Obesity increases pre-eclampsia (PE) risk. Adipose tissue inflammation may contribute to the clinical syndrome of PE. We compared adipose tissue macrophage infiltration and release of pro-inflammatory adipokines in PE and healthy pregnancy. Subcutaneous and visceral adipose tissue biopsies were collected from healthy ( n =13) and PE ( n =13) mothers. Basal and lipopolysaccharide (LPS) stimulated adipocyte TNFα, IL-6, CCL-2, and CRP release was measured. Adipose tissue cell densities of activated (cfms + ) and total (CD68 + ) macrophages were determined. In PE only, visceral adipose tissue TNFα release was increased after LPS stimulation (57 [76] versus 81 [97] pg/ml/µg DNA, P =0.030). Basal TNFα release was negatively correlated insulin sensitivity of visceral adipocytes ( r = −0.61, P =0.030) in PE. Visceral adipocyte IL-6 release was increased after LPS stimulation in PE only (566 [696] versus 852 [914] pg/ml/µg DNA, P =0.019). Visceral adipocyte CCL-2 basal (67 [61] versus 187 [219] pg/ml/µgDNA, P =0.049) and stimulated (46 [46] versus 224 [271] pg/ml/µg DNA, P =0.003) release was greater than in subcutaneous adipocytes in PE only. In PE, median TNF mRNA expression in visceral adipose tissue was higher than controls (1.94 [1.13–4.14] versus 0.8 [0.00–1.27] TNF / PPIA ratio, P =0.006). In visceral adipose tissue, CSF1R (a marker of activated macrophages) mRNA expression (24.8[11.0] versus 51.0[29.9] CSF1R/PPIA ratio, P =0.011) and activated (cfms+) macrophage count (6.7[2.6] versus 15.2[8.8] % cfms+/adipocyte, P =0.031) were higher in PE than in controls. In conclusion, our study demonstrates dysregulation of inflammatory pathways predominantly in visceral adipose tissue in PE. Inflammation of visceral adipose tissue may mediate many of the adverse metabolic effects associated with PE.

Increasing maternal obesity is a challenge that has an impact on all aspects of female reproduction. Lean and obese pregnant women gain similar fat mass, but lean women store fat in the lower-body compartment and obese women in central compartments. In the non-pregnant, central storage of fat is associated with adipocyte hypertrophy and represents a failure to adequately store excess fatty acids, resulting in metabolic dysregulation and ectopic fat accumulation (lipotoxicity). Obese pregnancy is associated with exaggerated metabolic adaptation, endothelial dysfunction and increased risk of adverse pregnancy outcome. We hypothesize that the preferential storage of fat in central rather than ‘safer’ lower-body depots in obese pregnancy leads to lipotoxicity. The combination of excess fatty acids and oxidative stress leads to the production of oxidized lipids, which can be cytotoxic and influence gene expression by acting as ligands for nuclear receptors. Lipid excess and oxidative stress provoke endothelial dysfunction. Oxidized lipids can inhibit trophoblast invasion and influence placental development, lipid metabolism and transport and can also affect fetal developmental pathways. As lipotoxicity has the capability of influencing both maternal endothelial function and placental function, it may link maternal obesity and placentally related adverse pregnancy outcomes such as miscarriage and pre-eclampsia. The combination of excess/altered lipid nutrient supply, suboptimal in utero metabolic environment and alterations in placental gene expression, inflammation and metabolism may also induce obesity in the offspring.

Plasma adiponectin is inversely associated with the risk of coronary heart disease in healthy people. However, adiponectin and BNP (B-type natriuretic peptide) are both known to be positively associated with a risk of poor outcome, and with each other, in ACS (acute coronary syndrome) patients. Serial changes in plasma adiponectin and BNP following ACS have not been assessed previously, and may clarify these apparently paradoxical associations. In the present study, adiponectin, BNP, classical risk markers and clinical parameters were measured in plasma from 442 consecutive ACS patients in an urban teaching hospital, with repeat measures at 7 weeks ( n =338). Patients were followed-up for 10 months. Poor outcome was defined as mortality or readmission for ACS or congestive heart failure ( n =90). In unadjusted analysis, the change in adiponectin (but not baseline or 7-week adiponectin) was significantly associated with the risk of an adverse outcome {odds ratio (OR), 5.42 [95% CI (confidence interval), 2.78–10.55]}. This association persisted after adjusting for classical risk factors and clinical markers, but was fully attenuated by adjusting for the 7-week BNP measurement [OR, 1.13 (95% CI, 0.27–4.92)], which itself remained associated with risk [OR, 5.86 (95% CI, 1.04–32.94)]. Adiponectin and BNP positively correlated at baseline and 7 weeks, and the change in both parameters over 7 weeks also correlated ( r =0.39, P <0.001). In conclusion, increases in plasma adiponectin (rather than absolute levels) after ACS are related to the risk of an adverse outcome, but this relationship is not independent of BNP levels. The results of the present study allude to a potential direct or indirect relationship between adiponectin and BNP post-ACS which requires further investigation.

The oxidation hypothesis for CHD (coronary heart disease) is attractive; however, the almost universal failure of antioxidant vitamin supplementation as a CVD (cardiovascular disease) risk modifier challenges the oxidation hypothesis, at least as a concept that easily ‘translates’ into clinical benefit for the population. At the same time, quality prospective data on lipid or protein oxidation markers as predictors of vascular events are sparse. In the present issue of Clinical Science , Woodward and co-workers provide much needed prospective data examining the relationship between markers of oxidative damage and CHD outcome in a general population. Despite noting the expected associations between several established CHD risk factors and CHD events, no significant link was observed between measured oxidation markers and CHD risk, a finding which further challenges the oxidation hypothesis for CHD.

Adiponectin and leptin, two adipose-tissue-derived proteins, have been reported to be elevated in women with established PE (pre-eclampsia). The aim of the present study was to investigate whether alterations in adiponectin and leptin levels predate the development of PE and FGR (fetal growth restriction) in women at increased risk of these complications, as assessed by Doppler examination of the uterine arteries during the second trimester of pregnancy. We also sought to investigate the circulating levels of adiponectin and leptin in women with established severe early-onset FGR. The study included three groups of pregnant women at 23–25 weeks: Group A ( n =44) with normal uterine artery Doppler waveforms, Group B ( n =49) with abnormal Doppler waveforms and normal fetal growth at the time of the examination, and Group C ( n =15) with established severe FGR and abnormal Doppler waveforms. All women had plasma adiponectin and leptin measured by sensitive immunoassays. In Group B, 19 women had a normal outcome, 17 delivered infants with FGR and 13 developed PE. The women who developed PE delivered smaller babies earlier than women with a normal outcome ( P <0.001). There were no significant differences in adiponectin levels between any of the groups (overall P =0.3). Leptin concentrations, expressed as MoM (multiples of the median) of Group A, were higher in women in Group C, i.e. established severe FGR at 2.5 (1.2–2.7) MoMs (overall P <0.001), compared with all of the other groups and subgroups. In conclusion, we found that, in pregnancies complicated by severe early-onset FGR, the maternal plasma concentration of leptin is twice as high as in normal pregnancies. However, the second trimester levels of maternal plasma adiponectin and leptin in pregnancies that subsequently develop PE and/or FGR are not significantly different from normal and, consequently, it is unlikely that these markers will be useful as predictors of these pregnancy complications.

The global increase in the prevalence of obesity has heralded a rise in associated liver injury namely NAFLD (non-alcoholic fatty liver disease). It is estimated that 20–30% of adult populations in developed countries have NAFLD and, although high quality data is currently lacking, the condition is clearly increasing in children also. NAFLD should be suspected in those with commonly available simple clinical signs and biochemistry consistent with insulin resistance. A small number of individuals with NAFLD, often considered a relatively benign condition, will progress to more severe stages of liver disease including NASH (non-alcoholic steatohepatitis) with or without fibrosis, cirrhosis and occasionally hepatocellular carcinoma. NAFLD is also commonly associated with an increased risk of developing Type 2 diabetes and treatable features of insulin resistance such as dyslipidaemia and dysglycaemia. Histological examination of liver tissue remains the only proven method to distinguish between simple steatosis and NASH, a condition far more likely to progress to cirrhosis. Identification of an imaging technique or non-invasive marker to achieve this distinction is therefore much sought after and would allow larger clinical trials and better clinical assessment. Case series and pilot studies of lifestyle advice, insulin sensitizers and other medications have shown improvements in liver histology and serum liver enzymes but robust randomized controlled studies are needed. Furthermore, the cost/benefit ratio of any new therapies, and any potential harms, must be evaluated carefully before being clinically advocated.

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.

Elevated circulating levels of NEFAs (non-esterified fatty acids) are associated with states of insulin resistance and increased risk of vascular disease. Previous animal and human studies have demonstrated NEFA-induced endothelial dysfunction of large conduit arteries, reversible by the antioxidant ascorbic acid. We therefore investigated the effect of NEFAs on carbachol-induced endothelium-dependent vasodilation of rat resistance arteries in vitro using the technique of wire myography. In addition, we investigated the effect of co-incubation of NEFAs and ascorbic acid. Cumulative concentration–response curves to carbachol (endothelium-dependent vasodilation) and SNAP ( S -nitroso- N -acetyl- DL -penicillamine; endothelium-independent vasodilation) were constructed. Those to carbachol were repeated following a 30 min incubation with either oleic acid (10 −4 M) or palmitic acid (10 −4 M), demonstrating significant impairment of endothelium-dependent vasodilation with both [ P <0.05, comparison of pD 2 values (the negative log concentration of agonist required to effect a 50% response)]. A cumulative concentration–response curve to carbachol was repeated following co-incubation with palmitic acid (10 −4 M) and the antioxidant ascorbic acid (10 −5 M), demonstrating an abolition of the previously observed endothelial dysfunction induced by palmitic acid. There was no impairment of vasodilation to SNAP following NEFA incubation. We conclude that NEFAs directly impair endothelial function in rat resistance arteries via an increase in oxidative stress at the vascular endothelium.

There is increasing evidence to implicate inflammation as an important precursor of endothelial dysfunction. This mechanistic link is apparent across the entire spectrum of inflammatory status, i.e. endothelial function is apparent following acute infection, and in subjects with chronic high-grade inflammation and, perhaps most importantly, persistent low-grade inflammation. The recognition of this relationship has present therapeutic ramifications, but also requires that future longitudinal studies determining the predictive ability of endothelial function measures for vascular events should incorporate markers of inflammation as potential confounders. In this issue of Clinical Science , Fichtlscherer and co-workers describe a link between endothelial function and sPLA 2 (secretory non-pancreatic type II phospholipase A 2 ) serum activity.

Low-grade chronic inflammation, characterized by elevated plasma concentrations of C-reactive protein (CRP), is associated with an increased risk of atherosclerotic cardiovascular disease. Endothelial cell activation is an early event in atherogenesis, and previous studies have reported correlations between indirect markers of endothelial cell activation and CRP concentration. Therefore, in the present study, we measured CRP concentration (and leptin concentration as an index of fat mass) in nine healthy subjects (mean age 53±8.1 years; body mass index 27±3.2 kg/m 2 ; mean arterial blood pressure 101±9.0 mmHg) undergoing measurement of basal endothelial nitric oxide (NO) synthesis using intra-brachial infusions of N G -monomethyl- l -arginine ( l -NMMA; a substrate inhibitor of endothelial NO synthase) and noradrenaline (a non-specific control vasoconstrictor). In univariate analysis, CRP concentration was correlated with (i) the percentage decrease in forearm blood flow (FBF) during l -NMMA infusion ( r = 0.85, P = 0.004); and (ii) the serum leptin concentration ( r = 0.65, P = 0.05). In multivariate analysis, the relationship between CRP concentration and the FBF response to l -NMMA remained significant when age and leptin ( t = 2.65, P = 0.045), age and BMI ( t = 3.69, P = 0.014), or age and low-density-lipoprotein-cholesterol plus high-density-lipoprotein-cholesterol ( t = 3.37, P = 0.044), were included in regression models. In contrast, the response of FBF to noradrenaline was not significantly related to CRP concentration. These data demonstrate for the first time a relationship between low-grade chronic inflammation and basal endothelial NO synthesis (measured using an invasive method), and support the notion that endothelial dysfunction is a critical intermediate phenotype in the relationship between inflammation and cardiovascular disease.