Exercise training is a potent stimulus to structural vascular remodeling, inducing an increased cross-sectional size of conduit and resistance arteries (4,6,10,18,23,27). Although some studies indicate that localized episodic increase in shear stress, associated with repeated exercise bouts, is an important stimulus to induce vascular remodeling (9,30), it is conceivable that systemic stimuli such as inflammatory and oxidative stress may contribute. It has also been proposed that systemic changes in hemodynamic stimuli associated with exercise, such as blood and transmural pressure, may induce remodeling (7,13,14).
Little is known about the relative effects of localized versus systemic factors on conduit artery wall and lumen remodeling in response to chronic exercise training in humans. Some studies have suggested that exercise training is associated with decreased conduit arterial wall thickness (WT) in men and women (2,17), and other studies in athletes have suggested that chronic exercise induces changes in lumen size (10,18). More recently, we reported that elite squash players possess larger racquet-arm brachial artery diameters compared with their nondominant arm, whereas no such difference was present in matched nonathletic control subjects (23). WT, in contrast, was lower in squash players than in controls, and this effect was not limb specific. One interpretation of these findings is that localized effects of chronic exercise are evident in the remodeling of arterial size, whereas arterial WT seems to be affected by systemic factors (19), but this finding has not been confirmed.
To further explore the question of local versus systemic structural arterial remodeling to chronic exercise, we used high-resolution ultrasound to measure conduit artery WT and diameter in the arms and legs of elite-level athletes engaged in predominantly upper limb (canoeists) or lower limb (i.e., runners/cyclists) sports. We also recruited wheelchair individuals who were either elite athletes or relatively inactive controls; all had full motor control of their upper body but limited or no sensory/motor function below the hip. Based on our recent findings (24), our hypothesis was that physical activity and inactivity would have systemic, rather than localized, effects on conduit artery WT, whereas localized effects would be present in terms of diameter remodeling.
We recruited upper limb (UL, n = 12) and lower limb (LL, n = 10) athletes and gender-matched healthy able-bodied controls (n = 16). The UL group included international-level male canoe paddlers who trained 21 ± 2 h·wk−1 for >2 yr. Approximately 75% of this training was upper limb specific. The LL group included (inter)national standard male >10-km runners (n = 7) and road cyclists (n = 3) who trained 17 ± 5 h·wk−1 for >2 yr (predominant lower limb–specific training). Sixteen healthy recreationally active controls were recruited who participated in exercise training <3 h·wk−1 at a recreational level. We also recruited 14 wheelchair-user subjects, including 10 complete thoracic spinal cord injured individuals and 4 individuals with spina bifida. These wheelchair-user subjects were either recreationally active (<3 h·wk−1; nine with spinal cord injury) or performed wheelchair basketball at the international level (one with spinal cord injury and four with spina bifida). Wheelchair athletes trained for an average of 16 ± 2 h·wk−1 for >2 yr.
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 Liverpool John Moores University (LL, UL, and able-bodied controls) and the Medical Ethics Committee of the Radboud University Nijmegen Medical Centre (wheelchair subjects). Written informed consent was obtained from all participants before the experimental procedures.
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. 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 carotid, brachial, and superficial femoral (SF) artery were then collected for assessment of resting diameter and WT using high-resolution ultrasound. Subjects were assessed off-season.
Conduit artery WT
Participants rested in the supine position for at least 20 min. HR and systolic and diastolic blood pressure (BP) were determined twice using an automated sphygmomanometer (Dinamap; GE Pro 300V2, Tampa, FL). Three standardized probe angles (posterior, lateral, and anterolateral) were used to determine resting WT and the diameter of the right carotid artery using a 10-MHz multifrequency linear array probe attached to a high-resolution ultrasound machine (T3000; Terason, Burlington, MA). An experienced sonographer obtained a longitudinal B-mode image of the carotid artery 2 cm proximal to the carotid bifurcation. Recording was performed during 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 SF arteries, from the participant’s dominant limb using the same procedures as described above. For practical reasons, two planes of assessment were used for the peripheral arteries.
Athlete and control subject height (Seca, Hamburg, Germany) and weight (Seca) measures were taken. Height in wheelchair-bound individuals was calculated using a tape in the supine posture. A dual-energy x-ray absorptiometry scanner (Hologic QDR Series Discovery A, Bedford, MA) was used to determine whole body and limb-specific adipose and lean tissue mass.
Arterial edge detection, wall tracking, and WT analysis
Posttest analysis of brachial and SF artery diameter and velocity was performed by a single observer using custom-designed edge detection and wall-tracking software, which is independent of investigator bias (20,33). Settings were recorded and maintained to establish consistency (21). 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. Analysis of carotid, brachial, and SF artery WT was also performed using a DICOM-based software package, which is observer independent and has been validated (20,21,33).
Statistical analyses were performed using SPSS 17.0 (SPSS, Chicago, IL) software. All data are reported as mean ± SD unless stated otherwise, whereas statistical significance was assumed at P < 0.05. We used a one-way ANOVA to examine differences between groups. Post hoc t-tests were used and reported to identify group differences when the ANOVA revealed a significant effect, using the LSD test to correct for multiple comparisons. Pearson correlations were used to assess relationships between arterial diameter, WT, and fat-free mass (FFM).
Systolic BP values were comparable between groups, although wheelchair users have significantly higher diastolic pressures than able-bodied controls (Table 1). Athletes from the LL group had significantly lower resting HR than wheelchair athletes, with LL and UL athletes possessing lower values than both control groups (Table 1). UL athletes had a significantly greater body weight compared with LL and wheelchair athletes and wheelchair controls (Table 1). UL athletes’ arm and leg FFM was significantly greater than all other groups. Wheelchair controls had nearly half the FFM in their legs than all other groups but greater arm FFM than able-bodied controls and LL athletes (Table 2).
Arterial Diameter and WT
Brachial artery diameter was significantly greater in UL athletes and wheelchair subjects (both controls and athletes) compared with able-bodied inactive controls (Fig. 1A). WT measures were, however, significantly smaller in all three athletic groups (UL, LL and wheelchair athletes) compared with the control groups (Fig. 1B). Brachial wall-to-lumen ratio (W/L) data were significantly smaller in all groups compared with able-bodied controls (Fig. 1C). A positive correlation between FFM and brachial diameter was significant across all groups (r = 0.50, P < 0.001), but no relationship was apparent between FFM and brachial artery WT (r = −0.08, P = 0.6).
LL athletes had the largest SF diameters, which were significant larger than those observed in able-bodied controls (Fig. 2A). Wheelchair users (both controls and athletes) had significantly smaller SF diameters than able-bodied controls and athletes (Fig. 2A). However, WT of able-bodied athletes (UL and LL) and wheelchair athletes was significantly lower than that in the control groups (Fig. 2B). W/L in the able-bodied athletes was significantly smaller than in the able-bodied control. The wheelchair control subjects possessed significantly higher W/L ratios than able-bodied controls and athletes (Fig. 2C). Lower limb FFM correlated with SF artery diameter across all groups (r = 0.77, P < 0.001), and a modest inverse correlation also existed between leg FFM and SF artery WT (r = −0.4, P < 0.05).
Resting diameter was comparable between all five groups (Table 2). However, WT and W/L in the athlete groups (UL, LL, and wheelchair athletes) were significantly lower compared with both able-bodied and wheelchair controls (Table 2).
The purpose of this study was to better understand local versus systemic effects of chronic exercise and inactivity on arterial diameter and WT by studying upper and lower limb–dominant athletic populations and subjects with spinal cord injury. We observed larger brachial artery diameters in canoeists and wheelchair subjects, whereas lower limb dominant athletes (i.e., runners and cyclists) possessed larger femoral arteries. Markedly reduced femoral diameters were evident in both wheelchair groups. These differences between groups are consistent with local effects of physical (in)activity on remodeling of conduit arterial lumen. We also observed lower WT in the carotid, brachial, and SF arteries in all athletic groups compared with their less active peers. These data suggest that, in contrast to localized remodeling of diameter, physical (in)activity is associated with systemic effects on conduit artery WT in humans in vivo.
We studied distinct groups to provide insight into the effect of chronic exposure to physical (in)activity of the upper or lower limbs. Consistent with previous cross-sectional (10,18,25) and longitudinal (2,18) observations, we found that chronic exercise training was associated with localized effect on arterial remodeling. Although we have adopted a cross-sectional design that may involve some selection bias, our data concur with findings of significantly larger vessels in the dominant limbs of elite racquet players (6,23,27).
A potential explanation for the localized remodeling of arterial diameter relates to the shear stress stimulus acting on the endothelium (30). In agreement with observations in animal studies (11,12,31), we recently found that adaptations in brachial artery function and size after handgrip exercise training in humans were prevented by decreasing exercise-induced shear stress (30). Other studies have provided mechanistic evidence relating shear stress to changes in vascular function and structure (9,31). Whereas this evidence implicates shear stress in changes in arterial size, there are numerous factors that influence arterial tone in humans and we cannot exclude the possibility that other stimuli, such as local changes in hemodynamic, metabolic, and vasoactive substances, may partly contribute, although limited evidence currently exists regarding such mechanisms and effects on arterial remodeling in humans. It should also be noted that arterial diameter correlated with FFM in both the upper and lower limbs in our subjects, suggesting that conduit artery diameter and lean tissue mass are related, perhaps by virtue of the increase in shear stress after metabolic vasodilation of a larger mass of muscle. At the very least, our data suggest the existence of localized changes in arterial diameter in response to physical (in)activity.
There are relatively few studies of the direct effect of exercise on artery WT in healthy humans (2,8,16,28,29). Most of these studies suggest an effect of exercise training on WT in vessels supplying the active muscle beds, whereas studies examining the effect of exercise on carotid artery are conflicting (22,28), possibly because of the duration of training and a priori WT. Few studies have directly examined local and systemic effects of exercise training on WT. Recently, we reported reduced brachial arterial WT in both the dominant and the nondominant forearms of elite squash players (24), in contrast to the differences apparent between the limbs in arterial diameter. These findings can be interpreted as evidence for a generalized or systemic effect of exercise training of wall remodeling (19). This is endorsed by the observation in the present study that lower WT was present in the carotid, brachial, and SF arteries of both upper and lower limb–trained athletes compared with their less active able-bodied controls. Wheelchair athletes also demonstrated lower carotid and brachial arterial WT compared with able-bodied and wheelchair controls. These novel observations further support the view that systemic effects of physical (in)activity may drive changes in conduit arterial WT.
The mechanisms responsible for changes in arterial WT in humans are not well described in humans. Increased shear stress is associated with arterial remodeling, at least of lumen diameter (11,31), and it may have contributed to the observations in the present study. However, it is notable that arteries in both physiologically active and less active vessel beds in the athletic groups, which would logically be chronically exposed to different shear stress forces, both exhibited lower WT. In a recent study, we also reported similar reductions in brachial artery WT after 8 wk of bilateral handgrip training, despite unilateral manipulation of the brachial artery shear stress (29). It is likely that systemic effects of exercise contribute to exercise-related changes in WT and systemic effects of shear stress cannot be entirely excluded as a mechanism. Alternate mechanistic explanations for changes in WT in response to exercise training include generation of circulating biochemical species, hormonal activation, or inflammation, although limited evidence currently exists relating these factors to arterial remodeling in humans. Brief, cyclic exposure to pressure/circumferential strain, such as that associated with exercise bouts, may contribute to antiatherogenic adaptation in the artery wall (13,14,32). Finally, the significant inverse correlation between leg FFM and femoral artery thickness is notable in our study and, to our knowledge, a novel observation. The relationship between skeletal muscle mass and artery WT deserves further investigation to determine which change occurs first and whether there is causation.
Our observation of systemic effects of exercise and inactivity may have potential clinical implications. Measurement of conduit arterial WT is a popular and frequently adopted surrogate measure of atherosclerosis, and previous studies have demonstrated the strong predictive capacity of the carotid arterial WT for future cardiovascular events (15,26). Our findings suggest that exercise, even in subjects with a complete (motor) lesion of the lower limbs, may produce beneficial effects on arterial WT above and below the lesion. This suggests that exercise training may have beneficial effects on the arterial wall, even in those regions that are not physically active. Such changes in the arterial wall may contribute to the cardioprotective effects of exercise training. Increases in artery diameter may also possess potential clinical relevance, and we have previously proposed that such changes in artery diameter and function may inform the design of exercise training interventions (3,5).
There are several limitations of the present study. Future studies should include longitudinal training designs to better study the role of localized and systemic mechanisms on arterial remodeling in athletic populations. To this end, we recently reported WT changes in response to localized (29), and whole body exercise (8), and other key studies have assessed the effect of training per se (2,28). Because advanced age is associated with an increase in WT (1), a potential limitation of this article is the age difference between wheelchair controls and athletes for the comparison of arterial WT between these groups. However, carotid, brachial, and femoral arterial WT in the wheelchair controls were comparable to (young) able-bodied controls, whereas WT in the wheelchair athletes was consistently lower than the able-bodied controls. Therefore, the age difference between wheelchair controls and athletes unlikely explain the difference in WT between groups.
In conclusion, the finding of the present study suggests that exercise and inactivity lead to opposite effects on remodeling of the arterial lumen, likely driven by local mechanisms. In contrast, remodeling of arterial WT is evident in the carotid, brachial, and SF arteries, suggesting the presence of a systemic effect of exercise on the conduit WT. Future studies should further elucidate the mechanisms and stimuli that underlie these novel observations.
Ms. Rowley is funded by Cardiac Risk in the Young UK. Professor Green is supported by a grant from the Australian Research Council and the National Heart Foundation of Australia. Dr. Thijssen is financially supported by the Netherlands Heart Foundation (E. Dekker stipend 2009T064).
The authors thank the British Canoe Union coaches and athletes, especially English Institute of Sport physiotherapist Julie Pearce and physiologist Dr. Jamie Pringle.
The authors gratefully thank the GBWBA for their assistance with this study.
None of the authors have conflict to disclosures.
The results of the present study do not constitute endorsement by the American College of Sports Medicine.
1. Davis PH, Dawson JD, Riley WA, Lauer RM. Carotid intimal–medial thickness is related to cardiovascular risk factors measured from childhood through middle age: the Muscatine study. Circ. 2001; 104: 2815–9.
2. Dinenno FA, Tanaka H, Monahan KD, et al.. Regular endurance exercise induces expansive arterial remodelling in the trained limbs of healthy men. J Physiol. 2001; 534 (1): 287–95.
3. Green DJ. Exercise training as vascular medicine: direct impacts on the vasculature in humans. Exerc Sport Sci Rev. 2009; 37 (4): 196–202.
4. Green DJ, Cable NT, Fox C, Rankin JM, Taylor RR. Modification of forearm resistance vessels by exercise training in young men. J Appl Physiol. 1994; 77 (4): 1829–33.
5. Green DJ, Cable NT, Joyner MJ, O’Driscoll G. Exercise and cardiovascular risk reduction: updating the rationale for exercise. J Appl Physiol. 2008; 105: 766–8.
6. Green DJ, Fowler DT, O’Driscoll JG, Blanksby BA, Taylor RR. Endothelium-derived nitric oxide activity in forearm vessels of tennis players. J Appl Physiol. 1996; 81 (2): 943–8.
7. Green DJ, Spence A, Halliwill JR, Cable NT, Thijssen DHJ. Exercise and vascular adaptation in humans. Exp Physiol. 2011; 96: 57–70.
8. Green DJ, Swart A, Exterkate A, et al.. Impact of age, sex and exercise on brachial and popliteal artery remodelling in humans. Atherosclerosis. 2010; 210: 525–30.
9. Hambrecht R, Adams V, Erbs S, et al.. Regular physical activity improves endothelial function in patients with coronary artery disease by increasing phosphorylation of endothelial nitric oxide synthase. Circulation. 2003; 107: 3152–8.
10. Huonker M, Schmid A, Schmid-Truckass A, Grathwohl D, Keul J. Size and blood flow of central and peripheral arteries in highly trained able-bodied and disabled athletes. J Appl Physiol. 2003; 95: 685–91.
11. Langille BL, O’Donnell F. Reductions in arterial diameter produced by chronic decreases in blood flow are endothelium-dependent. Nature. 1986; 231: 405–7.
12. Laughlin MH, McAllister RM. Exercise training–induced coronary vascular adaptation. J Appl Physiol. 1992; 73 (6): 2209–25.
13. Laughlin MH, Newcomer SC, Bender SB. Importance of hemodynamic forces as signals for exercise-induced changes in endothelial cell phenotype. J Appl Physiol. 2008; 104 (3): 588–600.
14. Laughlin MH, Roseguini B. Mechanisms for exercise training–induced increases in skeletal muscle blood flow capacity: differences with interval sprint training versus aerobic endurance training. J Physiol Pharmacol. 2008; 59: S71–S88.
15. Lorenz MW, Markus HS, Bots ML, Rosvall M, Sitzer M. Prediction of clinical cardiovascular events with carotid intima–media thickness: a systematic review and meta-analysis. Circulation. 2007; 115: 459–67.
16. Maiorana AJ, Naylor LH, Exterkate A, et al.. The impact of exercise training on conduit artery wall thickness and remodelling in chronic heart failure patients. Hypertension. 2011; 57: 56–62.
17. Moreau KL, Silver AE, Dinenno FA, Seals DR. Habitual aerobic exercise is associated with smaller femoral artery intima–media thickness with age in healthy men and women. Eur J Cardiovasc Prevent Rehab. 2006; 13: 805–11.
18. Naylor L, O’Driscoll G, Fitzsimons M, Arnolda L, Green DJ. Effects of training resumption on conduit arterial diameter in elite rowers. Med Sci Sports Exerc. 2006; 38 (1): 86–92.
19. Newcomer SC, Padilla J. Racket sports as a model of studying vascular adaptations: a comeback after a quarter of a century. J Appl Physiol. 2011; 110: 1156–7.
20. Potter K, Green DJ, Reed CJ, et al.. Carotid intima–media thickness measured on multiple frames: evaluation of a DICOM based software system. Cardiovasc Ultra. 2007; 5: 29.
21. Potter K, Reed CJ, Green DJ, Hankey GJ, Arnolda LF. Ultrasound settings significantly alter arterial lumen and wall thickness measurements. Cardiovasc Ultra. 2008; 6: 6.
22. Rauramaa R, Halonen P, Vaisanen SB, et al.. Effects of aerobic physical exercise on inflammation and atherosclerosis in men: the DNASCO study, a six-year randomized, controlled trial. Ann Intern Med. 2004; 140: 1007–14.
23. Rowley NJ, Dawson EA, Birk GK, et al.. Exercise and arterial adaptation in humans: uncoupling localized and systemic effects. J Appl Physiol. 2011; 110 (5): 1190–5.
24. Rowley NJ, Dawson EA, Birk GK, et al.. Exercise and arterial adaptation in humans: uncoupling localised and systemic effects. J Appl Physiol. 2011; 110: 1190–5.
25. Schmidt-Trucksass A, Schmid A, Brunner C, et al.. Arterial properties of the carotid and femoral artery in endurance-trained and paraplegic subjects. J Appl Physiol. 2000; 89: 1959–63.
26. Simon A, Megnien JL, Chironi G. The value of carotid intima–media thickness for predicting cardiovascular risk. Arterioscler Thromb Vasc Biol. 2010; 30: 182–5.
27. Sinoway LI, Musch TI, Minotti JR, Zelis R. Enhanced maximal metabolic vasodilation in the dominant forearms of tennis players. J Appl Physiol. 1986; 61: 673–8.
28. Tanaka T, Seals DR, Monahan KD, Clevenger CM, DeSouza CA, Dinenno FA. Regular aerobic exercise and the age-related increase in carotid artrey intima–medial thickness in healthy men. J Appl Physiol. 2002; 92: 1458–64.
29. Thijssen DH, Dawson EA, van de Munckhof I, et al.. Exercise-mediated changes in conduit artery wall thickness in humans: role of shear stress. Am J Physiol. 2011; 301: H241–6.
30. Tinken TM, Thijssen DHJ, Hopkins ND, Dawson EA, Cable NT, Green DJ. Shear stress mediates vascular adaptations to exercise training in humans. Hypertension. 2010; 55: 312–8.
31. Tuttle JL, Nachreiner RD, Bhuller AS, et al.. Shear level influences artery remodelling, wall dimension, cell density and eNOS expression. Am J Physiol. 2001; 281: H1380–9.
32. Whyte JJ, Laughlin MH. The effects of acute and chronic exercise on the vasculature. Acta Physiol. 2010; 199: 441–50.
33. Woodman RJ, Playford DA, Watts GF, et al.. Improved analysis of brachial artery ultrasound using a novel edge-detection software system. J Appl Physiol. 2001; 91 (2): 929–37.