Cross-sectional studies have consistently reported enlargement of conduit arteries in athletes relative to matched controls (2,10,27,33), indicating that exercise training may induce vascular enlargement (21). Exercise training intervention studies support these findings, with increases in resting conduit vessel diameter (2,16) reported following exercise training in young, healthy men. These studies used resting arterial diameter, a measure that is subject to the influence of sympathetic control and circulating and paracrine factors and that may provide a relatively poor index of arterial structure (18). We recently reported that resting brachial artery diameter does not correlate strongly with diameter measurements collected following vasodilator stimuli such as ischemia, suggesting that resting diameter may not provide an optimal assessment of changes in arterial structure in vivo (18). In addition, it is unclear whether elite athletes, who exhibit increased resting conduit vessel diameter as a result of long-term exercise training, can manifest further adaptations as a result of the resumption of exercise.
We hypothesized that elite athletes would exhibit increased arterial diameters relative to matched untrained individuals and that the resumption of intense exercise training would further enhance conduit artery structure. We therefore measured arterial diameters at rest and in response to ischemic vasodilator stimuli in elite rowers at the end of a period of suspension from structured exercise and again following resumption of intensive training. To determine whether changes in the stimulus to brachial artery vasodilation differed between groups or across time points of the study, we also measured shear rate profiles following cuff deflation in both groups.
MATERIALS AND METHODS
Seventeen male elite athletes from the Western Australian Institute of Sport rowing squad were recruited into the “athlete group.” All athletes had competed at national or international competition level; several were Olympic or World Championship athletes. At entry into the study, the mean characteristics of the group were age 20.9 ± 0.6 yr, height 187.9 ± 0.8 cm, weight 84.4 ± 1.3 kg, and body surface area (BSA) 2.1 ± 0.1 m2, resting HR 56 ± 2 bpm, resting systolic blood pressure (SBP) 125 ± 2 mm Hg, and resting diastolic blood pressure (DBP) 78 ± 2 mm Hg.
Eight untrained male control subjects, matched for age 22.2 ± 1.1 yr, height 187.3 ± 1.4 cm, weight 79.6 ± 2.5 kg, BSA 2.0 ± 0.1 m2, resting HR 59 ± 2 bpm, resting SBP 123 ± 2 mm Hg, and resting DBP 75 ± 3 mm Hg, were recruited from the student body of the University of Western Australia. Untrained controls were defined as individuals undertaking less than 3 h of moderate-intensity exercise per week.
All subjects were screened for cardiac abnormalities and cardiovascular disease using echocardiographic screening and questionnaires (3) before entering the study. Subjects who smoked or were on medications of any type were excluded. The study procedures were approved by the ethics committee of Royal Perth Hospital and all subjects gave written informed consent.
Athletes entered the study (baseline measures) at the beginning of their training cycle, that is, following the end of a 6-wk “off season” during which training was suspended. Interviews were conducted to confirm that the athletes had not been training or exercising regularly during this “off-season” phase; most had returned from an extensive vacation. To assess the effect of resumption of training, all measures were repeated following 3 and 6 months of training.
Training in the athletes consisted of two sessions of exercise per day, 6–7 d·wk−1. Morning sessions were “on water” and consisted of 2.5 h of training at, or near, competition pace, that is, approximately 80–90% HRmax. Afternoon sessions were 2 h in duration and consisted of general aerobic conditioning (e.g., 12-km timed runs) or resistance training (80–90% 1RM, 6–8 repetitions). The controls did not undertake formal training for any sport at entry or throughout the duration of the study. Activity levels of the controls were assessed during an interview and remained unchanged from entry to the end of the study.
V̇O2max data were measured in athletes at a session conducted at the Western Australian Institute of Sport. V̇O2 data were obtained in response to a maximum 2000-m ergometer effort on a modified Concept II rowing ergometer (Concept Inc., Vermont). The goal was to complete the 2000 m as quickly as possible, and involved a maximal effort from start to finish. A custom-built gas analysis system was used to determine V̇O2. Subjects were connected to a Hans Rudolph 2700 respiratory valve and inspired volume was measured during the test by a Morgan ventilometer (Mark II 225A), which was calibrated before testing using a five-point calibration procedure spanning the physiological range. Expired air passed through 35-mm Collins tubing into a 4-L mixing chamber. A small sample was directed to an Applied Electrochemistry S-3A oxygen analyzer and an Applied Electrochemistry CD-3A analyzer for determination of fractions of O2 and CO2 in expired air. The sample first passed through a thermoelectric cooling chamber for the removal of water vapor. A three-point calibration procedure spanning the physiological range of respiratory gases was applied before and after each test. Custom designed software was used to integrate the various inputs and to determine V̇O2. Data was collected over 30-s epochs with the two highest consecutive epochs taken as the V̇O2max.
Laboratory visits to determine vessel structure using high-resolution B-mode ultrasound imaging were held at Royal Perth Hospital. All measures were performed following a 4-h fast, 12-h abstinence from caffeine and/or alcohol, and 18 h after strenuous physical activity. Repeated measures were undertaken at the same time of day.
Patients rested supine with the nondominant arm extended and immobilized with foam supports at an angle of approximately 80° from the torso. HR was continuously monitored with a three-lead electrocardiograph and mean arterial pressure (MAP) was determined from an automated sphygmomanometer (Dinamap 8100, Critikon; Tampa, FL) on the contralateral arm. A rapid inflation/deflation pneumatic cuff was positioned on the imaged arm immediately distal to the olecranon process to provide a stimulus to forearm ischemia. A 10-MHz multifrequency linear array probe attached to a high-resolution ultrasound machine (Aspen; Acuson, Mountain View, CA) was used to image the brachial artery in the distal third of the upper arm. Ultrasound parameters were set to optimize longitudinal, B-mode images of the lumen/arterial wall interface. Doppler velocity measures were also obtained using a sample volume that was set at the lowest possible insonation angle (always <60°), parallel to the long axis of the vessel. When an optimal B-mode image and Doppler settings were attained, the probe was held stable in a stereotactic clamp and the probe position and settings were recorded and replicated for repeat measures in each subject.
Conduit artery measurements at rest and in response to ischemic stimuli.
After an initial 20-min resting period, baseline scans assessing resting vessel diameter (BADr) were recorded over 2 min. A rapid inflation/deflation pneumatic cuff, placed around the forearm immediately distal to the humeral epicondyles was then inflated to >200 mm Hg for either 5 or 10 min of occlusion (order randomized). A 20-min rest period was observed before the alternate ischemic stimulus was induced. Recordings commenced 30 s before cuff deflation and continued for 3 min after cuff deflation. Maximal brachial artery diameters following the release of the 5-min (BAD5) and 10-min (BAD10) occlusions were determined (see brachial artery diameter analysis), along with continuous Doppler velocity assessment following both stimuli.
Brachial artery diameter analysis.
Posttest analysis of brachial artery diameter was performed using custom-designed edge-detection and wall-tracking software that is independent of investigator bias (31). Briefly, the video signal was taken directly from the ultrasound machine and, using an IMAQ-PCI-1407 card, encoded and stored as a digital DICOM file on the PC. Subsequent analysis of these data was performed using custom-designed software written using icon-based graphical programming language and toolkit (LabVIEW™ 6.02; National Instruments, Austin, TX). A region of interest is drawn across the arterial lumen in an optimal section of the first B-mode frame and an edge-detection algorithm calculates approximately 300 measurements of diameter per frame, for each subsequent frame, at a rate of 60 Hz. The median diameter value from these approximately 300 measurements is then derived for each frame and plotted against time. From this array of data points, baseline diameter is calculated as the median value for a minimum of 10 s of data preceding cuff inflation. Peak arterial diameter following cuff deflation is calculated by applying a saltatorial smoothing algorithm that calculates median values within a moving window of 50 consecutive data points, with an overlap of 10 points per calculation. The maximum of these median values is then found to give the peak of the postdeflation diameters. We have shown that reproducibility of measurements using this semiautomated software is significantly better than manual methods, reduces observer error significantly, and possesses an intraobserver coefficient of variation of 6.7%. Further details of this analysis software and its detailed validation are available in recent publications (4,31).
Velocity, blood flow, and shear rate analysis.
Blood velocity (ν) was assessed at 60 Hz via edge detection of the Doppler envelope using a pixel-density and frequency algorithm. Blood flow, calculated as velocity multiplied by cross-sectional area (CSA), was calculated across the cardiac cycle (60 Hz) from these velocity measures, synchronized with the arterial diameter measures (above). All measures were analyzed for 80 s following the release of the cuff, a time period adequate to ensure that the maximal data are obtained (18). Shear rate, an estimate of shear stress, was calculated using the methods described by Pyke et al. (22); shear rate = mean blood velocity/vessel diameter. Area under the curve (AUC) analysis was performed for shear and velocity profiles from cuff deflation to 60 s postdeflation for each individual (22).
Statistical analyses were performed using SPSS 11.0 (SPSS, Chicago, IL) software. All data were reported as mean ± SE and statistical significance was assumed at P < 0.05. Unpaired t-tests were used to assess significance of difference between the athlete and control groups at baseline. Paired t-tests were used to assess within-subject differences between entry and training time points in each group, and significant differences between groups over time were assessed using two-way ANOVA.
Comparison of athletes and matched controls at entry.
There were no significant differences in hemodynamic measures, body weight, or BMI between the groups (Table 1). At baseline, the athletes possessed significantly larger resting brachial artery diameters compared with the controls (4.47 ± 0.10 and 3.84 ± 0.22 mm for athletes and controls, respectively, P < 0.05, Fig. 1). This finding of increased conduit artery structure was supported by larger BAD5 (4.70 ± 0.10 and 4.05 ± 0.36 mm for athletes and controls, respectively, P < 0.05) and BAD10 (4.93 ± 0.10 and 4.07 ± 0.25 mm for athletes and controls, respectively, P < 0.01) measurements in the athletes compared with controls (Fig. 1).
Effects of training in athletes.
The athletes were highly motivated and compliance to the training program was excellent (98% across the period of the study, with no individual missing more than 20 of 288 sessions).
V̇O2max test data collected in the athlete group increased from 5.37 ± 0.55 L·min−1 at baseline to 5.84 ± 0.10 L·min−1 at 3 months and 5.90 ± 0.10 L·min−1 at 6 months (both 3 and 6 months vs baseline P < 0.01).
Three months of exercise training in the athlete group significantly increased BADr from 4.47 ± 0.10 to 4.71 ± 0.10 mm (P < 0.01), BAD5 from 4.70 ± 0.10 to 4.94 ± 0.10 mm (P < 0.05), and BAD10 from 4.93 ± 0.10 to 5.12 ± 0.10 mm (P < 0.001) (Fig. 1). The data obtained at 6 months revealed that a further 3 months of training did not induce further changes in BADr (4.66 ± 0.13 mm), BAD5 (4.92 ± 0.13 mm), or BAD10 (5.07 ± 0.13 mm), relative to those seen at 3 months (Fig. 1), although the 6-month data remained significantly greater than at baseline (all P values = not significant (NS)).
Figures 2 and 3 depict diameter, velocity, and shear rate data through the brachial artery following release of 5 and 10 min of cuff occlusion, respectively. Data are for athletes at entry and at 3 and 6 months, with control subject data at entry provided for comparison purposes. Each data point represents the average of approximately 60 measures taken per second for each group. AUC analysis performed on these data revealed that shear rate following release of the 5-min cuff occlusion did not significantly differ between athletes at entry and controls. Shear rate was significantly lower, relative to entry data, at 6 months (P < 0.05) in the athletes, but did not achieve statistical significance between entry and 3 months (P = 0.09). Diameter data were significantly different across the postdeflation period between athletes and controls (P < 0.001) and a significant increase in diameter was also observed across these time points between entry and 3 months (P < 0.05) and entry and 6 months (P < 0.05) in the athletes. No significant differences were evident between the AUC data for velocity between or within the groups.
Shear rates following release of the 10-min occlusion were similar between the controls and athletes, and similar at entry and following 3 months of training in the athlete group. Shear rate and velocity were significantly lower following 6 months of training, compared with both entry (P < 0.05) and 3-month (P < 0.01) data. In keeping with the 5-min data, diameter data were significantly different across the postdeflation period between athletes and controls (P < 0.001) and a significant increase in diameter was also observed across these time points between entry and 3 months (P < 0.01) and entry and 6 months (P < 0.001) in the athletes.
The principal findings of the present study are that, despite possessing structurally enlarged conduit arteries as a result of long-term exercise, elite athletes who resume intense exercise training exhibit further increase in conduit vessel diameters, which is evident following 3 months of training, but not further modulated by longer-term exercise. These findings suggest that long-term exercise training modulates vessel structure in humans and that short-term intense training, even in those with preexisting arterial remodeling, is associated with further structural adaptation.
It has been known for many years that exercise training is associated with structural vascular enlargement; for example, autopsy studies demonstrate enlarged coronary arteries in athletes (1,20) and physically fit individuals (15,26), indicating that physical conditioning may induce a change in arterial caliber. Whereas several cross-sectional studies have reported enlargement of both conduit (2,10,27,33) and resistance (7,28) vessels in athletes relative to matched controls, none have longitudinally followed athletes, and few have investigated changes within subjects as a result of training. One recent study reported enhanced resting femoral artery diameter following aerobic (walking) exercise training in previously sedentary men (2). Unfortunately, no data were reported relating to arterial diameter in response to stimuli in this study. Resting arterial diameter, which is dependent on sympathetic nervous system tone and paracrine and circulating hormone modulation, may not be an optimal index of vascular structure and remodeling following exercise training, a stimulus that modulates each of these factors (18). Arterial diameter measurements in response to ischemic stimuli have traditionally been used to assess vessel structural change, based on the principle that provision of ischemic vasodilator stimuli diminishes the impact of functional differences between subjects or following interventions (19,29). In the present study, we observed training-induced enhancement of brachial artery diameter at rest and following both 5- and 10-min periods of ischemia, thereby providing evidence of arteriogenic adaptation across a range of dilator “doses.”
A possible mechanism responsible for exercise training–mediated conduit vessel enlargement relates to the effect of episodic increases in flow and shear stress related to exercise training. A link between long-term changes in flow and modification of vascular structure is supported by the classic study of Langille and O'Donnell (13), which examined rabbit carotid arteries after unilateral ligation–mediated long-term decreases in flow. The diameter of the ligated vessel exposed to a 70% reduction in flow for a period of 2 wk was significantly smaller than that of the contralateral control vessel. In addition, this change in vascular structure was dependent on the presence of the endothelium, indicating that changes in vessel structure secondary to long-term changes in flow may be dependent on the release of a labile factor from endothelial cells. A similar conclusion was derived from an earlier study that found that shear stress was autoregulated after initial perturbation by an arteriovenous fistula (11). The above data are consistent with the evolving hypothesis that exercise training induces structural enlargement of conduit vessels, which is dependent on shear stress–mediated nitric oxide (NO) release and may be an adaptive response that acts to mitigate the increases in wall stress brought about by repeated exercise bouts (8,12,14,21,25,30,32).
Although the hypothesis above provides a reasonable explanation for our observed changes in arterial diameter, a limitation of the present study is that we did not directly investigate NO vasodilator function using a pharmacological blocking agent, principally because of concerns regarding brachial artery cannulation in elite rowers. We did, however, determine shear rate responses in both the athletes and controls following the 5-min period of forearm cuff ischemia; the brachial arterial diameter response to this stimulus has been shown to be largely NO mediated (5). These data reveal that, although the shear responses following 5-min cuff ischemia were similar in the athletes and controls at entry, these levels of shear resulted from different velocity and diameter profiles between the groups. Controls exhibited significantly smaller arterial diameters, whereas the rowers exhibited a slightly larger (P = NS) velocity response following cuff deflation, possibly as a consequence of an increased ischemic stimulus in the athletes due to a larger forearm muscle mass. Although we did not directly measure forearm mass or volume in this study, we have previously demonstrated increased forearm girth, volume, and vasodilator capacity as a result of forearm training in healthy subjects (6).
Brachial artery shear rates were somewhat lower following training in the athletes, an effect that may have resulted from increased brachial diameter and/or decreased velocity. Diameter, velocity, and shear are, of course, interdependent and an interesting question therefore relates to the extent to which the increase in diameter observed posttraining caused the lower velocities or whether the lower shear rate posttraining was primarily due to the lower velocities per se. Because lower velocities posttraining are unlikely to have induced increased diameter responses, we contend that the increase in diameter may be the primary adaptation and determinant of the change in shear rate we observed posttraining. Furthermore, diameters were significantly different following training both at rest and immediately following cuff deflation, suggesting that the increase in vessel structure following training is the primary determinant of the decrease in shear observed following cuff ischemia at the time points at which we studied these subjects.
The discussion above raises some important questions about whether a component of the diameter changes we observed in the athletes with training, particularly those in response to the 5-min forearm occlusion, may be due to increased NO-mediated vasodilator function rather than simply a consequence of structural adaptation. As indicated above, flow-mediated dilation (FMD), the percentage of increase in brachial diameter following release of a 5-min period of distal cuff occlusion, is widely used as a surrogate measure of NO-mediated vasodilator function in vivo. When calculated in the present study, there were no significant changes between baseline and 3- and 6-month FMD data in the athletes (5.28 ± 0.64, 5.14 ± 0.42, and 5.50 ± 0.05%, respectively, P = NS), and these values were similar to that in the controls at entry (5.47 ± 0.89%). At face value, these data might be taken to indicate that vascular function did not change with resumption of training in the athletes. However, as elegantly demonstrated by the studies of Pyke et al. (22) and Pyke and Tschakovsky (23), FMD data should be related to the shear stress stimulus responsible for the induced diameter change. Figure 2 illustrates that shear rate was higher at entry in the athletes than at 3 and 6 months, suggesting a relative improvement in endothelial function with training from the FMD data; that is, a similar FMD response to a smaller shear stimulus infers improved arterial function. However, the diameter response used to calculate FMD occurs typically around 60 s following cuff release and is dependent on the preceding shear rate change across that time. As indicated above, we believe that structural enlargement of arterial diameters following training in the athletes likely affects the magnitude of shear across the postdeflation period; diameter values were higher at rest and immediately following cuff deflation, that is, before changes in shear could have imparted an influence. In fact, brachial artery diameters were higher across the entire postdeflation period following training in the athletes and also in response to 10 min ischemia, a near maximal dilator stimulus (18), which is largely NO independent (17).
There are several limitations of the present study. It would have been ideal to study the athletes at the end of their previous training cycle, 6 wk before their break from formal training. This was not possible for logistical reasons; most of the athletes were in Europe following the end-of-season world championships. It is difficult to induce voluntary detraining in athletes at this level, but we are confident that the entry measurements we collected represented the effects of 6 wk of relative detraining in this group. The presence of some degree of decrement in the training-induced vascular adaptation in the athletes at entry to the study is supported by the improvement noted after 3 months' resumption of training, whereas no differences in diameters were evident following 3 and 6 months of training. The fact that athletes exhibited significant arterial enlargement at the end of their detraining period, relative to controls, suggests that 6 wk of relative inactivity is not associated with complete reversal of the structural arterial enlargement associated with long-term training. Another limitation is that we cannot rule out the possibility that the increased diameter observed at 3 and 6 months may be a by-product of altered sympathetic tone, rather than a reflection of changes in vascular structure. Hijmering and colleagues (9) recently found that acute increases in sympathetic nerve activity can significantly decrease the dilator response to 5-min cuff occlusion. Despite the fact that physical conditioning is associated with deceased sympathetic activation, it seems unlikely that the increases in arterial diameter we observed are due to this, because they were manifest in resting subjects, and the effect of training on sympathetic activity is primarily evident during exercise or in response to sympathoexcitatory stimuli (24).
In conclusion, we observed that exercise training enhanced vessel diameter, even in trained athletes with prior evidence of vascular enlargement. We also observed that, relative to matched healthy controls, athletes exhibit enhanced conduit artery structure at rest and in response to vasodilator stimuli. Despite this evidence of long-term training effect on arterial structure, resumption of training further enhanced conduit vessel structure, an effect that occurred within 3 months.
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