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 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hypertension is a major healthcare problem afflicting nearly 50 million individuals in the United States. Despite its strong causal association with cardiovascular disease complications including myocardial infarction, heart failure, and stroke, the majority of patients with hypertension do not achieve optimal blood pressure control. The prevalence of hypertension is expected to increase with the aging population, growing obesity epidemic, and rising incidence of metabolic syndrome. Endothelial dysfunction and reduced nitric oxide (NO) bioactivity represent prominent pathophysiological abnormalities associated with hypertensive cardiovascular disease. Individuals with hypertension exhibit blunted epicardial and resistance vascular dilation to endothelium-derived nitric oxide (EDNO) agonists in the peripheral and coronary circulation that likely contributes to mechanisms of altered vascular tone in hypertension. The amino acid L-arginine serves as the principal substrate for vascular NO production. Numerous studies, though not uniformly, demonstrate a beneficial effect of acute and chronic L-arginine supplementation on EDNO production and endothelial function, and L-arginine has been shown to reduce systemic blood pressure in some forms of experimental hypertension. This brief review discusses the potential role of L-arginine in hypertension, and reviews possible mechanisms of L-arginine action including modulation of EDNO production, alteration of asymmetrical dimethylarginine (ADMA):L-arginine balance, and possible improvement of insulin sensitivity. In view of the rising prevalence of hypertension, randomized human clinical studies investigating the potential therapeutic role of L-arginine may be warranted.
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PMID:L-arginine and hypertension. 1546 90

The metabolic syndrome is a cluster of metabolic and vascular abnormalities that include central obesity, insulin resistance, hyperinsulinemia, glucose intolerance, hypertension, dyslipidemia, hypercoagulability and an increased risk of coronary and cerebral vascular disease. These metabolic and vascular abnormalities are the main cause of cardiovascular mortality in western societies. Endothelial dysfunction, an early step in the development of atherosclerosis, has been reported in obese nondiabetic individuals and in patients with Type 2 diabetes. It has also been observed in individuals at high risk for Type 2 diabetes, including those with impaired glucose tolerance and the normoglycemic first-degree relatives of Type 2 diabetic patients. Recent evidence points to adipocytes as a complex and active endocrine tissue whose secretory products, including free fatty acids and several cytokines (i.e., leptin, adiponectin, tissue necrosis factor-alpha, interleukin-6, and resistin) play a major role in the regulation of human metabolic and vascular biology. These adipocytokines have been claimed to be the missing link between insulin resistance and cardiovascular disease. Interventions designed to improve endothelial and/or adipose-tissue functions may reduce cardiovascular events in obese individuals with either the metabolic syndrome or Type 2 diabetes. Lifestyle modification in the form of caloric restriction and increased physical activity are the most common modalities used for treating those individuals at risk and is unanimously agreed to be the initial step in managing Type 2 diabetes. Several recent studies have demonstrated favorable impacts of lifestyle modifications in improving endothelial function and insulin sensitivity, in addition to altering serum levels of adipocytokines and possibly reducing cardiovascular events. This review discusses current knowledge of the role of lifestyle modifications in ameliorating cardiovascular risk in obese subjects with either the metabolic syndrome or Type 2 diabetes.
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PMID:Lifestyle modification and endothelial function in obese subjects. 1585 97

Atherosclerotic CVD is the most common cause of death in the West. Yet, its pathogenesis and early development are only partially understood. Central to the early atherosclerotic process is impairment of vascular endothelial function. Endothelial dysfunction can be measured non-invasively and is evident in children before clinical manifestations of atherosclerosis in adulthood. Factors in early life, such as conventional cardiovascular risk factors, or programming by perinatal growth and nutrition strongly affect endothelial function and hence the development of atherosclerosis and CVD. For instance, low birth weight and faster growth early in infancy have a detrimental effect on vascular structure and function. Childhood obesity, a key independent risk factor for CVD, also adversely affects early vascular health. Obesity is associated with endothelial dysfunction and greater arterial stiffness from as early as the first decade of life, while weight loss is beneficial. This effect on vascular function is probably mediated in part by low-grade inflammation and insulin resistance associated with obesity or by the production by adipose tissue of cytokine-like molecules, collectively termed adipokines. A high leptin concentration, in particular, is found in obese individuals and is strongly associated with vascular changes related to early atherosclerosis. The present review focuses on the early origins of endothelial dysfunction, emphasising the role of obesity. It also considers the mechanisms by which obesity impairs endothelial function, understanding of which will be important to further scientific knowledge and to improve public health.
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PMID:Endothelial dysfunction: role in obesity-related disorders and the early origins of CVD. 1587 18

Noninvasive assessment of vascular dysfunction in the pediatric population has taken advantage of the development of high-resolution ultrasound techniques. The most frequently used methods are the quantification of flow-mediated endothelium-dependent dilation of the brachial artery and measurement of the intima-media thickening of the carotid artery. Both reduced flow-mediated dilation and increased intima-media thickness have been proven to correlate with late cardiovascular events and/or mortality in adults. As these noninvasive methods can easily be applied in children, there have been recent investigations in high-risk pediatric patients harboring classical cardiovascular risk factors. Endothelial dysfunction and increased thickness of the intima media are currently observed in children with familial hypercholesterolemia, obesity, and type 1 diabetes mellitus. The association of early vascular dysfunction with a known risk factor is an important issue as these anomalies precede the formation of atherosclerotic plaques. Therefore, they may help in stratification of the risk for cardiovascular event and to better tailor therapeutic interventions in at risk children. Finally, these methods have been applied in specific pediatric populations, such as children with end-stage renal disease, chronic parenteral nutrition, HIV infection, and coarctation of the aorta. In these conditions, endothelial dysfunction and vascular remodeling are also present early in life and these data raise new possibilities in the understanding of the pathogenesis of atherosclerosis in these populations.
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PMID:Noninvasive assessment of arterial stiffness and risk of atherosclerotic events in children. 1605 29

Fibric acid is a synthetic ligand of the nuclear receptor peroxisome proliferator-activated receptor (PPAR)-alpha that is highly expressed in skeletal muscle and heart, where it promotes beta-oxidation of fatty acids to mediate hypolipidemic actions. PPAR-alpha regulates expression of key proteins involved in atherogenesis, vascular inflammation, plaque instability, and thrombosis. Thus, PPAR-alpha may exert direct antiatherogenic actions in the vascular wall. Endothelial dysfunction associated with the metabolic syndrome and other insulin-resistant states is characterized by impaired insulin-stimulated nitric oxide production from the endothelium and decreased blood flow to skeletal muscle. Thus, improvement in insulin sensitivity leads to improved endothelial function. This may be an additional mechanism whereby fibrates decrease the incidence of coronary heart disease. Adiponectin is a protein secreted specifically by adipose cells that may couple regulation of insulin sensitivity with energy metabolism and serve to link obesity with insulin resistance. In this review, we discuss the mechanisms underlying the vascular and metabolic effects of fibrates that may act synergistically to prevent or regress atherosclerosis and coronary heart disease.
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PMID:Beneficial vascular and metabolic effects of peroxisome proliferator-activated receptor-alpha activators. 1623 May 15

Obesity is associated with increased cardiovascular morbidity and amortality. Endothelial dysfunction, involved in the pathogenesis of cardiovascular events, has been demonstrated in obese patients with invasive techniques requiring artery catheterization. The aim of our investigation was to evaluate, with a non-invasive method readily employable on clinical grounds, impaired vasodilatation and its relationship with insulin resistance in uncomplicated obesity. 15 uncomplicated obese subjects (BMI = 36.6 +/- 3.2) and 10 lean controls (BMI = 22.9 +/- 1.25) were enrolled in this study. All subjects underwent measurement of endothelium-dependent (FBFr) vasodilatation by forearm venous occlusion pletysmography after increasing times of ischemia, and measurement of insulin sensitivity by the euglycemic hyperinsulinemic clamp technique (M index), by fasting glucose and insulin (HOMA-IR) and by oral glucose tolerance test (ISI index). Endothelium-independent (N-FBFr) vasodilatation was assessed as well. The FBFr was markedly blunted in obese patients versus lean controls (30 s: 2.12 +/- 0.34 vs. 3.63 +/- 0.22, P < 0.01; 60 s: 2.34 +/- 0.42 vs. 3.82 +/- 0.53, P < 0.01; 180 s: 3.20 +/- 0.45 vs. 7.15 +/- 0.35, P < 0.01; 300 s: 4.08 +/- 0.94 vs. 14.1 +/- 0.82, P < 0.001). The N-FBFr was not different in the two groups. High correlation was found between M index and FBFr at all ischemia times. HOMA-IR and ISI were not related with FBFr. The non-invasive evaluation of endothelial dysfunction by a simple and reliable method based on venous occlusive plethysmography shows high correlation between impaired endothelium-dependent vasodilatation and insulin resistance in uncomplicated obesity. This non-invasive test of endothelial function may be routinely performed in the assessment of cardiovascular risk in uncomplicated obesity.
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PMID:Non-invasive evaluation of endothelial dysfunction in uncomplicated obesity: relationship with insulin resistance. 1643 62

Endothelial dysfunction may precede development of type 2 diabetes. We tested the hypothesis that elevated levels of hemostatic markers of endothelial dysfunction, plasminogen activator inhibitor-1 (PAI-1) antigen, and von Willebrand factor (vWF) antigen predicted incident diabetes independent of other diabetes risk factors. We followed 2,924 Framingham Offspring subjects (54% women, mean age 54 years) without diabetes at baseline (defined by treatment, fasting plasma glucose > or =7 or 2-h postchallenge glucose > or =11.1 mmol/l) over 7 years for new cases of diabetes (treatment or fasting plasma glucose > or =7.0 mmol/l). We used a series of regression models to estimate relative risks for diabetes per interquartile range (IQR) increase in PAI-1 (IQR 16.8 ng/ml) and vWF (IQR 66.8% of control) conditioned on baseline characteristics. Over follow-up, there were 153 new cases of diabetes. Age- and sex-adjusted relative risks of diabetes were 1.55 per IQR for PAI-1 (95% CI 1.41-1.70) and 1.49 for vWF (1.21-1.85). These effects remained after further adjustment for diabetes risk factors (including physical activity; HDL cholesterol, triglyceride, and blood pressure levels; smoking; parental history of diabetes; use of alcohol, nonsteroidal anti-inflammatory drugs, exogenous estrogen, or hypertension therapy; and impaired glucose tolerance), waist circumference, homeostasis model assessment of insulin resistance, and inflammation (assessed by levels of C-reactive protein): the adjusted relative risks were 1.18 per IQR for PAI-1 (1.01-1.37) and 1.39 for vWF (1.09-1.77). We conclude that in this community-based sample, plasma markers of endothelial dysfunction increased risk of incident diabetes independent of other diabetes risk factors including obesity, insulin resistance, and inflammation.
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PMID:Hemostatic markers of endothelial dysfunction and risk of incident type 2 diabetes: the Framingham Offspring Study. 1644 91

Endothelial dysfunction contributes to cardiovascular diseases, including hypertension, atherosclerosis, and coronary artery disease, which are also characterized by insulin resistance. Insulin resistance is a hallmark of metabolic disorders, including type 2 diabetes mellitus and obesity, which are also characterized by endothelial dysfunction. Metabolic actions of insulin to promote glucose disposal are augmented by vascular actions of insulin in endothelium to stimulate production of the vasodilator nitric oxide (NO). Indeed, NO-dependent increases in blood flow to skeletal muscle account for 25% to 40% of the increase in glucose uptake in response to insulin stimulation. Phosphatidylinositol 3-kinase-dependent insulin-signaling pathways in endothelium related to production of NO share striking similarities with metabolic pathways in skeletal muscle that promote glucose uptake. Other distinct nonmetabolic branches of insulin-signaling pathways regulate secretion of the vasoconstrictor endothelin-1 in endothelium. Metabolic insulin resistance is characterized by pathway-specific impairment in phosphatidylinositol 3-kinase-dependent signaling, which in endothelium may cause imbalance between production of NO and secretion of endothelin-1, leading to decreased blood flow, which worsens insulin resistance. Therapeutic interventions in animal models and human studies have demonstrated that improving endothelial function ameliorates insulin resistance, whereas improving insulin sensitivity ameliorates endothelial dysfunction. Taken together, cellular, physiological, clinical, and epidemiological studies strongly support a reciprocal relationship between endothelial dysfunction and insulin resistance that helps to link cardiovascular and metabolic diseases. In the present review, we discuss pathophysiological mechanisms, including inflammatory processes, that couple endothelial dysfunction with insulin resistance and emphasize important therapeutic implications.
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PMID:Reciprocal relationships between insulin resistance and endothelial dysfunction: molecular and pathophysiological mechanisms. 1661 33

Endothelial dysfunction is associated with several vascular conditions as atherosclerosis, hypertension, hyperlipidemia and diabetes mellitus. In all these conditions insulin resistance (IR) is present. Cytokines are low molecular weight proteins with several endocrine and metabolic functions that participate of inflammation and immune response. Several of these cytokines are independent risk factors for cerebrovascular and coronary artery disease. The major sources of cytokines (adipokines) are the visceral and subcutaneous adipose tissues. Thus, increased adipose tissue mass is associated with alteration in adipokine production as over expression of tumor necrosis factor alpha, interleukin 6, plasminogen activator inhibitor 1, and under expression of adiponectin in adipocite tissue. The pro-inflammatory status associated with these changes provides a potential link between IR and endothelial dysfunction, the early stage in the atherosclerotic process, in obese individuals, and type 2 diabetic patients. Reduction of adipose tissue mass through weight reduction in association with exercise reduces TNF-alpha, IL-6, and PAI-1, increases adiponectin, and is associated with improved insulin sensitivity and endothelial function. This review will focus on the evidence for regulation of endothelial function by insulin and the adypokines such as adyponectin, leptin, resistin, IL-6 and TNF-alpha. Interaction between insulin signaling and adypokines will be discussed, as well as the concept that aberrant adypokine secretion in IR and/or obesity impairs endothelial function and contributes further to reduce insulin sensitivity.
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PMID:[Cytokines, endothelial dysfunction, and insulin resistance]. 1676 96

Endothelial dysfunction has been identified as a major predictor of future cardiovascular events and precedes the development of coronary artery disease (CAD). Regular physical exercise training--as part of a multifactorial intervention--corrects endothelial dysfunction, improves symptoms in patients with CAD, augments myocardial perfusion, and reduces mortality of these patients. This review discusses potential mechanisms, which might be responsible for the exercise training-mediated reduction of mortality in secondary prevention. The activation of stem cells, which are known to regenerate damaged endothelium and promote the development of new vessels by vasculogenesis, the regression of atherosclerosis, the formation of collaterals, and the partial correction of endothelial dysfunction as a consequence of molecular adaptations will be evaluated in this context. However, the positive effects of exercise training in primary and secondary prevention of cardiovascular diseases are not restricted to the correction of endothelial dysfunction. Regular physical activity, either alone or as part of a multifactorial intervention consisting of diet and exercise training, is known to promote effective weight loss. Especially in patients with metabolic syndrome, weight reduction beneficially effects blood glucose control. It increases the levels of vasculoprotective high-density lipoprotein and augments the physical exercise capacity of these individuals. Additionally, regular physical activity attenuates the diet-induced loss in fat-free body mass by 50%, improves body composition and counteracts the reduction in basal energy expenditure, which is another big advantage compared to diet alone in the treatment of obesity. Moreover, physical exercise training is essential to maintain a body weight that has been achieved by caloric restriction. It is important to look for exercise interventions that can easily be integrated in daily life and are not associated with an increased risk of trauma, even in severely obese individuals. Most importantly, patients should enjoy the proposed kind of physical exercise.
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PMID:[Exercise training in the treatment of coronary artery disease and obesity]. 1677 May 59


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