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      Endothelial Cell Dysfunction and the Vascular Complications Associated with Type 2 Diabetes: Assessing the Health of the Endothelium

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          Abstract

          Diabetes-associated vascular complications are collectively the major clinical problems facing patients with diabetes and lead to the considerably higher mortality rate than that of the general population. People with diabetes have a much higher incidence of coronary artery disease as well as peripheral vascular diseases in part because of accelerated atherogenesis. Despite the introduction of new therapies, it has not been possible to effectively reduce the high cardiovascular morbidity and mortality associated with diabetes. Of additional concern is the recognition by the World Health Organization that we are facing a global epidemic of type 2 diabetes. Endothelial dysfunction is an early indicator of cardiovascular disease, including that seen in type 2 diabetes. A healthy endothelium, as defined in terms of the vasodilator/blood flow response to an endothelium-dependent vasodilator, is an important indicator of cardiovascular health and, therefore, a goal for corrective interventions. In this review we explore the cellular basis for endothelial dysfunction in an attempt to identify appropriate new targets and strategies for the treatment of diabetes. In addition, we consider the question of biomarkers for vascular disease and evaluate their usefulness for the early detection of and their role as contributors to vascular dysfunction.

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          Most cited references163

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          Endothelial dysfunction, oxidative stress, and risk of cardiovascular events in patients with coronary artery disease.

          Endothelial function is impaired in coronary artery disease and may contribute to its clinical manifestations. Increased oxidative stress has been linked to impaired endothelial function in atherosclerosis and may play a role in the pathogenesis of cardiovascular events. This study was designed to determine whether endothelial dysfunction and vascular oxidative stress have prognostic impact on cardiovascular event rates in patients with coronary artery disease. Endothelium-dependent and -independent vasodilation was determined in 281 patients with documented coronary artery disease by measuring forearm blood flow responses to acetylcholine and sodium nitroprusside using venous occlusion plethysmography. The effect of the coadministration of vitamin C (24 mg/min) was assessed in a subgroup of 179 patients. Cardiovascular events, including death from cardiovascular causes, myocardial infarction, ischemic stroke, coronary angioplasty, and coronary or peripheral bypass operation, were studied during a mean follow-up period of 4.5 years. Patients experiencing cardiovascular events (n=91) had lower vasodilator responses to acetylcholine (P<0.001) and sodium nitroprusside (P<0.05), but greater benefit from vitamin C (P<0.01). The Cox proportional regression analysis for conventional risk factors demonstrated that blunted acetylcholine-induced vasodilation (P=0.001), the effect of vitamin C (P=0.001), and age (P=0.016) remained independent predictors of cardiovascular events. Endothelial dysfunction and increased vascular oxidative stress predict the risk of cardiovascular events in patients with coronary artery disease. These data support the concept that oxidative stress may contribute not only to endothelial dysfunction but also to coronary artery disease activity.
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            Long-term follow-up of patients with mild coronary artery disease and endothelial dysfunction.

            Coronary endothelial dysfunction is characterized by vasoconstrictive response to the endothelium-dependent vasodilator acetylcholine. Although endothelial dysfunction is considered an early phase of coronary atherosclerosis, there is a paucity of information regarding the outcome of these patients. Thus, this study was designed to evaluate the outcome of patients with mild coronary artery disease on the basis of their endothelial function. Follow-up was obtained in 157 patients with mildly diseased coronary arteries who had undergone coronary vascular reactivity evaluation by graded administration of intracoronary acetylcholine, adenosine, and nitroglycerin and intracoronary ultrasound at the time of diagnostic study. Patients were divided on the basis of their response to acetylcholine into 3 groups: group 1 (n=83), patients with normal endothelial function; group 2 (n=32), patients with mild endothelial dysfunction; and group 3 (n=42), patients with severe endothelial dysfunction. Over an average 28-month follow-up (range, 11 to 52 months), none of the patients from group 1 or 2 had cardiac events. However, 6 (14%) with severe endothelial dysfunction had 10 cardiac events (P<0.05 versus groups 1 and 2). Cardiac events included myocardial infarction, percutaneous or surgical coronary revascularization, and/or cardiac death. Severe endothelial dysfunction in the absence of obstructive coronary artery disease is associated with increased cardiac events. This study supports the concept that coronary endothelial dysfunction may play a role in the progression of coronary atherosclerosis.
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              Prognostic value of coronary vascular endothelial dysfunction.

              Whether patients at increased risk can be identified from a relatively low-risk population by coronary vascular function testing remains unknown. We investigated the relationship between coronary endothelial function and the occurrence of acute unpredictable cardiovascular events (cardiovascular death, myocardial infarction, stroke, and unstable angina) in patients with and without coronary atherosclerosis (CAD). We measured the change in coronary vascular resistance (DeltaCVR) and epicardial diameter with intracoronary acetylcholine (ACh, 15 micro g/min) to test endothelium-dependent function and sodium nitroprusside (20 micro g/min) and adenosine (2.2 mg/min) to test endothelium-independent vascular function in 308 patients undergoing cardiac catheterization (132 with and 176 without CAD). Patients underwent clinical follow-up for a mean of 46+/-3 months. Acute vascular events occurred in 35 patients. After multivariate analysis that included CAD and conventional risk factors for atherosclerosis, DeltaCVR with ACh (P=0.02) and epicardial constriction with ACh (P=0.003), together with increasing age, CAD, and body mass index, were independent predictors of adverse events. Thus, patients in the tertile with the best microvascular responses with ACh and those with epicardial dilation with ACh had improved survival by Kaplan-Meier analyses in the total population, as did those in the subset without CAD. Similar improvement in survival was also observed when all adverse events, including revascularization, were considered. Endothelium-independent responses were not predictive of outcome. Epicardial and microvascular coronary endothelial dysfunction independently predict acute cardiovascular events in patients with and without CAD, providing both functional and prognostic information that complements angiographic and risk factor assessment.
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                Author and article information

                Journal
                Vasc Health Risk Manag
                Vascular Health and Risk Management
                Vascular Health and Risk Management
                Dove Medical Press
                1176-6344
                1178-2048
                March 2005
                : 1
                : 1
                : 55-71
                Affiliations
                School of Medical Sciences, RMIT University, Bundoora West Campus Bundoora, VIC, Australia
                Author notes
                Correspondence: Chris R Triggle, School of Medical Sciences, RMIT University, Bundoora West Campus, Plenty Road, Bundoora, VIC 3083, Australia Tel +61 3 9925 6537 Fax +61 3 9925 6555 Email chris.triggle@ 123456rmit.edu.au
                Article
                10.2147/vhrm.1.1.55.58939
                1993929
                17319098
                a8702585-10bd-4035-9cb5-b4974efe7931
                © 2005 Dove Medical Press Limited. All rights reserved
                History
                Categories
                Review

                Cardiovascular Medicine
                c-reactive protein (crp),asymmetric dimethylarginine (adma),endothelial progenitor cells (epcs),endothelium,diabetes,nitric oxide (no)

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