Bariatric surgery prevents carotid wall thickness progression.

BACKGROUND: Bariatric surgery is a treatment option for patients with severe obesity and improves parameters of cardiovascular and/or metabolic disease. Carotid intima media thickness (C-IMT) is a surrogate measure of subclinical atherosclerosis. Previous studies showed short to mid-term arrest and even regression of C­IMT progression following bariatric surgery. We aimed to investigate the long-term effect of weight loss on C­IMT progression 10 years after bariatric surgery in comparison to a population-based control cohort. METHODS: In total, 21 eligible patients were examined preoperatively, at 5 and 10 years after bariatric surgery. Anthropometric parameters, plasma triglycerides, total cholesterol, high-density lipoprotein cholesterol (HDL-C), insulin, and glucose were assessed at all three study visits. C­IMT was measured via B­mode scans of the common carotid artery. C­IMT progression was measured in an age-matched and BMI-matched cohort selected from the population-based Bruneck study to compare with changes in C­IMT progression after bariatric surgery. RESULTS: C­IMT remained stable over the 10-year observation period after bariatric surgery. The control cohort showed a significant C­IMT progression over 10 years. The difference in C­IMT progression over 10 years was significant (p < 0.01) between both cohorts. CONCLUSION: Weight loss induced by bariatric surgery halts the natural progression of C­IMT over a 10-year observation period.

Postprandial endothelial dysfunction and CIMT after oral fat challenge in patients with type 2 diabetes mellitus with and without macrovascular disease - A preliminary study.

BACKGROUND: Very few studies have reported on association of postprandial lipids and endothelial dysfunction among patients with diabetes. Whether endothelial dysfunction particularly postprandial FMD is worse in patients with T2DM with macrovascular disease compared to those without and whether this difference is related to postprandial hypertriglyceridemia (PPHTg) is unclear. Therefore, present study was aimed to assess the relationship between PPHTg and endothelial function in patients with T2DM with and without macrovascular disease. METHOD: Endothelial dysfunction by FMD and CIMT were compared in patients with T2DM with and without macrovascular disease (n = 13 each group) and 13 age, sex and BMI matched healthy individuals after an oral fat challenge. RESULTS: There was significant postprandial deterioration of FMD 4-hr after fat challenge in patients with diabetes (P < 0.001) as well as healthy individuals (P = 0.004). Patients with diabetes with macrovascular disease had significantly lower fasting (5.7 ± 6.1% vs. 22.7 ± 10.0% and vs. 24.7 ± 5.3%) as well as postprandial (4-hr) (3.1 ± 5.0% vs. 15.3 ± 8.1% and vs. 15.4 ± 5.7%) FMD compared to other two groups. Fasting, postprandial as well as change in FMD and CIMT in patients with diabetes correlated significantly with fasting as well as postprandial triglycerides with stronger correlation in those with macrovascular disease. CONCLUSION: Study found significant endothelial dysfunction by FMD that shows substantial further deterioration postprandially following high fat meal in patients with diabetes with macrovascular disease compared to patients with diabetes without macrovascular disease and healthy individuals. Study also indicates that PPHTg is a contributor to endothelial dysfunction. However, more studies are required to corroborate these findings.

Early life factors and their relevance to intima-media thickness of the common carotid artery in early adulthood.

BACKGROUND: Early life factors may predispose an offspring to cardiovascular disease in later life; relevance of these associations may extend to ?healthy" people in Western populations. We examined the prospective associations between early life factors and adult carotid intima-media thickness (IMT), a surrogate marker of atherosclerosis, in a healthy German population. METHODS: We studied term participants (n = 265) of the DONALD Study, with bilateral sonographic measurements of IMT (4-8 measurements on both left and right carotid artery) at age 18-40 years and prospectively collected data on early life factors (maternal and paternal age at child birth, birth weight, gestational weight gain and full breastfeeding (>17weeks). Mean IMT values were averaged from mean values of both sides. Associations between early life factors and adult IMT were analyzed using multivariable linear regression models with adjustment for potential confounders. RESULTS: Adult mean IMT was 0.56mm, SD 0.03, (range: 0.41 mm-0.78 mm). Maternal age at child birth was of relevance for adult IMT, which was sex specific: Advanced maternal age at child birth was associated with an increased adult IMT among female offspring only (ß 0.03, SE 0.009 mm/decade, P = 0.003), this was not affected by adult waist circumference, BMI or blood pressure. Other early life factors were not relevant for IMT levels in males and females. CONCLUSION: This study suggests that advanced maternal age at child birth is of prospective relevance for adult IMT levels in a healthy German population and this association may be of adverse relevance for females only.

Similar progression of carotid intima-media thickness in 7-year surveillance of patients with mild SLE and controls, but this progression is still promoted by dyslipidaemia, lower HDL levels, hypertension, history of lupus nephritis and a higher prednisolone usage in patients.

Objective: To compare progression of subclinical atherosclerosis and factors promoting it in patients with SLE and controls. Methods: Consecutive patients with SLE and age-matched, sex-matched population controls from the SLEVIC cohort were assessed at inclusion and after 7 years with standardised data collection and carotid ultrasound. Effect of risk factors on carotid intima-media thickness (cIMT) progression was examined with adjusted linear mixed models. Results: A total of 77 patients and 74 controls, 68% and 61% of the original cohort, completed follow-up. The patients were (mean) 47 years old, 90% were women, and controls were 51 years old, 92% women. Patients had disease duration of (mean) 11 years, mild disease activity and low severity at both assessments. Baseline cIMT did not differ between the groups. An average absolute cIMT progression was 0.009 mm/year in patients and 0.011 mm/year in controls, intergroup difference p=0.9.Of factors at inclusion, dyslipidaemia, lower levels of high-density lipoprotein (HDL) and carotid plaque in patients and controls, and higher systolic blood pressure, total cholesterol:HDL and LDL:HDL ratios and triglycerides in patients were associated with cIMT progression. Of factors at follow-up, hypertension and blood lipids in patients and HDL in controls were significantly associated with cIMT progression. History of lupus nephritis and a higher average dose of prednisolone used since diagnosis were associated with cIMT progression in patients. Associations of risk factors with cIMT progression were stronger in presence of plaques. Conclusion: We observed a statistically comparable progression of cIMT in patients with mild SLE and controls over 7 years, which implies that progression of subclinical atherosclerosis in some patients with SLE could follow that of the general population. Traditional cardiovascular (CV) risk factors, history of lupus nephritis and higher use of corticosteroids promote cIMT progression in SLE. Detection of carotid plaque may add to CV risk stratification.

The Impact of Past and Current Alcohol Consumption Patterns on Progression of Carotid Intima-Media Thickness Among Women and Men Living with HIV Infection.

BACKGROUND: The relationship between alcohol consumption and atherosclerosis has not been sufficiently examined among people living with HIV (PLWH). METHODS: We analyzed data from PLWH in the Women's Interagency HIV Study (WIHS; n = 1,164) and the Multicenter AIDS Cohort Study (MACS; n = 387) with no history of cardiovascular disease (CVD). Repeated measures of intima-media thickness of the right common carotid artery (CCA-IMT) were assessed using B-mode ultrasound from 2004 to 2013. Current alcohol consumption was collected at time of CCA-IMT measurement and was categorized according to gender-specific weekly limits. Group-based trajectory models categorized participants into past 10-year consumption patterns (1994 to 2004). Multivariate generalized estimating equations were conducted to assess the association of past and current alcohol use patterns on change in CCA-IMT by cohort, controlling for age, race, cigarette and illicit drug use, probable depression, HIV RNA viral load, antiretroviral therapy exposure, and hepatitis C coinfection. RESULTS: Among the WIHS, past heavy alcohol consumption was associated with increased CCA-IMT level over time (ß = 8.08, CI 0.35, 15.8, p = 0.04), compared to abstinence. Among the MACS, compared to abstinence, all past consumption patterns were associated with increased CCA-IMT over time (past low: ß = 15.3, 95% CI 6.46, 24.2, p < 0.001; past moderate: ß = 14.3, CI 1.36, 27.2, p = 0.03; past heavy: ß = 21.8, CI 4.63, 38.9, p = 0.01). Current heavy consumption was associated with decreased CCA-IMT among the WIHS (ß = -11.4, 95% CI -20.2, -2.63, p = 0.01) and MACS (ß = -15.4, 95% CI -30.7, -0.13, p = 0.04). No statistically significant time by consumption pattern effects were found. CONCLUSIONS: In both cohorts, 10-year heavy consumption was associated with statistically significant increases in carotid artery thickness, compared to abstinence. Long-term patterns of drinking at any level above abstinence were particularly significant for increases in IMT among men, with heavy consumption presenting with the greatest increase. Our results suggest a potentially different window of risk among past and current heavy drinkers. Further studies are needed to determine whether alcohol consumption level is associated with intermediate measures of atherosclerosis. Alcohol screening and interventions to reduce heavy consumption may benefit PLWH who are at risk of CVD.

Sleep quality correlates with the carotid intima-media thickness in stroke-free community-dwelling adults living in rural Ecuador. The Atahualpa Project.

BACKGROUND/OBJECTIVES: Evidence of an association between sleep disorders and extracranial atherosclerosis is limited and has not been studied in remote rural settings, where living conditions and cardiovascular risk factors are different than in urban centers. We assessed the relationship between the carotid intima-media thickness (cIMT) and sleep quality in stroke-free individuals aged ≥40 years living in rural Ecuador. METHODS: Applying a population-based study design, participants underwent face-to-face interviews using the Pittsburgh Sleep Quality Index (PSQI) to assess sleep quality, and sonographic examinations for measurement of the carotid intima-media thickness (cIMT). The association between the cIMT and sleep quality (as the dependent variable) was assessed by means of generalized linear models, adjusted for relevant confounders. RESULTS: The mean age of 561 participants was 60.4 ± 12.6 years (58% women). The mean PSQI was 4.6 ± 2.2 points. Of those, 79 (14%) individuals had an increased cIMT (>1 mm). A model adjusted for demographics showed a significant association between increased cIMT and the PSQI score (ß: 0.602; 95% C.I.: 0.027-1.177; p = 0.040). This relationship was reduced when cardiovascular risk factors were added to the model (ß: 0.514; 95% C.I.: -0.072 - 1.101; p = 0.086). When the model was adjusted for demographics and psychological distress, the association between increased cIMT and the PSQI score became significant (ß: 0.573; 95% C.I.: 0.013-1.133; p = 0.045). In addition, both symptoms of depression (p = 0.032) and anxiety (p < 0.001) remained independently significant. CONCLUSIONS: This study shows an association between increased cIMT and the PSQI score, which is, at least, partly mediated by manifestations of psychological distress.

Early and late childhood telomere length predict subclinical atherosclerosis at age 14 yrs. - The CardioCAPS study.

INTRODUCTION: Carotid Intima Media Thickness (CIMT) is a marker of subclinical atherosclerosis, associated with cardiovascular risk in adults. Telomere length (TL) is a marker of cellular ageing. We sought to determine whether telomere length in early childhood and/or at 14-years is associated with CIMT in adolescence, in a community-based cohort study. METHODS: 118 children had TL measured at mean age 3.6-years and 165 children had TL and CIMT, measured at 14-years, from the community-based Childhood Asthma Prevention Study. RESULTS: TL in early childhood was significantly inversely associated with CIMT at 14 years, p = 0.04. TL in teenage life was also significantly inversely associated with CIMT at 14 years, p = 0.03. This latter association was no longer significant, however, after adjusting for early life TL. CONCLUSION: TL measured in early childhood and adolescence is significantly associated with CIMT at 14-years, suggesting that telomere length is a biological marker or even early determinant of late cardiovascular risk.

Associations of sclerostin with carotid artery atherosclerosis and all-cause mortality in Chinese patients undergoing maintenance hemodialysis.

BACKGROUND: Previous clinical studies found inconsistent relationship between circulating sclerostin levels and treatment outcome in patients undergoing maintenance hemodialysis (MHD). Therefore, this study aimed to assess the associations of sclerostin with carotid artery atherosclerosis and all-cause mortality in Chinese patients undergoing MHD. METHODS: This retrospective study assessed 84 patients undergoing MHD at the Nephrology Department of Beijing Hospital from January to April 2012, with a median follow-up of 61.2 months (range: 11.5 to 63 months). Carotid artery intima-media thicknesses (CIMTs) and atherosclerotic plaques were measured by B-mode Doppler ultrasound at baseline. Blood samples were collected for measuring serum sclerostin and soluble klotho (s-klotho) levels. The associations of sclerostin levels with carotid artery atherosclerosis was evaluated by correlation methods. Predictive factors of mortality were assessed by multivariate COX regression. RESULTS: Baseline serum sclerostin averaged 162.01 pmol/L, with an interquartile range of 121.69 to 225.22 pmol/L, while CIMT values were 1.35 ± 0.39 mm. Carotid artery atherosclerotic plaques were detected in 68 subjects (81%). Subjects with sclerostin levels above the median value had higher CIMT (p = 0.038) and higher prevalence of atherosclerotic plaque (p = 0.025). During follow-up, 27 patients died; Kaplan-Meier curves indicated that subjects with high sclerostin levels (above the median value at baseline) had shorter survival (log rank p = 0.011). In multivariate COX regression analysis, serum sclerostin (HR, 1.095; 95% confidence interval [CI] 1.022-1.174, p = 0.010) and albumin (HR, 0.742; 95%CI 0.612-0.900, p = 0.002) levels were independent predictors of all-cause mortality. CONCLUSIONS: Sclerostin is positively associated with CIMT. In addition, patients with low baseline serum sclerostin undergoing MHD show better survival.

Comparison of carotid plaque burden among healthy middle-aged men living in the US, Japan, and South Korea.

BACKGROUND: Carotid plaque has emerged as a marker of coronary heart disease (CHD) risk. Comparison of carotid plaque burden between different race/ethnic groups may provide a relative estimate of their future CHD risk. METHODS: We conducted a population-based study among apparently healthy middle-aged men aged 40-49 years (ERA JUMP study (n = 924)) and recruited 310 Whites in Pittsburgh, US, 313 Japanese in Otsu, Japan, and 301 Koreans in Ansan, South Korea. The number of carotid plaque and CHD risk factors was assessed using a standardized protocol across all centers. The burden of carotid plaque was compared between race/ethnic groups after adjustment for age and BMI, and after multivariable adjustment for other CHD risk factors using marginalized zero-inflated Poisson regression models. Cross-sectional associations of risk factors with plaque were examined. RESULTS: Whites (22.8%) had more than four-fold higher prevalence (p < 0.01) of carotid plaque than Japanese men (4.8%) while the prevalence among Koreans was 10.6%. These differences remained significant after adjustment for age, BMI as well as other risk factors - incidence density ratio (95% confidence interval) for plaque was 0.13 (0.07, 0.24) for Japanese and 0.32 (0.18, 0.58) for Koreans as compared to Whites. Age, hypertension and diabetes were the only risk factors significantly associated with presence of carotid plaque in the overall population. CONCLUSION: Whites have significantly higher carotid plaque burden than men in Japan and Korea. Lower carotid plaque burden among Japanese and Koreans is independent of traditional CVD risk factors.

Cross-sectional and longitudinal associations between serum uric acid and endothelial function in subjects with treated hypertension.

OBJECTIVES: The endothelial dysfunction-arterial stiffness-atherosclerosis continuum plays an important pathophysiological role in hypertension. The aim of this study was to investigate the cross-sectional association between serum uric acid (SUA) and vascular markers related to this continuum, and to assess the longitudinal association between SUA and endothelial function that represents the initial step of the continuum. METHODS: We evaluated the baseline associations between SUA levels and vascular markers that included flow-mediated vasodilatation (FMD), brachial-ankle pulse wave velocity (baPWV), and common carotid artery intima-media thickness (CCA-IMT) in 648 subjects receiving antihypertensive treatment. The longitudinal association between baseline SUA levels and FMD measured at 1.5 and 3 yr of follow-up was also investigated. RESULTS: At baseline, modest, but significant correlations were observed between SUA and FMD in females (r = -0.171), baPWV in males with SUA >368.78 µmol/L (r = -0.122) and in females with a SUA level ≤ 362.83 µmol/L (r = 0.217), mean CCA-IMT in females with a SUA level ≤ 333.09 µmol/L (r = 0.139), and max CCA-IMT in females with SUA level ≤ 333.09 µmol/L (r = 0.138). A longitudinal association between SUA and FMD was less observed in males. In females, the baseline SUA was associated significantly with FMD values at 1.5 yr (r = -0.211), and SUA levels >237.92 µmol/L were associated significantly and independently with FMD values at 3 yr (r = -0.166). CONCLUSIONS: Lower SUA levels were associated with better vascular markers of the continuum, especially in females. Furthermore, we observed a longitudinal association between SUA and endothelial function, suggesting SUA level may be a potential marker of the continuum in hypertension.

Relationship between Syntax Score and prognostic localization of coronary artery lesions with conventional risk factors, plasma profile markers, and carotid atherosclerosis (CAPP Study 2).

BACKGROUND: Data concerning the relationship between cardiovascular risk factors, plasmatic markers, carotid disease and extent of coronary lesions are lacking. OBJECTIVES: To evaluate the role of cardiovascular risk factors, plasmatic levels of high sensitivity C-reactive protein (hs-CRP), fibrinogen, lipoprotein(a), and carotid plaque extension in predicting the severity of coronary artery disease (CAD). METHODS: We analyzed 574 subjects undergoing first coronary angiography. For angiographic analysis, we used the Syntax Score and we defined the prognostic localization of CAD as a critical stenosis of the left main and/or proximal segment of left anterior descending artery. Levels of hs-CRP >3mg/L, lipoprotein(a) plasma levels >30mg/dL and plasma fibrinogen >300mg/dL were considered critical. Significant carotid disease (SCD) was defined by the presence of lesions producing a 50% diameter stenosis with a peak systolic velocity >125cm/s. A mean carotid intima media thickness (IMT) >0.9mm was considered abnormal. RESULTS: In the adjusted analysis the presence of SCD was found to be an independent predictor of high Syntax Score (p<0.001), while high fibrinogen levels were independently associated with the presence of CAD in prognostic localization (p=0.04). In the sub-group of patients without SCD, IMT >0.9mm was found to be an independent predictor of the presence of CAD (p<0.001). CONCLUSIONS: SCD strongly predicts high Syntax Score, while IMT shows excellent positive predictive value for the presence of CAD. In addition, high plasma fibrinogen levels are associated with coronary stenoses in prognostic localization.

Uric Acid, Metabolic Syndrome and Atherosclerosis: The Chicken or the Egg, Which Comes First?

BACKGROUND: A great debate in literature exists nowadays on the role of uric acid as a marker of cardiovascular and metabolic organ damage or a risk factor for cardiovascular and metabolic disease. METHODS: The study aimed to determine the relationship among serum uric acid and metabolic syndrome and atherosclerosis, by means of carotid intima media-thickness, in a cohort of 811 otherwise healthy overweight/obese subjects, without overt atherosclerosis not using any kind of drug. RESULTS: Uric acid levels were positively related to male gender, waist circumference, BMI, systolic and diastolic pressure levels, fasting insulin, fasting glucose, HOMA-IR, triglycerides, total cholesterol, LDL cholesterol, the presence of metabolic syndrome and the number of the components of metabolic syndrome and negatively related to HDL cholesterol levels. No correlation was found between uric acid and carotid intima media thickness. At the multiple regression analysis, only waist circumference and triglycerides (positively) and HDL-cholesterol (negatively) maintained an independent association with uric acid as dependent variable, while age, female gender and uric acid showed a significant independent association with metabolic syndrome as dependent variable. Moreover, the analysis of the odd ratios showed that the risk of developing metabolic syndrome was consistent with uric acid levels ranging from 3 mg/dl to 8 mg/dl. CONCLUSION: The presence of metabolic syndrome does not seem to provide hyperuricemia. By contrast, higher serum uric acid level may predict the risk of metabolic syndrome. Moreover, our results suggest that uric acid cannot be considered a risk factor for early atherosclerosis, at least when assessed using carotid ultrasound.

Longitudinal association among endothelial function, arterial stiffness and subclinical organ damage in hypertension.

OBJECTIVES: To examine the longitudinal mutual association between endothelial dysfunction and arterial stiffness, and also to determine which of the two variables was more closely associated with the progression of subclinical organ damage. METHODS: The brachial-ankle pulse wave velocity (baPWV), carotid intima-media thickness (CIMT), estimated glomerular filtration rate, microalbuminuria and flow-mediated vasodilatation of the brachial artery (FMD) were measured three times at 1.5-year intervals in 674 Japanese patients receiving antihypertensive treatment. RESULTS: The change of the baPWV during the study period was larger in the subjects with baseline FMD values in the lowest tertile as compared to those with baseline FMD values in the highest tertile. The change of the CIMT was smaller in the subjects with baseline baPWV values in the lowest tertile than in those with baseline baPWV values in the highest tertile. After the adjustment, the FMD value at the baseline was inversely associated with the baPWV at the end of the study period (beta=-0.07, p=0.01), although, the reverse association was not significant. The baPWV, but not the FMD value, at the baseline was associated with the CIMT (beta=0.06, p=0.04) measured at the end of the study period. CONCLUSIONS: In hypertension, endothelial dysfunction was associated with the progression of arterial stiffness, although the reverse association was not confirmed. The increased arterial stiffness rather than endothelial dysfunction may be more closely associated with the progression of atherosclerotic vascular damage, and the endothelial dysfunction-arterial stiffness-atherosclerosis continuum may be important in hypertension.

Circulating lipopolysaccharide-binding protein and carotid intima-media thickness in obstructive sleep apnea.

Circulating lipopolysaccharide-binding protein (LBP), a metabolic endotoxemia marker, was identified as an independent predictor of atherosclerosis. Although increases in carotid intima-media thickness (CIMT) were repeatedly reported in obstructive sleep apnea (OSA), neither the role of OSA in metabolic endotoxemia nor of LBP in early atherosclerosis were explored in patients with OSA. At a tertiary university hospital we investigated the relationships between OSA, LBP and CIMT in 117 men who underwent full polysomnography and CIMT assessment by B-mode ultrasound. Circulating LBP concentrations and average CIMT increased from patients without OSA to those with mild-moderate and severe OSA (from 32.1+/-10.3 to 32.3+/-10.9 to 38.1+/-10.3 microg.ml(-1), p=0.015; from 0.52+/-0.09 to 0.58+/-0.06 to 0.62+/-0.10 mm, p=0.004, respectively). Oxygen desaturation index (ODI) was a predictor of serum LBP levels independent of age, waist-to-hip ratio (WHR), smoking, hypertension, HDL cholesterol, triglycerides and fasting glucose [p (ANOVA)=0.002, r(2)=0.154], with no independent effect of the ODI*WHR interaction term on LBP. Furthermore, serum LBP predicted CIMT independently of known risk factors of atherosclerosis including obesity (p<0.001, r(2)=0.321). Our results suggest that OSA severity contributes to metabolic endotoxemia in patients with OSA independently of obesity, and that LBP might represent a contributing factor promoting early atherosclerosis in such patients.

Cardiovascular risk factors and carotid intima media thickness in young adults born small for gestational age after cessation of growth hormone treatment: a 5-year longitudinal study.

BACKGROUND: Growth hormone treatment reduces blood pressure and lipid concentrations. We assessed long-term changes in blood pressure, lipid concentrations, and carotid intima media thickness over a 5-year period after cessation of growth hormone treatment in adults born small for gestational age. METHODS: We did a longitudinal observational study at a medical centre in the Netherlands between April 1, 2004, and April 1, 2016. We included adults born small for gestational age who were treated with growth hormone (1 mg/m2 per day); treatment started during childhood until adult height. Participants were evaluated at cessation of treatment, and 6 months, 2 years, and 5 years later. We compared cardiovascular risk factors with untreated controls from the PROGRAM study. FINDINGS: We included 199 participants born small for gestational age and treated with growth hormone along with 285 controls: 51 untreated short adults born small for gestational age, 92 untreated adults born small for gestational age with spontaneous catch-up growth, and 142 adults born appropriate for gestational age. In the 6 months after treatment cessation, systolic blood pressure increased temporarily from 113·00 mm Hg (95% CI 111·18-114·82) to 116·92 mm Hg (115·07 to 118·77; p<0·001) and diastolic blood pressure increased temporarily from 62·19 mm Hg (60·99-63·38) to 66·51 mm Hg (65·14-67·89; p<0·001). At 5 years after treatment cessation, mean systolic blood pressure was 109·2 mm Hg (105·5-113·0) and mean diastolic blood pressure was 63·4 mm Hg (60·9-65·9), similar to the values at cessation. Lipid concentrations were non-significantly higher 5 years after treatment cessation (p values 0·09-0·21) than at treatment cessation. Cessation of growth hormone had no effect on carotid intima media thickness. At 5 years after cessation, total cholesterol was lower in adults treated with growth hormone (mean 4·21 mmol/L, 95% CI 4·04-4·38) than in untreated short adults born small for gestational age (4·66 mmol/L, 4·42-4·92; p=0·0030), as was mean LDL cholesterol (2·28 mmol/L, 2·14-2·43 vs 2·85 mmol/L, 2·62-3·10; p<0·0001); blood pressure and carotid intima media thickness did not differ between these two groups (p values >0·12). At 5 years after cessation, systolic blood pressure, diastolic blood pressure, lipid concentrations, and carotid intima media thickness of adults treated with growth hormone were not different to those in adults born small for gestational age who had spontaneous catch-up growth or adults born appropriate for gestational age. INTERPRETATION: Long-term growth hormone treatment in children born small for gestational age has no unfavourable effects on cardiovascular health in early adulthood and improves lipid profiles. FUNDING: Novo Nordisk (Netherlands).

Associations between the effort-reward imbalance model of workplace stress and indices of cardiovascular health: A systematic review and meta-analysis.

Work stress can increase the risk of cardiovascular disease by 50%, with increasing research focusing on the underlying mechanisms responsible for these associations. Our meta-analysis assessed the associations of the effort-reward imbalance (ERI) workplace stress model with indices of cardiovascular disease. The search term 'effort*reward*imbalance' produced 22 papers (129 associations, N=93,817) meeting inclusion criteria. Greater ERI was most associated with increased hypertension (r=0.26, p<0.001, N=1180), intima media thickness (r=0.23, p<.001, N=828) and fibrinogen (r=0.13, p=0.03, N=4315). Trait over-commitment was most associated with increased hypertension (r=0.24, p=0.02, N=899) and intima media thickness (r=0.19, p=0.02, N=828). Interventions aimed at reducing the impact of ERI and over-commitment on cardiovascular disease should consider concurrently assessing changes in physiological markers of cardiovascular disease.

Characterization of intravascular cellular activation in relationship to subclinical atherosclerosis in postmenopausal women.

OBJECTIVE: Mechanisms and interactions among intravascular cells contributing to development of subclinical atherosclerosis are poorly understood. In women, both menopausal status and pregnancy history influence progression of atherosclerosis. This study examined activation and interactions among blood elements with subclinical atherosclerosis in menopausal women with known pregnancy histories. METHODS: Carotid intima-media thickness (CIMT), as a marker of subclinical atherosclerosis, was measured using B-mode ultrasound in age- and parity-matched women [40 with and 40 without a history of preeclampsia] 35 years after the index pregnancy. Interactions among intravascular cells (38 parameters) were measured by flow cytometry in venous blood. Data analysis was by principal component which retained 7 independent dimensions accounting for 63% of the variability among 38 parameters. RESULTS: CIMT was significantly greater in women with a history of preeclampsia (P = 0.004). Platelet aggregation and platelet interactions with granulocytes and monocytes positively associated with CIMT in postmenopausal women independent of their pregnancy history (ρ = 0.258, P< 0.05). However, the association of the number of platelets, platelet activation and monocyte-platelet interactions with CIMT differed significantly depending upon pregnancy history (test for interaction, P<0.001). CONCLUSION: Interactions among actived intravascular cells and their association with subclinical atherosclerosis differ in women depending upon their pregnancy histories.

Surgical and pharmacological reassignment: influence on transsexual cardiovascular risk profile.

BACKGROUND/AIM: To evaluate and stratify early cardiovascular risk of transsexuals who underwent pharmacological and/or surgical gender reassignment. METHODS: Fifty-six transsexuals were divided into two groups: group 1 - underwent gonadectomy (orchiectomy for transwomen and hystero-annessiectomy for transmen); group 2 - hormone replacement therapy alone. All participants underwent carotid artery intima-media thickness (C-IMT) and flow-mediated vasodilation (FMD) of brachial artery evaluations. RESULTS: FMD was lower in patients who had undergone gonadectomy compared with non-surgically treated patients (Group 1: 5.711 vs Group 2: 7.339, P < 0.0001). Mean C-IMT was higher in group 1 than group 2 (group 1: 0.733 vs group 2: 0.582). The duration of hormone therapy correlates positively with mean C-IMT (B = 0.001) and negatively with FMD (%) (B = - 0.007). CONCLUSIONS: Cardiovascular risk, which is expressed in terms of endothelial (FMD) and morphological (C-IMT) dysfunction, increases in subjects undergoing gonadectomy compared with those receiving cross-sex reassignment therapy alone.

A Cytokine-Like Protein Dickkopf-Related Protein 3 Is Atheroprotective.

BACKGROUND: Dickkopf-related protein 3 (DKK3) is a secreted protein that is involved in the regulation of cardiac remodeling and vascular smooth muscle cell differentiation, but little is known about its role in atherosclerosis. METHODS: We tested the hypothesis that DKK3 is atheroprotective using both epidemiological and experimental approaches. Blood DKK3 levels were measured in the Bruneck Study in 2000 (n=684) and then in 2005 (n=574). DKK3-deficient mice were crossed with apolipoprotein E-/- mice to evaluate atherosclerosis development and vessel injury-induced neointimal formation. Endothelial cell migration and the underlying mechanisms were studied using in vitro cell culture models. RESULTS: In the prospective population-based Bruneck Study, the level of plasma DKK3 was inversely related to carotid artery intima-media thickness and 5-year progression of carotid atherosclerosis independently from standard risk factors for atherosclerosis. Experimentally, we analyzed the area of atherosclerotic lesions, femoral artery injury-induced reendothelialization, and neointima formation in both DKK3-/-/apolipoprotein E-/- and DKK3+/+/apolipoprotein E-/- mice. It was demonstrated that DKK3 deficiency accelerated atherosclerosis and delayed reendothelialization with consequently exacerbated neointima formation. To explore the underlying mechanisms, we performed transwell and scratch migration assays using cultured human endothelial cells, which exhibited a significant induction in cell migration in response to DKK3 stimulation. This DKK3-induced migration activated ROR2 and DVL1, activated Rac1 GTPases, and upregulated JNK and c-jun phosphorylation in endothelial cells. Knockdown of the ROR2 receptor using specific siRNA or transfection of a dominant-negative form of Rac1 in endothelial cells markedly inhibited cell migration and downstream JNK and c-jun phosphorylation. CONCLUSIONS: This study provides the evidence for a role of DKK3 in the protection against atherosclerosis involving endothelial migration and repair, with great therapeutic potential implications against atherosclerosis.

Association of Vegetable Nitrate Intake With Carotid Atherosclerosis and Ischemic Cerebrovascular Disease in Older Women.

BACKGROUND AND PURPOSE: A short-term increase in dietary nitrate (NO3-) improves markers of vascular health via formation of nitric oxide and other bioactive nitrogen oxides. Whether this translates into long-term vascular disease risk reduction has yet to be examined. We investigated the association of vegetable-derived nitrate intake with common carotid artery intima-media thickness (CCA-IMT), plaque severity, and ischemic cerebrovascular disease events in elderly women (n=1226). METHODS: Vegetable nitrate intake, lifestyle factors, and cardiovascular disease risk factors were determined at baseline (1998). CCA-IMT and plaque severity were measured using B-mode carotid ultrasound (2001). Complete ischemic cerebrovascular disease hospitalizations or deaths (events) over 14.5 years (15 032 person-years of follow-up) were obtained from the West Australian Data Linkage System. RESULTS: Higher vegetable nitrate intake was associated with a lower maximum CCA-IMT (B=-0.015, P=0.002) and lower mean CCA-IMT (B=-0.012, P=0.006). This relationship remained significant after adjustment for lifestyle and cardiovascular risk factors (P≤0.01). Vegetable nitrate intake was not a predictor of plaque severity. In total 186 (15%) women experienced an ischemic cerebrovascular disease event. For every 1 SD (29 mg/d) higher intake of vegetable nitrate, there was an associated 17% lower risk of 14.5-year ischemic cerebrovascular disease events in both unadjusted and fully adjusted models (P=0.02). CONCLUSIONS: Independent of other risk factors, higher vegetable nitrate was associated with a lower CCA-IMT and a lower risk of an ischemic cerebrovascular disease event.