Risk Factor For Early Atherosclerosis Research Articles

Evaluation of epicardial adipose tissue thickness and carotid intima-media thickness in children with Behçet's disease.

Behçet's disease (BD) is a systemic vasculitis affecting all sizes of arteries and veins. Approximately 5-10% of patients with BD are present during childhood. The chronic nature of the disease may lead to serious cardiovascular complications over time including early atherosclerosis. Increased levels of epicardial adipose tissue (EAT) and carotid intima-media thickness (CIMT) are considered early signs of subclinical atherosclerosis. Ongoing chronic inflammation may cause to increase in both EAT and CIMT. In this study, we aimed to evaluate CIMT and EAT in children with BD and determine their relationship with the clinical manifestations and course of the disease. This cross-sectional study evaluated 30 patients with juvenile-onset BD and age-sex-matched 20 healthy controls. The CIMT and EAT thickness were measured by the same paediatric cardiologist. The association between clinical features, baseline disease activity, disease duration, EAT thickness and CIMT was also evaluated. Thirty children with BD and 20 age-sex-matched healthy volunteers enrolled in the study. The most common BD-related feature was oral aphthous (n=30), followed by mucocutaneous findings (n=22). Uveitis was observed in 5 patients, vascular involvement in 4, neurological involvement in 4, and gastrointestinal involvement in 2. All patients were inactive at the time of evaluation. The EAT thickness was significantly higher in patients while CIMT levels revealed no significant differences. However, there was no correlation between disease duration, baseline disease activity, and EAT thickness. Increased EAT thickness may be a risk factor for early atherosclerosis in patients with BD. The EAT thickness was found to be significantly higher in paediatric BD patients. Confirmation of results in larger series may provide better insight into early screening for risk factors in these patients.

Cleaning of the blood vessels

The integrity of blood vessels is critical to vascular homeostasis, whose disruption is involved in atherosclerosis (AS), causing stroke and myocardial infarction. Therefore, detecting early AS is essential to avoid severe complications. An arteriograph is the best device for detecting early AS by measuring the rigidity of the blood vessels. To date, there are no safe and effective treatments to clean the blood vessels from lipid accumulation and calcium deposition, which are involved in the onset of AS. For this purpose, we have developed a 4-weeks non-pharmacological protocol, consisting of intravenous laser blood irradiation, injections of glutathione and carnosine, and oral supplementation with phosphatidylcholine, aimed at patients with risk factors for early AS. We observed a significant amelioration of lipids parameters and PWVao, an indicator of the existence of asymptomatic AS, confirming the efficacy of our protocol. Besides, all other health issues must be improved.

Lipoprotein(a) and carotid intima-media thickness in children with familial hypercholesterolaemia in the Netherlands: a 20-year follow-up study

Elevated lipoprotein(a) and familial hypercholesterolaemia are both independent risk conditions for cardiovascular disease. Although signs of atherosclerosis can be observed in children with familial hypercholesterolaemia, it is unknown whether elevated lipoprotein(a) is an additional risk factor for atherosclerosis in these young patients. Therefore, we aimed to assess the contribution of lipoprotein(a) concentrations to arterial wall thickening (as measured by carotid intima-media thickness) in children with familial hypercholesterolaemia who were followed up into adulthood. We conducted a 20-year follow-up study of 214 children (aged 8-18 years) with heterozygous familial hypercholesterolaemia who were randomly assigned in a statin trial in Amsterdam (Netherlands) between Dec 7, 1997, and Oct 4, 1999. At baseline, and at 2, 10, and 20 years thereafter, blood samples were taken and carotid intima-media thickness was measured. Linear mixed-effects models were used to evaluate the association between lipoprotein(a) and carotid intima-media thickness during follow-up. We adjusted for sex, age, corrected LDL-cholesterol, statin use, and BMI. Our study population comprised 200 children who had a carotid intima-media thickness measurement and a measured lipoprotein(a) concentration from at least one visit available. Mean age at baseline was 13·0 years (SD 2·9), 106 (53%) children were male, and 94 (47%) were female. At baseline, median lipoprotein(a) concentration was 18·5 nmol/L (IQR 8·7-35·5) and mean carotid intima-media thickness was 0·4465 mm (SD 0·0496). During follow-up, higher lipoprotein(a) concentrations contributed significantly to progression of carotid intima-media thickness (β adjusted 0·0073 mm per 50 nmol/L increase in lipoprotein(a) [95% CI 0·0013-0·0132]; p=0·017). Our findings suggest that lipoprotein(a) concentrations contribute significantly to arterial wall thickening in children with familial hypercholesterolaemia who were followed-up until adulthood, suggesting that lipoprotein(a) is an independent and additional risk factor for early atherosclerosis in those already at increased risk. Lipoprotein(a) measurement in young patients with familial hypercholesterolaemia is crucial to identify those at potentially highest risk for cardiovascular disease. Silence Therapeutics.

Correlation of fasting and postprandial triglyceride levels and carotid artery intimal medial thickness in type 2 diabetic patients

Background: Although the prevalence of both type 1 and type 2 diabetes mellitus is increasing worldwide, the prevalence of type 2 DM is rising more rapidly, because of sedentary lifestyle, increasing obesity and increased life expectancy. Objectives: To study correlation between fasting and postprandial triglyceride levels and Carotid artery intimal medial thickness (CIMT) in Type 2 Diabetic Patients. Material and Methods: This cross sectional observation study was done in Department of General Medicine, Mysore Medical College and Research Institute, Mysore, Karnataka, India during January 2019 to June 2020. Sample size was 50 and Simple Random sampling method was used. Results: The mean carotid IMT of subjects with postprandial triglycerides < 200 with normal fasting triglyceride was 0.92±0.33. The mean carotid IMT of subjects with postprandial triglyceride 200-299 with normal fasting triglyceride was 1.52±0.57. The mean carotid IMT of subjects with postprandial triglycerides ≥300 with normal fasting triglycerides was 1.66±0.45. Conclusion: postprandial hypertriglyceridemia, despite normal fasting triglyceride levels, may be an independent risk factor for early atherosclerosis in type 2 diabetes. Hence evaluating not only for FTG but also PPTG level during clinical assessment of patients with type 2 diabetes is important.

Preclinical Aortic Atherosclerosis in Adolescents With Chronic Disease.

Background Adolescents with chronic disease are often exposed to inflammatory, metabolic, and hemodynamic risk factors for early atherosclerosis. Since postmortem studies have shown that atherogenesis starts in the aorta, the CDACD (Cardiovascular Disease in Adolescents with Chronic Disease) study investigated preclinical aortic atherosclerosis in these adolescents. Methods and Results The cross-sectional CDACD study enrolled 114 adolescents 12 to 18years old with chronic disorders including juvenile idiopathic arthritis, cystic fibrosis, obesity, corrected coarctation of the aorta, and healthy controls with a corrected atrial septal defect. Cardiovascular magnetic resonance was used to assess aortic pulse wave velocity and aortic wall thickness, as established aortic measures of preclinical atherosclerosis. Cardiovascular magnetic resonance showed a higher aortic pulse wave velocity, which reflects aortic stiffness, and higher aortic wall thickness in all adolescent chronic disease groups, compared with controls (P<0.05). Age (β=0.253), heart rate (β=0.236), systolic blood pressure (β=-0.264), and diastolic blood pressure (β=0.365) were identified as significant predictors for aortic pulse wave velocity, using multivariable linear regression analysis. Aortic wall thickness was predicted by body mass index (β=0.248) and fasting glucose (β=0.242), next to aortic lumen area (β=0.340). Carotid intima-media thickness was assessed using ultrasonography, and was only higher in adolescents with coarctation of the aorta, compared with controls (P<0.001). Conclusions Adolescents with chronic disease showed enhanced aortic stiffness and wall thickness compared with controls. The enhanced aortic pulse wave velocity and aortic wall thickness in adolescents with chronic disease could indicate accelerated atherogenesis. Our findings underscore the importance of the aorta for assessment of early atherosclerosis, and the need for tailored cardiovascular follow-up of children with chronic disease.

1099-P: Truncal Fat–to–Leg Fat Ratio and Carotid Plaque Score in Patients with Type 2 Diabetes

High truncal fat is known to be a risk factor for cardiovascular disease (CVD) , but high leg fat has a protective effect on CVD. We investigated the association between truncal fat-to-leg fat ratio (TLR) and carotid plaque score PS) in patients with type 2 diabetes (T2D) . A total of 1966 participants aged over 30 years and having T2D were recruited. Truncal fat, leg fat, and appendicular muscle mass (ASM) were measured using dual-energy X-ray absorptiometry and Carotid intima-media thickness (CIMT) and PS were assessed using high-resolution B-mode ultrasonography. High PS was defined as PS ≥ 3. The prevalence of plaque and high PS were 72.0% and 40.0%, respectively. Patients with high PS were more likely to be old, male, and hypertensive and had higher systplic blood pressure (SBP) , diabetic duration (DD) , serum creatinine (Cr) , and TLR, but lower values of diastolic BP, truncal and leg fat, HDL, and estimated glomerular filtration rate (eGFR) than those without high PS. Participants in the highest TLR tertile group were older and more hypertensive and had higher DD, SBP, waist circumference (WC) , body mass index (BMI) , HOMA-IR, glycated A1c (HbA1c) , triglycerides (TG) , serum Cr, CIMT, and PS, but lower ASM/BMI, HDL, and eGFR than those in the lowest TLR tertile group. The prevalence of high PS progressively increased with increasing TLR tertiles (Lowest vs. Middle vs. Highest = 33.4 vs. 41.0 vs. 45.7%, respectively, p &amp;lt; 0.001) . After adjusting age and sex, the odd ratios (ORs) and 95% confidence intervals (CIs) for high PS were 1.39 (1.- 1.79, p = 0.01) in the middle and 1.65 (1.28 - 2.11, p = &amp;lt; 0.001) in the highest tertile groups. After further adjusting for hypertesnsion, WC, BMI, SBP, DD, HbA1c, HOMA-IR, HDL cholesterol, TG, and eGFR, the ORs and 95% CIs in the middle and highest tertile groups remained significant. In conclusion, higher TLR was independently associated with carotid PS in patients with T2D. Therefore, we suggest that high TLR may be a risk factor for early atherosclerosis in patients with T2D. Disclosure J.Shin: n/a.

P1271 Systolic dysfunction in obese and extreme obese patients and preliminary results after bariatric surgery

Abstract Background Obesity is known to be associated with left ventricular (LV) diastolic dysfunction, heart failure and some risk factors for early atherosclerosis: diabetes mellitus, arterial hypertention, dyslipidemia. Very few studies investigate extremely obese patients and how this condition impairs LV systolic function. The aim of the study is to explore the effect of obesity and extreme obesity on LV systolic function in patients without diabetes mellitus and the effect of bariatric surgery on that function. Methods We prospectively investigated 55 patients with obesity class 1 and 2 and 23 patients with extreme obesity who underwent bariatric surgery. The participants were grouped according to body mass index (obesity class 1 and 2 BMI ≥ 30 ≤ 40 kg/m2 and extreme obesity ≥ 40 kg/m2). Systolic function was assessed by ejection fraction by Simpson and Teicholz, global longitudinal strain, Tei index. Results In the studied groups statistical analysis proved the relation between all investigated echographic parameters and BMI. The mean left ventricular ejection fraction and GLS values were 55% (±10%) vs. − 17.3% (±3.3%) for obese and 51% (±8%) vs. − 16.5% (2.3%) for extreme obese (p &amp;lt; 0.05). Patiets with extreme obesity, who underwent bariatric surgery increased LV ejection fraction faster and more than patients who underwent only diatry and medical treatment. 5.0 (9.0) % vs. 3.0 (10.0) % (p &amp;lt; 0.05). Conclusion Obesity and extreme obesity impair all studied parameters for LV systolic function. Bariatric surgery is treatment option for extreme obesity patients and a possibility for significant and fast improvement of LV systolic parameters.

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

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. 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. 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. 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.

Evaluation of carotid artery dynamics &amp; correlation with cardiac &amp; hepatic iron in β-thalassaemia patients

Background & objectives:Early atherosclerosis and vascular complication have been described in thalassaemia patients. There is lack of data or guidelines regarding monitoring of vascular health in thalassaemia. This study was conducted to compare carotid artery structural and functional indices such as carotid artery intima-media thickness (CIMT), stiffness index (SI) and Young's elastic modulus (YEM) in β-thalassemia patients with age and sex matched controls, and to correlate these parameters with serum ferritin, cardiac iron, and hepatic iron.Methods:This cross-sectional study included 53 β-thalassaemia patients receiving regular blood transfusions. Carotid artery indices such as CIMT, SI, and YEM were calculated by duplex ultrasound and colour Doppler. Serum ferritin levels were measured by chemiluminescence. Cardiac and hepatic iron estimation were done using MRI T2* sequences analyzed by a special thalassaemia software.Results:Mean CIMT of cases and controls were 0.48 ± 0.04 and 0.44±0.02 mm, respectively and these were significantly different (P<0.001). Similarly significant differences were noted in SI and YEM of cases (2.45±0.79 and 96.12±34.85, respectively) as compared to controls (1.98±0.54 and 68.60±24.29, respectively) (P<0.001). There was significant inverse correlation between stiffness index and cardiac iron overload assessed by MRI cardiac T2* (P=0.03). Mean SI and YEM of cases were (2.1736 ± 0.2986 and 107.3± 41.6, respectively) significantly higher among non-splenectomized patients compared to splenectomized patients (2.0136 ± 0.263 and 86.9 ± 25.2, respectively) (P<0.05).Interpretation & conclusions:CIMT and arterial stiffness indices were significantly increased in β-thalassaemia patients compared to controls which was indicative of early atherogenic changes. This study supports the hypothesis that iron overload is a risk factor for early atherosclerosis and cardiovascular disease.

Role of lipoprotein (a) in the development of ischemic stroke and other cardiovascular diseases

The paper gives the data available in the literature on the role of a level of elevated lipoprotein (a) (Lp (a)) in the development of ischemic stroke and other cardiovascular diseases. It shows the normal level of Lp (a) and the typical distribution of its concentration for people of European origin and representatives of other races. There is evidence on the genetic determination and variability of the Apo (a) gene. The paper presents the results of the recent large survey of 8000 patients with coronary heart disease and 8000 control persons, which has studied candidate genes for cardiovascular diseases. It indicates the role of Lp (a) as a risk factor for early atherosclerosis and describes main pathomorphological mechanisms. The propositions that it is necessary to screen Lp (a) in different risk groups, its target level, and possible methods for correcting the elevated Lp (a) level are given.

Relationship between Abdominal Aortic Intima Media Thickness and Central Obesity in Children

Background: Childhood obesity is one of the important risk factors for early atherosclerosis. We aimed to evaluate the effect of obesity on abdominal aortic intima media thickness (aaIMT) in children. Methods: We consecutively recruited 60 obese and 28 healthy children from the outpatient clinic of pediatrics. In all patients, BMI, waist circumference (WC) and hip circumference (HC) were measured, and fasting serum lipid profile, plasma glucose and plasma insulin were studied. Homeostasis model assessment-estimated insulin resistance (HOMA-IR) was calculated for the obese group. All children underwent ultrasonography to evaluate hepatosteatosis and to measure aaIMT. Results: There was a significant difference between the groups in terms of aaIMT, insulin, glucose, HOMA-IR, total cholesterol, low-density lipoprotein, triglyceride and hepatosteatosis. aaIMT was 1.12 ± 0.25 and 0.61 ± 0.18 mm in the obese and nonobese groups, respectively (p < 0.001). In the obese group, there was a positive correlation between aaIMT and WC, WC/height ratio, BMI, HC and hepatosteatosis (p < 0.05 for all), with the highest significance for WC. Conclusions: This study showed that aaIMT was significantly higher in obese children than in nonobese children, and that WC was a strong predictor for aaIMT. Early detection of an increased aaIMT in obese children may guide the follow-up of these patients in terms of developing atherosclerosis and its complications.

Pediatric CKD and Cardivascular Disease

Children and adolescents with chronic kidney disease (CKD) are at high risk for cardiovascular morbidity and mortality. This review provides a comprehensive overview of the possible risk factors for early atherosclerosis in children with CKD. Endothelial dysfunction, a precursor of atherosclerosis, starts early in renal disease, as indicated by increased carotid artery intima media thickness, carotid arterial wall stiffness, impaired flow mediated dilatation, and coronary artery calcification, which are frequently present in children with CKD. Many risk factors for atherosclerosis, such as hypertension, dyslipidemia, renal bone disease, hyperhomocysteinemia, and uremia-related cardiovascular risk factors are associated with CKD. All of these risk factors are modifiable and optimal clinical management can delay or prevent cardiovascular disease. Another strategy to decrease the risk of premature cardiac disease and death in children with CKD is to slow the progression of renal disease.

Is autoimmune thyroiditis a risk factor for early atherosclerosis in premenopausal women even if in euthyroid status?

Autoimmune thyroiditis (AIT) is a systemic disease. It is well-known that overt thyroid dysfunction is a cardiovascular risk factor. However, the influence of euthyroid status is unclear. The aim of this study was to evaluate the metabolic parameters and carotid intima-media thickness (CIMT) in euthyroid premenopausal women with AIT. Fourty-eight premenopausal women and 18 age-matched healthy controls attending the Endocrinology and Metabolism Clinic from 2008 to 2009 were enrolled to this cross-sectional study. Patients were divided into 2 groups according to TSH levels; patients in group 1 (n = 23) had TSH levels ≤ 2.5 μIU/mL and patients in group 2 had TSH levels > 2.5 μIU/mL (n = 25). All participants were evaluated by ultrasound for CIMT (mean of three segments in both carotid arteries) by the same experienced investigator. Fasting venous blood samples were collected to evaluate insulin resistance (HOMA-IR), TSH, FT4, plasma lipids, high-sensitive CRP (Hs-CRP), homocysteine, and fibrinogen. Carotid intima-media thickness was found to be significantly higher in patients than the controls (p < 0.001). However, there was no significant difference in average CIMT between group 1 and 2 (0.66 ± 0.08 vs 0.63 ± 0.09 mm). Anti-Tg levels were independently associated with CIMT in the patient group (p = 0.014). There were no significant correlations between serum TSH levels and BMI; waist circumference, serum lipids, and glucose levels. However, there was a positive significant correlation between TSH levels and blood pressure in the patients (for systolic blood pressure r = 0.466, p = 0.001, for diastolic blood pressure r = 0.372, p = 0.009). In the present study, it was shown that CIMT is increased in euthyroid premenopausal women with autoimmune thyroiditis compared to age-matched healthy controls.

Abstract P301: Association of Toenail Cadmium Levels with Measures of Sub-Clinical Atherosclerosis: The Coronary Artery Risk Development in Young Adults (CARDIA) Trace Element Study

Background: Experimental studies have suggested that cadmium (Cd) exposure is a potential risk factor for early atherosclerosis and cardiovascular diseases as it can disrupt integrity of the endothelial cell layer. However, longitudinal data in humans relating Cd levels to sub-clinical atherosclerosis are lacking. Methods: 2589 participants from the CARDIA Study, aged 20-32 years in 1987 (baseline) with up to 18 years of follow-up were included in the analyses to examine prospectively the associations of toenail Cd concentrations with carotid intima-media thickness (CIMT) and coronary artery calcium score (CAC score). Toenail clippings were collected in 1987 and Cd was assessed by instrumental neutron-activation analysis. Common (c), bulb (b), and internal (i) CIMTs were measured in 2005 and CAC score in 2000 and 2005. CAC presence (score, &gt;0 Agatston units) and CAC progression (incident CAC in 2005 or increase in CAC score by ≥10 Agatston units) were defined based on CAC score. General linear regression or logistic regression was used as appropriate. Results: Median Cd levels were 0.003, 0.006, 0.012 and 0.039 μ g/g from 1 st - 4 th quartile. We observed a positive linear relation of Cd levels with cCIMT, but not bCIMT and iCIMT ( Table 1 ). Null associations between Cd levels and CAC progression [Q 4 vs . Q 1 : OR=1.11 (95% CI: 0.73, 1.68); P trend =0.14] or presence of CAC [Q 4 vs . Q 1 : OR=1.05 (0.73, 1.53); P trend =0.56] were documented. Conclusions: In this young adult cohort, toenail Cd levels were positively associated with cCIMT, but not bCIMT, iCIMT and CAC score. Further studies are needed to determine whether there is an atherosclerotic mechanism linking Cd exposure to the risk of cardiovascular disease. Table 1 Multivariable-adjusted carotid intima-media thickness (mm) by toenail cadmium levels No. of participants Quartile of toenail cadmium levels P trend Q1 Q2 Q3 Q4 cCIMT 2587 0.781 (0.773-0.790) 0.784 (0.776-0.793) 0.789 (0.781-0.798) 0.791 (0.781-0.798) 0.03 bCIMT 2527 1.010 (0.990-0.1.031) 1.002 (0.982-1.022) 0.981 (0.962-1.001) 1.001 (0.980-1.022) 0.17 iCIMT 2436 0.787 (0.772-0.802) 0.790 (0.776-0.804) 0.784 (0.770-0.798) 0.778 (0.763-0.793) 0.86 Data are geometric means (95%CIs) adjusted for age, gender, race, study center, body mass index, physical activity, education, smoking status, alcohol consumption, systolic blood pressure, LDL/HDL, HOMA, body mass index, long-chain omega-3 polyunsaturated fatty acids intake with toenail zinc, chromium, lead and mass weight. cCIMT : common carotid intima-media thickness; bCIMT : bulb carotid intima-media thickness; iCIMT : internal carotid intima-media thickness.

Age Modification of the Association of Lipoprotein, Lipid, and Lipoprotein Ratio With Carotid Intima–Media Thickness (from the Multi-Ethnic Study of Atherosclerosis [MESA

Multiple studies have demonstrated an age-related attenuation in risk associations of lipoproteins and lipoprotein ratios with cardiovascular disease events. We recently reported a similar age-related attenuation in risk associations of lipoproteins and lipoprotein ratios with coronary artery calcium. We assessed risk associations of lipoproteins and lipoprotein ratios with carotid intima-media thickness (CIMT), which has not been reported previously. We performed multivariable linear regression using data from the Multi-Ethnic Study of Atherosclerosis (MESA). MESA participants were community-dwelling adults 45 to 84 years of age without clinically apparent cardiovascular disease at baseline, and 4,961 met inclusion criteria for these analyses. In fully adjusted models, differences in CIMT were similar across the MESA age spectrum, with differences in internal CIMT per SD increase in low-density lipoprotein of 0.037 mm (95% confidence interval 0.018 to 0.055) for those 45 to 54 years old and 0.087 mm (95% confidence interval 0.027 to 0.146) for those 75 to 84 years old (p for interaction = 0.2). Similarly, the difference in internal CIMT per SD increase in the total/high-density lipoprotein cholesterol ratio was 0.029 mm (95% confidence interval 0.009 to 0.049) for those 45 to 54 years old and 0.101 mm (95% confidence interval 0.033, 0.169) for those 75 to 84 years old (p for interaction = 0.03). In general, risk associations of lipoproteins and lipoprotein ratios were associated with similar differences in CIMT across all age categories. In conclusion, abnormal lipoproteins and lipoprotein ratios in middle-aged and older patients are powerful risk factors for early atherosclerosis as manifested by an increased CIMT.

Cigarette smoke extract induces prolonged endoplasmic reticulum stress and autophagic cell death in human umbilical vein endothelial cells

Consumption of cigarette smoke (CS) is a well-known risk factor for early atherosclerosis; yet, the underlying mechanisms of smoking-associated atherosclerosis are poorly understood. Based on the previous results indicating that CS-induced endothelial cell death neither shows typical features of apoptosis nor of necrosis, we investigated the role of autophagy in CS extract (CSE)-induced cell death of human umbilical vein endothelial cells (HUVECs). Here, we demonstrate that overexpression of the classical apoptosis inhibitor BCL-XL had no protective effect on CSE-induced cell death, whereas the autophagy inhibitor 3-methyladenin and an shRNAi-mediated knockdown of the autophagy mediator ATG5 significantly delayed cell death. Our results indicate that CSE induces an excess accumulation of misfolded proteins in the endoplasmic reticulum (ER) and consequently the onset of the unfolded protein response. We provide evidence that the ER-resident kinase PERK is a major transducer of ER stress leading to phosphorylation of eIF2α and attenuation of protein synthesis. Finally, we show that prolonged ER stress in cells subjected to CS is followed by activation of an autophagic programme. CSE-induced autophagy is characterized by an increase in LC3 II/I ratio and activation ATG12. The autophagic signalling pathway via energy depletion and consequent activation AMP-activated protein kinase could be excluded. Our results confirm and extend previous findings reporting on the induction of autophagy by CSE in the lung. We show that protein damage caused by CSE activates autophagy, ultimately resulting in necrotic death of HUVECs. Via this mechanism, cigarette smoking may contribute to the deterioration of vascular endothelial function and the initiation of atherosclerosis.

Endothelial dysfunction and inflammation induced by iron oxide nanoparticle exposure: Risk factors for early atherosclerosis

More recently, the correlation between exposure to nanoparticles and cardiovascular diseases is of particular concern in nanotoxicology related fields. Nanoparticle-triggered endothelial dysfunction is hypothesized to be a dominant mechanism in the development of the diseases. To test this hypothesis, iron oxide nanoparticles (Fe 2O 3 and Fe 3O 4), as two widely used nanomaterials and the main metallic components in particulate matter, were selected to assess their potential risks on human endothelial system. The direct effects of iron oxide nanoparticles on human aortic endothelial cells (HAECs) and the possible effects mediated by monocyte (U937 cells) phagocytosis and activation were investigated. In the study, HAECs and U937 cells were exposed to 2, 20, 100 μg/mL of 22-nm-Fe 2O 3 and 43-nm-Fe 3O 4 particles. Our results indicate that cytoplasmic vacuolation, mitochondrial swelling and cell death were induced in HAEC. A significant increase in nitric oxide (NO) production was induced which coincided with the elevation of nitric oxide synthase (NOS) activity in HAECs. Adhesion of monocytes to the HAECs was significantly enhanced as a consequence of the up-regulation of intracellular cell adhesion molecule-1 (ICAM-1) and interleukin-8 (IL-8) expression, all of which are considered as early steps of atheroscelerosis. Phagocytosis and dissolution of nanoparticles by monocytes were found to simultaneously provoke oxidative stress and mediate severe endothelial toxicity. We conclude that intravascular iron oxide nanoparticles may induce endothelial system inflammation and dysfunction by three ways: (1) nanoparticles may escape from phagocytosis that interact directly with the endothelial monolayer; (2) nanoparticles are phagocytized by monocytes and then dissolved, thus impact the endothelial cells as free iron ions; or (3) nanoparticles are phagocytized by monocytes to provoke oxidative stress responses.

Scan–Rescan reproducibility of carotid bifurcation geometry from routine contrast‐enhanced MR angiography

To demonstrate the feasibility of rapid and reliable geometric characterization of normal carotid bifurcation geometry from routine 3D contrast-enhanced magnetic resonance (MR) angiograms. Repeat scans of 61 participants, acquired as part of the Atherosclerosis Risk in Communities (ARIC) Carotid MRI substudy, were digitally segmented using automated 3D level set methods, relying on an operator only to select the branch endpoints and thresholds for the 3D lumen surface initialization. Geometric factors characterizing the 3D lumen geometry were then extracted automatically. Of 122 scans, 117 could be segmented within 5 minutes each, with 40% being of sufficiently high quality to require less than 2 minutes each. Irrespective of scan quality, geometric factors were found to be highly reproducible, with intraclass correlation coefficients (ICCs) typically above 0.9. The reconstructed lumen surfaces were reproducible to <0.3 mm on average, comparable to previous MRI-based reproducibility studies. Owing to the automated nature of the analysis, operator reliability was near-perfect (ICC >0.99), with lumen surface differences <0.1 mm. The 3D geometry of the carotid bifurcation can be characterized rapidly and with a high degree of consistency, even for suboptimal image qualities. This bodes well for large-scale retrospective or prospective studies aimed at teasing out the influence of local vs. systemic risk factors for early atherosclerosis.

Non-Toxic Cadmium Concentrations Induce Vascular Inflammation and Promote Atherosclerosis

Cadmium is a potential new risk factor for early atherosclerosis and cardiovascular diseases in humans, yet pathogenetic mechanisms are still a matter of debate. In-depth histological analysis of 18 sections taken from 6 cadmium-fed ApoE-/- mice and 12 sections from 5 litter-mates not exposed to cadmium by light and scanning electron microscopy was performed. Cadmium-fed mice showed a marked increase in lesion load (plaque area) and severity as classified according to the American Heart Association vascular lesion grading. All inflammatory markers studied (CD68, CD3, CD25, vascular cell adhesion molecule 1 (VCAM-1), and heat shock protein 60 (Hsp60)) yielded a higher expression in cadmium-fed mice. Statistical difference was achieved for VCAM-1 and Hsp60 (P=0.03 and P=0.02). The shoulder region of atherosclerotic plaques in cadmium-fed mice showed a prominent retraction of endothelial cells on electron microscopy. Our data indicate that cadmium exposure amplifies the development of vessel pathology in atherosclerosis susceptible ApoE-/- mice and suggests upregulation of VCAM-1 and Hsp60 and endothelial leakage as potential pathomechanisms.

Leptin Receptor Lys109Arg and Gln223Arg Polymorphisms Are Associated with Early Atherosclerosis

Leptin is a hormone expressed by the leptin gene, primarily in adipocytes, controlling food intake and energy expenditure. The effects of leptin are mediated by its receptor (LEPR) located in the central nervous system and other tissues, including adipocytes and endothelial cells. The aim of this study was to characterize two polymorphisms of LEPR, Lys109Arg (rs1137100) and Gln223Arg (rs1137101), as risk factors for early atherosclerosis. This connection has not been studied before. This study was performed in the randomly selected, middle-aged control subjects (n=526) from our well-defined OPERA (Oulu Project Elucidating Risk of Atherosclerosis) study. Analysis of covariance (ANCOVA) was performed to study the associations between genotypes, intima media thickness (IMT) measurements, and risk factors for atherosclerosis. Subjects with the genotype Lys109Arg had the lowest body mass index (BMI) (P = 0.035), whereas Arg109Arg homozygotes had the highest total cholesterol (P=0.021) when adjusted for sex and age. Gln223Arg associated independently with systolic blood pressure (P=0.036). There were no differences in leptin concentrations between the genotypes. The adjusted (sex, age, BMI, smoking status, low-density lipoprotein cholesterol, systolic blood pressure, and fasting blood glucose) means for the IMT measurements were lowest in the Arg109 and Arg223 homozygotes (P=0.042 and P=0.041, ANCOVA, respectively). The variations in the LEPR gene are independently associated with early atherosclerosis and some of its risk factors. These variations could possibly affect leptin signaling and thereby modify the effects of leptin on the atherosclerotic process.