Autopsy and angiographic studies performed in athletes (Currens and White
1961; Pelliccia et al.
1990) and physically fit individuals (Hildick-Smith et al.
2000; Mann et al.
1972; Rose et al.
1967) suggest that physical conditioning induces an increase in arterial cross sectional area, also referred to as “arterial remodelling”. Similarly, cross-sectional studies have consistently reported enlargement of skeletal muscle conduit (Ben Driss et al.
1997; Dinenno et al.
2001; Huonker et al.
1996,
2003; Kool et al.
1991; Schmidt-Trucksass et al.
2000; Wijnen et al.
1991; Zeppilli et al.
1995) and resistance (Green et al.
1996; Sinoway et al.
1986) vessels in athletes relative to matched controls, indicating that exercise training may induce arterial enlargement (Prior et al.
2003). Findings from animal studies regarding epicardial and resistance coronary vasculature concur (Brown
2003). The studies described below have primarily utilised longitudinal designs in which subjects were followed across a training program.
Resistance vessel remodelling
Sinoway et al. performed two of the earliest studies which specifically addressed the question of the impact of exercise training on resistance vessel “structure”. They measured blood flow responses using stain-gauge plethysmography and utilised a metabolic stimulus (ischemia or ischemic exercise) to achieve maximal, or peak, forearm blood flow responses. By using a stimulus that induced peak localised dilation (Patterson and Whelan
1955; Takeshita and Mark
1980), without inducing reflex changes in vasomotor control, they sought to assess the impact of exercise training on structural vascular adaptations, independent of central regulatory changes. As mentioned above, maximal or peak blood-flow responses in response to ischemic stimuli have commonly been used to assess resistance vessel structural adaptations in various settings (Conway
1963; Folkow et al.
1955; Sivertsson
1970), based on the assumption that peak reactive hyperemia in response to a maximal vasodilator diminishes the impact of functional differences between subjects or following interventions (Patterson and Whelan
1955; Takeshita and Mark
1980). Peak reactive hyperemic stimuli used in this context include 10 minutes of limb ischemia; the blood flow response to which cannot be increased by co-infusion of vasodilator agents (Takeshita and Mark
1980). More recently, periods of ischemia combined with ischemic exercise have been utilized to induce peak blood flow responses (Naylor et al.
2005). While plethysmography has commonly been used for peak blood flow assessment, Doppler ultrasound methodology can also be used to directly measure blood flow through conduit arteries in humans (Green et al.
2002b; Hughson et al.
1996,
2001; Radegran
1997; Radegran and Saltin
1998,
1999) at a higher temporal resolution (Naylor et al.
2005).
Sinoway et al. demonstrated that the preferred arms of tennis players exhibit much higher peak vasodilator responses to 5 and 10 min periods of forearm ischemia + exercise than the non-preferred limbs of these athletes or either limb of non-tennis playing control subjects (Sinoway et al.
1986). A subsequent study demonstrated that 4 weeks of hand-grip exercise training significantly enhanced the peak dilator response to a 10 min period of forearm ischemia in the trained, but not untrained, contralateral forearm (Sinoway et al.
1987). The authors concluded that exercise training enhances the intrinsic ability of skeletal muscle resistance vessels to dilate (Clausen et al.
1973; Gleser
1973; Saltin et al.
1976; Yasuda and Miyamura
1983). The findings were unlikely to result from changes in sympathetic tone, as Takeshita and Mark demonstrated that peak blood flow responses following 10 min ischemic stimuli were not altered by lower body negative pressure induced increases in sympathetic outflow (Sinoway et al.
1986; Takeshita and Mark
1980). In addition, Klausen et al. (
1982) had previously demonstrated that, when cardiac output is not a limiting factor during leg exercise, training is associated with increased maximal leg blood flows due to enhanced vasodilator capacity.
The increases in peak vasodilator capacity observed by Sinoway were also not associated with muscle hypertrophy, as the training program did not alter maximal workload performed or forearm circumference, and because plethysmographic flow responses are normalised to dL of forearm tissue (Sinoway et al.
1986,
1987). Finally, training–induced increases in skin blood flow were discounted, as an index of skin blood flow did not change with training (Sinoway et al.
1987).
The enhanced intrinsic vasodilator capacity of active muscle beds following training may conceivably result from the well established increase in capillary density that occurs with training (Andersen and Henriksson
1977). However, as explained by Snell et al. (
1987), muscle blood flow may not predominantly depend upon capillary density (Maxwell et al.
1980). Whilst capillaries regulate transit time and O
2 extraction, they contribute much less resistance to flow than upstream arterioles (Brown
2003; Kassab et al.
1993; Laughlin and Ripperger
1987). In addition, electrical stimulation experiments suggest that the time-course of adaptation in capillary density (rapid ~4 days) (Brown et al.
1976) is dissociated from adaptations in hyperemic flows (14–28 days) (Hudlicka et al.
1977). Adaptations observed in maximal blood flow or conductance responses with training therefore most likely reflect changes in the caliber or cross-sectional area of the resistance arteries, i.e. arterial remodelling, rather than increases in capillarity (Brown
2003).
In addition to the studies of Sinoway described above, several other studies have observed increased resistance artery vasodilator capacity in response to localized small muscle group exercise training. Green et al. confirmed the Sinoway findings and added the observation that no significant change in either endothelium-dependent or -independent NO vasodilator function was apparent in trained limbs of healthy young subjects (Green et al.
1994,
1996). Martin observed enhanced maximal calf conductance following swim training in middle-aged men and women (Martin et al.
1987) and also in older subjects following walking/running exercise (Martin et al.
1990). Two studies performed in subjects with heart failure observed enhanced calf vasodilator capacity following lower limb exercise training (Demopoulos et al.
1997; Dziekan et al.
1998), whilst other studies induced increased peak common femoral artery blood flows in response to voluntary and electrically stimulated thigh exercise (Thijssen et al.
2005). Finally, some studies have reported enhanced upper limb resistance artery vasodilator capacity following predominantly lower limb exercise training interventions (Maiorana et al.
2001b; Silber et al.
1991), although the generalisability of this vascular adaptation remains somewhat controversial (Green et al.
2008a; Thijssen and Hopman
2008) ("
Local versus systemic adaptations to exercise").
Conduit artery remodelling
Several cross-sectional and longitudinal studies suggest that exercise training is associated with enlargement of skeletal muscle conduit arteries in humans. In an early study which utilized M-mode echocardiography, Zeppilli et al. observed significantly increased large artery (aorta, carotid, subclavian arteries) size in endurance trained athletes, relative to matched sedentary controls (Zeppilli et al.
1995). These differences persisted after correction for body surface area differences between the athletes and controls. Wheelchair athletes demonstrated enhanced dimensions in the aortic arch and subclavian artery, but lower values in the abdominal aorta and mesenteric artery. These findings essentially extended previous reports of enlargement in conduit arteries of athletes compared to control subjects (Kool et al.
1991; Wijnen et al.
1991). Later findings by Huonker et al. suggested that larger elastic arteries (e.g., aorta) show less adaptability than smaller conduit arteries (subclavian, femoral) supplying peripheral limb muscle groups (Huonker et al.
1996,
2003; Schmidt-Trucksass et al.
2000). One of these studies observed diminished femoral artery diameters in paraplegic subjects, as well as in the affected, but not unaffected, limbs of below-knee amputees, whereas cyclists possessed larger femoral arteries than these subjects and healthy controls and tennis players larger subclavian arteries in their racket arm than the contralateral limb (Huonker et al.
2003). Together, these cross-sectional data strongly suggest that chronic exercise training or detraining are associated with arterial remodelling. However, few of these studies corrected findings for between-subjects scaling factors which can potentially generate misleading interpretations (Naylor et al.
2008).
One way to avoid the problems associated with between-subject comparisons is to examine the impact of an exercise training intervention on skeletal muscle conduit artery adaptations. In small sample studies of healthy young men, Miyachi et al. observed significant increases in the dimensions of the ascending and abdominal aorta following 8 weeks of cycle ergometer training (Miyachi et al.
1998) and of the femoral artery in the trained, but not untrained limb, after 6 weeks of one-legged cycle exercise (Miyachi et al.
2001). These training effects were reversed following detraining (Miyachi et al.
2001). The authors concluded that regional, rather than systemic, factors are responsible for conduit artery remodelling as a result of training. Change in femoral artery diameter explained 70% of the variance in change in
\( \dot{V}{\text{O}}_{{ 2 {\text{ max}}}} \) with training, reinforcing the tight nexus that exists between conduit artery remodelling and enhanced central hemodynamic adaptation to training (Klausen et al.
1982). These data also infer that exercising limb changes in shear rate, rather than systemic changes in blood pressure or artery transmural pressure, are responsible for conduit artery adaptation (Laughlin et al.
2008). Finally, in a study submitted concurrent with that of Miyachi (Miyachi et al.
2001), enhanced resting femoral artery diameter was observed following aerobic (walking) exercise training in previously sedentary men (Dinenno et al.
2001).
In all of the above studies, resting arterial diameter has been used as an index of arterial remodelling. However, resting diameter is dependent upon sympathetic nervous system tone, as well as paracrine and circulating hormonal modulation. As these competing vasodilator and constrictor influences impact upon resting tone, baseline artery diameter may not be an optimal index of vascular structure and remodelling following exercise training, a stimulus which modulates each of these factors (Naylor et al.
2005). Therefore, it has been proposed that peak artery diameter may serve as a more appropriate assessment of conduit structure (Naylor et al.
2005) than resting measurements. This suggestion is reinforced by the data of Haskell et al. (
1993), who observed no differences using quantitative angiography in the cross-sectional area of coronary arteries in athletes at rest, relative to matched sedentary control subjects, despite marked increases in maximal dilator capacity in response to pharmacological stimulation (GTN). These investigators suggested that, in the basal state when myocardial O
2 demand is not elevated, the coronary arteries of athletes may exhibit greater vascular tone (Haskell et al.
1993). In summary, then, a strong argument can be made that, just as assessment of resistance vessel vasodilator capacity requires the application of a peak vasodilator stimulus, studies of conduit artery remodelling should attempt to assess maximal diameter or cross-sectional areas. We recently demonstrated, at least in the brachial artery, that peak conduit and resistance vessel structure can be simultaneously assessed using ultrasound Doppler approach and a combination of ischemic exercise or pharmacological stimulation (Naylor et al.
2005). In another study, Naylor et al. observed training-induced enhancement of brachial artery diameter at rest and following a 10-min period of ischemia, thereby providing evidence for arteriogenic adaptation in response to a peak dilator stimulus (Takeshita and Mark
1980). The findings of this study in elite rowers suggest that chronic exercise induces marked arterial remodelling, and also that resumption of exercise training after a brief sojourn is also associated with further structural adaptation in highly trained individuals (Naylor et al.
2006).
Coronary artery remodelling
Training-induced adaptations in large and small coronary artery diameter in animals have been expertly reviewed by Laughlin and McAllister (
1992) and Brown (
2003). These reviews indicate that well-conducted exercise studies suggest increased coronary flow capacity, a measure of resistance artery structural remodelling, as well as large epicardial arterial remodelling after training.
The earliest studies regarding coronary structural adaptation in humans involved autopsy analysis. In a series of necropsy experiments (Rose et al.
1967), blind analysis of plaque free segments of the right main coronary artery internal diameter was undertaken in subjects who died from myocardial infarction and a group of “controls” who had no evidence of post-mortem infarction. All measurements were undertaken at a constant distension pressure (80 mmHg). Subjects were classified according to whether they had been engaged in light, moderate or heavy physical activity occupations (Rose et al.
1967). The authors reported a 75% greater coronary artery diameter in control versus infarction subjects within the active and heavy physical activity occupational groups. This paper has been widely quoted in evidence that exercise is associated with coronary artery enlargement. However, whilst mean diameter in control subjects was somewhat larger (0.1 >
P > 0.05) in those engaged in “active”, compared to “light” physically active occupations (3.90 vs 4.30 mm), there was a surprising lack of effect for those in “heavy” occupations, compared to the light group (3.90 vs. 3.98 mm). The majority of the difference between infarction and control subjects within each occupational category was, in fact, evident in the diameter of the infarction subjects, whose diameters were lower in the more active groups (3.82, 3.22, 2.94 mm for light, active and heavy). This evidence is therefore open to the interpretation that, in those with small coronary arteries, higher activity levels are associated with greater risk of infarction.
Another widely quoted paper on the impact of exercise on coronary dimensions relates to the autopsy of Clarence De Mer (Currens and White
1961), who ran 100 marathons and 1,000 distance races and won the Boston marathon 7 times. His coronary artery dimensions were quoted as being “two or three times the normal diameter”. However, the cardiac findings must be considered with some caution, as the post-mortem was performed after the heart was embalmed and had a trocar passed through it in several places. Unconfirmed reports also suggest that the examination may have occurred post-exhumation (Thompson
2004).
A final historical report relating to the impact of exercise on coronary artery size relates to autopsy studies performed on 50 tribal Masai from Tanzania and Kenya (Mann et al.
1972). The coronary intimal thickness of the older Masai exceeded that of a cohort of US subjects aged 60–69 years and there was widespread presence of atheroma, similar to that expected in American men of similar age. However, symptomatic cardiovascular disease was rare in these subjects (Mann et al.
1964) and the autopsies revealed that the coronary lumen displayed marked enlargement, such that the intimal thickening was not compromising. The Masai were remarkable fit (Mann et al.
1965) and the authors speculated that they were protected from the clinical manifestations of atherosclerosis by physical fitness, which caused their coronary arteries to enlarge.
The advent of trans-thoracic echocardiography encouraged an ambitious cross-sectional study of coronary artery size in 125 male athletes, selected from an initial sample of 625 subjects on the basis of acceptable image quality (Pelliccia et al.
1990). Using a 3.25 MHz transducer to assess proximal epicardial diameter in the short axis view using M-mode echocardiography performed approximately 1 cm from the aortic ostium, these authors reported a correlation between coronary size and LV mass and wall thicknesses. A weak correlation was also evident for coronary size and
\( \dot{V}\,{\text{O}}_{{ 2 {\text{max}}}} \). The authors concluded from this correlational analysis that training-induced myocardial hypertrophy involves a proportionate increase in coronary lumen size (Pelliccia et al.
1990). A cross-sectional study performed a decade later compared distal LAD diameter and blood flow, assessed using transthoracic echocardiography, in healthy control subjects and athletes during nitroglycerine administration and intravenous adenosine infusion. The diameter increase to nitroglycerine was greater in athletes (14.1%) than controls (8.8%) and coronary flow reserve was also greater in the athletes. At least some of the increased flow reserve was attributed to lower resting coronary flow in athletes, associated with relative bradycardia. The increase in peak flow was similar to that in controls when data were scaled for LV mass. Although the findings of this study were limited by the use of flow reserve in the absence of differences in peak flows, the limited spatial resolution of echocardiography as a technique for imaging coronary arteries and the systemic infusion of a dilator agent which may have induced different reflex coronary responses, it nonetheless suggests that epicardial coronary diameters are increased in athletes.
A number of studies have performed quantitative angiography to assess the impact of exercise training on coronary artery structure. In the study by Haskell et al., no differences in the cross-sectional area of resting coronary arteries were observed in athletes, relative to matched sedentary control subjects, despite marked increases in maximal dilator capacity in response to nitroglycerine. The investigators concluded that the arteries of highly trained middle aged men exhibit greater dilating capacity than those who are sedentary (Haskell et al.
1993).
The intervention studies of Hambrecht et al. provide further insight. In the 10 stable CAD patients randomised to exercise training for a period of 4 weeks (Hambrecht et al.
2000b), intra-coronary infusion of ACh revealed higher epicardial diameter responses than controls, indicating that endothelium-dependent vasodilator function was enhanced ("
Coronary vascular function"). Interestingly, the endothelium-independent epicardial dilator responses to GTN and adenosine were unaffected by training, suggesting no change in coronary conduit artery remodelling in response to this short period of exercise training. Resting arterial diameters, pre versus post intervention in each group, were not reported. Coronary velocity and flow reserve, measured using a Doppler flow-wire, revealed increased coronary flow reserve responses to adenosine, suggesting enhanced vasodilator capacity of coronary resistance vessels. This study can therefore be interpreted as indicating that short-term exercise training in humans increases resistance vessel vasodilator capacity without inducing conduit artery remodelling. However, a follow-up study, involving a further 6 months of home based exercise training, reported enhanced adenosine-mediated coronary flow reserve
and coronary artery diameter, apparently evident at 4 weeks (Gielen et al.
2003). In a further experiment involving assessment of left internal mammary artery adaptations to 4 weeks of exercise training in patients awaiting coronary bypass graft surgery, the training group exhibited enhanced adenosine-induced diameter and peak blood flow velocity responses, suggesting increased coronary conduit and resistance artery adaptation (Hambrecht et al.
2003). There is therefore some inconsistency between these studies in terms of the reported conduit artery responses but, in general, evidence was provided for enhanced conduit and resistance vessel vasodilator capacity.
In common with the study of Haskell, no effects of exercise were reported by Hambrecht et al. in terms of resting resistance or conduit artery characteristics in the studies described above. This is further reinforced by a final experiment in which the effects of percutaneous coronary intervention with stenting (PCI) were compared to exercise training in a 12 month randomised trial of 101 male subjects. Relative to the PCI group, exercise training significantly enhanced cardiopulmonary fitness and cost approximately half as much due to fewer rehospitalisations or repeat procedures. At 12 months follow-up, the PCI group exhibited significantly increased lumen diameter (0.53–2.57 mm) and decreased relative stenosis diameter (80.7–11.8%), whereas exercise training had no impact on arterial stenotic size (0.66–0.69 mm, 77.9–76.5%). Despite this, there was significantly higher event-free survival in the exercise training group (88 vs. 70%). The implication of this study is that, whilst coronary interventions treat only a short segment of the diseased coronary tree, exercise training exerts beneficial effects on disease progression in the entire arterial bed.
Local versus systemic adaptations to exercise
A series of studies which investigated the impact of exercise training on vascular function in humans (Maiorana et al.
2000a,
b,
2001a,
2002; Walsh et al.
2003a;
b; Watts et al.
2004a,
b) involved a similar exercise training intervention, a combination of resistance and aerobic exercise, performed under close supervision, in which upper limb exercise was avoided. In some of these studies upper limb conduit artery function (Maiorana et al.
2001a; Walsh et al.
2003a,
b; Watts et al.
2004a,
b) was examined, whilst in others the resistance vessel adaptations were assayed using intra-brachial infusions of acetylcholine, sodium nitroprusside and sometimes
l-NMMA. All of these studies demonstrated improvement in upper limb endothelial function following lower limb training (Green et al.
2004; Maiorana et al.
2003), despite subjects being expressly requested to avoid hand-grip exercise. Hambrecht et al. (Linke et al.
2001) also observed systemic vascular effects of lower limb exercise. In addition, a review of the literature preceding these publications (Green et al.
2004) unearthed other studies indicating improvement in upper limb vascular function as a result of predominantly lower limb exercise (Clarkson et al.
1999; DeSouza et al.
2000; Hambrecht et al.
1998; Kingwell et al.
1997b), although many of these did not report whether subjects were specifically requested to avoid incidental hand-gripping. More recent studies have largely reinforced evidence that lower limb exercise generates changes in upper limb vascular function (e.g., Clarkson et al.
1999; DeSouza et al.
2000; Fuchsjager-Mayrl et al.
2002; Goto et al.
2003; Wisloff et al.
2007; Higashi et al.
1999a; Linke et al.
2001; Maiorana et al.
2000a,
2001b; Schmidt et al.
2002; Walsh et al.
2003a,
b) (Kingwell et al.
1997b) (see Table
1).
Table 1
Summary of exercise training studies of conduit and/or resistance vessel function in healthy humans and subjects with cardiovascular disease and risk factors undertaking localised (LT), resistance (RT) or whole-body training (WBT)
Healthy subjects |
Young | LT (4–6) |
↔
↑
Tinken Hypertension ( 2009) |
↔
↑
| |
↔
|
Young | WBT (8–12) |
↑
Rakobowchuk Am J Phys ( 2008) |
↑
↔
Kingwell Cardiov Res ( 1997a) Bergholm Atheroscl ( 1999) |
↑
| |
Young | RT (12) |
↔
|
↑
|
↑
| |
Middle-aged | WBT (8–12) | |
↔
| |
Older | LT (8) |
↑
↔
| |
↔
| |
Older | WBT (8) |
↔
Thijssen Acta Phys ( 2007a) Moriguchi Hypert Res ( 2005) |
↑
Thijssen J Appl Phys ( 2007b) |
↑
Thijssen Acta Phys ( 2007a) |
↔
Thijssen Acta Phys ( 2007a) |
CHF | WBT (4–8) |
↑
Guazzi J Appl Physiol ( 2004) |
↑
↔
Bank J Card Fail (1998) | | |
| WBT (12–52) |
↔
Kobiyashi Circ J (2003)
↑
Belardinelli Eur J CPR ( 2006) Kobiyashi Circ J (2003) |
↑
| | ↑ leg Dziekan Am Heart J ( 1998) ↔ arm Dziekan Am Heart J (1998) |
Post-MI | WBT (4–12) |
↑
| | | |
| RT (4) |
↑
| | | |
CAD | WBT (52) |
↑
Gokce Am J Cardiol ( 2002b) Edwards Am J Cardiol ( 2004)
↔
Paul J Card Reh Prev ( 2007) | | | |
Hypertension | LT (8) |
↑
| | | |
Hypertension | WBT (12) |
↑
Westhoff Kidn BP Res ( 2007) |
↑
| |
↑
|
Hypercholesterolemia | WBT (4–8) |
↑
Walsh Eur Heart J ( 2003b) |
↑
Walsh Eur Heart J ( 2003b) | | |
Obesity | WBT (8–52) |
↑
Hamdy Diabetes Care ( 2003) Kelly J Pediatr (2004) |
↑
Sciacqua Diab Care ( 2003) |
↑
↔
| |
Diabetes | WBT (8–26) |
↑
Fuchsjager Diab Care ( 2002) |
↑
| | |
PAD | WBT (6) |
↑
Andreozzi Int Angiol ( 2007) Brendle Am J Cardiol ( 2001) | | | |
In terms of generalised effects of training on vascular structure, a number of studies have investigated the impact of leg exercise training on forearm vasodilator capacity as an index of resistance artery remodelling. Silber et al. (
1991) observed a significant increase in forearm peak reactive hyperemic flows following bicycle ergometer training during which arm exercise was minimized. They concluded that vascular responses to conditioning stimuli can involve vascular beds not specifically involved in the training stimulus. They furthermore suggested that this effect may be dependent upon the mass of muscle involved in the training stimulus, as hand-grip training studies were not associated with contra-lateral limb adaptations (Green et al.
1994,
1996; Sinoway et al.
1986,
1987). Whilst some other studies involving predominantly lower limb exercise have observed evidence for upper limb resistance artery remodelling (Maiorana et al.
2000b), others have not observed such an effect (Demopoulos et al.
1997; Dziekan et al.
1998; Walsh et al.
2003b). However, some of the latter studies (Demopoulos et al.
1997; Dziekan et al.
1998) utilized a reactive hyperemic stimulus involving only 5 min of forearm ischemia, a stimulus which has repeatedly been demonstrated as insufficient to induce a true maximal hyperemic responses (Naylor et al.
2005; Sinoway et al.
1986; Takeshita and Mark
1980). Studies of conduit arteries have not typically observed adaptation in non-exercised regions in healthy subjects (Dinenno et al.
2001; Huonker et al.
2003; Tanaka et al.
2002).
A mechanistic explanation for generalised changes in arterial structure and function may relate to the impact of lower limb exercise on blood flow and shear stress patterns in inactive arterial beds. Shear stress provides a major physiological signal to improvement in endothelial function (Pohl et al.
1986; Rubanyi et al.
1986) and also adaptation in arterial size (Langille and O’Donnell
1986; Tronc et al.
1996; Tuttle et al.
2001). This effect is, at least in part, transduced by nitric oxide. Recent data suggests that lower limb exercise such as cycling induces a pattern of blood flow change in the brachial artery of the inactive upper limb characterized by increases in anterograde flow during systole as cardiac output increases, along with large increases in retrograde flows during diastole (Green et al.
2002b). The “amplitude” of flow and shear rate changes increases with exercise intensity (Thijssen et al.
2009). The shear stress sensitive endothelium is therefore not exposed to a smooth increase in laminar anterograde flows as lower limb exercise intensity increases, but rather, large oscillations in shear as blood is dragged in both directions across the cell membrane. This flow pattern in the brachial artery of the resting upper limb during lower limb exercise is associated with NO release (Green et al.
2002a), which in fact exceeds that associated with hand grip exercise, even when both types of exercise cause similar mean or average blood flows into the limb (Green et al.
2005). It seems, therefore, that the mode and intensity of exercise performed has important impacts on the pattern of flow, even when bulk or mean flows are similar over time (Thijssen et al.
2009). If endothelial phenotype is indeed sensitive to flow and shear stress patterns (Laughlin et al.
2008), then different types of exercise may logically result in different endothelial adaptations and, consequently, different degrees of change in the health of the vessel wall and its predisposition to atherogenic change (Goto et al.
2003; Green et al.
2008c; Wisloff et al.
2007).
Time-course of vascular adaptation to exercise
There have been few studies of the time-course of arterial functional or structural adaptation to exercise training in humans. However, 2–4 week training in rats increased endothelial NO synthesis in skeletal muscle arterioles and vasodilator responses to ACh and
l-arginine. SNP responses were unaltered, suggesting enhanced endothelial function, but unchanged smooth muscle cell sensitivity to NO (Sun et al.
1994). A study of similar duration demonstrated augmented dilator response, which were partially abolished by
l-NMMA infusion in rats (Koller et al.
1995). In another study, 4 weeks of training not only enhanced ACh-induced vasodilation of the rat aorta but also increased eNOS protein levels in aortic tissue (Delp and Laughlin
1997; Delp et al.
1993). Eight weeks of running in rabbits increased ACh reactivity in the aorta and pulmonary arteries, but not in the carotid artery (Chen and Li
1993), whilst 4 weeks of exercise in rats improved flow-induced dilation in skeletal muscle arteries, but not in mesenteric vessels (Sun et al.
1998). Improved endothelium-dependent vasodilation has been observed after as few as 7 days of endurance training in pigs in peripheral conduit vessels (McAllister and Laughlin
1997) as well as coronary conduit arteries (Laughlin et al.
2003a). These findings suggest that increased production of endothelial NO occurs rapidly in response to exercise training, particularly in arteries supplying active regions.
Studies performed over a longer duration have not consistently shown augmented endothelial function. Endothelium-dependent vasodilation was unaltered after 16–20 weeks of training in pigs (McAllister et al.
1996) and 16 weeks in rats (Kingwell et al.
1997a) (Laughlin
1995). There is also evidence that changes in eNOS expression are also time dependent. Expression of eNOS protein and enhanced ACh-mediated relaxation (Johnson et al.
2001) were evident after 1 week of training in pigs, whereas changes were not present after 16 weeks (Johnson and Laughlin
2000). These data suggest that long-term training is not consistently associated with enhanced vascular function. However, it should be borne in mind that prolonged exercise training enlarges arterial diameters in animals (Kramsch et al.
1981; Lash and Bohlen
1992; Leon and Bloor
1968; Wyatt and Mitchell
1978). As previously proposed (Laughlin
1995), it is conceivable that vascular remodelling, an endothelium and NO-dependent phenomenon (Gibbons and Dzau
1994; Kamiya and Togawa
1980; Langille and O’Donnell
1986; Prior et al.
2003; Rudic et al.
1998; Zarins et al.
1987), may partly supplant the need for acutely responsive vasodilator mechanisms to normalise shear stress during exercise bouts.
A time-dependent change in conduit and resistance artery endothelial function is found in the coronary circulation. Early animal studies indicated that training increased vasodilator responses in dogs (DiCarlo et al.
1989) and transport capacity in swine (Laughlin et al.
1989). Sessa et al. were the first to report that eNOS gene expression is enhanced by exercise training in the coronary arteries. They observed increased nitrite and NO production, and eNOS gene expression, following 10 days of training in dogs (Sessa et al.
1994). Exercise training also enhanced conduit artery NO-mediated dilation after 7–10 days of treadmill exercise training in another study of dogs (Wang et al.
1993). No changes were evident in response to SNP. Laughlin et al
. (
2003a) observed an improvement in conduit artery endothelial function in coronary arteries after 7 days of exercise training in pigs. In contrast, in the same study (Laughlin et al.
2003a), they did not demonstrate a change in resistance artery endothelial function after short-term exercise training. Interestingly, the same group also demonstrated that 16–20 week exercise training in pigs did not increase coronary conduit artery endothelial function (Laughlin
1995), while they demonstrated the presence of increased eNOS mRNA (Woodman et al.
1997) and increased bradykinin induced vasodilation (Muller et al.
1994) in coronary resistance vessels, suggesting that enhanced NO and endothelium-dependent dilation was persisting in these vessels. Finally, however, 16–22 weeks of training augmented vasodilator responses to adenosine in the large epicardial arteries of pigs, even after removal of the endothelium. This evidence suggests that changes in vasomotor response in coronary arteries with longer-term training might be due, at least in part, to adaptations within smooth muscle (Oltman et al.
1992). As recently reviewed by Laughlin et al., the animal data suggest that coronary arteries follow a time-dependent adaptation to exercise training, which is different between conduit and resistance arteries. Whilst smaller coronary arterioles exhibit enhanced endothelium dependent vasodilation after longer term training, larger coronary arteries adapt rapidly to training and then return towards baseline levels when exercise training continues (Laughlin et al.
2008).
In summary, animal studies suggest that short-term exercise training enhances eNOS and NO production and bioactivity, producing a short term buffer to the increased shear associated with exercise. After extended training, at least in the peripheral circulation, the increased production of NO and possibly other mediators induces structural changes in the vessels resulting in an increase in lumen diameter (Brown
2003; Prior et al.
2003). Shear stress may therefore be “structurally” normalised and endothelial NO activity returns towards initial levels.
Very little data exists regarding the time-course of arterial functional and structural adaptation to exercise training in humans. However, we recently completed a study in which measures of brachial and popliteal artery function and structure were collected every 2 weeks across an 8 week exercise training program in healthy young male subjects (Tinken et al.
2008). The results indicated that functional adaptation preceded changes in artery peak vasodilator capacity (Fig.
2). These findings support the notion that functional adaptations may be superseded by structural changes including artery remodelling may normalise shear stress. They confirm previous reports that endothelial function rapidly adapts to training and detraining (Haram et al.
2006; Pullin et al.
2004).
Healthy subjects versus subjects with cardiovascular disease
The detailed effects of exercise training in various populations with endothelial dysfunction are summarised in the Table
1 and fully reviewed elsewhere (Green et al.
2004; Maiorana et al.
2003). In subjects with cardiovascular risk factors and disease, exercise training of localised muscle groups (Hambrecht et al.
2000b; Hornig et al.
1996; Katz et al.
1997), and whole body exercise predominantly involving the lower limbs (Gielen et al.
2003; Gokce et al.
2002b; Hambrecht et al.
1998,
2000b,
2003; Higashi et al.
1999a; Linke et al.
2001; Maiorana et al.
2000a,
2001a; Schmidt et al.
2002; Walsh et al.
2003a,
b), are associated with improvement in measures of NO vasodilator function. There is consistency in the literature pertaining to exercise training mediated improvement in vascular function in groups in whom it is initially depressed. In contrast, studies of healthy subjects, with presumably normal endothelial function, are less compelling (Bergholm et al.
1999; Clarkson et al.
1999; Franke et al.
1998; Green et al.
1994; Kingwell et al.
1997b; Maiorana et al.
2001b; Thijssen et al.
2007a) and improvement may be limited to older subjects or those who undertake greater volumes of training (Green et al.
2004; Maiorana et al.
2001b). Collectively, these findings suggest that subjects with impaired endothelial function may be more amenable to improvement in NO function as a result of training than healthy subjects.
Optimal exercise training regimens
Several studies raise the possibility that different modalities or intensities of exercise may impact upon the magnitude of vascular adaptation observed. Bergholm et al. reported that 3 months of high intensity running reduced endothelium-dependent function but not endothelium-independent function (Bergholm et al.
1999). The degree of endothelial dysfunction following training was greatest in subjects with the largest improvements in
\( \dot{V}\,{\text{O}}_{{ 2 {\text{max}}}}. \) The authors postulated that the training-induced decrease in circulating antioxidant levels may adversely affect endothelial function in the highly trained or overtrained state. Goto et al. (
2003) studied the effects low (
\( 25\% \dot{V}{\text{O}}_{{ 2 {\text{ max}}}} \)), moderate (
\( 50\% \dot{V}{\text{O}}_{{ 2 {\text{ max}}}} \)) and high (
\( 75\% \dot{V}{\text{O}}_{{ 2 {\text{ max}}}} \)) intensity training in young men. Endothelium-dependent forearm vasodilation improved in the moderate intensity group only. This occurred
in the absence of changes in oxidative stress. In
the high intensity group, endothelial function did not improve, but there was evidence for increased oxidative stress. Taken together, the findings of Bergholm and Goto suggest that low intensity exercise may fall below a given threshold for improvement in endothelial function, whilst moderate intensity exercise enhances NO bioavailability. Any improvement in vascular function resulting from high-intensity exercise may be abrogated by excess oxidative stress. However, this hypothesis clearly requires further testing, as it is also evident that higher intensity training may enhance antioxidant defence against oxidative stress (Adams et al.
2005; Ennezat et al.
2001; Fukai et al.
2000).
In terms of the impact of exercise modality on vascular adaptation, the majority of studies indicating improvement in vascular function have utilised aerobic, or large muscle group dynamic exercise modalities, such as walking, running or cycling (see Table
1). Some studies which have combined aerobic and weight resisted exercises have also demonstrated generalised improvements in vascular function (Maiorana et al.
2000b,
2001a; Walsh et al.
2003a,
b; Watts et al.
2004a). Studies of resistance training have not observed changes in conduit artery function, but suggest that arterial remodelling may occur (Rakobowchuk et al.
2005). Importantly, recent studies suggest that different modes of exercise, even when performed at similar relative intensities, generate distinct patterns of blood flow and shear stress through active and inactive vessel beds, raising the possibility of different shear mediated signals for adaptation (Thijssen et al.
2009). Differences in blood pressure and transmural pressure between exercise modes may also contribute to differences in the adaptations evident (Laughlin et al.
2008). Recent studies also suggest differences in endothelial adaptations to exercise of differing modalities in heart failure and healthy subjects (Schjerve et al.
2008; Wisloff et al.
2007).
Summary: Exercise training and vascular adaptation
Collectively, the above data from both animal and human studies of exercise training suggest that functional and structural adaptations of the vasculature to exercise training alter with training duration and intensity and the vessel beds involved. Exercise training is associated with significant reductions in primary (Hakim et al.
1999; Myers et al.
2002; Sesso et al.
2000) and secondary vascular events (Jolliffe et al.
2001). The effects of exercise on cardiovascular risk factors do not account for the magnitude of risk reduction (Green et al.
2008c; Mora et al.
2007). Exercise exerts direct effects on the vasculature by virtue of the impact of repetitive intermittent increases in shear stress on the vascular endothelium, which responds by transducing functional and structural vascular adaptations which ultimately decrease atherosclerotic risk. Changes in transmural wall pressure may also represent a signal for chronic adaptation (Laughlin et al.
2008). Hence, exercise-induced improvements in vessel wall function and structure represent a “vascular conditioning” effect, which provides a plausible mechanistic explanation for the cardioprotective benefits of exercise, independent of the impact of exercise on traditional CV risk factors.
The clinical relevance of the vascular adaptations to exercise training was recently highlighted in a study which compared the effects of percutaneous coronary intervention with stenting (PCI) to exercise training alone in 101 male subjects (Hambrecht et al.
2004). After 12 months follow-up, the PCI group exhibited significantly increased lumen diameter (0.53–2.57 mm) and decreased relative stenosis diameter (80.7–11.8%), whereas exercise training had no impact on stenotic characteristics (0.66–0.69 mm, 77.9–76.5%). Despite this, there was significantly higher event-free survival in the exercise training group (88 vs. 70%). This study reinforces the fact that coronary intervention treats a short segment of the diseased coronary tree, whilst exercise training exerts beneficial effects on endothelial function and disease progression in the entire arterial bed. The authors concluded that, in contrast to exercise training, interventional cardiology represents a palliative care measure with respect to the underlying atherosclerotic disease process and that exercise training should be a cornerstone of primary and secondary prevention efforts.