Bayesian dynamic network modelling: an application to metabolic associations in cardiovascular diseases.

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.

Where is VALDO? VAscular Lesions Detection and segmentatiOn challenge at MICCAI 2021.

Imaging markers of cerebral small vessel disease provide valuable information on brain health, but their manual assessment is time-consuming and hampered by substantial intra- and interrater variability. Automated rating may benefit biomedical research, as well as clinical assessment, but diagnostic reliability of existing algorithms is unknown. Here, we present the results of the VAscular Lesions DetectiOn and Segmentation (Where is VALDO?) challenge that was run as a satellite event at the international conference on Medical Image Computing and Computer Aided Intervention (MICCAI) 2021. This challenge aimed to promote the development of methods for automated detection and segmentation of small and sparse imaging markers of cerebral small vessel disease, namely enlarged perivascular spaces (EPVS) (Task 1), cerebral microbleeds (Task 2) and lacunes of presumed vascular origin (Task 3) while leveraging weak and noisy labels. Overall, 12 teams participated in the challenge proposing solutions for one or more tasks (4 for Task 1-EPVS, 9 for Task 2-Microbleeds and 6 for Task 3-Lacunes). Multi-cohort data was used in both training and evaluation. Results showed a large variability in performance both across teams and across tasks, with promising results notably for Task 1-EPVS and Task 2-Microbleeds and not practically useful results yet for Task 3-Lacunes. It also highlighted the performance inconsistency across cases that may deter use at an individual level, while still proving useful at a population level.

Does 3D-speckle tracking echocardiography improve prediction of major cardiovascular events in a multi-ethnic general population? A Southall and Brent Revisited (SABRE) cohort study.

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.

Sex-differences in associations of LV structure and function measured by echocardiography with long-term risk of mortality and cardiovascular morbidity.

Background: Three-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. Methods: 922 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). Results: There 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 <0.1). In men increased LV volumes and LVSI and decreased LVRI and EF were associated with higher mortality, but associations were null or reversed in women (hazard ratios (95% CI) men vs. women: EDV 1.25 (1.05, 1.48) vs. 0.54 (0.26, 1.10); ESV, 1.36 (1.12, 1.63) vs. 0.59 (0.33, 1.04); LVRI, 0.79 (0.64, 0.96) vs. 1.70 (1.03, 2.80); LVSI, 1.27 (1.05, 1.54) vs. 0.61 (0.32, 1.15); and EF, 0.78 (0.66, 0.93) vs. 1.27 (0.69, 2.33). Similar sex differences were observed for associations with the composite cardiovascular outcome. Adjustment for LV diastolic stiffness and arterial stiffness marginally attenuated these differences. Conclusions: 3DE measures of LV volume and remodeling are associated with all-cause mortality and cardiovascular morbidity; however, some associations differ by sex. Sex-differences in LV remodeling patterns may influence mortality and morbidity risk in the general population.

Characterisation of ethnic differences in DNA methylation between UK-resident South Asians and Europeans.

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.

Cerebral perfusion in untreated, controlled, and uncontrolled hypertension.

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.

Accelerated vascular aging: Ethnic differences in basilar artery length and diameter, and its association with cardiovascular risk factors and cerebral small vessel disease.

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.

Skeletal Muscle Tissue Saturation Changes Measured Using Near Infrared Spectroscopy During Exercise Are Associated With Post-Occlusive Reactive Hyperaemia.

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 (ß-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 (ß-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 (ß-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.

Antihypertensive treatment effect on exercise blood pressure and exercise capacity in older adults.

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 ±â€ŠSD: 73 ±â€Š6.6 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.

Relationship Between Image Quality and Bias in 3D Echocardiographic Measures: Data From the SABRE (Southall and Brent Revisited) Study.

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.

Genetic and observational evidence: No independent role for cholesterol efflux over static high-density lipoprotein concentration measures in coronary heart disease risk assessment.

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.

Impact of afterload and infiltration on coexisting aortic stenosis and transthyretin amyloidosis.

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. 99mTc-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.

Inflammatory status, body composition and ethnic differences in bone mineral density: The Southall and Brent Revisited Study.

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 ß (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.

Carotid atherosclerosis in people of European, South Asian and African Caribbean ethnicity in the Southall and Brent revisited study (SABRE).

Background: Atherosclerotic 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. Aim: To 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. Methods: Cardiovascular 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). Results: Prevalence 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. Conclusion: Prevalence 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.

Corrigendum: Imaging Protocol, Feasibility, and Reproducibility of Cardiovascular Phenotyping in a Large Tri-Ethnic Population-Based Study of Older People: The Southall and Brent Revisited (SABRE) Study.

[This corrects the article DOI: 10.3389/fcvm.2020.591946.].

Association between sleep quality and type 2 diabetes at 20-year follow-up in the Southall and Brent REvisited (SABRE) cohort: a triethnic analysis.

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.

Metformin and carotid intima-media thickness in never-smokers with type 1 diabetes: The REMOVAL trial.

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.

Sex differences in the contribution of different physiological systems to physical function in older adults.

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 ß-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 ß-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.

Antihypertensive Medication Use and Its Effects on Blood Pressure and Haemodynamics in a Tri-ethnic Population Cohort: Southall and Brent Revisited (SABRE).

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.

Establishing reference intervals for triglyceride-containing lipoprotein subfraction metabolites measured using nuclear magnetic resonance spectroscopy in a UK population.

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.