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High blood pressure is a major risk factor for cardiovascular disease and is influenced by both environmental and genetic factors. Epigenetic processes including DNA methylation potentially mediate the relationship between genetic factors, the environment and cardiovascular disease. Despite an increased risk of hypertension and cardiovascular disease in individuals of South Asians compared to Europeans, it is not clear whether associations between blood pressure and DNA methylation differ between these groups. We performed an epigenome-wide association study and differentially methylated region (DMR) analysis to identify DNA methylation sites and regions that were associated with systolic blood pressure, diastolic blood pressure and hypertension. We analyzed samples from 364 European and 348 South Asian men (first generation migrants to the UK) from the Southall And Brent REvisited cohort, measuring DNA methylation from blood using the Illumina Infinium® HumanMethylation450 BeadChip. One CpG site was found to be associated with DBP in trans-ancestry analyses (i.e. both ethnic groups combined), while in Europeans alone seven CpG sites were associated with DBP. No associations were identified between DNA methylation and either SBP or hypertension. Comparison of effect sizes between South Asian and European EWAS for DBP, SBP and hypertension revealed little concordance between analyses. DMR analysis identified several regions with known relationships with CVD and its risk factors. This study identified differentially methylated sites and regions associated with blood pressure and revealed ethnic differences in these associations. These findings may point to molecular pathways which may explain the elevated cardiovascular disease risk experienced by those of South Asian ancestry when compared to Europeans.

Heart rate variability (HRV) is a cardiac autonomic marker with predictive value in cardiac patients. Ultra-short HRV (usHRV) can be measured at scale using standard and wearable ECGs, but its association with cardiovascular events in the general population is undetermined. We aimed to validate usHRV measured using ≤ 15-s ECGs (using RMSSD, SDSD and PHF indices) and investigate its association with atrial fibrillation, major adverse cardiac events, stroke and mortality in individuals without cardiovascular disease. In the National Survey for Health and Development (n = 1337 participants), agreement between 15-s and 6-min HRV, assessed with correlation analysis and Bland–Altman plots, was very good for RMSSD and SDSD and good for PHF. In the UK Biobank (n = 51,628 participants, 64% male, median age 58), after a median follow-up of 11.5 (11.4–11.7) years, incidence of outcomes ranged between 1.7% and 4.3%. Non-linear Cox regression analysis showed that reduced usHRV from 15-, 10- and 5-s ECGs was associated with all outcomes. Individuals with low usHRV (< 20th percentile) had hazard ratios for outcomes between 1.16 and 1.29, p  < 0.05, with respect to the reference group. In conclusion, usHRV from ≤ 15-s ECGs correlates with standard short-term HRV and predicts increased risk of cardiovascular events in a large population-representative cohort.

Development of cholesteryl ester transfer protein (CETP) inhibitors for coronary heart disease (CHD) has yet to deliver licensed medicines. To distinguish compound from drug target failure, we compared evidence from clinical trials and drug target Mendelian randomization of CETP protein concentration, comparing this to Mendelian randomization of proprotein convertase subtilisin/kexin type 9 (PCSK9). We show that previous failures of CETP inhibitors are likely compound related, as illustrated by significant degrees of between-compound heterogeneity in effects on lipids, blood pressure, and clinical outcomes observed in trials. On-target CETP inhibition, assessed through Mendelian randomization, is expected to reduce the risk of CHD, heart failure, diabetes, and chronic kidney disease, while increasing the risk of age-related macular degeneration. In contrast, lower PCSK9 concentration is anticipated to decrease the risk of CHD, heart failure, atrial fibrillation, chronic kidney disease, multiple sclerosis, and stroke, while potentially increasing the risk of Alzheimer’s disease and asthma. Due to distinct effects on lipoprotein metabolite profiles, joint inhibition of CETP and PCSK9 may provide added benefit. In conclusion, we provide genetic evidence that CETP is an effective target for CHD prevention but with a potential on-target adverse effect on age-related macular degeneration. Despite being studied in clinical trials, CETP inhibitors are not yet an approved treatment for coronary heart disease. Here, by analyzing results from clinical trials and drug target mendelian randomization studies, the authors demonstrate that previous failure of CETP inhibitors are likely compound and not drug target-related.

Exercise capacity is a strong independent predictor of cardiovascular and all-cause mortality. The utilization of well-established submaximal tests of exercise capacity such as the 6-min walk test (6MWT), 3-min step test (3MST) and 10-chair rise test (10CRT) in the community would improve patient care but requires remote monitoring technology. Consumer grade smartwatches provide such an opportunity, however, their accuracy in measuring physiological responses to these tests is unclear. The aim of this study was to determine the accuracy of consumer grade smartwatches in assessing exercise capacity to develop a framework for remote, unsupervised testing. 16 healthy adults (7 male (44%), age median 27 [interquartile range (IQR) 26,29] years) performed 6MWTs using two protocols: (1) standard—straight 30 m laps (6MWT-standard) and 2) continuous lap—circular 240 m laps around a park (6MWT-continuous lap), 3MSTs and 10CRTs. Each one of these four tests was performed three times across two clinic visits. Each participant was fitted with a Garmin Vivoactive4 and Fitbit Sense smartwatch to measure three parameters: distance, step counts and heart rate (HR) response. Reference measures were a meter-wheel, hand tally counter and ECG, respectively. Mean HR was measured at rest, peak exercise and recovery. Agreement was measured using Bland–Altman analysis for repeated measures and summarized as median absolute percentage errors (MAPE). Distance during 6MWT-continuous lap had better agreement than during 6MWT-standard for both Garmin (MAPE: 6.4% [3.0, 10.4%] versus 20.1% [13.9, 28.4%], p  < 0.001) and Fitbit (8.0% [2.9, 10.1% versus 18.8% [15.2, 28.1%], p  < 0.001). Garmin measured step count more accurately than Fitbit (MAPE: 1.8% [0.9, 2.9%] versus 8.0% [2.6, 12.3%], p  < 0.001). Irrespective of test, both devices showed excellent accuracy in measuring HR at rest and recovery (≤ 3%), while accuracy decreased during peak exercise (Fitbit: ~ 12% and Garmin: ~ 7%). In young adults without mobility difficulties, exercise capacity can be measured remotely using standardized tests and consumer grade smartwatches.

Continuous wave near infrared spectroscopy (CW NIRS) provides non-invasive technology to measure relative changes in oxy- and deoxy-haemoglobin in a dynamic environment. This allows determination of local skeletal muscle O2 saturation, muscle oxygen consumption (V˙O2) and blood flow. This article provides a brief overview of the use of CW NIRS to measure exercise-limiting factors in skeletal muscle. NIRS parameters that measure O2 delivery and capacity to utilise O2 in the muscle have been developed based on response to physiological interventions and exercise. NIRS has good reproducibility and agreement with gold standard techniques and can be used in clinical populations where muscle oxidative capacity or oxygen delivery (or both) are impaired. CW NIRS has limitations including: the unknown contribution of myoglobin to the overall signals, the impact of adipose tissue thickness, skin perfusion during exercise, and variations in skin pigmentation. These, in the main, can be circumvented through appropriate study design or measurement of absolute tissue saturation. CW NIRS can assess skeletal muscle O2 delivery and utilisation without the use of expensive or invasive procedures and is useable in large population-based samples, including older adults. •An overview of CW NIRS to measure O2 utilisation and delivery is presented.•CW NIRS is cheap, non-invasive, portable and useable in population-based samples.•It is useful for understanding underlying mechanisms of deterioration in capacity.

ObjectiveAccess to health services and adequate care is influenced by sex, ethnicity, socioeconomic position (SEP) and the burden of comorbidities. Our study aimed to assess whether the COVID-19 pandemic further deepened these already existing health inequalities.DesignCross-sectional study.SettingData were collected from five longitudinal age-homogenous British cohorts (born in 2000-2002, 1989-1990, 1970, 1958 and 1946).ParticipantsA web survey was sent to the cohorts. Anybody who responded to the survey was included, resulting in 14 891 eligible participants.Main outcomes measuredThe survey provided data on cancelled surgical or medical appointments, and the number of care hours received in a week during the first UK COVID-19 national lockdown.InterventionsUsing binary or ordered logistic regression, we evaluated whether these outcomes differed by sex, ethnicity, SEP and having a chronic illness. Adjustment was made for study design, non-response weights, psychological distress, presence of children or adolescents in the household, COVID-19 infection, key worker status, and whether participants had received a shielding letter. Meta-analyses were performed across the cohorts, and meta-regression was used to evaluate the effect of age as a moderator.ResultsWomen (OR 1.40, 95% CI 1.27 to 1.55) and those with a chronic illness (OR 1.84, 95% CI 1.65 to 2.05) experienced significantly more cancellations during lockdown (all p<0.0001). Ethnic minorities and those with a chronic illness required a higher number of care hours during the lockdown (both OR≈2.00, all p<0.002). SEP was not associated with cancellation or care hours. Age was not independently associated with either outcome in the meta-regression.ConclusionThe UK government’s lockdown approach during the COVID-19 pandemic appears to have deepened existing health inequalities, impacting predominantly women, ethnic minorities and those with chronic illnesses. Public health authorities need to implement urgent policies to ensure equitable access to health and care for all in preparation for a fourthwave.

In this Perspectives article, Captur et al . explain the fundamental principles of fractal geometry, and summarize cardiovascular studies in which fractal methods have been used to investigate disease mechanisms. The authors propose that clinical researchers can deploy innovative fractal solutions to common cardiac problems, which might ultimately translate into advancements in patient care. For clinicians grappling with quantifying the complex spatial and temporal patterns of cardiac structure and function (such as myocardial trabeculae, coronary microvascular anatomy, tissue perfusion, myocyte histology, electrical conduction, heart rate, and blood-pressure variability), fractal analysis is a powerful, but still underused, mathematical tool. In this Perspectives article, we explain some fundamental principles of fractal geometry and place it in a familiar medical setting. We summarize studies in the cardiovascular sciences in which fractal methods have successfully been used to investigate disease mechanisms, and suggest potential future clinical roles in cardiac imaging and time series measurements. We believe that clinical researchers can deploy innovative fractal solutions to common cardiac problems that might ultimately translate into advancements for patient care.

Children with obesity typically have larger left ventricular heart dimensions during adulthood. However, whether this is due to a persistent effect of adiposity extending into adulthood is challenging to disentangle due to confounding factors throughout the lifecourse. We conducted a multivariable mendelian randomization (MR) study to separate the independent effects of childhood and adult body size on 4 magnetic resonance imaging (MRI) measures of heart structure and function in the UK Biobank (UKB) study. Strong evidence of a genetically predicted effect of childhood body size on all measures of adulthood heart structure was identified, which remained robust upon accounting for adult body size using a multivariable MR framework (e.g., left ventricular end-diastolic volume (LVEDV), Beta = 0.33, 95% confidence interval (CI) = 0.23 to 0.43, P = 4.6 × 10 −10 ). Sensitivity analyses did not suggest that other lifecourse measures of body composition were responsible for these effects. Conversely, evidence of a genetically predicted effect of childhood body size on various other MRI-based measures, such as fat percentage in the liver (Beta = 0.14, 95% CI = 0.05 to 0.23, P = 0.002) and pancreas (Beta = 0.21, 95% CI = 0.10 to 0.33, P = 3.9 × 10 −4 ), attenuated upon accounting for adult body size. Our findings suggest that childhood body size has a long-term (and potentially immutable) influence on heart structure in later life. In contrast, effects of childhood body size on other measures of adulthood organ size and fat percentage evaluated in this study are likely explained by the long-term consequence of remaining overweight throughout the lifecourse.

Augmentation index (AIx) is widely used as a measure of wave reflection. We compared the relationship between AIx and age, height and sex with 'gold standard' measures of wave reflection derived from measurements of pressure and flow to establish how well AIx measures wave reflection. Measurements of carotid pressure and flow velocity were made in the carotid artery of 65 healthy normotensive individuals (age 21-78 yr; 43 male) and pulse wave analysis, wave intensity analysis and wave separation was performed; waveforms were classified into type A, B or C. AIx, the time of the first shoulder (T(s)), wave reflection index (WRI) and the ratio of backward to forward pressure (P(b)/P(f)) were calculated. AIx did not correlate with log WRI or P(b)/P(f). When AIx was restricted to positive values AIx and log WRI were positively correlated (r = 0.33; p = 0.04). In contrast log WRI and P(b)/P(f) were closely correlated (r = 0.66; p<0.001). There was no correlation between the T(s) and the timing of Pb or the reflected wave identified by wave intensity analysis. Wave intensity analysis showed that the morphology of type C waveforms (negative AIx) was principally due to a forward travelling (re-reflected) decompression wave in mid-systole. AIx correlated positively with age, inversely with height and was higher in women. In contrast log WRI and P(b)/P(f) showed negative associations with age, were unrelated to height and did not differ significantly by gender. AIx has serious limitations as a measure of wave reflection. Negative AIx values derived from Type C waves should not be used as estimates of wave reflection magnitude.

Previous studies have found that diabetes and its mechanistic factors (e.g., glycaemia) are associated with poorer cognitive and brain health. There is also growing evidence of sex differences in how diabetes manifests itself and impacts the brain. The mechanisms through which this association manifests itself are still poorly understood, but the possible role of inflammation has been proposed. This study aims to explore whether the relationship between mid-life glycaemia and brain volumes in later-life in women is mediated by systemic inflammation. The sample consisted of female participants from the National Survey of Health and Development (NSHD) who underwent neuroimaging as part of the Insight 46 sub-study. Path analysis models were then constructed between glycaemic markers (age 60−64) and brain health outcomes (age 69−71) with adjustments for social and metabolic confounders (age 60−64). Although fasting glucose was associated with higher GlycA levels (β = 0.05 [0.01, 0.10], p = 0.005), associations with CRP and IL-6 were weaker and not statistically significant (e.g., IL-6: β = 0.10 [−0.04, 0.30], p = 0.102). However, we did not find evidence that inflammatory markers were associated with brain volume outcomes (e.g., IL-6 and whole brain volume: β = −3.4 [−8.1, 1.3], p = 0.092; IL-6 and grey matter volume: β = −0.4 [−1.9, 1.0], p = 0.512). Consequently, indirect (mediated) effects via systemic inflammation were not observed. This suggests that alternative mechanisms beyond inflammation may contribute to the relationship between mid-life glycaemia and later-life brain health.