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Brachial artery diameter measurement: A tool to simplify non-invasive vascular assessment

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Abstract

Aim

The mechanisms of vascular remodeling have attracted great interest since it is a phenomenon related to cardiovascular diseases. We would like to examine studies that contributed to clarify the remodeling mechanisms, to explore the different faces of atherosclerosis process.

Data synthesis

A number of invasive and non-invasive vascular assessment methods were developed, to detect the early sign of atherosclerosis. It became clear that the invasive tests were not applicable to large-scale studies. Consequently, a non-invasive test was developed. Studies showed that the endothelial function evaluation is a predictor of future cardiac events in individuals at cardiovascular risk and in those with established disease. However, analyzing several works, an interesting concept emerged, i.e., the inverse relation between endothelium-dependent dilation and vessel size, since large vessel tend not to dilate significantly. This notion emphasized the role of basal diameter on vascular response. In particular, as brachial artery diameter is the measure on which FMD is based, it could add more information in clinical evaluation, simplifying the assessment. Several studies showed that morphological change of brachial artery is a better indicator of the extent of coronary disease rather than FMD. Other studies showed that brachial diameter has predictive significance in the stratification of cardiovascular risk.

Conclusion

Brachial diameter is a useful and simple tool. It should be incorporated into the overall assessment of cardiovascular risk but further studies are warranted to determine the final place of brachial diameter assessment in routine clinical setting.

Introduction

Despite the advances in scientific research, the factors regulating normal and pathological adaptive mechanisms of the vascular tree remain unclear. The mechanisms underlying vascular remodeling have attracted great interest since this phenomenon is strongly related to the development of cardiovascular diseases. For this reason, since the initial investigation of Glagov [1], a number of invasive and non-invasive vascular assessment methods have been developed, aiming to detect the early signs of vascular changes. In biological organisms the same phenomenon may carry out different consequences and it may become manifest with different features, as sides of the same coin. Bearing this in mind, we would like to examine previous studies that contributed to clarify the vascular remodeling pathophysiology and relevance aiming to explore different faces of early atherosclerosis signs.

The involvement of endothelium in the atherosclerotic remodeling was recognized a century ago [2], nevertheless other relevant aspects have been recently proposed and several studies are still ongoing to dissect the precise mechanisms underlying vascular remodeling. In fact, the endothelium plays a pivotal role lining the entire vascular system whose functional impairment (endothelial dysfunction), represents the initiation of the atherosclerotic disease.

Stimuli of different nature on endothelial cells, such as the exposure to oxidized lipoproteins, high homocystein levels, inflammatory cytokines accumulation of advanced glycation end products (AGEs), and aging [3], [4], [5], [6], [7] have a deleterious effect on vascular homeostatic function and regulation. Furthermore, mechanical forces generated by the blood pulsatile flow through blood vessels can also contribute to the endothelial cells dysfunction and to the development of some clinical complications [8], [9], [10]. It may be argued that all these adaptive mechanisms could be more appropriately considered as a normal vascular response, and they may be named as endothelial activation. A chronically prolonged endothelial activation may subsequently result in the occurrence of what it is so called endothelial dysfunction. The endothelium releases various vasoactive factors. Among these there are vasodilators, such as nitric oxide (NO), prostacyclin (PGI2) and endothelium derived hyperpolarizing factor (EDHF), as well as vasoconstrictors, such as thromboxane (TXA2) and endothelin-1 (ET-1).

NO plays a key role in the endothelial layer homeostasis. NO is released from endothelial cells and it acts on vascular smooth muscle maintaining the vessel tone and allowing the vasodilatory response [10], [11], [12], [13]. However, after endothelium damage or removal, an endothelium-independent vasodilatation, in response to an NO donor such as glyceryltrinitrate (GTN), can occur [12]. Moreover, PGI2 could also contribute to the vasodilatory response [14] while TxA2 may act in the opposite direction with vasoconstriction properties [15]. Thus, the vascular structure is dynamic and continuously prone to modifications. The possibility to evaluate anatomical or functional parameters is important to understand the endothelial or, globally, the vascular wall state.

Endothelial cells are located on the vessel intima stratus and they display different features depending on which vessel type they reside in [16]. In addition, endothelial cells can exhibit various responses to different stimuli in specific vascular beds [17], [18], [19]. This suggests that endothelial dysfunction may occur in selective vascular beds. The key role of the endothelium in the atherosclerotic disease process has led to the development of a wide range of methods to identify, early in time, the atherosclerotic disease and, consequently, the subjects at high cardiovascular risk [20].

Initial information on the human endothelial function were obtained through the infusion of acetylcholine in epicardial arteries [21], [22]. Successively, endothelial function was commonly assessed in the peripheral circulation [23], [24], [25].

However, it became clear that these invasive procedures were not feasible for large-scale studies. More recently, a non-invasive ultrasound-based test to assess artery vascular function has been developed [26]. With this method, the brachial artery diameter (BAD) percentage change is measured as a fraction of the diameter after reactive hyperemia and the basal diameter value. It is supposed that the flow-mediated dilation (FMD) is mediated by the local endothelial release of NO [27], since the blood flow produces shear forces on the endothelium and stimulates NO release. Thus, an impaired vasodilatation may indicate a poor endothelial function. The FMD was initially measured at peaks 60–90 s after cuff release. It was immediately clear that FMD value was highly dependent on the technique used, as well as on the degree of the operator's experience. Thus, due to possible operator variations, there is no full consensus on the standardization between laboratories [27]. Nevertheless, this technique is largely diffused, probably since several studies reported close correlations between peripheral and coronary endothelial function [28]. This assessment method of endothelial function was considered very useful to predict future cardiac events in individuals at risk and in those with an established cardiovascular disease (CVD); indeed, it was showed that endothelial dysfunction was common in individuals with the presence of risk factors for CVD [29], [30], [31], [32].

Other non-invasive vascular tests, performed with ultrasonography, include FMD measured in other districts (i.e.: radial and femoral artery), pulse wave analysis, pulse wave velocity measurement, pulse amplitude tonometry and strain-gauge plethysmography flow [33], [34], [35], [36], [37], [38]. The additive value of all these methods, alongside the traditional risk factors screening, remains uncertain in terms of individual risk prediction as well as for brachial FMD.

The ultrasound-based investigations of vascular reactivity are now considered by far the main techniques to ascertain the early stage of atherosclerosis. However, if we examine an out breaking and historical work from 1998 by Celermajer DS [39], an interesting concept emerges: there is an inverse relationship between the endothelium-dependent dilation and the vessel size. In this view since large vessels tend not to dilate significantly, the basal diameter may account for a large proportion of FMD value. Celermajer’s observations opened the door to understand the deep impact and the key role of the basal diameter on vascular response. In particular, it is intuitive that the BAD is the measure on which FMD is based, thus, beyond FMD assessment, BAD evaluation could provide some excellent information on vascular system. There are interesting investigations regarding the vessel size evaluation confirming this assumption. In a case–control study on untreated hypertensive subjects without atherosclerotic disease but with left ventricular hypertrophy [40], it was found a higher carotid artery diameter, a higher BAD, and a higher cross-sectional area of these vessels when compared to the control group. This study, which was not examining the endothelial function, showed that patients with complicated hypertension had a concomitant change in the carotid, brachial and left ventricular geometry. This could represent a systemic remodeling phenomenon modulated by common factors [40].Yet, Kozakova [42], in a cross-sectional study, showed that the free-fat mass and the waist girth influenced the common carotid artery luminal diameter and, consequently, another important parameter such as the intima-media thickness (IMT), independently of other risk factors. Other authors [42] showed a correlation between BAD, several cardiovascular risk factors and IMT, suggesting that arterial remodeling may be a systemic process [42]. Of interest, in this study, it was found a lack of correlation between FMD and the cardiovascular risk factors [42]. Other investigations are in line with these data. In fact, it was found both common carotid diameter and BAD enlarged in post-menopausal women affected by carotid atherosclerosis when compared to not affected controls [43]. In this study it was also found a significant difference in IMT between groups [43]. It is also relevant a study on carotid artery diameter and BAD that were found enlarged in post-menopausal women affected by metabolic syndrome compared to control group, with also a greater IMT and carotid plaques association [44].

All of these studies could lead to speculate that the artery diameter enlargement, properly defined as vascular remodeling, could be a generalized vascular response, becoming manifest in subjects with cardiovascular risk factors, or with high IMT and/or carotid plaque presence. BAD seems associated to subclinical atherosclerosis lesion in other vascular district, while the FMD seems not always correlated with most cardiovascular risk factors or with artery disease [42], [45]. In fact, it was showed that FMD varies not only in relation to metabolic factors but also under the influence of many stimuli (i.e.: medical agents, caffeine use, recent smoking, menstrual cycle phase, physical exercise) [46], [47], [48]. FMD represents a quick vascular response in contrast to the artery diameter enlargement and the IMT (or the plaques presence), which may be different signs of the same disease, as multiple faces of the same coin. This is corroborated by the well established concept that atherosclerosis, in the form of plaques or IMT, occurs in specific areas of disturbed flow (i.e.: branched or curved arteries), in contrast to straight arterial regions (i.e.: brachial artery) that are well protected from atherosclerotic lesions [49] but that are capable of enlargement under, still unknown, stimuli derived from atherosclerosis development in other vascular bed. Artery enlargement could not be considered as a pure compensatory or protective phenomenon, as it was believed in the past. In fact, long ago, arterial remodeling was thought to be the result of the vessel wall outward displacement only in segments developing a plaque (a focal enlargement process) [50], [51]. It was, also, thought that when the compensatory enlargement became insufficient the vessel undergo to luminal narrowing. In light of the more recent studies remodeling may be now considered as a generalized process, involving also vessel not affected by atherosclerotic lesions. Indeed, since outward coronary artery remodeling may represent an early stage of coronary disease in women with chest pain, it is possible to speculate that brachial artery diameter could be a predictor of coronary artery disease, as confirmed by some observations [52], [53].

Thus, in contrast to the past, there is now evidence that the external artery expansion or vascular remodeling may represent not only a compensatory, local, mechanism [54], [55] but also a more general and systemic phenomenon.

Based on current knowledge, the mechanisms underlying the close relationship between the atherosclerosis occurring at the site of disturbed flow (i.e.: carotid bifurcation) and the arterial enlargement in the other tracts (i.e.: brachial artery) may be speculated. In animals models undergoing bilateral or unilateral common carotid ligation a concomitant enlargement of the luminal size downstream was shown (i.e.: basilar artery) [56]. Thus, it is possible that the blood flow could initiate a structural change in the artery wall (remodeling) through an impaired hemodynamic homeostasis [57]. Wall shear stress against the vascular wall could be a strong determinant of arterial remodeling and it could be reduced after an anatomic adaptation [58], [59].

In addition, changes in wall shear stress probably could be sensed by endothelial cells, which may subsequently produce signals leading to vascular remodeling [57], [60]. In fact, endothelial cells can produce factors such as matrix metalloproteinases, causing extracellular matrix degradation, luminal expansion of the vessel wall and also the release of other growth factors [61], [62], [63], [64], [65], [66]. It is conceivable that the internal elastic lamina fragmentation could be the main mechanism leading to diameter enlargement through, for instance, elastin disruption after the loss of wall integrity [64], [65], [66].

In this view, the atherosclerotic plaques, IMT, as well as artery diameter enlargement could be considered a measurable morphologic outcome of the same generalized process, rather than a triggering event. Moreover they could be considered as a consequence of a long-term exposure to risk factor. In this contest, BAD measurement may represents an important biomarker to implement the risk assessment in subjects with well-known cardiovascular risk factors. In fact, some studies showed a brachial artery enlargement in post-menopausal women affected by diabetes, metabolic syndrome, obesity with abdominal fat distribution, when compared to a control population [44], [67], [68], [69] as well as in other condition [40], [42]. Furthermore, upon confirmation of the early appearance of artery morphological changes in the natural history of atherosclerosis [69], a value of measuring artery diameter as an early biomarker in apparent healthy individuals may be advocated.

BAD certainly represents a simple parameter to assess. Although BAD and FMD measure two different pathophysiological aspects and it is important to evaluate FMD for some purposes, it became apparent that, in assessing parameters that could reveal subclinical atherosclerosis, one should consider appropriateness and feasibility aspects like variability. In this context, BAD is better than FMD since the last one is affected by an intra-observer coefficient of variation (CV) of more than 30% while the CV of BAD is less than 5% [70], [71], [72], [73]. Furthermore, many factors have been shown to limit FMD reproducibility [73], [46], [47], [48], but they do not affect BAD measurement.

Several studies showed that morphological change of brachial artery is a better proxy of the extent and severity of coronary artery disease when compared to FMD [74], [75], [76]. Other studies showed that BAD has predictive value in the stratification of cardiovascular risk [77]. Finally, studies on heritability of FMD suggesting a different pathophysiological mechanisms between endothelial dysfunction and remodeling may be also taken into account [78], [79].

BAD has the potential to become a powerful tool in cardiovascular events prediction [42], [75] but certainly it must be widely and prospectively evaluated to become part of the clinical routine.

Regarding the method for BAD measurement, the subjects usually undergo B-mode ultrasonography of the brachial artery by the use of a high-resolution ultrasound duplex system instrument with a 5- to 12-MHz linear array multifrequency transducer [43]. All the examinations should be performed using the same ultrasonographer. All patients should be rested, and they should be in the supine position for at least 10 min before the study. They should be kept in this position throughout the entire procedure. ECG leads should be connected to the ultrasound recorder for a continuous heart rate monitoring and to guarantee that all measurements are performed in end-diastole phase.

Longitudinal image of the brachial artery of the non-dominant arm must be acquired proximal to the antecubital fossa where the optimal ultrasound image can be obtained. To evaluate artery diameters, the images must be magnified and depth and gain settings must be set to optimize the image of the vessel wall, specifically, the media–adventitia interface (“m” line). The end-diastolic diameter of the vessel, defined as the distance between near-wall and far-wall junctions of the media and adventitia, should be measured over four cardiac cycles with the use of digital calipers and the average must be then calculated.

Section snippets

Conclusion

Several non-invasive imaging techniques have the potential to focus on different stages of the atherosclerotic process. BAD may have the potential to become an important biomarker of functional changes in the vessel, and could as well be seen as a tool to achieve morphological information [40], [41], [42], [43], [44], [74], [75]. BAD is the measure on which FMD is based, thus, its evaluation could provide additional excellent information on vascular system and it may contribute to clarify the

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