Vascular Dysfunction In Patients Research Articles

N(carboxymethyl)lysine as a biomarker for microvascular complications in type 2 diabetic patients

Hyperglycemia is linked to vascular dysfunction in patients with diabetes mellitus, either directly or through advanced glycation end product (AGE) formation. Experimental evidence has indicated the possible involvement of AGEs in the genesis of vascular complications. We investigated whether serum levels of AGEs and of the glycoxidation compound carboxymethyl-lysine (CML) were increased and correlated with vascular complications in type II diabetes mellitus. Serum levels of AGEs and CML-human serum protein (CML-HSP) were measured by a specific immunoassay in 51 men and 26 women aged 58 +/- 6.1 years (mean +/- SD) who had been treated for type II diabetes mellitus for 11 +/- 8 years, and in a non-diabetic control group consisting of 39 men and 21 women aged 55.5 +/- 7.5 years. Patients with macroalbuminuria or abnormal creatinine clearance were excluded from the study. The serum levels of AGEs were significantly increased in patients with type II diabetes compared to controls (P<0.001). Blood levels of CML-HSP were significantly increased in diabetic patients compared to normal subjects [35.3 +/- 27.4 and 9.3 +/- 7.2 (mean +/- SD) pmol/mg of protein, respectively; P<0.0001]. In diabetic patients with retinopathy or microalbuminuria (urinary albumin excretion: UAE > 30 mg/24 h), CML-HSP levels were significantly higher (P<0.02), and even more elevated in patients with both complications. In patients with type II diabetes, CML-HSP levels that are at variance with the HbA(1c) index for blood glucose may be a biomarker of glycoxidation, and related to the development of microvascular complications.

Relationship between vascular dysfunction in peripheral arteries and ischemic episodes during daily life in patients with ischemic heart disease and hypercholesterolemia

Background It is well established that endothelial dysfunction is present in patients with ischemic heart disease and hypercholesterolemia. Some of these patients will have signs of transient myocardial ischemia during Holter monitoring. We sought to describe the correlation between daily life ischemia and signs of endothelial dysfunction as assessed by means of brachial vasoreactivity. Methods We included in the study 131 patients with documented ischemic heart disease and a serum cholesterol level of ≥5 mmol/L before the institution of lipid-lowering treatment and dietary intervention. Results Satisfactory 48-hour Holter recordings and ultrasound scans of the brachial artery were obtained in 119 patients. During 5712 hours of ambulatory monitoring, 181 episodes of transient ST-segment depression with a mean duration of 52 ± 66 minutes were recorded in 31 patients. The mean percentage dilatation of the brachial artery after occlusion was 4.38% ± 5.66%; after nitroglycerin administration, it was 13.86% ± 7.06%. By means of Spearman correlation analysis, the number of ischemic episodes and degree of flow-mediated vasodilatation and nitroglycerin-mediated vasodilatation were significantly negatively correlated (r = −0.249, P =.006 and r = −0.302, P =.02, respectively). In a linear regression model, the presence of ischemic episodes was a significant predictor of impaired flow-mediated vasodilatation (β = −3.31, P <.01), even after the adjustment for vessel size and classic cardiovascular risk factors. Conclusions These results indicate a significant relationship between ischemic episodes and vascular dysfunction in patients with ischemic heart disease and hypercholesterolemia and may justify an aggressive preventive therapy targeted directly at the endothelium. (Am Heart J 2002;144:108-14.)

Basal nitric oxide production is not reduced in patients with noninsulin-dependent diabetes mellitus.

Vascular disease is the leading cause of morbidity, disability and death in patients with noninsulin-dependent diabetes mellitus. Abnormalities in endothelium-derived nitric oxide (NO) have been demonstrated to be involved in the pathogenesis of vascular disease. By measuring hemodynamic responses to a NO synthase agonist or antagonist, previous studies have shown the presence of NO deficiency in patients with noninsulin-dependent diabetes mellitus, a method of assessing bioactive NO formation. However, direct biochemical evidence that this is the case, has not been produced. In vivo NO is metabolized into nitrate, an end breakdown product of NO, which can be used as an index of endogenous NO formation. To investigate further whether decreased basal synthesis of NO may be a major cause of endothelium-mediated vascular dysfunction in patients with noninsulin-dependent diabetes mellitus, the plasma nitrite/nitrate levels of 15 patients were examined and compared with 13 normal controls. The results showed that in basal conditions plasma nitrite/nitrate levels were not reduced in diabetic patients compared with normal controls (37.3 +/- 14.7 versus 29.4 +/- 8.6 mumol/l). It was concluded that in noninsulin-dependent diabetes mellitus patients, endothelium-derived basal NO formation is not impaired. This study, taken with previous observations, suggests that factors other than diminished basal NO production, such as reduced bioavailability of NO probably due to the augmented production of superoxide anion with subsequently increased inactivation of NO, contribute to the high incidence of vascular disease in patients with noninsulin-dependent diabetes mellitus.

Recombinant advanced glycation end product receptor pharmacokinetics in normal and diabetic rats.

Vascular dysfunction in patients with diabetes mellitus is related to advanced glycation end product (AGE) formation. We previously showed that AGEs produce an increase in vascular permeability and generated an oxidant stress after binding to the receptor (RAGE) present on endothelium. RAGE, a 35-kDa protein that belongs to the immunoglobulin superfamily, has been cloned from a rat lung cDNA library, and recombinant rat soluble RAGE (rR-RAGE) has been produced in insect cells. The sequence of RAGE is highly conserved between human and rat. We studied the biological effect of rR-RAGE and pharmacokinetics of 125I-rR-RAGE after intravenous or intraperitoneal administration in normal and streptozotocin-induced diabetic rats. rR-RAGE prevented albumin or inulin transfer through a bovine aortic endothelial cell monolayer, restored the hyperpermeability observed in diabetic rats or induced in normal rats by diabetic rat red blood cells, and corrected the reactive oxygen intermediate production after intravenous or intraperitoneal administration. After intravenous injection of 125I-rR-RAGE, the distribution half-life was longer (p < or = 0.01) in diabetic (0.15 and 4.01 hr) than in normal (0.02 and 0.21 hr) rats, as was the case for the elimination half-lives (diabetic, 57.17 hr; normal, 26.02 hr; p < or = 0.01). Distribution volume was higher in diabetic than in normal rats (6.94 and 3.24 liter/kg, respectively; p = 0.049). Our study showed that rR-RAGE was biologically active in vivo and slowly cleared, which suggests it could be considered as a potential therapy.