The -374T/A RAGE polymorphism protects against future cardiac events in nondiabetic patients with coronary artery disease.

BACKGROUND: The -374T/A polymorphism of the Receptor for Advanced Glycation End products (RAGE) may exert a protective effect toward the development of atherosclerosis. No data are currently available on the potential prognostic role of this polymorphism in patients with angiographically proven coronary artery disease (CAD). Hereto we sought to address this issue in a large consecutive cohort of patients undergoing coronary revascularization. METHODS: A total of 643 CAD patients who underwent myocardial revascularization were followed for 4.2 years (interquartile range: 2.2-8.1 years). The rates of major cardiac adverse events (death, nonfatal myocardial infarction, and unstable angina) were compared according to the -374T/A RAGE polymorphism. RESULTS: During a median follow-up period of 4.2 years, the study endpoint was reached by 126/643 patients (19.6%). We observed adverse cardiac events in 13.4% of patients with AA, 17.5% of those with AT, and 24.2% of those with TT genotype (p <0.05). In univariate Cox proportional hazard analysis, the AA genotype was significantly related to a better outcome in nondiabetic patients (hazard ratio: 0.47, 95% CI: 0.20-0.96; p <0.05). No association was found with adverse events in diabetic subjects. After allowance for potential confounders, the AA genotype remained a significant prognostic factor in the nondiabetic group (adjusted HR: 0.41, 95% CI: 0.17-0.94, p <0.05). CONCLUSIONS: The -374T/A RAGE polymorphism is an independent protective factor for cardiac events in nondiabetic patients with CAD. The effect of this genetic variant seems to be attenuated in diabetics, who have chronic RAGE upregulation.

Prognostic significance of plasma osteopontin levels in patients with chronic stable angina.

AIMS: Levels of the secreted glycophosphoprotein osteopontin (OPN) have been associated with the presence and extent of coronary artery disease (CAD). The present study assessed the relationship between plasma OPN concentrations and prognosis in patients with chronic stable angina (CSA). METHODS AND RESULTS: OPN was measured in baseline plasma samples from 799 patients with stable angina pectoris and angiographically documented CAD. Participants were prospectively followed-up for a median of 2.7 years (maximum 4.1 years). The primary study endpoint was the composite of non-fatal myocardial infarction and death from cardiovascular causes. In the univariate Cox proportional hazard analysis, the log-transformed OPN level [hazard ratio (HR) 1.79, 95% CI 1.35-2.36, P < 0.001] was significantly related to adverse outcome. In addition, hypertension, levels of C-reactive protein, and statin use were associated with future adverse events. Levels of OPN (HR, 1.88; P < 0.001) and C-reactive protein (HR, 1.42; P = 0.003), as well as the presence of hypertension (HR, 2.39; P = 0.008) remained statistically significant, independent predictors of adverse cardiovascular outcome in a multivariable Cox proportional hazard analysis. CONCLUSION: Baseline levels of OPN are an independent predictor of future adverse cardiac events in patients with CSA and may be useful for risk stratification.

Association of plasma eotaxin levels with the presence and extent of angiographic coronary artery disease.

Eotaxin (CCL11) is an eosinophil-specific chemoattractant which has been found to be highly expressed at sites of vascular pathology. In the present study, we aimed to evaluate the association of plasma eotaxin levels with the presence and extent of angiographic coronary artery disease (CAD). Three hundred and fifty six consecutive patients attending for elective coronary angiography were investigated. Compared with 111 patients without CAD, 245 with CAD showed higher eotaxin concentrations [median (interquartile range): 76.0 (56.3-103.0)pg/ml versus 116.0 (80.5-162.0)pg/ml, respectively; P<0.001]. Importantly, a significant Spearman correlation was found between eotaxin levels and the extent score of coronary artery stenosis (r=0.449, P<0.001). A stepwise increase in plasma levels of eotaxin was also found depending on the number of >50% coronary stenosis: median value 76.0 pg/ml in CAD(-) subjects, 96.0 pg/ml in 1-vessel disease, 128.0 pg/ml in 2-vessel disease, and 129.0 pg/ml in 3-vessel disease (P<0.001 for trend). After confounding variables were controlled for, multiple stepwise regression analysis demonstrated that plasma eotaxin was an independent predictor of angiographic extent of CAD (beta=0.426, P<0.001). Our data suggest that increased eotaxin levels are associated with the presence of CAD and that circulating levels of this chemokine may reflect the extent of coronary atherosclerosis.

Decreased plasma levels of soluble receptor for advanced glycation end-products in patients with essential hypertension.

OBJECTIVES: Advanced glycation end-products (AGE) may cause vascular stiffening by forming crosslinks through the collagen molecule or by interaction with their cellular transductional receptor (RAGE). A secreted isoform of RAGE, termed soluble RAGE (sRAGE), may contribute to the removal/detoxification of AGE by acting as a decoy. Here we studied the plasma sRAGE levels in hypertensive and normotensive human subjects. We also investigated the relationship between blood pressure parameters and plasma sRAGE concentrations. DESIGN: A cross-sectional case-control study. SETTING AND PARTICIPANTS: The outpatient clinic of a university teaching hospital. Participants were 147 never-treated patients with essential hypertension (87 men and 60 women, aged 50 +/- 10 years) and 177 normotensive controls (118 men and 59 women, aged 49 +/- 10 years). MAIN OUTCOME MEASURES: Plasma sRAGE levels determined by enzyme-linked immunosorbent assay, systolic blood pressure (SBP), diastolic blood pressure, pulse pressure (PP) and mean arterial pressure. RESULTS: The plasma concentration of sRAGE [median (interquartile range)] was 1206 (879-1658) pg/ml in hypertensive subjects and 1359 (999-2198) pg/ml in normotensive controls (P = 0.002). Simple correlation analysis revealed that log-transformed sRAGE levels were inversely correlated with SBP (r = -0.11; P < 0.001) and PP (r = -0.23; P < 0.001). Forward-selection multiple regression analysis revealed that log-transformed sRAGE levels were determined more strongly by PP (F = 3.127, P < 0.001). CONCLUSIONS: Plasma sRAGE levels are decreased in patients with essential hypertension and are inversely related to PP. Our results raise the possibility that sRAGE may play a role in arterial stiffening and its complications.

-374T/A polymorphism of the RAGE gene promoter in relation to severity of coronary atherosclerosis.

BACKGROUND: We have recently reported that homozygosity for the minor A-allele of RAGE (receptor for advanced glycation end products) -374T/A polymorphism may exert a protective effect toward the development of angiographic coronary artery disease (CAD). Here we focused on the putative involvement of this functional RAGE polymorphism on the severity of coronary atherosclerosis as assessed by angiography. METHODS: In a total of 234 consecutive Caucasian patients with angiographically proven CAD, the severity of coronary atherosclerosis was assessed by the number of diseased vessels (greater than 50% stenosis). Genotyping for the -374T/A variant was performed by means of PCR-RFLPs. RESULTS: The mean number of diseased vessels was significantly lower in patients with the AA genotype (1.47+/-0.68) than in those with the AT or TT genotype (1.88+/-0.82, p=0.029). After confounding variables were controlled for, the number of diseased vessels remained significantly different in the AA genotype carriers from that in the AT or TT carriers (p=0.041, ANCOVA). CONCLUSIONS: Our data suggest that the RAGE -374T/A polymorphism is one of the likely candidate determinants for the genetic variance of disease phenotype in coronary atherosclerosis.

Plasma levels of soluble receptor for advanced glycation end products and coronary artery disease in nondiabetic men.

OBJECTIVE: The receptor for advanced glycation end products (RAGE) is a cell surface receptor whose signaling pathway has been implicated in atherogenesis. RAGE has an endogenous secretory receptor form, called soluble RAGE (sRAGE), that could exert antiatherogenic effects by acting as a decoy. We sought to determine whether a decreased plasma level of sRAGE could be independently associated with the prevalence of coronary artery disease (CAD) in nondiabetic men. METHODS AND RESULTS: Plasma levels of sRAGE were determined in 328 nondiabetic male patients with angiographically proved CAD and in 328 age-matched healthy controls. The concentration of sRAGE in plasma was significantly lower (P<0.0001) in CAD cases [median (interquartile range): 966 (658-1372) pg/mL] than in control subjects [1335 (936-1954) pg/mL]. In logistic regression analysis, the multivariate-adjusted odds ratio for the presence of CAD was 6.719 (95% confidence interval, 3.773 to 11.964; P<0.0001) when the lowest quartile of the sRAGE level was compared with the highest quartile. CONCLUSIONS: Our findings indicate that low levels of sRAGE in plasma are independently associated with the presence of CAD in nondiabetic men and suggest that sRAGE is one of the clinically important molecules associated with atherosclerosis.

Relationship between the -374T/A RAGE gene polymorphism and angiographic coronary artery disease.

The receptor for advanced glycation end products (RAGE) is thought to play a critical role in diabetic atherosclerosis. Accordingly, a functional -374T/A polymorphism in RAGE gene promoter has been associated with macrovascular complications in type 1 diabetic patients. However, the extent to which this common variant influences the risk of coronary artery disease (CAD) in the general population remains to be determined. We genotyped the -374T/A RAGE polymorphism in 259 non-diabetic individuals, of whom 175 had angiographically documented coronary artery disease (CAD patients) and 84 had normal coronary angiography (CAD-free control subjects). Homozygosity for the -374A allele was found in 9.7% of the CAD patients versus 22.6% of the CAD-free subjects (p=0.005). By means of a multiple logistic regression analysis, the AA genotype of the -374T/A polymorphism was shown to be independently associated with a reduced risk of CAD (adjusted odds ratio 0.33, 95% CI 0.15 to 0.73; p=0.006). Our observations suggest that the -374T/A polymorphism of the RAGE gene may reduce susceptibility to CAD, thus exerting a protective effect on coronary risk. Future pathophysiological studies may be worthwhile to clarify the mechanisms behind this association.