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Aims Atrial fibrillation (AF) is an important risk factor for stroke, which is commonly asymptomatic, particularly in older patients, and often undetected until cardiovascular events occur. Development of novel technology has helped to improve detection of AF. However, the longer-term benefit of systematic electrocardiogram (ECG) screening on cardiovascular outcomes is unclear. Methods and results In the original REHEARSE-AF study, patients were randomized to twice-weekly portable electrocardiogram (iECG) assessment or routine care. After discontinuing the trial portable iECG assessment, electronic health record data sources provided longer-term follow-up analysis. Cox regression was used to provide unadjusted and adjusted hazard ratios (HR) [95% confidence intervals (CI)] for clinical diagnosis, events, and anticoagulant prescriptions during the follow-up period. Over the median 4.2-year follow-up, although a greater number of patients were diagnosed with AF in the original iECG group (43 vs. 31), this was not significant (HR 1.37, 95% CI 0.86–2.19). No differences were seen in the number of strokes/systemic embolisms or deaths between the two groups (HR 0.92, 95% CI 0.54–1.54; HR 1.07, 95% CI 0.66–1.73). Findings were similar when restricted to those with CHADS-VASc ≥ 4. Conclusion A 1-year period of home-based, twice-weekly screening for AF increased diagnoses of AF for the screening period but did not lead to increased diagnoses of AF or a reduction in cardiovascular-related events or all-cause death over a median of 4.2 years, even in those at highest risk of AF. These results suggest that benefits of regular ECG screening over a 1-year period are not maintained after cessation of the screening protocol.

Supplemental Digital Content is available in the text., Increases in aortic pulse wave velocity, a measure of arterial stiffness, can lead to elevated systolic blood pressure and increased cardiac afterload in adulthood. These changes are detectable in childhood and potentially originate in utero, where an adverse early life environment can alter DNA methylation patterns detectable at birth. Here, analysis of epigenome-wide methylation patterns using umbilical cord blood DNA from 470 participants in the Southampton’s Women’s Survey identified differential methylation patterns associated with systolic blood pressure, pulse pressure, arterial distensibility, and descending aorta pulse wave velocity measured by magnetic resonance imaging at 8 to 9 years. Perinatal methylation levels at 16 CpG loci were associated with descending aorta pulse wave velocity, with identified CpG sites enriched in pathways involved in DNA repair (P=9.03×10−11). The most significant association was with cg20793626 methylation (within protein phosphatase, Mg2+/Mn2+ dependent 1D; β=−0.05 m/s/1% methylation change, [95% CI, −0.09 to −0.02]). Genetic variation was also examined but had a minor influence on these observations. Eight pulse wave velocity-linked dmCpGs were associated with prenatal modifiable risk factors, with cg08509237 methylation (within palmitoyl-protein thioesterase-2) associated with maternal oily fish consumption in early and late pregnancy. Lower oily fish consumption in early pregnancy modified the relationship between methylation and pulse wave velocity, with lower consumption strengthening the association between cg08509237 methylation and increased pulse wave velocity. In conclusion, measurement of perinatal DNA methylation signatures has utility in identifying infants who might benefit from preventive interventions to reduce risk of later cardiovascular disease, and modifiable maternal factors can reduce this risk in the child.

OBJECTIVE Little is known about the role of physical activity accumulation in cardiovascular disease risk for children with type 1 diabetes. Improved insight to identify factors of influence in key health outcomes could be provided by considering the entire physical activity profile. METHODS Pulse wave velocity (PWV), augmentation index and heart rate variability (HRV) were assessed cross-sectionally in children with (n = 29, 12.1 ± 2.1 years) and without (n = 19, 12.1 ± 2.1 years) type 1 diabetes. Time spent sedentary and in each physical activity intensity, intensity gradient and average acceleration were derived from seven consecutive days of monitoring with wrist-worn accelerometry. Comparison between groups and influence of physical activity accumulation on cardiovascular metrics were explored with linear mixed models. RESULTS Diabetic children demonstrated a higher PWV and a greater volume of light physical activity (p

Objectives Cardiovascular (CV) mortality in RA patients is 50% higher than in the general population. There is increasing recognition that systemic inflammation is a major driver of this. IL-6 is implicated in cardiovascular disease (CVD) in the general population but its role in CVD in RA is undefined. Of the two modes of IL-6 signalling, trans-signalling is pro-inflammatory whereas classical signalling is linked with inflammation resolution. This study examines the role of IL-6 trans-signalling in CVD in a mouse model and patients with RA. Methods Myography determined the effect of IL-6 trans-signalling blockade, using sgp130Fc, on aortic constriction in murine collagen-induced arthritis. Serum CCL2 and sVCAM-1 as soluble biomarkers of sIL-6R trans-signalling were investigated in a human cross-sectional study. An observational longitudinal study investigated the association between these biomarkers and progression of subclinical atherosclerosis in early RA by measuring carotid intima-media thickness (CIMT). Results sgp130Fc reduced arthritis severity, serum CCL2 and sVCAM-1 and restored vascular function in collagen-induced arthritis (CIA). In established RA, sVCAM-1 correlated with the 28-joint DAS (DAS28) and CV risk. In early RA, baseline DAS28 was associated with CIMT change at 6 months. CIMT ‘rapid progressors’ at 12 months had higher baseline sVCAM-1, haemoglobin A1c, cholesterol:high-density lipoprotein cholesterol ratio and LDL cholesterol. Conclusions IL-6 trans-signalling plays a pivotal role in vascular dysfunction in CIA. In early RA, sVCAM-1 was associated with progression of subclinical atherosclerosis. Inflammation from RA onset in CVD-susceptible individuals may accelerate atherosclerosis. IL-6 trans-signalling blockade may be beneficial to RA patients and perhaps for atherosclerosis in the general population.

Aims To explore differences in the use of lipid lowering therapy and/or achievement of lipid guideline targets in patients with and without prior depression and influence of sex in very high-risk coronary patients. Methods & findings A retrospective observational cohort study was conducted using individual-level linked electronic health record data in patients who underwent percutaneous coronary intervention (2012–2017) in Wales. The cohort comprised of 13,781 patients (27.4% female), with 26.1% having prior depression. Lipid levels were recorded in 10,050 patients of whom 25% had depression. History of depression was independently associated with not having lipids checked (OR 0.79 95%CI 0.72–0.87 p Conclusion Patients with prior depression were less likely to have their lipids monitored and achieve guideline targets within 1-year. Females with depression are the least likely to be tested and achieve lipid targets, suggesting not only a greater risk of future events, but also an opportunity to improve care.

Background Updatable estimates of COVID-19 onset, progression, and trajectories underpin pandemic mitigation efforts. To identify and characterise disease trajectories, we aimed to define and validate ten COVID-19 phenotypes from nationwide linked electronic health records (EHR) using an extensible framework. Methods In this cohort study, we used eight linked National Health Service (NHS) datasets for people in England alive on Jan 23, 2020. Data on COVID-19 testing, vaccination, primary and secondary care records, and death registrations were collected until Nov 30, 2021. We defined ten COVID-19 phenotypes reflecting clinically relevant stages of disease severity and encompassing five categories: positive SARS-CoV-2 test, primary care diagnosis, hospital admission, ventilation modality (four phenotypes), and death (three phenotypes). We constructed patient trajectories illustrating transition frequency and duration between phenotypes. Analyses were stratified by pandemic waves and vaccination status. Findings Among 57 032 174 individuals included in the cohort, 13 990 423 COVID-19 events were identified in 7 244 925 individuals, equating to an infection rate of 12·7% during the study period. Of 7 244 925 individuals, 460 737 (6·4%) were admitted to hospital and 158 020 (2·2%) died. Of 460 737 individuals who were admitted to hospital, 48 847 (10·6%) were admitted to the intensive care unit (ICU), 69 090 (15·0%) received non-invasive ventilation, and 25 928 (5·6%) received invasive ventilation. Among 384 135 patients who were admitted to hospital but did not require ventilation, mortality was higher in wave 1 (23 485 [30·4%] of 77 202 patients) than wave 2 (44 220 [23·1%] of 191 528 patients), but remained unchanged for patients admitted to the ICU. Mortality was highest among patients who received ventilatory support outside of the ICU in wave 1 (2569 [50·7%] of 5063 patients). 15 486 (9·8%) of 158 020 COVID-19-related deaths occurred within 28 days of the first COVID-19 event without a COVID-19 diagnoses on the death certificate. 10 884 (6·9%) of 158 020 deaths were identified exclusively from mortality data with no previous COVID-19 phenotype recorded. We observed longer patient trajectories in wave 2 than wave 1. Interpretation Our analyses illustrate the wide spectrum of disease trajectories as shown by differences in incidence, survival, and clinical pathways. We have provided a modular analytical framework that can be used to monitor the impact of the pandemic and generate evidence of clinical and policy relevance using multiple EHR sources. Funding British Heart Foundation Data Science Centre, led by Health Data Research UK.

BACKGROUND/OBJECTIVES: Subclinical cardiovascular disease (CVD) is cross-sectionally associated with frailty, but the relationship between subclinical CVD and incident frailty has not been reported. We aimed to assess this prospective association. DESIGN: Longitudinal analysis of data from the British Regional Heart Study, a prospective cohort study. PARTICIPANTS: 1057 men, aged 71-92 years, robust or pre-frail at baseline, and without a clinical diagnosis of CVD. MEASUREMENTS: Participants underwent baseline measurement of carotid-femoral pulse wave velocity (cfPWV), carotid intima-media thickness (CIMT), carotid distensibility coefficient (DC), and ankle-brachial pressure index (ABPI), and had questionnaire-based frailty assessment after three years. Frailty status was based on the Fried phenotype. Multivariate logistic regressions examined associations between incident frailty and tertile of cfPWV, CIMT, DC, and ABPI group (

Purpose Cardiometabolic risk, including arterial stiffness, is increasing in youth. Those with asthma are suggested to be particularly at risk of cardiovascular disease. Efficient and effective strategies are required to prevent the atherosclerotic process in youth. The purpose of this study was to investigate the effect of 6 months high-intensity interval training (HIIT) on cardiometabolic risk in youth with and without asthma. Methods 65 adolescents (31 mild asthma; 34 non-asthma) were recruited, 32 (16 asthma) of whom were randomly allocated to receive HIIT three times per week for 6 months. At baseline, mid-intervention, post-intervention and at a 3-month follow-up, anthropometric, metabolic and vascular determinants of cardiometabolic risk were assessed. Following principal component analysis (PCA), linear mixed models were used to assess the influence of asthma, HIIT and their interaction. Results Seven factors were identified which explained 88% of the common variance shared among the parameters. Those with asthma demonstrated lower arterial stiffness factor scores mid-intervention (P = 0.047) and lower cholesterol factor scores post-intervention (P = 0.022) but there was no effect of the intervention, or interaction effects, on any PCA-identified factor, at any time-point. HIIT was associated with a lower low-density lipoprotein and diastolic blood pressure at mid-intervention. Discussion Neither arterial stiffness nor clustered cardiometabolic risk are influenced by HIIT in adolescents with or without asthma, despite important changes in blood lipid and pressure profiles. Blood pressure, augmentation and pulse wave velocity should be considered physiologically distinct constructs and as potential markers of cardiovascular health.

INTRODUCTION: Physical activity declines in adolescence, especially among those in deprived areas. Research suggests this may result from accessibility barriers (e.g., cost and locality). The Active Children Through Individual Vouchers Evaluation RCT aimed to improve the fitness and heart health of teenagers in Wales with the help of teenagers who co-produced the study.STUDY DESIGN: This study was a mixed-method RCT.SETTING/PARTICIPANTS: Before data collection, which took place at baseline, 6 months, and 12 months for both arms, 7 schools were randomized by an external statistician (4 intervention schools, n=524; 3 control schools, n=385).INTERVENTION: The Active Children Through Individual Vouchers Evaluation intervention included provision of activity vouchers (£20 per month), a peer mentoring scheme, and support worker engagement for 12 months between January and December 2017. Data analysis occurred February-April 2018.MAIN OUTCOME MEASURES: Data included measures of cardiovascular fitness, cardiovascular health (blood pressure and pulse wave analysis), motivation, and focus groups.RESULTS: The intervention showed a trend to improve the distance ran (primary outcome) and was significant in improving the likelihood of intervention teenagers being fit (OR=1.21, 95% CI=1.07, 1.38, p=0.002). There was a reduction in teenagers classified as having high blood pressure (secondary outcome) in the intervention group (baseline, 5.3% [28/524]; 12 months, 2.7% [14/524]). Data on where teenagers used vouchers and evidence from focus groups showed that teenagers wanted to access more unstructured, informal, and social activities in their local areas.CONCLUSIONS: Active Children Through Individual Vouchers Evaluation identified methods that may have a positive impact on cardiovascular fitness, cardiovascular health, and perspectives of activity. Consulting with teenagers, empowering them, and providing more local opportunities for them to take part in activities that are fun, unstructured, and social could positively impact teenage physical activity.TRIAL REGISTRATION: ISRCTN, ISRCTN75594310.

Aims There is mixed evidence for an association between depression and/or anxiety and carotid intima-media thickness, and limited information on the related role of dyslipidaemia. Here we report associations between depression and/or anxiety and intima-media thickness in the Whitehall II cohort, considering the moderating effects of sex and dyslipidaemia. Methods A total of 2822 men and 1112 women (61 ± 6 years) were studied during phase 7 (2002–2004) of the Whitehall II study. Intima-media thickness and lipid levels were assessed, and questionnaires (general health questionnaire and the Centre for Epidemiologic Studies depression scale) were completed. Linear regression was used to explore relationships between depression and/or anxiety and intima-media thickness and the moderating effects of sex and dyslipidaemia. Results A total of 1461 participants were categorised with depression and/or anxiety. The association between depression and/or anxiety and intima-media thickness differed between men and women so analyses were undertaken separately by sex. In men, intima-media thickness was significantly associated with dyslipidaemia ( P = 0.002) but not depression and/or anxiety ( P = 0.29). In women, both dyslipidaemia and depression and/or anxiety were independently associated with intima-media thickness ( P = 0.028 and P = 0.031). The greatest intima-media thickness was in women with both depression and/or anxiety and dyslipidaemia. These results were replicated when the general health questionnaire score was substituted for depression and/or anxiety and non-high-density lipoprotein cholesterol for dyslipidaemia. Conclusions Depression and/or anxiety is associated with increased intima-media thickness in women but not in men. Dyslipidaemia is associated with intima-media thickness in both men and women. Women with both depression and/or anxiety and dyslipidaemia are potentially at the greatest risk of cardiovascular disease.

ObjectiveThis paper explores what aspects of a multicomponent intervention were deemed strengths and weaknesses by teenagers and the local council when promoting physical activity to young people.DesignQualitative findings at 12 months from a mixed method randomised control trial.MethodsActive Children Through Incentive Vouchers—Evaluation (ACTIVE) gave teenagers £20 of activity enabling vouchers every month for a year. Peer mentors were also trained and a support worker worked with teenagers to improve knowledge of what was available. Semistructured focus groups took place at 12 months to assess strengths and weaknesses of the intervention. Eight focus groups (n=64 participants) took place with teenagers and one additional focus group was dedicated to the local council’s sport development team (n=8 participants). Thematic analysis was used to analyse the data.ResultsTeenagers used the vouchers on three main activities: trampolining, laser tag or the water park. These appeal to both genders, are social, fun and require no prior skill or training. Choice and financial support for teenagers in deprived areas was considered a strength by teenagers and the local council. Teenagers did not engage with a trained peer mentor but the support worker was considered helpful.ConclusionsThe ACTIVE Project’s delivery had both strengths and weakness that could be used to underpin future physical activity promotion. Future interventions should focus on improving access to low cost, fun, unstructured and social activities rather than structured organised exercise/sport. The lessons learnt from this project can help bridge the gap between what is promoted to teenagers and what they actually want from activity provision.Trial registration numberISRCTN75594310

BackgroundIt remains uncertain whether cystatin C is a superior marker of renal function than creatinine in older adults. We have investigated the association between estimated glomerular filtration rate (eGFR) using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations based on creatinine (CKD-EPIcr) and cystatin C (CKD-EPIcys), and cardiovascular risk markers and mortality in older adults.MethodsThis is a cross-sectional and prospective study of 1639 British men aged 71–92 years followed up for an average of 5 years for mortality. Cox survival model and receiving operating characteristic analysis were used to assess the associations.ResultsThe prevalence of chronic kidney disease (CKD) was similar using the two CKD-EPI equations, although cystatin C reclassified 43.9% of those with stage 3a CKD (eGFR 45–59 mL/min/1.732, moderate damage) to no CKD. However, CKD stages assessed using both CKD-EPIcr and CKD-EPIcys were significantly associated with vascular risk markers and with all-cause and cardiovascular disease mortality. In all men with CKD (eGFR 2), the HRs (95% CI) for all-cause mortality after adjustment for cardiovascular risk factors compared with those with no CKD were 1.53 (1.20 to 1.96) and 1.74 (1.35 to 2.23) using CKD-EPIcr and CKD-EPIcys, respectively. Comparisons of the two CKD equations showed no significant difference in their predictive ability for mortality (difference in area under the curve p=0.46).ConclusionDespite reclassification of CKD stages, assessment of CKD using CKD-EPIcys did not improve prediction of mortality in older British men >70 years. Our data do not support the routine use of CKD-EPIcys for identifying CKD in the elderly British male population.

Background Frailty is associated with incident cardiovascular disease (CVD). However, its association with subclinical CVD, which precedes the onset of a CVD event, remains uncertain. Non-invasive vascular markers provide valuable proxy indicators of CVD risk, permitting investigation of risk burden and the development of subclinical CVD. N-terminal pro brain natriuretic peptide (NT-proBNP) and cardiac troponin T (cTNT) are markers of cardiac injury and are strong risk predictors of CVD events such as heart failure and myocardial infarction respectively. Our aim was to examine the association of subclinical cardiovascular markers with frailty in men without a diagnosis of CVD. Methods In 2010–2012, 1622 surviving men aged 71–92 years were examined and completed a questionnaire as part of a cross-sectional study from a cohort of men from 24 British towns initially recruited in 1978–1980. Using the Fried phenotype, frailty was defined by the presence of ≥3 of the following components: unintentional weight loss, low grip strength, low physical activity, slow walking pace and exhaustion. Carotid intima media thickness (CIMT) and carotid distensibility coefficient (DC) were measured using ultrasound. A Vicorder device was used to measure pulse wave velocity (PWV) and ankle brachial pressure index (ABPI). Fasting blood samples were analysed for NT-proBNP and cTNT. Multivariable logistic regression was used for analyses. Results Three hundred and three participants (19%) were frail and 876 (54%) were pre-frail. In men without CVD, frail individuals were significantly more likely to be older, physically inactive, have a smoking history and co-morbidities such as peripheral vascular disease and diabetes compared to non-frail individuals (p 1.2, PWV and CIMT) were not associated with frailty (p>0.05). Pre-frailty was also associated with raised cardiac markers (p Conclusion Frailty is strongly associated with subclinical CVD markers (NT-proBNP, cTNT and DC), even in the absence of prevalent CVD. Further research is needed to determine whether this association is causal and to understand the underlying mechanisms. Our study findings support the need for screening older individuals with frailty, with the objective of identifying those with an underlying increased risk of CVD and its adverse outcomes.

Background It is recommended that young people should engage in 60 min of moderate-to-vigorous activity (MVPA) a day for health benefits, but few teenagers actually meet this recommendation. Policy-makers play a vital role in designing physical activity initiatives, but they generally do this with little or no input from the intervention recipients. This study explores the recommendations made by teenagers to improve activity provision, uptake and sustainability of physical activity engagement for both themselves and their peers. Methods Thirteen focus groups were carried out in seven secondary schools in South Wales, United Kingdom. Participants (n = 78) were recruited from a larger mixed-method randomised control trial, which involved the implementation of a voucher scheme to promote physical activity in teenagers (aged 13–14). Thematic analysis was undertaken to identify key issues from the perspective of the teenage participants. Results Six key recommendations were identified following analysis of the focus groups: i) Lower/remove the cost of activities without sacrificing the quality, ii) Make physical activity opportunities more locally accessible, iii) Improve the standards of existing facilities, iv) Make activities more specific to teenagers v) Give teenagers a choice of activities/increase variety of activity and vi) Provide activities that teenage girls enjoy (e.g., fun, sociable and not competitive sport). Throughout the focus groups, the increased opportunity to participate in unstructured activity was a key recommendation echoed by both boys and girls in all themes. Conclusion There is a disconnect between what is available and what teenagers want to do. Policy-makers and those involved in physical activity delivery (e.g., schools, local council and local activity providers) should include young people in designing interventions and facilities to ensure they are meeting the needs of this age group and providing the right opportunities for teenagers to be active. That is unstructured, local, low cost, fun, sociable opportunities and the right facilities to be active. Electronic supplementary material The online version of this article (10.1186/s12889-018-5274-3) contains supplementary material, which is available to authorized users.

Background and aims The soluble receptor for advanced glycation end products (sRAGE) has been implicated in diabetic vascular complications. We have examined the association between sRAGE and cardiac markers [NT-proBNP and cardiac troponin T (cTnT)] and subclinical vascular markers in older men with and without diabetes. Methods We performed a cross-sectional study of 1159 men aged 71–92 years with no history of cardiovascular disease (myocardial infarction, stroke, heart failure, coronary artery bypass graft operation or angioplasty). Prevalent diabetes included men with a doctor diagnosis of diabetes, men with fasting glucose ≥7 mmol/l or HbA1c ≥ 6.5% (N = 180). Subclinical vascular measurements included carotid intima media thickness (cIMT), arterial stiffness [pulse wave velocity (PWV)], central aortic blood pressure and arterial wave reflections [central augmentation pressure (AP) and augmentation index (AIx)]. Results sRAGE was strongly and positively associated with renal dysfunction in men with and without diabetes. sRAGE was significantly and positively associated with NT-proBNP (but not cTnT) and AP and AIx in both groups of men after adjustment for CVD risk and metabolic risk markers, renal function and inflammation. However, no association was seen between sRAGE and central aortic blood pressure, cIMT or arterial stiffness as determined by PWV in either group. Conclusions Higher plasma sRAGE was associated with increased NT-proBNP and markers of arterial wave reflections in men both with and without diabetes. Increased sRAGE may contribute to or be a marker of worsening cardiac dysfunction or HF. Further studies with cardiac imaging data are required to confirm this., Highlights • In men with no diagnosed CVD, sRAGE is associated with the cardiac marker NT-proBNP. • sRAGE also related positively to markers of arterial wave reflection. • These associations were present in both men with and without diabetes. • Whether sRAGE predicts worsening cardiac dysfunction and heart failure needs testing.

Many teenagers are insufficiently active despite the health benefits of physical activity (PA). There is strong evidence to show that inactivity and low fitness levels increase the risk of non-communicable diseases such as coronary heart disease (CHD), type 2 diabetes and breast and colon cancers (Lee et al. Lancet 380:219–29, 2012). A major barrier facing adolescents is accessibility (e.g. cost and lack of local facilities). The ACTIVE project aims to tackle this barrier through a multi-faceted intervention, giving teenagers vouchers to spend on activities of their choice and empowering young people to improve their fitness and PA levels. ACTIVE is a mixed methods randomised control trial in 7 secondary schools in Swansea, South Wales. Quantitative and qualitative measures including PA (cooper run test (CRT), accelerometery over 7 days), cardiovascular (CV) measures (blood pressure, pulse wave analysis) and focus groups will be undertaken at 4 separate time points (baseline, 6 months,12 months and follow-up at 18 months). Intervention schools will receive a multi-component intervention involving 12 months of £20 vouchers to spend on physical activities of their choice, a peer mentor scheme and opportunities to attend advocacy meetings. Control schools are encouraged to continue usual practice. The primary aim is to examine the effect of the intervention in improving cardiovascular fitness. This paper describes the protocol for the ACTIVE randomised control trial, which aims to increase fitness, physical activity and socialisation of teenagers in Swansea, UK via a voucher scheme combined with peer mentoring. Results can contribute to the evidence base on teenage physical activity and, if effective, the intervention has the potential to inform future physical activity interventions and policy. ISRCTN75594310 (Assigned 06/03/2017).

Background Cardiovascular (CV) mortality in patients with rheumatoid arthritis (RA) is up to 50% higher than the general population. Whilst traditional CV risk factors such as smoking, diabetes and hypertension contribute to this increased mortality in RA, they do not fully explain the increase in risk. The British Society for Rheumatology, National Institute for Health and Clinical Excellence and European League Against Rheumatism (EULAR) recommend annual assessment of CV risk in RA patients. Furthermore, EULAR recommends multiplying such traditional CV risk scores by 1.5 for RA patients who meet two of three criteria consisting of (1) disease duration >10 years, (2) positive rheumatoid factor or anti-cyclic citrullinated peptide (anti-CCP) serology, (3) presence of severe extra-articular manifestation, to account for the unexplained increased CV risk in RA. Objectives This study assessed CV risk by QRISK2 score and used carotid ultrasound to determine cardiovascular risk and prevalence of subclinical atherosclerosis at the time of diagnosis of RA. Methods Patients ≥18 years-old with early RA, defined by ACR/EULAR 2010 criteria and diagnosis of RA Results 40 patients, 10 males and 30 females with early RA were recruited. Mean age was 55.7±14.8 years. Rheumatoid factor and anti-CCP antibodies were positive in 62% and 80% of patients respectively. Mean BMI was 27.2±5.9. Twenty-nine percent were current smokers. Mean DAS28 was 3.8±1.3. According to the QRISK2, 54% of patients had >10% risk of CV disease over 10 years. Carotid ultrasound was conducted in 35 patients. Mean CIMT was 0.71±0.19 mm. 10 patients (29%) had carotid plaques. Fourteen patients (40%) had either plaque or CIMT >0.9mm, both considered markers of high CV risk. These patients were termed “ultrasound positive” patients. The sensitivity and specificity of the QRISK2 to predict US positive patients was 82% and 56% respectively. The positive predictive value of the QRISK2 was 63% and the negative predictive value of the QRISK2 was 88%. No patients met >1 criteria for EULAR adjustment of risk as all patients had early RA and none had severe extra-articular manifestations. Conclusions Many patients with early RA have significant CV disease at the time of diagnosis. This suggests subclinical CV disease may be developing before patients become symptomatic. More than half of the patients with early RA fulfil current NICE guidelines for starting lipid-lowering therapy, although of these, over one-third had no subclinical disease on carotid ultrasound. There is scope to improve the sensitivity and specificity of the QRISK2 calculation in RA patients, perhaps with a biomarker. Acknowledgements This work was funded by Arthritis Research UK, grant number 20760 Disclosure of Interest None declared

ObjectiveTo examine the predictors of cardiovascular health in teenagers (aged 13–14 years).MethodsMeasures of arterial stiffness (augmentation index (AIx)), blood pressure and cardiovascular fitness were taken from 234 teenage children (n=152 boys) and subsequently linked to routine data (birth and general practice records, education data and hospital admission data). Deprivation at school and at individual level was measured at birth, at 1 year old, at 13 years old and at secondary school using the Welsh Index of Multiple Deprivation. Multivariate regression analysis determined associations between routinely collected data and cardiovascular measures.ResultsTeenagers had higher AIx (2.41 (95% CI 1.10 to 3.72)), ran fewer metres (−130.08 m (95% CI −234.35 to −25.78)) in the Cooper Run Test if they attended a more deprived school. However, higher individual level deprivation was associated with greater fitness (199.38 m (95% CI 83.90 to 314.84)). Higher systolic blood pressure was observed in first born children (10.23 mm Hg (95% CI 1.58 to 18.88)) and in those who were never breastfed (4.77 mm Hg (95% CI 1.10 to 8.42)).ConclusionsImproving heart health in deprived areas requires multilevel action across childhood namely, active play and programmes that promote physical activity and fitness and, the promotion of breastfeeding. Recognition of the important early indicators and determinants of cardiovascular health supports further development of the evidence base to encourage policy-makers to implement preventative measures in young people.

Objectives: The aim of this study was to assess the potential benefits of inorganic nitrite in 2 clinical models: stress-induced myocardial ischemia and whole-arm ischemia-reperfusion. Background: Inorganic nitrite, traditionally considered a relatively inert metabolite of nitric oxide, may exert vasomodulatory and vasoprotective effects. Despite promising results from animal models, few have shown effectiveness in human model systems, and none have fully translated to the clinical setting. Methods: In 10 patients with inducible myocardial ischemia, saline and low-dose sodium nitrite (NaNO2) (1.5 μmol/min for 20 min) were administered in a double-blind fashion during dobutamine stress echocardiography, at separate visits and in a random order; long-axis myocardial function was quantified by peak systolic velocity (Vs) and strain rate (SR) responses. In 19 healthy subjects, flow-mediated dilation was assessed before and after whole-arm ischemia-reperfusion; nitrite was given before ischemia or during reperfusion. Results: Comparing saline and nitrite infusions, Vs and SR at peak dobutamine increased in regions exhibiting ischemia (Vs from 9.5 ± 0.5 cm/s to 12.4 ± 0.6 cm/s, SR from −2.0 ± 0.2 s−1 to −2.8 ± 0.3 s−1), whereas they did not change in normally functioning regions (Vs from 12.6 ± 0.4 cm/s to 12.6 ± 0.6 cm/s, SR from −2.6 ± 0.3 s−1 to −2.3 ± 0.1 s−1) (p < 0.001, analysis of variance). With NaNO2, the increment of Vs (normalized for increase in heart rate) increased only in poorly functioning myocardial regions (+122%, p < 0.001). Peak flow-mediated dilation decreased by 43% after ischemia-reperfusion when subjects received only saline (6.8 ± 0.7% vs. 3.9 ± 0.7%, p < 0.01); administration of NaNO2 before ischemia prevented this decrease in flow-mediated dilation (5.9 ± 0.7% vs. 5.2 ± 0.5%, p = NS), whereas administration during reperfusion did not. Conclusions: Low-dose NaNO2 improves functional responses in ischemic myocardium but has no effect on normal regions. Low-dose NaNO2 protects against vascular ischemia-reperfusion injury only when it is given before the onset of ischemia.

Background: Sleep disturbance is common, especially amongst older adults. The association between night-time sleep duration, cardiovascular disease (CVD), metabolic disorders and mortality has been extensively reported, with studies showing a U-shaped association. Less is known about the influence of daytime sleep and attention has more recently turned to excessive daytime sleepiness which has been associated with increased CVD, heart failure and mortality. We aimed to investigate the association between sleep patterns and cardiovascular risk markers in older adults including metabolic risk markers, cardiac markers and early markers of atherosclerosis [arterial stiffness and carotid intima-media thickness (CIMT)] with particular focus on day sleep. Methods: Cross sectional study of 1722 surviving men aged 71-92 examined in 2010-2012 across 24 British towns, from a prospective study initiated in 1978-1980. Men with a history of heart attack or heart failure (n = 251) were excluded from the analysis. Self-reported sleep duration (night and day) was based on a questionnaire; insomnia was defined as self-reported difficulty falling asleep. Participants were invited for a physical examination which included non-invasive assessment of vascular measures including CIMT and arterial stiffness (carotid distensibility and pulse wave velocity (PWV)). Results: Analysis of the data confirmed previous reports of a U-shaped association between night-time sleep duration and HbA1c, even following adjustment for confounding factors including age, BMI, physical activity and social class. Men who reported insomnia had significantly higher mean triglyceride, glucose and insulin (p = 0.02, 0.04 and 0.01 in the age-adjusted model). Increasing daytime sleep duration was associated with higher fasting glucose and insulin levels which remained significant (p = 0.02 and 0.01 respectively) after adjustment for prevalent diabetes. Compared to those with no daytime sleep, men with daytime sleep > 1 hour had a higher risk of raised N-terminal pro brain natriuretic peptide (NT-proBNP) of ≥400pg/ml, the diagnostic threshold for heart failure [OR (95% CI) = 1.88 (1.15, 3.1)], reduced lung function (forced expiratory volume in 1s) and elevated von Willebrand factor (vWF), a marker of endothelial dysfunction. These patterns were not seen for night-time sleep or insomnia. Sleeping patterns were unrelated to CIMT and arterial stiffness. Conclusions: Day sleep of > 1 hour may be an early indicator of heart failure. Clinically, this is important in the assessment of older patients who seek medical advice for excessive daytime sleepiness, in whom indicators of heart failure should be sought and further investigations carried out if necessary.

Reactive hyperaemia induces a slowing of pulse wave velocity (PWV) in conduit arteries of healthy subjects (flow-mediated slowing (FMS)). This could be an alternative method for assessing peripheral vasomotor function to the gold standard method of flow-mediated dilatation (FMD) a more expensive and technically demanding technique. We aimed to assess the reproducibility of FMS in healthy participants and to test its ability to detect differences in vasomotor function in patients with familial hypercholesterolaemia (FH) and post-lipoprotein apheresis (LA) treatment.Altogether 25 healthy participants were studied on two occasions to assess reproducibility of FMS. In a case control study of 22 patients with FH and matched healthy controls, FMD and FMS were compared. An intervention study in 12 patients with FH looked at the impact of a single LA treatment on FMS assessed pre and post treatment.FMS demonstrated good reproducibility (coefficient of variation (CoV) 7.3%). Patients with FH had reduced FMS in comparison to matched healthy controls (FMS% FH -15.13 ± 5.04% vs controls -18.41 ± 5.15%, p = 0.023), with no difference in FMD% between the two groups. A single LA treatment significantly improved FMS (pre -18.81 ± 9.84 vs post -24.09 ± 7.61%, p = 0.016).FMS is a reproducible technique, which is able to detect differences in vasomotor function both in a condition associated with endothelial dysfunction and following an acute intervention known to improve endothelial function. This simple technique has potential for accessible assessment of vasomotor function in clinical studies.

Stress influences the risk of cardiovascular disease. Acute mental stress can induce both low-grade inflammation and endothelial dysfunction. The relationship between inflammatory responses to stress and future endothelial function is unexplored. Knowledge on the impact of other cardiovascular risk factors, such as dyslipidaemia, on such relationships is also limited We investigated the relationship between inflammatory responses to an acute mental stress challenge and endothelial function plus the influence of dyslipidaemia on the associations. Interleukin-6 (IL-6), tumor necrosis factor α (TNFα) and fibrinogen were assessed at baseline, immediately following standardized behavioural tasks and 45 minutes post-task in 158 participants. Blood pressure and heart rate responses were measured. Flow-mediated dilatation (FMD) was measured 3 years later. Fibrinogen and IL-6 increased post-stress (p=

Background The balance between endothelial injury and repair in childhood is poorly understood. We examined this relationship in healthy children, in adults and in children with familial hypercholesterolaemia (FH). Methodology Circulating endothelial cells (CECs) were measured as a marker of vascular injury, with vascular repair assessed by counting colony forming units (CFUs), also known as endothelial progenitor cells. Results CEC number increased with age. Children with FH had elevated CECs compared to healthy children , with similar levels numerically to those found in healthy adults. CFU numbers were higher in healthy children than either healthy adults or children with FH. Endothelium dependent vascular function, measured by flow-mediated dilatation (FMD), was positively associated with CFU number, even following adjustment for confounding risk variables. Conclusion Levels of CECs increase and CFUs decrease with age. In childhood, before the onset of clinically detectable cardiovascular dysfunction, children with a major risk factor for atherosclerotic disease have levels of these indices of vascular injury and repair approaching those seen in adults.

Background: Both the Sphygmocor (S) and Vicorder (V) devices can be used for Pulse Wave Analysis (PWA) and Velocity (PWV). We investigated if there were differences in the associations between markers of Cardiovascular Disease (CVD) and PWA and PWV variables as assessed by the two devices. Methods: 1,722 men (78.5 ± 4.7 yrs) from the British Regional Heart Study underwent PWA and PWV with the Sphygmocor and Vicorder devices. Carotid artery Intima-media Thickness (cIMT), NT-proBNP and Left Ventricle Hypertrophy (LVH) detected by ECG were also assessed. Multiple regression was used to investigate the associations between cIMT, NT-proBNP and LVH with each of the following measures, central Augmentation Pressure (cAP) Augmentation Index (cAIx) Blood Pressure (cBP) and carotid to femoral PWV. Results: Men with data obtained from both devices were included (PWA n = 1,373, PWV n = 1,122). Following adjustment for CVD risk factors, Sphygmocor cAP, cAIx and cBP were all positively associated with LVH (p < 0.05), the relationship between Sphygmocor PWV and LVH was negative (OR 0.87 95% CI 0.78–0.97). There were no associations between LVH and Vicorder variables. cAP measured by both devices and cAIx by Vicorder were predictors of NT-proBNP levels (ScAP Beta 0.097 p < 0.05, VcAP Beta 0.153 p < 0.001 & VcAIx Beta 0.129 p < 0.001). Vicorder cBP was the only predictor of cIMT (Beta 0.057 p < 0.05). Conclusion: The same measures from two devices were predictors of different indicators of CVD. Further exploration is needed to understand these differences, but device used needs to be taken into consideration when comparing findings of these variables with other published results.

Background— Endothelial dysfunction develops early and has been shown to predict the development of clinical complications of atherosclerosis. However, the relationship between early endothelial dysfunction and the progression of arterial disease in the general population is unknown. We investigated endothelial dysfunction, risk factors, and progression of carotid intima-media thickness (cIMT) in late-middle-aged individuals at low to intermediate cardiovascular risk in a prospective study between 1997 and 2005. Methods and Results— Brachial artery flow-mediated dilatation and cIMT were measured in 213 nonsmoking British civil servants recruited from a prospective cohort (Whitehall II study). Participants (age, 45 to 66 years) were free of clinical cardiovascular disease and diabetes mellitus. Risk factors and Framingham Risk Score were determined at baseline. cIMT was repeated 6.2±0.4 years later. At baseline, age, blood pressure, low-density lipoprotein cholesterol, and Framingham Risk Score correlated with cIMT. However, only flow-mediated dilatation, not risk factors or Framingham Risk Score, was associated with average annual progression of cIMT. This relationship remained significant after adjustment for risk factors whether entered as separate variables or as Framingham Risk Score. Further adjustment for waist circumference, triglycerides, and employment grade had no significant effect. Conclusions— Systemic endothelial function was associated with progression of preclinical carotid arterial disease over a 6-year period and was more closely related to cIMT changes than conventional risk factors. Thus, the relationship between endothelial dysfunction and adverse outcome is likely to be due not only to destabilization of established disease in high-risk populations but also to its impact on the evolution of the atherosclerotic substrate. Flow-mediated dilatation testing provides an integrated vascular measure that may aid the prediction of structural disease evolution and represents a potential short- to intermediate-term outcome measure for evaluation of preventive treatment strategies.

The processes through which psychological stress influences cardiovascular disease are poorly understood, but may involve activation of hemodynamic, neuroendocrine and inflammatory responses. We assessed the relationship between carotid arterial stiffness and inflammatory responses to acute psychophysiologic stress. Participants were 155 healthy men and women aged 55.3, SD 2.7 years. Blood samples for the assessment of plasma fibrinogen, tumor necrosis factor (TNF) alpha and interleukin (IL) 6 were drawn at baseline, immediately following standardized behavioral tasks, and 45 min later. Carotid artery stiffness was measured ultrasonically three years later, and blood pressure and heart rate responses were recorded. The tasks induced substantial increases in blood pressure and heart rate, together with increased fibrinogen, TNFalpha and IL-6 concentration. Carotid stiffness was positively associated with body mass, waist/hip ratio, blood pressure, low density lipoprotein cholesterol, and C-reactive protein, and inversely with high density lipoprotein and grade of employment. Baseline levels of inflammatory variables were not related to carotid artery stiffness. But carotid stiffness was greater in participants with larger fibrinogen (p=0.037) and TNFalpha (p=0.036) responses to psychophysiological stress. These effects were independent of age, gender, grade of employment, smoking, body mass, waist/hip ratio, systolic and diastolic pressure, high and low density lipoprotein cholesterol, and C-reactive protein. There were no associations between carotid stiffness and stress responses in IL-6, blood pressure, or heart rate. We conclude that individual differences in inflammatory responses to psychophysiological stress are independently related to structural changes in artery walls that reflect increased cardiovascular disease risk.

Background—Cardiac allograft vasculopathy is the major limiting factor to the long-term success of pediatric heart transplantation. Cytomegalovirus (CMV) has been shown to be a significant risk factor for the development of cardiac allograft vasculopathy. Recent work has demonstrated CMV DNA in leukocytes in the absence of direct allograft infection, suggesting that vascular changes may not be limited to the allograft.Method and Results—Systemic arterial endothelial function was assessed with high-resolution ultrasound to determine brachial artery flow-mediated dilation in 50 pediatric heart transplant recipients (8 to 17 years of age; 27 male). Patients were separated into 2 groups according to CMV status: those without evidence of CMV replication after transplantation (n=38; 19 male) and patients with evidence of viremia after transplantation (n=12; 8 male). No patient had detectable viremia at the time of study. Flow-mediated dilation was significantly impaired in patients with evidence of CMV replication after transplantation (6.64±1.12%, mean±SE) compared with those without (9.48±0.56%;P=0.02). This difference remained after adjustment for age, time since transplantation, and medication. Pretransplantation recipient and donor CMV status and traditional CMV risk were not associated with flow-mediated dilation.Conclusions—CMV replication after cardiac transplantation is associated with chronic endothelial dysfunction in the systemic circulation in children. The implication for both systemic and coronary vascular health requires prospective evaluation.

Cardiovascular disease is increasingly recognized as a life-limiting problem in young patients with chronic kidney disease, but there are few studies in children that describe its determinants. We studied the association of intact parathyroid hormone (iPTH) levels and their management on vascular structure and function in 85 children, ages 5-18 years, who had received dialysis for > or =6 months. Compared to controls, dialysis patients had increased carotid intima-media thickness and pulse-wave velocity. All vascular measures positively correlated with serum phosphorus levels, while carotid intima-media thickness and cardiac calcification score also correlated with iPTH levels. Patients with mean time-integrated iPTH levels less than twice the upper limit of normal (n = 41) had vascular measures that were comparable to age-matched controls, but those with iPTH levels greater than twice the upper limit of normal (n = 44) had greater carotid intima-media thickness, stiffer vessels, and increased cardiac calcification than controls. Patients with increased carotid intima-media thickness had stiffer vessels and a greater prevalence of cardiac calcification. There was a strong dose-dependent correlation between vitamin D and all vascular measures, and calcium intake from phosphate binders weakly correlated with carotid intima-media thickness. In conclusion, both iPTH level and dosage of vitamin D are associated with vascular damage and calcification in children on dialysis.

Low physical activity (PA) and high levels of sedentary time (ST) are associated with higher cardiovascular disease (CVD) risk among older people. However, their independent contribution and importance of duration of PA and ST bouts remain unclear. We investigated associations between objectively measured PA, ST and non-invasive vascular measures, markers of CVD risk. Cross-sectional study of 1216 men from the British Regional Heart Study, mean age 78.5 years, measured in 2010–2012. Carotid intima thickness (CIMT), distensibility coefficient (DC) and plaque presence were measured using ultrasound; pulse wave velocity (cfPWV) and augmentation index (AIx) using a Vicorder. PA and ST were measured using hip-worn ActiGraph GT3X accelerometers. After adjusting for covariates, each additional 1000 steps per day was associated with a 0.038 m/s lower cfPWV (95% CI = − 0.076, 0.0003), 0.095 10− 3 kPa− 1 higher DC (95% CI = 0.006, 0.185), 0.26% lower AIx (95% CI = − 0.40, − 0.12) and a 0.005 mm lower CIMT (95% CI = − 0.008, − 0.001). Moderate and vigorous PA (MVPA) was associated with lower AIx and CIMT, light PA (LPA) with lower cfPWV and CIMT and ST with higher cfPWV, AIx and CIMT and lower DC. LPA and ST were highly correlated (r = − 0.62). The independence of MVPA and ST or MVPA and LPA was inconsistent across vascular measures. Bout lengths for both PA and ST were not associated with vascular measures. In our cross-sectional study of older men, all PA regardless of intensity or bout duration was beneficially associated with vascular measures, as was lower ST. LPA was particularly relevant for cfPWV and CIMT., Highlights • We examined physical activity, sedentary time and vascular measures in older men. • Higher PA and lower ST were beneficially associated with cfPWV, DC, AIx and CIMT. • More minutes of moderate and vigorous PA were associated with a lower AIx and CIMT. • More light PA was associated with a lower cfPWV and CIMT. • Bout lengths of MVPA, LPA and ST were not associated with vascular measures.

Objective: Vascular disease is highly prevalent in the elderly. This study aimed to evaluate arterial phenotype in elderly men and compare carotid-femoral pulse wave velocity (cfPWV) assessed by two techniques (Sphygmocor (S)and Vicorder (V)). Methods: 1722 men (72-92 years), participants in the British Regional Heart Study, underwent ultrasound assessment of carotid intima-media thickness (cIMT), carotid distensibility coefficient and presence of carotid plaque. cfPWV and ankle brachial pressure index (ABPI) were also assessed. 123 men returned for between visit reproducibility assessments. Results: Good reproducibility was demonstrated in all measures (Gwet's agreement=0.8 for plaque, intraclass correlation=0.65 for ABPI and coefficient of variation 90% of men for all measures except cfPWV(S) and ABPI. In 1122 men with both cfPWV(V) and cfPWV(S) data, cfPWV(S) was greater than cfPWV(V) (mean difference=0.23,95%CI 0.10 to 0.37 m/s). cfPWV(V) was higher at low cfPWV values and cfPWV(S) was higher at high cfPWV values. Correlation of V transit time (TT) against S carotid and femoral TT demonstrated that the slope of the regression line for femoral TT was steeper than for carotid TT, resulting in a proportionally greater subtraction of carotid TT from femoral TT at higher PWVs. Conclusions: Reproducible, satisfactory quality non-invasive measurements of vascular phenotype were obtainable in a large proportion of elderly men. The discrepancy in results between the two PWV measures may partly be due to the differential impact of subtracting carotid TT when deriving cfPWV(S) across the clinical PWV range.

Background: Both the Sphygmocor (S) and Vicorder (V) devices can be used for pulse wave analysis (PWA). However, large studies comparing data from both devices are lacking. Methods: 1,722 men (78.5±4.7yrs) from the British Regional Heart Study underwent PWA with S and V devices. Brachial blood pressure (BP) was assessed by V and by Omron- HEM907 (S). Measures of central Augmentation Pressure (cAP) Augmentation Index (cAIx) and central (c) BP were compared. Results: Data were successfully obtained in 1,380 (80%) with S and 1,706 (99%) with V. 1,373 men had both S and V data. cAP and cAIx were higher in S than V (17±9 vs 13 ± 5 mmHg and 29±10 vs 21±6% respectively, both p < 0.001), and were significantly correlated (cAP r = 0.65 cAIx r = 0.48 p < 0.001), but with greater differences at higher values. Brachial BP readings were greater with V vs Omron (mean difference 1.1±9.7/3.7±6.3 mmHg). Mean cBP was higher in V than S (139±17 vs 131 ± 19 mmHg) and despite strong correlation between measures (0.87 p < 0.001), cBP was more likely to be greater with S than V cBP at higher cBPs. These differences between V + S remained directionally consistent even after adjustment for risk factors (with multiple regression analysis) and when S PWA results were recalculated using V BP in a subsample (n = 58). Conclusion: PWA evaluations were more frequently successful with using V than S in elderly men. Differences in cAP, cAIx and cBP found between devices were not due to differences in BP calibration values. Further research is needed to understand the causes and clinical implications of these differences

Lipoprotein-apheresis (apheresis) removes LDL-cholesterol in patients with severe dyslipidemia. However, reduction is transient, indicating that the long-term cardiovascular benefits of apheresis may not solely be due to LDL removal. Microparticles (MPs) are submicron vesicles released from the plasma membrane of cells. MPs, particularly platelet-derived MPs, are increasingly being linked to the pathogenesis of many diseases. We aimed to characterize the effect of apheresis on MP size, concentration, cellular origin, and fatty acid concentration in individuals with familial hypercholesterolemia (FH). Plasma and MP samples were collected from 12 individuals with FH undergoing routine apheresis. Tunable resistive pulse sensing (np200) and nanoparticle tracking analysis measured a fall in MP concentration (33 and 15%, respectively; P < 0.05) pre- to post-apheresis. Flow cytometry showed MPs were predominantly annexin V positive and of platelet (CD41) origin both pre- (88.9%) and post-apheresis (88.4%). Fatty acid composition of MPs differed from that of plasma, though apheresis affected a similar profile of fatty acids in both compartments, as measured by GC-flame ionization detection. MP concentration was also shown to positively correlate with thrombin generation potential. In conclusion, we show apheresis nonselectively removes annexin V-positive platelet-derived MPs in individuals with FH. These MPs are potent inducers of coagulation and are elevated in CVD; this reduction in pathological MPs could relate to the long-term benefits of apheresis.

Psychosocial factors such as depression (D) and anxiety (A) and dyslipidemia are associated with increased risk of cardiovascular disease (CVD). Carotid intima-media thickness (IMT) is an indicator of subclinical disease and predictor of CVD events. There is mixed evidence on the association of D/A

Increased arterial stiffness is a feature of both ageing and exposure to cardiovascular risk factors and predisposes patients to myocardial hypertrophy, ischemia and dysfunction. Subendocardial viability ratio (SEVR - an indicator of myocardial perfusion relative to cardiac work load, lower values

Stress influences the risk of cardiovascular disease (CVD). Acute mental stress (AMS) can induce both low-grade inflammation and endothelial dysfunction. The relationship between inflammatory stress responses and emergence of endothelial dysfunction is unexplored. We investigated associations

Background and Purpose— UK black African-Caribbean adults have higher risks of stroke than white Europeans and have been shown to have increased carotid intima-media thickness (cIMT). We examined whether corresponding ethnic differences in cIMT were apparent in childhood and, if so, whether these could be explained by ethnic differences in cardiovascular risk markers. Methods— We conducted a 2-stage survey of 939 children (208 white European, 240 black African-Caribbean, 258 South Asian, 63 other Asian, 170 other ethnicity), who had a cardiovascular risk assessment and measurements of cIMT at mean ages of 9.8 and 10.8 years, respectively. Results— Black African-Caribbean children had a higher cIMT than white Europeans (mean difference, 0.014 mm; 95% CI, 0.008–0.021 mm; P Conclusions— UK black African-Caribbean children have higher cIMT levels in childhood; the difference is not explained by conventional cardiovascular risk markers. There may be important opportunities for early cardiovascular prevention, particularly in black African-Caribbean children.

Mutations in prominin 1 (PROM1) have been shown to result in retinitis pigmentosa, macular degeneration and cone-rod dystrophy. Because of the putative role of PROM1 in hippocampal neurogenesis, we examined two kindreds with the same R373C PROM1 missense mutation using our established paradigm to study brain structure and function. As the protein encoded by PROM1, known as CD133, is used to identify stem/progenitor cells that can be found in peripheral blood and reflect endothelial reparatory mechanisms, other parameters were subsequently examined that included measures of vascular function, endothelial function and angiogenic capacity. We found that aspects of endothelial function assayed ex vivo were abnormal in patients with the R373C PROM1 mutation, with impaired adhesion capacity and higher levels of cellular damage. We also noted renal infections, haematuria and recurrent miscarriages possibly reflecting consequences of abnormal tubular modelling. Further studies are needed to confirm these findings.

Introduction Many patients with Peyronie's disease (PD) have one or more risk factors (RFs) for atherosclerosis and endothelial dysfunction. It is well recognized that such RFs commonly lead to the development of systemic vascular abnormalities. While not necessarily so, this may implicate vascular dysfunction in its pathogenesis. The cause of PD remains obscure despite intense research over the years and investigating the role of vascular dysfunction in the pathogenesis of PD is a novel approach worth undertaking. Aim To test our hypothesis that PD is associated with systemic vascular changes even in the absence of RFs for atherosclerosis and endothelial dysfunction. Methods Vascular function was assessed using high‐resolution brachial artery ultrasound in 23 PD patients (aged 30–65 years) without RFs for endothelial dysfunction and atherosclerosis, and 23 age‐matched healthy controls. Endothelium‐dependent, flow‐mediated brachial artery dilation was measured in response to increased shear stress (reactive hyperemia induced by 5 minutes of forearm ischemia). This response was contrasted with that of 400 µg sublingual glyceryl trinitrate, an endothelium‐independent vasodilator. Anthropometric characteristics, blood pressure, fasting lipids, and glucose were also measured. Main Outcome Measure Endothelium‐dependent, flow‐mediated brachial artery dilation and glyceryl trinitrate‐induced endothelium‐independent vasodilation. Results Endothelium‐dependent flow‐mediated dilation (FMD) was impaired in PD patients compared to controls (5.62 ± 0.58% vs. 7.46 ± 0.56%, P = 0.03). In contrast, responses to glyceryl trinitrate were similar in PD patients and controls as were blood pressure, lipid, and glucose values. FMD remained impaired after multivariable adjustment for potential confounders. Conclusion Patients with Peyronie's disease have evidence of systemic vascular changes in the way of systemic conduit artery endothelial impairment even in the absence of RFs for atherosclerosis and endothelial dysfunction. These wider vascular abnormalities in PD are likely to be of clinical relevance and require further study. Agrawal V, Ellins E, Donald A, Minhas S, Halcox J, and Ralph DJ. Systemic vascular endothelial dysfunction in Peyronie's disease. J Sex Med 2008;5:2688–2693.

Objective There is growing evidence that the presence of the cell stress protein heat shock protein (HSP) 60 in the circulation, is associated with risk of coronary heart disease. In this study, we measured the association between plasma HSP60 and carotid arterial stiffness in middle-aged men and women.Methods Six hundred and forty-seven men and women aged 50-72 years and free of cardiovascular disease and medication were tested. Carotid artery distensibility coefficient was assessed ultrasonically as a measure of arterial stiffness, and plasma HSP60 was assessed using a sensitive immunoassay.Results We found a significant, independent association between high plasma levels of HSP60 and increased carotid stiffness. Carotid distensibility coefficient was also related to diabetes, adiposity, blood pressure, lipids, plasma interleukin-6 and C-reactive protein. After adjusting for these factors, the odds of HSP60 concentration of at least 1000 ng/ml were 1.79 (95% confidence intervals 1.06-3.04) for participants in the lowest compared with the highest tertile of the distensibility coefficient.Conclusion HSP60 is a potent activator of vascular endothelial cells and smooth muscle cells. Thus, it is possible that long-term stimulation of these cell populations by blood-borne HSP60 acts to drive blood vessel changes resulting in decreased arterial elasticity. J Hypertens 26: 2389-2392 (C) 2008 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Background It is increasingly recognised that cardiovascular disease (CVD) and cardiovascular ageing are processes which may begin well before later life. However, few prospective epidemiological studies have distinguished the influence of key cardiovascular risk factor exposures at different stages of the life course to relevant markers of cardiovascular disease and ageing in later life. We aimed to examine the associations between established cardiovascular risk factors at three points during adult life (median 45, 65 and 78 years) and carotid intima media thickness (cIMT) and carotid-femoral pulse wave velocity (CFPWV) at 78 years. Methods The British Regional Heart Study is a prospective study of cardiovascular disease originally based on 7735 men aged 40–59 years from 24 British towns. Men took part in cardiovascular risk assessments providing information on cigarette smoking, body mass index [BMI], SBP, DBP, total, HDL-cholesterol, non-HDL cholesterol, plasma glucose) at median ages 45, 65 and 78 years and had measurements of cIMT (ultrasound) and CFPWV (Vicorder) at 78 years. Life course modelling approaches were used to define models of accumulation, sensitive period and mobility for the development of risk. Results Among 3137 surviving men, 1696 men (54%) had cIMT measurements and 1577 had CFPWV measurements at 78 years. cIMT was positively associated with BMI levels at 45, 65 and 78 years (stronger at 45 and 65), with SBP at 45, 65 and 78 years (stronger at 45 and 65), with plasma glucose and HDL-cholesterol (inversely) at 78 years and with cigarette smoking at 45 years. Life course models suggested risk accumulation over all three age points for BMI and SBP but were inconclusive for the other risk factors. CFPWV was positively associated with SBP at 45, 65 and 78 years (strongest at 78 years), with DBP at 65 and 78 years (stronger at 78 years) and with non-HDL cholesterol at 78 years only. Life course models suggested a sensitive period at 78 years for both SBP and DBP but were inconclusive for the other risk factors. These results were not materially affected by adjustment for blood pressure and lipid lowering medications. Conclusion Established CVD risk factors (particularly blood pressure) are strong influences on these markers of cardiovascular disease and ageing. The influence of BP on cIMT appeared to be cumulative, while the influence of BP on CFPWV mainly reflected recent BP. Cardiovascular ageing is likely to be influenced both by longer-term risk accumulation and by recent risk factor exposures.

Background Although both low physical activity (PA) and high sedentary behaviour (SB) levels may increase cardiovascular disease (CVD) risk among older people, the independence of their effects on CVD risk and the impact of PA and SB bouts of differing durations remain uncertain. We have therefore examined the associations between objectively measured PA of different intensities and bout durations, SB of different bout durations, and carotid intima-media thickness (CIMT), a non-invasive marker of CVD risk, among older men. Methods We used cross sectional data from community-dwelling men aged 71–91 years (British Regional Heart Study) (71–91 years) recruited from 24 primary care practices. Men wore an Actigraph GT3x accelerometer to quantify physical activity and sedentary behaviour, and had CIMT measured using ultrasound. We used linear regression models to investigate whether CIMT was independently associated with (i) total physical activity (counts per minute, cpm), (ii) moderate and vigorous physical activity (MVPA, >1040 cpm), (iii) light activity (LPA, 100–1040 cpm) and (iv) sedentary behaviour (SB, Results 1438/3137 men (46%) had data for CIMT, all covariates and >= 600 min/day of accelerometer data. 239 men with pre-existing CVD were excluded, leaving 1199 in analyses. After adjusting for accelerometer wear time, season, region of residence, age, social class, living alone, smoking and alcohol consumption, both higher total PA and higher LPA were associated with lower CIMT, and SB with higher CIMT. Each additional 1000 cpm/day of total PA was associated with a 0.0012 mm (95% CI –0.0022, –0.0002) lower CIMT and each additional 30 min/day of LPA with a 0.007 mm (95% CI –0.012, –0.002) lower CIMT. A non-significant inverse association was observed between MVPA and CIMT. Conversely, each additional 30 min/day of SB was associated with a 0.005 mm higher CIMT (95% CI 0.002, 0.009). The associations between LPA, SB and CIMT were little affected by adjustment for MVPA. We found no associations between CIMT and bouts of different durations of LPA, SB or MVPA, independent of total amounts of LPA, SB or MVPA respectively. Conclusion Our findings suggest that LPA reduces CVD risk and that sedentary time is detrimental. Few older adults meet current guidelines for physical activity, which include moderate and/or vigorous activity. Light activity may also be important for older adults, and studies such as this may inform future discussions of physical activity recommendations for this age group.

Introduction: Endothelial function is impaired in sickle cell anemia (SCA) and may be prognostic of severity of pathophysiology underlying many complications. Poor nutritional status is documented in SCA in all income settings, yet no strategies exist to improve nutrition. Poor nutritional status and hemoglobin predict death and hospitalization in Tanzanian SCA patients (Cox, et al. Haematologica 96, 2011, Makani et al. PloSONE 6, 2011). The objectives are to determine the combined effect of two ready-to-use-supplementary food (RUSF) interventions on the primary endpoints of endothelial function, assessed by flow mediated dilatation (FMD), growth and body composition and hemoglobin (secondary endpoint). Methods: Tanzanian children (N=119) (HbSS) aged 8-11.9 years were enrolled in V-FIT (ISRCTN74331412/NCT01718054) in Aug to Nov 2012. Children received in random order a daily RUSF providing 500 kcal, 1 RDA of vitamins and minerals & 1mg folate (Nutriset, France), plus weekly anti-malarial prophylactic chloroquine syrup (150/225mg base) (Wallace manufacturing chemicals, UK), or a vascular-RUSF (RUSFv) fortified with arginine and citrulline (average 0.2g/kg/d & 0.1g/kg/d) plus daily chloroquine syrup (3mg base/kg/d). Patients and investigators were blind to the different interventions. Each intervention was received for 4 months with 4 month washout periods on either side (Figure 1A). Clinic visits were conducted at baseline and at the end of each intervention/washout period when endothelium-dependent and -independent vasodilatation were assessed (Donald et al. JACC 51, 2008), plus height, weight and body composition by impedance (Tanita BC418). Random effects models were used, adjusting for repeated measures within individuals. In multivariable analyses models were a priori adjusted for gender. Possible temporal effects were modelled via Fourier transformation of visit dates and included in models for growth and hemoglobin. Effects of the interventions on FMDmax were adjusted for arterial diameter before vasodilation induction, which was negatively correlated with FMDmax and for magnitude of reactive hyperaemia during induction of vasodilation, which was not correlated with FMDmax. Results: 115/119 (60% male; mean age at enrolment 10.0, 95% CI 9.8 – 10.2 years) enrolled patients completed the trial and all clinic visits. Endpoints at baseline and the adjusted and unadjusted effects of the interventions are shown in Table 1. FMDmax, baseline brachial diameter, absolute change in blood flow velocity during reactive hyperemia, hemoglobin, height velocity, weight and lean mass gain all increased on the RUSF (Fig 1B-F). Discussion: We demonstrate that providing extra protein, energy and micronutrients improves hemoglobin, vascular endothelial function and growth. It is possible that the effects observed are limited to the RUSFv, and/or from unadjusted for temporal effects. Unblinded analysis of the effect of RUSFv vs. RUSF on these endpoints, plasma amino acids and arginase are planned. Currently the only intervention for children with SCA is hydroxyurea, which although it improves hemoglobin and reduces hemolysis, does not appear to affect growth while its effect on vascular physiology is unknown (Wang et al. J Pediatr 140, 2002). In addition to specific nutrients, general improvement in nutrition may result in improvement in important intermediate endpoints in SCA. Future research should investigate effects of nutritional supplementation on clinical endpoints. Abstract 4087. Table 1. Endpoints at enrolment and combined effect of RUSF interventions. Baseline N=119 RUSF coefficient [95% CI] P-value Adjusted RUSF coefficient [95% CI] Adjusted P-value Endothelial function, mean [SD] FMDmax % 7.66 [3.37] 0.66 [0.15 – 1.17] 0.011 0.98 [0.42 – 1.54] 0.001 Baseline brachial diameter, mm 2.61 [0.35] 0.05 [0.03 – 0.09] Disclosures No relevant conflicts of interest to declare.