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. See page 879The receptor for advanced glycation end products (RAGE) is a transmembrane receptor of the immunoglobulin superfamily that engages diverse ligands relevant to the pathogenesis of atherosclerosis 4 and that is highly hyperexpressed at sites of vascular pathology. 5 Numerous lines of evidence indicate that ligand-triggered RAGE-dependent cellular activation results in several deleterious effects, including activation of nuclear factor-B, increased expression of cytokines and adhesion molecules, and induction of oxidative stress. 6 -8 One class of RAGE ligands includes glycoxidation products, termed advanced glycation end products (AGEs), which accumulate at an extremely high rate in the diabetic state. 9,10

These findings suggest that at peak exercise a non-autonomic mechanism, possibly intrinsic to the heart muscle, may determine heart rate fluctuations in synchrony with ventilation in the intact as well as in the denervated human heart.

The receptor for advanced glycation end products (RAGE) is a cell-bound receptor of the immunoglobulin superfamily which may be activated by a variety of proinflammatory ligands including advanced glycoxidation end products, S100/calgranulins, high mobility group box 1, and amyloid beta-peptide. RAGE has a secretory splice isoform, soluble RAGE (sRAGE), that lacks the transmembrane domain and therefore circulates in plasma. By competing with cell-surface RAGE for ligand binding, sRAGE may contribute to the removal/neutralization of circulating ligands thus functioning as a decoy. Clinical studies have recently shown that higher plasma levels of sRAGE are associated with a reduced risk of coronary artery disease, hypertension, the metabolic syndrome, arthritis and Alzheimer's disease. Increasing the production of plasma sRAGE is therefore considered to be a promising therapeutic target that has the potential to prevent vascular damage and neurodegeneration. This review presents the state of the art in the use of sRAGE as a disease marker and discusses the therapeutic potential of targeting sRAGE for the treatment of inflammation-related diseases such as atherosclerosis, arthritis and Alzheimer's disease.

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.

Background-Erectile dysfunction (ED) is associated with coronary artery disease (CAD). In diabetic patients, CAD is often silent. Among diabetic patients with silent CAD, the prevalence of ED has never been evaluated. We investigated whether ED is associated with asymptomatic CAD in type 2 diabetic patients. Methods and Results-We evaluated the prevalence of ED in 133 uncomplicated diabetic men with angiographically verified silent CAD and in 127 diabetic men without myocardial ischemia at exercise ECG, 48-hour ambulatory ECG, and stress echocardiography. The groups were comparable for age and diabetes duration. Patients were screened for ED using the validated International Index of Erectile Function (IIEF-5) questionnaire. The prevalence of ED was significantly higher in patients with than in those without silent CAD (33.8% versus 4.7%; Pϭ0.000). Multiple logistic regression analysis showed that ED, apolipoprotein(a) polymorphism, smoking, microalbuminuria, HDL, and LDL were significantly associated with silent CAD; among these risk factors, ED appeared to be the most efficient predictor of silent CAD (OR, 14.8; 95% CI, 3.8 to 56.9). Conclusions-Our study first shows a strong and independent association between ED and silent CAD in apparently uncomplicated type 2 diabetic patients. If our findings are confirmed, ED may become a potential marker to identify diabetic patients to screen for silent CAD. Moreover, the high prevalence of ED among diabetics with silent CAD suggests the need to perform an exercise ECG before starting a treatment for ED, especially in patients with additional cardiovascular risk factors.

Baseline levels of OPN are an independent predictor of future adverse cardiac events in patients with CSA and may be useful for risk stratification.

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OBJECTIVE -In patients with uncomplicated diabetes, there is low probability of finding significant coronary artery disease (CAD) by noninvasive tests. Therefore, screening for its presence is not justified, and it is important to find reliable predictors of silent CAD to identify patients with uncomplicated diabetes for further screening. The relationship between lipoprotein(a) [Lp(a)], apolipoprotein(a) [apo(a)] polymorphism, and silent CAD has never been studied. We investigated the association of Lp(a) and apo(a) polymorphism with angiographically documented asymptomatic CAD in type 2 diabetic patients without evident complications. RESEARCH DESIGN AND METHODS-A total of 1,323 diabetic patients without any clinical and electrocardiographic evidence of CAD were evaluated. Of 121 patients with highly positive results of exercise electrocardiography (ECG) (n ϭ 30) or positive results on exercise thallium scintigraphy (n ϭ 91), 103 subjects showed angiographically documented CAD (CAD group). Of 1,106 patients with negative results on exercise ECG, 103 subjects without CAD (NO CAD group) were selected and matched by age, gender, and duration of diabetes to patients in the CAD group. In patients in the NO CAD group, results of exercise ECG, 48-h ambulatory ECG, and stress echocardiography were negative for CAD.RESULTS -The CAD group had higher Lp(a) levels (21.7 Ϯ 17.7 vs. 15.2 Ϯ 19.0 mg/dl; P ϭ 0.0093) than the NO CAD group, and a percentage of subjects had at least one small apo(a) isoform (68.9 vs. 29.1%; P ϭ 0.0000) higher than the NO CAD group. Logistic regression analysis showed that apo(a) phenotypes (odds ratio [OR] 8.13, 95% CI 3.65-21.23), microalbuminuria (5.38, 2.44 -11.88), smoking (2.72, 1.31-5.64), and Lp(a) levels (2.41, 1.15-5.03) were predictors of asymptomatic CAD. CONCLUSIONS -Our investigation reports the first evidence of an independent association of Lp(a) and apo(a) polymorphism with asymptomatic CAD. This suggests that Lp(a) levels and apo(a) phenotypes could be used together with other risk factors as markers of asymptomatic CAD in patients with diabetes. Diabetes Care 25:1418 -1424, 2002D iabetes is associated with a more than threefold-increased risk of coronary artery disease (CAD) (1). In patients with diabetes, CAD is often asymptomatic (2-4). Asymptomatic CAD is a strong predictor of future coronary events and early death, especially in patients with diabetes (5,6). Early identification of diabetic patients with silent CAD can allow reduction of mortality and morbidity for cardiovascular events (7,8). In patients with uncomplicated diabetes, there is low probability of finding significant CAD by noninvasive tests. Therefore, screening for its presence is not justified (2), and it is important to find reliable predictors of silent CAD to identify patients with uncomplicated diabetes for further screening.Lipoprotein(a) [Lp(a)] is a powerful risk factor for CAD (9). Recent studies report that the polymorphism of the specific apolipoprotein of Lp(a), called apolipoprotein(a) [apo(a)], ...