Chronic cranberry juice consumption reduced carotid femoral pulse wave velocity-a clinically relevant measure of arterial stiffness. The uncontrolled pilot study suggested an acute benefit; however, no chronic effect on measures of endothelial vasodilator function was found. This trial was registered at clinicaltrials.gov as NCT00553904.

Background Abnormal endothelial function promotes atherosclerotic vascular disease in diabetes. Experimental studies indicate that disruption of endothelial insulin signaling through the activity of protein kinase C-β (PKCβ) and nuclear factor κB (NFκB) reduces nitric oxide availability. We sought to establish whether similar mechanisms operate in the endothelium in human diabetes mellitus. Methods and Results We measured protein expression and insulin response in freshly isolated endothelial cells from patients with Type 2 diabetes mellitus (n=40) and non-diabetic controls (n=36). Unexpectedly, we observed 1.7-fold higher basal endothelial nitric oxide synthase (eNOS) phosphorylation at serine 1177 in patients with diabetes (P=0.007) without a difference in total eNOS expression. Insulin stimulation increased eNOS phosphorylation in non-diabetic subjects but not in diabetic patients (P=0.003) consistent with endothelial insulin resistance. Nitrotyrosine levels were higher in diabetic patients indicating endothelial oxidative stress. PKCβ expression was higher in diabetic patients and was associated with lower flow-mediated dilation (r=−0.541, P=0.02) Inhibition of PKCβ with LY379196 reduced basal eNOS phosphorylation and improved insulin-mediated eNOS activation in patients with diabetes. Endothelial NFκB activation was higher in diabetes and was reduced with PKCβ inhibition. Conclusions We provide evidence for the presence of altered eNOS activation, reduced insulin action and inflammatory activation in the endothelium of patients with diabetes. Our findings implicate PKCβ activity in endothelial insulin resistance.

Epidemiological studies suggest that consumption of wine, grape products, and other foods containing polyphenols is associated with decreased risk for cardiovascular disease. The benefits of wine consumption appear to be greater than other alcoholic beverages. Experimental studies indicate that grape polyphenols could reduce atherosclerosis by a number of mechanisms, including inhibition of oxidation of LDL and other favorable effects on cellular redox state, improvement of endothelial function, lowering blood pressure, inhibition of platelet aggregation, reducing inflammation, and activating novel proteins that prevent cell senescence, e.g. Sirtuin 1. Translational studies in humans support these beneficial effects. More clinical studies are needed to confirm these effects and formulate dietary guidelines. The available data, however, strongly support the recommendation that a diet rich in fruits and vegetables, including grapes, can decrease the risk for cardiovascular disease.

We observed no effect of grape juice on ambulatory blood pressure in this cohort of relatively healthy individuals with modestly elevated blood pressure. Secondary analyses suggested favorable effects on nocturnal dip and glucose homeostasis that may merit further investigation. This trial was registered at clinicaltrials.gov as NCT00302809.

ObjectiveAlmonds reduce cardiovascular disease risk via cholesterol reduction, anti-inflammation, glucoregulation, and antioxidation. The objective of this randomized, controlled, cross-over trial was to determine whether the addition of 85 g almonds daily to a National Cholesterol Education Program (NCEP) Step 1 diet (ALM) for 6 weeks would improve vascular function and inflammation in patients with coronary artery disease (CAD).Research design and methodsA randomized, controlled, crossover trial was conducted in Boston, MA to test whether as compared to a control NCEP Step 1 diet absent nuts (CON), incorporation of almonds (85 g/day) into the CON diet (ALM) would improve vascular function and inflammation. The study duration was 22 weeks including a 6-weeks run-in period, two 6-weeks intervention phases, and a 4-weeks washout period between the intervention phases. A total of 45 CAD patients (27 F/18 M, 45–77 y, BMI = 20-41 kg/m2) completed the study. Drug therapies used by patients were stable throughout the duration of the trial.ResultsThe addition of almonds to the CON diet increased plasma α-tocopherol status by a mean of 5.8 %, reflecting patient compliance (P ≤0.05). However, the ALM diet did not alter vascular function assessed by measures of flow-mediated dilation, peripheral arterial tonometry, and pulse wave velocity. Further, the ALM diet did not significantly modify the serum lipid profile, blood pressure, C-reactive protein, tumor necrosis factor-α or E-selectin. The ALM diet tended to decrease vascular cell adhesion molecule-1 by 5.3 % (P = 0.064) and increase urinary nitric oxide by 17.5 % (P = 0.112). The ALM intervention improved the overall quality of the diet by increasing calcium, magnesium, choline, and fiber intakes above the Estimated Average Requirement (EAR) or Recommended Dietary Allowance (RDA).ConclusionsThus, the addition of almonds to a NECP Step 1 diet did not significantly impact vascular function, lipid profile or systematic inflammation in CAD patients receiving good medical care and polypharmacy therapies but did improve diet quality without any untoward effect.Trial registrationThe trial was registered with the ClinicalTrials.Gov with the identifier: NCT00782015.

Objective-Under physiological conditions, arteries remodel in response to changes in blood flow to maintain local shear stress. Risk factors and developing atherosclerosis may be associated with maladaptive remodeling that produces relatively large arteries with low levels of shear stress. Recent studies have shown that the brachial artery and other peripheral arteries are enlarged in patients with risk factors and cardiovascular disease, and we tested the hypothesis that this finding represents maladaptive remodeling. Methods and Results-We measured brachial artery diameter and flow by ultrasound and calculated shear stress in a diverse cohort of 1583 subjects (age 53Ϯ17 years, 62% male, and 51% with coronary artery disease and/or peripheral arterial disease). In a stepwise linear regression model, age (PϽ0.001), gender (PϽ0.001), body mass index (PϽ0.001), hypertension (Pϭ0.005), and hypercholesterolemia (Pϭ0.02) were associated with larger brachial diameter. Older age was associated with lower shear stress (PϽ0.01), consistent with maladaptive remodeling. However, body mass index, hypertension, hypercholesterolemia, and prevalent atherosclerosis were associated with proportionate changes in blood flow and no difference in shear stress compared to reference groups, suggesting adaptive remodeling. Conclusions-These findings suggest that enlargement of the brachial artery in the setting of obesity, hypertension, hypercholesterolemia, and atherosclerosis reflects adaptive remodeling. The results provide further support for the concept that arterial remodeling is an important homeostatic response that is maintained despite the presence of risk factors and developing atherosclerosis. Key Words: remodeling Ⅲ risk factors Ⅲ atherosclerosis Ⅲ shear stress Ⅲ brachial artery L ong-term changes in arterial blood flow stimulate parallel changes in arterial size. 1-3 Increased flow stimulates outward remodeling, whereas decreased flow produces a physiological reduction in arterial size. Such adaptive remodeling depends on normal endothelial function and activation of a local and self-limited inflammatory response in the arterial wall. 4 -6 Studies suggest that changes in shear stress at the endothelial surface provide the signal for remodeling. Because shear stress relates inversely to the cube of the lumen radius, an increase in lumen diameter after an increase in flow represents a homeostatic response that tends to restore shear stress toward baseline. [1][2][3] Arterial remodeling contributes to the development and clinical expression of atherosclerosis. As described by Glagov, coronary arteries initially undergo adaptive outward remodeling as atherosclerotic plaques impinge on the arterial lumen, although this mechanism is overwhelmed with increasing plaque burden. 7 Consistent with the idea that remodeling involves local inflammation, proinflammatory risk factors may be associated with excessive arterial remodeling that results in larger arteries with relatively low shear stress. 8,9 Low shear stress promotes a proat...

Inflammation is critical for atherosclerosis development and may be a target for risk-reduction therapy. In experimental studies, activation of the inflammatory regulator, nuclear factor kappa B (NFlB), contributes to endothelial activation and reduced nitric oxide production. We treated patients with coronary artery disease with sulfasalazine, an inhibitor of NFκB, and placebo in a randomized, double-blind, crossover study design. Brachial artery flow-mediated dilation (FMD) and digital vascular function were measured at baseline and after each 6-week treatment period. Of the 53 patients enrolled in the crossover study, 32 (age 60 ± 10, 22% female) completed all the visits, with a high rate of study withdrawal due to gastrointestinal side effects. In a subset of 10 participants, we compared the effects of 4 days of sulfasalazine treatment (n = 5) to no treatment (n = 5) on NFκB-regulated gene expression in peripheral blood mononuclear cells. Tumor necrosis factor α-stimulated expression of CD69 and NFlB subunit p50 was significantly blunted after 4 days of sulfasalazine treatment but not after no treatment. However, FMD and digital vasodilator response did not significantly change from baseline with long-term sulfasalazine treatment. Short-term sulfasalazine inhibited NFlB activity; however, long-term treatment was poorly tolerated and did not improve endothelial function. Our findings suggest that sulfasalazine therapy is not the optimal anti-inflammatory treatment for reversing endothelial dysfunction in cardiovascular disease. Further studies are warranted to investigate the potential for NFlB inhibition to reduce cardiovascular risk.