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Background: Cognitive function has an important role in determining the quality of life of older adults. Cardiovascular disease (CVD) is common in older people and may compromise cognitive performance; however, the extent to which this is related to carotid atherosclerosis is unclear. Aim: We investigated associations between carotid atherosclerosis and cognitive function and neuroimaging markers of brain health in a UK multi-ethnic community-based sample including older people of European, South Asian, and African-Caribbean ethnicity. Methods: Carotid plaques and intima-media thickness (cIMT) were assessed using ultrasound in 985 people (mean age 73.2y, 56 % male). Associations of carotid atherosclerosis with cognitive function (memory, executive function, language and CSI-D, a global measure of cognitive state) and neuroimaging measures (total brain volume, hippocampal volume, white matter (WM) lesion volume and coalescence score) were analysed using regression analyses, with and without adjustment for potential confounders using two models: 1) adjustment for age, sex, and ethnicity; 2) model 1 plus education, physical activity category, body mass index, hypertension, diabetes, total and high density lipoprotein cholesterol, atrial fibrillation, smoking, previous CVD, alcohol consumption, and presence of chronic kidney disease. Results: People with carotid plaque or higher cIMT had lower CSI-D score, poorer memory poorer executive function and higher WM lesion volume and coalescence. Language was poorer in people with plaque but was not correlated with cIMT. Associations with plaque were preserved after full adjustment (model 2) but relationships for cIMT were attenuated. Associations with other plaque characteristics were generally unconvincing after adjustment. Conclusions: This multi-ethnic cohort study provides evidence that presence of carotid plaque, is associated with poorer cognitive function and brain health.

Introduction 4.2 million individuals in the UK have type 2 diabetes, a known risk factor for dementia and mild cognitive impairment (MCI). Diabetes treatment may modify this association, but existing evidence is conflicting. We therefore aimed to assess the association between metformin therapy and risk of incident all-cause dementia or MCI compared with other oral glucose-lowering therapies (GLTs).Research design and methods We conducted an observational cohort study using the Clinical Practice Research Datalink among UK adults diagnosed with diabetes at ≥40 years between 1990 and 2019. We used an active comparator new user design to compare risks of dementia and MCI among individuals initially prescribed metformin versus an alternative oral GLT using Cox proportional hazards regression controlling for sociodemographic, lifestyle and clinical confounders. We assessed for interaction by age and sex. Sensitivity analyses included an as-treated analysis to mitigate potential exposure misclassification.Results We included 211 396 individuals (median age 63 years; 42.8% female), of whom 179 333 (84.8%) initiated on metformin therapy. Over median follow-up of 5.4 years, metformin use was associated with a lower risk of dementia (adjusted HR (aHR) 0.86 (95% CI 0.79 to 0.94)) and MCI (aHR 0.92 (95% CI 0.86 to 0.99)). Metformin users aged under 80 years had a lower dementia risk (aHR 0.77 (95% CI 0.68 to 0.85)), which was not observed for those aged ≥80 years (aHR 0.95 (95% CI 0.87 to 1.05)). There was no interaction with sex. The as-treated analysis showed a reduced effect size compared with the main analysis (aHR 0.90 (95% CI 0.83 to 0.98)).Conclusions Metformin use was associated with lower risks of incident dementia and MCI compared with alternative GLT among UK adults with diabetes. While our findings are consistent with a neuroprotective effect of metformin against dementia, further research is needed to reduce risks of confounding by indication and assess causality.

Background People who live alone experience greater levels of mental illness; however, it is unclear whether the COVID-19 pandemic had a disproportionately negative impact on this demographic.Objective To describe the mental health gap between those who live alone and with others in the UK prior to and during the COVID-19 pandemic.Methods Self-reported psychological distress and life satisfaction in 10 prospective longitudinal population surveys (LPSs) assessed in the nearest pre-pandemic sweep and three periods during the pandemic. Recorded diagnosis of common and severe mental illnesses between March 2018 and January 2022 in electronic healthcare records (EHRs) within the OpenSAFELY-TPP.Findings In 37 544 LPS participants, pooled models showed greater psychological distress (standardised mean difference (SMD): 0.09 (95% CI: 0.04; 0.14); relative risk: 1.25 (95% CI: 1.12; 1.39)) and lower life satisfaction (SMD: −0.22 (95% CI: −0.30; −0.15)) for those living alone pre-pandemic. This gap did not change during the pandemic. In the EHR analysis of c.16 million records, mental health conditions were more common in those who lived alone (eg, depression 26 (95% CI: 18 to 33) and severe mental illness 58 (95% CI: 54 to 62) more cases more per 100 000). For common mental health disorders, the gap in recorded cases in EHRs narrowed during the pandemic.Conclusions People living alone have poorer mental health and lower life satisfaction. During the pandemic, this gap in self-reported distress remained; however, there was a narrowing of the gap in service use.Clinical implications Greater mental health need and potentially greater barriers to mental healthcare access for those who live alone need to be considered in healthcare planning.

Abstract Background Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery. Results To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N = 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3–5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism. Conclusions Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.

Abstract While there is growing evidence of associations between infections and dementia risk, associations with cognitive impairment and potential structural correlates of cognitive decline remain underexplored. Here we aimed to investigate the presence and nature of any associations between common infections, cognitive decline and neuroimaging parameters. The UK Biobank is a large volunteer cohort (over 500,000 participants recruited aged 40–69) with linkage to primary and secondary care records. Using linear mixed effects models, we compared participants with and without a history of infections for changes in cognitive function during follow-up. Linear regression models were used to investigate the association of infections with hippocampal and white matter hyperintensity (WMH) volume. 16,728 participants (median age 56.0 years [IQR 50.0–61.0]; 51.3% women) had baseline and follow-up cognitive measures. We found no evidence of an association between the presence of infection diagnoses and cognitive decline for mean correct response time (slope difference [infections versus no infections] = 0.40 ms, 95% CI: −0.17–0.96 per year), visual memory (slope difference 0.0004 log errors per year, 95% CI: −0.003–0.004, fluid intelligence (slope difference 0.007, 95% CI: −0.010–0.023) and prospective memory (OR 0.88, 95% CI: 0.68–1.14). No evidence of an association was found between infection site, setting or frequency and cognitive decline except for small associations on the visual memory test. We found no association between infections and hippocampal or WMH volume. Limitations of our study include selection bias, potential practice effects and the relatively young age of our cohort. Our findings do not support a major role for common midlife infections in contributing to cognitive decline for this cohort. Further research is warranted in individuals with more severe infections, for infections occurring later in life.

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 MicroRNA-146a-5p (miR-146a-5p) is a key regulator of inflammatory processes. Expression of miR-146a-5p is altered in target organs of diabetic complications and deficiency of miR-146a-5p has been implicated in their pathogenesis. We investigated if serum miR-146a-5p levels were independently associated with micro/macrovascular complications of type 1 diabetes (DM1). Methods A nested case–control study from the EURODIAB PCS of 447 DM1 patients was performed. Cases (n = 294) had one or more complications of diabetes, whereas controls (n = 153) did not have any complication. Total RNA was isolated from all subjects and miR-146a-5p levels measured by qPCR. Both the endogenous controls U6 snRNA and the spike (Cel-miR-39) were used to normalize the results. Logistic regression analysis was carried out to investigate the association of miR-146a-5p with diabetes complications. Results MiR-146a-5p levels were significantly lower in cases [1.15 (0.32–3.34)] compared to controls [1.74 (0.44–6.74) P = 0.039]. Logistic regression analysis showed that levels of miR-146a-5p in the upper quartile were inversely associated with reduced odds ratio (OR) of all complications (OR 0.34 [95% CI 0.14–0.76]) and particularly with cardiovascular diseases (CVD) (OR 0.31 [95% CI 0.11–0.84]) and diabetic retinopathy (OR 0.40 [95% CI 0.16–0.99]), independently of age, sex, diabetes duration, A1c, hypertension, AER, eGFR, NT-proBNP, and TNF-α. Conclusions In this large cohort of DM1 patients, we reported an inverse and independent association of miR-146a-5p with diabetes chronic complications and in particular with CVD and retinopathy, suggesting that miR-146a-5p may be a novel candidate biomarker of DM1 complications.

There is an increasing body of evidence suggesting that vascular disease could contribute to cognitive decline and overt dementia. Of particular interest is atherosclerosis, as it is not only associated with dementia, but could be a potential mechanism through which cardiovascular disease directly impacts brain health. In this work, we evaluated the differences in functional near infrared spectroscopy (fNIRS)-based measures of brain activation, task performance, and the change in central hemodynamics (mean arterial pressure (MAP) and heart rate (HR)) during a Stroop color-word task in individuals with atherosclerosis, defined as bilateral carotid plaques (n = 33) and healthy age-matched controls (n = 33). In the healthy control group, the left prefrontal cortex (LPFC) was the only region showing evidence of activation when comparing the incongruous with the nominal Stroop test. A smaller extent of brain activation was observed in the Plaque group compared with the healthy controls (1) globally, as measured by oxygenated hemoglobin (p = 0.036) and (2) in the LPFC (p = 0.02) and left sensorimotor cortices (LMC)(p = 0.008) as measured by deoxygenated hemoglobin. There were no significant differences in HR, MAP, or task performance (both in terms of the time required to complete the task and number of errors made) between Plaque and control groups. These results suggest that carotid atherosclerosis is associated with altered functional brain activation patterns despite no evidence of impaired performance of the Stroop task or central hemodynamic changes.

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.

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

Abstract Background The T 1 Mapping and Extracellular volume (ECV) Standardization (T1MES) program explored T 1 mapping quality assurance using a purpose-developed phantom with Food and Drug Administration (FDA) and Conformité Européenne (CE) regulatory clearance. We report T 1 measurement repeatability across centers describing sequence, magnet, and vendor performance. Methods Phantoms batch-manufactured in August 2015 underwent 2 years of structural imaging, B 0 and B 1, and “reference” slow T 1 testing. Temperature dependency was evaluated by the United States National Institute of Standards and Technology and by the German Physikalisch-Technische Bundesanstalt. Center-specific T 1 mapping repeatability (maximum one scan per week to minimum one per quarter year) was assessed over mean 358 (maximum 1161) days on 34 1.5 T and 22 3 T magnets using multiple T 1 mapping sequences. Image and temperature data were analyzed semi-automatically. Repeatability of serial T 1 was evaluated in terms of coefficient of variation (CoV), and linear mixed models were constructed to study the interplay of some of the known sources of T 1 variation. Results Over 2 years, phantom gel integrity remained intact (no rips/tears), B 0 and B 1 homogenous, and “reference” T 1 stable compared to baseline (% change at 1.5 T, 1.95 ± 1.39%; 3 T, 2.22 ± 1.44%). Per degrees Celsius, 1.5 T, T 1 (MOLLI 5s(3s)3s) increased by 11.4 ms in long native blood tubes and decreased by 1.2 ms in short post-contrast myocardium tubes. Agreement of estimated T 1 times with “reference” T 1 was similar across Siemens and Philips CMR systems at both field strengths (adjusted R 2 ranges for both field strengths, 0.99–1.00). Over 1 year, many 1.5 T and 3 T sequences/magnets were repeatable with mean CoVs

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: : Healthcare workers (HCWs) have increased rates of SARS-CoV-2 infection compared with the general population. We aimed to understand ethnic differences in SARS-CoV-2 seropositivity among hospital healthcare workers depending on their hospital role, socioeconomic status, Covid-19 symptoms and basic demographics. Methods: A prospective longitudinal observational cohort study. 1364 HCWs at five UK hospitals were studied with up to 16 weeks of symptom questionnaires and antibody testing (to both nucleocapsid and spike protein) during the first UK wave in five NHS hospitals between March 20 and July 10 2020. The main outcome measures were SARS-CoV-2 infection (seropositivity at any time-point) and symptoms. Registration number: NCT04318314. Findings: 272 of 1364 HCWs (mean age 40.7 years, 72% female, 74% White, ≥6 samples per participant) seroconverted, reporting predominantly mild or no symptoms. Seropositivity was lower in Intensive Therapy Unit (ITU) workers (OR=0.44 95%CI 0.24, 0.77; p=0.0035). Seropositivity was higher in Black (compared to White) participants, independent of age, sex, role and index of multiple deprivation (OR=2.61 95%CI 1.47-4.62 p=0.0009). No association was seen between White HCWs and other minority ethnic groups. Interpretation: In the UK first wave, Black ethnicity (but not other ethnicities) more than doubled HCWs likelihood of seropositivity, independent of age, sex, measured socio-economic factors and hospital role.

Purpose: To define and compare cardiovascular (CV) health scores (CHS) from adolescence (17 yrs) to emerging adulthood (24 yrs) using longitudinal data from a large British birth cohort. Methods: 3142 participants from the Avon Longitudinal Study of Parents and Children (ALSPAC) study attended clinical investigations at 17.8 ± 0.4 yrs and 24.0 ± 0.8 yrs (38% male). CV health was assessed using smoking status, body mass index (BMI), plasma glucose, cholesterol, sitting brachial blood pressure, left ventricle (LV) hypertrophy, arterial stiffness (carotid-to-femoral pulse wave velocity) and atherosclerosis (carotid intima-media thickness) metrics. Prevalence was stratified into poor (0_points), intermediate (1_point) and ideal (2_points) health categories and a composite, individual-level CHS for all 8 metrics was calculated (total range, 0–16 points). Prevalence of ideal health was assessed using ANOVA and linear mixed modelling assessed age##sex modifications. Results: Overall CHS was high at 17 yrs but from 17–24 yrs the proportion of ideal scores decreased for all metrics, in both sexes (Table). The average overall CHS decreased from 14.97 ± 1.1 to 13.99 ± 1.4 in males (p < 0.0001) and 14.82 ± 1.2 to 14.28 ± 1.4 in females (p < 0.0001, age##sex p = 0.0001). Significant sex differences were observed in the proportion of individuals with ideal health at both ages, with males having a higher CHS than females at 17 yrs but a lower CHS at 24 yrs. Male Female Sex differences Age 17 yrs 24 yrs 17 yrs 24 yrs 17 24 Age##sex Score 0 1 2 0 1 2 p 0 1 2 0 1 2 p p p p Smoking 22.6 19.3 58.1 27.8 35.6 36.6

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.

Introduction Diabetes is observed to increase cancer risk, leading to hypothesized direct effects of either hyperglycemia or medication. We investigated associations between glycosylated hemoglobin (HbA1c) across the whole glycemic spectrum and incidence of 16 cancers in a population sample with comprehensive adjustment for risk factors and medication.Research design and methods Linked data from the UK Biobank and UK cancer registry for all individuals with baseline HbA1c and no history of cancer at enrollment were used. Incident cancer was based on International Classification of Diseases – 10th Edition diagnostic codes. Age-standardized incidence rates were estimated by HbA1c category. Associations between HbA1c, modeled as a restricted cubic spline, and cancer risk were estimated using Cox proportional hazards models.Results Among 378 253 individuals with average follow-up of 7.1 years, 21 172 incident cancers occurred. While incidence for many of the 16 cancers was associated with hyperglycemia in crude analyses, these associations disappeared after multivariable adjustment, except for pancreatic cancer (HR 1.55, 95% CI 1.22 to 1.98 for 55 vs 35 mmol/mol), and a novel finding of an inverse association between HbA1c and premenopausal breast cancer (HR 1.27, 95% CI 1.00 to 1.60 for 25 vs 35 mmol/mol; HR 0.71, 95% CI 0.54 to 0.94 for 45 vs 35 mmol/mol), not observed for postmenopausal breast cancer. Adjustment for diabetes medications had no appreciable impact on HRs for cancer.Conclusions Apart from pancreatic cancer, we did not demonstrate any independent positive association between HbA1c and cancer risk. These findings suggest that the potential for a cancer-inducing, direct effect of hyperglycemia may be misplaced.

BackgroundWave intensity analysis provides valuable information on ventriculo-arterial function, hemodynamics, and energy transfer in the arterial circulation. Widespread use of wave intensity analysis is limited by the need for concurrent measurement of pressure and flow waveforms. We describe a method that can estimate wave intensity patterns using only non-invasive pressure waveforms (pWIA).MethodsRadial artery pressure and left ventricular outflow tract (LVOT) flow velocity waveforms were recorded in 12 participants in the Southall and Brent Revisited (SABRE) study. Pressure waveforms were analyzed using custom-written software to derive the excess pressure (Pxs) which was scaled to peak LVOT velocity and used to calculate wave intensity. These data were compared with wave intensity calculated using the measured LVOT flow velocity waveform. In a separate study, repeat measures of pWIA were performed on 34 individuals who attended two clinic visits at an interval of ≈1 month to assess reproducibility and reliability of the method.ResultsPxs waveforms were similar in shape to aortic flow velocity waveforms and the time of peak Pxs and peak aortic velocity agreed closely. Wave intensity estimated using pWIA showed acceptable agreement with estimates using LVOT velocity tracings and estimates of wave intensity were similar to values reported previously in the literature. The method showed fair to good reproducibility for most parameters.ConclusionThe Pxs is a surrogate of LVOT flow velocity which, when appropriately scaled, allows estimation of aortic wave intensity with acceptable reproducibility. This may enable wider application of wave intensity analysis to large studies.

BackgroundType 2 diabetes mellitus (T2DM) disproportionately affects individuals of nonwhite ethnic origin. Timely and appropriate initiation and intensification of glucose-lowering therapy is key to reducing the risk of major vascular outcomes. Given that ethnic inequalities in outcomes may stem from differences in therapeutic management, the aim of this study was to identify ethnic differences in the timeliness of initiation and intensification of glucose-lowering therapy in individuals newly diagnosed with T2DM in the United Kingdom.Methods and findingsAn observational cohort study using the Clinical Practice Research Datalink was conducted using 162,238 adults aged 18 and over diagnosed with T2DM between 1990 and 2017 (mean age 62.7 years, 55.2% male); 93% were of white ethnicity (n = 150,754), 5% were South Asian (n = 8,139), and 2.1% were black (n = 3,345). Ethnic differences in time to initiation and intensification of diabetes treatment were estimated at three time points (initiation of noninsulin monotherapy, intensification to noninsulin combination therapy, and intensification to insulin therapy) using multivariable Cox proportional hazards regression adjusted for factors a priori hypothesised to be associated with initiation and intensification: age, sex, deprivation, glycated haemoglobin (HbA1c), body mass index (BMI), smoking status, comorbidities, consultations, medications, calendar year, and clustering by practice. Odds of experiencing therapeutic inertia (failure to intensify treatment within 12 months of HbA1c >7.5% [58 mmol/mol]), were estimated using multivariable logistic regression adjusted for the same hypothesised confounders. Noninsulin monotherapy was initiated earlier in South Asian and black groups (South Asian HR 1.21, 95% CI 1.08-1.36, p < 0.001; black HR 1.29, 95% CI 1.05-1.59, p = 0.017). Correspondingly, no ethnic differences in therapeutic inertia were evident at initiation. Intensification with noninsulin combination therapy was slower in both nonwhite ethnic groups relative to white (South Asian HR 0.80, 95% CI 0.74-0.87, p < 0.001; black HR 0.79, 95% CI 0.70-0.90, p < 0.001); treatment inertia at this stage was greater in nonwhite groups relative to white (South Asian odds ratio [OR] 1.45, 95% CI 1.23-1.70, p < 0.001; black OR 1.43, 95% CI 1.09-1.87, p = 0.010). Intensification to insulin therapy was slower again for black groups relative to white groups (South Asian HR 0.49, 95% CI 0.41-0.58, p < 0.001; black HR 0.69, 95% CI 0.53-0.89, p = 0.012); correspondingly, treatment inertia was significantly higher in nonwhite groups at this stage relative to white groups (South Asian OR 2.68, 95% CI 1.89-3.80 p < 0.001; black OR 1.82, 95% CI 1.13-2.79, p = 0.013). At both stages of treatment intensification, nonwhite groups had fewer HbA1c measurements than white groups. Limitations included variable quality and completeness of routinely recorded data and a lack of information on medication adherence.ConclusionsIn this large UK cohort, we found persuasive evidence that South Asian and black groups intensified to noninsulin combination therapy and insulin therapy more slowly than white groups and experienced greater therapeutic inertia following identification of uncontrolled HbA1c. Reasons for delays are multifactorial and may, in part, be related to poorer long-term monitoring of risk factors in nonwhite groups. Initiatives to improve timely and appropriate intensification of diabetes treatment are key to reducing disparities in downstream vascular outcomes in these populations.

The commonest causes of dementia are Alzheimer’s disease and vascular cognitive impairment. Although these conditions have been viewed as distinct entities, there is increasing evidence that neurodegenerative and vascular pathologies interact or overlap to cause cognitive decline, and that at least in some cases individuals at risk of cognitive decline exhibit abnormal cardiovascular physiology long before emergence of disease. However, the mechanisms linking haemodynamic disturbances with cognitive impairment and the various pathologies that cause dementia are poorly understood. A sub-sample of 502 participants from the Medical Research Council National Survey of Health and Development (NSHD) have participated in the first visit of a neuroscience sub-study referred to as Insight 46, where clinical, cognitive, imaging, and lifestyle data have been collected for the purpose of elucidating the pathological changes preceding dementia. This paper outlines the cardiovascular phenotyping performed in the follow-up visit of Insight 46, with the study participants now aged 74. In addition to standard cardiovascular assessments such as blood pressure measurements, echocardiography, and electrocardiography (ECG), functional Near Infrared Spectroscopy (fNIRS) has been included to provide an assessment of cerebrovascular function. A detailed description of the fNIRS protocol along with preliminary results from pilot data is presented. The combination of lifestyle data, brain structure/function, cognitive performance, and cardiovascular health obtained not only from Insight 46, but also from the whole NSHD provides an exciting opportunity to advance our understanding of the cardiovascular mechanisms underlying dementia and cognitive decline, and identify novel targets for intervention.

[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.

Abstract Introduction Adult obesity is associated with greater arterial stiffness however in youth the relationship is unclear. We investigated associations between arterial stiffness and adiposity and explored the contribution of blood pressure from adolescence to emerging adulthood (17–24 yrs). Methods 3885 individuals (2152 female) had measurements of carotid-femoral pulse wave velocity (PWV), DXA total fat mass (TFM) and mean arterial pressure (MAP). Measurements were repeated aged 24 yrs (n = 1659). Linear regression and mixed models assessed sex—stratified associations between PWV, TFM and MAP, and age interactions. Results From 17–24 yrs PWV, TFM and MAP increased (Table 1). TFM showed a weak negative association with PWV in males at 17 yrs and 24 yrs. A positive association was observed in females at 17 yrs which was stronger at 24 yrs (pinteraction = 0.03). After adjustment for MAP the negative association was stronger in males and a negative association emerged in females aged 17 yrs; at 24 yrs the association remained positive in females. Adjustment for smoking, socioeconomic status and education attenuated associations in females aged 24, but otherwise had minimal effects. MAP was positively associated with PWV in both males and females at 17 yrs and 24 yrs; however, the association was weaker at 24 yrs, especially in males (pinteraction < 0.0001). Conclusion The association between adiposity and arterial stiffness differs by sex, is modified by age and influenced by blood pressure. In emerging adolescence, a positive association is seen between adiposity and PWV in women, suggesting that this may be an important time to control adiposity to provide long term cardiovascular benefits. Table 1 17 years 24 years Male Female Male Female Male Female mean ± SD mean ± SD mean ± SD mean ± SD Mean difference ± SD PWV (m/s) 6.1 ± 0.7 5.5 ± 0.6 6.7 ± 1.2 6.1 ± 0.7 0.65 ± 0.1** 0.55 ± 0.9** TFM (kg) 13.0 ± 8.8 20.9 ± 8.5 20.3 ± 9.3 24.5 ± 10.3 7.3 ± 6.5** 3.7 ± 6.5** MAP (mmHg) 83.0 ± 6.5 80.8 ± 6.5 85.5 ± 7.7 81.3 ± 7.7 2.5 ± 7.4** 0.5 ± 7.4* Regression analysis PWV and TFM β (95% CI) β (95% CI) β (95% CI) β (95% CI) TFM##age p-value Age −0.004 (−0.10, 0.03) 0.083 (0.004, 0.0)** −0.072 (−0.18, 0.04) 0.17 (0.10, 0.23)** 0.3 0.03 + MAP −0.13 (−0.20, −0.06)** −0.020 (−0.07, 0.03) −0.12 (−0.24, −0.001)* 0.10 (0.03, 0.17)** 0.16 0.05 + SES education and smoking −0.13 (−0.2, −0.06)** −0.025 (−0.08, 0.03) −0.13 (−0.26, 0.0007)* 0.05 (−0.025, 0.12) 0.4 0.7 PWV and MAP MAP##age p-value Age 0.16 (0.10, 0.22)** 0.24 (0.20, 0.28)** 0.06 (−0.04, 0.15) 0.20 (0.13, 0.26)**

Introduction: In adults, aging is associated with a rise in blood pressure (BP) and a disproportionate increase in central systolic blood pressure (cSBP) relative to brachial SBP (bSBP) (i.e. reduced aortic to radial pulse pressure amplification (PPamp)). But changes in brachial and central BP have not been studied in the transition from adolescence to early adulthood when PPamp is greatest. We therefore investigated changes in BP over this age period in a large population-based birth cohort. Methods: 1835 participants (1099 female) in the Avon Longitudinal Study of Parents and Children (ALSPAC) underwent repeat clinic examination, including measurements of brachial and central BP, aged 17 yrs and 24 yrs. Measures at 17 to 24 yrs were compared with paired t-tests. Results: Aged 17 yrs the difference between bSBP and cSBP was 19.7 ± 4.7 mmHg, while at 24yrs the difference was 18.2 ± 4.6 mmHg (age interaction p < 0.001). From 17 to 24 yrs diastolic BP increased, bSBP decreased and cSBP increased, PPamp decreased while augmentation index (AIx) increased (Table 1). Table 1 Variables Mean ± SD at 17 Mean ± SD at 24 Difference (95% CI) p bSBP (mmHg) 116.2 ± 11.5 115.3 ± 11.0 −0.93 (−1.4, −0.47) 0.001 cSBP (mmHg) 96.5 ± 0.2 97.1 ± 0.2 0.58 (0.17, 0.99) 0.006 DBP (mmHg) 64.5 ± 0.2 66.6 ± 0.2 2.1 (1.7, 2.5)

Background: Measurement of wave intensity (WI) requires simultaneous or quasi-simultaneous measurement of pressure and flow limiting its use. Previous work in dogs [1] and humans [2] has shown that the excess pressure waveforms calculated using reservoir analysis correspond closely with aortic flow waveforms. This offers a potential method to estimate WI using only pressure waveforms (pWI). We investigated the feasibility of this approach and agreement with established methods. Methods: 262 participants (68.3 (SD = 5.5); 74% male) without aortic stenosis or heart failure were recruited from a UK-based longitudinal study, Southall and Brent Revisited. Central pressure waveforms, aortic flow velocity and carotid WI were measured using tonometry (Sphygmocor, AtCor), echocardiography (iE33, Philips) and ultrasonography (SSD-5500, Aloka) respectively. Reservoir analysis was performed as previously described [2] and excess pressure waveforms were calibrated to flow velocity assuming a peak velocity of 1 m/s. Method agreement was assessed as mean difference (MD), limits of agreement (LOA) and concordance coefficient (CC). Results: Analysis failed in 9 individuals; results for those with analysable data are shown in Table 1. Aortic pWI was higher than aortic WI but showed good concordance (logW1: MD(LOA) = −0.41(−0.73, −0.09) CC = 0.7; logW2: MD(LOA) = −0.41 (−0.73, −0.09); CC = 0.7). Agreement of pWI with carotid WI showed no bias and concordance was fair to poor (logW1: MD (LOA) = −0.16 (−1.30, 0.99) CC = 0.3; logW2: MD (LOA) = −0.02 (−1.23, 1.2); CC = 0.1). Table 1Results Variables N Median/(%) p25 p75 Age, y 207 67.9 63.6 71.9 BMI, kg/m2 207 26.6 24.1 30.1 Systolic BP, mmHg 207 139 126 148 Diastolic BP, mmHg 207 76 70 82 Heart rate, bpm 207 66 59 74.5 Male sex, % 150 72.5 Ethnicity European 88 (42.5%) South Asian 75 (36.2%) African Caribbean 44 (21.3%) Current smoker 18 (8.8%) Diabetes 65 (31.4%) Hypertension 130 (62.8%) Aorta W1, mmHg.m.s−3 207 7103 5041 9910 W2, mmHg.m.s−3 207 1637 1147 2518 pW1, mmHg.m.s−3 207 10,526 7677 14,336 pW2, mmHg.m.s−3 207 2491 1779 3560 time W1 to W2, s 207 0.25 0.23 0.27 Peak velocity, m/s 207 1.34 1.2 1.46 Carotid artery W1, mmHg.m.s-3 207 8714 6550 12,883 W2, mmHg.m.s-3 207 2327 1471 3227 time W1 to W2, s 207 0.29 0.27 0.31 Peak velocity, m/s 207 1.10 0.92 1.30 BMI, body mass index; BP, blood pressure; p25, 25th centile; p75, 75th centile; pW1, peak intensity of initial forward compression wave (W1) estimated using pressure only; pW2, peak intensity of initial forward compression wave (W2) estimated using pressure only; W1, peak intensity of initial forward compression wave (W1) calculated using aortic velocity; W2, peak intensity of initial forward compression wave (W2) calculated using aortic velocity. Conclusion: Estimation of aortic WI from pressure waveforms using reservoir analysis is feasible.

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.

Abstract Background Altered regulation of extracellular matrix (ECM) composition by matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinase (TIMPs) may contribute to arterial stiffening. We investigated associations between circulating MMP-1, -2, -3, -9, -10 and TIMP-1, and carotid-femoral pulse wave velocity (cfPWV) and pulse pressure (PP), as markers of arterial stiffness in type 1 diabetic patients. Methods Individuals with type 1 diabetes from three different cohorts were included in this study: EURODIAB Prospective Complications study (n = 509), LEACE (n = 370) and PROFIL (n = 638). Linear regression analyses were used to investigate cross-sectional associations between circulating levels of MMP-1, -2, -3, -9, -10, and TIMP-1 and cfPWV (n = 614) as well as office PP (n = 1517). Data on 24-h brachial and 24-h central PP were available in 638 individuals from PROFIL. Analyses were adjusted for age, sex, duration of diabetes, HbA1c, mean arterial pressure (MAP), and eGFR, and additionally for other cardiovascular risk factors and presence of vascular complications. Results After adjustment for potential confounders and presence of vascular complications, circulating MMP-3 was associated with cfPWV [β per 1 SD higher lnMMP3 0.29 m/s (0.02; 0.55)]. In addition, brachial and central 24-h PP measurements in PROFIL were significantly associated with MMP-2 [(1.40 (0.47:2.33) and 1.43 (0.63:2.23)]. Pooled data analysis showed significant associations of circulating levels of MMP-1 and MMP-2 with office PP [β per 1 SD higher lnMMP-1 and lnMMP-2 = − 0.83 mmHg (95% CI − 1.50; − 0.16) and = 1.33 mmHg (0.55; 2.10), respectively]. Conclusions MMPs-1, -2, and -3 are independently associated with markers of arterial stiffening in patients with type 1 diabetes and may become therapeutic targets.

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

Background The “healthy obese” hypothesis suggests the risks associated with excess adiposity are reduced in those with higher muscle quality (mass/strength). Alternative possibilities include loss of muscle quality as people become unwell (reverse causality) or unmeasured confounding. Methods and Results We conducted a cohort study using the UK Biobank (n=452 931). Baseline body mass index (BMI) was used to quantify adiposity and handgrip strength (HGS) used for muscle quality. Outcomes were fatal and non‐fatal cardiovascular disease, and mortality. As a secondary analysis we used waist‐hip‐ratio or fat mass percentage instead of BMI, and skeletal muscle mass index instead of HGS. In a subsample, we used gene scores for BMI, waist‐hip‐ratio and HGS in a Mendelian randomization (MR). BMI defined obesity was associated with an increased risk of all outcomes (hazard ratio [HR] range 1.10–1.82). Low HGS was associated with increased risks of cardiovascular and all‐cause mortality (HR range 1.39–1.72). HRs for the association between low HGS and cardiovascular disease events were smaller (HR range 1.05–1.09). There was no suggestion of an interaction between HGS and BMI to support the healthy obese hypothesis. Results using other adiposity metrics were similar. There was no evidence of an association between skeletal muscle mass index and any outcome. Factorial Mendelian randomization confirmed no evidence for an interaction. Low genetically predicted HGS was associated with an increased risk of mortality (HR range 1.08–1.19). Conclusions Our analyses do not support the healthy obese concept, with no evidence that the adverse effect of obesity on outcomes was reduced by improved muscle quality. Lower HGS was associated with increased risks of mortality in both observational and MR analyses, suggesting reverse causality may not be the sole explanation.

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 (

Objective: Exaggerated exercise blood pressure (BP) is associated with higher left-ventricular mass index (LVMI). Paradoxically, exercise BP and LVMI may be higher with greater fitness, but underlying factors are poorly understood. This study aimed to determine the influence of fitness on exercise BP and its relationship with LVMI in adolescents. Methods: 4835 adolescents from the Avon Longitudinal Study of Parents and Children, aged 15.4(0.3) years, 49% male completed a submaximal cycle test. Exercise BP was measured immediately on test cessation and fitness calculated as physical work capacity 170 adjusted for lean body-mass. LVMI (n = 1589), cardiac output (CO, n = 1628) and total peripheral resistance (TPR, n = 1628) were measured by echocardiography 2.4 (0.4) years later. Results: Each unit of fitness was associated with a 6.46 mmHg increase (95% CI: 5.83, 7.09) in exercise systolic BP. Exercise systolic BP increased step-wise by third of fitness (difference 6.06 mmHg, 95% CI:4.99, 7.13 first vs. middle; 11.13 mmHg, 10.05, 12.20 middle vs. highest). Each 5 mmHg increase in exercise systolic BP was associated with 0.25 g/m2. 7 (0.16–0.35) greater LVMI, attenuated with adjustment for fitness. There was evidence of an interaction between fitness and exercise BP on LVMI, more-marked in the middle fitness third (difference -0.27g/m2.7, -0.51,0.04 vs. first third), but similar in lowest and highest fitness thirds. CO increased (difference 0.06 L/min, -0.05,0.17; 0.23 L/min, 0.12,0.34), TPR decreased (difference -0.13AU, -0.84,0.59; -1.08AU, -0.1.80,-0.35 with fitness. Conclusion: Fitness may modify associations between exercise BP and LVMI in adolescence. Higher CO, but lower TPR suggests a physiological exercise BP-LVMI relationship with higher fitness, rather than pathological elevations in exercise BP and LVMI.

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

Background Cardiovascular risk factors vary between ethnicities but little is known about their differential effects on white matter hyperintensities (WMH), an indicator of brain aging and burden of cerebrovascular disease. Methods and Results Brain magnetic resonance imaging scans from 213 people of South Asian and 256 of European ethnicity (total=469) were analyzed for global and regional WMH load. Associations with cardiovascular risk factors and a composite cardiovascular risk score (National Cholesterol Education Programme Adult Treatment Panel III) were compared by ethnicity, diabetes mellitus, smoking, and hypertension status. Distributional patterns of WMH were similar by ethnicity but the vulnerability to specific risk factors differed. Associations between WMH and age or National Cholesterol Education Programme Adult Treatment Panel III scores were stronger in South Asians compared with Europeans. For instance, a year of age led to an excess of 3.8% (confidence interval=[0.2, 7.6]; P=0.04) of WMH load in frontal regions in South Asians compared with Europeans. In the diabetic subgroup, South Asians had more WMH than Europeans (+63.3%, confidence interval=[14.1, 133.9]; P=0.007), particularly in the deeper regions (+102% confidence interval=[24, 329]; P=0.004). In the population as a whole, diabetes mellitus was not, or only weakly, related to an increase in WMH volume (12.4%, confidence interval=[−10.7, 41.3]; P=0.32), and diabetes mellitus duration was a positive predictor of frontal periventricular WMH load in Europeans but not in South Asians. In turn, diastolic blood pressure was positively associated with WMH volumes in South Asians but not in Europeans. Hypertension was not associated with WMH load (P=0.9). Conclusions Distribution patterns of WMH are similar in South Asians and Europeans but older age and higher cardiovascular risk are associated with more WMH in South Asians.

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: Hypertension has adverse effects on microvascular function but there are limited methods that permit non-invasive assessment of the microcirculation in man in vivo. We used Near Infrared Spectroscopy (NIRS) to assess microvascular reactive hyperaemia in skeletal muscle following a short period of ischemia. We tested if differences between normotensive and hypertensive individuals could be detected. Methods: Older adults enrolled in a population-based cohort study underwent measurements of oxy-Hb changes during a 30-second arterial occlusion and hyperaemic response using NIRS (Portamon, Artinis). Time-to-peak hyperaemic response was calculated. Hypertension diagnosis was determined by questionnaire and clinic blood pressure (BP) (diastolic BP > 90 mmHg or systolic BP > 140 mmHg). Diabetes diagnosis and information about medication were determined by questionnaire. Data are mean (SD) or adjusted mean±SEM. Multivariable linear regression was used. Associations with hypertension were adjusted for age, gender, ethnicity and presence of diabetes. Results: 129 participants (99 = male, 72(6) years old, 74(57%) hypertensive participated). Time-to-peak hyperaemic response was significantly longer in hypertensive than normotensive participants after adjustment for age and gender (12.5±0.49 versus 10.5±0.57seconds, p = 0.06). This association persisted after adjustment for ethnicity and the presence of diabetes (12.6±0.50 versus 10.5±0.57, p = 0.03). Conclusion: Hypertension is associated with impairment of post-ischemic reactive hyperaemia in skeletal muscle microvasculature. Differences between hypertensive and normotensive older adults can be detected non-invasively using NIRS.

Objectives: Masked hypertension (MH) is associated with hypertension-related markers of organ damage, but is undetectable by clinic (resting) BP. Exaggerated systolic BP response to submaximal exercise reveals MH in adults, but it is unknown whether this is the case during adolescence. We aimed to determine if exercise BP was raised in adolescents with MH, and associations with markers of organ damage. Methods: 585 adolescents (aged 17.7 ± 0.3 years; 41.9% male) from the Avon longitudinal study of parents and children (ALSPAC), completed a step-exercise test with post-exercise BP, resting (clinic) BP and 24-hour ambulatory BP (ABP). MH was defined on the basis of guideline adult thresholds as clinic BP ≤ 140/90 mmHg and 24 h ABP ≥ 130/80 mmHg, or paediatric thresholds (age, sex and height percentiles). Assessment of markers of organ damage including left-ventricular mass (LVM) and carotid-femoral pulse wave velocity (PWV) was also undertaken. Results: 45 (7.7%) participants were classified with MH. Resting and post-exercise SBP were higher in those with MH vs. normotensives (126.1 ± 7.3 mmHg vs. 114.7 ± 10.0 mmHg, p < 0.001; 152.2 ± 17.3 vs 141.1 ± 15.1 mmHg, p = 0.001). A post-exercise SBP threshold of 150 mmHg revealed MH (AUC = 0.69, 95% CI: 0.61–0.76, p < 0.001) and was associated with greater LVM index (30.2 ± 6.5 vs. 27.6 ± 5.8 g/m2.7, p < 0.001) and PWV (5.9 ± 0.6 vs. 5.7 ± 0.7 m/s, p = 0.01). Conclusions: This is the first study within adolescents demonstrating post-exercise SBP can reveal MH and an association with markers of organ damage. Exaggerated exercise BP might be a warning signal of underlying high BP and increased cardiovascular risk undetected by clinic BP.

Background: It has been proposed that high blood pressure (BP) in young people is due to high cardiac output (CO) with normal total peripheral resistance (TPR) – a hyperkinetic/hyperdynamic circulation. We investigated this in a large, population- based cohort of adolescents. Methods: The study was conducted on 2091 participants in the Avon Longitudinal Study of Parents and Children (ALSPAC), a prospective population-based birth cohort study, aged 17. BP measurement and echocardiography was performed and heart rate (HR), stroke volume (SV) and TPR calculated. Data are means (SD). Results: Table 1 shows selected characteristics of the sample. Higher quintiles of systolic BP were associated with higher SV, higher HR and higher TPR. However, the proportional contribution made by SV, HR and TPR to mean arterial pressure differed little by systolic BP quintile (stroke volume (32–34%) heart rate (25–29%) and TPR (39–41%)). Variable Males (n = 939) Females (n = 1152) All (n = 2091) y (0.3) (0.3) (0.3) kg/m2 (3.7) (4.2) (4.0) mmHg 11)/64(8) 9)/65(7) 11)/65(8) bpm 0 0 0 L/min 1.0) 0.8) 0.9) ml 3 1 3 mmHg ml/min (5.9) (6.0) (6.0) Conclusions: Higher blood pressure is attributable to a combination of higher cardiac output (i.e. SV×HR) and higher TPR in a population-based sample of adolescents. There is no evidence of a disproportionate contribution from CO at higher BP levels.

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

Background: Maximum aerobic capacity (VO2max) is associated with lower cardiovascular and total mortality. Step tests can be used to provide an estimate of (VO2max) in epidemiological or home-based studies. We compared different methods of estimation of VO2max and heart rate recovery and evaluated the relationship of these estimates with cardiovascular risk factors. Methods: Data were analysed from 2286 participants in the Tecumseh Community Health Study (>16 y and

Background: High blood pressure (BP) is a major risk factor for elevated LV mass (LVM) in adults. Evidence suggests that BP tracks from childhood into adolescence and adulthood, however findings on the association between childhood BP and LVM are inconsistent and the temporal relationship between BP in childhood and elevated LVM in adolescence is unknown. Methods: Echocardiography and sitting brachial systolic BP (SBP) measurements were performed on 2065 17yr olds. 1377 participants (742 females, 635 males) had complete BP data measured at age 7yrs, 9yrs, 11yrs and 15yrs. LVM was calculated and indexed to height2.7 (LVMI). Linear regression was used to investigate associations. Results: Elevated LVMI at 17yrs was associated with increased SBP at all ages in females and in males at 9yrs, 11yrs, 15yrs and 17yrs (Table 1). Adjustment for cardiometabolic risk factors at age 17 (age, free-fat mass, height, height2 and smoking (Model 1)) did not substantially attenuate all LVMI and BP associations and associations at earlier ages remained significant after further adjustment for SBP at age 17. Age (yrs) Unadjusted Model 1 Model 1+ SBP at 17yrs Male Female Male Female Male Female 7 0.01±0.03 0.09±0.02** 0.02±0.03 0.06±0.02** −0.02±0.03 0.07±0.02** 9 0.06±0.03* 0.06±0.02* 0.02±0.02 −0.007±0.02 0.02±0.02 −0.006±0.8 11 0.15±0.03** 0.06±0.02** 0.09±0.03** 0.008±0.02 0.09±0.03** 0.009±0.02 15 0.05±0.02* 0.06±0.02** 0.02±0.02 0.04±0.02* 0.02±0.02 0.03±0.02* 17 0.16±0.03** 0.14±0.02** 0.13±0.03** 0.09±0.02** Data are β±SE(g/m 2.7) *= p

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.