Clinical investigation of subclinical vascular disease in psychosocial stress and dyslipidaemia

Cardiovascular disease is a major cause of death and ill health across the world. Psychosocial factors are increasingly being recognised as potential cardiovascular risk factors, contributing to the development and progression of atherosclerotic disease. However, the pathways between psychosocial factors and cardiovascular disease are not yet fully understood. The aims of this thesis were to explore the associations between psychosocial factors (both chronic and acute stress) and measures of subclinical vascular disease, and to further develop and validate, a new method of assessing vasomotor function. Women with both depression and anxiety were found to have increased carotid intima-media thickness and this relationship was found to be influenced by the presence of dyslipidaemia. When looking at the inflammatory responses to an acute mental stress challenge it was shown that those participants who had an elevated fibrinogen response 45 minutes after the stress challenge had poorer endothelial function 3 years later, as assessed by flow-mediated dilatation. These findings suggest that both chronic and acute stress may play a role in the development of cardiovascular disease. Good reproducibility was demonstrated with the new method for assessing vasomotor function following further development of the protocol for the method. The technique was able to detect differences in vasomotor function between a group of patients with Familial Hypercholesterolaemia compared with age and gender matched controls. In addition it was also able to detect improvement in vasomotor function following a single lipoprotein apheresis treatment in patients with Familial Hypercholesterolaemia undergoing long-term treatment. These studies demonstrated the potential of this method for use in non-specialist vascular research laboratories and out in the field for the assessment of vasomotor function

Clinical investigation of subclinical vascular disease in psychosocial stress and dyslipidaemia

Cardiovascular disease is a major cause of death and ill health across the world. Psychosocial factors are increasingly being recognised as potential cardiovascular risk factors, contributing to the development and progression of atherosclerotic disease. However, the pathways between psychosocial factors and cardiovascular disease are not yet fully understood. The aims of this thesis were to explore the associations between psychosocial factors (both chronic and acute stress) and measures of subclinical vascular disease, and to further develop and validate, a new method of assessing vasomotor function. Women with both depression and anxiety were found to have increased carotid intima-media thickness and this relationship was found to be influenced by the presence of dyslipidaemia. When looking at the inflammatory responses to an acute mental stress challenge it was shown that those participants who had an elevated fibrinogen response 45 minutes after the stress challenge had poorer endothelial function 3 years later, as assessed by flow-mediated dilatation. These findings suggest that both chronic and acute stress may play a role in the development of cardiovascular disease. Good reproducibility was demonstrated with the new method for assessing vasomotor function following further development of the protocol for the method. The technique was able to detect differences in vasomotor function between a group of patients with Familial Hypercholesterolaemia compared with age and gender matched controls. In addition it was also able to detect improvement in vasomotor function following a single lipoprotein apheresis treatment in patients with Familial Hypercholesterolaemia undergoing long-term treatment. These studies demonstrated the potential of this method for use in non-specialist vascular research laboratories and out in the field for the assessment of vasomotor function

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 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=<0.001 &0.003) but TNFα was unchanged (p=0.09). An independent negative association between FMD and change in fibrinogen at 45 minutes (β=-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

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

Low-Dose Sodium Nitrite Attenuates Myocardial Ischemia and Vascular Ischemia-Reperfusion Injury in Human Models

ObjectivesThe 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.BackgroundInorganic 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.MethodsIn 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.ResultsComparing 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 &lt; 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 &lt; 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 &lt; 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.ConclusionsLow-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

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

What works best when implementing a physical activity intervention for teenagers? Reflections from the ACTIVE Project: a qualitative study

Objective This 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. Design Qualitative findings at 12 months from a mixed method randomised control trial. Methods Active 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. Results Teenagers 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. Conclusions The 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

Predictors of cardiovascular health in teenagers (aged 13–14 years): a cross-sectional study linked with routine data

Objective To examine the predictors of cardiovascular health in teenagers (aged 13–14 years). Methods Measures of arterial stiffness (augmentation index [AI]), 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 (WIMD) Multivariate regression analysis determined associations between routinely collected data and cardiovascular measures. Results Teenagers had higher augmentation index (2.41 [95% CI: 1.10 to 3.72]), ran fewer metres (-130.08 metres [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 metres [95% CI: 83.90 to 314.84]). Higher systolic blood pressure was observed in first born children (10.23 mmHg [95% CI: 1.58 to 18.88]) and in those who were never breastfed (4.77 mmHg [95% CI: 1.10 to 8.42]). Conclusions Improving heart health in deprived areas requires multi-level 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