Abstract-Our aim was to determine the usefulness of circulating oxidized low density lipoprotein (LDL) in the identification of patients with coronary artery disease (CAD). A total of 304 subjects were studied: 178 patients with angiographically proven CAD and 126 age-matched subjects without clinical evidence of cardiovascular disease. The Global Risk Assessment Score (GRAS) was calculated on the basis of age, total and high density lipoprotein cholesterol, blood pressure, diabetes mellitus, and smoking. Levels of circulating oxidized LDL were measured in a monoclonal antibody 4E6 -based competition ELISA. Compared with control subjects, CAD patients had higher levels of circulating oxidized LDL (PϽ0.001) and a higher GRAS (PϽ0.001). The sensitivity for CAD was 76% for circulating oxidized LDL (55% for men and 81% for women) compared with 20% (24% for men and 12% for women) for GRAS, with a specificity of 90%. Logistic regression analysis revealed that the predictive value of oxidized LDL was additive to that of GRAS (PϽ0.001). Ninety-four percent of the subjects with high (exceeding the 90th percentile of distribution in control subjects) circulating oxidized LDL and high GRAS had CAD (94% of the men and 100% of the women Key Words: atherosclerosis Ⅲ coronary artery disease Ⅲ diagnosis Ⅲ lipoproteins M ajor independent risk factors for coronary artery disease (CAD) are advancing age, elevated blood pressure, elevated serum total and LDL cholesterol levels, low serum HDL cholesterol level, diabetes mellitus, and cigarette smoking. 1-3 The Framingham Heart Study 1 has elucidated the quantitative relationship between these risk factors and CAD. It has shown that the major risk factors are additive in predictive power. Accordingly, the total risk of a person can be estimated by a summing of the risk imparted by each of the major risk factors. Recently, the American Heart Association and the American College of Cardiology issued a scientific statement that assessed the Global Risk Assessment Scoring (GRAS) as a guide to primary prevention. 4 GRAS is based on age, total and HDL cholesterol levels, systolic blood pressure, diabetes mellitus, and smoking. Predisposing factors such as obesity, physical inactivity, and family history of premature CAD are not included in GRAS.Elevated levels of oxidized LDL have previously been detected in the plasma of CAD patients. 5-7 Therefore, we determined the predictive value of circulating oxidized LDL for CAD. Logistic regression analysis was used to determine whether the predictive value of circulating oxidized LDL was additive to that of GRAS. Finally, the correlation between circulating oxidized LDL and major cardiovascular risk factors in subjects without clinical evidence of CAD was studied. Methods Study DesignThe present study included 304 subjects (aged Ͼ45 years). Seventyeight patients with angiographically proven CAD have previously been described. 6 Blood samples from these patients were collected from 1993 to 1994 and were analyzed within 1 month after collection. Bl...

Increased LDL oxidation is associated with coronary artery disease. The predictive value of circulating oxidized LDL is additive to the Global Risk Assessment Score for cardiovascular risk prediction based on age, gender, total and HDL cholesterol, diabetes, hypertension, and smoking. Circulating oxidized LDL does not originate from extensive metal ion-induced oxidation in the blood but from mild oxidation in the arterial wall by cell-associated lipoxygenase and/or myeloperoxidase. Oxidized LDL induces atherosclerosis by stimulating monocyte infiltration and smooth muscle cell migration and proliferation. It contributes to atherothrombosis by inducing endothelial cell apoptosis, and thus plaque erosion, by impairing the anticoagulant balance in endothelium, stimulating tissue factor production by smooth muscle cells, and inducing apoptosis in macrophages. HDL cholesterol levels are inversely related to risk of coronary artery disease. HDL prevents atherosclerosis by reverting the stimulatory effect of oxidized LDL on monocyte infiltration. The HDL-associated enzyme paraoxonase inhibits the oxidation of LDL. PAF-acetyl hydrolase, which circulates in association with HDL and is produced in the arterial wall by macrophages, degrades bioactive oxidized phospholipids. Both enzymes actively protect hypercholesterolemic mice against atherosclerosis. Oxidized LDL inhibits these enzymes. Thus, oxidized LDL and HDL are indeed antagonists in the development of cardiovascular disease.

The object of this study was to establish the association between the metabolic syndrome and oxidized LDL (oxLDL) and to determine the risk for coronary heart disease (CHD) in relation to the metabolic syndrome and levels of oxLDL. OxLDL was measured in plasma from 3,033 elderly participants in the Health, Aging, and Body Composition study. The metabolic syndrome was defined according to criteria established in the Third Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. We observed that the metabolic syndrome was associated with higher levels of oxLDL due to a higher fraction of oxLDL, not to higher levels of LDL cholesterol. Individuals with the metabolic syndrome had twice the odds of having high oxLDL (>1.90 mg/dl) compared with those not having the metabolic syndrome, after adjusting for age, sex, ethnicity, smoking status, and LDL cholesterol. Among those participants who had the metabolic syndrome at study entry, incidence rates of future CHD events were 1.6-fold higher, after adjusting for age, sex, ethnicity, and smoking status. OxLDL was not an independent predictor of total CHD risk. However, those with high oxLDL showed a greater disposition to myocardial infarction (relative risk 2.25, 95% confidence interval 1.22-4.15). We concluded that the metabolic syndrome, a risk factor for CHD, is associated with higher levels of circulating oxLDL that are associated with a greater disposition to atherothrombotic coronary disease.

Background-Obesity-associated dyslipidemia in humans is associated with increased low-density lipoprotein (LDL) oxidation. Mice with combined leptin and LDL receptor deficiency are obese and show severe dyslipidemia and insulin resistance. We investigated the association between oxidation of apolipoprotein B-containing lipoproteins, high-density lipoprotein (HDL) antioxidant defense, and atherosclerosis in these mice. Methods and Results-LDL receptor knockout (LDLR Ϫ/Ϫ ), leptin-deficient (ob/ob), double-mutant (LDLR Ϫ/Ϫ ;ob/ob), and C57BL6 mice were fed standard chow. Double-mutant mice had higher levels of non-HDL (PϽ0.001) and HDL (PϽ0.01) cholesterol and of triglycerides (PϽ0.001). They also had higher oxidative stress, evidenced by higher titers of autoantibodies against malondialdehyde-modified LDL (PϽ0.001). C57BL6 and ob/ob mice had no detectable lesions. Lesions covered 20% of total area of the thoracic abdominal aorta in double-mutant mice compared with 3.5% in LDLR Ϫ/Ϫ mice (PϽ0.01). Higher macrophage homing and accumulation of oxidized apolipoprotein B-100 -containing lipoproteins were associated with larger plaque volumes in the aortic root of double-mutant mice (PϽ0.01). The activity of the HDL-associated antioxidant enzymes paraoxonase and lecithin:cholesterol acyltransferase (LCAT) (ANOVA; PϽ0.0001 for both) was lower in double-mutant mice. Adenovirus-mediated LCAT gene transfer in double-mutant mice increased plasma LCAT activity by 64% (PϽ0.01) and reduced the titer of autoantibodies by 40% (PϽ0.01) and plaque volume in the aortic root by 42% (PϽ0.05) at 6 weeks. Conclusions-Dyslipidemia and insulin resistance in obese LDL receptor-deficient mice are associated with increased oxidative stress and impaired HDL-associated antioxidant defense, evidenced by decreased paraoxonase and LCAT activity. Transient LCAT overexpression was associated with a reduction of oxidative stress and atherosclerosis.

Gene transfer of PAF-AH inhibited injury-induced neointima formation and spontaneous atherosclerosis in apolipoprotein E-deficient mice. Our data indicate that PAF-AH, by reducing oxidized lipoprotein accumulation, is a potent protective enzyme against atherosclerosis.

Background-Weight loss in obese insulin-resistant but not in insulin-sensitive persons reduces coronary heart disease risk. To what extent changes in gene expression are related to atherosclerosis and cardiovascular function is unknown. Methods and Results-We studied the effect of diet restriction-induced weight loss on gene expression in the adipose tissue, the heart, and the aortic arch and on atherosclerosis and cardiovascular function in mice with combined leptin and LDL-receptor deficiency. Obesity, hypertriglyceridemia, and insulin resistance are associated with hypertension, impaired left ventricular function, and accelerated atherosclerosis in those mice. Compared with lean mice, peroxisome proliferator-activated receptors (PPAR)-␣ and PPAR-␥ expression was downregulated in obese double-knockout mice. Diet restriction caused a 45% weight loss, an upregulation of PPAR-␣ and PPAR-␥, and a change in the expression of genes regulating glucose transport and insulin sensitivity, lipid metabolism, oxidative stress, and inflammation, most of which are under the transcriptional control of these PPARs. Changes in gene expression were associated with increased insulin sensitivity, decreased hypertriglyceridemia, reduced mean 24-hour blood pressure and heart rate, restored circadian variations of blood pressure and heart rate, increased ejection fraction, and reduced atherosclerosis. PPAR-␣ and PPAR-␥ expression was inversely related to plaque volume and to oxidized LDL content in the plaques. Conclusions-Induction of PPAR-␣ and PPAR-␥ in adipose tissue, heart, and aortic arch is a key mechanism for reducing atherosclerosis and improving cardiovascular function resulting from weight loss. Improved lipid metabolism and insulin signaling is associated with decreased tissue deposition of oxidized LDL that increases cardiovascular risk in persons with the metabolic syndrome. Key Words: atherosclerosis Ⅲ circadian rhythm Ⅲ genes Ⅲ lipoproteins Ⅲ obesity I nsulin resistance is now receiving increasing attention not only as a precursor to type 2 diabetes but also as a predictor of increased risk of cardiovascular disease. 1 Fat distributed in the abdominal region is a risk factor for type 2 diabetes and cardiovascular disease and is associated closely with insulin resistance. 2 Weight loss in insulin-resistant but not in insulinsensitive obese persons reduces their risk of coronary heart disease (CHD). 3 It is not known, however, to what extent changes in the intra-abdominal adipose gene expression profile are important for the reduction of the risk. 4 Several adipokines, and more specifically peroxisome proliferator-activated receptors (PPARs), regulate a number of the processes that contribute to the development of atherosclerosis, including dyslipidemia, arterial hypertension, endothelial dysfunction, insulin resistance, and vascular remodeling. Adipokines are preferentially expressed in intraabdominal adipose tissue, and the secretion of proinflammatory adipokines is elevated with increasing adiposity. Approaches to re...

BackgroundVisceral obesity is associated with the rising incidence of type 2 diabetes and metabolic syndrome. Low-grade chronic inflammation and oxidative stress synergize in obesity and obesity-induced disorders.ObjectiveWe searched a cluster of molecules that support interactions between these stress conditions in monocytes.Methods RNA expressions in blood monocytes of two independent cohorts comprising 21 and 102 obese persons and 46 age-matched controls were determined by microarray and independently validated by quantitative RT-PCR analysis. The effect of three-month weight loss after bariatric surgery was determined. The effect of RNA silencing on inflammation and oxidative stress was studied in human monocytic THP-1 cells.Results Interleukin-1 receptor-associated kinase-3 (IRAK3), key inhibitor of IRAK/NFκB-mediated chronic inflammation, is downregulated in monocytes of obese persons. Low IRAK3 was associated with high superoxide dismutase-2 (SOD2), a marker of mitochondrial oxidative stress. A comparable expression profile was also detected in visceral adipose tissue of the same obese subjects. Low IRAK3 and high SOD2 was associated with a high prevalence of metabolic syndrome (odds ratio: 9.3; sensitivity: 91%; specificity: 77%). By comparison, the odds ratio of high-sensitivity C-reactive protein, a widely used marker of systemic inflammation, was 4.3 (sensitivity: 69%; specificity: 66%). Weight loss was associated with an increase in IRAK3 and a decrease in SOD2, in association with a lowering of systemic inflammation and a decreasing number of metabolic syndrome components. We identified the increase in reactive oxygen species in combination with obesity-associated low adiponectin and high glucose and interleukin-6 as cause of the decrease in IRAK3 in THP-1 cells in vitro.ConclusionIRAK3 is a key inhibitor of inflammation in association with obesity and metabolic syndrome. Our data warrant further evaluation of IRAK3 as a diagnostic and prognostic marker, and as a target for intervention.

The growing prevalence of obesity explains the rising interest in bariatric surgery. Compared with non-surgical treatment options, bariatric surgery results in greater and sustained improvements in weight loss, obesity associated complications, all-cause mortality and quality of life. These encouraging metabolic and weight effects come with a downside, namely the risk of nutritional deficiencies. Particularly striking is the risk to develop iron deficiency. Postoperatively, the prevalence of iron deficiency varies between 18 and 53 % after Roux-en-Y gastric bypass and between 1 and 54 % after sleeve gastrectomy. Therefore, preventive strategies and effective treatment options for iron deficiency are crucial to successfully manage the iron status of patients after bariatric surgery. With this review, we discuss the risks and the contributing factors of developing iron deficiency after bariatric surgery. Furthermore, we highlight the discrepancy in the diagnosis of iron deficiency, iron deficiency anaemia and anaemia and highlight the evidence supporting the current nutritional recommendations in the field of bariatric research. In conclusion, we advocate for more nutrition-related research in patient populations in order to provide strong evidence-based guidelines after bariatric surgery.