Impact of exercise training on arterial wall thickness in humans

Clinical relevance of carotid artery wall thickness

Large follow-up trials, such as the ARIC (Atherosclerosis Risk in Communities) study [13,14] and the Rotterdam study [15–17], have established that carotid IMT is associated with increased risk for adverse cerebral events (e.g. stroke), which is independent of other risk factors [13,15,17]. Carotid IMT may possess superior predictive capacity for stroke than other measures of atherosclerotic risk, such as the presence of carotid plaques and the ankle–arm index [16].

Increased carotid IMT is also associated with increased risk for cardiac (e.g. angina pectoris and myocardial infarction) [13,15,18–20] and peripheral vascular events (e.g. peripheral artery disease and hypertension) [21,22]. The annual change in carotid artery IMT represents a surrogate marker for systemic atherosclerosis and provides prognostic information [11]. A meta-analysis found that a 0.1 mm increase in carotid artery IMT is associated with an increase in age- and sex-adjusted relative risk of 18% for stroke and 15% for myocardial infarction [23]. A recent study confirmed the independent predictive capacity of carotid IMT in asymptomatic subjects and indicated that carotid IMT provided similar risk stratification as the FRS (Framingham Risk Score) [24].

Clinical relevance of wall thickness in peripheral arteries

Arteries of the lower limbs are subject to the development of atherosclerosis, plaque formation and clinical complications (e.g. intermittent claudication). Indeed, thickening of the arterial wall in older subjects is even found in arteries of the upper limbs, such as the brachial artery [25,26], in which plaque formation/rupture is not typically observed. The presence of arterial wall thickening in atherosclerosis-prone and -resistant vessels supports the idea that wall thickening occurs systemically [27]. Whether an age-related increase in wall thickness in these vessels reflects systemic atherosclerotic remodelling or benign age-related thickening of the wall (in some or all vessels) is currently unknown.

Studies have also established the clinical and prognostic value of peripheral artery wall thickness measures. For example, increased femoral artery IMT strongly relates to traditional cardiovascular risk factors, such as blood pressure, waist circumference, cholesterol, insulin and smoking status [28–30]. Thickening of the femoral wall also correlates with measures of peripheral atherosclerotic disease, such as the ankle–brachial index [31], and a significant relationship is present between femoral IMT and the FRS [29,32]. This strong association with cardiovascular risk factors suggests that femoral IMT may possess prognostic relevance. Studies have found associations between femoral IMT and restenosis after percutaneous coronary intervention [33] and with the severity and extent of coronary artery disease [34].

Advanced age is associated with the thickening of atherosclerosis-resistant arteries, such as the brachial artery [25,26]. A correlation exists between brachial and carotid IMT [35], and the extent of atherosclerosis is also correlated between the brachial, carotid and coronary arteries [36]. These studies suggest that upper limb arterial wall thickening may be clinically and prognostically relevant. In a large population-based study, brachial artery IMT related strongly to the FRS in older subjects, with lipid levels [i.e. HDL (high-density lipoprotein); inversely] and oxidative stress [i.e. oxLDL (oxidized low-density lipoprotein); positively] related to brachial IMT [37]. Increased brachial IMT also correlates, independent of other cardiovascular risk factors, with the presence of coronary artery disease [38,39]. Previous studies also found that increased brachial IMT predicts future cardiovascular events in subjects undergoing coronary angiography [40] and that brachial IMT progression is linked with worsening disease severity in patients with heart failure [41]. Collectively, these findings suggest that brachial IMT is related to cardiovascular risk and may have a prognostic role in the prediction of cardiovascular events.

PA (physical activity) and carotid arterial wall thickness

Studies which have examined the relationship between carotid IMT and daily PA levels have typically adopted a cross-sectional design and used questionnaires to assess PA (Table 1). When combined, studies including a total of >28000 subjects found an inverse relationship between self-reported PA and carotid IMT [42–47]. This association is supported by the finding that higher a priori PA levels are related to attenuated 3- or 6-year increases in carotid IMT [42,47]. It must be noted that self-reported PA represents a subjective measure and correlates only modestly with direct measures of physical fitness [48]. Owing to these limitations, questionnaires may only provide meaningful data in large cohorts and with specifically designed instruments to assess PA. Yamada et al. [49], in a small sample (n=149), found no relationship between IMT and PA level assessed using a non-specific questionnaire.

The limitations of PA measurement may explain inconsistent findings regarding the inverse correlation between PA levels and carotid IMT. For example, the association between higher leisure-time PA levels and lower carotid IMT in one analysis was present in never-smokers, but not smokers [45]. Data derived from the Tromso Study, a large population-based trial, identified sex and age as modulators of the inverse relationship between PA and carotid atherosclerosis [43,44]. More specifically, the inverse relationship between PA and carotid artery atherosclerosis was observed in men, but not women [43,44]. These researchers also found that the protective effects of a higher PA were more pronounced in older cohorts (i.e. 60–69 and >70 years) [43].

In summary, although measures of self-reported PA should be interpreted with caution, these studies indicate an inverse relationship between PA levels and carotid IMT. Moreover, limited cross-sectional evidence suggests that the effects of PA on carotid IMT may be more prominent in older subjects and in men.

Physical fitness and carotid arterial wall thickness

The ‘gold-standard’ measure of cardiorespiratory fitness in humans involves direct assessment of peak or maximal oxygen consumption in response to an exercise test (Table 1). Cross-sectional studies, predominantly performed in middle-aged and older humans, have reported that low fitness correlates independently with increased carotid IMT [50–52] and the presence of carotid plaque [53]. Studies which have used surrogate measures of fitness in relatively large cohorts have observed that higher walking speeds correlate with a lower carotid IMT [54–56]. Although measurement of fitness and IMT at a single time point does not provide information about progression, Lakka et al. [57] examined the 4-year change in carotid IMT and found that lower fitness in middle-aged men was the strongest independent predictor of a 4-year increase in carotid IMT [57].

Effect of exercise training on carotid arterial wall thickness

One of the first studies to examine the effect of exercise training on atherosclerosis examined carotid artery IMT in 137 endurance-trained and sedentary men and found no significant difference between the groups [58]. Subsequent studies performed in younger [59] or older [60] cohorts also observed no difference in carotid atherosclerosis between endurance-trained subjects and sedentary controls. A recent study [61], however, found a significantly lower carotid artery IMT in elite squash players compared with less active controls. The difference in training intensity and/or load may explain these disparate results, as elite squash players exercised >22 h/week at high intensity [61], whereas others classified endurance training when exercising >3 h/week [59] or >5 days/week [58,60].

Longitudinal studies involving exercise training have directly examined the effect of 8–12 weeks of aerobic exercise in middle-aged [58] and older [62] subjects, but found no evidence that exercise training altered carotid artery IMT. Similarly, 8-week resistance training in young men did not alter carotid artery wall thickness [63]. In another study, Rauramaa et al. [64] examined the 6-year change in carotid IMT in 140 middle-aged men who performed aerobic exercise training or no intervention. They found no effect of exercise training, but a ~40% lower 6-year progression of carotid IMT when participants on statins (n=15) were excluded, suggesting that the anti-atherosclerotic effects of statins may mask the impact of exercise. Another study examined the effect of a 4-year lifestyle intervention (PA+diet) in middle-aged women and found attenuated progression of carotid atherosclerosis in peri- and post-menopausal women, but not pre-menopausal women [65] (Table 2).

In summary, exercise training appears to have a modest effect on carotid artery atherosclerosis in young subjects (Figure 1) and changes may require intense exercise or interventions performed over prolonged time periods.

Effect of exercise training on wall thickness in peripheral arteries

A limited number of cross-sectional studies have examined the effect of exercise training on the wall thickness of peripheral arteries. In contrast with findings in the carotid artery, lower femoral artery IMT was observed in endurance-trained men and women compared with their sedentary peers [66,67]. Moreau et al. [60] extended this observation by comparing femoral and carotid artery IMT between endurance-trained athletes and sedentary controls. Although they confirmed the lower femoral artery IMT in athletes, no significant differences were observed between groups for carotid IMT. These findings suggest that exercise training may have a larger effect on remodelling of the arterial wall in peripheral arteries (that supply the active regions) than in the carotid arteries. Recently, Rowley et al. [61] provided further support for this proposal (Figure 2) when they reported that elite squash players demonstrate a lower femoral, brachial and carotid artery IMT than sedentary controls. These findings support the presence of a generalized lower arterial wall thickness in highly trained athletes, than in controls.

Longitudinal training studies have also assessed changes in peripheral arterial wall thickness. Dinenno et al. [66] directly examined the impact of a 3-month aerobic exercise training programme on femoral artery IMT in middle-aged men and found a significant reduction in wall thickness. In addition, in older subjects, a decrease in peripheral arterial wall thickness (i.e. popliteal and brachial artery) was found after a 6-month aerobic exercise training [26], whereas no changes were observed after 8 weeks of training [62]. In a recent study, it was demonstrated that the increase in femoral IMT during 8 weeks of bed rest in young men can be (partly) prevented by (resistive) vibration exercise training [68]. Finally, a recent handgrip exercise training study found that localized exercise training can lead to a small, but significant, decreases in brachial artery wall thickness [69]. Taken together, exercise training studies performed in healthy subjects indicate that remodelling occurs in response to prolonged training interventions in peripheral arteries supplying the active skeletal muscle.

Role of local haemodynamic stimuli: shear stress

Shear stress plays an important role in the regulation of large artery remodelling [92], and the development of carotid atheromatous plaques has been linked with the presence of low mean shear rate [93]. Development of carotid plaques has also been related to oscillatory shear stress [93,94]. Such oscillatory shear patterns are characterized by shear that is not unidirectional, but rather goes in both directions, i.e. forward and backward. This observation is in agreement with studies performed in vitro [95] and in vivo [96], which reported a pro-atherogenic endothelial cell phenotype or function when these cells were exposed to increased levels of shear into the backward direction (i.e. retrograde shear stress). Specifically, oscillatory shear has been associated with decreased endothelial NOS (nitric oxide synthase) mRNA and increased VCAM-1 (vascular cell-adhesion molecule-1), ICAM-1 (intercellular adhesion molecule-1) and ET-1 (endothelin-1) [97,98]. Although exercise leads to an increase in shear in exercising and non-exercising regions [99,100], few studies have examined whether shear stress contributes to arterial wall remodelling.

Recently, we compared brachial artery wall thickness and diameter between the preferred and non-preferred limbs of elite squash players, with the assumption that the preferred limb of squash players receives a larger shear stress stimulus than the non-preferred limb over a prolonged period [61]. This model allows the isolation of localized effects on arterial function and structure, given that central haemodynamics and sympathetic nervous system tone are controlled for using bilateral limb comparisons. Interestingly, wall thickness did not differ between the preferred and non-preferred limbs, despite a larger arterial diameter on the preferred side (Figure 2). In another study, we directly examined the role of shear stress by performing bilateral handgrip exercise training, while unilaterally manipulating shear stress using cuff inflation during repeated exercise bouts [69]. Although shear was kept near resting levels during handgrip exercise in one arm, exercise training induced a similar decrease in brachial artery wall thickness bilaterally. These studies suggest that systemic, rather than localized, shear stress plays an important role in adaptations of the arterial wall in response to exercise training.

Role of systemic haemodynamic stimuli: arterial pressure

During the cardiac cycle, blood pressure rapidly fluctuates and produces stretch on the arterial wall. Data collected in vitro demonstrate that chronic increases in blood pressure result in pro-atherogenic endothelial cell phenotypes, which are characterized by lower eNOS (endothelial NOS) mRNA expression and higher levels of VCAM-1, ICAM-1, ET-1 and ROS (reactive oxygen species) [98]. These findings support the clinical observation that a chronic increase in blood pressure relates to a thicker carotid arterial wall [101]. Moreover, a previous study in humans found that chronic elevations in local distending pressure in the carotid artery importantly contribute to arterial wall thickening [102]. Interestingly, exercise increases arterial pressure and, consequently, leads to a larger stretch on the arterial wall during exercise. Nonetheless, chronic exercise training is associated with a lower arterial wall thickness (Tables 2 and 4). It can therefore be speculated that up-regulation of pro- (e.g. VCAM-1, ICAM-1, ET-1 and ROS) and anti-atherogenic (e.g. eNOS) genes differ when the pressure stimulus involves chronic elevation compared with the transient, episodic and cyclical increases in blood pressure which occur in response to exercise [97,98]. Although findings are conflicting and primarily relate to responses of individual cells (excluding the cross-talk between cells), some evidence indicates that short-term cyclic elevation in pressure induces anti-atherogenic changes in the arterial wall (for a review, see [97]). However, this is speculative at present and research in this area is in its infancy. Future studies are needed to clarify the role of specific patterns of blood pressure as stimuli for arterial wall remodelling.

Role of systemic non-haemodynamic stimuli