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Review
Low-flow mediated constriction: the yin to FMD’s yang? Expert Rev. Cardiovasc. Ther. 12(5), 557–564 (2014)
Ruth E Humphreys1, Daniel J Green1,2, N Timothy Cable1,3, Dick HJ Thijssen1,4 and Ellen A Dawson*1 1 Research Institute for Sport and Exercise Science, Liverpool John Moores University, Tom Reilly Building, Byrom Street, Liverpool L3 3AF, UK 2 School of Sport Science, Exercise and Health, The University of Western Australia, Crawley, Perth, 6009, Western Australia 3 Department of Sports Science, ASPIRE Academy, Qatar 4 Department of Physiology, Radboud University Medical Center, The Netherlands *Author for correspondence: Tel.: +31 0151 904 6264 Fax: +31 0151 904 6284 [email protected]
Given the prevalence of cardiovascular disease (CVD), early detection is crucial. Although traditional cardiovascular risk factors relate to future CVD, the predictive value of these risk factors can be relatively limited. Contemporary scientific attention has focused on alternative direct measures of arterial function. Based on the ability of the endothelium to acutely dilate in response to an increase in flow, ‘flow mediated dilation’ (FMD) was introduced approximately 20 years ago and is now an established non-invasive index of endothelial function predictive of future cardiovascular events. Recently, ‘low-flow mediated constriction’ (L-FMC) has been proposed as a complementary addition to FMD. The technique is based on the constrictor response to decreased flow and is claimed to improve the sensitivity and specificity of FMD. The aim of this review is to examine literature pertaining to this novel technique and to provide insight into the potential use of L-FMC in future research. KEYWORDS: cardiovascular prognosis • cardiovascular risk • composite end point • endothelial function • flow-mediated dilation • low-flow-mediated constriction
Endothelial function & cardiovascular risk
Cardiovascular disease (CVD) is the world’s leading cause of mortality, attributing to approximately 30% of all deaths [1]. The earliest detectable manifestation of atherosclerosis comes in the guise of endothelial dysfunction, which occurs long before the clinical presentation of CVD [2]. The mono-layered innermost lining of all vessels, the endothelium is crucial for maintaining vascular tone [3] and arterial health principally through the production of anti-atherogenic autacoids [4,5]. Dysfunction of the endothelium accelerates pro-atherosclerotic events, leading to the progression of atherosclerosis and CVD. Maintenance of a healthy endothelium through exercise training and lifestyle interventions is critical for both primary [6] and secondary prevention [7] of cardiovascular risk. A recent review suggested that risk factor algorithms fail to adequately predict future acute coronary events [8], endorsing the development of alternative techniques. Measurement of endothelial (dys)function in humans
Several methods have been adopted to assess arterial function. Among others, assessment of
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pulse pressure and its ratio to stroke volume can infer total arterial compliance, which has been cited as an independent predictor of cardiovascular events [9]. Aortic pulse wave velocity, an index of arterial stiffness, has also been identified as an independent predictor of allcause mortality and cardiovascular risk [10]. In addition, a plethora of plasma biomarkers, including highly sensitive C-reactive protein, are believed to represent endothelial function and predict future disease [11]. Over the past two decades, the non-invasive assessment of endothelial vasomotor function via the technique of ‘flow-mediated dilation’ (FMD) has been thoroughly refined and widely adopted within the literature [12–14]. The method is based on the ability of the endothelium to release vasoactive substances in response to a marked increase in blood flow, or more specifically, shear stress, which acts upon the endothelium. Typically examined in peripheral conduit arteries supplying the upper or lower limbs (ranging in diameter from 2 to 10 mm), ischemia is induced by blocking downstream blood flow via inflation of a supra-systolic pressure cuff placed around the arm or leg. Upon cuff release, a large increase
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in blood flow is initiated to the downstream vessels, resulting in an increase in shear stress on the conduit artery wall. The dilatory response from the conduit artery is recorded and is indicative of endothelial dys(function). This frequently used measure is endothelium-dependent [15,16] and partly mediated by nitric oxide (NO) [15], an anti-atherogenic vasodilator [17]. Clinical populations with increased cardiovascular risk exhibit lower FMD responses [18–20]. Furthermore, FMD has been recognized as having predictive capacity for future CVD, although this capacity may differ according to the particular protocol [21] and clinical group [22] studied. Finally, assessment of vascular function via FMD has identified that endothelial dysfunction can be detected years before clinical presentation of structural abnormalities and/or established risk factors [12,23,24]. Taken together, the bulk of scientific evidence indicates that FMD represents a useful tool to examine endothelial function and has independent predictive capacity for future CVD. Low-flow-mediated constriction: a history
While the FMD technique is based on the ability of arteries to dilate in response to increases in blood flow, ‘low-flow-mediated constriction’ (L-FMC) relies on the ability of arteries to constrict when blood flow is attenuated. In 1987, Levenson and colleagues were the first to describe human brachial artery vasoconstriction in vivo during an acute reduction of blood flow induced by inflation of a supra-systolic wrist cuff for 60 s [25]. This was later reinforced by Anderson and Mark [26], who inflated a blood pressure cuff around the forearm for 10 min to 200 mmHg and performed measurement of the brachial artery using Doppler ultrasound. Cuff inflation induced ‘circulatory arrest’, a condition later renamed ‘low-flow’, which subsequently provoked significant vasoconstriction. The presence of an L-FMC response was observed in further experiments both in the brachial [27,28] and radial arteries [29,30]. How do you measure L-FMC?
The assessment of L-FMC was re-visited as a measure of vascular function by Gori and colleagues in 2008 [31]. In line with work performed 20 years earlier, the proposed method involves evaluation of the response to an acute reduction in blood flow in the radial artery. Using ultrasound, the decrease in arterial diameter is assessed after 5 min of supra-systolic cuff occlusion, where the cuff is applied distal to the placement of the probe, at the wrist. L-FMC is then calculated as the relative change (i.e., decrease) in diameter in relation to baseline resting diameter (FIGURE 1). Previous studies have argued that by focusing on dilation in response to an increase in blood flow, FMD may simplify the complexity of vasomotor control by concentrating solely on vasodilator pathways [32]. L-FMC, in contrast, examines the constriction of an artery in response to a decrease in flow. The reduced diameter during conditions of low-flow may be largely linked to baseline tone. In other words, a large constriction during the low-flow condition could be a consequence of low basal tone (and therefore larger baseline diameter), which allows the artery to respond with a strong constriction when 558
exposed to a low-flow state. Likewise, a small constriction may reflect a situation where baseline resting tone is high (resulting in a smaller baseline diameter), allowing little space for further constriction during L-FMC. Although basal tone impacts upon relative changes in L-FMC (and FMD), underlying endothelial dysfunction, acute hormonal or sympathetic stimulation and fluctuations in oxidative stress may also impact upon L-FMC. The interaction between discreet changes in basal tone and these other stimuli is multifaceted, and adds to the complexity of understanding vasomotor control and function. As with FMD, the matter of reproducibility and repeatability of L-FMC is extremely pertinent. Recent large multicenter studies have highlighted that reproducible short- and mediumterm FMD evaluation is attainable, so long as standardized protocols are adhered to [33,34]. Early, small sample L-FMC studies have revealed that L-FMC is reproducible in the brachial artery [35], and that repeatability and reproducibility of L-FMC is comparable to FMD in the radial artery [31]. Further large multicenter studies are required to better understand reproducibility and repeatability of L-FMC. What mechanisms underlie L-FMC?
Theoretically, the mechanisms that contribute to L-FMC may include those which increase vasoconstriction and/or decrease vasodilation, although these have not yet been thoroughly examined. A recent study from Dawson et al. investigated whether L-FMC is endothelium-dependent by assessing L-FMC before and after denudation of the radial artery endothelium [36]. Interestingly, a significantly diminished magnitude in L-FMC was observed after denudation, providing human in vivo evidence that L-FMC is, at least partly, mediated through the endothelium. When examining the potential vasoactive substances that mediate L-FMC, an early blockade study focused on the potential importance of NO. In contrast to the well-established contribution of NO to FMD [15], this study found that L-FMC was not altered by infusion of the NOblocker NG-monomethyl-L-arginine and concluded that L-FMC is not NO-mediated [31]. Interestingly, inhibition of other potent endothelium-dependent vasodilators (endothelium-derived hyperpolarizing factor [EDHF] and prostaglandins) induced a diminished magnitude in L-FMC in healthy volunteers [31]. The authors inferred that withdrawal of EDHF and/or cyclooxygenase-related vasodilators before baseline diameter measurement may contribute to a decrease in L-FMC. However, since expected changes in baseline diameter were not presented (D baseline diameter -0.01 mm), this somewhat complicates interpretation of the contributing roles of EDHF and prostaglandins to both basal tone and L-FMC. On the other hand, constriction during low-flow may (also) be induced by an increase in vasoconstrictor stimulus. In support of this, Spieker and colleagues found that the low-flow-mediated constrictor response of the radial artery was abolished following blockade of endothelin-1 (ET-1) [30]. Conversely, a more recent study found that a larger brachial L-FMC was not associated with changes in plasma ET-1 levels [35]. However, it should be Expert Rev. Cardiovasc. Ther. 12(5), (2014)
L-FMC: a novel technique to assess vascular function
Review
Dmax
Artery diameter
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FMD =
Dmin – Dbase Dbase
x 100 max – Dmin Composite = D x 100 endpoint Dbase
Dbase L-FMC =
Dmax – Dbase Dbase
x 100
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Figure 1. Schematic representation of concurrent L-FMC and FMD assessment in the radial artery, as proposed by Gori et al. (2008), with mathematical equations for calculation of FMD, L-FMC and the composite end point. Dbase: Vessel diameter at baseline; Dmin: Minimum vessel diameter during last 30 s of cuff inflation; Dmax: Maximum vessel diameter during the first 3 min post cuff deflation; FMD: Flow-mediated dilation; L-FMC: Low-flow-mediated constriction; Composite end point: Sum of L-FMC and FMD.
emphasized that ET-1 plasma levels correlate poorly with the contribution of ET-1 to vascular tone [37]. Taken together, while there is some evidence that L-FMC is endothelium-dependent and may be mediated through a combination of an increase in vasoconstrictors (such as ET-1) and decrease in vasodilators (EDHF and prostaglandins), mechanisms contributing to L-FMC in the brachial or radial artery remain unclear and should be subject to future research. Is there site specificity for L-FMC?
One potential benefit of L-FMC is that it can be measured concurrently with FMD. However, initial studies utilizing L-FMC were based on investigations in the radial artery, while the majority of FMD literature is focused on the brachial artery. Important differences in magnitude and kinetics of vasomotor FMD responses have been reported between these conduit arteries, due in part to differences in structure and/or exposure to vasoactive stimuli [38,39]. In line with these distinct FMD responses between arteries, previous studies examining informahealthcare.com
brachial L-FMC have shown no diameter change in healthy subjects during low-flow [40,41], while others have found an increase [42] or decrease [27,35] in brachial artery diameter during forearm occlusion. Based on the apparent heterogeneity in vascular responses between different arterial beds, Weissgerber and colleagues examined the L-FMC response in the radial and brachial artery of pregnant and non-pregnant women [43]. While confirming the presence of L-FMC in the radial artery, no such response was observed in the brachial artery of the same women. Likewise, a small, but significant increase (i.e., dilation rather than constriction) in diameter during cuff occlusion was observed in the brachial artery of children and healthy young subjects, although no significant change was reported in older subjects [42]. An important methodological difference when examining L-FMC is that assessment of the radial, but not the brachial artery, is performed in relatively close proximity to the occlusion cuff. The impact of measuring diameter change during cuff inflation in close proximity to the occluding cuff, and 559
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potential presence of tissue displacement or changes in pressure, is unclear at this stage. Despite this, coherent evidence of vasoconstriction under conditions of low-flow in the radial artery remains [31,36,43–45]. Moreover, different responses in the radial and brachial arteries are not necessarily indicative of a limitation to the L-FMC technique, since important clinical information may be fathomed from these varying responses. The apparent heterogeneity of artery responses to low-flow conditions has implications for the validity of L-FMC as a surrogate for the coronary arteries. Given that dilator responses show strong correlations between the coronary and brachial arteries [46,47], future studies should examine the potential for L-FMC as a surrogate marker of coronary artery constrictor responses. Arguably, the clinical relevance would be limited if responses in the periphery do not mirror those observed in epicardial arteries. One previous study observed a weak (r2 = 0.1) yet significant (p < 0.001) correlation between L-FMC and an index of coronary flow velocity. However, caution is warranted when interpreting correlations between vascular beds when the stimuli are not similar. This is especially noteworthy since the exact stimuli for L-FMC are not fully understood. Although shear rate is hypothesized to contribute to the diameter response in L-FMC [31], a recent study reported no significant correlation between the reduction in shear rate during cuff occlusion and magnitude of L-FMC [43]. Clearly, further research is required to understand L-FMC responses, underlying stimuli and mechanisms. In addition more work is needed to quantify heterogeneity between arteries and to assess the predictive value of L-FMC for cardiac events. Can L-FMC identify subjects with CVD?
L-FMC has been assessed in both healthy [31,43–45,48–50] and clinical [31,35,36,44,45,48] populations. Diminished radial artery L-FMC is reported in clinical populations such as hypertension, smokers, coronary artery disease (CAD) [31] and heart failure [44], and has also been shown in the brachial artery of those with multiple cardiovascular risk factors [48]. This is often accompanied by a reduced FMD [31,44,45,48], which supports the hypothesis that L-FMC is associated with endothelial dysfunction. Moreover, investigation of radial L-FMC in patients with one, two and three vessel CAD demonstrated a ‘dosedependent’ decline in L-FMC with increased severity of disease [45]. However, some studies have presented conflicting results. No difference was demonstrated in radial L-FMC between pregnant and non-pregnant women [43], which is perhaps unusual since pregnant women typically present with larger FMD [51], although another study identified that hormonal fluctuation during the menstrual cycle did not impact upon L-FMC [50]. Furthermore, patients with myocardial infarction showed greater brachial L-FMC than those with stable atherosclerosis, despite the presumption that the former had greater endothelial dysfunction [35]. Interestingly, while radial L-FMC responses seem to be consistently attenuated in the radial artery of those with cardiovascular risk factors [31,44,45], both diminished [48] and improved [40,41] 560
L-FMC responses have been shown in the brachial artery. Future research should confirm whether there are real differences in vessel responsiveness between the brachial and radial arteries in groups with cardiovascular risk factors and disease. Is there evidence of predictive capacity?
Differences in L-FMC between healthy subjects and clinical groups in the radial artery provide some early indication of a potential predictive capacity. However, to date, no research has directly examined the predictive capacity of L-FMC (or the combination of L-FMC and FMD as a composite end point) in a follow-up longitudinal study. This is a significant gap in the literature that will limit adoption of L-FMC into clinical practice and research. Although a moderate cross-sectional correlation between brachial FMD and L-FMC has been shown in healthy subjects, this was not apparent in clinical populations [35]. Moreover, no correlation between FMD and L-FMC was found in the radial artery of healthy subjects or those with cardiovascular risk factors [31]. Studies have also examined the cross-sectional correlation of L-FMC with cumulative risk factor scores. The SYNTAX score is used by clinicians to grade the severity and complexity of CAD in patients [52]. A recent paper found that radial artery L-FMC, but not FMD, was modestly related to the SYNTAX score in a subset of CAD patients [45]. In contrast, using an alternative CVD risk algorithm: the ‘coronary stenosis index’ [53], a significant correlation between the index and FMD, but not L-FMC, was found [35]. Interpretation of (the absence of) correlations between L-FMC and established predictors of CVD remain obscure. While the lack of such relation may suggest that L-FMC possesses no predictive capacity, one may also argue that it is explained by the fact that L-FMC provides predictive information that is independent of these other markers. Future studies adopting a prospective, follow-up study design in which L-FMC is measured alongside traditional and novel markers of cardiovascular risk, should help to answer this clinically and scientifically important question. FMD + L-FMC: a composite end point?
While the measurement of L-FMC itself may have importance, the summative ‘score’ of FMD and L-FMC may provide further insight into vascular health (FIGURE 1) [31]. The ‘composite end point’ (also referred to as ‘total vessel reactivity’ [49] or ‘modified FMD’ [48]) is indicative of constrictor/dilator reserve (i.e., the ability of a vessel to both dilate and constrict). However, one should realize that such summative end points may also increase the coefficient of variance, potentially limiting their applicability. It should also be noted that total vessel reactivity [49] and modified FMD [48] are calculated relative to the minimum diameter during cuff occlusion and not baseline diameter [31]. Although seemingly only a subtle mathematical modification, conclusions could be statistically and clinically different to those using the composite end point. The use of the composite end point has been shown to improve detection Expert Rev. Cardiovasc. Ther. 12(5), (2014)
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L-FMC: a novel technique to assess vascular function
of endothelial dysfunction in patients already diagnosed with hypertension, CAD or heart failure [44]. However, use of FMD and L-FMC together as separate (yet complementary) parameters may also help to determine vascular dys(function). Previous work has demonstrated that L-FMC (as a complementary measure alongside FMD) may have further value than the summative composite end point, by reducing false-positive and false-negative results/predictions [44]. Nevertheless, the use of an aggregate measure in addition to FMD seems promising, although uniformity in definition and calculation, as well as better insight into its potential clinical relevance, is essential. What is the impact of intervention on L-FMC?
Exercise training is a well-established, potent, non-pharmacological intervention with strong cardioprotective effects [54,55]. It is generally accepted that exercise training in subjects with cardiovascular risk leads to improvement in FMD [20,56,57], although this may be time dependent [58]. Accordingly, it might be expected that exercise training and/or acute exercise would result in augmentation of L-FMC. Rakobowchuk and colleagues recently examined brachial artery L-FMC responses before and after systemic interval training in healthy subjects [49]. Their 6-week protocol compared the impact of high intensity versus moderate intensity interval training on brachial artery L-FMC and found small, yet statistically significant, improvements in L-FMC and the composite end point following both protocols; although FMD was not significantly improved post-intervention. The larger L-FMC after exercise training suggests that baseline diameter may be under more vasodilator control, allowing for a larger relative L-FMC when exposed to vasoconstrictors under conditions of low-flow. The time course of L-FMC adaptation across a period of training is yet to be explored. Recently, we examined the impact of a 6-week handgrip training program on radial artery L-FMC in patients recovering from radial catheterization [36]. Previous research has demonstrated that the catheterization procedure is associated with an impaired FMD [59]. In this study [36], we demonstrated that handgrip training recovered radial artery L-FMC, FMD and the composite end point compared with impaired dilator and constrictor responses in the control group. These data support the notion that exercise training may improve L-FMC responses and, therefore, vasoconstrictor/dilator control of the resting, baseline artery diameter. What are the avenues for future research?
L-FMC is typically calculated as a change from baseline diameter. Research pertaining to FMD has established that, as a ratio measure, changes in the resting baseline can influence the relative response [42]. For instance, arteries with smaller diameters typically exhibit larger %FMD responses, partly by virtue of the mathematical method of calculation [60]. In circumstances where cross-sectional comparisons are made, or where large changes occur in baseline diameter in repeated measures experiments, the interpretation of FMD as an index of artery informahealthcare.com
Review
functional capacity becomes more nuanced. This concept is equally relevant to baseline changes and the interpretation of LFMC. If baseline diameter decreases, in the face of similar absolute changes in diameter under conditions of low-flow/ shear, then L-FMC will be exaggerated. At the same time, if there is a fixed floor in terms of absolute constriction, then movement of the baseline toward this floor value will effectively attenuate the %L-FMC value. These issues serve to highlight the fact that %L-FMC is a ratio variable and that interpretation can be complicated if the baseline changes, something that is conceivable in the context of interventions that modify the relative contribution of dilator versus constrictor agents to basal vascular tone. The use of the composite end point or alternative measure of constrictor/dilator reserve may theoretically diminish this complexity. However, such indices, as currently applied, also involve the use of a baseline diameter value, which in itself modifies the magnitude of the calculated response. Finally, a salient lesson from the FMD literature is that standardized techniques, including consistent methods of analysis and data presentation between laboratories [14], are essential if the approach is to retain its integrity. Future studies should address these issues and work toward agreed methods and protocols. Expert commentary & five-year view
This article has summarized the current available evidence from the scientific literature around L-FMC, highlighted some limitations and suggested areas for future investigation. The use of L-FMC is still in its infancy, but preliminary findings provide some support for the hypothesis that radial L-FMC responses are impaired in populations with CV disease and/or risk. The data from brachial L-FMC are less clear. Pharmacological blockade and invasive studies support the idea that L-FMC is endothelium-dependent and probably mediated by the release of vasoconstrictors and the inhibition of dilator substances under low-flow conditions. However, much information is currently lacking on the exact mechanisms (e.g., link with sympathetic nervous system) that contribute to L-FMC, and a number of important methodological/practical issues remain unresolved (i.e., heterogeneity between vessels, importance of measuring in close proximity to the cuff, impacts of baseline diameter changes and shifts in basal tone). However, the main gap in our knowledge relates to the lack of information about the potential predictive capacity of L-FMC and the composite end point for future cardiovascular events. Taken together, the addition of a ‘constrictor-side’ to the FMD-response, without any methodological modifications to the current protocol, is appealing. Accounting for both vasodilator and constrictor characteristics represents a strong rationale and may improve the predictive capacity of FMD. However, important steps need to be taken before this procedure can be applied in practice. We need to understand the response, explore the potential predictive capacity and clinical value, and also become uniform in the description and calculation of the L-FMC (and/or composite end point). 561
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Financial & competing interests disclosure
DHJ Thijssen receives funding from the E Dekker stipend (Netherlands Heart Foundation, 2009T064). DJ Green receives research funding support from the National Heart Foundation of Australia and the Australian Research Council. The authors have no
other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.
Key issues Expert Review of Cardiovascular Therapy Downloaded from informahealthcare.com by Washington University Library on 01/01/15 For personal use only.
• Low-flow-mediated constriction (L-FMC) is a novel technique proposed for use alongside, but not instead of flow-mediated dilation. • Early mechanistic studies have suggested L-FMC is endothelium-dependent, and possibly mediated by the release of vasoconstrictors and/or inhibition of vasodilators. Further blockade studies are required to pin-point precise mechanisms in order to truly understand the clinical importance of L-FMC. • Heterogeneity in L-FMC responses seem to be present between the brachial and radial arteries. • Currently, no data are available to support the potential prognostic impact of L-FMC or the composite end point. • Further research is necessary to answer fundamental methodological questions in order to formulate a standardized approach.
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Inaugural low-flow-mediated constriction (L-FMC) paper of the new era, proposing underlying mechanisms and also presenting diminished L-FMC data in patients with risk factors.
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Gori T, Parker JD, Munzel T. Flow-mediated constriction: further insight into a new measure of vascular function. Eur Heart J 2011;32(7):784-7
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coronary intervention on L-FMC, which additionally describes a lack of correlation between L-FMC and a risk factor algorithm. 36.
Dawson EA, Alkarmi A, Thijssen DH, et al. Low-flow mediated constriction is endothelium-dependent: effects of exercise training after radial artery catheterization. Circ Cardiovasc Interv 2012;5(5):713-19
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Gori T, Muxel S, Damaske A, et al. Endothelial function assessment: flow-mediated dilation and constriction provide different and complementary information on the presence of coronary artery disease. Eur Heart J 2012;33(3): 363-71
•
Contemporary paper identifying progressive decline in L-FMC with increasing severity of coronary artery disease, also highlighting a significant linear relationship between the SYNTAX score and L-FMC.
•
Key paper highlighting attenuated L-FMC following acute endothelial damage, suggesting that L-FMC is endothelium-dependent.
46.
37.
Thijssen DH, Rongen GA, Smits P, Hopman MT. Physical (in)activity and endothelium-derived constricting factors: overlooked adaptations. J Physiol 2008; 586(2):319-24
Anderson TJ, Uehata A, Gerhard MD, et al. Close relation of endothelial function in the human coronary and peripheral circulations. J Am Coll Cardiol 1995;26(5): 1235-41
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Thijssen DH, Dawson EA, Black MA, et al. Heterogeneity in conduit artery function in humans: impact of arterial size. Am J Physiol Heart Circ Physiol 2008;295(5): H1927-34
Takase B, Uehata A, Akima T, et al. Endothelium-dependent flow-mediated vasodilation in coronary and brachial arteries in suspected coronary artery disease. Am J Cardiol 1998;82(12):1535-9.A7-8
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Thijssen DH, Willems L, van den Munckhof I, et al. Impact of wall thickness on conduit artery function in humans: is there a "Folkow" effect? Atherosclerosis 2011;217(2):415-19
Harrison M, Parkhurst K, Tarumi T, et al. Low flow-mediated constriction: prevalence, impact and physiological determinant. Clin Physiol Funct Imaging 2011;31(5):394-8
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Recent paper describing attenuated L-FMC in the brachial artery of those with clinical risk factors.
49.
Rakobowchuk M, Harris E, Taylor A, et al. Heavy and moderate interval exercise training alters low-flow-mediated constriction but does not increase circulating progenitor cells in healthy humans. Exp Physiol 2012;97(3):375-85
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First paper identifying augmentation of L-FMC after an exercise training program.
50.
Rakobowchuk M, Parsloe ER, Gibbins SE, et al. Prolonged low flow reduces reactive hyperemia and augments low flow mediated constriction in the brachial artery independent of the menstrual cycle. PLoS One 2013;8(2):e55385
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Dørup I, Skajaa K, Sørensen KE. Normal pregnancy is associated with enhanced endothelium-dependent flow-mediated vasodilation. Am J Physiol 1999;276(3): H821-H5
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Sianos G, Morel MA, Kappetein AP, et al. The SYNTAX Score: an angiographic tool grading the complexity of coronary artery disease. EuroIntervention 2005;1(2):219-27
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Kaku B, Mizuno S, Ohsato K, et al. The correlation between coronary stenosis index and flow-mediated dilation of the brachial artery. Jpn Circ J 1998;62(6):425-30
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Filitti V, Giral P, Simon A, et al. Enhanced constriction of the peripheral large artery in response to acute induction of a low-flow state in human hypercholesterolemia. Arterioscler Thromb 1991;11(1):161-6 Stadler RW, Ibrahim SF, Lees RS. Measurement of the time course of peripheral vasoactivity: results in cigarette smokers. Atherosclerosis 1998;138(1): 197-205
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Thijssen DH, van Bemmel MM, Bullens LM, et al. The impact of baseline diameter on flow-mediated dilation differs in young and older humans. Am J Physiol Heart Circ Physiol 2008;295(4): H1594-8
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Weissgerber TL, Davies GA, Tschakovsky ME. Low flow-mediated constriction occurs in the radial but not the brachial artery in healthy pregnant and nonpregnant women. J Appl Physiol 2010; 108(5):1097-105
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Key methodological paper highlighting heterogeneity of L-FMC in the radial and brachial arteries.
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Gori T, Grotti S, Dragoni S, et al. Assessment of vascular function: flow-mediated constriction complements the information of flow-mediated dilatation. Heart 2010;96(2):141-7
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Green DJ. Exercise training as vascular medicine: direct impacts on the vasculature in humans. Exerc Sport Sci Rev 2009;37(4): 196-202
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Mora S, Cook N, Buring JE, et al. Physical activity and reduced risk of cardiovascular events: potential mediating mechanisms. Circulation 2007;116(19):2110-18
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Maiorana AJ, Naylor LH, Exterkate A, et al. The impact of exercise training on conduit artery wall thickness and remodeling in chronic heart failure patients. Hypertension 2011;57(1):56-62
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Swift DL, Earnest CP, Blair SN, Church TS. The effect of different doses of aerobic exercise training on endothelial function in postmenopausal women with elevated blood pressure: results from the DREW study. Br J Sports Med 2012; 46(10):753-8 Tinken TM, Thijssen DH, Black MA, et al. Time course of change in vasodilator function and capacity in response to exercise training in humans. J Physiol 2008; 586(Pt 20):5003-12
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Dawson EA, Rathore S, Cable NT, et al. Impact of introducer sheath coating on endothelial function in humans after transradial coronary procedures. Circ Cardiovasc Interv 2010;3(2):148-56
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Atkinson G, Batterham AM, Thijssen DH, Green DJ. A new approach to improve the specificity of flow-mediated dilation for indicating endothelial function in cardiovascular research. J Hypertens 2013; 31(2):287-91
Expert Rev. Cardiovasc. Ther. 12(5), (2014)
Review
Low-flow mediated constriction: the yin to FMD’s yang? Expert Rev. Cardiovasc. Ther. 12(5), 557–564 (2014)
Ruth E Humphreys1, Daniel J Green1,2, N Timothy Cable1,3, Dick HJ Thijssen1,4 and Ellen A Dawson*1 1 Research Institute for Sport and Exercise Science, Liverpool John Moores University, Tom Reilly Building, Byrom Street, Liverpool L3 3AF, UK 2 School of Sport Science, Exercise and Health, The University of Western Australia, Crawley, Perth, 6009, Western Australia 3 Department of Sports Science, ASPIRE Academy, Qatar 4 Department of Physiology, Radboud University Medical Center, The Netherlands *Author for correspondence: Tel.: +31 0151 904 6264 Fax: +31 0151 904 6284 [email protected]
Given the prevalence of cardiovascular disease (CVD), early detection is crucial. Although traditional cardiovascular risk factors relate to future CVD, the predictive value of these risk factors can be relatively limited. Contemporary scientific attention has focused on alternative direct measures of arterial function. Based on the ability of the endothelium to acutely dilate in response to an increase in flow, ‘flow mediated dilation’ (FMD) was introduced approximately 20 years ago and is now an established non-invasive index of endothelial function predictive of future cardiovascular events. Recently, ‘low-flow mediated constriction’ (L-FMC) has been proposed as a complementary addition to FMD. The technique is based on the constrictor response to decreased flow and is claimed to improve the sensitivity and specificity of FMD. The aim of this review is to examine literature pertaining to this novel technique and to provide insight into the potential use of L-FMC in future research. KEYWORDS: cardiovascular prognosis • cardiovascular risk • composite end point • endothelial function • flow-mediated dilation • low-flow-mediated constriction
Endothelial function & cardiovascular risk
Cardiovascular disease (CVD) is the world’s leading cause of mortality, attributing to approximately 30% of all deaths [1]. The earliest detectable manifestation of atherosclerosis comes in the guise of endothelial dysfunction, which occurs long before the clinical presentation of CVD [2]. The mono-layered innermost lining of all vessels, the endothelium is crucial for maintaining vascular tone [3] and arterial health principally through the production of anti-atherogenic autacoids [4,5]. Dysfunction of the endothelium accelerates pro-atherosclerotic events, leading to the progression of atherosclerosis and CVD. Maintenance of a healthy endothelium through exercise training and lifestyle interventions is critical for both primary [6] and secondary prevention [7] of cardiovascular risk. A recent review suggested that risk factor algorithms fail to adequately predict future acute coronary events [8], endorsing the development of alternative techniques. Measurement of endothelial (dys)function in humans
Several methods have been adopted to assess arterial function. Among others, assessment of
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pulse pressure and its ratio to stroke volume can infer total arterial compliance, which has been cited as an independent predictor of cardiovascular events [9]. Aortic pulse wave velocity, an index of arterial stiffness, has also been identified as an independent predictor of allcause mortality and cardiovascular risk [10]. In addition, a plethora of plasma biomarkers, including highly sensitive C-reactive protein, are believed to represent endothelial function and predict future disease [11]. Over the past two decades, the non-invasive assessment of endothelial vasomotor function via the technique of ‘flow-mediated dilation’ (FMD) has been thoroughly refined and widely adopted within the literature [12–14]. The method is based on the ability of the endothelium to release vasoactive substances in response to a marked increase in blood flow, or more specifically, shear stress, which acts upon the endothelium. Typically examined in peripheral conduit arteries supplying the upper or lower limbs (ranging in diameter from 2 to 10 mm), ischemia is induced by blocking downstream blood flow via inflation of a supra-systolic pressure cuff placed around the arm or leg. Upon cuff release, a large increase
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in blood flow is initiated to the downstream vessels, resulting in an increase in shear stress on the conduit artery wall. The dilatory response from the conduit artery is recorded and is indicative of endothelial dys(function). This frequently used measure is endothelium-dependent [15,16] and partly mediated by nitric oxide (NO) [15], an anti-atherogenic vasodilator [17]. Clinical populations with increased cardiovascular risk exhibit lower FMD responses [18–20]. Furthermore, FMD has been recognized as having predictive capacity for future CVD, although this capacity may differ according to the particular protocol [21] and clinical group [22] studied. Finally, assessment of vascular function via FMD has identified that endothelial dysfunction can be detected years before clinical presentation of structural abnormalities and/or established risk factors [12,23,24]. Taken together, the bulk of scientific evidence indicates that FMD represents a useful tool to examine endothelial function and has independent predictive capacity for future CVD. Low-flow-mediated constriction: a history
While the FMD technique is based on the ability of arteries to dilate in response to increases in blood flow, ‘low-flow-mediated constriction’ (L-FMC) relies on the ability of arteries to constrict when blood flow is attenuated. In 1987, Levenson and colleagues were the first to describe human brachial artery vasoconstriction in vivo during an acute reduction of blood flow induced by inflation of a supra-systolic wrist cuff for 60 s [25]. This was later reinforced by Anderson and Mark [26], who inflated a blood pressure cuff around the forearm for 10 min to 200 mmHg and performed measurement of the brachial artery using Doppler ultrasound. Cuff inflation induced ‘circulatory arrest’, a condition later renamed ‘low-flow’, which subsequently provoked significant vasoconstriction. The presence of an L-FMC response was observed in further experiments both in the brachial [27,28] and radial arteries [29,30]. How do you measure L-FMC?
The assessment of L-FMC was re-visited as a measure of vascular function by Gori and colleagues in 2008 [31]. In line with work performed 20 years earlier, the proposed method involves evaluation of the response to an acute reduction in blood flow in the radial artery. Using ultrasound, the decrease in arterial diameter is assessed after 5 min of supra-systolic cuff occlusion, where the cuff is applied distal to the placement of the probe, at the wrist. L-FMC is then calculated as the relative change (i.e., decrease) in diameter in relation to baseline resting diameter (FIGURE 1). Previous studies have argued that by focusing on dilation in response to an increase in blood flow, FMD may simplify the complexity of vasomotor control by concentrating solely on vasodilator pathways [32]. L-FMC, in contrast, examines the constriction of an artery in response to a decrease in flow. The reduced diameter during conditions of low-flow may be largely linked to baseline tone. In other words, a large constriction during the low-flow condition could be a consequence of low basal tone (and therefore larger baseline diameter), which allows the artery to respond with a strong constriction when 558
exposed to a low-flow state. Likewise, a small constriction may reflect a situation where baseline resting tone is high (resulting in a smaller baseline diameter), allowing little space for further constriction during L-FMC. Although basal tone impacts upon relative changes in L-FMC (and FMD), underlying endothelial dysfunction, acute hormonal or sympathetic stimulation and fluctuations in oxidative stress may also impact upon L-FMC. The interaction between discreet changes in basal tone and these other stimuli is multifaceted, and adds to the complexity of understanding vasomotor control and function. As with FMD, the matter of reproducibility and repeatability of L-FMC is extremely pertinent. Recent large multicenter studies have highlighted that reproducible short- and mediumterm FMD evaluation is attainable, so long as standardized protocols are adhered to [33,34]. Early, small sample L-FMC studies have revealed that L-FMC is reproducible in the brachial artery [35], and that repeatability and reproducibility of L-FMC is comparable to FMD in the radial artery [31]. Further large multicenter studies are required to better understand reproducibility and repeatability of L-FMC. What mechanisms underlie L-FMC?
Theoretically, the mechanisms that contribute to L-FMC may include those which increase vasoconstriction and/or decrease vasodilation, although these have not yet been thoroughly examined. A recent study from Dawson et al. investigated whether L-FMC is endothelium-dependent by assessing L-FMC before and after denudation of the radial artery endothelium [36]. Interestingly, a significantly diminished magnitude in L-FMC was observed after denudation, providing human in vivo evidence that L-FMC is, at least partly, mediated through the endothelium. When examining the potential vasoactive substances that mediate L-FMC, an early blockade study focused on the potential importance of NO. In contrast to the well-established contribution of NO to FMD [15], this study found that L-FMC was not altered by infusion of the NOblocker NG-monomethyl-L-arginine and concluded that L-FMC is not NO-mediated [31]. Interestingly, inhibition of other potent endothelium-dependent vasodilators (endothelium-derived hyperpolarizing factor [EDHF] and prostaglandins) induced a diminished magnitude in L-FMC in healthy volunteers [31]. The authors inferred that withdrawal of EDHF and/or cyclooxygenase-related vasodilators before baseline diameter measurement may contribute to a decrease in L-FMC. However, since expected changes in baseline diameter were not presented (D baseline diameter -0.01 mm), this somewhat complicates interpretation of the contributing roles of EDHF and prostaglandins to both basal tone and L-FMC. On the other hand, constriction during low-flow may (also) be induced by an increase in vasoconstrictor stimulus. In support of this, Spieker and colleagues found that the low-flow-mediated constrictor response of the radial artery was abolished following blockade of endothelin-1 (ET-1) [30]. Conversely, a more recent study found that a larger brachial L-FMC was not associated with changes in plasma ET-1 levels [35]. However, it should be Expert Rev. Cardiovasc. Ther. 12(5), (2014)
L-FMC: a novel technique to assess vascular function
Review
Dmax
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Figure 1. Schematic representation of concurrent L-FMC and FMD assessment in the radial artery, as proposed by Gori et al. (2008), with mathematical equations for calculation of FMD, L-FMC and the composite end point. Dbase: Vessel diameter at baseline; Dmin: Minimum vessel diameter during last 30 s of cuff inflation; Dmax: Maximum vessel diameter during the first 3 min post cuff deflation; FMD: Flow-mediated dilation; L-FMC: Low-flow-mediated constriction; Composite end point: Sum of L-FMC and FMD.
emphasized that ET-1 plasma levels correlate poorly with the contribution of ET-1 to vascular tone [37]. Taken together, while there is some evidence that L-FMC is endothelium-dependent and may be mediated through a combination of an increase in vasoconstrictors (such as ET-1) and decrease in vasodilators (EDHF and prostaglandins), mechanisms contributing to L-FMC in the brachial or radial artery remain unclear and should be subject to future research. Is there site specificity for L-FMC?
One potential benefit of L-FMC is that it can be measured concurrently with FMD. However, initial studies utilizing L-FMC were based on investigations in the radial artery, while the majority of FMD literature is focused on the brachial artery. Important differences in magnitude and kinetics of vasomotor FMD responses have been reported between these conduit arteries, due in part to differences in structure and/or exposure to vasoactive stimuli [38,39]. In line with these distinct FMD responses between arteries, previous studies examining informahealthcare.com
brachial L-FMC have shown no diameter change in healthy subjects during low-flow [40,41], while others have found an increase [42] or decrease [27,35] in brachial artery diameter during forearm occlusion. Based on the apparent heterogeneity in vascular responses between different arterial beds, Weissgerber and colleagues examined the L-FMC response in the radial and brachial artery of pregnant and non-pregnant women [43]. While confirming the presence of L-FMC in the radial artery, no such response was observed in the brachial artery of the same women. Likewise, a small, but significant increase (i.e., dilation rather than constriction) in diameter during cuff occlusion was observed in the brachial artery of children and healthy young subjects, although no significant change was reported in older subjects [42]. An important methodological difference when examining L-FMC is that assessment of the radial, but not the brachial artery, is performed in relatively close proximity to the occlusion cuff. The impact of measuring diameter change during cuff inflation in close proximity to the occluding cuff, and 559
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potential presence of tissue displacement or changes in pressure, is unclear at this stage. Despite this, coherent evidence of vasoconstriction under conditions of low-flow in the radial artery remains [31,36,43–45]. Moreover, different responses in the radial and brachial arteries are not necessarily indicative of a limitation to the L-FMC technique, since important clinical information may be fathomed from these varying responses. The apparent heterogeneity of artery responses to low-flow conditions has implications for the validity of L-FMC as a surrogate for the coronary arteries. Given that dilator responses show strong correlations between the coronary and brachial arteries [46,47], future studies should examine the potential for L-FMC as a surrogate marker of coronary artery constrictor responses. Arguably, the clinical relevance would be limited if responses in the periphery do not mirror those observed in epicardial arteries. One previous study observed a weak (r2 = 0.1) yet significant (p < 0.001) correlation between L-FMC and an index of coronary flow velocity. However, caution is warranted when interpreting correlations between vascular beds when the stimuli are not similar. This is especially noteworthy since the exact stimuli for L-FMC are not fully understood. Although shear rate is hypothesized to contribute to the diameter response in L-FMC [31], a recent study reported no significant correlation between the reduction in shear rate during cuff occlusion and magnitude of L-FMC [43]. Clearly, further research is required to understand L-FMC responses, underlying stimuli and mechanisms. In addition more work is needed to quantify heterogeneity between arteries and to assess the predictive value of L-FMC for cardiac events. Can L-FMC identify subjects with CVD?
L-FMC has been assessed in both healthy [31,43–45,48–50] and clinical [31,35,36,44,45,48] populations. Diminished radial artery L-FMC is reported in clinical populations such as hypertension, smokers, coronary artery disease (CAD) [31] and heart failure [44], and has also been shown in the brachial artery of those with multiple cardiovascular risk factors [48]. This is often accompanied by a reduced FMD [31,44,45,48], which supports the hypothesis that L-FMC is associated with endothelial dysfunction. Moreover, investigation of radial L-FMC in patients with one, two and three vessel CAD demonstrated a ‘dosedependent’ decline in L-FMC with increased severity of disease [45]. However, some studies have presented conflicting results. No difference was demonstrated in radial L-FMC between pregnant and non-pregnant women [43], which is perhaps unusual since pregnant women typically present with larger FMD [51], although another study identified that hormonal fluctuation during the menstrual cycle did not impact upon L-FMC [50]. Furthermore, patients with myocardial infarction showed greater brachial L-FMC than those with stable atherosclerosis, despite the presumption that the former had greater endothelial dysfunction [35]. Interestingly, while radial L-FMC responses seem to be consistently attenuated in the radial artery of those with cardiovascular risk factors [31,44,45], both diminished [48] and improved [40,41] 560
L-FMC responses have been shown in the brachial artery. Future research should confirm whether there are real differences in vessel responsiveness between the brachial and radial arteries in groups with cardiovascular risk factors and disease. Is there evidence of predictive capacity?
Differences in L-FMC between healthy subjects and clinical groups in the radial artery provide some early indication of a potential predictive capacity. However, to date, no research has directly examined the predictive capacity of L-FMC (or the combination of L-FMC and FMD as a composite end point) in a follow-up longitudinal study. This is a significant gap in the literature that will limit adoption of L-FMC into clinical practice and research. Although a moderate cross-sectional correlation between brachial FMD and L-FMC has been shown in healthy subjects, this was not apparent in clinical populations [35]. Moreover, no correlation between FMD and L-FMC was found in the radial artery of healthy subjects or those with cardiovascular risk factors [31]. Studies have also examined the cross-sectional correlation of L-FMC with cumulative risk factor scores. The SYNTAX score is used by clinicians to grade the severity and complexity of CAD in patients [52]. A recent paper found that radial artery L-FMC, but not FMD, was modestly related to the SYNTAX score in a subset of CAD patients [45]. In contrast, using an alternative CVD risk algorithm: the ‘coronary stenosis index’ [53], a significant correlation between the index and FMD, but not L-FMC, was found [35]. Interpretation of (the absence of) correlations between L-FMC and established predictors of CVD remain obscure. While the lack of such relation may suggest that L-FMC possesses no predictive capacity, one may also argue that it is explained by the fact that L-FMC provides predictive information that is independent of these other markers. Future studies adopting a prospective, follow-up study design in which L-FMC is measured alongside traditional and novel markers of cardiovascular risk, should help to answer this clinically and scientifically important question. FMD + L-FMC: a composite end point?
While the measurement of L-FMC itself may have importance, the summative ‘score’ of FMD and L-FMC may provide further insight into vascular health (FIGURE 1) [31]. The ‘composite end point’ (also referred to as ‘total vessel reactivity’ [49] or ‘modified FMD’ [48]) is indicative of constrictor/dilator reserve (i.e., the ability of a vessel to both dilate and constrict). However, one should realize that such summative end points may also increase the coefficient of variance, potentially limiting their applicability. It should also be noted that total vessel reactivity [49] and modified FMD [48] are calculated relative to the minimum diameter during cuff occlusion and not baseline diameter [31]. Although seemingly only a subtle mathematical modification, conclusions could be statistically and clinically different to those using the composite end point. The use of the composite end point has been shown to improve detection Expert Rev. Cardiovasc. Ther. 12(5), (2014)
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L-FMC: a novel technique to assess vascular function
of endothelial dysfunction in patients already diagnosed with hypertension, CAD or heart failure [44]. However, use of FMD and L-FMC together as separate (yet complementary) parameters may also help to determine vascular dys(function). Previous work has demonstrated that L-FMC (as a complementary measure alongside FMD) may have further value than the summative composite end point, by reducing false-positive and false-negative results/predictions [44]. Nevertheless, the use of an aggregate measure in addition to FMD seems promising, although uniformity in definition and calculation, as well as better insight into its potential clinical relevance, is essential. What is the impact of intervention on L-FMC?
Exercise training is a well-established, potent, non-pharmacological intervention with strong cardioprotective effects [54,55]. It is generally accepted that exercise training in subjects with cardiovascular risk leads to improvement in FMD [20,56,57], although this may be time dependent [58]. Accordingly, it might be expected that exercise training and/or acute exercise would result in augmentation of L-FMC. Rakobowchuk and colleagues recently examined brachial artery L-FMC responses before and after systemic interval training in healthy subjects [49]. Their 6-week protocol compared the impact of high intensity versus moderate intensity interval training on brachial artery L-FMC and found small, yet statistically significant, improvements in L-FMC and the composite end point following both protocols; although FMD was not significantly improved post-intervention. The larger L-FMC after exercise training suggests that baseline diameter may be under more vasodilator control, allowing for a larger relative L-FMC when exposed to vasoconstrictors under conditions of low-flow. The time course of L-FMC adaptation across a period of training is yet to be explored. Recently, we examined the impact of a 6-week handgrip training program on radial artery L-FMC in patients recovering from radial catheterization [36]. Previous research has demonstrated that the catheterization procedure is associated with an impaired FMD [59]. In this study [36], we demonstrated that handgrip training recovered radial artery L-FMC, FMD and the composite end point compared with impaired dilator and constrictor responses in the control group. These data support the notion that exercise training may improve L-FMC responses and, therefore, vasoconstrictor/dilator control of the resting, baseline artery diameter. What are the avenues for future research?
L-FMC is typically calculated as a change from baseline diameter. Research pertaining to FMD has established that, as a ratio measure, changes in the resting baseline can influence the relative response [42]. For instance, arteries with smaller diameters typically exhibit larger %FMD responses, partly by virtue of the mathematical method of calculation [60]. In circumstances where cross-sectional comparisons are made, or where large changes occur in baseline diameter in repeated measures experiments, the interpretation of FMD as an index of artery informahealthcare.com
Review
functional capacity becomes more nuanced. This concept is equally relevant to baseline changes and the interpretation of LFMC. If baseline diameter decreases, in the face of similar absolute changes in diameter under conditions of low-flow/ shear, then L-FMC will be exaggerated. At the same time, if there is a fixed floor in terms of absolute constriction, then movement of the baseline toward this floor value will effectively attenuate the %L-FMC value. These issues serve to highlight the fact that %L-FMC is a ratio variable and that interpretation can be complicated if the baseline changes, something that is conceivable in the context of interventions that modify the relative contribution of dilator versus constrictor agents to basal vascular tone. The use of the composite end point or alternative measure of constrictor/dilator reserve may theoretically diminish this complexity. However, such indices, as currently applied, also involve the use of a baseline diameter value, which in itself modifies the magnitude of the calculated response. Finally, a salient lesson from the FMD literature is that standardized techniques, including consistent methods of analysis and data presentation between laboratories [14], are essential if the approach is to retain its integrity. Future studies should address these issues and work toward agreed methods and protocols. Expert commentary & five-year view
This article has summarized the current available evidence from the scientific literature around L-FMC, highlighted some limitations and suggested areas for future investigation. The use of L-FMC is still in its infancy, but preliminary findings provide some support for the hypothesis that radial L-FMC responses are impaired in populations with CV disease and/or risk. The data from brachial L-FMC are less clear. Pharmacological blockade and invasive studies support the idea that L-FMC is endothelium-dependent and probably mediated by the release of vasoconstrictors and the inhibition of dilator substances under low-flow conditions. However, much information is currently lacking on the exact mechanisms (e.g., link with sympathetic nervous system) that contribute to L-FMC, and a number of important methodological/practical issues remain unresolved (i.e., heterogeneity between vessels, importance of measuring in close proximity to the cuff, impacts of baseline diameter changes and shifts in basal tone). However, the main gap in our knowledge relates to the lack of information about the potential predictive capacity of L-FMC and the composite end point for future cardiovascular events. Taken together, the addition of a ‘constrictor-side’ to the FMD-response, without any methodological modifications to the current protocol, is appealing. Accounting for both vasodilator and constrictor characteristics represents a strong rationale and may improve the predictive capacity of FMD. However, important steps need to be taken before this procedure can be applied in practice. We need to understand the response, explore the potential predictive capacity and clinical value, and also become uniform in the description and calculation of the L-FMC (and/or composite end point). 561
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Financial & competing interests disclosure
DHJ Thijssen receives funding from the E Dekker stipend (Netherlands Heart Foundation, 2009T064). DJ Green receives research funding support from the National Heart Foundation of Australia and the Australian Research Council. The authors have no
other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.
Key issues Expert Review of Cardiovascular Therapy Downloaded from informahealthcare.com by Washington University Library on 01/01/15 For personal use only.
• Low-flow-mediated constriction (L-FMC) is a novel technique proposed for use alongside, but not instead of flow-mediated dilation. • Early mechanistic studies have suggested L-FMC is endothelium-dependent, and possibly mediated by the release of vasoconstrictors and/or inhibition of vasodilators. Further blockade studies are required to pin-point precise mechanisms in order to truly understand the clinical importance of L-FMC. • Heterogeneity in L-FMC responses seem to be present between the brachial and radial arteries. • Currently, no data are available to support the potential prognostic impact of L-FMC or the composite end point. • Further research is necessary to answer fundamental methodological questions in order to formulate a standardized approach.
Papers of special note have been highlighted as: • of interest 1.
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