Endothelial dysfunction is involved in the development of atherosclerosis, which precedes asymptomatic structural vascular alterations as well as clinical manifestations of cardiovascular disease (CVD). Endothelial function can be assessed non-invasively using the flow-mediated dilation (FMD) technique. Flow-mediated dilation represents an endothelium-dependent, largely nitric oxide (NO)-mediated dilatation of conduit arteries in response to an imposed increase in blood flow and shear stress. Flow-mediated dilation is affected by cardiovascular (CV) risk factors, relates to coronary artery endothelial function, and independently predicts CVD outcome. Accordingly, FMD is a tool for examining the pathophysiology of CVD and possibly identifying subjects at increased risk for future CV events. Moreover, it has merit in examining the acute and long-term impact of physiological and pharmacological interventions in humans. Despite concerns about its reproducibility, the available evidence shows that highly reliable FMD measurements can be achieved when specialized laboratories follow standardized protocols. For this purpose, updated expert consensus guidelines for the performance of FMD are presented, which are based on critical appraisal of novel technical approaches, development of analysis software, and studies exploring the physiological principles underlying the technique. Uniformity in FMD performance will (i) improve comparability between studies, (ii) contribute to construction of reference values, and (iii) offer an easy accessible and early marker of atherosclerosis that could complement clinical symptoms of structural arterial disease and facilitate early diagnosis and prediction of CVD outcomes.

Expert consensus and evidence-based recommendations for the assessment of flow-mediated dilation in humans

Background—Adverse events in utero may predispose to cardiovascular disease in adulthood. The underlying mechanisms are unknown. During preeclampsia, vasculotoxic factors are released into the maternal circulation by the diseased placenta. We speculated that these factors pass the placental barrier and leave a defect in the circulation of the offspring that predisposes to a pathological response later in life. The hypoxia associated with high-altitude exposure is expected to facilitate the detection of this problem. Methods and Results—We assessed pulmonary artery pressure (by Doppler echocardiography) and flow-mediated dilation of the brachial artery in 48 offspring of women with preeclampsia and 90 offspring of women with normal pregnancies born and permanently living at the same high-altitude location (3600 m). Pulmonary artery pressure was roughly 30% higher (mean±SD, 32.1±5.6 versus 25.3±4.7 mm Hg; P<0.001) and flow-mediated dilation was 30% smaller (6.3±1.2% versus 8.3±1.4%; P<0.0001) in offspring o...

Pulmonary and Systemic Vascular Dysfunction in Young Offspring of Mothers With Preeclampsia

Background—Assisted reproductive technology (ART) involves the manipulation of early embryos at a time when they may be particularly vulnerable to external disturbances. Environmental influences during the embryonic and fetal development influence the individual's susceptibility to cardiovascular disease, raising concerns about the potential consequences of ART on the long-term health of the offspring. Methods and Results—We assessed systemic (flow-mediated dilation of the brachial artery, pulse-wave velocity, and carotid intima-media thickness) and pulmonary (pulmonary artery pressure at high altitude by Doppler echocardiography) vascular function in 65 healthy children born after ART and 57 control children. Flow-mediated dilation of the brachial artery was 25% smaller in ART than in control children (6.7±1.6% versus 8.6±1.7%; P<0.0001), whereas endothelium-independent vasodilation was similar in the 2 groups. Carotid-femoral pulse-wave velocity was significantly (P<0.001) faster and carotid intima-medi...

Systemic and Pulmonary Vascular Dysfunction in Children Conceived by Assisted Reproductive Technologies

Background—Because traditional nonsteroidal antiinflammatory drugs are associated with increased risk for acute cardiovascular events, current guidelines recommend acetaminophen as the first-line analgesic of choice on the assumption of its greater cardiovascular safety. Data from randomized clinical trials prospectively addressing cardiovascular safety of acetaminophen, however, are still lacking, particularly in patients at increased cardiovascular risk. Hence, the aim of this study was to evaluate the safety of acetaminophen in patients with coronary artery disease. Methods and Results—The 33 patients with coronary artery disease included in this randomized, double-blind, placebo-controlled, crossover study received acetaminophen (1 g TID) on top of standard cardiovascular therapy for 2 weeks. Ambulatory blood pressure, heart rate, endothelium-dependent and -independent vasodilatation, platelet function, endothelial progenitor cells, markers of the renin-angiotensin system, inflammation, and oxidative ...

Acetaminophen Increases Blood Pressure in Patients With Coronary Artery Disease

Objective: Impaired flow-mediated dilation (FMD) isassociated with cardiovascular risk factors and providesprognostic information. Despite the noninvasive nature ofthis technique, a major limitation to its widespread use islow reproducibility. The aim of this study was to evaluateimpact of methodological standardization amongdifferent investigation sites on brachial artery FMDreproducibility.Methods: Seven Italian centers recruited 135 healthyvolunteers, aged 20–60 years. FMD was assessed byhigh-resolution ultrasound equipped with a stereotacticprobe-holding device. Certified sonographers recordedbrachial artery scans at baseline (day 1a), 1 h after (day1b), and 1 month later (day 30). Endothelium-independentvasodilation (EIVD) to sublingual glyceril-trinitrate wasrecorded at day 1 and day 30. FMD and EIVD were blindlyevaluated at the coordinating center by an automatededge detection system. The intra-session (day 1a versus1b) and inter-session (day 1a versus 30) coefficients ofvariation were calculated.Results: FMD was not significantly (P¼0.91) differentat day 1a, day 1b and day 30 (6.52 2.9, 6.42 3.1,6.57 2.8%, respectively). The FMD intra-sessioncoefficient of variation was 9.9 8.4% (from 7.6 to11.9% across centers). The FMD inter-session coefficient ofvariation was 12.9 11.6% (from 11.6 to 16.1% acrosscenters). Inter-session coefficient of variation for EIDV was19.7 16.8%.Conclusions: This study shows a homogeneous coefficientof variation for FMD among different centers. The inter-session coefficient of variation was similar to the intra-session coefficient of variation, representing the intrinsicFMD variability. We demonstrate for the first time thatrigorous and standardized procedure may providereproducible FMD assessment to study endothelial functionin multicenter clinical trials.Keywords: endothelial function, flow-mediated dilation,multicenter study, reproducibilityAbbreviations: ANOVA, analysis of variance; BP, bloodpressure; CI, confidence intervals; EIDV, endothelium-independent vasodilation; FMD, flow mediated dilation;GTN, glyceril trinitrate; SD, standard deviation

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Assessment of flow-mediated dilation reproducibility: a nationwide multicenter study

The measurement of the brachial artery diameter is frequently used in clinical studies for evaluating the flow-mediated dilation and, in conjunction with the blood pressure value, for assessing arterial stiffness. This paper presents a system for computing the brachial artery diameter in real-time by analyzing B-mode ultrasound images. The method is based on a robust edge detection algorithm which is used to automatically locate the two walls of the vessel. The measure of the diameter is obtained with subpixel precision and with a temporal resolution of 25 samples/s, so that the small dilations induced by the cardiac cycle can also be retrieved. The algorithm is implemented on a standalone video processing board which acquires the analog video signal from the ultrasound equipment. Results are shown in real-time on a graphical user interface. The system was tested both on synthetic ultrasound images and in clinical studies of flow-mediated dilation. Accuracy, robustness, and intra/inter observer variability of the method were evaluated

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E. Poggianti

Papers

A System for Real-Time Measurement of the Brachial Artery Diameter in B -Mode Ultrasound Images