Tauseef Khan

Lifelong patterns of BMI and cardiovascular phenotype in individuals aged 60–64 years in the 1946 British birth cohort study: an epidemiological study

BACKGROUND Excess body fat is associated with an increase in risk of type 2 diabetes and hypertension in adulthood and these risks can adversely affect progression of arterial disease. We aimed to assess the impact of lifelong patterns of adiposity on cardiovascular risk factors and carotid intima media thickness (cIMT) in later life in participants in the 1946 British birth cohort study. METHODS The National Survey of Health and Development Study was a nationally representative sample of 5362 singleton births to married parents in England, Scotland, and Wales, stratified by social class, during 1 week in March 1946. Our present study is based on the 60% of participants still alive and with a known present address in England, Scotland, or Wales who attended a clinic assessment after invitation aged 60-64 years. We included participants with lifetime adiposity measures, cardiovascular risk factors, and cIMT measured at 60-64 years. Participants were classified as normal weight or overweight or obese at each age (36, 43, 53, and 60-64 years) in adulthood, and childhood overweight was defined. Patterns of BMI change were identified and we used BMI to define adiposity status. We used multivariable linear regression to establish the cross-sectional association of BMI category at age 60-64 years with cIMT, adjusted for various confounders. FINDINGS We included 1273 (45%) of 2856 participants eligible in 2006-10 (at age 60-64 years) in this study. Compared with normal weight, overweight and obesity were associated with higher cIMT (0·029 mm, 95% CI 0·014-0·043) and systolic blood pressure (7·95 mm Hg, 5·86-10·0). Increased cIMT, systolic blood pressure, leptin, prevalence of diabetes, and reduced adiponectin were all associated with duration of exposure to adult adiposity (p<0·0001 for all). We noted little additional effect of childhood overweight. Individuals who dropped a BMI category in adulthood had lower cIMT (-0·034 mm, -0·056 to -0·013) and leptin concentrations (-0·4 ng/mL, -0·47 to -0·32), even when this change was not maintained, than did those who never lost weight. INTERPRETATION Longer exposure to high adiposity in adulthood had a cumulative adverse effect on cardiovascular phenotype in later life. Reductions in BMI category, even if not sustained, were associated with decreases in cIMT and improvements in cardiovascular risk-factor profile, suggesting that weight loss, at any age in adulthood, is worthwhile because it might result in long-term cardiovascular benefit. FUNDING Medical Research Council and the British Heart Foundation.

Variability and reproducibility of flow-mediated dilatation in a multicentre clinical trial

AIMS The aim of this study was to assess the reproducibility of flow-mediated dilatation (FMD) in a multicentre setting. METHODS AND RESULTS This study was performed as part of the dal-VESSEL trial in which FMD was measured in 19 vascular imaging centres in six European countries. A subgroup of patients who were allocated in the placebo group and scanned twice at each trial time point (substudy) was analysed. Intra-sonographer variability was calculated from FMD measurements 48 h apart. Centre variability and short-, medium-, and long-term reproducibility of FMD were calculated at 48 h and at 3 and 9 months intervals, respectively. Intra- and inter-reader variability was assessed by re-analysing the FMD images by three certified readers at two time intervals, 7 days apart. Sixty-seven patients were included. Variability between centres was comparable at 48 h and 3 months interval but almost doubled at 9 months. The mean absolute difference in %FMD was 1.04, 0.99, and 1.45% at the three time intervals, respectively. Curves were generated to indicate the number of patients required for adequate power in crossover and parallel study designs. CONCLUSION This study demonstrates for the first time that in a multicentre setting reproducible FMD measurements can be achieved for short- and medium-term evaluation, which are comparable with those reported from specialized laboratories. These findings justify the use of FMD as an outcome measure for short- and medium-term assessment of pharmacological interventions.

Structural and functional changes in HDL with low grade and chronic inflammation

OBJECTIVE HDL functionality has been shown to be impaired in inflammatory conditions, including coronary artery disease. The present study aims to determine the impact of low grade and acute inflammation on HDL function and structure. APPROACH AND RESULTS i) The endothelial protective effects of HDL were compared between 26 periodontal patients and 26 age and sex matched controls by measuring paraoxonase activity in serum and nitric oxide bioavailability and superoxide production in endothelial cells. Paraoxonase activity and nitric oxide bioavailability were reduced, while superoxide production was increased (p<0.01) in periodontal patients compared to controls. ii) HDL function, including cholesterol efflux and vascular cell adhesion molecule-1 expression, was subsequently measured in the periodontal patients following an inflammatory stimulus. There was an acute deterioration in HDLs endothelial protective function, without change in cholesterol efflux, after 24h (p<0.01 for all). These functional changes tracked increases of inflammatory markers and altered HDL composition. Finally, HDL function returned to baseline levels after resolution of inflammation. CONCLUSION This study demonstrates that even minor alterations in systemic inflammation can impair the endothelial protective effects of HDL. These functional changes were independent of cholesterol efflux and were associated with remodeling of the HDL proteome. All measures of HDLs endothelial protective functions recovered with resolution of inflammation. These findings suggest that HDL dysfunction may represent a novel mechanism linking inflammation with progression of atheroma.

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

Background Mendelian randomization (MR) studies of body mass index (BMI) and cardiovascular health in mid-to-late life suggest causal relationships, but the nature of these has not been explored systematically at younger ages. Using complementary MR and recall-by-genotype (RbG) methodologies, our objective was to estimate the causal effect of BMI on detailed measures of cardiovascular health in a population of young healthy adults. Methods and Findings Data from the Avon Longitudinal Study of Parents and Children were used. For MR analyses, a genetic risk score (GRS) comprising 97 independent single nucleotide polymorphisms (SNPs) and constructed using external weighting was used as an instrument to test the causal effect of each unit increase in BMI (kg/m2) on selected cardiovascular phenotypes measured at age 17 (N=7909). An independent enriched sample from the same cohort participated in a RbG study at age 21, which enabled more detailed cardiovascular phenotyping (N=418; 191/227 from the lower/upper ∼30% of a genome-wide GRS distribution predicting variation in BMI). The causal effect of BMI on the additional cardiovascular phenotypes was assessed by comparing the two recalled groups. Difference in mean BMI between RbG groups was 3.85kg/m2 (95% CI: 2.53, 4.63; P=6.09×1011). In both MR and RbG analyses, results indicated that higher BMI causes higher blood pressure (BP) and left ventricular mass (indexed to height2.7, 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=3.87×10−06 and per 3.58kg/m2 using RbG: 1.65g/m2.7 95% CI: 0.83, 2.47; P=0.0001). Additionally, RbG results indicated 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). Neither analysis supported a causal role of higher BMI on heart rate. Conclusions Complementary MR and RbG causal methodologies, together with a range of appropriate sensitivity analyses, showed that higher BMI is likely to cause worse cardiovascular health, specifically higher BP and LVMI, even in youth. These consistent results support efforts to prevent or reverse obesity in the young.

Systemic effects of periodontitis treatment in patients with type 2 diabetes: a 12 month, single-centre, investigator-masked, randomised trial

BACKGROUND Chronic inflammation is believed to be a major mechanism underlying the pathophysiology of type 2 diabetes. Periodontitis is a cause of systemic inflammation. We aimed to assess the effects of periodontal treatment on glycaemic control in people with type 2 diabetes. METHODS In this 12 month, single-centre, parallel-group, investigator-masked, randomised trial, we recruited patients with type 2 diabetes, moderate-to-severe periodontitis, and at least 15 teeth from four local hospitals and 15 medical or dental practices in the UK. We randomly assigned patients (1:1) using a computer-generated table to receive intensive periodontal treatment (IPT; whole mouth subgingival scaling, surgical periodontal therapy [if the participants showed good oral hygiene practice; otherwise dental cleaning again], and supportive periodontal therapy every 3 months until completion of the study) or control periodontal treatment (CPT; supra-gingival scaling and polishing at the same timepoints as in the IPT group). Treatment allocation included a process of minimisation in terms of diabetes onset, smoking status, sex, and periodontitis severity. Allocation to treatment was concealed in an opaque envelope and revealed to the clinician on the day of first treatment. With the exception of dental staff who performed the treatment and clinical examinations, all study investigators were masked to group allocation. The primary outcome was between-group difference in HbA1c at 12 months in the intention-to-treat population. This study is registered with the ISRCTN registry, number ISRCTN83229304. FINDINGS Between Oct 1, 2008, and Oct 31, 2012, we randomly assigned 264 patients to IPT (n=133) or CPT (n=131), all of whom were included in the intention-to-treat population. At baseline, mean HbA1c was 8·1% (SD 1·7) in both groups. After 12 months, unadjusted mean HbA1c was 8·3% (SE 0·2) in the CPT group and 7·8% (0·2) in the IPT group; with adjustment for baseline HbA1c, age, sex, ethnicity, smoking status, duration of diabetes, and BMI, HbA1c was 0·6% (95% CI 0·3-0·9; p<0·0001) lower in the IPT group than in the CPT group. At least one adverse event was reported in 30 (23%) of 133 patients in the IPT group and 23 (18%) of 131 patients in the CPT group. Serious adverse events were reported in 11 (8%) patients in the IPT group, including one (1%) death, and 11 (8%) patients in the CPT group, including three (2%) deaths. INTERPRETATION Compared with CPT, IPT reduced HbA1c in patients with type 2 diabetes and moderate-to-severe periodontitis after 12 months. These results suggest that routine oral health assessment and treatment of periodontitis could be important for effective management of type 2 diabetes. FUNDING Diabetes UK and UK National Institute for Health Research.

HIGHER ADIPOSITY EXPOSURE SINCE CHILDHOOD IS ASSOCIATED WITH INCREASED ARTERIAL STIFFNESS IN YOUNG FEMALES: THE ALSPAC STUDY

Increased adiposity has been associated with worse cardiovascular (CV) outcome. We examined whether exposure to adiposity in childhood and adolescence has a cumulative adverse effect on CV risk factor profile and arterial stiffness in young adulthood. The study population consisted of 4364 subjects

THE ASSOCIATION OF WAIST CIRCUMFERENCE AND PHYSICAL ACTIVITY IN ADOLESCENCE ON ARTERIAL STIFFNESS IN YOUNG ADULTHOOD

Greater physical activity (PA) has been consistently shown to improve cardiovascular (CV) health and a number of studies suggested that it can modify the adverse effect of adiposity on arterial disease in adults. However its role in adolescence remains largely unexplored. In the largest longitudinal