Updating the study protocol: Insight 46 - a longitudinal neuroscience sub-study of the MRC National Survey of Health and Development - phases 2 and 3.

BACKGROUND: Although age is the biggest known risk factor for dementia, there remains uncertainty about other factors over the life course that contribute to a person's risk for cognitive decline later in life. Furthermore, the pathological processes leading to dementia are not fully understood. The main goals of Insight 46-a multi-phase longitudinal observational study-are to collect detailed cognitive, neurological, physical, cardiovascular, and sensory data; to combine those data with genetic and life-course information collected from the MRC National Survey of Health and Development (NSHD; 1946 British birth cohort); and thereby contribute to a better understanding of healthy ageing and dementia. METHODS/DESIGN: Phase 1 of Insight 46 (2015-2018) involved the recruitment of 502 members of the NSHD (median age = 70.7 years; 49% female) and has been described in detail by Lane and Parker et al. 2017. The present paper describes phase 2 (2018-2021) and phase 3 (2021-ongoing). Of the 502 phase 1 study members who were invited to a phase 2 research visit, 413 were willing to return for a clinic visit in London and 29 participated in a remote research assessment due to COVID-19 restrictions. Phase 3 aims to recruit 250 study members who previously participated in both phases 1 and 2 of Insight 46 (providing a third data time point) and 500 additional members of the NSHD who have not previously participated in Insight 46. DISCUSSION: The NSHD is the oldest and longest continuously running British birth cohort. Members of the NSHD are now at a critical point in their lives for us to investigate successful ageing and key age-related brain morbidities. Data collected from Insight 46 have the potential to greatly contribute to and impact the field of healthy ageing and dementia by combining unique life course data with longitudinal multiparametric clinical, imaging, and biomarker measurements. Further protocol enhancements are planned, including in-home sleep measurements and the engagement of participants through remote online cognitive testing. Data collected are and will continue to be made available to the scientific community.

Technical development and feasibility of a reusable vest to integrate cardiovascular magnetic resonance with electrocardiographic imaging.

BACKGROUND: Electrocardiographic imaging (ECGI) generates electrophysiological (EP) biomarkers while cardiovascular magnetic resonance (CMR) imaging provides data about myocardial structure, function and tissue substrate. Combining this information in one examination is desirable but requires an affordable, reusable, and high-throughput solution. We therefore developed the CMR-ECGI vest and carried out this technical development study to assess its feasibility and repeatability in vivo. METHODS: CMR was prospectively performed at 3T on participants after collecting surface potentials using the locally designed and fabricated 256-lead ECGI vest. Epicardial maps were reconstructed to generate local EP parameters such as activation time (AT), repolarization time (RT) and activation recovery intervals (ARI). 20 intra- and inter-observer and 8 scan re-scan repeatability tests. RESULTS: 77 participants were recruited: 27 young healthy volunteers (HV, 38.9 ± 8.5 years, 35% male) and 50 older persons (77.0 ± 0.1 years, 52% male). CMR-ECGI was achieved in all participants using the same reusable, washable vest without complications. Intra- and inter-observer variability was low (correlation coefficients [rs] across unipolar electrograms = 0.99 and 0.98 respectively) and scan re-scan repeatability was high (rs between 0.81 and 0.93). Compared to young HV, older persons had significantly longer RT (296.8 vs 289.3 ms, p = 0.002), ARI (249.8 vs 235.1 ms, p = 0.002) and local gradients of AT, RT and ARI (0.40 vs 0.34 ms/mm, p = 0,01; 0.92 vs 0.77 ms/mm, p = 0.03; and 1.12 vs 0.92 ms/mm, p = 0.01 respectively). CONCLUSION: Our high-throughput CMR-ECGI solution is feasible and shows good reproducibility in younger and older participants. This new technology is now scalable for high throughput research to provide novel insights into arrhythmogenesis and potentially pave the way for more personalised risk stratification. CLINICAL TRIAL REGISTRATION: Title: Multimorbidity Life-Course Approach to Myocardial Health-A Cardiac Sub-Study of the MRC National Survey of Health and Development (NSHD) (MyoFit46). National Clinical Trials (NCT) number: NCT05455125. URL: https://clinicaltrials.gov/ct2/show/NCT05455125?term=MyoFit&draw=2&rank=1.

Pulse wave velocity during re-feeding and with weight gain in underweight female adolescents with anorexia nervosa.

Anorexia Nervosa (AN) causes harmful underweight and important cardiovascular acute complications however less is known about longer-term cardiovascular risk. We measured carotid femoral pulse wave velocity (PWV) in a group of underweight young women with AN at baseline and weekly as they were refed and gained weight. PWV decreased over time and was negatively associated with increasing BMI and calorific meal content suggesting potential positive cardiovascular benefits for refeeding and weight gain in AN and supports current consensus for the importance of weight gain in underweight young women with AN.

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

Measuring local haemodynamics in skeletal muscle has the potential to provide valuable insight into the oxygen delivery to tissue, especially during high demand situations such as exercise. The aim of this study was to compare the skeletal muscle microvascular response during post-occlusive reactive hyperaemia (PORH) with the response to exercise, each measured using near-infrared spectroscopy (NIRS) and to establish if associations exist between muscle measures and exercise capacity or sex. Participants were from a population-based cohort study, the Southall and Brent Revisited (SABRE) study. Skeletal muscle measures included changes in tissue saturation index at the onset of exercise (∆TSIBL-INC) and across the whole of exercise (∆TSIBL-EE), time to 50%, 95% and 100% PORH, rate of PORH recovery, area under the curve (AUC) and total oxygenated Haemoglobin (oxy-Hb) change during PORH. Exercise capacity was measured using a 6-min stepper test (6MST). Analysis was by multiple linear regression. In total, 558 participants completed the 6MST with NIRS measures of TSI (mean age±SD: 73 ± 7years, 59% male). A sub-set of 149 participants also undertook the arterial occlusion. Time to 100% PORH, recovery rate, AUC and ∆oxy-Hb were all associated with ∆TSIBL-EE (ß-coefficient (95%CI): 0.05 (0.01, 0.09), p = 0.012; -47 (-85, -9.9), p = 0.014; 1.7 (0.62, 2.8), p = 0.002; 0.04 (0.002.0.108), p = 0.041, respectively). Time to 95% & 100% PORH, AUC and ∆oxy-Hb were all associated with ∆TSIBL-INC (ß-coefficient (95%CI): -0.07 (-0.12,-0.02), p = 0.02; -0.03 (-0.05, -0.003), p = 0.028; 0.85 (0.18, 1.5), p = 0.013 & 0.05 (0.02, 0.09), p = 0.001, respectively). AUC and ∆Oxy-Hb were associated with steps achieved (ß-coefficient (95%CI): 18.0 (2.3, 33.7), p = 0.025; 0.86 (0.10, 1.6), p = 0.027). ∆TSIBL-EE was associated with steps and highest VO2 (1.7 (0.49, 2.9), p = 0.006; 7.7 (3.2, 12.3), p = 0.001). ∆TSIBL-INC was associated with steps and VO2 but this difference was attenuated towards the null after adjustment for age, sex and ethnicity. ∆TSIBL-EE was greater in women (3.4 (0.4, 8.9) versus 2.1 (0.3, 7.4), p = 0.017) and ∆TSIBL-INC was lower in women versus men (2.4 (0.2, 10.2) versus 3.2 (0.2, 18.2), p = 0.016). These Local microvascular NIRS-measures are associated with exercise capacity in older adults and several measures can detect differences in microvascular reactivity between a community-based sample of men and women.

Association between carotid atherosclerosis and brain activation patterns during the Stroop task in older adults: An fNIRS investigation.

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

Study protocol: MyoFit46-the cardiac sub-study of the MRC National Survey of Health and Development.

BACKGROUND: The life course accumulation of overt and subclinical myocardial dysfunction contributes to older age mortality, frailty, disability and loss of independence. The Medical Research Council National Survey of Health and Development (NSHD) is the world's longest running continued surveillance birth cohort providing a unique opportunity to understand life course determinants of myocardial dysfunction as part of MyoFit46-the cardiac sub-study of the NSHD. METHODS: We aim to recruit 550 NSHD participants of approximately 75 years+ to undertake high-density surface electrocardiographic imaging (ECGI) and stress perfusion cardiovascular magnetic resonance (CMR). Through comprehensive myocardial tissue characterization and 4-dimensional flow we hope to better understand the burden of clinical and subclinical cardiovascular disease. Supercomputers will be used to combine the multi-scale ECGI and CMR datasets per participant. Rarely available, prospectively collected whole-of-life data on exposures, traditional risk factors and multimorbidity will be studied to identify risk trajectories, critical change periods, mediators and cumulative impacts on the myocardium. DISCUSSION: By combining well curated, prospectively acquired longitudinal data of the NSHD with novel CMR-ECGI data and sharing these results and associated pipelines with the CMR community, MyoFit46 seeks to transform our understanding of how early, mid and later-life risk factor trajectories interact to determine the state of cardiovascular health in older age. TRIAL REGISTRATION: Prospectively registered on ClinicalTrials.gov with trial ID: 19/LO/1774 Multimorbidity Life-Course Approach to Myocardial Health- A Cardiac Sub-Study of the MCRC National Survey of Health and Development (NSHD).

Inflammatory pathways amongst people living with HIV in Malawi differ according to socioeconomic status.

BACKGROUND: Non-communicable diseases (NCDs) are increased amongst people living with HIV (PLWH) and are driven by persistent immune activation. The role of socioeconomic status (SES) in immune activation amongst PLWH is unknown, especially in low-income sub-Saharan Africa (SSA), where such impacts may be particularly severe. METHODS: We recruited Malawian adults with CD4<100 cells/ul two weeks after starting ART in the REALITY trial (NCT01825031), as well as volunteers without HIV infection. Clinical assessment, socioeconomic evaluation, blood draw for immune activation markers and carotid femoral pulse wave velocity (cfPWV) were carried out at 2- and 42-weeks post-ART initiation. Socioeconomic risk factors for immune activation and arterial stiffness were assessed using linear regression models. RESULTS: Of 279 PLWH, the median (IQR) age was 36 (31-43) years and 122 (44%) were female. Activated CD8 T-cells increased from 70% amongst those with no education to 88% amongst those with a tertiary education (p = 0.002); and from 71% amongst those earning less than 10 USD/month to 87% amongst those earning between 100-150 USD/month (p = 0.0001). Arterial stiffness was also associated with higher SES (car ownership p = 0.003, television ownership p = 0.012 and electricity access p = 0.029). Conversely, intermediate monocytes were higher amongst those with no education compared to a tertiary education (12.6% versus 7.3%; p = 0.01) and trended towards being higher amongst those earning less than 10 USD/month compared to 100-150 USD/month (10.5% versus 8.0%; p = 0.08). Water kiosk use showed a protective association against T cell activation (p = 0.007), as well as endothelial damage (MIP1ß, sICAM1 and sVCAM1 p = 0.047, 0.026 and 0.031 respectively). CONCLUSIONS: Socioeconomic risk factors for persistent inflammation amongst PLWH in SSA differ depending on the type of inflammatory pathway. Understanding these pathways and their socioeconomic drivers will help identify those at risk and target interventions for NCDs. Future studies assessing drivers of inflammation in HIV should include an SES assessment.

Determinants of Intima-Media Thickness in the Young: The ALSPAC Study.

OBJECTIVES: This study characterized the determinants of carotid intima-media thickness (cIMT) in a large (n > 4,000) longitudinal cohort of healthy young people age 9 to 21 years. BACKGROUND: Greater cIMT is commonly used in the young as a marker of subclinical atherosclerosis, but its evolution at this age is still poorly understood. METHODS: Associations between cardiovascular risk factors and cIMT were investigated in both longitudinal (ages 9 to 17 years) and cross-sectional (ages 17 and 21 years) analyses, with the latter also related to other measures of carotid structure and stress. Additional use of ultra-high frequency ultrasound in the radial artery at age 21 years allowed investigation of the distinct layers (i.e., intima or media) that may underlie observed differences. RESULTS: Fat-free mass (FFM) and systolic blood pressure were the only modifiable risk factors positively associated with cIMT (e.g., mean difference in cIMT per 1-SD increase in FFM at age 17: 0.007 mm: 95% confidence interval [CI]: 0.004 to 0.010; p < 0.001), whereas fat mass was negatively associated with cIMT (difference: -0.0032; 95% CI: 0.004 to -0.001; p = 0.001). Similar results were obtained when investigating cumulative exposure to these factors throughout adolescence. An increase in cIMT maintained circumferential wall stress in the face of increased mean arterial pressure when increases in body mass were attributable to increased FFM, but not fat mass. Risk factor-associated differences in the radial artery occurred in the media alone, and there was little evidence of a relationship between intimal thickness and any risk factor. CONCLUSIONS: Subtle changes in cIMT in the young may predominantly involve the media and represent physiological adaptations as opposed to subclinical atherosclerosis. Other vascular measures may be more appropriate for the identification of arterial disease before adulthood.

Circulating microparticles are increased amongst people presenting with HIV and advanced immune suppression in Malawi and correlate closely with arterial stiffness: a nested case control study.

Background: We aimed to investigate whether circulating microparticle (CMPs) subsets were raised amongst people presenting with human immunodeficiency virus (HIV) and advanced immune suppression in Malawi, and whether they associated with arterial stiffness. Methods: Antiretroviral therapy (ART)-naïve adults with a new HIV diagnosis and CD4 <100 cells/µL had microparticle characterisation and carotid femoral Pulse Wave Velocity (cfPWV) at 2 weeks post ART initiation. HIV uninfected controls were matched on age, systolic blood pressure (BP) and diastolic BP in a 1:1 ratio.  Circulating microparticles were identified from platelet poor plasma and stained for endothelial, leucocyte, monocyte and platelet markers. Results: The median (IQ) total CMP count for 71 participants was 1 log higher in HIV compared to those without (p<0.0001) and was associated with arterial stiffness (spearman rho 0.47, p<0.001). In adjusted analysis, every log increase in circulating particles showed a 20% increase in cfPWV (95% confidence interval [CI] 4 - 40%, p=0.02). In terms of subsets, endothelial and platelet derived microparticles were most strongly associated with HIV. Endothelial derived E-selectin+ CMPs were 1.3log-fold higher and platelet derived CD42a+ CMPs were 1.4log-fold higher (both p<0.0001). Endothelial and platelet derived CMPs also correlated most closely with arterial stiffness (spearman rho: E-selectin+ 0.57 and CD42a 0.56, both p<0.0001). Conclusions: Circulating microparticles associate strongly with arterial stiffness among people living with HIV in Malawi. Endothelial damage and platelet microparticles are the predominant cell origin types and future translational studies could consider prioritising these pathways.

Study Protocol - Insight 46 Cardiovascular: A Sub-study of the MRC National Survey of Health and Development.

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

Inflammatory Phenotypes Predict Changes in Arterial Stiffness Following Antiretroviral Therapy Initiation.

BACKGROUND: Inflammation drives vascular dysfunction in HIV, but in low-income settings causes of inflammation are multiple, and include infectious and environmental factors. We hypothesized that patients with advanced immunosuppression could be stratified into inflammatory phenotypes that predicted changes in vascular dysfunction on ART. METHODS: We recruited Malawian adults with CD4 <100 cells/µL 2 weeks after starting ART in the REALITY trial (NCT01825031). Carotid femoral pulse-wave velocity (cfPWV) measured arterial stiffness 2, 12, 24, and 42 weeks post-ART initiation. Plasma inflammation markers were measured by electrochemiluminescence at weeks 2 and 42. Hierarchical clustering on principal components identified inflammatory clusters. RESULTS: 211 participants with HIV grouped into 3 inflammatory clusters representing 51 (24%; cluster-1), 153 (73%; cluster-2), and 7 (3%; cluster-3) individuals. Cluster-1 showed markedly higher CD4 and CD8 T-cell expression of HLADR and PD-1 versus cluster-2 and cluster-3 (all P < .0001). Although small, cluster-3 had significantly higher levels of cytokines reflecting inflammation (IL-6, IFN-γ, IP-10, IL-1RA, IL-10), chemotaxis (IL-8), systemic and vascular inflammation (CRP, ICAM-1, VCAM-1), and SAA (all P < .001). In mixed-effects models, cfPWV changes over time were similar for cluster-2 versus cluster-1 (relative fold-change, 0.99; 95% CI, .86-1.14; P = .91), but greater in cluster-3 versus cluster-1 (relative fold-change, 1.45; 95% CI, 1.01-2.09; P = .045). CONCLUSIONS: Two inflammatory clusters were identified: one defined by high T-cell PD-1 expression and another by a hyperinflamed profile and increases in cfPWV on ART. Further clinical characterization of inflammatory phenotypes could help target vascular dysfunction interventions to those at highest risk. CLINICAL TRIALS NETWORK: NCT01825031.

Association between fat mass through adolescence and arterial stiffness: a population-based study from The Avon Longitudinal Study of Parents and Children.

BACKGROUND: The link between adiposity, metabolic abnormalities, and arterial disease progression in children and adolescents remains poorly defined. We aimed to assess whether persistent high adiposity levels are associated with increased arterial stiffness in adolescence and any mediation effects by common metabolic risk factors. METHODS: We included participants from the Avon Longitudinal Study of Parents and Children (ALSPAC) who had detailed adiposity measurements between the ages 9-17 years and arterial stiffness (carotid to femoral pulse wave velocity [PWV]) measured at age 17 years. Body-mass index (BMI) and waist-to-height ratio were calculated from weight, height, and waist circumference measurements whereas fat mass was assessed using repeated dual-energy x-ray absorptiometry (DEXA) scans. We used total and trunk fat mass indices (FMIs) to classify participants as normal (<75th percentile) or high (>75th percentile) FMI. We classified participants as being metabolically unhealthy if they had three or more of the following risk factors: high levels of systolic blood pressure, triglycerides, or glucose (all >75th percentile) or low levels of high-density lipoprotein (<25th percentile). We used multivariable linear regression analysis to assess the relationship between PWV and exposure to adiposity, and tested for linear trend of PVW levels across ordinal groups. We used latent class growth mixture modelling analysis to assess the effect of longitudinal changes in adiposity indices through adolescence on arterial stiffness. FINDINGS: We studied 3423 participants (1866 [54·5%] female and 1557 [45·5%] male). Total fat mass was positively associated with PWV at age 17 years (0·004 m/s per kg, 95% CI 0·001-0·006; p=0·0081). Persistently high total FMI and trunk FMI between ages 9 and 17 years were related to greater PWV (0·15 m/s per kg/m2, 0·05-0·24; p=0·0044 and 0·15 m/s per kg/m2, 0·06-0·25; p=0·0021) compared with lower FMI. Metabolic abnormalities amplified the adverse effect of high total FMI on arterial stiffness (PWV 6·0 m/s [95% CI 5·9-6·0] for metabolically healthy participants and 6·2 m/s [5·9-6·4] for metabolically unhealthy participants). Participants who restored normal total FMI in adolescence (PWV 5·8 m/s [5·7-5·9] for metabolically healthy and 5·9 m/s [5·6-6·1] for metabolically unhealthy) had comparable PWV to those who had normal FMI throughout (5·7 m/s [5·7-5·8] for metabolically healthy and 5·9 m/s [5·8-5·9] for metabolically unhealthy). INTERPRETATION: Persistently high fat mass during adolescence was associated with greater arterial stiffness and was further aggravated by an unfavourable metabolic profile. Reverting to normal FMI in adolescence was associated with normal PWV, suggesting adolescence as an important period for interventions to tackle obesity in the young to maximise long-term vascular health. FUNDING: UK Medical Research Council, Wellcome Trust, British Heart Foundation, and AFA Insurances.

HIV-Related Arterial Stiffness in Malawian Adults Is Associated With the Proportion of PD-1-Expressing CD8+ T Cells and Reverses With Antiretroviral Therapy.

BACKGROUND: The contribution of immune activation to arterial stiffness and its reversibility in human immunodeficiency virus (HIV)-infected adults in sub-Saharan Africa is unknown. METHODS: HIV-uninfected and HIV-infected Malawian adults initiating antiretroviral therapy (ART) with a CD4+ T-cell count of <100 cells/µL were enrolled and followed for 44 weeks; enrollment of infected adults occurred 2 weeks after ART initiation. We evaluated the relationship between carotid femoral pulse wave velocity (cfPWV) and T-cell activation (defined as HLA-DR+CD38+ T cells), exhaustion (define as PD-1+ T cells), and senescence (defined as CD57+ T cells) and monocyte subsets, using normal regression. RESULTS: In 279 HIV-infected and 110 HIV-uninfected adults, 142 (37%) had hypertension. HIV was independently associated with a 12% higher cfPWV (P = .02) at baseline and a 14% higher cfPWV at week 10 (P = .02), but the increases resolved by week 22. CD4+ and CD8+ T-cell exhaustion were independently associated with a higher cfPWV at baseline (P = .02). At 44 weeks, arterial stiffness improved more in those with greater decreases in the percentage of CD8+ T cells and the percentage of PD-1+CD8+ T cells (P = .01 and P = .03, respectively). When considering HIV-infected participants alone, the adjusted arterial stiffness at week 44 tended to be lower in those with higher baseline percentage of PD-1+CD8+ T cells (P = .054). CONCLUSIONS: PD-1+CD8+ T-cells are associated with HIV-related arterial stiffness, which remains elevated during the first 3 months of ART. Resources to prevent cardiovascular disease in sub-Saharan Africa should focus on blood pressure reduction and individuals with a low CD4+ T-cell count during early ART.

Early vascular damage from smoking and alcohol in teenage years: the ALSPAC study.

Aims: To determine the impact of smoking and alcohol exposure during adolescence on arterial stiffness at 17 years. Methods and results: Smoking and alcohol use were assessed by questionnaires at 13, 15, and 17 years in 1266 participants (425 males and 841 females) from the ALSPAC study. Smoking status (smokers and non-smoker) and intensity ('high' ≥100, 'moderate' 20-99, and 'low or never' <20 cigarettes in lifetime) were ascertained. Participants were classified by frequency (low or high) and intensity of drinking [light (LI <2), medium (MI 3-9), and heavy (HI >10 drinks on a typical drinking day)]. Carotid to femoral pulse wave velocity (PWV) was assessed at 17 years [mean ± standard deviation and/or mean difference (95% confidence intervals)]. Current smokers had higher PWV compared with non-smokers (P = 0.003). Higher smoking exposure was associated with higher PWV compared with non-smokers [5.81 ± 0.725 vs. 5.71 ± 0.677 m/s, mean adjusted difference 0.211 (0.087-0.334) m/s, P = 0.001]. Participants who stopped smoking had similar PWV to never smokers (P = 0.160). High-intensity drinkers had increased PWV [HI 5.85 ± 0.8 vs. LI 5.67 ± 0.604 m/s, mean adjusted difference 0.266 (0.055-0.476) m/s, P = 0.013]. There was an additive effect of smoking intensity and alcohol intensity, so that 'high' smokers who were also HI drinkers had higher PWV compared with never-smokers and LI drinkers [mean adjusted increase 0.603 (0.229-0.978) m/s, P = 0.002]. Conclusion: Smoking exposure even at low levels and intensity of alcohol use were associated individually and together with increased arterial stiffness. Public health strategies need to prevent adoption of these habits in adolescence to preserve or restore arterial health.

Submaximal exercise blood pressure and cardiovascular structure in adolescence.

PURPOSE: Dynamic exercise results in increased systolic blood pressure (BP). Irrespective of resting BP, some individuals may experience exaggerated rise in systolic BP with exercise, which in adulthood is associated with risk of hypertension, and cardiovascular (CV) disease. It is unknown if exercise BP is associated with markers of CV structure during adolescence. We examined this question in a large adolescent cohort taking account of the possible confounding effect of body composition and BP status. METHODS: 4036 adolescents (mean age 17.8 ±â€¯0.4 years, 45% male), part of a UK population-based birth cohort study completed a sub-maximal step-test with BP immediately post-exercise. Sub-samples underwent comprehensive echocardiography for assessment of cardiac structure; arterial structure including aortic pulse wave velocity (PWV) and carotid intima-media thickness; and assessment of body composition by dual-energy X-ray absorptiometry (DXA). RESULTS: Each 5 mm Hg higher post-exercise systolic BP was associated with CV structure, including 0.38 g/m2.7 (95% CI: 0.29, 0.47) greater left-ventricular mass index (LVMI), and 0.04 m/s (95% CI: 0.03, 0.04) greater aortic PWV. Adjustment for age, total body fat, lean mass and BP status attenuated, but did not abolish associations with LVMI (0.14 g/m2.7 per 5 mm Hg of post-exercise systolic BP; 95% CI 0.21, 0.39) or aortic PWV (0.03 m/s per 5 mm Hg of post-exercise systolic BP; 95% CI: 0.02, 0.04). CONCLUSION: Submaximal exercise systolic BP is associated with markers of CV structure in adolescents. Given the clinical relevance of exercise BP in adulthood, such associations may have implications for CV disease screening in young people and risk in later life.

Assessing the causal role of body mass index on cardiovascular health in young adults: Mendelian randomization and recall-by-genotype analyses.

Background: Body mass index (BMI) has been suggested to be causally related to cardiovascular health in mid-to-late life, but this has not been explored systematically at younger ages - nor with detailed cardiovascular phenotyping. Recall-by-Genotype (RbG) is an approach that enables the collection of precise phenotypic measures in smaller studies, whilst maintaining statistical power and ability for causal inference. Methods: In this study, we used a combination of conventional multivariable regression analysis, Mendelian randomization (MR) and sub-sample RbG methodologies to estimate the causal effect of BMI on gross-level and detailed cardiovascular health in healthy participants from the Avon Longitudinal Study of Parents and Children at age 17 (N=1420-3108 for different outcomes) and an independent sample from the same cohort (for RbG) study at age 21 (N=386-418). Results: In both MR and RbG analyses, results suggested that higher BMI causes higher blood pressure (BP) and left ventricular mass index (LVMI) in young adults (e.g., difference in LVMI per kg/m2 using MR: 1.07g/m2.7; 95% CI: 0.62, 1.52; P=3.87x10-06 and per 3.58kg/m2 using RbG: 1.65g/m2.7 95% CI: 0.83, 2.47; P=0.0001). Additionally, RbG results suggested a causal role of higher BMI on higher stroke volume (SV: difference per 3.58kg/m2: 1.49ml/m2.04; 95% CI: 0.62, 2.35; P=0.001) and cardiac output (CO: difference per 3.58kg/m2: 0.11l/min/m1.83; 95% CI: 0.03, 0.19; P=0.01) but no strong evidence for a causal role on systemic vascular resistance or total arterial compliance. Neither analysis supported a causal role of higher BMI on heart rate. Conclusions: Complementary MR and RbG causal methodologies, together with a range of sensitivity analyses, suggest that higher BMI is likely to cause worse cardiovascular health, specifically higher BP and LVMI, even in youth. Higher BMI also resulted in increased CO in the RbG study, which appeared to be solely driven by SV, as neither MR nor RbG analyses suggested a causal effect of BMI on heart rate. These consistent results support efforts to reduce BMI from a young age to prevent later adverse cardiovascular health and illustrate the potential for phenotypic resolution with maintained analytical power using RbG.

Know Your Heart: Rationale, design and conduct of a cross-sectional study of cardiovascular structure, function and risk factors in 4500 men and women aged 35-69 years from two Russian cities, 2015-18.

Russia has one of the highest rates of cardiovascular disease in the world. The International Project on Cardiovascular Disease in Russia (IPCDR) was set up to understand the reasons for this. A substantial component of this study was the Know Your Heart Study devoted to characterising the nature and causes of cardiovascular disease in Russia by conducting large cross-sectional surveys in two Russian cities Novosibirsk and Arkhangelsk. The study population was 4542 men and women aged 35-69 years recruited from the general population. Fieldwork took place between 2015-18. There were two study components: 1) a baseline interview to collect information on socio-demographic characteristics and cardiovascular risk factors, usually conducted at home, and 2) a comprehensive health check at a primary care clinic which included detailed examination of the cardiovascular system. In this paper we describe in detail the rationale for, design and conduct of these studies.

Intimal and medial arterial changes defined by ultra-high-frequency ultrasound: Response to changing risk factors in children with chronic kidney disease.

BACKGROUND: Patients with chronic kidney disease (CKD) are exposed to both traditional 'Framingham' and uremia related cardiovascular risk factors that drive atherosclerotic and arteriosclerotic disease, but these cannot be differentiated using conventional ultrasound. We used ultra-high-frequency ultrasound (UHFUS) to differentiate medial thickness (MT) from intimal thickness (IT) in CKD patients, identify their determinants and monitor their progression. METHODS: Fifty-four children and adolescents with CKD and 12 healthy controls underwent UHFUS measurements using 55-70MHz transducers in common carotid and dorsal pedal arteries. Annual follow-up imaging was performed in 31 patients. RESULTS: CKD patients had higher carotid MT and dorsal pedal IT and MT compared to controls. The carotid MT in CKD correlated with serum phosphate (p<0.001, r = 0.42), PTH (p = 0.03, r = 0.36) and mean arterial pressure (p = 0.03, r = 0.34). Following multivariable analysis, being on dialysis, serum phosphate levels and mean arterial pressure remained the only independent predictors of carotid MT (R2 64%). Transplanted children had lower carotid and dorsal pedal MT compared to CKD and dialysis patients (p = 0.02 and p = 0.01 respectively). At 1-year follow-up, transplanted children had a decrease in carotid MT (p = 0.01), but an increase in dorsal pedal IT (p = 0.04) that independently correlated with annualized change in BMI. CONCLUSIONS: Using UHFUS, we have shown that CKD is associated with exclusively medial arterial changes that attenuate when the uremic milieu is ameliorated after transplantation. In contrast, after transplantation intimal disease develops as hypertension and obesity become prevalent, representing rapid vascular remodeling in response to a changing cardiovascular risk factor profile.

Evidence for contemporary arterial stiffening in obese children and adolescents using pulse wave velocity: A systematic review and meta-analysis.

INTRODUCTION: Pulse wave velocity (PWV) and augmentation index (AI) may provide information on future cardiovascular risk. Reports are conflicting on whether obese children show evidence of raised PWV and AI. METHODS: Systematic review and meta-analysis of published studies using EMBASE, Web-of-Science and PUBMED databases for studies reporting PWV and AI in obese versus non-obese controls( 90% in PWV and AI meta-analyses). CONCLUSION: There is moderate evidence that obese children have increased arterial stiffening, especially in central arteries. This supports concerns about future CVD risk in obese children. Developing effective obesity interventions must remain a health priority.