Endothelial Function Assessment by Flow-Mediated Dilation Method: A Valuable Tool in the Evaluation of the Cardiovascular System.

Cardiovascular diseases (CVDs) in the course of atherosclerosis are one of the most critical public health problems in the world. Endothelial cells synthesize numerous biologically active substances involved in regulating the functions of the cardiovascular system. Endothelial dysfunction is an essential element in the pathogenesis of atherosclerosis. Thus, the assessment of endothelial function in people without overt CVD allows for a more accurate estimate of the risk of developing CVD and cardiovascular events. The assessment of endothelial function is primarily used in scientific research, and to a lesser extent in clinical practice. Among the tools for assessing endothelial function, we can distinguish biochemical and physical methods, while physical methods can be divided into invasive and non-invasive methods. Flow-mediated dilation (FMD) is based on the ultrasound assessment of changes in the diameter of the brachial artery as a result of increased blood flow. FMD is a non-invasive, safe, and repeatable test, but it must be performed by qualified and experienced medical staff. The purpose of this paper is to present the literature review results on the assessment of endothelial function using the FMD method, including its methodology, applications in clinical practice and research, limitations, and future perspectives.

Volumetric coronary endothelial function assessment: a feasibility study exploiting stack-of-stars 3D cine MRI and image-based respiratory self-gating.

Abnormal coronary endothelial function (CEF), manifesting as depressed vasoreactive responses to endothelial-specific stressors, occurs early in atherosclerosis, independently predicts cardiovascular events, and responds to cardioprotective interventions. CEF is spatially heterogeneous along a coronary artery in patients with atherosclerosis, and thus recently developed and tested non-invasive 2D MRI techniques to measure CEF may not capture the extent of changes in CEF in a given coronary artery. The purpose of this study was to develop and test the first volumetric coronary 3D MRI cine method for assessing CEF along the proximal and mid-coronary arteries with isotropic spatial resolution and in free-breathing. This approach, called 3D-Stars, combines a 6 min continuous, untriggered golden-angle stack-of-stars acquisition with a novel image-based respiratory self-gating method and cardiac and respiratory motion-resolved reconstruction. The proposed respiratory self-gating method agreed well with respiratory bellows and center-of-k-space methods. In healthy subjects, 3D-Stars vessel sharpness was non-significantly different from that by conventional 2D radial in proximal segments, albeit lower in mid-portions. Importantly, 3D-Stars detected normal vasodilatation of the right coronary artery in response to endothelial-dependent isometric handgrip stress in healthy subjects. Coronary artery cross-sectional areas measured using 3D-Stars were similar to those from 2D radial MRI when similar thresholding was used. In conclusion, 3D-Stars offers good image quality and shows feasibility for non-invasively studying vasoreactivity-related lumen area changes along the proximal coronary artery in 3D during free-breathing.

In vitro vascular toxicity assessment of NitDOX, a novel NO-releasing doxorubicin.

The conjugation of doxorubicin (DOX) with nitric oxide (NO)-releasing groups gave rise to novel anthracyclines, such as nitrooxy-DOX (NitDOX), capable to overcome multidrug resistance. The widely described anthracycline cardiovascular toxicity, however, might limit their clinical use. This study aimed to investigate NitDOX-induced effects, as potential hazard, on vascular smooth muscle A7r5 and endothelial EA.hy926 cell viability, on the mechanical activity of freshly and cultured rat aorta rings, as well as on Cav1.2 channels of A7r5 cells. DOX was used as a reference compound. Although an increase in intracellular radicals and a reduction in mitochondrial potential occurred upon treatment with both drugs, A7r5 and EA.hy926 cells proved to be more sensitive to DOX than to NitDOX. Both compounds promoted comparable effects in A7r5 cells, whereas NitDOX was less active than DOX in inducing DNA damage and in eliciting apoptotic-mediated cell death revealed as an increase in sub-diploid-, DAPI- and annexin V-positive- EA.hy926 cell percentage. Moreover, in EA.hy926 cells, NitDOX doubled basal NO content, while preincubation with the NO-scavenger PTIO increased NitDOX-induced cytotoxicity. DOX exhibited a negligible contracturing effect in endothelium-intact rings, while NitDOX induced a significant ODQ-sensible, vasodilation in endothelium-denuded rings. In arteries cultured with both drugs for 7 days, NitDOX prevented either phenylephrine- or KCl-induced contraction at a concentration 10-fold higher than that of DOX. These results demonstrate that NitDOX displays a more favourable vascular toxicity profile than DOX. Taking into account its greater efficacy against drug-resistant cells, NitDOX is worth of further investigations in preclinical and clinical settings.

Feasibility of coronary endothelial function assessment using arterial spin labeled CMR.

Coronary endothelial dysfunction (CED) is an independent predictor of cardiovascular disease, but its assessment has been limited to invasive coronary angiography. Myocardial perfusion imaging using arterial spin labeled (ASL) cardiac magnetic resonance (CMR) may be an effective non-invasive alternative for detection of CED. Thirty-four patients were recruited: 10 healthy volunteers, 13 at high-risk for coronary artery disease (CAD), and 11 with established CAD. ASL-CMR was performed continuously in a single mid-short axis slice during rest, stress, and recovery. Stress was induced with sustained isometric handgrip exercise, an endothelial dependent stressor. Myocardial perfusion (MP) during rest, peak stress, and recovery were calculated and compared. After excluding subjects unable to complete the protocol or who exhibited poor data quality, 6 healthy, 10 high-risk, and 7 CAD patients were included in the analysis. Average MP (ml/g/min) was 1.31 ± 1.23, 1.61 ± 1.12, and 1.40 ± 0.97 at rest, and 1.64 ± 1.49, 2.31 ± 1.61, and 2.84 ± 1.77 during stress, for the CAD, high-risk and healthy group, respectively. The average MP response (MPstress - MPrest , ml/g/min) was 0.32 ± 1.93, 0.69 ± 1.34, and 1.44 ± 1.46 for CAD, high-risk and healthy group, respectively. MP during handgrip stress was significantly lower for both the CAD (p = 0.0005) and high-risk groups (p = 0.05) compared to the healthy volunteers. In only the healthy subjects, MP was significantly higher in stress compared to rest (p = 0.0002). Participants with CAD had significantly lower MP response compared to healthy volunteers, as detected by ASL-CMR. These findings support the feasibility of ASL-CMR for non-invasive assessment of CED.

A stochastic model for cell adhesion to the vascular wall.

Cell dynamics in the vicinity of the vascular wall involves several factors of mechanical or biochemical origins. It is driven by the competition between the drag force of the blood flow and the resistive force generated by the bonds created between the circulating cell and the endothelial wall. Here, we propose a minimal mathematical model for the adhesive interaction between a circulating cell and the blood vessel wall in shear flow when the cell shape is neglected. The bond dynamics in cell adhesion is modeled as a nonlinear Markovian Jump process that takes into account the growth of adhesion complexes. Performing scaling limits in the spirit of Joffe and Metivier (Adv Appl Probab 18(1):20, 1986), Ethier and Kurtz (Markov processes: characterization and convergence, Wiley, New York, 2009), we obtain deterministic and stochastic continuous models, whose analysis allow to identify a threshold shear velocity associated with the transition from cell rolling and firm adhesion. We also give an estimation of the mean stopping time of the cell resulting from this dynamics. We believe these results can have strong implications for the understanding of major biological phenomena such as cell immunity and metastatic development.

Assessment of Vascular Tone Responsiveness using Isolated Mesenteric Arteries with a Focus on Modulation by Perivascular Adipose Tissues.

Altered vascular tone responsiveness to pathophysiological stimuli contributes to the development of a wide range of cardiovascular and metabolic diseases. Endothelial dysfunction represents a major culprit for the reduced vasodilatation and enhanced vasoconstriction of arteries. Adipose (fat) tissues surrounding the arteries play important roles in the regulation of endothelium-dependent relaxation and/or contraction of the vascular smooth muscle cells. The cross-talks between the endothelium and perivascular adipose tissues can be assessed ex vivo using mounted blood vessels by a wire myography system. However, optimal settings should be established for arteries derived from animals of different species, ages, genetic backgrounds and/or pathophysiological conditions.

Assessment of Lower-limb Vascular Endothelial Function Based on Enclosed Zone Flow-mediated Dilation.

This paper proposes a novel non-invasive method for assessing the vascular endothelial function of lower-limb arteries based on the dilation rate of air-cuff plethysmograms measured using the oscillometric approach. The principle of evaluating vascular endothelial function involves flow-mediated dilation. In the study conducted, blood flow in the dorsal pedis artery was first monitored while lower-limb cuff pressure was applied using the proposed system. The results showed blood flow was interrupted when the level of pressure was at least 50 mmHg higher than the subject's lower-limb systolic arterial pressure and that blood flow velocity increased after cuff release. Next, values of the proposed index, %ezFMDL, for assessing the vascular endothelial function of lower-limb arteries were determined from 327 adult subjects: 87 healthy subjects, 150 subjects at high risk of arteriosclerosis and 90 patients with cardiovascular disease (CAD). The mean values and standard deviations calculated using %ezFMDL were 30.5 ± 12.0% for the healthy subjects, 23.6 ± 12.7% for subjects at high risk of arteriosclerosis and 14.5 ± 15.4% for patients with CAD. The %ezFMDL values for the subjects at high risk of arteriosclerosis and the patients with CAD were significantly lower than those for the healthy subjects (p < 0.01). The proposed method may have potential for clinical application.

Reactive hyperemia-peripheral arterial tonometry is useful for assessment of not only endothelial function but also stenosis of the digital artery.

BACKGROUND: Although reactive hyperemia-peripheral arterial tonometry (RH-PAT) is widely used for assessment of endothelial function, RH index (RHI) cannot be measured in some cases when pulse wave amplitude (PWA) is very low. Decrease in PWA is mainly caused by proper palmar digital artery (PPDA) stenosis. The purpose of this study was to evaluate the relationship between PWA measured by RH-PAT and stenosis of the PPDA measured by digital subtraction angiography and to evaluate the limitation of assessment of endothelial function measured by RHI in patients with PPDA stenosis. METHODS: We measured baseline PWA in 51 fingers including the first to third fingers of both hands in 10 patients who had PPDA stenosis and in 66 fingers that were the first fingers of both hands in 33 subjects who had no PPDA stenosis. Severe stenosis was defined as over 75% by lower percent diameter stenosis between two PPDAs in a finger. RESULTS: PWA was significantly correlated with stenosis of the digital artery (r=-0.55; P<0.0001). A PWV value of 300mV was the optimal cut-off value for severe stenosis (sensitivity, 84.0%; specificity, 88.5%). Log RHI was significantly lower in patients with PPDA stenosis than in subjects without PPDA stenosis (0.33±0.27 versus 0.73±0.27, P=0.007). CONCLUSIONS: RH-PAT may be useful for assessment of not only endothelial function but also PPDA stenosis. RHI may be underestimated in patients with PPDA stenosis. We should pay attention to low baseline PWA when measuring RHI. CLINICAL TRIAL REGISTRATION INFORMATION: URL for clinical trial: http://UMIN; registration number for clinical trial: UMIN000003409.

Reproducibility and agreement of different non-invasive methods of endothelial function assessment.

Flow-mediated dilatation (FMD) is an established, but investigator-demanding method, used to non-invasively determine nitric oxide (NO)-dependent endothelial function in humans. Local thermal hyperemia (LTH) or post-occlusive reactive hyperemia (PORH) of the skin measured with a laser Doppler flow imager may be a less demanding alternative of FMD. We investigated the reproducibility of the different measures of vascular function, their interrelationship and the NO-dependency of LTH. Measurements were performed twice in 27 healthy men (8 smokers), one week apart. Local application of NG-monomethyl-l-arginine (L-NMMA) by means of iontophoresis was used to determine the NO-dependency of LTH. Using L-NMMA, the peak and plateau responses of LTH were reduced by 31% (p < .001) and 65% (<0.001), respectively. For all measurements the coefficient of variation (CV) was higher in smokers than in non-smokers. For non-smokers the CV of FMD was 12%, of LTH peak response 17%, of LTH plateau response 12%, of PORH peak response 14% and of PORH area under the curve response 11%. FMD correlated weakly with the PORH peak and area under the curve response (r = 0.39 and 0.43, p < .05), whereas the LTH-plateau response correlated with the PORH peak response (r = 0.68, p < .01) in non-smokers, but FMD and LTH peak or plateau responses were unrelated. In conclusion, the LTH plateau response is for two-third NO-dependent, but unrelated to FMD. Furthermore, despite easy to perform the LTH responses are not more reproducible than FMD. Given the weak associations, the different methods of vascular function assessment are not interchangeable.

Assessment of flow-mediated dilatation in the superficial femoral artery using a sustained shear stress stimulus via calf plantar-flexion exercise.

NEW FINDINGS: What is the central question of this study? The aim was to establish the ability of a newly designed leg exercise technique to produce sustained elevations in shear rate that stimulate flow-mediated dilatation (FMD) in the superficial femoral artery and to determine the repeat trial stability of the FMD response. What is the main finding and its importance? Calf plantar-flexion exercise can be used to increase shear stress and stimulate FMD in the superficial femoral artery. However, the magnitude of FMD varied systematically when multiple trials were repeated in short succession. The superficial femoral artery (SFA) is susceptible to vascular disease, and a technique to assess flow-mediated dilatation (FMD) in this vessel in response to a sustained shear stress stimulus could provide important information about endothelial function. The aim of this study was to establish the ability of a newly designed SFA leg exercise-FMD (LEX-FMD) technique to produce sustained elevations in shear rate, which stimulate FMD, and to determine the repeat trial stability of the FMD response. The SFA FMD stimulated by reactive hyperaemia (RH) and calf plantar-flexion exercise (LEX) was assessed via ultrasound in 19 healthy men (n = 10) and women (n = 9). The two experimental visits included either four trials of LEX-FMD or four trials of RH-FMD. The shear stress stimulus was estimated as the shear rate (blood velocity/SFA diameter). Results are expressed as the means ± SD. The LEX steady-state shear rate was consistent between trials (P = 0.176), whereas the RH shear rate area under the curve was higher in trial 1 versus trials 2-4 (P < 0.05). The %RH-FMD (four-trial mean 4.9 ± 2.5%) and absolute RH-FMD were not significantly different between trials (P = 0.465 and P = 0.359, respectively). Both %LEX-FMD and absolute LEX-FMD were higher during trial 3 (4.8 ± 3.4%) than trial 1 (3.6 ± 2.7%; P = 0.026 and P = 0.026, respectively). The magnitude of RH-FMD and LEX-FMD did not differ (P = 0.241). These results indicate that calf plantar-flexion exercise can be used to increase shear stress and stimulate FMD in the SFA. However, although SFA RH-FMD was stable across four trials, LEX-FMD varied systematically when multiple trials were repeated in rapid succession.

Assessment of Vascular Health With Photoplethysmographic Waveforms From the Fingertip.

Although the flow-mediated dilation (FMD) index is considered the most reliable indicator of vascular endothelial function, previous studies have proved that the dilatation index (DI) measured by the highly reproducible air pressure sensing system (APSS) is just as accurate in effectively determining endothelial function. Besides, not only is APSS cheaper than the instrument for FMD ratio measurement, but operation of the former is also simple to facilitate its domestic use. However, APSS had the pitfall of being time consuming because of the large amount of computation involved. This paper attempted to validate a new self-developed endothelial function screening (EFS) device that utilized the photoplethysmography (PPG) system for acquiring PPG waveform signals from the index finger through an infrared sensor and a pressure cuff for applying pressure on ipsilateral upper arm for eliciting reactive hyperemic response to assess vascular health. The mean peak amplitude of the signals during the hyperemic phase was divided by that of the baseline to produce an EFS ratio. About 52 volunteers of age 34.76 ± 15.23 years without history of cardiovascular diseases were recruited for vascular endothelial function evaluation using the EFS device and the APSS. Bland-Altman analysis showed good consistency between the EFS ratio and DI. Besides, linear regression analysis demonstrated highly significant correlation between the two sets of data (p < 0.001, r2 = 0.6261) In conclusion, this paper, which attempted to validate a self-developed, economical, and time-efficient device that can be operated in a domestic setting, demonstrated that the EFS device yielded consistent results on vascular endothelial function comparable to those acquired through APSS.

Assessment of asymmetrical dimethylarginine metabolism in patients with critical illness.

BACKGROUND: Critically ill patients experience metabolic disorders including hypercatabolic state and hyperglycaemia, and these are associated with poor outcome. Hyperglycaemia and asymmetrical dimethylarginine (ADMA) are reported to have significant influences on endothelial dysfunction. The aim of this study was to examine the relationship between plasma ADMA and related arginine metabolism in patients with critical illness. MATERIALS AND METHOSDS: Two venous blood samples (EDTA) (104 patients), on admission and follow-up sample in the last day in intensive care unit (ICU) (died or discharge sample median 7, interquartile range (IQR) 6-8, range 5-15). Plasma ADMA, arginine, homoarginine and SDMA were measured by high-performance liquid chromatography (HPLC). RESULT: ADMA (P < 0·01) and SDMA (P < 0·05) were elevated, and homoarginine was decreased (P < 0·05) in nonsurvivors and was directly associated with predicted mortality rate (P < 0·05 and P < 0·001), Sequential Organ Failure Assessment (SOFA) (P < 0·05, P < 0·001), ICU stay (P < 0·05, P < 0·001) and mortality (P < 0·01, P < 0·05). ADMA was directly associated with SDMA (P < 0·001), albumin (P < 0·05), ICU stay and mortality (P < 0·01). SDMA was directly associated with creatinine (P < 0·001) and Acute physiology and Chronic Health Evaluation II score (P < 0·001). In the follow-up measurements, there was a significant decrease in SOFA score (P < 0·01), homoarginine (P < 0·01), aminotransferase (P < 0·01), Laboratory Glucose (P < 0·01) and albumin (P < 0·01). In contrast, there was an increase in arginine (P < 0·01), ADMA (P < 0·01), ADMA:SDMA ratio (P < 0·01) and the norepinephrine administration (P < 0·01). CONCLUSION: In the present longitudinal study, ADMA metabolism was altered in patients with critical illness and was associated with disease severity and mortality.

Ultrasound Assessment of Endothelial Function: A Technical Guideline of the Flow-mediated Dilation Test.

Cardiovascular disease is the primary cause of mortality and a major cause of disability worldwide. The dysfunction of the vascular endothelium is a pathological condition characterized mainly by a disruption in the balance between vasodilator and vasoconstrictor substances and is proposed to play an important role in the development of atherosclerotic cardiovascular disease. Therefore, a precise evaluation of endothelial function in humans represents an important tool that could help better understand the etiology of multiple cardio-centric pathologies. Over the past twenty-five years, many methodological approaches have been developed to provide an assessment of endothelial function in humans. Introduced in 1989, the FMD test incorporates a forearm occlusion and subsequent reactive hyperemia that promotes nitric oxide production and vasodilation of the brachial artery. The FMD test is now the most widely utilized, non-invasive, ultrasonic assessment of endothelial function in humans and has been associated with future cardiovascular events. Although the FMD test could have clinical utility, it is a physiological assessment that has inherited several confounding factors that need to be considered. This article describes a standardized protocol for determining FMD including the recommended methodology to help minimize the physiological and technical issues and improve the precision and reproducibility of the assessment.

Assessment and Imaging of the Cerebrovascular Glycocalyx.

The glycocalyx is a gel-like layer lining the luminal surface of the endothelium. The glycocalyx exerts an important barrier role because it prevents exposure of plasma components to the endothelial surface. Disruption of the glycocalyx by local inflammation or ischemia results in decreased glycocalyx thickness which is associated with a number of vascular diseases. The cerebrovascular glycocalyx has sparsely been studied, but is of great interest because of its potential role in cerebrovascular disease. In this review, we describe all existing techniques to visualize the glycocalyx and designate techniques that may be suitable for studying the cerebrovascular glycocalyx. A total of seven imaging techniques are discussed thoroughly, including transmission electron microscopy, intravital microscopy, micro-particle image velocimetry, confocal laser scanning microscopy, two-photon laser scanning microscopy, orthogonal polarization spectral imaging and sidestream dark field/oblique imaging. Measurement of serum concentrations of glycocalyx-specific constituents is another method for glycocalyx analysis. Also, we have reviewed the methods of glycocalyx analysis by using these imaging techniques. So far, the cerebrovascular glycocalyx has only been studied in vitro. However, other cerebral microcirculatory properties have been studied in vivo. This suggests that the cerebrovascular glycocalyx can be studied in vivo by using some of the described techniques, when specific software is subjoined to the analysis. In conclusion, we have summarized techniques available for glycocalyx assessment, and explained the significance and technical possibilities regarding cerebrovascular glycocalyx visualization. Cerebrovascular glycocalyx assessment would add valuable information to our understanding of the pathophysiology of cerebrovascular disease. Moreover, as a part of the blood-brain barrier, more knowledge on the cerebrovascular glycocalyx may lead to better understanding of neurodegenerative conditions that are caused by a compromised blood-brain barrier including Alzheimer`s disease, vascular dementia, multiple sclerosis and epilepsy.

Adapting coculture in vitro models of the blood-brain barrier for use in cancer research: maintaining an appropriate endothelial monolayer for the assessment of transendothelial migration.

Although brain metastases are the most common brain tumors in adults, there are few treatment options in this setting. To colonize the brain, circulating tumor cells must cross the blood-brain barrier (BBB), which is situated within specialized, restrictive microvascular endothelium. Understanding how cancer cells manage to transmigrate through the BBB might enable this process to be prevented. In vitro models are dedicated tools for characterizing the cellular and molecular mechanisms that underlie transendothelial migration process, as long as they accurately mimic the brain endothelium's in vivo characteristics. The objective of the present study was to adapt an existing in vitro model of the human BBB for use in studying cancer cell transmigration. The model is based on the coculture of endothelial cells (ECs, derived from cord blood hematopoietic stem cells) and brain pericytes. To allow the migration of cancer cells into the lower compartment, our model had to be transposed onto inserts with a larger pore size. However, we encountered a problem when culturing ECs on large (3-µm)-pore inserts: the cells crossed the membrane and formed a non-physiological second layer on the lower face of the insert. Using 3-µm-pore inserts (in a 12-well plate format), we report here on a method that enables the maintenance of a single monolayer of ECs on the insert's upper face only. Under these chosen conditions, the ECs exhibited typical BBB properties found in the original model (including restricted paracellular permeability and the expression of continuous tight junctions). This modified in vitro model of the human BBB enabled us to investigate the migratory potential of the MDA-MB-231 cell line (derived from highly metastatic human breast cancer cells). Last, the results obtained were compared with the rate of transmigration through endothelia with no BBB features.

Adventitial ablation technique that permits the assessment of adventitial-dependent contribution to microvascular contractile function.

Resistance arteries have been implicated as a major contributing factor in the sequela of disease conditions such as hypertension and diabetes and, as such, are a major focus of cardiovascular research. The paracrine influence of the intimal endothelial layer of resistance arteries is well established. Considering the growing body of evidence substantiating a functionally relevant vascular adventitia, in this study we have established a technique that permits determination of the functional influence of the adventitial layer on resistance artery tone. Isolating adventitial-dependent function, analogous to isolating endothelial function, has potentially significant implications for studying the as yet unexplored role of the microvascular adventitial layer in modulating acute vascular contractile function.

MRI-based assessment of endothelial function in mice in vivo.

While a healthy endothelium serves to maintain vascular haemostasis, a malfunctioning endothelium leads to various cardiovascular diseases, including atherothrombosis. Endothelial dysfunction is characterized by increased vascular permeability, impaired endothelium-dependent responses and various pro-inflammatory and pro-thrombotic changes in endothelial phenotype, all of which could provide the basis for an in vivo diagnosis of endothelial dysfunction. In the present review, we briefly summarize the magnetic resonance imaging (MRI)-based methods available for assessing endothelial function in animal models, especially in mice. These methods are aimed to assess biochemical phenotype using molecular imaging, endothelium-dependent responses or changes in endothelial permeability. All these approaches provide a complementary insight into the endothelial dysfunction in vivo and may offer a unique opportunity to study endothelium-based mechanisms of diseases and endothelial response to treatment.

Comprehensive assessment of vascular health in patients; towards endothelium-guided therapy.

Endothelial function has diagnostic, prognostic and therapeutic significance. A number of non-invasive techniques were introduced for its assessment, including flow-mediated dilation (FMD), finger plethysmography (RH-PAT) and digital thermal monitoring (DTM). All these methods can be performed simultaneously. In addition, various methods for measuring arterial wall stiffness are available such as: pulse wave analysis (PWA), pulse wave velocity (PWV), pulse contour analysis (PCA) and carotid wall distensibility coefficient (DC). Finally, carotid intima-media thickness (cIMT) and ankle brachial index (ABI) are used as surrogate read-outs of atherosclerosis. Here, we briefly describe the advantages, limitations and interrelationships of various methods used for the assessment of endothelial function, arterial stiffness, and present the concept of an integrated evaluation of vascular health based on multiple methods. This strategy may be useful to stratify cardiovascular risk and represents a step towards multiparametric assessment of endothelium for effective endothelium-guided therapy in patients with cardiovascular diseases.

Differences in angiotensin (1-7) between men and women.

UNLABELLED: In experimental animal models of hypertension, angiotensin (1-7) [ANG-(1-7)] is higher in females compared with males; however, it is less clear whether the same applies to humans. Therefore, this study sought to compare circulating concentrations of ANG-(1-7) in apparently healthy men and women under normal physiological conditions. With the use of a cross-sectional experimental design, blood was collected in EDTA anticoagulant from 42 volunteers (21 men and 21 women; and age range, 19-48 yr) for analysis of plasma concentrations of ANG-(1-7) and ANG II. Blood pressure was measured and vascular endothelial function was determined (n = 25) using the brachial artery flow-mediated dilation (FMD) test. As a result, women exhibited a higher circulating concentration of ANG-(1-7) (P = 0.04) compared with men, whereas values of ANG II were similar between groups. Baseline arterial diameter, peak diameter, and shear rate were significantly greater (P < 0.02) in men compared with women. No significant differences in FMD, FMD normalized for shear, or time to peak dilation were observed between men and women. In addition, a positive correlation between ANG-(1-7) and FMD (P = 0.04) and negative association between ANG-(1-7) with ANG II (P = 0.01) were only identified in men, whereas a positive relationship between ANG-(1-7) and diastolic blood pressure (P = 0.03) was observed in women. IN CONCLUSION: , women exhibit significantly higher plasma concentrations of ANG-(1-7) compared with men. In addition, this study describes a relationship between ANG-(1-7), vascular function, and diastolic blood pressure that appears to be sex dependent.