Associations between inflammation, coagulation, cardiac strain and injury, and subclinical vascular disease with frailty in older men: a cross-sectional study.

BACKGROUND: Inflammation, coagulation activation, endothelial dysfunction and subclinical vascular disease are cross-sectionally associated with frailty. Cardiac-specific biomarkers are less-well characterised. We assessed associations between these and frailty, in men with, and without, cardiovascular disease (CVD). METHODS: Cross-sectional analysis of 1096 men without, and 303 with, CVD, aged 71-92, from the British Regional Heart Study. Multinominal logistic regression was performed to examine the associations between frailty status (robust/pre-frail/frail) and, separately, C-reactive protein (CRP), interleukin-6 (IL-6), tissue plasminogen activator (tPA), D-dimer, von Willebrand factor (vWF), high-sensitivity cardiac troponin-T (hs-cTnT), N-terminal pro B-type natriuretic peptide (NT-proBNP) (all natural log-transformed), and, in men without CVD, carotid intima-media thickness (CIMT), carotid-femoral pulse wave velocity (cfPWV), carotid distensibility coefficient (DC), and ankle-brachial pressure index (ABPI), adjusted for age, renal function, BMI, social class, smoking, polypharmacy, cognition, multimorbidity and systolic blood pressure. Explanatory variables with p < 0.05 were carried forward into mutually-adjusted analysis. RESULTS: In men without CVD, higher CRP, IL-6, vWF, tPA, hs-cTnT, NT-proBNP, cfPWV, and lower DC were significantly associated with frailty; mutually-adjusted, log IL-6 (OR for frailty = 2.02, 95%CI 1.38-2.95), log hs-cTnT (OR = 1.95, 95%CI 1.24-3.05) and DC (OR = 0.92, 95%CI 0.86-0.99) retained associations. In men with CVD, higher CRP, IL-6, and hs-cTnT, but not vWF, tPA, NT-proBNP or D-dimer, were significantly associated with frailty; mutually-adjusted, log hs-cTnT (OR 3.82, 95%CI 1.84-7.95) retained a significant association. CONCLUSIONS: In older men, biomarkers of myocardial injury are associated with frailty. Inflammation is associated with frailty in men without CVD. Carotid artery stiffness is associated with frailty in men without CVD, independently of these biomarkers.

The role of interleukin-6 trans-signalling on cardiovascular dysfunction in inflammatory arthritis.

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.

Association of physical activity metrics with indicators of cardiovascular function and control in children with and without type 1 diabetes.

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 < 0.01), a more negative intensity gradient (p < 0.01), a lower average acceleration and less time in bouted moderate-to-vigorous physical activity (MVPA; p < 0.05). Overall, intensity gradient was strongly correlated with average acceleration, MVPA and bouted MVPA (r2 = 0.89, r2 = 0.80, r2 = 0.79, respectively; all p < 0.05), while average acceleration was correlated with MVPA and bouted MVPA (r2 = 0.85, r2 = 0.83, respectively; p < 0.05). Accounting for disease status, intensity gradient and average acceleration were significant predictors of HRV indices (p < 0.05) and PWV (p < 0.01, p < 0.05, respectively). CONCLUSION: Overall, MVPA was most associated with central stiffness, highlighting the importance of meeting activity guidelines. Diabetic children demonstrated poorer cardiovascular health than their counterparts, likely attributable to a lower intensity and physical activity volume, identifying physical activity intensity as a key target for future interventions.

Carotid artery wave intensity in mid- to late-life predicts cognitive decline: the Whitehall II study.

AIMS: Excessive arterial pulsatility may contribute to cognitive decline and risk of dementia via damage to the fragile cerebral microcirculation. We hypothesized that the intensity of downstream-travelling pulsatile waves measured by wave intensity analysis in the common carotid artery during mid- to late-life would be associated with subsequent cognitive decline. METHODS AND RESULTS: Duplex Doppler ultrasound was used to calculate peak forward-travelling compression wave intensity (FCWI) within the common carotid artery in 3191 individuals [mean ± standard deviation (SD), age = 61 ± 6 years; 75% male] assessed as part of the Whitehall II study in 2003-05. Serial measures of cognitive function were taken between 2002-04 and 2015-16. The relationship between FCWI and cognitive decline was adjusted for sociodemographic variables, genetic and health-related risk factors, and health behaviours. Mean (SD) 10-year change in standardized global cognitive score was -0.39 (0.18). Higher FCWI at baseline was associated with accelerated cognitive decline during follow-up [difference in 10-year change of global cognitive score per 1 SD higher FCWI = -0.02 (95% confidence interval -0.04 to -0.00); P = 0.03]. This association was largely driven by cognitive changes in individuals with the highest FCWI [Q4 vs. Q1-Q3 = -0.05 (-0.09 to -0.01), P = 0.01], equivalent to an age effect of 1.9 years. Compared to other participants, this group was ∼50% more likely to exhibit cognitive decline (defined as the top 15% most rapid reductions in cognitive function during follow-up) even after adjustments for multiple potential confounding factors [odds ratio 1.49 (1.17-1.88)]. CONCLUSION: Elevated carotid artery wave intensity in mid- to late-life predicts faster cognitive decline in long-term follow-up independent of other cardiovascular risk factors.

Teenage recommendations to improve physical activity for their age group: a qualitative study.

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.

Increased fibrinogen responses to psychophysiological stress predict future endothelial dysfunction implications for cardiovascular disease?

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 min post-task in 158 participants. Blood pressure and heart rate responses were measured. Flow-mediated dilatation (FMD) was measured 3years later. Fibrinogen and IL-6 increased post-stress (p⩽0.001 & 0.003) but TNFα was unchanged (p=0.09). An independent negative association between FMD and change in fibrinogen at 45 min (ß=-0.047 p=0.016) remained after multiple adjustment (baseline fibrinogen, baseline diameter, reactive hyperaemia, age, gender and other cardiovascular risk factors). There was no association between FMD and change in IL-6 or TNFα. There were no differences in the responses to stress between those with and without dyslipidaemia. However, there was an interaction between the presence of dyslipidaemia and immediate change in fibrinogen with stress which was associated with FMD. Those participants with dyslipidaemia who had a greater change in fibrinogen had lower FMD. We conclude that elevated fibrinogen responses to stress are associated with future endothelial dysfunction which may reflect increased cardiovascular risk.

Active children through individual vouchers - evaluation (ACTIVE): protocol for a mixed method randomised control trial to increase physical activity levels in teenagers.

BACKGROUND: 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. DESIGN: 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. DISCUSSION: 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. TRIAL REGISTRATION: ISRCTN75594310 (Assigned 06/03/2017).

Objectively measured physical activity, sedentary time and subclinical vascular disease: Cross-sectional study in older British men.

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 78.5years, 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 0.038m/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 0.005mm 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.

Lipoprotein-apheresis reduces circulating microparticles in individuals with familial hypercholesterolemia.

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.

Incident atrial fibrillation and adverse clinical outcomes during extended follow-up of participants recruited to the remote heart rhythm sampling using the AliveCor heart monitor to screen for atrial fibrillation: the REHEARSE-AF study.

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.

Ethnic differences in carotid intima-media thickness between UK children of black African-Caribbean and white European origin.

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<0.0001). cIMT levels in South Asian and other Asian children were however similar to those of white Europeans. Among all children, cIMT was positively associated with age, systolic and diastolic blood pressure and inversely with combined skinfold thickness and serum triglyceride. Mean triglyceride was lower among black African-Caribbeans than white Europeans; blood pressure and skinfold thickness did not differ appreciably. However, adjustment for these risk factors had little effect on the cIMT difference between black African-Caribbeans and white Europeans. 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.

Levels of circulating endothelial cells and colony-forming units are influenced by age and dyslipidemia.

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 hypercholesterolemia (FH). METHODS: 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 as compared with 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 dilatations, was positively associated with CFU number, even after 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 indexes of vascular injury and repair approaching those seen in adults.

Achievement of European Society of Cardiology/European Atherosclerosis Society lipid targets in very high-risk patients: Influence of depression and sex.

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<0.001). Patients with prior depression were less likely to achieve targets for low density lipoprotein cholesterol (LDL-C <1.8mmol/l), non-high density lipoprotein cholesterol (non-HDL-C <2.6mmol/l) and triglycerides (<2.3mmol/l) than patients without depression (OR 0.86 95%CI 0.78-0.96 p = 0.007, OR 0.80 95%CI 0.69-0.92 p = 0.003 & OR 0.69 95CI% 0.61-0.79 p<0.001 respectively). Females were less likely to achieve targets for LDL-C and non-HDL-C than males (OR 0.55 95%CI 0.50-0.61 p<0.001 & OR 0.63 95%CI 0.55-0.73 p<0.001). There was an additive effect of depression and sex; females with depression were not only least likely to be tested (OR 0.74 95%CI 0.65-0.84 p<0.001) but also (where levels were known) less likely to achieve LDL-C (OR 0.47 95%CI 0.41-0.55 p<0.001) and non-HDL-C targets (OR 0.50 95%CI 0.41-0.60 p<0.001). It was not possible to look at the influence of medication adherence on achievement of lipid targets due to limitations of the use of anonymised routinely-held clinical care data. 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.

Subclinical cardiovascular disease and risk of incident frailty: The British Regional Heart Study.

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 (<0.9, 0.9-1.4, ≥1.4). RESULTS: 865 men were examined and completed the 3 year follow-up questionnaire, of whom 78 became frail. Adjusted for age, prefrailty, body mass index, diabetes, smoking, atrial fibrillation, blood pressure, renal function, and incident CVD, higher CIMT was associated with greater odds of incident frailty (2nd tertile OR 1.62, 95% CI 0.78-3.35, 3rd tertile OR 2.61, 95% CI 1.30-5.23, p = 0.007, trend p = 0.006). cfPWV showed a weaker, non-significant association (2nd tertile OR 1.79, 95% CI 0.85-3.78, 3rd tertile OR 1.73, OR 0.81-3.72, p = 0.16, trend p = 0.20). There was no clear association between incident frailty and DC or ABPI. In subgroup analyses, CIMT was significantly associated with incident frailty in men ≥80 years (3rd tertile OR 6.99, 95%CI 1.42-34.5), but not in men aged 75-80 or < 75 years. CONCLUSION: Subclinical CVD, as measured by CIMT, is associated with greater risk of incident frailty in older men over three year follow-up, independent of the development of clinically-apparent stroke, heart failure, or myocardial infarction, and may be a modifiable risk factor for frailty. This association may be stronger in very old age.

Influence of Maternal Lifestyle and Diet on Perinatal DNA Methylation Signatures Associated With Childhood Arterial Stiffness at 8 to 9 Years.

[Figure: see text].

Endothelial function predicts progression of carotid intima-media thickness.

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.

Associations of depression-anxiety and dyslipidaemia with subclinical carotid arterial disease: Findings from the Whitehall II Study.

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.

Active Children Through Individual Vouchers Evaluation: A Mixed-Method RCT.

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.

Endothelial dysfunction and cytomegalovirus replication in pediatric heart transplantation.

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.

Chronic kidney disease, cardiovascular risk markers and total mortality in older men: cystatin C versus creatinine.

BACKGROUND: It 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. METHODS: This 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. RESULTS: The 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 <60 mL/min/1.732), 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). CONCLUSION: Despite 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.