Birthweight, childhood growth and left ventricular structure at age 60-64 years in a British birth cohort study

Background: High left ventricular mass (LVM) is an independent predictor of cardiovascular disease and mortality, but information relating LVM in older age to growth in early life is limited. We assessed the relationship of birthweight, height and body mass index (BMI) and overweight across childhood and adolescence with later life left ventricular (LV) structure. Methods: We used data from the MRC National Survey of Health and Development (NSHD) on men and women born in 1946 in Britain and followed up ever since. We use regression models to relate prospective measures of birthweight and height and BMI from ages 2–20 years to LV structure at 60–64 years. Results: Positive associations of birthweight with LVM and LV end diastolic volume (LVEDV) at 60–64 years were largely explained by adult height. Higher BMI, greater changes in BMI and greater accumulation of overweight across childhood and adolescence were associated with higher LVM and LVEDV and odds of concentric hypertrophy. Those who were overweight at two ages in early life had a mean LVM 11.5 g (95% confidence interval: -2.19,24.87) greater, and a mean LVEDV 10.0 ml (3.7,16.2) greater, than those who were not overweight. Associations were at least partially mediated through adult body mass index. Body size was less consistently associated with relative wall thickness (RWT), with the strongest association being observed with pubertal BMI change [0.007 (0.001,0.013) per standard deviation change in BMI 7–15 years]. The relationships between taller childhood height and LVM and LVEDV were explained by adult height. Conclusions: Given the increasing levels of overweight in contemporary cohorts of children, these findings further emphasize the need for effective interventions to prevent childhood overweight

Childhood Bradycardia Associates With Atrioventricular Conduction Defects in Older Age: A Longitudinal Birth Cohort Study

Background: This study explored the association between childhood bradycardia and later‐life cardiac phenotype using longitudinal data from the 1946 National Survey of Health and Development (NSHD) birth cohort. // Methods and Results: Resting heart rate was recorded at 6 and 7 years of age to provide the bradycardia exposure defined as a childhood resting heart rate <75 bpm. Three outcomes were studied: (1) echocardiographic data at 60 to 64 years of age, consisting of ejection fraction, left ventricular mass index, myocardial contraction fraction index, and E/e′; (2) electrocardiographic evidence of atrioventricular or ventricular conduction defects by 60 to 64 years of age; and (3) all‐cause and cardiovascular mortality. Generalized linear models or Cox regression models were used, and adjustment was made for relevant demographic and health‐related covariates, and for multiple testing. Mixed generalized linear models and fractional polynomials were used as sensitivity analyses. One in 3 older adults with atrioventricular conduction defects had been bradycardic in childhood, with defects being serious (Mobitz type II second‐degree atrioventricular block or higher) in 12%. In fully adjusted models, childhood bradycardia was associated with 2.91 higher odds of atrioventricular conduction defects (95% CI, 1.59–5.31; P=0.0005). Associations persisted in random coefficients mixed generalized linear models (odds ratio, 2.50; 95% CI, 1.01–4.31). Fractional polynomials confirmed a linear association between the log odds of atrioventricular conduction defects at 60 to 64 years of age and resting heart rate at 7 years of age. There was no association between bradycardia in childhood and mortality outcomes or with echocardiographic parameters and ventricular conduction defects in older age. // Conclusions: Longitudinal birth cohort data indicate that childhood bradycardia trebles the odds of having atrioventricular conduction defects in older age, 88% of which are benign. In addition, it does not influence mortality or heart size and function. Future research should concentrate on identifying children at risk

Body mass index, waist circumference, and chronic disease risk factors in australian adolescents

Objective: To determine the association between measures of adiposity (body mass index and waist circumference) and risk factors for heart disease, type 2 diabetes, fatty liver disease, and the clustering of risk factors in middle adolescence. Design: Cross-sectional study. Setting: Secondary schools in Sydney. Participants: Grade 10 students (N = 496; 58.4% boys; mean [SD] age, 15.4 [0.4] years). Main Exposures: Height, weight, waist circumference, blood pressure, and fasting blood samples. Outcome Measures: Participants were categorized as overweight or obese using the International Obesity Task Force cut points and the UK waist circumference cut points. Blood was analyzed for high- and low-density lipoprotein cholesterol, triglycerides, insulin, glucose, alanine aminotransferase, γ-glutamyltransferase, and high-sensitivity C-reactive protein levels, and the results were categorized as normal or abnormal according to published guidelines where possible. Associations between overweight and obesity and risk factors were explored using logistic regression. Clustering of risk factors within individuals was also explored. Results: Insulin (P < .001), alanine aminotransferase (P < .001), γ-glutamyltransferase (P = .005), high-density lipoprotein cholesterol (P < .001), highsensitivity C-reactive protein (P < .001), and blood pressure (P < .001) were significantly associated with overweight and obesity in adolescent boys. In adolescent girls, insulin, high-density lipoprotein cholesterol (P < .001), and high-sensitivity C-reactive protein (P < .001) were significantly associated with overweight and obesity. Obese adolescent boys and girls were significantly more likely to have 2 or more risk factors (boys: 73.5% vs 7.6%; girls: 44.4% vs 5.4%; P < .001 for both) than nonoverweight adolescents. Conclusions: Overweight and obese adolescents, especially boys, are at substantial risk for chronic conditions. Waist circumference is not a better predictor of metabolic risk factors than is body mass index. ©2008 American Medical Association. All rights reserved

Longitudinal birth cohort study finds that life-course frailty associates with later-life heart size and function.

A frailty index (FI) counts health deficit accumulation. Besides traditional risk factors, it is unknown whether the health deficit burden is related to the appearance of cardiovascular disease. In order to answer this question, the same multidimensional FI looking at 45-health deficits was serially calculated per participant at 4 time periods (0-16, 19-44, 45-54 and 60-64 years) using data from the 1946 Medical Research Council (MRC) British National Survey of Health and Development (NSHD)-the world's longest running longitudinal birth cohort with continuous follow-up. From these the mean and total FI for the life-course, and the step change in deficit accumulation from one time period to another was derived. Echocardiographic data at 60-64 years provided: ejection fraction (EF), left ventricular mass indexed to body surface area (LVmassi, BSA), myocardial contraction fraction indexed to BSA (MCFi) and E/e'. Generalized linear models assessed the association between FIs and echocardiographic parameters after adjustment for relevant covariates. 1375 participants were included. For each single new deficit accumulated at any one of the 4 time periods, LVmassi increased by 0.91-1.44% (p < 0.013), while MCFi decreased by 0.6-1.02% (p < 0.05). A unit increase in FI at age 45-54 and 60-64, decreased EF by 11-12% (p < 0.013). A single health deficit step change occurring between 60 and 64 years and one of the earlier time periods, translated into higher odds (2.1-78.5, p < 0.020) of elevated LV filling pressure. Thus, the accumulation of health deficits at any time period of the life-course associates with a maladaptive cardiac phenotype in older age, dominated by myocardial hypertrophy and poorer function

The Duffin-Schaeffer Conjecture with extra divergence II

This paper takes a new step in the direction of proving the Duffin-Schaeffer Conjecture for measures arbitrarily close to Lebesgue. The main result is that under a mild `extra divergence' hypothesis, the conjecture is true.Comment: 7 page

Cardiovascular Risk Factors from Early Life Predict Future Adult Cardiac Structural and Functional Abnormalities: A Systematic Review of the Published Literature

Background: Clinical practice evaluates cardiovascular risk based on current risk factor (RF) levels [Blood pressure (BP), body mass index (BMI) and glycaemic control] largely disregarding previous risk-factor history over the totality of the life course. RFs are related to contemporaneous echocardiographic measures of cardiac structure and function which in turn are independently related to cardiovascular morbidity and mortality in cross-sectional studies. However, the effect of lifetime or earlier RF history on future echocardiographic changes has never been systematically examined. Methods: A systematic review of the published literature identified 24 studies relating either earlier BP, BMI, glycaemic control or a combination to future cardiac structure and/or function. Results: The majority of studies showed that elevated BP and BMI in earlier life and greater cumulative burden of these factors resulted in worse cardiac structure up to 24 years later. Studies examining glycaemic control as a RF were few, but poorer glycaemic control in young adults was associated with increased future left ventricular mass. While only 5 papers related RFs to future cardiac function, all RFs were positively associated with worse future diastolic function. Conclusions: BP, BMI and glycaemic control measures in childhood, adolescence and early adulthood and subsequent longitudinal trajectories of BP and BMI are predictive of future abnormalities in cardiac structure and function. Lifetime RF history should be used to inform clinical practice. Further research is required to enable the identification of any sensitive periods in the life course to enable prevention when it is most likely to be effective

Association between resting heart rate across the life course and all-cause mortality: longitudinal findings from the Medical Research Council (MRC) National Survey of Health and Development (NSHD)

Background: Resting heart rate (RHR) is an independent risk factor for mortality. Nevertheless, it is unclear whether elevations in childhood and mid-adulthood RHR, including changes over time, are associated with mortality later in life. We sought to evaluate the association between RHR across the life course, along with its changes and all-cause mortality. / Methods: We studied 4638 men and women from the Medical Research Council (MRC) National Survey of Health and Development (NSHD) cohort born during 1 week in 1946. RHR was obtained during childhood at ages 6, 7 and 11, and in mid-adulthood at ages 36 and 43. Using multivariable Cox regression, we calculated the HR for incident mortality according to RHR measured at each time point, along with changes in mid-adulthood RHR. / Results: At age 11, those in the top fifth of the RHR distribution (≥97 bpm) had an increased adjusted hazard of 1.42 (95% CI 1.04 to 1.93) for all-cause mortality. A higher adjusted risk (HR, 95% CI 2.17, 1.40 to 3.36) of death was also observed for those in the highest fifth (≥81 bpm) at age 43. For a >25 bpm increased change in the RHR over the course of 7 years (age 36–43), the adjusted hazard was elevated more than threefold (HR, 95% CI 3.26, 1.54 to 6.90). After adjustment, RHR at ages 6, 7 and 36 were not associated with all-cause mortality. / Conclusions: Elevated RHR during childhood and midlife, along with greater changes in mid-adulthood RHR, are associated with an increased risk of all-cause mortality

Circulating gluten-specific, but not CMV-specific, CD39⁺ regulatory T cells have an oligoclonal TCR repertoire

Objectives: Understanding the T cell receptor (TCR) repertoire of regulatory CD4+ T-cell (Treg) populations is important for strategies aiming to re-establish tolerance in autoimmune diseases. We studied circulating deamidated gluten-epitope-specific CD39+ Tregs in patients with coeliac disease following an oral gluten challenge, and we used cytomegalovirus (CMV)-specific CD39+ Tregs from healthy controls as a comparator population. Methods: We used the OX40 assay to isolate antigen-specific Tregs by induced surface co-expression of CD25, OX40 and CD39. RACE PCR amplification and Sanger sequencing of the TCR β chain were used to analyse repertoire diversity. Results: We found that, following oral gluten challenge, circulating gluten-specific CD39+ Tregs had an oligoclonal TCR repertoire that contained public clonotypes. Conversely, the TCR repertoire of CMV-epitope-specific CD39+ Tregs from healthy controls was polyclonal. Discussion: These data indicate that a biased TCR repertoire is not inherent to CD39+ Tregs, and, in this case, is apparently driven by the HLA-DQ2.5-restricted deamidated gluten peptide in coeliac disease patients. Conclusion: This is the first assessment of the TCR repertoire within circulating human Tregs specific for foreign antigen. These data enhance our understanding of antigen-specific CD4+ responses in the settings of chronic inflammation and infection and may help guide immunomonitoring strategies for CD4+ T cell-based therapies, particularly for coeliac disease

The relationship between pubertal timing and markers of vascular and cardiac structure and function in men and women aged 60-64 years

Earlier age at menarche has been associated with higher risk of coronary heart disease, but the mechanisms underlying the association remain unclear. We assessed the relationship of pubertal timing, in both men (n = 672) and women (n = 713), with vascular (carotid intima-media thickness (cIMT), pulse wave velocity (PWV)) and cardiac (left ventricular (LV) structure and function) measures recorded at age 60-64 yrs in a British birth cohort study. Regression models found that earlier menarche was associated with higher (more adverse) LV mass, LV end diastolic volume and left atrial volume, but not with other cardiac measures, cIMT or PWV. Associations were attenuated after adjustment for either adult or childhood BMI (e.g. mean difference in LV mass per year later menarche: -4.2 g (95% CI:-7.0,-1.4) reducing to -2.2 g (95% CI:-4.7,0.4) after adjustment for adult BMI). There were no associations among men, despite those fully mature at 15 yrs having higher blood pressure than the least mature group by 10.21 mmHg (95% CI:19.45,0.98). Any effect of pubertal timing on vascular and cardiac structure and function is likely to be small and primarily confounded by pre-pubertal BMI and/or mediated through adult adiposity