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 (β-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 (β-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 (β-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

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 [version 2; peer review: 2 approved, 1 approved with reservations]

BACKGROUND: We aim to investigate whether circulating microparticle (CMPs) subsets were raised amongst people presenting with a new diagnosis of HIV and advanced immune suppression in Malawi, and whether they associated with arterial stiffness. Methods: Microparticle characterisation and carotid femoral Pulse Wave Velocity (cfPWV) were carried out in a cohort of adults with a new HIV diagnosis and CD4 <100 cells/µL at 2 weeks post ART initiation. HIV uninfected controls were matched on age, systolic 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. METHODS: Microparticle characterisation and carotid femoral Pulse Wave Velocity (cfPWV) were carried out in a cohort of adults with a new HIV diagnosis and CD4 <100 cells/µL at 2 weeks post ART initiation. HIV uninfected controls were matched on age, systolic 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% 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 PLWH in Malawi. Endothelial and platelet microparticles are the predominant cell origin types, indicating that platelet driven endothelial dysfunction pathways warrant further investigation in HIV associated arterial stiffness

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

AimsTo determine the impact of smoking and alcohol exposure during adolescence on arterial stiffness at 17 years.Methods and resultsSmoking 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' 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].ConclusionSmoking 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

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 &gt; 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 &lt; 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 might 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.

We aim to investigate whether circulating microparticle (CMPs) subsets were raised amongst people presenting with a new diagnosis of HIV and advanced immune suppression in Malawi, and whether they associated with arterial stiffness. : Microparticle characterisation and carotid femoral Pulse Wave Velocity (cfPWV) were carried out in a cohort of adults with a new HIV diagnosis and CD4 <100 cells/µL at 2 weeks post ART initiation. HIV uninfected controls were matched on age, systolic 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.  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% 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).  Circulating microparticles associate strongly with arterial stiffness among PLWH in Malawi. Endothelial and platelet microparticles are the predominant cell origin types, indicating that platelet driven endothelial dysfunction pathways warrant further investigation in HIV associated arterial stiffness

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 (MIP1β, 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

Inflammatory phenotypes predict changes in arterial stiffness following antiretroviral therapy initiation

Abstract 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 &amp;lt;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 &amp;lt; .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 &amp;lt; .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

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