Mechanisms Driving the Effect of Weight Loss on Arterial Stiffness

Aims Arterial stiffness decreases with weight loss in overweight and obese adults, but the mechanisms by which this occurs are poorly understood. We aimed to elucidate these mechanisms. Methods We evaluated carotid-femoral pulse wave velocity (cfPWV), a measure of aortic stiffness, and brachial-ankle pulse wave velocity (baPWV), a mixed measure of central and peripheral arterial stiffness, in 344 young adults (mean age 38 yrs, mean body mass index (BMI) 32.9 kg/m2, 23% male) at baseline, 6 and 12 months in a behavioral weight loss intervention. Linear mixed effects models were used to evaluate associations between weight loss and arterial stiffness and to examine the degree to which improvements in obesity-related factors explained these associations. Pattern-mixture models using indicator variables for dropout pattern and Markov Chain Monte Carlo multiple imputation were used to evaluate the influence of different missing data assumptions. Results At 6 months (7% mean weight loss from baseline), there was a statistically significant median decrease of 47.5 cm/s (interquartile range (IQR) -44.5, 148) in cfPWV (p<0.0001) and a mean decrease of 11.7 cm/s (standard deviation (SD) 91.4) in baPWV (p=0.049). At 12 months (6% mean weight loss from baseline) only cfPWV remained statistically significantly reduced from baseline (p=0.02). Change in BMI (p=0.01) was statistically significantly positively associated with change in cfPWV after adjustment for changes in mean arterial pressure (MAP) or any other measured obesity-related factor. Common carotid artery diameter (p=0.003) was associated and heart rate (p=0.08) and MAP (p=0.07) marginally associated longitudinally with cfPWV. Reductions in heart rate (p<0.0001) and C-reactive protein (p=0.02) were associated with reduced baPWV, and each removed the statistical significance of the effect of weight loss on baPWV. Pattern-mixture modeling revealed several differences between completers and non-completers in the models for cfPWV, but marginal parameter estimates changed little from the original models for either PWV measure. Conclusions The public health importance of this thesis is that firstly, weight loss improves arterial stiffness in overweight and obese young adults. Secondly, its effect on baPWV may be explained by concurrent reductions in heart rate and inflammation. Missing data did not appear to bias these results

Relationship of ankle blood pressures to cardiovascular events in older adults.

BACKGROUND AND PURPOSE - Low values of ankle-arm systolic blood pressure ratio predict mortality and cardiovascular events. High values, associated with arterial calcification, also carry risk for mortality. We focus on the extent to which low and high ankle-arm index values as well as noncompressible arteries are associated with mortality and cardiovascular events, including stroke in older adults. METHODS - We followed 2886 adults aged 70 to 79 for a mean of 6.7 years for vital status and cardiovascular events (coronary heart disease, stroke, and congestive heart failure). RESULTS - Normal ankle-arm index values of 0.91 to 1.3 were found in 80%, low values of ≤0.9 were found in 13%, high values of >1.3 were obtained in 5%, and noncompressible arteries were found in 2% of the group. Increased mortality was associated with both low and high ankle-arm index values beginning at levels of <1.0 or ≥1.4. Subjects with low ankle-arm index values or noncompressible arteries had significantly higher event rates than those with normal ankle blood pressures for all end points. For coronary heart disease, hazard ratios associated with a low ankle-arm index, high ankle-arm index, and noncompressible arteries were 1.4, 1.5, and 1.7 (P<0.05 for all) after controlling for age, gender, race, prevalent cardiovascular disease, diabetes, and major cardiovascular risk factors. Noncompressible arteries carried a particularly high risk of stroke and congestive heart failure (hazard ratio=2.1 and 2.4, respectively). CONCLUSIONS - Among older adults, low and high ankle-arm index values carry elevated risk for cardiovascular events. Noncompressible leg arteries carry elevated risk for stroke and congestive heart failure specifically. © 2008 American Heart Association, Inc

Role of sex steroids, intrahepatic fat and liver enzymes in the association between SHBG and metabolic features

BACKGROUND: SHBG and liver enzymes levels are both associated with the risk of type 2 diabetes. However, the relationship between SHBG with liver enzymes and intrahepatic fat content remain poorly understood. OBJECTIVE: To investigate whether SHBG is correlated with glucose and lipids levels and whether this association depends on fatty liver content, liver enzymes or sex hormone concentrations. DESIGN AND PATIENTS: We studied 233 dysmetabolic men with measures of plasma SHBG, total testosterone, 17β-oestradiol, glucose, adiponectin, liver enzymes and hepatokines. Intrahepatic liver fat and visceral fat contents were measured by magnetic resonance imaging in 108 of these individuals. RESULTS: After adjustment for age, SHBG concentration was inversely correlated with fasting glucose (βstandardized  = -0·21, P = 0·0007), HbA1c (βstandardized  = -0·27, P &lt; 0·0001), triglycerides (βstandardized  = -0·19, P = 0·003) and positively correlated with HDL-Cholesterol (βstandardized  = 0·14, P = 0·03). These correlations persisted after adjustment for either total testosterone or 17β-oestradiol levels. SHBG was not related to either fetuin A or FGF 21 concentrations. The inverse association of SHBG with HbA1c and glycaemia was not altered after adjusting for liver markers but was no longer significant after adjustment for hepatic fat content. CONCLUSION: The significant association between SHBG and fasting glycaemia, HbA1c and lipid levels in dysmetabolic men was not related to either sex hormones or markers of liver function, but was dependent on intrahepatic fat. This suggests that intrahepatic fat, but not alterations in liver function markers, may be involved in the association between SHBG and glucose and lipid metabolism

Arterial stiffening in western diet-fed mice is associated with increased vascular elastin, transforming growth factor-ß, and plasma neuraminidase

Consumption of excess fat and carbohydrate (Western diet, WD) is associated with alterations in the structural characteristics of blood vessels. This vascular remodeling contributes to the development of cardiovascular disease, particularly as it affects conduit and resistance arteries. Vascular remodeling is often associated with changes in the elastin-rich internal elastic lamina (IEL) and the activation of transforming growth factor (TGF)-ß. In addition, obesity and type II diabetes have been associated with increased serum neuraminidase, an enzyme known to increase TGF-ß cellular output. Therefore, we hypothesized that WD-feeding would induce structural modifications to the IEL of mesenteric resistance arteries in mice, and that these changes would be associated with increased levels of circulating neuraminidase and the up-regulation of elastin and TGF-ß in the arterial wall. To test this hypothesis, a WD, high in fat and sugar, was used to induce obesity in mice, and the effect of this diet on the structure of mesenteric resistance arteries was investigated. 4-week old, Post-weaning mice were fed either a normal diet (ND) or WD for 16 weeks. Mechanically, arteries from WD-fed mice were stiffer and less distensible, with marginally increased wall stress for a given strain, and a significantly increased Young's modulus of elasticity. Structurally, the wall cross-sectional area and the number of fenestrae found in the internal elastic lamina (IEL) of mesenteric arteries from mice fed a WD were significantly smaller than those of arteries from the ND-fed mice. There was also a significant increase in the volume of elastin, but not collagen in arteries from the WD cohort. Plasma levels of neuraminidase and the amount of TGF-ß in mesenteric arteries were elevated in mice fed a WD, while ex vivo, cultured vascular smooth muscle cells exposed to neuraminidase secreted greater amounts of tropoelastin and TGF-ß than those exposed to vehicle. These data suggest that consumption of a diet high in fat and sugar causes stiffening of the vascular wall in resistance arteries through a process that may involve increased neuraminidase and TGF-ß activity, elevated production of elastin, and a reduction in the size and number of fenestrae in the arterial IEL

Long-term health benefits and costs of measurement of carotid intima-media thickness in prevention of coronary heart disease

OBJECTIVE: Recently, it was demonstrated that information on carotid intima-media thickness (CIMT) and plaque may improve coronary heart disease (CHD) risk prediction through reclassification of some individuals to the correct risk category using the Framingham risk score. Our objective was to assess the currently unknown cost-effectiveness of CIMT measurements in primary prevention. METHODS: A hypothetical cohort of men and women aged 50-59 years and at intermediate or high CHD risk based on data from the Atherosclerosis Risk in Communities Study was simulated using a Markov model. Myocardial infarction (MI) events were used as a proxy for CHD. The effectiveness of pharmaceutical treatment was varied in the analysis. Sensitivity analysis was performed to obtain robust results. RESULTS: CIMT-based reclassification induced a 1% lower absolute risk of MI and 0.01-0.02 increase in quality-adjusted life years (QALYs) for men, and a 1-3% lower risk, and 0.03-0.05 increase in QALYs for women, over a period of 20-30 years. Corresponding costs were an additional $100 per man, and a cost-saving of$200-300 per woman. Over a 10-year period CIMT measurements were cost-effective with a probability of 66% (men), and 94% (women). Over a 30-year period, CIMT measurements had acceptable cost-effectiveness for men and women. CONCLUSION: Performing CIMT measurements in asymptomatic men and women aged 50-59 years results in additional, but small, health benefits. It takes time for these health benefits to outweigh the initial CIMT measurement costs. Our results support CIMT measurements for cardiovascular risk stratification, in particular for women, when focusing on long-term health

Regional body composition as a determinant of arterial stiffness in the elderly. The Hoorn Study.

Regional body composition as a determinant of arterial stiffness in the elderly: The Hoorn Study. Snijder MB, Henry RM, Visser M, Dekker JM, Seidell JC, Ferreira I, Bouter LM, Yudkin JS, Westerhof N, Stehouwer CD. Institute for Research in Extramural Medicine, VU University Medical Center, Amsterdam, The Netherlands. [email protected] OBJECTIVE: To estimate the relation of precisely measured regional body composition with peripheral and central arterial stiffness in the elderly. METHODS: We investigated 648 participants (mean age 69.0 +/- 6.0 years) of the Hoorn Study, a population-based cohort study. Trunk fat, leg fat, trunk lean and leg lean mass were distinguished by dual-energy X-ray absorptiometry. We used ultrasound to measure the distensibility and compliance of the carotid, femoral and brachial arteries, and carotid Young's elastic modulus, as estimates of peripheral stiffness. As estimates of central stiffness we measured carotid-femoral transit time, aortic augmentation index and systemic arterial compliance. RESULTS: After adjustment for sex, age, height, mean arterial pressure, leg lean and leg fat mass, a larger trunk fat mass was consistently associated with higher peripheral arterial stiffness (standardized beta (beta) of mean Z-scores of all three large arteries -0.24, P < 0.001). In contrast, larger leg fat mass (beta = 0.15, P = 0.009) and leg lean mass (beta = 0.09, P = 0.20) were associated with lower peripheral arterial stiffness. Trunk or leg fat mass were not associated with central arterial stiffness. Leg lean mass, however, was consistently associated with lower central arterial stiffness (beta = 0.29, P < 0.001). CONCLUSIONS: Trunk fat mass may have adverse effects on peripheral, but not on central arterial stiffness, while leg fat was not harmful and may have a slight protective effect. Larger leg lean mass was the most important determinant of lower central arterial stiffness. These results provide a pathophysiological framework to explain not only the higher cardiovascular risk in individuals with larger trunk fat mass, but also the reduced cardiovascular risk in individuals with larger leg lean and fat mas

Synthesis of β‐Cyclodextrin Containing Copolymer via “Click” Chemistry and Its Self‐Assembly in the Presence of Guest Compounds

We report the synthesis of a hydrophilic copolymer with one polyethylene glycol (PEG) block and one β‐cyclodextrin (β‐CD) containing block by a “click” reaction between azido‐substituted β‐CD and propargyl flanking copolymer. 1 H NMR study suggested a highly efficient conjugation of β‐CD units by this approach. The obtained copolymer was used as a host macromolecule to construct assemblies in the presence of hydrophobic guests. For assemblies containing a hydrophobic polymer, their size can be simply adjusted by simply changing the content of hydrophobic component. By serving as a guest molecule, hydrophobic drugs can also be loaded accompanying the formation of nanoparticles, and the drug payload is releasable. Therefore, the copolymer synthesized herein can be employed as a carrier for drug delivery. The synthesis of β‐cyclodextrin containing block copolymer via a “click” reaction is reported. The self‐assembly of this newly synthesized copolymer in the presence of guest compounds can lead to the formation of core–shell structured nanoparticles. These assemblies can be employed as novel delivery vehicles for therapeutics.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/91173/1/marc_201100814_sm_suppl.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/91173/2/664_ftp.pd

Ankle brachial index combined with Framingham risk score to predict cardiovascular events and mortality - A meta-analysis

CONTEXT: Prediction models to identify healthy individuals at high risk of cardiovascular disease have limited accuracy. A low ankle brachial index (ABI) is an indicator of atherosclerosis and has the potential to improve prediction. OBJECTIVE: To determine if the ABI provides information on the risk of cardiovascular events and mortality independently of the Framingham risk score (FRS) and can improve risk prediction. DATA SOURCES: Relevant studies were identified. A search of MEDLINE (1950 to February 2008) and EMBASE (1980 to February 2008) was conducted using common text words for the term ankle brachial index combined with text words and Medical Subject Headings to capture prospective cohort designs. Review of reference lists and conference proceedings, and correspondence with experts was conducted to identify additional published and unpublished studies. STUDY SELECTION: Studies were included if participants were derived from a general population, ABI was measured at baseline, and individuals were followed up to detect total and cardiovascular mortality. DATA EXTRACTION: Prespecified data on individuals in each selected study were extracted into a combined data set and an individual participant data meta-analysis was conducted on individuals who had no previous history of coronary heart disease. RESULTS: Sixteen population cohort studies fulfilling the inclusion criteria were included. During 480,325 person-years of follow-up of 24,955 men and 23,339 women, the risk of death by ABI had a reverse J-shaped distribution with a normal (low risk) ABI of 1.11 to 1.40. The 10-year cardiovascular mortality in men with a low ABI (< or = 0.90) was 18.7% (95% confidence interval [CI], 13.3%-24.1%) and with normal ABI (1.11-1.40) was 4.4% (95% CI, 3.2%-5.7%) (hazard ratio [HR], 4.2; 95% CI, 3.3-5.4). Corresponding mortalities in women were 12.6% (95% CI, 6.2%-19.0%) and 4.1% (95% CI, 2.2%-6.1%) (HR, 3.5; 95% CI, 2.4-5.1). The HRs remained elevated after adjusting for FRS (2.9 [95% CI, 2.3-3.7] for men vs 3.0 [95% CI, 2.0-4.4] for women). A low ABI (< or = 0.90) was associated with approximately twice the 10-year total mortality, cardiovascular mortality, and major coronary event rate compared with the overall rate in each FRS category. Inclusion of the ABI in cardiovascular risk stratification using the FRS would result in reclassification of the risk category and modification of treatment recommendations in approximately 19% of men and 36% of women. CONCLUSION: Measurement of the ABI may improve the accuracy of cardiovascular risk prediction beyond the FRS

A decision analytic model to investigate the cost-effectiveness of poisoning prevention practices in households with young children

Background: Systematic reviews and a network meta-analysis show home safety education with or without the provision of safety equipment is effective in promoting poison prevention behaviours in households with children. This paper compares the cost-effectiveness of home safety interventions to promote poison prevention practices. Methods: A probabilistic decision-analytic model simulates healthcare costs and benefits for a hypothetical cohort of under 5 year olds. The model compares the cost-effectiveness of home safety education, home safety inspections, provision of free or low cost safety equipment and fitting of equipment. Analyses are conducted from a UK National Health Service and Personal Social Services perspective and expressed in 2012 prices. Results: Education without safety inspection, provision or fitting of equipment was the most cost-effective strategy for promoting safe storage of medicines with an incremental cost-effectiveness ratio of £2888 (95 % credible interval (CrI) £1990–£5774) per poison case avoided or £41,330 (95%CrI £20,007–£91,534) per QALY gained compared with usual care. Compared to usual care, home safety interventions were not cost-effective in promoting safe storage of other household products. Conclusion: Education offers better value for money than more intensive but expensive strategies for preventing medicinal poisonings, but is only likely to be cost-effective at £30,000 per QALY gained for families in disadvantaged areas and for those with more than one child. There was considerable uncertainty in cost-effectiveness estimates due to paucity of evidence on model parameters. Policy makers should consider both costs and effectiveness of competing interventions to ensure efficient use of resources

Comparison of SWAN and WISE Menopausal Status Classification Algorithms

Background: Classification of menopausal status is important for epidemiological and clinical studies as well as for clinicians treating midlife women. Most epidemiological studies, including the Study of Women's Health Across the Nation (SWAN), classify women based on self-reported bleeding history. Methods: The Women's Ischemia Syndrome Evaluation (WISE) study developed an algorithm using menstrual and reproductive history and serum hormone levels to reproduce the menopausal status classifications assigned by the WISE hormone committee. We applied that algorithm to women participating in SWAN and examined characteristics of women with concordant and discordant SWAN and WISE classifications. Results: Of the 3215 SWAN women with complete information at baseline (1995–1997), 2466 (76.7%) received concordant classifications (kappa = 0.52); at the fifth annual follow-up visit, of the 1623 women with complete information, 1154 (72.7%) received concordant classifications (kappa = 0.57). At each time point, we identified subgroups of women with discordant SWAN and WISE classifications. These subgroups, ordered by chronological age, showed increasing trends for menopausal symptoms and follicle-stimulating hormone (FSH) and a decreasing trend for estrogen (p < 0.001). Conclusions: The WISE algorithm is a useful tool for studies that have access to blood samples for hormone data unrelated to menstrual cycle phase, with or without an intact uterus, and no resources for adjudication. Future studies may want to combine aspects of the SWAN and WISE algorithms by adding hormonal measures to the series of bleeding questions in order to determine more precisely where women are in the perimenopausal continuum.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/63232/1/jwh.2006.15.1184.pd