Endothelial dysfunction is now considered an important early event in the development of atherosclerosis, which precedes gross morphological signs and clinical symptoms. The assessment of flow-mediated dilation (FMD) was introduced almost 20 years ago as a noninvasive approach to examine vasodilator function in vivo. FMD is widely believed to reflect endothelium-dependent and largely nitric oxide-mediated arterial function and has been used as a surrogate marker of vascular health. This noninvasive technique has been used to compare groups of subjects and to evaluate the impact of interventions within individuals. Despite its widespread adoption, there is considerable variability between studies with respect to the protocols applied, methods of analysis, and interpretation of results. Moreover, differences in methodological approaches have important impacts on the response magnitude, can result in spurious data interpretation, and limit the comparability of outcomes between studies. This review results from a collegial discussion between physiologists with the purpose of developing considered guidelines. The contributors represent several distinct research groups that have independently worked to advance the evidence base for improvement of the technical approaches to FMD measurement and analysis. The outcome is a series of recommendations on the basis of review and critical appraisal of recent physiological studies, pertaining to the most appropriate methods to assess FMD in humans.

Defining new approaches for the prevention and treatment of atherosclerosis is an important priority. Recently, measurement of endothelial function in patients has emerged as a useful tool for atherosclerosis research. Risk factors are associated with impaired endothelial function, and clinical syndromes relate, in part, to a loss of endothelial control of vascular homeostasis. Recent studies have shown that the severity of endothelial dysfunction relates to cardiovascular risk. A growing number of interventions known to reduce cardiovascular risk have been shown to improve endothelial function. This work suggests that studies of endothelial function could be used in the care of patients and as a surrogate marker for the evaluation of new therapeutic strategies. This article will review this growing literature in an effort to evaluate the current clinical utility of endothelial dysfunction.

Background Endothelial dysfunction contributes to the development of atherosclerosis in patients with diabetes mellitus, but the mechanisms of endothelial dysfunction in this setting are incompletely understood. Recent studies have shown altered mitochondrial dynamics in diabetes mellitus with increased mitochondrial fission and production of reactive oxygen species (ROS). We investigated the contribution of altered dynamics to endothelial dysfunction in diabetes. Methods and Results We observed mitochondrial fragmentation (P=0.002) and increased expression of fission-1 protein (Fis1, P<0.0001) in venous endothelial cells freshly isolated from patients with diabetes mellitus (n=10) compared to healthy controls (n=9). In cultured human aortic endothelial cells exposed to 30 mM glucose, we observed a similar loss of mitochondrial networks and increased expression of Fis1 and dynamin-related protein-1 (Drp1), proteins required for mitochondrial fission. Altered mitochondrial dynamics was associated with increased mitochondrial ROS production and a marked impairment of agonist-stimulated activation of endothelial nitric oxide synthase (eNOS) and cGMP production. Silencing Fis1 or DRP1 expression with siRNA blunted high glucose-induced alterations in mitochondrial networks, ROS production, eNOS activation, and cGMP production. An intracellular ROS scavenger provided no additional benefit, suggesting that increased mitochondrial fission may impair endothelial function via increased ROS. Conclusions These findings implicate increased mitochondrial fission as a contributing mechanism for endothelial dysfunction in diabetic states.

Objectives-Sedentary lifestyle increases the risk of cardiovascular disease and diabetes. Vascular dysfunction contributes to atherogenesis and has been linked to insulin resistance. Methods and Results-We measured insulin sensitivity by glucose tolerance test and vascular function by ultrasound and venous occlusion plethysmography in 20 healthy subjects (14 men, 6 women) at baseline and during 5 days of bed rest.Bed rest led to a 67% increase in the insulin response to glucose loading (PϽ0.001) suggesting increased insulin resistance and produced increases in total cholesterol and triglycerides. Bed rest led to decreased reactive hyperemia in the forearm (1317Ϯ404 to 1112Ϯ260 mL/min, Pϭ0.01) and the calf (28.5Ϯ7.0 to 22.2Ϯ8.7 mL/min/dL, Pϭ0.003) indicating impaired microvascular function. Bed rest decreased brachial artery diameter and increased systolic blood pressure suggesting increased basal arterial tone. There were no changes in circulating inflammatory markers arguing against systemic inflammation as a mechanism for vascular dysfunction in this setting. Conclusions-Physical inactivity was associated with the development of insulin resistance, dyslipidemia, increased blood pressure, and impaired microvascular function in healthy volunteers. 3 Despite compelling evidence that physical inactivity is detrimental to cardiovascular health, over one quarter of all Americans engage in no leisure time physical activity. 4 The pathways leading from a sedentary lifestyle to insulin resistance and atherosclerosis are incompletely understood.Dysfunction of the vascular endothelium contributes to atherogenesis 5 and has been linked to sedentary lifestyle. In cross-sectional studies, sedentary individuals have impaired endothelial vasomotor function compared with those who are physically active. 6 Sedentary individuals also display impaired reactive hyperemia, 7 which is the increase in blood flow that occurs after transient ischemia and is a complex response that reflects both endothelium-dependent and endothelium-independent dilation of resistance vessels. 8 States of insulin resistance, including type 2 diabetes mellitus and obesity, are also associated with endothelial dysfunction. 9 Previous studies have demonstrated that short periods of inactivity lead to insulin resistance in humans. 10 -12 We hypothesized that insulin resistance induced by short-term physical inactivity would be associated with vascular dysfunction. This finding would lend further support to basic studies suggesting that insulin resistance and vascular dysfunction share common mechanisms. 13 Thus, we assessed vascular function and glucose tolerance before and after a 5-day period of strict bed rest in healthy subjects. Materials and Methods SubjectsHealthy nonsmoking volunteers were recruited for this study by newspaper and internet advertisement. Subjects were eligible if they had no clinical history of hypertension, diabetes mellitus, or hyperlipidemia, and were not taking any prescription medications. We sought individuals with preserved ...

alpha-Lipoic acid (LA), a naturally occurring dithiol compound, has long been known as an essential cofactor for mitochondrial bioenergetic enzymes. Aside from its enzymatic role, in vitro and in vivo studies suggest that LA also acts as a powerful micronutrient with diverse pharmacologic and antioxidant properties. Pharmacologically, LA improves glycemic control, polyneuropathies associated with diabetes mellitus, and effectively mitigates toxicities associated with heavy metal poisoning. As an antioxidant, LA directly terminates free radicals, chelates transition metal ions (e.g. iron and copper), increases cytosolic glutathione and vitamin C levels and prevents toxicities associated with their loss. These diverse actions suggest that LA acts by multiple mechanisms both physiologically and pharmacologically, many of which are only now being explored. Herein, we review the known biochemical properties of LA with particular reference to how LA may be an effective agent to ameliorate certain pathophysiologies of many chronic diseases.