GONZALES, JOAQUIN U.; MIEDLAR, JULIE A.; PARKER, BETH A.; PROCTOR, DAVID N.
Exercise-induced conduit artery dilation has been reported in numerous peripheral arteries supplying blood flow to locally active muscle including the brachial artery during handgrip exercise (6,12), the deep femoral artery during leg exercise (15), and the superficial femoral artery after cycling exercise (3). In contrast, few studies report common femoral artery (CFA) dilation during single-leg knee extensor exercise (4,5), with the majority of studies reporting no overall change in CFA diameter (7,9,15). In fact, it has generally been accepted that Doppler-based studies can calculate CFA blood flow during leg exercise using only the diameter measured at rest (8).
Most studies measuring CFA diameter during knee extensor exercise have been performed in men (7,9,15). However, our laboratory recently reported modest but significant CFA dilation (6%) during single-leg knee extensor exercise in younger women, which was in contrast to men and older women, who, on average, showed little to no average change in CFA diameter (5). The greater prevalence of exercise-induced CFA dilation in younger women could be the result of smaller resting CFA diameters (10), which may result in a higher exercise-induced shear stress stimulus for vasodilation (6). This possibility would be consistent with the inverse association noted between baseline conduit artery size and the magnitude of flow-mediated dilation after cuff occlusion (2,14).
To our knowledge, no study has closely examined the relationship among CFA diameter, shear rate, and dilatory responsiveness in the context of age and sex. Therefore, the purpose of this study was to determine whether resting CFA diameter is related to the dilatory response of the CFA to knee extensor exercise in healthy women and men. We hypothesized that resting diameter would be associated with the magnitude of exercise-induced dilation in younger women but that groups with arteries of larger dimension would show no correlation with resting diameter.
Data collected for a previous study (5) were used for the present investigation. Fifteen younger women (22.1 ± 0.6 yr), 15 younger men (24.1 ± 0.9 yr), 18 older women (66.7 ± 0.9 yr), and 13 older men (70.6 ± 1.5 yr) were included in this study. All participants were normally active (average group V˙O2max percentiles ranged from 34% to 54% of age-predicted) on the basis of normative values (1), had a resting blood pressure ≤140/90 mm Hg, and were free of overt chronic diseases as evaluated by medical history questionnaire, physical examination, and blood lipid profile. Younger women were studied in days 1-7 of their menstrual cycle to standardize the influence of sex hormones on endothelial vasodilator function and were asked to refrain from caffeine for ≥12 h before testing. This study was approved by the Office for Research Protections at The Pennsylvania State University in agreement with the guidelines set forth by the Declaration of Helsinki.
After obtaining written informed consent, participants performed single-leg knee extensor exercise in a semireclined position (≤45° from horizontal) with knees flexed at an angle of 90°. The participant's torso and thighs were strapped to the chair to reduce extraneous movement during exercise. The left foot was placed in a boot that was connected to the pedal arm of a cycle ergometer (Monark, Varberg, Sweden) that was located behind the participant. Knee extensions with the left leg followed a nearly full range of motion (90°-170°) and were performed at 40 contractions per minute. The exercise protocol consisted of 3-min stages in the following order: quiet rest, unloaded passive exercise (manual external movement of lower leg), knee extensions against no resistance (0 W), and knee extensions as resistance increased every 3 min (women = 4.8-W, men = 4-W step increments) until the participant could no longer maintain cadence. To minimize variance within groups, we analyzed functional responses up to 14.4 W in women and up to 16 W in men (all subjects completed these stages).
Diameter and blood flow velocity of the left CFA were measured distal to the inguinal ligament, above the bifurcation into the superficial and profunda femoral branch using a Doppler ultrasound machine (HDI 5000; Philips, Bothell, WA) equipped with a high-resolution 7- to 4-MHz linear array transducer. For velocity measurements, the artery was insonated at a constant angle of 60°, with the sample volume adjusted to cover the width of the artery while diameter measurements were obtained with the artery insonated perpendicularly. High-resolution diameter measurements were taken in two-dimensional mode during the second minute of each condition or work rate, images were stored on VHS tape and digitized at four frames per second using Brachial Imaging software (Medical Imaging Applications, Iowa City, IA), and diameter was measured across the cardiac cycle using edge-detection software (Brachial Analyzer Software; Medical Imaging Applications). To determine between-day variability in these measurements, resting and exercise (at 14 W for women and 16 W for men) diameters were compared with those measured on a separate day (familiarization visit) in all subjects. The coefficients of variation of resting and exercise diameter were 1.9%, 2.8%, 4.1%, 5.4% and 1.8%, 2.4%, 3.5%, 5.6% for younger women, younger men, older women, and older men, respectively. Velocity measurements were obtained continuously at rest and during exercise and were sampled in real time (400 Hz) using the PowerLab system (AD Instruments, Castle Hill, Australia). Data were later analyzed for mean blood velocity.
Hemodynamic calculations were derived from average values taken during steady-state conditions. Mean blood velocity values were calculated from the last minute of rest, passive exercise, and each work rate. Femoral artery blood flow for each condition or work rate was calculated by multiplying the cross-sectional area (πr2) of the CFA with mean blood velocity. Shear rate (s−1) was calculated using the equation: (4 × mean blood velocity)/diameter, where blood velocity is in centimeters per second (cm·s−1) and diameter is in centimeters (cm) (11).
Pearson correlation coefficients were used to assess the univariate relationship between percent CFA dilation and other variables. Multiple stepwise regression analysis was subsequently used to obtain the correlates that best predicted exercise-induced CFA dilation, with P ≤ 0.05 for inclusion. To reduce the multicollinearity that exists between diameter and peak shear rate, these variables were centered, and an interactive term was created. Between-group comparisons for resting CFA diameter, percent CFA dilation, and shear rate were made using a one-way ANOVA. When a significant main effect or interaction was observed, comparisons were assessed using the Tukey post hoc test. Statistical analyses and regression modeling were performed using SigmaStat 3.0 and SigmaPlot 11.0 software (Systat Software, Chicago, IL), respectively. All data are reported as mean ± SEM, and statistical significance was set at P < 0.05.
Diameter, blood velocity, and shear rate measured at rest and during exercise for women and men are presented in Table 1. On average, women had smaller CFA diameters than men (P < 0.05). Shear rate measured at rest was highest in younger women and lowest in older men (P < 0.05). The shear rate response to exercise (from rest to last stage) was greater in women than in men (P < 0.05). Younger women showed greater (P < 0.01) CFA dilation (range = 0%-16%) during knee extensor exercise than older women (range = 0%-8%), younger men (range = 0%-5%), and older men (range = 0%-2%) even after normalizing CFA dilation to shear rate (Table 1).
Resting diameter of the CFA was inversely correlated with exercise-induced dilation in younger women (r = −0.82, P = 0.0001), in older women (r = −0.73, P < 0.001), in younger men (r = 0.66, P < 0.01) but not in older men (r2 = −0.17, P = 0.56; Fig. 1). These relationships remained significant after correcting CFA dilation to the area under the curve for the shear rate response to exercise (younger women: r = −0.74, P = 0.001; older women: r = −0.66, P = 0.002; younger men: r = −0.60, P = 0.01).
FIGURE 1-Interindivi...Image Tools
Analysis of all subject data at peak exercise revealed an inverse relationship between resting diameter and peak shear rate (r = −0.83, P = 0.001) such that larger diameters had lower peak shear rates (Fig. 2A). Using piecewise regression with all subject data, a threshold diameter of 0.79 cm (P < 0.0001) was identified above which little to no dilation was present, indicating low shear stimuli for dilation (Fig. 2B). The dilatory response of the CFA to shear rate during graded knee extensor exercise showed a continuum across all four groups that is best described as a curvilinear rise in CFA dilation with increased shear rate (Fig. 3).
In univariate analysis of all subject data, age (r = −0.34, P = 0.006), sex (r = 0.34, P = 0.007), resting diameter (r = −0.57, P < 0.001), and peak shear rate (r = 0.54, P < 0.001) were all significant correlates of CFA dilation. Using stepwise multivariate analysis, the best predictive model for CFA dilation consisted of one factor, resting diameter, for all subjects (r2 = 0.33, P < 0.001), younger women (r2 = 0.68, P < 0.001), and older women (r2 = 0.54, P < 0.001). A two-factor model consisting of resting diameter and age (r2 = 0.60, P < 0.001) was found to best predict CFA dilation for women (combined younger and older groups), whereas resting diameter and V˙O2max (per fat-free mass) were the best two predictors of CFA dilation for younger men (r2 = 0.62, P < 0.001). No significant predictors of CFA dilation were found for men (combined younger and older groups) or older men.
Our laboratory has previously demonstrated modest but significant CFA dilation during single-leg knee extensor exercise in younger women, which was in contrast to men and older women who showed little to no average change in CFA diameter (5). To further investigate this difference, CFA diameter and shear rate responses to knee extensor exercise were examined from a previously published study (5) to investigate the relationship among diameter, shear rate, and exercise-induced CFA dilation in women and men. The main findings of the present study are that (i) the CFA dilatory response to knee extensor exercise is inversely associated with resting diameter, which is largely determined by women and men with diameters below 0.79 cm; (ii) resting diameter was the best independent predictor for CFA dilation in all groups except older men; and (iii) the dilatory responsiveness of the CFA to shear rate exhibits a curvilinear function, indicating that the absence of significant CFA dilation in individuals with larger CFA diameters is due to the lower shear stimuli for dilation.
Knee extensor exercise-induced CFA dilation.
On the basis of the relatively large size of the CFA, it is generally believed that the CFA does not significantly increase in diameter during knee extensor exercise (8). On average, adult men are reported to have CFA diameters ranging from 0.8 to 1.0 cm (10). In the present study, younger men had CFA diameters ranging from 0.74 to 0.93 cm, whereas older men had diameters ranging from 0.72 to 1.2 cm. Consistent with previous work examining men (7,9,15), the present study found that groups of younger and older men exhibit little average change in CFA diameter during graded knee extensor exercise. Despite the small average change in diameter during exercise, within-group comparisons found that younger men with CFA diameters below a certain threshold (∼0.79 cm) exhibited considerable dilation (>2%) in response to exercise. This was not found in older men who had the largest vascular dimensions (i.e., majority of men above 0.8 cm).
Older women had a similar average resting CFA diameter compared with younger women, although older women, on average, exhibited little exercise-induced dilation. The diminished ability of older women to exhibit CFA dilation in response to knee extensor exercise was evidenced by (a) blunted CFA dilation in comparison to findings in younger women and younger men with similar resting diameters (Figs. 1 and 2B), (b) attenuated CFA responsiveness to shear rate during graded exercise compared with younger women (Fig. 3), and (c) age being a significant predictor for CFA dilation in women (combined younger and older women) using stepwise multivariate analysis. Therefore, it seems that age-associated factors may reduce exercise-induced CFA dilation in healthy women. Future studies are warranted to determine whether the attenuated exercise-induced CFA dilation presently observed in older women is the result of decreased nitric oxide bioavailability or structural changes that alter signal transduction of shear stimuli for smooth muscle relaxation.
It is not clear from our data what determines the size or dilatory capacity of the CFA. We did not find maximal aerobic capacity (V˙O2max), blood lipids, or anthropometric measurements (body surface area) to correlate to resting diameter or the magnitude of exercise-induced dilation in any group (data not shown). In younger women, thigh muscle mass was positively correlated to resting diameter (r = 0.52, P = 0.04) and negatively correlated to the magnitude of peak CFA dilation (r = −0.60, P = 0.01), suggesting that the amount of leg tissue influenced CFA size in this group.
Role of shear stress in CFA dilatory response to exercise.
In the present study, CFA dilation was induced by single-leg knee extensions during graded increases in exercise intensity (3-min stages). It is well known that vasodilation of resistance vessels located close to the site of contracting muscle decreases vascular resistance that allows for a rise in blood flow and shear stress in upstream vessels. In an elegantly designed study, Pyke et al. (6) demonstrated that the magnitude of brachial artery dilation during dynamic forearm exercise is closely linked to mean shear rate independent of the pattern or mode by which shear stress was increased. These authors also found no brachial artery dilation during exercise when controlling shear rate near baseline, suggesting that conducted vasodilation due to muscle activation (metabolic byproducts and myogenic response) did not contribute to the stimuli for exercise-induced conduit artery dilation. These findings suggest that exercise-induced dilation of limb conduit vessel in humans is primarily caused by shear stress.
We have demonstrated for the first time that the CFA is also responsive to changes in shear rate during knee extensor exercise. The magnitude of CFA dilation was related to resting diameter such that smaller arteries (<0.79 cm) were exposed to higher shear stimuli for exercise-induced CFA dilation compared with that of larger arteries. Women and men, irrespective of age, fell within a similar shear-dilatory response continuum, indicating that this is not a sex-specific observation. However, it is still unknown from the results of the present study or our current understanding if intrinsic factors modify the shear-dilatory responsiveness in arteries of different size. For instance, Wray et al. (15) have demonstrated that the CFA is unresponsive to shear rates up to 300 s−1 in younger men who had resting CFA diameters >1 cm. This is similar to mean shear rates reached by younger women in the present study (range of diameters = 0.59-0.81 cm), indicating that larger CFA either require a greater shear stimulus for vasodilation or are structurally limited for further expansion. However, this between-study comparison is based on the assumption of similar shear rate estimates despite different Doppler systems and technicians.
It is well known that the magnitude of flow-mediated dilation after cuff ischemia is inversely correlated with resting arterial diameter (2). Recently, Thijssen et al. (14) have shown that the association between resting diameter and flow-mediated dilation diminishes as conduit artery diameter increases such that larger conduit arteries (diameters >0.7 cm) exhibit no association between arterial size and flow-mediated dilation. One possible mechanism that could explain this phenomenon is higher shear rates inherent in smaller arteries. However, previous studies demonstrate a partial role for shear stress in explaining the relationship between resting diameter and flow-mediated dilation (13,14). In the present study, the area under the curve for the shear rate response to exercise explained 7%-12% of the variance in the relationship between resting CFA diameter and exercise-induced dilation. A similar variance was explained when exercise-induced dilation was corrected for the absolute change in shear rate or the peak shear rate measured during the last stage of exercise (data not shown). Because exercise-induced dilation is mediated by mean shear rate (6), the inability to abolish CFA dilation by normalizing to shear rate in the present study could suggest that normalization of CFA dilation to shear rate was confounded by the range of diameters above the threshold for dilation (i.e., vessels that may not respond to a given level of shear stimuli by having the same dilatory response). This variability cannot be explained by the findings in the present study, but it does not seem to be age or sex specific.
The CFA dilatory responses described in the present study were assessed under specific conditions during submaximal dynamic single-leg knee extensor exercise and may not be found for other work rates, contraction frequencies, or modes of exercise. For instance, CFA diameter measured during knee extensor exercise in the upright posture can be larger than diameters measured during exercise in the reclined/supine position, which may reduce the likelihood of observing significant exercise-induced CFA dilation when upright (4). Second, diameter measurements were taken in two-dimensional mode (B mode) to optimize imaging; thus, shear rate was calculated from blood velocity measured at a different time point. However, we do not believe that this method limited our ability to examine the influence of shear rate on CFA dilatory responses given that both diameter and blood velocity measurements were taken during the steady-state phase of exercise (>2 min into each stage). In addition, previous studies found mean shear rate to be the main stimulus for conduit artery dilation (6), and we found shear-dilatory relationships in the younger groups. Lastly, the participants in the present study were healthy women and men of average fitness level with no chronic disease, so our results may not be generalized to other populations. However, a healthy average-fit population may be an ideal group to examine CFA dilatory responses to knee extensor exercise because other groups (e.g., people with cardiovascular risk factors or endurance-trained individuals) may have larger diameters and possibly limited shear-mediated CFA dilation.
The present study raises important considerations when investigating dilatory responses to exercise between individuals with different-sized arteries. The range of diameters across age and sex groups in the present study did not allow for sex comparisons to be made between groups containing the same range of diameters; thus, the dilator responsiveness to a given magnitude or range of shear rate could not be directly compared between women and men. In addition, the strong relationship between diameter and peak shear rate (r = −0.83) made it difficult to clearly determine the independent contribution of each variable to exercise-induced CFA dilation. Although stepwise regression analysis found resting diameter to be the strongest predictor of CFA dilation, removal of diameter from the regression model resulted in the peak shear rate being the best predictor with a lower but similar explained variance compared with resting diameter (r2 = 0.33 vs 0.28). Therefore, we cannot conclude with absolute certainty that diameter is the major determinant of CFA dilation, especially when one considers the increased random measurement error (during both diameter and blood velocity measurements) associated with calculating shear rate compared with measuring diameter alone. Rather, to apportion the effect of diameter and shear rate on CFA dilation, comparisons will need to be made between groups with the same range of diameter and the same shear stimuli across these diameters. Such comparisons would necessitate recruitment of individuals with unusually large (women) or small (men) CFA diameters because the dimensions of this vessel are generally scaled according to body and/or leg muscle size.
The main finding of the present study is that the CFA dilates during submaximal knee extensor exercise in women and men, but in a threshold nature that is related to resting diameter and to inherent differences in shear rate. The absence of significant CFA dilation during exercise in individuals with larger baseline CFA diameters is due to the lower shear stimuli for dilation. Collectively, these findings not only have implications for understanding the size-dependent responses of conduit arteries to increases in shear rate but also provide potential insight into age and sex differences in vascular reactivity.
This study was funded in part by grant R01 AG018246 (to D.N. Proctor) from the National Institutes of Health and grant M01 RR-10732 (to GCRC) from the Division of Research Resources.
The authors thank Sarah Smith for assistance with data analysis, Sandy Smithmyer for assistance with subject recruitment, and the GCRC medical staff at University Park for assistance with subject screening.
The results of this study do not constitute endorsement by the authors or by the American College of Sports Medicine.
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