INTRODUCTION: ACCOUNTING FOR THE RISK REDUCTION ASSOCIATED WITH EXERCISE
Exercise decreases the risk of cardiovascular (CV) events, and the magnitude of this benefit can exceed that associated with antihypertensive and lipid-lowering interventions. A similar magnitude of exercise benefit is observed in meta-analyses of secondary prevention studies, including studies undertaken in the contemporary era of pharmacological risk factor management and revascularization (7).
The effects of exercise on traditional CV risk factors fail to fully account for this impressive impact of exercise on CV and coronary risk. Indeed, a recent study of approximately 27,000 subjects found that, in combination, traditional and novel risk factors explained around 59% of the exercise benefit in terms of reduction in CV disease risk and only 35% of the reduction in coronary artery disease risk (24) (Fig. 1). These data infer that a significant proportion of the benefit of exercise, in terms of preventing CV and coronary artery events, remains unaccounted for and reinforces the suggestion that improvement in traditional risk factors cannot solely account for the magnitude of risk reduction associated with exercise training.
In the past decade or so, we have studied the effects of exercise training on the vasculature in healthy humans and those with CV disease and risk factors (10,22). Our particular focus has been on the impact of exercise training on endothelium-derived nitric oxide (NO), a molecule that possesses numerous antiatherogenic properties. Despite consistently observing changes in artery function and remodeling in laboratory-based, closely supervised, and randomized controlled trials, we rarely observed changes in CV risk factors (12). In recent years we have therefore focused on studying the direct effects of exercise, mediated through shear stress changes, on vascular adaptations in humans. This article summarizes the rationale for our hypothesis that the magnitude and pattern of shear associated with exercise may influence the time course of adaptation in vascular function and remodeling in humans.
ARTERY FUNCTION: EFFECT OF EXERCISE TRAINING IN HUMANS
Studies of small muscle group exercise training provide a model of the impact of localized activity on vasomotor control, excluding changes in central hemodynamics and reflex CV regulation that accompany training of larger muscle groups. In the first study directly assessing the impact of exercise training on NO-mediated vascular function in human arteries, we examined forearm blood flow responses to NO donors and antagonists in healthy young subjects and failed to observe any effect of training (6). Similarly, no effect of chronic exercise existed when we compared the limbs of elite racket sportsmen (9). In contrast, studies of small muscle group exercise in subjects with CV diseases typically demonstrated improvement in NO-dependent responses in both resistance and conduit arteries (10).
These findings led us to speculate that subjects with impaired endothelial function may be more amenable to training-induced improvement in vascular function than healthy subjects (22), an idea that has largely been reinforced by studies undertaken using whole-body exercise (running, cycling, walking, weight training) (10). For example, studies of the effect of large muscle group exercise training on conduit or resistance vessel function in healthy subjects have been inconsistent, whereas the large majority of studies performed in subjects with impaired endothelial function document improvements with training at both resistance and conduit artery level (10). These include studies in patients with heart failure, CAD, hypertension, hypercholesteremia, obesity, and diabetes.
Perhaps the most comprehensive and elegant of all exercise training studies has been performed by Hambrecht and colleagues (13). They studied the impact of a 4-wk cycle exercise on the internal mammary artery of CAD subjects awaiting coronary artery bypass surgery. Training improved in vivo and in vitro acetylcholine (ACh) responses and adenosine-mediated blood flows, indicating that both conduit and resistance artery endothelium-dependent vasodilator function were enhanced. Training also increased endothelial NO synthase (eNOS) mRNA and protein expression and shear stress-related eNOS phosphorylation, suggesting that a shear stress-dependent mechanism may be responsible for the enhanced NO bioactivity with training. These data are particularly powerful when considered in the context of another important study from this group (14), which compared 12 months' treatment with exercise training versus contemporary percutaneous coronary intervention (PCI) with stenting, on clinical symptoms, exercise capacity, myocardial perfusion, cost-effectiveness, and clinical end points. In contrast to PCI/stenting, exercise did not affect stenosis size at 12 months. But exercise did result in superior event-free survival at lower cost. It was concluded that in contrast to the impact of exercise, coronary interventions must be regarded as a palliative therapy with regard to the underlying process of atherosclerosis.
Taken together, the studies described above provide strong evidence for the impact of exercise training on vascular function in humans. These studies also indirectly implicate episodic increases in arterial shear stress as a key stimulus to this adaptation (see The Shear Stress Pattern and Endothelial Responses section). The magnitude, or perhaps the time course, of benefit may differ between subjects who possess healthy and impaired endothelial function a priori.
ARTERY REMODELING: EFFECT OF EXERCISE TRAINING IN HUMANS
Peak blood flows (or derived peak vascular resistance or conductance) have traditionally been used as indirect determinants of resistance vessel arterial remodeling in humans (27), whereas more recent imaging modalities have facilitated direct visualization of the impact of training on conduit artery size (25).
Some years ago, we reported that tennis players exhibit higher vasodilator capacity in preferred, versus nonpreferred, limbs (9), and that handgrip training in young subjects enhanced peak dilator responses in the trained, but not untrained, forearm (6). These data are confirmed by, or confirmed, other studies that indicate that training induces resistance vessel remodeling in humans (27). Such adaptations are unlikely to result from changes in sympathetic tone, and muscle hypertrophy is not obligatory (27). Adaptations in maximal blood flow or conductance responses with training likely reflect changes in the caliber or cross-sectional area of the resistance arteries, or arterial remodeling, rather than angiogenic increases in capillarity, because maximal muscle blood flow does not predominantly depend upon capillary density (28), capillaries contribute much less resistance to flow than upstream arterioles and the time course of adaptation in capillary density (∼4 d) is distinct from that of adaptation in hyperemic flows (14-28 d) (2).
Remodeling of larger conduit arteries also occurs in response to training. Zeppilli and colleagues (34) observed increased large artery size in endurance trained athletes, relative to sedentary controls, which persisted after scaling correction for body surface area. Wheelchair athletes demonstrated enhanced dimensions in the aortic arch and subclavian artery but lower values in the abdominal aorta and mesenteric artery. Later findings by Huonker et al. (16) suggested that training effects were limb specific in athletes. Longitudinal training studies of healthy men have reported significant increases in the dimensions of the ascending and abdominal aorta and of the femoral artery in the trained, but not untrained, limb after 6 wk of one-legged cycle exercise (23). Enhanced resting femoral artery diameter was also observed after walking training in sedentary men (4), and we observed further outward conduit artery remodeling in response to training in subjects who were already highly trained, with evidence of preexisting arterial remodeling (25).
When considered alongside evidence indicating that coronary artery size and dilator capacity are enhanced in athletes or trained subjects (15), these studies strongly support the contention that exercise training is associated with resistance and conduit artery remodeling in humans. The mechanisms responsible are not currently known (see The Shear Stress Pattern and Endothelial Responses section), but chronic changes in shear stress induce arterial remodeling that is endothelium and NO dependent (33).
RELATIONSHIP BETWEEN CHANGES IN ARTERY FUNCTION AND REMODELING IN RESPONSE TO TRAINING
Studies of the time course of functional or structural arterial adaptation to exercise training have predominantly been performed in animals. Short-term exercise training enhances eNOS and NO production and bioactivity, whereas extended training induces changes in vascular remodeling (19), an endothelium and NO-dependent phenomenon (33). The apparent differential in the time course of change in function and structure in animals has given rise to the proposal by Laughlin (17), that remodeling may partly supplant the need for acutely responsive vasodilator mechanisms.
In humans, Tinken et al. (31) recently studied the impact of exercise training on vascular function and remodeling in brachial and popliteal arteries. Artery function and structure were assessed every 2 wk across an 8-wk exercise program in healthy young men. Vascular function adapted rapidly to training, whereas arterial size increased toward the end of the training period, as function returned to baseline levels. These results support the notion, initially advanced by Laughlin (17), that shear stress-mediated arterial remodeling, which is at least partly NO dependent, acts to mitigate the increases in shear stress brought about by repeated exercise bouts. It is important to stress that these findings will require further studies of the impact of training on shear levels both at rest and during exercise (Fig. 2).
DO CHANGES IN ARTERY FUNCTION AND REMODELING OCCUR AT ALL ARTERIAL LEVELS?
Although the evidence provided indicates that training can enhance conduit and resistance artery function and remodeling in humans, no clear pattern emerges regarding the impact of training at different levels of the arterial tree. Indeed, we observed no correlation between the changes in NO-mediated resistance and conduit artery function after training in humans (11), and differences in eNOS content have been reported in arteries of different caliber in animals (20). Larger vessels may possess greater capacity for NO production, and it is, therefore, conceivable that NO-related adaptations to exercise training may be vessel caliber dependent. In this context, it may be relevant that larger coronary arteries adapt rapidly to exercise training (18) in animals, whereas endothelium-dependent vasodilation in smaller arterioles occurs after a longer period.
Although no time course experiments of simultaneously assessed function and structure responses in conduit and resistance vessels have been undertaken in humans, some indirect evidence is available. For example, large elastic arteries seem to be less adaptable than smaller conduit arteries supplying peripheral limb muscle groups (16).
With regard to microvascular adaptation, we recently investigated the effects of exercise training using microdialysis and laser Doppler flow assessments in the skin (1) (Fig. 3). The NO component of heat-induced increase in cutaneous conductance was diminished in the older sedentary subjects compared with older fit and young subjects, and exercise training in the older sedentary group enhanced NO vasodilator function in response to incremental heating (P < 0.05). Similarly, the NO contribution to ACh dose-response curves was impaired in the older sedentary versus older fit subjects, and training reversed this phenomenon. These findings indicate that maintaining a high level of fitness, or undertaking exercise training, prevents age-related decline in indices of physiological and pharmacological microvascular NO-mediated vasodilator function. Because higher levels of NO confer antiatherogenic benefit, we concluded that this study may have potential implications for the prevention of microvascular dysfunction in humans.
IS SHEAR STRESS A SYSTEMIC STIMULUS TO VASCULAR ADAPTATION IN RESPONSE TO TRAINING?
In the series of studies we undertook involving large muscle group training, we specifically avoided exercise that involved the upper limbs but, nonetheless, observed improvement in measures of upper limb vascular function. Other groups have also reported systemic effects of lower limb exercise on vascular function (3,21). There have also been reports of significant increases in forearm vasodilator capacity (i.e., peak reactive hyperemic flows) after lower limb training (26), suggestive of a generalized effect of training on arterial structural remodeling. Generalized effects of training on arterial remodeling are likely dependent upon the mass of muscle engaged in training, as handgrip training studies are not associated with contralateral limb remodeling (6,9,27).
The observation of a probable systemic effect of exercise training, along with the evolving comprehension of the role of shear stress in functional and structural arterial adaptation, encouraged us to perform some simple descriptive experiments aimed at describing upper limb blood flows during acute bouts of lower limb exercise. We used Doppler ultrasound to calculate mean blood flow changes in the brachial artery during incremental levels of lower limb cycle ergometry (8). The results essentially reinforced historical findings that had used plethysmography or measurement of limb arterio-venous oxygen difference; that is, mean blood flows in the upper limb did not increase substantially during lower limb exercise (Fig. 4). However, we were intrigued by the biphasic nature (initial decrease, subsequent increase) of the mean blood flow responses and, because we had developed a system that combined edge detection and wall tracking for arterial diameter assessment with synchronized Doppler envelope detection (8), we subsequently constructed curves that displayed blood flow changes across the cardiac cycle. These data revealed that although the mean flows changed modestly and in a biphasic manner, this in fact disguised a large underlying change in the pattern of flow (and shear) (Fig. 4). Along with increases in anterograde flow during systole as cardiac output increased, we observed substantial increases in the magnitude of retrograde brachial artery flows during diastole while cycling (8) (Fig. 4). Significant volumes of blood therefore flow backward toward the heart during diastole, a phenomenon that is not as apparent during localized handgrip exercise (5) or some other forms of lower limb exercise (29) (Fig. 5). We also observed an impact of brachial NO blockade during incremental cycling (5), indicating that a generalized stimulus to NO function does indeed result from large muscle group exercise, even in the inactive upper limbs.
THE SHEAR STRESS PATTERN AND ENDOTHELIAL RESPONSES
For us, the observation of large retrograde flows, oscillatory patterns of flow, and differences in flow patterns between exercise modalities raised a new series of questions. If shear stress is a key stimulus to adaptation in both artery function and structure in response to exercise training, does the pattern of shear stress associated with different forms of exercise modulate endothelial adaptation?
We recently completed a series of experiments aimed at characterizing the impact of different patterns of blood flow and shear on acute NO-mediated endothelial function and also manipulation of the shear stimulus during exercise training. In the first experiment, we induced increases in the magnitude of retrograde flow through the brachial artery using a cuff placed below the cubital crease, which we inflated to different subdiastolic pressures for a period of 30 min (30). Flow-mediated dilation (FMD), a largely endothelium- and NO-dependent phenomenon, was simultaneously assessed in both the cuffed and contralateral control (uncuffed) arms, immediately before and after the 30-min intervention periods. Cuff inflation (25, 50, 75 mm Hg) at rest did not alter the magnitude of antegrade flow or shear stress, but stepwise increases in retrograde flow/shear were evident along with dose-dependent decreases in FMD. This experiment, somewhat reminiscent of Harvey's simple methodology in its simple use of tourniquets and flow assessment, indicates that unopposed increases in retrograde flow and shear rate may have a detrimental impact on endothelial function in vivo.
In a corollary experiment, we examined FMD in both arms of healthy young men before and after 30-min interventions consisting of bilateral forearm heating, recumbent leg cycling, and bilateral handgrip exercise (32). During each of these interventions, a cuff inflated to 60 mm Hg was placed on one arm to unilaterally manipulate the shear rate stimulus. In the noncuffed arm, antegrade flow and shear increased similarly in response to each intervention, and FMD also increased. In contrast, cuffed arm antegrade flow and shear rate were lower than in the noncuffed arm for all conditions, and the increases in FMD observed in the contralateral uncuffed limb were abolished.
On one level, our previous data indicating that oscillatory flow patterns in the inactive upper limbs during cycle exercise were associated with enhanced NO-mediated vasodilation (5,8) were hard to reconcile with the finding that retrograde flows induced by cuff placement decrease FMD (30). However, taken together, we would propose (Fig. 6) that increases in antegrade blood flow and shear provide an important stimulus to acute increase in endothelial function in humans that may also prevent impairment in endothelial function associated with concurrent increases in the retrograde pattern. These new findings clearly require further investigation and substantiation. Research into the direct impact of shear on the vasculature in humans is in its infancy, but the above hypothesis concurs with some findings relating to the impact of different patterns of flow and shear on endothelial phenotype in animals (17,18). The pattern of shear associated with episodic exercise, in particular, the retrograde versus antegrade components of blood flow and shear, may have relevance for magnitude and time course of adaptation in vascular function and remodeling in humans.
Exercise training reduces CV events in humans. Effects on traditional CV risk factors do not fully account for the magnitude of risk reduction associated with exercise. Some of the beneficial impact of exercise training on vascular function and arterial remodeling may be associated with the direct effects of episodic changes of shear stress during repeated bouts of exercise. Such direct vascular conditioning effects provide a plausible mechanistic explanation for some of the cardioprotective benefits of exercise. That is, each exercise bout may be thought of as providing a direct dose of vascular medicine. However, different types or forms of exercise, and perhaps even different intensities, are associated with different antegrade and retrograde patterns of shear stress. The efficacy of training interventions may, therefore, depend upon the nature of the shear stress stimulus presented to the endothelium during episodic exercise bouts. Future research should focus on the direct impact of training on vascular function and remodeling.
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Keywords:©2009 The American College of Sports Medicine
shear stress; nitric oxide; arterial remodeling; vascular conditioning; flow-mediated dilation; FMD