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Endothelial Function

October 2008

Endothelial functionEndothelial dysfunction: from molecular mechanisms to measurement, clinical implications, and therapeutic opportunities.

Endothelial dysfunction has been implicated as a key factor in the development of a wide range of cardiovascular diseases, but its definition and mechanisms vary greatly between different disease processes. This review combines evidence from cell-culture experiments, in vitro and in vivo animal models, and clinical studies to identify the variety of mechanisms involved in endothelial dysfunction in its broadest sense. Several prominent disease states, including hypertension, heart failure, and atherosclerosis, are used to illustrate the different manifestations of endothelial dysfunction and to establish its clinical implications in the context of the range of mechanisms involved in its development. The size of the literature relating to this subject precludes a comprehensive survey; this review aims to cover the key elements of endothelial dysfunction in cardiovascular disease and to highlight the importance of the process across many different conditions.

Antioxid Redox Signal. 2008 Sep;10(9):1631-74

Impaired endothelial and smooth muscle functions and arterial stiffness appear before puberty in obese children and are associated with elevated ambulatory blood pressure.

AIMS: To determine whether impaired brachial endothelial (flow-mediated dilation, FMD) and smooth muscle function (nitroglycerin-mediated dilation, NTGMD), and remodelling of the common carotid artery (CCA) develop before puberty in obese children. METHODS AND RESULTS: Arterial intima-media thickness (IMT), FMD and NTGMD were measured by high-resolution ultrasound in 48 obese and 23 lean pre-pubertal children (8.8 +/- 1.5 years old). We assessed central pulse pressure, incremental elastic modulus (Einc), casual and ambulatory systolic (SBP) and diastolic blood pressure (DBP), and body fatness by DXA. Obese children had significantly lower FMD (4.5 +/- 4.0 vs. 8.3 +/- 1.7%), NTGMD (19.0 +/- 9.0 vs. 25.8 +/- 6.1%), and increased Einc (13.9 +/- 5.2 vs. 10.4 +/- 5.2 mmHg/10(2)), ambulatory SBP (121.3 +/- 12.6 vs. 106.6 +/- 7.1, mmHg), and DBP (69.1 +/- 5.7 vs. 63.7 +/- 4.5) than lean subjects, whereas IMT was not augmented. Ambulatory systolic hypertension was present in 47% of obese subjects. FMD, NTGMD, and Einc were correlated with body fatness, body mass index, and blood pressure (BP). CONCLUSION: Impaired endothelial and smooth muscle functions and altered wall material develop before puberty in obese children, however remodelling of the CCA is not yet present. Arterial dysfunction may be considered as the first marker of atherosclerosis and is associated with elevated BP. Ambulatory blood pressure monitoring may be a potential tool to improve risk stratification in obese children.

Eur Heart J. 2008 Mar;29(6):792-9

Phenotypic heterogeneity of the endothelium: I. Structure, function, and mechanisms.

Endothelial cells, which form the inner cellular lining of blood vessels and lymphatics, display remarkable heterogeneity in structure and function. This is the first of a 2-part review focused on phenotypic heterogeneity of blood vessel endothelium. This review provides an historical perspective of our understanding of endothelial heterogeneity, discusses the scope of phenotypic diversity across the vascular tree, and addresses proximate and evolutionary mechanisms of endothelial cell heterogeneity. The overall goal is to underscore the importance of phenotypic heterogeneity as a core property of the endothelium.

Circ Res. 2007 Feb 2;100(2):158-73

Pathophysiology, diagnosis and prognostic implications of endothelial dysfunction.

Endothelial dysfunction (ED) in the setting of cardiovascular risk factors such as hypercholesterolemia, hypertension, diabetes mellitus, chronic smoking as well as in patients with heart failure has been shown to be at least in part dependent on the production of reactive oxygen species (ROS) such as superoxide and the subsequent decrease in vascular bioavailability of nitric oxide (NO). Methods to quantify endothelial dysfunction include forearm plethysmography, flow-dependent dilation of the brachial artery, finger-pulse plethysmography, pulse curve analysis, and quantitative coronary angiography after intracoronary administration of the endothelium-dependent vasodilator acetylcholine. Superoxide sources include the NADPH oxidase, xanthine oxidase, and mitochondria. Superoxide produced by the NADPH oxidase may react with NO released by the endothelial nitric oxide synthase (eNOS) thereby generating peroxynitrite (ONOO-), leading to eNOS uncoupling and therefore eNOS-mediated superoxide production. The present review will discuss current concepts of how to assess endothelial function, prognostic implications of ED, mechanisms underlying ED with focus on oxidative stress and circulating biomarkers, which have been proposed to indicate endothelial dysfunction and/or damage, respectively.

Ann Med. 2008;40(3):180-96

Sustained benefits in vascular function through flavanol-containing cocoa in medicated diabetic patients a double-masked, randomized, controlled trial.

OBJECTIVES: Our goal was to test feasibility and efficacy of a dietary intervention based on daily intake of flavanol-containing cocoa for improving vascular function of medicated diabetic patients. BACKGROUND: Even in fully medicated diabetic patients, overall prognosis is unfavorable due to deteriorated cardiovascular function. Based on epidemiological data, diets rich in flavanols are associated with a reduced cardiovascular risk. METHODS: In a feasibility study with 10 diabetic patients, we assessed vascular function as flow-mediated dilation (FMD) of the brachial artery, plasma levels of flavanol metabolites, and tolerability after an acute, single-dose ingestion of cocoa, containing increasing concentrations of flavanols (75, 371, and 963 mg). In a subsequent efficacy study, changes in vascular function in 41 medicated diabetic patients were assessed after a 30-day, thrice-daily dietary intervention with either flavanol-rich cocoa (321 mg flavanols per dose) or a nutrient-matched control (25 mg flavanols per dose). Both studies were undertaken in a randomized, double-masked fashion. Primary and secondary outcome measures included changes in FMD and plasma flavanol metabolites, respectively. RESULTS: A single ingestion of flavanol-containing cocoa was dose-dependently associated with significant acute increases in circulating flavanols and FMD (at 2 h: from 3.7 +/- 0.2% to 5.5 +/- 0.4%, p < 0.001). A 30-day, thrice-daily consumption of flavanol-containing cocoa increased baseline FMD by 30% (p < 0.0001), while acute increases of FMD upon ingestion of flavanol-containing cocoa continued to be manifest throughout the study. Treatment was well tolerated without evidence of tachyphylaxia. Endothelium-independent responses, blood pressure, heart rate, and glycemic control were unaffected. CONCLUSIONS: Diets rich in flavanols reverse vascular dysfunction in diabetes, highlighting therapeutic potentials in cardiovascular disease.

J Am Coll Cardiol. 2008 Jun 3;51(22):2141-9

Cocoa flavanols lower vascular arginase activity in human endothelial cells in vitro and in erythrocytes in vivo.

The availability of l-arginine can be a rate-limiting factor for cellular NO production by nitric oxide synthases (NOS). Arginase competes with NOS for l-arginine as the common substrate. Increased arginase activity has been linked to low NO levels, and an inhibition of arginase activity has been reported to improve endothelium-dependent vasorelaxation. Based on the above, we hypothesized that an increase in the circulating NO pool following flavanol consumption could be correlated with decreased arginase activity. To test this hypothesis we (a) investigated the effects of (-)-epicatechin and its structurally related metabolites on endothelial arginase expression and activity in vitro; (b) evaluated the effects of dietary flavanol-rich cocoa on kidney arginase activity in vivo; and (c) assessed human erythrocyte arginase activity following flavanol-rich cocoa beverage consumption in a double-blind intervention study with cross-over design. The results demonstrate that cocoa flavanols lower arginase-2 mRNA expression and activity in HUVEC. Dietary intervention with flavanol-rich cocoa caused diminished arginase activity in rat kidney and, erythrocyte arginase activity was lowered in healthy humans following consumption of a high flavanol beverage in vivo.

Arch Biochem Biophys. 2008 Aug 15;476(2):211-5

Acute dark chocolate and cocoa ingestion and endothelial function: a randomized controlled crossover trial.

BACKGROUND: Studies suggest cardioprotective benefits of dark chocolate containing cocoa. OBJECTIVE: This study examines the acute effects of solid dark chocolate and liquid cocoa intake on endothelial function and blood pressure in overweight adults. DESIGN: Randomized, placebo-controlled, single-blind crossover trial of 45 healthy adults [mean age: 53 y; mean body mass index (in kg/m(2)): 30]. In phase 1, subjects were randomly assigned to consume a solid dark chocolate bar (containing 22 g cocoa powder) or a cocoa-free placebo bar (containing 0 g cocoa powder). In phase 2, subjects were randomly assigned to consume sugar-free cocoa (containing 22 g cocoa powder), sugared cocoa (containing 22 g cocoa powder), or a placebo (containing 0 g cocoa powder). RESULTS: Solid dark chocolate and liquid cocoa ingestion improved endothelial function (measured as flow-mediated dilatation) compared with placebo (dark chocolate: 4.3 +/- 3.4% compared with -1.8 +/- 3.3%; P < 0.001; sugar-free and sugared cocoa: 5.7 +/- 2.6% and 2.0 +/- 1.8% compared with -1.5 +/- 2.8%; P < 0.001). Blood pressure decreased after the ingestion of dark chocolate and sugar-free cocoa compared with placebo (dark chocolate: systolic, -3.2 +/- 5.8 mm Hg compared with 2.7 +/- 6.6 mm Hg; P < 0.001; and diastolic, -1.4 +/- 3.9 mm Hg compared with 2.7 +/- 6.4 mm Hg; P = 0.01; sugar-free cocoa: systolic, -2.1 +/- 7.0 mm Hg compared with 3.2 +/- 5.6 mm Hg; P < 0.001; and diastolic: -1.2 +/- 8.7 mm Hg compared with 2.8 +/- 5.6 mm Hg; P = 0.014). Endothelial function improved significantly more with sugar-free than with regular cocoa (5.7 +/- 2.6% compared with 2.0 +/- 1.8%; P < 0.001). CONCLUSIONS: The acute ingestion of both solid dark chocolate and liquid cocoa improved endothelial function and lowered blood pressure in overweight adults. Sugar content may attenuate these effects, and sugar-free preparations may augment them.

Am J Clin Nutr. 2008 Jul;88(1):58-63

GliSODin, a vegetal sod with gliadin, as preventative agent vs. atherosclerosis, as confirmed with carotid ultrasound-B imaging.

Prevention of cardiovascular disease should target high-risk subjects based on genetic/familial factors, blood chemistry, blood pressure, body mass index (BMI), and a history of/or current cigarette smoking. We selected active adults (n=76) aged 30-60 and investigated these risk factors, in order to recommend preventive measures. Another interesting variable is the preclinical status or atheroma of the arterial (carotid) wall or lumen. We also investigated the presence of oxidative stress in, and the anti-oxidant status of these subjects. We studied the anti-oxidative efficacy of superoxide dismutase (SOD) and variations of malondialdehyde (MDA). Supplementation with GliSODin, a vegetal SOD associated with gliadin, was effective in controlling the thickness of the carotid artery intima and media layers as measured by ultrasonography-B. We could demonstrate the preventive efficacy of GliSODin at a preclinical stage in subjects with risk factors of cardiovascular disease.

Eur Ann Allergy Clin Immunol. 2007 Feb;39(2):45-50

Cocoa reduces blood pressure and insulin resistance and improves endothelium-dependent vasodilation in hypertensives.

Consumption of flavanol-rich dark chocolate (DC) has been shown to decrease blood pressure (BP) and insulin resistance in healthy subjects, suggesting similar benefits in patients with essential hypertension (EH). Therefore, we tested the effect of DC on 24-hour ambulatory BP, flow-mediated dilation (FMD), and oral glucose tolerance tests (OGTTs) in patients with EH. After a 7-day chocolate-free run-in phase, 20 never-treated, grade I patients with EH (10 males; 43.7+/-7.8 years) were randomized to receive either 100 g per day DC (containing 88 mg flavanols) or 90 g per day flavanol-free white chocolate (WC) in an isocaloric manner for 15 days. After a second 7-day chocolate-free period, patients were crossed over to the other treatment. Noninvasive 24-hour ambulatory BP, FMD, OGTT, serum cholesterol, and markers of vascular inflammation were evaluated at the end of each treatment. The homeostasis model assessment of insulin resistance (HOMA-IR), quantitative insulin sensitivity check index (QUICKI), and insulin sensitivity index (ISI) were calculated from OGTT values. Ambulatory BP decreased after DC (24-hour systolic BP -11.9+/-7.7 mm Hg, P<0.0001; 24-hour diastolic BP -8.5+/-5.0 mm Hg, P<0.0001) but not WC. DC but not WC decreased HOMA-IR (P<0.0001), but it improved QUICKI, ISI, and FMD. DC also decreased serum LDL cholesterol (from 3.4+/-0.5 to 3.0+/-0.6 mmol/L; P<0.05). In summary, DC decreased BP and serum LDL cholesterol, improved FMD, and ameliorated insulin sensitivity in hypertensives. These results suggest that, while balancing total calorie intake, flavanols from cocoa products may provide some cardiovascular benefit if included as part of a healthy diet for patients with EH.

Hypertension. 2005 Aug;46(2):398-405