Prevention of cardiovascular risk in women who had hypertension during pregnancy after 36 weeks gestation.

OBJECTIVE: To analyse preventive interventions of women with cardiovascular risk factors postpartum. METHODS: 3.5 years postpartum, women with history of hypertension in pregnancy were invited for a questionnaire, 1 year after a cardiovascular risk assessment. RESULTS: Two hundred and fifty-seven women completed the questionnaire. At risk factor analyses, 35% had hypertension, 37% abnormal lipid- or glucose levels, 63% BMI ≥ 25 and 19% smoked. One year later, 36% of women with hypertension used anti-hypertensives, 0% of women with abnormal laboratory findings used anti-cholesterol and 1% anti-diabetes medication, 31% of the obese women achieved BMI reduction (≥ 5%), 42% of the women who smoked, quit. CONCLUSION: A minority improved their risk profile.

Inflammation increases plasma angiopoietin-like protein 4 in patients with the metabolic syndrome and type 2 diabetes.

BACKGROUND: Angiopoietin-like protein 4 (ANGPTL4) inhibits lipoprotein lipase and associates with dyslipidemia. The expression of ANGPTL4 is regulated by free fatty acids (FFA) that activate lipid-sensing peroxisome proliferator-activated receptors (PPARs), but FFA can also activate pattern recognition receptors including Toll-like receptor 4 (TLR4) in macrophages. OBJECTIVE: To assess whether systemic low-grade inflammation is a determinant for plasma ANGPTL4 levels in patients with the metabolic syndrome (MetS) and type 2 diabetes mellitus (T2DM). DESIGN: We studied 335 male participants: healthy controls (Controls), patients with the MetS without inflammation (MetS-I) and with low-grade inflammation (MetS+I), and patients with T2DM. All patients without diabetes included in the present study were initially matched for waist circumference. In plasma, ANGPTL4, C reactive protein (CRP) and metabolic parameters were determined. Underlying mechanisms were examined using human macrophages in vitro. RESULTS: As compared with Controls, plasma ANGPTL4 levels were increased in patients with MetS-I, MetS+I, and T2DM. Furthermore, ANGPTL4 was increased in T2DM compared with MetS-I. In fact, plasma CRP correlated positively with plasma ANGPTL4. In vitro studies showed that TLR 3/4 activation largely increased the expression and release of ANGPTL4 by macrophages. CONCLUSIONS: Plasma ANGPTL4 levels in humans are predicted by CRP, a marker of inflammation, and ANGPTL4 expression by macrophages is increased by inflammatory stimuli.

Peripheral cannabinoid 1 receptor blockade activates brown adipose tissue and diminishes dyslipidemia and obesity.

The endocannabinoid system is an important player in energy metabolism by regulating appetite, lipolysis, and energy expenditure. Chronic blockade of the cannabinoid 1 receptor (CB1R) leads to long-term maintenance of weight loss and reduction of dyslipidemia in experimental and human obesity. The molecular mechanism by which CB1R blockade reverses dyslipidemia in obesity has not yet been clarified. In this study, we showed that CB1R blockade with the systemic CB1R blocker rimonabant enhanced whole-body energy expenditure and activated brown adipose tissue (BAT), indicated by increased expression of genes involved in BAT thermogenesis and decreased lipid droplet size in BAT. This was accompanied by selectively increased triglyceride (TG) uptake by BAT and lower plasma TG levels. Interestingly, the effects on BAT activation were still present at thermoneutrality and could be recapitulated by using the strictly peripheral CB1R antagonist AM6545, indicating direct peripheral activation of BAT. Indeed, CB1R blockade directly activated T37i brown adipocytes, resulting in enhanced uncoupled respiration, most likely via enhancing cAMP/PKA signaling via the adrenergic receptor pathway. Our data indicate that selective targeting of the peripheral CB1R in BAT has therapeutic potential in attenuating dyslipidemia and obesity.

Brown adipose tissue volume in healthy lean south Asian adults compared with white Caucasians: a prospective, case-controlled observational study.

BACKGROUND: Individuals of south Asian origin have a very high risk of developing type 2 diabetes compared with white Caucasians. We aimed to assess volume and activity of brown adipose tissue (BAT), which is thought to have a role in energy metabolism by combusting fatty acids and glucose to produce heat and might contribute to the difference in incidence of type 2 diabetes between ethnic groups. METHODS: We enrolled Dutch nationals with south Asian ancestry and matched Caucasian participants at The Rijnland Hospital (Leiderdorp, Netherlands). Eligible participants were healthy lean men aged 18-28 years, and we matched groups for BMI. We measured BAT volume and activity with cold-induced (18)F-fluorodeoxyglucose ((18)F-FDG) PET CT scans, and assessed resting energy expenditure, non-shivering thermogenesis, and serum parameters. This study is registered with the Netherlands Trial Register, number 2473. FINDINGS: Between March 1, 2013, and June 1, 2013, we enrolled 12 participants in each group; one Caucasian participant developed hyperventilation after (18)F-FDG administration, and was excluded from all cold-induced and BAT measurements. Compared with Caucasian participants, south Asian participants did not differ in age (mean 23.6 years [SD 2.8] for south Asians vs 24.6 years [2.8] for Caucasians) or BMI (21.5 kg/m(2) [2.0] vs 22.0 kg/m(2) [1.6]), but were shorter (1.74 m [0.06] vs 1.85 m [0.04]) and lighter (65.0 kg [8.5] vs 75.1 kg [7.2]). Thermoneutral resting energy expenditure was 1297 kcal per day (SD 123) in south Asian participants compared with 1689 kcal per day (193) in white Caucasian participants (difference -32%, p=0.0008). On cold exposure, shiver temperature of south Asians was 2.0°C higher than Caucasians (p=0.0067) and non-shivering thermogenesis was increased by 20% in white Caucasians (p<0.0001) but was not increased in south Asians. Although the maximum and mean standardised uptake values of (18)F-FDG in BAT did not differ between groups, total BAT volume was lower in south Asians (188 mL [SD 81]) than it was in Caucasians (287 mL [169]; difference -34%, p=0.04). Overall, BAT volume correlated positively with basal resting energy expenditure in all assessable individuals (ß=0.44, p=0.04). INTERPRETATION: Lower resting energy expenditure, non-shivering thermogenesis, and BAT volumes in south Asian populations might underlie their high susceptibility to metabolic disturbances, such as obesity and type 2 diabetes. Development of strategies to increase BAT volume and activity might help prevent and treat such disorders, particularly in south Asian individuals. FUNDING: Dutch Heart Foundation (2009T038) and Dutch Diabetes Research Foundation (2012.11.1500).

Association of lung function measurements and visceral fat in men with metabolic syndrome.

BACKGROUND: Several studies have reported a positive relationship between lung function impairment and the metabolic syndrome. This is most usually explained by abdominal adiposity. We hypothesized that the main determinant of the association between lung function impairment and abdominal obesity is the presence of visceral fat. METHODS: The present study is a cross-sectional analysis of 98 non-diabetic men aged between 50 and 70 years with the metabolic syndrome. The amount of visceral and subcutaneous adipose tissue was determined by an MRI scan. The association between visceral fat and measures of lung function (FEV1, FVC, exhaled and NO) was assessed using linear regression. RESULTS: 98 participants were included in this analysis. There was a linear inverse association between visceral fat and both FEV1 and FVC. None of the other different fat-related measurements (subcutaneous fat, waist circumference and BMI) or features of the metabolic syndrome were found to be associated with these lung function measurements. CONCLUSION: In non-diabetic subjects with the metabolic syndrome and a lung function that is within the normal range, visceral fat is negatively correlated with FEV1 and FVC.

Cost-effectiveness analysis of cardiovascular risk factor screening in women who experienced hypertensive pregnancy disorders at term.

OBJECTIVES: To assess the cost-effectiveness of post-partum screening on cardiovascular risk factors and subsequent treatment in women with a history of gestational hypertension or pre-eclampsia at term. STUDY DESIGN: Two separate Markov models evaluated the cost-effectiveness analysis of hypertension (HT) screening and screening on metabolic syndrome (MetS), respectively, as compared to current practice in women with a history of term hypertensive pregnancy disorders. Analyses were performed from the Dutch health care perspective, using a lifetime horizon. One-way sensitivity analyses and Monte Carlo simulation evaluated the robustness of the results. RESULTS: Both screening on HT and MetS in women with a history of gestational hypertension or pre-eclampsia resulted in increase in life expectancy (HT screening 0.23year (95% CI -0.06 to 0.54); MetS screening 0.14years (95% CI -0.16 to 0.45)). The gain in QALYs was limited, with HT screening and MetS screening generating 0.04 QALYs (95% CI -0.12 to 0.20) and 0.03 QALYs (95% CI -0.14 to 0.19), resulting in costs to gain one QALY of €4228 and €28,148, respectively. Analyses for uncertainty showed a chance of 74% and 75%, respectively, that post-partum screening is cost-effective at a threshold of €60,000/QALY. CONCLUSIONS: According to the available knowledge post-partum screening on cardiovascular risk factors and subsequent treatment in women with a history of gestational hypertension or pre-eclampsia at term is likely to be cost-effective.

Induction of labour or expectant monitoring in hypertensive pregnancy disorders at term: do women's postpartum cardiovascular risk factors differ between the two strategies?

OBJECTIVE: Cardiovascular disease (CVD) is the leading cause of death in women in the western world. Several studies have described the association between hypertensive pregnancy disorders and CVD in later life. Our aim was to compare postpartum cardiovascular risk factors in women who had a shorter and women who had a longer exposure to endothelial activation during their term hypertensive pregnancy. STUDY DESIGN: We studied a subsample of women with pregnancy-induced hypertension or mild preeclampsia at term, who had participated in the randomized HYPITAT trial comparing induction of labour (IOL cohort) (n=110) or expectant monitoring (EM cohort) (n = 91). We assessed, 2.5 years postpartum, cardiovascular risk factors, i.e. blood pressure, anthropometrics, glucose, HbA1C, insulin, HOMA score, total cholesterol, HDL cholesterol, triglycerides, high sensitive CRP, micro-albumin and metabolic syndrome, and compared these risk factors between the induction and expectant groups. RESULTS: The mean time from randomization to delivery was 3.3 days in the induction group and 10.3 days in the expectant group (p<.001), generating a difference in exposure of 7 days. After a mean follow-up period of 2.5 years, the prevalence of hypertension (IOL 34%; EM 37%, p = .66) and metabolic syndrome (IOL 26%; EM 27%, p = 1.0) was similar in both groups. Furthermore, systolic and diastolic blood pressure, BMI, waist circumference, glucose, HbA1C, insulin, HOMA score, lipids, HsCRP-levels and micro-albumin were all comparable between women who had induction of labour and those who had expectant monitoring. CONCLUSION: In women with hypertensive disorders in pregnancy at term, induction of labour does not affect the clinical and biochemical cardiovascular profile at 2.5 years postpartum.

BMP7 activates brown adipose tissue and reduces diet-induced obesity only at subthermoneutrality.

BACKGROUND/AIMS: Brown adipose tissue (BAT) dissipates energy stored in triglycerides as heat via the uncoupling protein UCP-1 and is a promising target to combat hyperlipidemia and obesity. BAT is densely innervated by the sympathetic nervous system, which increases BAT differentiation and activity upon cold exposure. Recently, Bone Morphogenetic Protein 7 (BMP7) was identified as an inducer of BAT differentiation. We aimed to elucidate the role of sympathetic activation in the effect of BMP7 on BAT by treating mice with BMP7 at varying ambient temperature, and assessed the therapeutic potential of BMP7 in combating obesity. METHODS AND RESULTS: High-fat diet fed lean C57Bl6/J mice were treated with BMP7 via subcutaneous osmotic minipumps for 4 weeks at 21 °C or 28 °C, the latter being a thermoneutral temperature in which sympathetic activation of BAT is largely diminished. At 21 °C, BMP7 increased BAT weight, increased the expression of Ucp1, Cd36 and hormone-sensitive lipase in BAT, and increased total energy expenditure. BMP7 treatment markedly increased food intake without affecting physical activity. Despite that, BMP7 diminished white adipose tissue (WAT) mass, accompanied by increased expression of genes related to intracellular lipolysis in WAT. All these effects were blunted at 28 °C. Additionally, BMP7 resulted in extensive 'browning' of WAT, as evidenced by increased expression of BAT markers and the appearance of whole clusters of brown adipocytes via immunohistochemistry, independent of environmental temperature. Treatment of diet-induced obese C57Bl6/J mice with BMP7 led to an improved metabolic phenotype, consisting of a decreased fat mass and liver lipids as well as attenuated dyslipidemia and hyperglycemia. CONCLUSION: Together, these data show that BMP7-mediated recruitment and activation of BAT only occurs at subthermoneutral temperature, and is thus likely dependent on sympathetic activation of BAT, and that BMP7 may be a promising tool to combat obesity and associated disorders.

Cardiovascular risk estimation in women with a history of hypertensive pregnancy disorders at term: a longitudinal follow-up study.

BACKGROUND: Cardiovascular disease is associated with major morbidity and mortality in women in the Western world. Prediction of an individual cardiovascular disease risk in young women is difficult. It is known that women with hypertensive pregnancy complications have an increased risk for developing cardiovascular disease in later life and pregnancy might be used as a cardiovascular stress test to identify women who are at high risk for cardiovascular disease. In this study we assess the possibility of long term cardiovascular risk prediction in women with a history of hypertensive pregnancy disorders at term. METHODS: In a longitudinal follow-up study, between June 2008 and November 2010, 300 women with a history of hypertensive pregnancy disorders at term (HTP cohort) and 94 women with a history of normotensive pregnancies at term (NTP cohort) were included. From the cardiovascular risk status that was known two years after index pregnancy we calculated individual (extrapolated) 10-and 30-year cardiovascular event risks using four different risk prediction models including the Framingham risk score, the SCORE score and the Reynolds risk score. Continuous data were analyzed using the Student's T test and Mann-Whitney U test and categorical data by the Chi-squared test. A poisson regression analysis was performed to calculate the incidence risk ratios and corresponding 95% confidence intervals for the different cardiovascular risk estimation categories. RESULTS: After a mean follow-up of 2.5 years, HTP women had significantly higher mean (SD) extrapolated 10-year cardiovascular event risks (HTP 7.2% (3.7); NTP 4.4% (1.9) (p<.001, IRR 5.8, 95% CI 1.9 to 19)) and 30-year cardiovascular event risks (HTP 11% (7.6); NTP 7.3% (3.5) (p<.001, IRR 2.7, 95% CI 1.6 to 4.5)) as compared to NTP women calculated by the Framingham risk scores. The SCORE score and the Reynolds risk score showed similar significant results. CONCLUSIONS: Women with a history of gestational hypertension or preeclampsia at term have higher predicted (extrapolated) 10-year and 30-year cardiovascular event risks as compared to women with a history of uncomplicated pregnancies. Further large prospective studies have to evaluate whether hypertensive pregnancy disorders have to be included as an independent variable in cardiovascular risk prediction models for women.

Overexpression of angiopoietin-like protein 4 protects against atherosclerosis development.

OBJECTIVE: Macrophage foam cells play a crucial role in several pathologies including multiple sclerosis, glomerulosclerosis, and atherosclerosis. Angiopoietin-like protein 4 (Angptl4) was previously shown to inhibit chyle-induced foam cell formation in mesenteric lymph nodes. Here we characterized the regulation of Angptl4 expression in macrophages and examined the impact of Angptl4 on atherosclerosis development. APPROACH AND RESULTS: Macrophage activation elicited by pathogen-recognition receptor agonists decreased Angptl4 expression, whereas lipid loading by intralipid and oxidized low-density lipoprotein increased Angptl4 expression. Consistent with an antilipotoxic role of Angptl4, recombinant Angptl4 significantly decreased uptake of oxidized low-density lipoprotein by macrophages, via lipolysis-dependent and -independent mechanisms. Angptl4 protein was detectable in human atherosclerotic lesions and localized to macrophages. Transgenic overexpression of Angptl4 in atherosclerosis-prone apolipoprotein E*3-Leiden mice did not significantly alter plasma cholesterol and triglyceride levels. Nevertheless, Angptl4 overexpression reduced lesion area by 34% (P<0.05). In addition, Angptl4 overexpression decreased macrophage content (-41%; P<0.05) and numbers of monocytes adhering to the endothelium wall (-37%; P<0.01). Finally, plasma Angptl4 was independently and negatively associated with carotid artery sclerosis measured by 3-T MRI in subjects with metabolic syndrome and low-grade systemic inflammation. CONCLUSIONS: Angptl4 suppresses foam cell formation to reduce atherosclerosis development. Stimulation of Angptl4 in macrophages by oxidized low-density lipoprotein may protect against lipid overload.

Relationship between carotid intima media thickness and helminth infections on Flores Island, Indonesia.

OBJECTIVE: To examine the association between helminth infections and atherosclerosis. BACKGROUND: Chronic helminth infection, which can lead to poor nutritional status and anti-inflammatory response, might protect against the development of atherosclerosis. METHODS: A cross-sectional study was performed in Flores, Indonesia, an area highly endemic for soil-transmitted helminths (STH). Stool samples from 675 participants aged 18-80 years were collected and screened for Trichuris trichiura by microscopy and for Ascaris lumbricoides, Necator americanus, Ancylostoma duodenale, and Strongyloides stercoralis by qPCR. We collected data on body mass index (BMI), waist to hip ratio (WHR), blood pressure, fasting blood glucose (FBG), lipid, high sensitive C-reactive protein (hs-CRP), total immunoglobulin-E (TIgE) and Escherichia coli lipopolysaccharide stimulated cytokines (tumor necrosis factor and interleukin-10). In a subset of 301 elderly adults (≥40 years of age) carotid intima media thickness (cIMT) was measured. RESULTS: Participants with any STH infection had lower BMI (kg/m2) (mean difference -0.66, 95%CI [-1.26, -0.06]), WHR (-0.01, [-0.02, -0.00]), total cholesterol (mmol/L) (-0.22, [-0.43, -0.01]) and LDL-cholesterol (mmol/L) (-0.20, [-0.39, -0.00]) than uninfected participants. After additional adjustment for BMI the association between helminth infection and total cholesterol (mean difference -0.17, 95%CI [-0.37, 0.03]) as well as LDL-cholesterol (-0.15, [-0.33, 0.04]) was less pronounced. BMI, WHR, and total cholesterol were negatively associated with number species of helminth co-infections. Participants with high TIgE, an indicator of exposure to helminths, had lower FBG, TC, and HDL. The association between TIgE and TC and HDL remained significant after adjustment with BMI. No clear association was found between STH infection or TIgE and mean cIMT. CONCLUSIONS: This cross-sectional study presents evidence that helminth infections were negatively associated with risk factors for cardiovascular disease, an association at least partially mediated by an effect on BMI. The significance of this finding needs to be determined.

Cardiovascular risk factors in women who had hypertensive disorders late in pregnancy: a cohort study.

OBJECTIVE: The purpose of this study was to determine cardiovascular risk factors in women with a history of hypertensive pregnancy disorders at term (HTP) 2.5 years after pregnancy. STUDY DESIGN: In a multicenter cohort study in The Netherlands from June 2008 through November 2010, cardiovascular risk factors were compared between women with a history of HTP (HTP cohort, n = 306) and women with a history of normotensive pregnancies at term (NTP cohort, n = 99). HTP women had participated in a randomized, longitudinal trial assessing the effectiveness of induction of labor in women with hypertensive pregnancy disorders at term. All women were assessed 2.5 years after pregnancy for blood pressure, anthropometrics, glucose, glycosylated hemoglobin, insulin, homeostatic model assessment score, total cholesterol, high-density lipoprotein cholesterol, triglycerides, high-sensitivity C-reactive protein, and microalbumin and metabolic syndrome. RESULTS: After a mean follow-up period of 2.5 years, hypertension (HTP, 34%; NTP, 1%; P < .001) and metabolic syndrome (HTP, 25%; NTP, 5%; P < .001) were more prevalent in HTP women compared with NTP women. HTP women had significantly higher systolic and diastolic blood pressure, higher body mass index, and higher waist circumference. Glucose, glycosylated hemoglobin, insulin, homeostatic model assessment score, total cholesterol, triglycerides, and high-sensitivity C-reactive protein levels were significantly higher and high-density lipoprotein cholesterol was significantly lower in HTP women. CONCLUSION: In women with a history of HTP, hypertension and metabolic syndrome are more common, and they have higher levels of biochemical cardiovascular risk factors 2.5 years after pregnancy.

Site-specific coupling between vascular wall thickness and function: an observational MRI study of vessel wall thickening and stiffening in hypertension.

OBJECTIVES: The objective of this study was to evaluate associations between aortic pulse wave velocity (PWV) and aortic and carotid vessel wall thickness (VWT) using cardiovascular magnetic resonance imaging (MRI) in patients with hypertension as compared with healthy adult volunteers. MATERIALS AND METHODS: Local medical ethics approval was obtained and the participants gave informed consent. Fifteen patients with hypertension (5 men and 10 women; mean [SD] age, 49 [14] years) and 15 age- and sex-matched healthy volunteers were prospectively included and compared. All participants underwent MRI examination for measuring aortic and carotid VWT and aortic PWV with well-validated MRI techniques at 1.5- and 3-T MRI systems: PWV was assessed from velocity-encoded MRI and VWT was assessed by using dual-inversion black-blood gradient-echo imaging techniques. Paired t tests were used for testing differences between the volunteers and the patients and Pearson correlation (r) and univariable and multivariable stepwise linear regression analyses were used to test associations between aortic and carotid arterial wall thickness and stiffness. RESULTS: Mean values for aortic PWV and aortic and carotid VWT (indexed for body surface area [BSA]) were all significantly higher in patients with hypertension as compared with the healthy volunteers (ie, aortic PWV, 7.0 ± 1.4 m/s vs 5.7 ± 1.3 m/s; aortic VWT/BSA, 0.12 ± 0.03 mL/m vs 0.10 ± 0.03 mL/m; carotid VWT/BSA, 0.04 ± 0.01 mL/m vs 0.03 ± 0.01 mL/m; all P < 0.01). Aortic PWV was highly correlated with aortic VWT/BSA (r = 0.76 and P = 0.002 in the patients vs r = 0.63 and P = 0.02 in the volunteers), and in the patients, aortic PWV was moderately correlated with carotid VWT/BSA (r = 0.50; P = 0.04). In the volunteers, correlation between aortic PWV and carotid VWT/BSA was not significant (r = 0.40; P = 0.13). In addition, aortic VWT/BSA was significantly correlated with carotid VWT/BSA, in both the patients (r = 0.60; P = 0.005) and volunteers (r = 0.57; P = 0.007). CONCLUSIONS: In the patients with hypertension and the healthy volunteers, the aortic PWV is associated more strongly with aortic wall thickness than with carotid wall thickness, reflecting site-specific coupling between vascular wall thickness and function.

Biochemical cardiovascular risk factors after hypertensive pregnancy disorders: a systematic review and meta-analysis.

The objective of this study was to perform a systematic review and meta-analysis of studies assessing biochemical cardiovascular risk factors in women with previous hypertensive pregnancy disorders and women with previous normotensive pregnancies. Data were collected from PubMed and EMBASE (from inception to February 28, 2011) supplemented by manual searches of bibliographies. Included were cohort studies and case-control studies assessing biochemical cardiovascular risk factors in women with previous hypertensive pregnancy disorders compared with women with previous normotensive pregnancies. Of 2573 studies reviewed for eligibility, quality, and data extraction, 22 were included in the review, of which 15 could be meta-analyzed. The pooled mean differences for the outcomes of interest were 0.17 mmol/L (95% confidence interval [CI], 0.08-0.25 mmol/L) for glucose (10 studies), 3.46 mU/mL (95% CI, 2.34-4.58 mU/mL) for insulin (5 studies), 0.13 mmol/L (95% CI, 0.05-0.21) for triglycerides (10 studies), 0.22 mmol/L (95% CI, 0.11-0.33 mmol/L) for total cholesterol (11 studies), -0.11 mmol/L (95% CI, -0.18 to -0.04 mmol/L) for high-density lipoprotein cholesterol (10 studies), and 0.21 mmol/L (95% CI, 0.10-0.32) for low-density lipoprotein cholesterol (9 studies), all in the disadvantage in women with previous hypertensive pregnancy disorders. Analyses for preeclampsia alone showed similar results. CONTINUED LEARNING OBJECTIVES: After completing this CME activity, physicians should be better able to assess the long-term cardiovascular consequences after hypertensive pregnancy disorders, evaluate and interpret the evidence regarding biochemical cardiovascular risk factor assessment after pregnancy, and counsel women with a history of hypertensive pregnancy disorders as to the effectiveness of cardiovascular risk factor assessment in the primary prevention of cardiovascular disease. CONCLUSIONS: Women with previous hypertensive pregnancy disorders have higher glucose, insulin, triglycerides, total cholesterol, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol levels measured after pregnancy compared with women with previous normotensive pregnancies. These biochemical cardiovascular risk factors may identify women who will benefit from primary prevention of cardiovascular disease. TARGET AUDIENCE: Obstetricians and gynecologists, family physicians.

Angiogenic factors in women ten years after severe very early onset preeclampsia.

BACKGROUND: Women with a history of mainly severe and early onset preeclampsia have an increased risk of future cardiovascular disease. During these complicated pregnancies increased levels of anti-angiogenic factors can be found. We hypothesize that women with a history of severe very early onset preeclampsia still have increased levels of these biomarkers years after this pregnancy, resulting in increased risk for cardiovascular disease. METHODS: Twenty women with severe early onset preeclampsia before 24 weeks' gestation, who delivered between 1993-2003 in a tertiary referral centre and twenty matched controls with uncomplicated pregnancies and healthy term infants, were addressed for participation in the study. Venous plasma samples were analyzed for basic fibroblast growth factor (bFGF), placental growth factor (PLGF), soluble fms-like tyrosine kinase-1 (sFlt-1), vascular endothelial growth factor (VEGF), E- and P-selectin, soluble intercellular adhesion molecule-3 (sICAM-3) and thrombomodulin by ELISA. RESULTS: Sixteen case subjects and 18 control subjects consented participation. The median time interval index pregnancy to study was 9.4 and 9.7 years for cases and controls, respectively. Median levels for cases-controls (p-value) were not different; bFGF: 17.43-11.11 pg/mL (0.33), sFlt-1: 102.98-101.92 pg/ml (0.84), PLGF: 3.57-4.20 pg/mL (0.38), VEGF: 64.05-45.72 pg/mL (0.73), E-selectin: 5.11-4.68 ng/mL (0.20), P-selectin: 85.35-71.69 ng/mL (0.69), sICAM-3: 0.42-0.63 ng/mL (0.41) and Thrombomodulin: 0.92-0.93 ng/mL (0.59). CONCLUSION: There were no differences in angiogenic biomarkers between women with a history of severe early onset preeclampsia versus uncomplicated pregnancy almost 10 years later, suggesting that these angiogenic factors will not contribute to the early detection of women at risk for future cardiovascular disease.

E-selectin is elevated in cord blood of South Asian neonates compared with Caucasian neonates.

OBJECTIVE: To test the hypothesis that the increased risk of type 2 diabetes mellitus and coronary artery disease in South Asian subjects could be caused by the presence of endothelial dysfunction in early life. We studied markers of endothelial dysfunction in umbilical cord blood of South Asian neonates and compared these with that of Caucasian control subjects. STUDY DESIGN: From South Asian (n = 57) and Caucasian (n = 21) neonates, cord blood was collected and levels of glucose, insulin, lipids, and markers of endothelial dysfunction (E-selectin, intercellular adhesion molecule 1, vascular cell adhesion molecule 1) and inflammation (C-reactive protein) were measured. RESULTS: Plasma E-selectin levels were significantly higher in South Asian neonates (46.7 versus 33.5 ng/mL, P < .001), and levels of intercellular adhesion molecule 1 and vascular cell adhesion molecule 1 did not differ. Furthermore, South Asian neonates had hyperinsulinemia (P = .043), dyslipidemia (with significantly higher triglyceride and lower high-density lipoprotein cholesterol levels), and higher C-reactive protein levels (75.7 versus 43.8 ng/mL, P = .009). CONCLUSIONS: South Asian newborns are characterized by elevated E-selectin levels in line with the hypothesis that endothelial dysfunction is present early in life. In addition, hyperinsulinemia, dyslipidemia, and inflammation are present. Because many pathogenic variables for coronary artery disease and type 2 diabetes are already present at birth in South Asian patients, the question arises whether rigorous childhood lifestyle intervention could be beneficial.

Automatic lumen and outer wall segmentation of the carotid artery using deformable three-dimensional models in MR angiography and vessel wall images.

PURPOSE: To develop and validate an automated segmentation technique for the detection of the lumen and outer wall boundaries in MR vessel wall studies of the common carotid artery. MATERIALS AND METHODS: A new segmentation method was developed using a three-dimensional (3D) deformable vessel model requiring only one single user interaction by combining 3D MR angiography (MRA) and 2D vessel wall images. This vessel model is a 3D cylindrical Non-Uniform Rational B-Spline (NURBS) surface which can be deformed to fit the underlying image data. Image data of 45 subjects was used to validate the method by comparing manual and automatic segmentations. Vessel wall thickness and volume measurements obtained by both methods were compared. RESULTS: Substantial agreement was observed between manual and automatic segmentation; over 85% of the vessel wall contours were segmented successfully. The interclass correlation was 0.690 for the vessel wall thickness and 0.793 for the vessel wall volume. Compared with manual image analysis, the automated method demonstrated improved interobserver agreement and inter-scan reproducibility. Additionally, the proposed automated image analysis approach was substantially faster. CONCLUSION: This new automated method can reduce analysis time and enhance reproducibility of the quantification of vessel wall dimensions in clinical studies.

Hepatocyte-specific IKKß expression aggravates atherosclerosis development in APOE*3-Leiden mice.

OBJECTIVE: The liver is the key organ involved in systemic inflammation, but the relation between hepatic inflammation and atherogenesis is poorly understood. Since nuclear factor-κB (NF-κB) is a central regulator of inflammatory processes, we hypothesized that chronically enhanced hepatic NF-κB activation, through hepatocyte-specific expression of IκB kinase-ß (IKKß) (LIKK), will aggravate atherosclerosis development in APOE*3-Leiden (E3L) mice. METHODS AND RESULTS: E3L.LIKK and E3L control littermates were fed a Western-type diet for 24 weeks. E3L.LIKK mice showed a 2.3-fold increased atherosclerotic lesion area and more advanced atherosclerosis in the aortic root with less segments without atherosclerotic lesions (11% vs. 42%), and more segments with mild (63% vs. 44%) and severe (26% vs. 14%) lesions. Expression of LIKK did not affect basal levels of inflammatory parameters, but plasma cytokine levels tended to be higher in E3L.LIKK mice after lipopolysaccharide (LPS) administration. E3L.LIKK mice showed transiently increased plasma cholesterol levels, confined to (V)LDL. This transient character resulted in a mild (+17%) increased cumulative plasma cholesterol exposure. CONCLUSION: We conclude that selective activation of NF-κB in hepatocytes considerably promotes atherosclerosis development which is (at least partly) explained by an increased sensitivity to proinflammatory triggers and transiently increased plasma cholesterol levels.

Effect of lifestyle intervention plus rosiglitazone or placebo therapy on left ventricular mass assessed with cardiovascular magnetic resonance in the metabolic syndrome.

BACKGROUND: To evaluate the effect of lifestyle intervention in conjunction with rosiglitazone or placebo therapy on left ventricular (LV) mass, using cardiovascular magnetic resonance (CMR) in the metabolic syndrome. METHODS: The present study was a pre-specified substudy of a double-blind randomized controlled trial evaluating the effect of lifestyle intervention in conjunction with rosiglitazone or placebo therapy on carotid artery atherosclerosis in the metabolic syndrome. From this original study population, 10 subjects from the placebo group and 10 from the rosiglitazone group were randomly selected. At baseline and follow-up (52 weeks), clinical and laboratory measurements were assessed and a CMR-examination was performed to evaluate LV mass indexed for body surface area (LV mass-I). Subsequently, the effect of therapy (rosiglitazone vs. placebo) and clinical and laboratory variables on LV mass-I was evaluated. RESULTS: In both groups, body mass index, waist circumference, systolic and diastolic blood pressure significantly decreased during follow-up. Interestingly, LV mass-I significantly decreased in the placebo group (48.9 ± 5.3 g/m2 vs. 44.3 ± 5.6 g/m2, p < 0.001) indicating reverse remodeling, whereas LV mass-I remained unchanged in the rosiglitazone group (54.7 ± 9.9 g/m2 vs. 53.7 ± 9.2 g/m2, p = 0.3). After correction for systolic and diastolic blood pressure and triglyceride, the kind of therapy (rosiglitazone vs. placebo) remained the only significant predictor of LV mass-I reduction. CONCLUSIONS: Lifestyle intervention resulted in a reduction of LV mass-I in the metabolic syndrome, indicating reverse remodeling. However, rosiglitazone therapy may have inhibited this positive reverse remodeling. TRIAL REGISTRATION: Current Controlled Trials ISRCTN54951661.