Lynne Cherry

Adiponectin and Coronary Heart Disease A Prospective Study and Meta-Analysis

Background— There is uncertainty about the association between circulating concentrations of adiponectin and coronary heart disease (CHD) risk. We report new data from a prospective study in the context of a meta-analysis of previously published prospective studies. Methods and Results— We measured baseline adiponectin levels in stored serum samples of 589 men with fatal CHD or nonfatal myocardial infarction and in 1231 controls nested within a prospective study of 5661 men (aged 40 to 59 years) recruited during 1978–1980, as well as in paired samples obtained 4 years apart from 221 of these participants. Baseline adiponectin concentrations correlated (P<0.0001) positively with HDL cholesterol (r=0.33) and inversely with C-reactive protein (r=−0.11) and BMI (r=−0.21), and the year-to-year consistency of adiponectin values was comparable to those of blood pressure and total cholesterol levels. No significant difference between median adiponectin levels at baseline was observed between cases and controls (10.2 versus 10.8 &mgr;g/mL; P=0.5), despite the fact that body mass index, HDL, and C-reactive protein were all significant predictors of events in this cohort. The odds ratio for CHD was 0.89 (95% CI, 0.67 to 1.18) in a comparison of men in the top third of adiponectin concentrations compared with those in the bottom third, similar to a meta-analysis (including the present study) of 7 prospective studies involving a total of 1318 CHD cases (odds ratio, 0.84 [95% CI, 0.70 to 1.01]). Conclusions— In contrast to the strong associations previously reported between adiponectin levels and risk of type 2 diabetes, any association with CHD risk is comparatively moderate and requires further investigation.

Short- and Long-Term Changes in Plasma Inflammatory Markers Associated With Preeclampsia

Preeclampsia is characterized by hypertension, dyslipidemia, and increased systemic inflammatory response and has been associated with an increased maternal risk of cardiovascular disease later in life. Low-grade chronic inflammation is a risk factor for cardiovascular disease. This study examined changes in inflammatory markers prospectively during pregnancy, the current inflammatory status of women who had a pregnancy complicated by preeclampsia 20 years previously against matched controls, and the association between inflammatory genes and risk of preeclampsia in a case (n=106) control (n=212) study. In control pregnancies (n=34), mean interleukin-10 (IL-10) levels increased 38% (P=0.012) and tumor necrosis factor-&agr; (TNF-&agr;) by 33% (P=0.024) between the first and third trimesters. The mean preeclampsia group IL-10 and TNF-&agr; rose by 43% (P=0.013 and P=0.0065, respectively) from the first to the third trimester. In women with preeclampsia only, plasma IL-6 increased from the first to the third trimester (1.66 [2.04] to 2.94 [2.47] pg/mL; P=0.0004). Twenty years after the index pregnancy, women who had had preeclampsia demonstrated significantly higher IL-6 to IL-10 ratio (3.96 [6.07] versus 2.12 [1.89]; P=0.034) compared with a healthy index pregnancy 20 years previously, that persisted after adjustment for smoking and current body mass index. The IL-1&bgr; (C-511T), IL-6 (G-174C), TNF-&agr; (G-308A), E-selectin (S128R), intercellular adhesion molecule-1 (K469E), and C-reactive protein (C1059G) polymorphisms were not associated with risk of developing preeclampsia. In conclusion, preeclampsia is associated with short- and long-term changes in inflammatory status.

Association between general and central adiposity in childhood, and change in these, with cardiovascular risk factors in adolescence: prospective cohort study.

Objectives To examine the prospective associations between body mass index (BMI), waist circumference, and fat mass in childhood and cardiovascular risk factors at age 15-16. Design Prospective cohort study. Setting Avon Longitudinal Study of Parents and Children. Participants 5235 children aged 9-12 at start of study. Main exposures BMI, waist circumference, and fat mass determined by dual energy x ray absorptiometry, assessed at age 9-12 and at age 15-16. Main outcome measures Systolic and diastolic blood pressure and concentrations of fasting glucose, insulin, triglycerides, low density lipoprotein cholesterol, and high density lipoprotein cholesterol assessed at age 15-16. Results In girls a 1 SD greater BMI at age 9-12 was associated with cardiovascular risk factors at age 15-16 in fully adjusted models: odds ratio 1.23 (95% confidence interval 1.10 to 1.38) for high systolic blood pressure (≥130 mm Hg); 1.19 (1.03 to 1.38) for high concentration of low density lipoprotein cholesterol (≥2.79 mmol/l); 1.43 (1.06 to 1.92) for high concentration of triglycerides (≥1.7 mmol/l); 1.25 (1.08 to 1.46) for low concentration of high density lipoprotein cholesterol (<1.03 mmol/l); and 1.45 (1.22 to 1.73) for high concentration of insulin (≥16.95 IU/l). Equivalent results in boys were 1.24 (1.13 to 1.37) for systolic blood pressure; 1.30 (1.07 to 1.59) for low density lipoprotein cholesterol; 1.96 (1.51 to 2.55) for triglycerides; 1.39 (1.22 to 1.57) for high density lipoprotein cholesterol, and 1.84 (1.56 to 2.17) for insulin. BMI was associated with high fasting glucose (≥5.6 mmol/l) only in boys (1.18, 1.03 to 1.36). With these binary outcomes there was statistical evidence that associations differed between girls and boys for fasting glucose (P=0.03) and insulin (P<0.001). When risk factors were examined as continuous outcomes there was evidence for stronger associations of BMI with more adverse levels in boys than girls for fasting insulin, glucose, and triglyceride concentrations (all interaction P≤0.03). BMI, waist circumference, and fat mass were all strongly correlated with each other (r=0.89-0.94), and associations of the three with cardiovascular outcomes were of similar magnitude with statistical evidence of consistency in associations (all P>0.2 for heterogeneity). When waist circumference or fat mass or both were added to models including BMI they did not increase the variation in cardiovascular risk factors already explained by BMI and confounders alone. Girls who were overweight/obese at age 9-12 but were normal weight by 15-16 had similar odds of adverse levels of risk factors to those who were normal weight at both ages. In boys odds of high systolic blood pressure, high concentrations of triglycerides and insulin, and low concentrations of high density lipoprotein cholesterol remained higher in this group compared with those who were normal weight at both ages but were lower than in those who remained overweight/obese at both ages. Conclusions Measurements of waist circumference or directly assessed fat mass in childhood do not seem to be associated with cardiovascular risk factors in adolescence any more strongly than BMI. Girls who favourably alter their overweight status between childhood and adolescence have cardiovascular risk profiles broadly similar to those who were normal weight at both time points, but boys who change from overweight to normal show risk factor profiles intermediate between those seen in boys who are normal weight at both ages or overweight at both ages.

Associations of Pregnancy Complications With Calculated Cardiovascular Disease Risk and Cardiovascular Risk Factors in Middle Age The Avon Longitudinal Study of Parents and Children

Background— The nature and contribution of different pregnancy-related complications to future cardiovascular disease (CVD) and its risk factors and the mechanisms underlying these associations remain unclear. Methods and Results— We studied associations of pregnancy diabetes mellitus, hypertensive disorders of pregnancy, preterm delivery, and size for gestational age with calculated 10-year CVD risk (based on the Framingham score) and a wide range of cardiovascular risk factors measured 18 years after pregnancy (mean age at outcome assessment, 48 years) in a prospective cohort of 3416 women. Gestational diabetes mellitus was positively associated with fasting glucose and insulin, even after adjustment for potential confounders, whereas hypertensive disorders of pregnancy were associated with body mass index, waist circumference, blood pressure, lipids, and insulin. Large for gestational age was associated with greater waist circumference and glucose concentrations, whereas small for gestational age and preterm delivery were associated with higher blood pressure. The association with the calculated 10-year CVD risk based on the Framingham prediction score was odds ratio 1.31 (95 confidence interval, 1.11–1.53) for preeclampsia and 1.26 (95 confidence interval, 0.95–1.68) for gestational diabetes mellitus compared with women without preeclampsia and without gestational diabetes mellitus, respectively. Conclusions— Hypertensive disorders of pregnancy and pregnancy diabetes mellitus are independently associated with an increased calculated 10-year CVD risk. Preeclampsia may be the better predictor of future CVD because it was associated with a wider range of cardiovascular risk factors. Our results suggest that pregnancy may be an important opportunity for early identification of women at increased risk of CVD later in life.

Cardiovascular risk parameters in men with ankylosing spondylitis in comparison with non-inflammatory control subjects: relevance of systemic inflammation

Men with AS (ankylosing spondylitis) are at elevated risk for CHD (coronary heart disease) but information on risk factors is sparse. We compared a range of conventional and novel risk factors in men with AS in comparison with healthy controls and, in particular, determined the influence of systemic inflammation. Twenty-seven men with confirmed AS and 19 controls matched for age were recruited. None of the men was taking lipid-lowering therapy. Risk factors inclusive of plasma lipids, IL-6 (interleukin-6), CRP (C-reactive protein), vWF (von Willebrand factor), fibrin D-dimer, ICAM-1 (intercellular cell-adhesion molecule-1) and fibrinogen were measured, and blood pressure and BMI (body mass index) were determined by standard techniques. A high proportion (70%) of men with AS were smokers compared with 37% of controls (P = 0.024). The AS patients also had a higher BMI. In analyses adjusted for BMI and smoking, men with AS had significantly higher IL-6 and CRP (approx. 9- and 6-fold elevated respectively; P < 0.001), fibrinogen (P = 0.013) and vWF (P = 0.008). Total cholesterol and HDL-C (high-density lipoprotein cholesterol) were lower (P < 0.05 and P = 0.073 respectively) in AS and thus the ratio was not different. Pulse pressure was also significantly higher in AS (P = 0.007). Notably, adjustment for IL-6 and CRP levels rendered all case-control risk factor differences, except pulse pressure, non-significant. In accordance with this finding, IL-6 correlated positively (r = 0.74, P < 0.001) with fibrinogen, but negatively (r = -0.46, P = 0.016) with total cholesterol concentration. In conclusion, men with AS have perturbances in several CHD risk factors, which appear to be driven principally by systemic inflammatory mediators. Inflammation-driven atherogenesis potentially contributes to the excess CHD risk in AS.

High Molecular Weight Adiponectin Is Not Associated with Incident Coronary Heart Disease in Older Women: A Nested Prospective Case-Control Study

CONTEXT Adiponectin levels appear weakly linked to incident vascular disease, but the high molecular weight (HMW) fraction may be more relevant. OBJECTIVE Our objective was to test whether HMW adiponectin, the key biologically active fraction, is linked to incident coronary heart disease (CHD) events. DESIGN, PARTICIPANTS, AND MAIN OUTCOME MEASURES: We assessed the association between HMW adiponectin (measured by ELISA) and CHD risk in a prospective (4-yr) case-control study nested within the British Womens Heart and Health Study. All women were postmenopausal. SETTING Women were seen in a primary care setting. RESULTS Among both cases (n = 167) and controls (n = 333), HMW adiponectin positively correlated with age and high-density lipoprotein cholesterol and inversely correlated with waist to hip ratio, fasting insulin, fasting glucose, homeostasis model assessment for insulin resistance scores, C-reactive protein, and triglycerides, in similar fashion to total adiponectin. The age-adjusted relative risk ratio for a doubling of HMW adiponectin was 0.96 (95% confidence interval, 0.78-1.18), and adjustment for any of the potential confounding or mediating variables did not substantively alter this. Additional adjustments for childhood social class, alcohol consumption, hormone replacement therapy use, statin, aspirin, or blood pressure medication did not alter the null association. When we examined the effect of HMW adiponectin by quarters of its distribution, there was no evidence of any associations (P trend = 0.71). There was also no association of the ratio of HMW adiponectin to total adiponectin with CHD risk; age-adjusted relative risk per doubling of the ratio was 1.10 (95% confidence interval, 0.80-1.50). CONCLUSIONS Despite associations with total adiponectin and insulin resistance, our data go against any apparent association between HMW adiponectin levels and incident CHD events.

Associations of adiponectin with metabolic and vascular risk parameters in the British Regional Heart Study reveal stronger links to insulin resistance-related than to coronory heart disease risk-related parameters.

Background and aim:Adiponectin is considered by many to be part of the ‘common soil’ linking type 2 diabetes and coronary heart disease (CHD). We examined the relationship between adiponectin and insulin resistance, metabolic, inflammatory and haemostatic risk factors and hepatic function.Methods and results:The study was carried out in 3640 non-diabetic men aged 60–79 years drawn from general practices in 24 British towns and who were not on warfarin. Adiponectin was associated with waist circumference (inversely), alcohol intake (positively) and physical activity (nonlinearly); no association was seen with cigarette smoking, prevalent CHD or stroke. After adjustment for these factors, adiponectin was significantly inversely associated with insulin resistance, triglyceride, C-reactive protein (but not interleukin 6), tissue plasminogen activator and alanine aminotransferase and positively associated with high-density lipoprotein cholesterol (HDL-cholesterol) and Factor VIII, factors associated with diabetes. No association was seen with cholesterol, smoking, systolic blood pressure or coagulation factors. Risk of the metabolic syndrome decreased significantly with increasing adiponectin.Conclusion:Adiponectin is inversely associated with factors strongly associated with the development of diabetes. Limited associations with the established major risk factors for CHD suggest adiponectin may be a stronger marker of risk for diabetes than for CHD.

Lack of effect of TNFα blockade therapy on circulating adiponectin levels in patients with autoimmune disease: results from two independent prospective studies

Background Adiponectin is an anti-inflammatory and potentially antiatherogenic molecule. Some recent reports suggest that tumour necrosis factor α (TNFα) blockade therapy increases circulating adiponectin levels, but data are sparse and inconsistent. Methods Data from a double-blind placebo controlled study of onercept in 126 patients with psoriatic arthritis (PsA) and from pre- and post-adalimumab treatment in 171 patients with rheumatoid arthritis (RA) were used to examine the effect of TNFα blockade therapy on adiponectin. Results Despite expected associations of adiponectin with gender and baseline high-density lipoprotein cholesterol and triglyceride, adiponectin levels did not change over time with TNFα blockade therapy in either group. The mean±SD absolute change in adiponectin levels was −0.23±4.6 μg/ml in patients with PsA treated with combined onercept 50 mg and onercept 100 mg (vs placebo, p=0.60) and 0.28±3.23 μg/ml in patients with RA treated with adalimumab (vs baseline, p=0.66). Conclusion These results do not support a significant effect of TNFα blockade therapy on circulating adiponectin levels in patients with autoimmune disease.

The association of insulin-like growth factor 1 (IGF-1) with incident coronary heart disease in women: findings from the prospective British Women's Heart and Health Study

OBJECTIVE To examine the association of insulin-like-growth factor 1 (IGF-1) with coronary heart disease (CHD) in women. METHODS Prospective (4 year) case-control study nested within the British Womens Heart and Health Study. With 167 cases and 333 controls. Serum IGF-1 concentrations (on serum stored at -80 degrees C for a median of 4 years) were determined using a two-site immunoenzymometric assay. RESULTS Among both cases and controls IGF-1 was inversely correlated with waist:hip ratio, fasting insulin, HOMA-IR, CRP, triglyceride levels and systolic blood pressure, and was positively correlated with HDL-C levels. The confounder-adjusted (age, socioeconomic position, smoking and physical activity) relative risk ratio for a 1 standard deviation (S.D.) increase in IGF-1 was 0.92 (95% CI: 0.75, 1.12) and additional adjustment for metabolic risk factors (waist:hip ratio, systolic blood pressure, high-density lipoprotein cholesterol, triglycerides, glucose, insulin and C-reactive protein) attenuated this to 0.98 (95% CI: 0.80, 1.21). There was no evidence of non-linear associations and the risk of CHD was similar across quarters of the distribution of IGF-1. CONCLUSIONS Despite associations with established CHD risk factors in this, and other studies, our findings suggest that higher IGF-1 levels are not associated with CHD in older British women. The contradictory evidence to date in this area highlights the need for further large-scale prospective studies and use of genetic epidemiology studies to determine the nature of the association between IGF-1 and CHD.

Simvastatin prevents inflammation-induced aortic stiffening and endothelial dysfunction

AIMS The aim of this study was to determine whether simvastatin would protect against inflammation-induced aortic stiffening and endothelial dysfunction. METHODS Aortic pulse wave velocity (aPWV) and flow-mediated dilatation (FMD) were assessed three times, at baseline, after a 14 day administration of simvastatin or placebo and 8 h after Salmonella typhi vaccination in 50 healthy subjects. RESULTS Following vaccination there was a significant increase in aPWV in the placebo group (5.80 ± 0.87 vs. 6.21 ± 0.97 m s⁻¹, 95% CI 0.19, 0.62, P= 0.002) but not the simvastatin group (5.68 ± 0.73 vs. 5.72 ± 0.74 m s⁻¹, 95% CI -0.19, 0.27, P= 0.9; P= 0.016 for comparison). Whereas FMD response was reduced in the placebo group (6.77 ± 4.10 vs. 5.27 ± 2.88%, 95% CI -2.49, -0.52, P= 0.02) but not in the simvastatin group (7.07 ± 4.37 vs. 7.17 ± 9.94%, 95% CI -1.1, 1.3. P= 0.9, P < 0.001 for comparison). There was no difference in the systemic inflammatory response between groups following vaccination. However, there was a significant reduction in serum apolipoprotein A-I (Apo A-I) in the placebo, but not in the simvastatin, group. CONCLUSIONS Simvastatin prevents vaccination-induced aortic stiffening and endothelial dysfunction. This protective mechanism may be due to preservation of the Apo A-I lipid fraction, rather than pleiotropic anti-inflammatory effects of statins.