment (e.g. locomotor dysfunction: OR 1.37, 0.90-1.91); indeed a reduced risk of ADL impairment appeared after multivariable adjustment (OR from 0.99, 0.68-1.45 to 0.59, 0.38-0.93), compared with Europeans. CONCLUSIONS:Substantially elevated risk of disability was observed among Indian Asian participants, unexplained by known factors. A greater understanding of determinants of disability and normative functional beliefs of healthy aging is required in this population to inform intervention efforts to prevent disability.