Medicine & Science in Sports & Exercise:
Why Isn’t Flow-Mediated Dilation Enhanced in Athletes?
GREEN, DANIEL J.1,2; ROWLEY, NICOLA1; SPENCE, ANGELA2; CARTER, HOWARD2; WHYTE, GREG1; GEORGE, KEITH1; NAYLOR, LOUISE H.2; CABLE, N. TIMOTHY1; DAWSON, ELLEN A.1; J. THIJSSEN, DICK H.1,3
1Research Institute for Sport and Exercise Science, Liverpool John Moores University, Liverpool, UNITED KINGDOM; 2School of Sport Science, Exercise and Health, The University of Western Australia, Crawley, Perth, Western Australia, AUSTRALIA; and 3Department of Physiology, Radboud University Nijmegen Medical Centre, Nijmegen, THE NETHERLANDS
Address for correspondence: Daniel Green, Ph.D., School of Sports Science, Exercise and Health, The University of Western Australia, Crawley, WA 6009, Perth, Australia; E-mail: firstname.lastname@example.org.
Submitted for publication May 2012.
Accepted for publication July 2012.
Purpose: Studies performed in animals and humans strongly suggest that exercise training and physical activity enhance arterial endothelial function. Studies of athletes have, however, been less definitive.
Methods: We recruited a range of Olympic and world class athletes who participate in upper or lower limb predominant activities and examined brachial and superficial femoral artery diameter responses to 5-min ischemia (flow-mediated dilation [FMD]) and glyceryl trinitrate, wall thickness (WT) and wall-to-lumen ratio using Doppler and two-dimensional ultrasound. Subjects were elite male canoe paddlers (n = 12), squash players (n = 13), lower limb dominant athletes (i.e., runners/cyclists/triathletes, n = 13), or age- and sex-matched control subjects (n = 16).
Results: Athletes demonstrated lower superficial femoral artery FMD than controls (P < 0.05), whereas in the brachial artery, a lower FMD was found in squash players (P < 0.05). Both arteries showed a significant inverse correlation between diameter and FMD (P < 0.05), and a significant inverse relationship was apparent between wall-to-lumen ratio and FMD in the superficial femoral artery (P < 0.05).
Conclusions: Although artery FMD was lower in athletes, artery size was larger and WT smaller than controls. The apparent reduction in artery FMD may relate to the profound structural remodeling in the diameter and WT of the conduit arteries of athletes. These findings have implications for the interpretation of FMD data, particularly as it pertains to the effect of athletic endeavor on cardiovascular health.
It is well established that exercise training can improve endothelial function (11,35), at least partly due to episodic increases in wall shear stress (20,38,40). Although the majority of these studies have been undertaken in subjects with cardiovascular disease and risk factors (11), it is also possible to enhance endothelial function in healthy young subjects who undertake exercise training (16,37). At the same time, exercise training can induce conduit artery remodeling, including increases in artery diameter (14,28,29) as well as decreases in wall thickness (WT) (33).
An intriguing observation is that several studies that have examined resistance artery blood flow changes during intra-arterial infusions of vasoactive drugs or conduit artery flow-mediated dilation (FMD) have not reported enhanced endothelial function in response to high levels of exercise training. For example, a study that assessed resistance vessel responses to intrabrachial infusion of acetylcholine demonstrated lower dose–response curves in the preferred than that in the nonpreferred limb of elite tennis players (10), suggesting similar or lower vascular function in the arm that is more trained. These findings were supported by another study, which compared resistance vessel function in young athletes and sedentary controls (9). Similarly, most studies of conduit vessel FMD have not demonstrated enhanced function (8,24,27), although this finding is not universal (6,41). The reason for these disparate results is uncertain but may relate to inherent structural changes in the artery and the interaction between artery structure and function.
Previous studies have found evidence of arterial remodeling due to exercise training, with smaller WT and larger diameters in elite athletes when compared with healthy controls (28,29). We and others found that the FMD is strongly related to structural characteristics of the arterial wall, such as WT (36) and diameter (3,30,34), with larger diameters and smaller WT associated with a lower FMD. These structural adaptations seem to depend on the type of exercise undertaken (28,29). The inclusion of a range of elite athletes and therefore the differences in arterial structural characteristics between and within subjects allow us to better examine the relation between artery structure and FMD. We therefore recruited a range of elite athletes who participate in either upper or lower limb dominant exercises and studied the FMD, size, and WT of their brachial and superficial femoral arteries. We hypothesized that the FMD will be lower in athletes, and more specifically in arteries in the limbs that receive more training and that these changes will be, at least partly, related to the larger diameter and smaller wall-to-lumen (W:L) ratio.
We recruited canoe paddlers (CP; n = 12, upper limb dominant exercise), squash players (SQ; n = 13, upper and lower limb exercise), runners/cyclists/triathletes (LL; n = 13, lower limb dominant) and age- and gender-matched healthy able-bodied controls (n = 16). The CP group included international level male CP who trained 21 ± 2 h·wk−1 for >2 yr. On the basis of self-reported training details, approximately 75% of this training was upper limb specific. The SQ group included international level male Great Britain SQ (who played ≥2 yr at international/national level and trained for >22 h·wk−1), with 80% being sport specific (self-reported training details), including game play, unilateral racket, and shadowing skills. The LL group included international/national standard male >10-km runners (n = 7), road cyclists (n = 2), and triathletes (n = 4) who trained 17 ± 5 h·wk−1 for >2 yr (predominant lower limb specific training). Recreationally active sex- and age-matched controls were recruited, who participated in exercise training <3 h·wk−1 at a recreational level. Subjects who smoked or those on medications of any type were excluded from the study. All participants were free from known cardiovascular disease, diabetes, insulin resistance, hypercholesterolemia, and hypertension. The study procedures were approved by the Ethics Committee of the Liverpool John Moores University, and studies conformed to the Declaration of Helsinki. Written informed consent was gained from all participants before the experimental procedures. It should be noted that although the effect of localized versus systemic exercise on WT and diameter in these subjects has previously been reported (28,29), the FMD data, which form the basis of this article and relationships between FMD and other arterial parameters, have not been previously presented.
Participants reported on one occasion after fasting for 6 h, abstaining from alcohol and beverages containing caffeine (e.g., coffee, tea, energy drinks) for 12 h and refraining from any intense training sessions 24 h before testing (32). After familiarization and completion of a brief training history questionnaire, subjects rested for at least 20 min in the supine position. Baseline ultrasound scans of the brachial and superficial femoral artery were then collected for an assessment of resting diameter and WT using high-resolution ultrasound. We also measured endothelium-dependent dilation using a 5-min ischemic stimulus (i.e., FMD) and endothelium-independent dilation (i.e., oral administration of glyceryl trinitrate [GTN]). Subjects were assessed off-season.
Conduit artery WT
Participants rested in the supine position for at least 15 min. Heart rate and mean arterial pressure were determined twice using an automated sphygmomanometer (Dinamap; GE Pro 300V2, Tampa, FL). Two standardized probe angles were used to determine resting WT and the diameter of the right brachial and superficial femoral artery using a 10-MHz multifrequency linear array probe attached to a high-resolution ultrasound machine (T3000, Terason, Burlington, MA). The sonographer obtained a longitudinal B-mode image of the brachial artery in the distal one-third part of the upper arm. Recording was performed for a 10-s period. Settings were adjusted to focus on the far wall of the arterial lumen interface and the media adventitia. WT data were then collected from the brachial and superficial femoral arteries using the same procedures as described previously.
Endothelium-dependent vasodilation (FMD)
Brachial and superficial femoral artery dilation to a 5-min ischemic stimulus was performed to examine the endothelium-dependent dilation using recent consensus guidelines (32). Brachial artery FMD was examined in the dominant limb, with the arm extended and positioned at an angle of approximately 80° from the torso. A rapid inflation and deflation pneumatic cuff (D.E. Hokanson, Bellevue, WA) was positioned around the forearm immediately distal to the olecranon process. A 10-MHz multifrequency linear array probe (T3000; Terason) was used to image the brachial artery in the distal one-third of the upper arm. Ultrasound parameters were set to optimize the longitudinal B-mode images of the lumen–arterial wall interface and were then held stable for a 1-min baseline recording of the image and Doppler velocity. Continuous Doppler velocity assessment was collected using a 60° insonation angle, which did not vary during each study. The occlusion cuffs were inflated to >200 mm Hg to completely block the arterial inflow for 5 min. Diameter and flow recordings resumed 30 s before cuff deflation and continued for 3 min thereafter. We then examined the superficial femoral artery FMD using the methodological procedures described previously. Subjects rested in the supine position, with the lower leg slightly elevated using approximately 15-cm-thick foam. Pneumatic cuffs were positioned on the proximal two-thirds of the thigh. Superficial femoral artery diameter was examined approximately 5 cm distal from the femoral bifurcation into the deep and superficial femoral artery (17).
Endothelium-independent vasodilation (GTN)
Brachial and superficial femoral artery vasodilation was examined simultaneously using a single sublingual administration of GTN. After a 1-min assessment of the baseline brachial or superficial femoral artery diameter and velocity, the sublingual administration of GTN (400 μg) was followed by a 10-min recording of both arteries simultaneously using identical ultrasound machines and settings. GTN were not obtained for the femoral artery from the SQ for logistical reasons.
Posttest analysis of brachial and superficial femoral artery diameter and red blood cell velocity were performed using a custom-designed edge detection and a wall-tracking software, which is largely independent of investigator bias (43). FMD and GTN responses are presented as the relative (%) rise from the preceding baseline diameter and are calculated on the basis of standardized algorithms applied to data which had undergone automated observer-independent edge detection and wall tracking (see previous studies for further detail ). We calculated the shear rate stimulus responsible for endothelium-dependent FMD% after cuff deflation. The area under the shear rate curve (SRAUC), calculated for data up to the point of maximal postdeflation diameter (FMD%), was calculated for each individual. In accordance with recent guidelines (32), we have presented the FMD% SR data in a table but have not normalized for these data due to the limitations of this approach.
Posttest analysis of arterial WT was performed by a single observer using custom-designed edge detection and wall-tracking software, which is validated and largely independent of investigator bias (25,26). Settings were recorded and maintained to establish consistency (25,26). The software is written in the icon-based graphical programming language (LabVIEW 7.0™) and uses an IMAQ™ vision tool kit for image handling and analysis routines with arterial analysis using edge detection methods.
Statistical analyses were performed using the Statistical Package for the Social Sciences (version 17.0; SPSS Inc., Chicago, IL) software. All data are reported as mean (SD) unless stated otherwise, whereas statistical significance was assumed at P < 0.05. One-way ANOVA was used to assess differences in our outcome parameters between groups (i.e., WT, diameter, FMD and GTN). Post hoc comparisons were made using least square difference test for multiple corrections to examine which groups differed. We also used a Pearson correlation coefficient to examine the relation between baseline diameter or WT and endothelium-dependent (FMD) or endothelium-independent dilation (GTN) in the brachial and superficial femoral artery.
The LL athlete group demonstrated a significantly lower body weight than the CP group, whereas heart rate was significantly lower in all athlete groups compared with the control group (Table 1). Systolic blood pressure was significantly lower in SQ than controls, whereas height was larger in all athlete groups compared with controls (Table 1). Other subject characteristics did not differ between groups (Table 1).
Superficial Femoral Artery
Superficial femoral artery FMD differed significantly across groups (P = 0.007; Fig. 1). Post hoc analysis revealed that all athlete groups demonstrated a significantly lower FMD% than controls (Fig. 1). We found no differences between groups in the shear rate area-under-the-curve stimulus (Table 2). Baseline superficial femoral artery diameter tended to be different across groups (P = 0.07; Fig. 1). A significant inverse correlation was found between superficial femoral artery diameter and FMD (Fig. 2A). GTN response did not differ across groups (Table 2).
Superficial femoral artery WT and W:L ratios also differed across groups, with the athlete groups demonstrating a significantly smaller WT and W:L ratio than the normal active controls (both P < 0.001, Table 2 and Fig. 1, respectively). We found no differences in WT or W:L ratio between the different athlete groups (Table 2). W:L ratio correlated significantly with FMD% (Fig. 2C).
Brachial artery FMD was significantly different across groups (P = 0.034; Fig. 3 and Table 2). Post hoc analysis revealed that the comparison between controls and SQ reached statistical significance (Fig. 3). We found no differences between groups in the shear rate area-under-the-curve stimulus (Table 2). GTN responses were different across groups (P = 0.02), with post hoc analysis revealing a significant difference between the SQ and the controls (Table 2). Baseline brachial artery diameter in the athlete groups was significantly larger than that in the control group, with the upper limb dominant athlete groups (i.e., CP and SQ) demonstrating the largest brachial artery diameter (P = 0.001, Table 2 and Fig. 3). A significant inverse correlation was found between brachial artery diameter and FMD (Fig. 2B).
Brachial artery WT and W:L ratios differed significantly across groups, with all athlete groups showing a significantly smaller WT and W:L ratio than the normal active controls (both P < 0.001, Table 2 and Fig. 3, respectively). We found no differences in WT or W:L ratio between the different athlete groups (Table 2). The brachial artery W:L ratio to FMD% correlation was 0.29 (P = 0.06) (Fig. 2D).
Our results indicate that femoral artery FMD was lower in all athlete groups compared with controls, whereas brachial artery FMD was significantly lower in SQ, who are reliant upon upper limb exercise. The absence of any increase in FMD in the athletic groups is also apparent in the GTN administration. Our data indicate that FMD and GTN responses are not enhanced in the brachial or femoral arteries of athletic subjects.
There are relatively few previous studies of arterial function in elite athletes. In a study of resistance vessel function involving the construction of dose–response curves to intra-arterial infusion of endothelium-dependent and endothelium-independent vasodilator substances, the preferred limb of elite level tennis players exhibited similar or somewhat lower responsiveness than the contralateral nonpreferred limb (10). This study had the advantage of a within-subjects design, which eliminated many of the confounding factors that complicate comparisons of athletes and control subjects. Subsequent studies supported this initial finding because no differences were found in forearm responses to incremental doses of acetylcholine between young athletes and their sedentary controls (9). Other cross-sectional studies have also not observed increases in arterial function in athletic groups in conduit arteries (8,24,27). It is important to acknowledge, however, that some studies have observed higher brachial artery FMD in athletes (6,41). The reasons for the disparity in the findings of these studies are unclear. Both studies, like the present one, involved between-group comparisons. As described previously, previous studies involving within-subjects comparisons, which may be less prone to variability, have suggested that vascular function is not enhanced in the athletic limb (10). It is difficult to speculate on the potential influence of baseline arterial diameter on the FMD results in these studies, one of which did not report these (6). Although Walther et al. (41) reported concomitant larger diameters and FMDs in athletes compared to controls, no correlation between diameter and FMD was reported in this article. It is also pertinent to indicate that both studies reported FMD values (i.e., 10%–17%) that high compared with the broader FMD literature. It is possible that specific differences may exist in some athlete groups, for example, Walther et al. (41) studied swimmers, who were not included in other studies. Nonetheless, we conclude on the basis of the current study of different athletes with complimentary findings in upper and lower limb arteries, along with the majority of previous experiments in both conduit and resistance arteries, that athletes do not exhibit the enhanced FMD or vascular function. This is paradoxical because enhanced conduit artery FMD might be expected because of the effect of exercise training and repeated episodic exposure to arterial shear stress.
We believe there are several possible explanations for our observations of lower FMD in athletes. Although largely forgotten or disregarded, it has been known for many years that a principal determinant of FMD is baseline arterial diameter (3). Indeed, we recently demonstrated that baseline artery size is strongly correlated with FMD across arteries of different dimension both within and between subjects (34). Importantly, this relationship between artery diameter and flow-induced function cannot be explained on the basis of smaller arteries being exposed to larger shear stress during the FMD technique (1,34). This is supported by the finding that a strong relationship was also found between artery diameter and the artery response to GTN, a shear-independent response (34). In the present study, we found a strong inverse relationship between arterial diameter in the limbs of athletes and their FMD (Fig. 2). Although the correlation between these factors was highly significant, artery diameter clearly does not fully account for the variance in FMD.
It is well established that remodeling of arterial lumen dimension is endothelium dependent (19) and that shear stress is an important stimulus (40). On the basis of extensive research pertaining to the effects of exercise training in various animal models, Laughlin proposed that the initial response to training involves enhancement in arterial function and up-regulation of endothelium-derived vasodilator pathways, followed by remodeling such that the artery increases in size (20). This structural adaptation may be associated with a normalization of artery FMD. We recently provided some support for this finding in humans (37), by providing evidence for the role of arterial shear stress in both the initial functional and subsequent structural phases of the response to exercise training in healthy young subjects (38). The structural adaptations observed in the athletes in our study may also be associated with normalization of the exercise-induced elevations in shear stress levels. The repeated exposure of the arteries of elite athletes to the exercise-induced elevations in shear likely results in outward remodeling of conduit arteries (40), possibly in keeping with the homeostatic regulation of shear stress (39). Taken together, these previous studies inform our current findings in several ways. First, they reinforce the possibility that athletes may exhibit enhancement in endothelial function in the early phases of their training response but that this may not be detectable after prolonged training exposure. Second, they suggest that the lack of enhancement in FMD responses of athletes may reflect normal function at a larger structural “set point.” The important implications of these and previous (34) findings pertaining to the relationship between artery size and function are that conduit arterial function should be considered in the context of the baseline artery size and conclusion regarding the health of arteries should not be simplistically based on the observation of impairment in FMD alone.
A second explanation for our observation of lower FMD in athletes relates to the effect of arterial WT on function. In the present study, we observed decreased WT in the arteries of athletes compared with control subjects as reported previously in these subjects (28,29) and in those of other studies (4). There are also studies indicating that exercise training within subjects can lead to decreases in WT, at least of peripheral arteries (see Thijssen et al. ). The relevance of decreases in WT to the magnitude of FMD relates to extensive studies from the 1950s undertaken by Folkow et al. (7). They suggested that, for a given level of vascular smooth muscle shortening, arteries that possess larger W:L ratios exhibit increase vasoconstrictor function. This accepted mechanical relationship between W:L and function implies that arteries with decreased W:L will exhibit diminished functional responses. Indeed, in a recent study, we provided the first evidence in humans that conduit artery W:L is strongly related to the magnitude of dilator responses (36). This study provides further evidence for the strong relationship between W:L and FMD and extends these findings via the observation that these relationships are also present in (the larger) arteries of elite athletes. The explanation for decreased WT in athletes is currently unknown, but our recent data suggests that, in contrast to the situation for remodeling of arterial diameter, the stimulus may be systemic rather than localized in nature. There are several logical candidates, which have been recently reviewed (21,23) and might include episodic increases in pulse pressure, tangential, or cyclical wall stress, or oxidative stress.
A final explanation for the observation that FMD is not increased in athletes relates to the competing effects on FMD of the sympathetic nervous system. Evidence suggests that elevated SNS outflow decreases the magnitude of FMD (13), although other studies have indicated that the method of eliciting increased SNS activity may be important (5). Although some suggest that athletes exhibit altered autonomic balance favoring increased parasympathetic tone and diminished sympathetic outflow, there is also evidence that SNS outflow at rest may be increased in the face of vascular remodeling and enhanced vasodilator reserve (12,31). Further research will be required to assess possible interactions between vasodilator mechanisms and the autonomic SNS in athletes.
On the basis of the previously mentioned considerations, we propose that the diminished femoral FMD in all athlete groups and lower brachial FMD in SQ in the present study may not reflect true decreases in FMD but normal function given the apparent remodeling of arterial size and WT. Increased WT of some arteries, specifically the carotids, has been linked to increases in CV risk (22), but higher FMD has also been suggested as cardioprotective (15). In any event, we think it appropriate to exercise caution when drawing implications for CV risk based on the FMD data from our small cohort of different athletes. It is, however, relevant that some epidemiological data suggest that endurance athletes and those engaged in mixed endurance and strength activities exhibit lower age and sex-adjusted risk for all-cause mortality than nonathletic controls, and this is largely attributable to the lower risk of ischemic vascular events (18). Interestingly, that study suggested rather modest risk reduction and an increased risk of the development of hypertension in power-trained athletes, and very little is currently known regarding vascular morphology and function in these athletes (18).
Although we attempted to recruit athletes engaged in predominantly upper or lower limb training, it should be noted that SQ and triathletes also engage in training that uses both upper and lower limbs and that we adopted a cross-sectional comparison rather than a within-subject longitudinal approach. Similarly, the training stimulus within upper or lower-limb dominant sports may differ, which may result in different FMD responses and structural adaptations. Differences between individuals or groups in SRAUC may contribute to our findings. However, we found no significant differences in SRAUC between groups, whereas a significant correlation was present when examining the relation between W:L ratio and GTN response, a shear-independent dilator response. Therefore, differences in SRAUC unlikely relate to our major findings. Finally, we did not include an assessment of arterial compliance. This is of special importance because previous data have demonstrated a relation between conduit artery FMD and compliance (42).
In conclusion, we provide evidence that prolonged exercise training is associated with limb-dependent change in artery size and a lower peripheral artery WT. Femoral artery FMD in all athlete groups and brachial artery FMD in SQ is lower than controls. This “reduction” in FMD may relate to the profound structural remodeling apparent in the conduit arteries of athletes, a suggestion that has implications for the use of the FMD as a simple surrogate for cardiovascular risk.
Prof. Green received research funding support from the National Heart Foundation of Australia and the Australian Research Council.
Dr Thijssen is recipient of the E. Dekker stipend (Netherlands Heart Foundation, 2009-T064).
Dr Rowley was supported by funding from by Cardiac Risk in the Young.
DJG, EAD, and DHJT wrote the manuscript, and all authors significantly contributed as a reviewer/reviser. DJG, GW, KG, NTC, and DHJT are responsible for the concept and design of the study. NR, AS, HC, LHN, and EAD performed data acquisition. NR, EAD, and DHJT performed data analysis, and DJG, GW, KG, LHN, NTC, EAD, and DHJT performed data interpretation. KG, LHN, EAD, and DHJT advised on statistical procedures.
None of the authors has declared a conflict of interest.
The results of the present study do not constitute endorsement by the American College of Sports Medicine.
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FLOW-MEDIATED DILATION; ARTERIAL DIAMETER; HIGH-RESOLUTION ULTRASOUND; DOPPLER; ARTERIAL WALL THICKNESS
©2013The American College of Sports Medicine
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