Introduction

Metabolic syndrome (MetS), a cluster of risk factors including central obesity, insulin resistance, dyslipidemia, and arterial hypertension, is a well-known predictor of cardiovascular (CV) disease [1]. General population studies have shown that about one quarter to one third of adults have MetS and its prevalence continues to increase [2, 3] being recognized as a major public health issue. MetS is also associated with a chronic inflammatory and prothrombotic state [1] and with increased oxidative stress [4], which promotes vascular arterial wall remodeling and arterial stiffness (AS) [5, 6]. A large number of studies have documented that AS increases with the number of MetS components [7••, 8] as each risk factor acts independently through different mechanisms with adverse effects on the structure and function of the vascular system. On the opposite side, several authors observed a favorable effect of regular physical activity on arterial elasticity [9, 10••], which is confined to aerobic endurance training. In a recent meta-analysis, aerobic but not resistance exercise was associated with a significant reduction of AS [10••]. This protective role may be independent from weight loss [9], blood pressure (BP) reduction [11••], or improvement of lipid profile [11••, 12].

Parameters of Arterial Distensibility

The most popular index of large artery stiffness is pulse wave velocity (PWV) which was included in the 2007 European Society of Hypertension Guidelines [13] because of its good CV predictive value. PWV was confirmed by the 2013 ESH/ESC guidelines as a useful marker for reclassifying intermediate-risk patients into a higher or lower CV risk class [14]. Also, in the most recent American Society of Hypertension Guidelines, this index was included among the parameters useful for estimating CV target organ damage and atherosclerosis [15]. However, other indices can provide complementary information in the assessment of arterial elasticity. The augmentation index (AIx) gives an estimate of wave reflection [16, 17] and has been found to be a predictor of mortality and CV events independently of peripheral pressures [18, 19].

In the last decades, other distensibility parameters have been proposed as they proved to be predictive of increased risk of CV morbidity and mortality [20]. Among these, parameters determined by diastolic pulse contour wave analysis have attracted the interest of some investigators, because they provide information on the characteristics not only of large capacitance arteries but also of smaller conduit arteries [20]. Another interesting index of arterial distensibility derived from the analysis of the pulse wave contour is central BP, which usually is lower than the corresponding brachial BP, due to the phenomenon known as pressure amplification [21], which is inversely correlated to AS. Central BP has been found to be a stronger determinant of target organ damage [22, 23] than brachial BP and a stronger predictor of hypertension development [23], CV events [24], and kidney disease [25].

Several noninvasive techniques have been proposed to measure AS parameters. The majority of the authors have used applanation tonometry performed with Shygmocor device (AtCor Medical, Australia), which acquires sequential waveforms at the radial artery. Besides measuring central BP, the device also returns the radial AIx. PWV is determined by simultaneous applanation tonometry and electrocardiographic recording and is calculated as the ratio of the distance between the two recording sites (radial and carotid artery) and the time of travel of the pulse wave over this distance [26]. Other devices, such as Omron HEM-9000AI (Omron, Japan), a cuff-based technique, calculate central systolic BP from the second systolic peak. Another possible estimation of the central systolic BP is through direct tonometry of the carotid artery, a procedure that was validated against invasive pressure [27]. Finally, ultrasound or MRI techniques can give an estimation of aortic BP by measuring the local wall distension usually at the carotid level.

Factors Affecting Arterial Distensibility

Several modifiable and unmodifiable risk factors can affect arterial distensibility. Among the unmodifiable risk factors, aging plays the most important role. In particular, age together with BP has been shown to account for up to 70% of the variance in AS [28]. Hypertension, diabetes, and smoking also have an important influence on the progression of AS assessed by PWV. According to some authors, patients with hypertension have a higher annual progression rate of PWV almost three times higher than normotensive subjects [29•]. Lipid abnormalities have also been considered as important determinants of stiffening [30], and the two factors combined showed a synergistic effect (4× higher) [29•]. The role of smoking appeared more controversial. Terentes-Pritnzios et al. [29•] did not find any significant progression in vascular stiffening according to smoking habits. In contrast, a number of studies have found that chronic cigarette smoking is associated with increased AS [31, 32]. Also, central BP was found to be unfavorably affected by smoking habits. In a study [33] involving 344 untreated young to middle-age (mean age 37 ± 10 years), stage I hypertensive subjects from the HARVEST cohort, we observed that central systolic BP and pulse pressure were higher in smokers than in non-smokers (systolic BP 121.9 ± 13.1 mmHg in non-smokers, 127.2 ± 16.5 mmHg in light smokers, 126.7 ± 15.3 mmHg in those who smoked > 5 cigarettes/day, p = 0.009; pulse pressure 37.7 ± 9.8, 41.5 ± 13.1, and 41.9 ± 10.5 mmHg, respectively, p = 0.005). Also, AIx was higher in smokers than in non-smokers (p = 0.024). Finally, in a two-way ANCOVA analysis, systolic BP amplification markedly declined across the three age groups (p = 0.0002) and from non-smokers to smokers (p = 0.0001), with a significant interaction between smoking and age group (p = 0.05), indicating that in young hypertensives, smoking has a detrimental effect on central BP accelerating the age-related decline in BP amplification.

Contrary to the observation by Terentes-Pritnzios et al. [29•], AS was found by most investigators to be greater in patients with diabetes mellitus [34] and in subjects with MetS [35]. Insulin resistance and chronic hyperinsulinemia increase the local activity of renin-angiotensin-aldosterone system and the expression of angiotensin II receptors in vascular tissue, leading to vessel wall hypertrophy and fibrosis [36]. Moreover, impaired glucose tolerance promotes non-enzymatic glycation and cross-linking of collagen [37]. Another factor promoting AS is high salt intake [38], which increases BP and sympathetic tone, favoring the development of cardiac hypertrophy and large artery stiffening. An abnormal response of the renin-angiotensin-aldosterone system to high sodium level and a reduction in the bioavailability of nitric oxide were proposed as other possible mechanisms for sodium-dependent AS [39]. In a recent meta-analysis of 11 randomized controlled trials [40•], the pooled analysis showed that a lower sodium intake, measured by 24-h sodium urinary excretion, was associated with a lower average PWV (RR − 2.84, 95% CI − 5.08 to − 0.51), though this trend reached the level of statistical significance only in two studies [41, 42].

Arterial Distensibility, Obesity, and the Metabolic Syndrome

Among the modifiable risk factors for AS, several authors demonstrated that the MetS and its components can increase the risk of AS [4, 7••, 43]. Several studies have documented an increase in AS level according not only to the presence/absence of MetS [44, 45••] but also to the number of MetS components [45••]. In the TRIPLE A-Stiffness study, a multicenter longitudinal study performed in a large European population, the authors investigated the values of AS according to the presence or absence of MetS and observed a higher PWV in patients with MetS (9.65 ± 2.57 m/s) compared to those without it (8.42 ± 2.09 m/s, p < 0.001). This difference remained statistically significant also after adjustment for age and sex (p < 0.001) [45••]. Moreover, the authors explored the effect of different MetS components on AS and observed that the presence of any of these five components (waist circumference, triglycerides, HDL cholesterol, BP, and serum glucose) was associated with higher PWV values (all age- and sex-adjusted p < 0.0001). In multivariate analysis, older age, BP, glycaemia, and HDL cholesterol components were demonstrated to be independent determinants of high PWV [45••]. Sex, waist circumference, and triglycerides did not show an independent effect on AS in this study [45••].

As mentioned above, the larger the number of the MetS components, the greater the increase in PWV, as shown by Lopes-Vicente et al. [7••]. These authors examined 64 patients with 3 to 5 components of MetS (n = 8 with 5 components, n = 27 with 4 components, and n = 29 with 3 components) and 17 control subjects. The increase in the number of risk factors was associated with a progressive impairment of PWV: mean value was 7.2 ± 0.3 m/s in control group, 7.5 ± 0.2 m/s in the group with 3 risk factors (p = n.s vs controls), 7.9 ± 0.2 m/s in the group with 4 risk factors (p = 0.047 vs control), and 8.5 ± 0.4 m/s in the group with 5 risk factors (p = 0.011 vs controls and p = 0.012 vs group with 3 risk factors) [7••]. Discrepant results have been found in the literature about the specific importance of the single MetS components due to regional differences in subjects’ characteristics and to the different selection criteria used for enrolling the study participants. In general, high BP, waist circumference, and high blood glucose showed the strongest impact on AS [44].

The mechanisms whereby MetS and visceral obesity with the associated sedentary lifestyle may favor AS are manifold including increased sympathetic activity with the associated fast heart rate, enhanced activity of the renin-angiotensin-aldosterone system, and production of inflammatory cytokines. Impairment of endothelial function with the associated reduction of nitric oxide availability and increased production of reactive oxygen species are other factors that promote AS [29•, 35, 36, 43]. In addition, MetS and obesity are associated with high levels of leptin and decreased adiponectin which facilitates vascular smooth muscle cell proliferation and migration, thereby increasing collagen synthesis [46].

Arterial Distensibility and Physical Activity

A large number of epidemiologic studies have documented an association between regular physical activity and decline in the risk of CV and all-cause mortality [47, 48]. According to data from the Framingham Heart study, life expectancy is 3.7 years longer in physically active subjects compared to sedentary people [49]. Due to its multiple positive and protective effects, physical activity is included in all guidelines as one of the main non-pharmacological measures for the treatment of hypertension [14, 15], diabetes [50], and ischemic heart disease [51].

The protective role of regular exercise in attenuating CV disease and mortality risk may be due to several different factors including a decrease in BP and BMI, better lipid profile, and improvement of insulin sensitivity [52,53,54]. The decrease in BP has been documented in several meta-analytic studies. Cornelissen et al. [55] investigated the effect of at least 4 weeks of exercise on BP in healthy subjects, examining different types of physical activity: endurance, dynamic resistance, combined training, and isometric resistance. All types of exercise, except combined training, were able to reduce both systolic and diastolic BP: endurance − 3.5 (confidence limits − 4.6 to − 2.3)/− 2.5 (− 3.2 to − 1.7) mmHg, dynamic resistance − 1.8 (− 3.7 to − 0.011)/− 3.2 (− 4.5 to − 2.0) mmHg, and isometric resistance − 10.9 (− 14.5 to − 7.4)/− 6.2 (− 10.3 to − 2.0). Of note, the BP reduction with aerobic exercise was particularly elevated among hypertensive individuals, − 8.3 (− 10.7 to − 6.0)/− 5.2 (− 6.8 to − 3.4) mmHg [55].

Another important mechanism that contributes to the reduction of CV risk is the effect of exercise on body fatness and metabolic variables. The influence of regular aerobic endurance training on waist circumference, lipid profile, glucose, and HOMA index was reported in another meta-analysis by Cornelissen et al. [53]. The authors observed that all components of the MetS were improved by exercise, but the strongest effects were found for HDL cholesterol, serum glucose, fasting insulin, and the HOMA index (Fig. 1). These effects can explain why aerobic physical activity can retard the age-related decline in arterial elasticity measured with PWV [56], as shown in a recent meta-analysis [10••]. Although there were some neutral studies, the majority of published data were in favor of a beneficial effect of aerobic exercise on PWV (0.63 m/s, 95% CI − 0.90 to − 0.35) [10••]. In addition, exercise was proved effective in improving small artery compliance in young hypertensive adults [57].

Fig. 1
figure 1

Changes in metabolic data induced by endurance training. Meta-analysis of 39 trials. a Changes in cholesterol level. b Changes in serum glucose and triglyceride levels. c Changes in insulin level and HOMA index. Adapted from Cornelissen VA et al. [53]

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One of the main mechanisms underlying the favorable effect of exercise on AS is the reduction of heart rate. Studies in human beings have shown that there is a progressive increase in PWV with increasing hear rate with pacing independent from pressure changes [58], documenting that heart rate is cross-sectionally associated with AS. This effect has been quantified as an increase of 0.17 m/s for each 10 beats/min increment in heart rate [58]. A positive association between heart rate and AS has been documented also in longitudinal studies by Tomiyama et al. [59] and by Benetos et al. [60] either among normotensive or hypertensive subjects. Heart rate, however, has an opposite effect on other determinants of arterial distensibility such as central systolic BP and AIx. Several cross-sectional studies have shown that a lower resting hear rate is associated with higher aortic systolic BP and AIx [17, 61]. This negative relationship has been attributed to a shift of the backward wave reflected from the periphery into late systole secondary to the prolongation of left ventricle ejection time and to the increase in stroke volume at low heart rates [16, 17, 62]. This finding led some authors to claim that heart rate reduction in hypertension is detrimental because it may favor the risk of CV events [62]. However, a recent meta-analysis of 16 studies [10••] has shown that regular physical activity reduced the AIx by 2.63%.

In a recent analysis of the short-term and long-term effects of heart rate on arterial distensibility [63•], Palatini et al. confirmed the negative relationship of heart rate with AIx recorded in the same session. However, ambulatory heart rate turned out to be an independent positive predictor of AIx and central BP measured 8 years later (Fig. 2). These findings suggest that heart rate reduction in the long run has a favorable effect and not a detrimental one on all parameters of arterial distensibility and contribute to explain why people with lower heart rate have a reduced risk of CV events and mortality in hypertension.

Fig. 2
figure 2

Relationship of baseline night-time heart rate with central systolic blood pressure and the augmentation index measured 8 years later in 346 participants from the HARVEST cohort. Adapted from Palatini P et al. [63•]. SBP indicates systolic blood pressure

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In summary, training-induced bradycardia may have an unfavorable effect on central hemodynamic due to the prolongation of ejection time so that the reflected wave may return in systole. On the other hand, improved small artery compliance and reduced peripheral resistance in athletes can decrease the magnitude of the reflected wave. The different combination of these effects can account for the discordant findings in previous literature. Differences in subject characteristics (age, cardiorespiratory fitness levels, etc.), study methodologies, and lack of adjustment for important confounding factors are other possible sources of between-study variability. Other mechanisms by which the reduction of the sympathetic tone associated with physical training can improve endothelial function and arterial elasticity are the decrease in peripheral vasoconstriction and the prevention of small artery remodeling with an increase in the lumen/wall ratio [64] and the cross-sectional area of the microcirculation [65]. Also, humoral factors may contribute to the beneficial effect of dynamic sport activities on small artery distensibility. Maeda et al. [66] after 8 weeks of exercise observed a reduction in endothelin-1 and an increase in nitric oxide concentrations with an inverse correlation between these two factors. Reductions of inflammatory cytokines and of oxidative stress are other mechanisms by which exercise can prevent AS in MetS [67].

Effect of Exercise on Arterial Distensibility in Subjects with the Metabolic Syndrome

From the above data, one can understand why physical activity may retard the development of AS in people with the MetS. Indeed, several cross-sectional studies have shown that exercise can have beneficial effects on arterial distensibility in this clinical condition. Within a group of participants with the MetS, Pasha et al. [68] observed that carotid β-stiffness index was lower in the individuals who performed regular physical activity than in those who were sedentary. In the former, the β-stiffness index was similar to that in a group of healthy individuals, indicating that physical activity may be effective in mitigating the adverse effects of high BP, visceral adiposity, and metabolic abnormalities on the vessel wall. In a similar study, Bohn and coworkers [69] explored the effect of different levels of physical activity (sedentary, light, moderate-to-vigorous), among 197 middle-age patients (116 without and 81 with MetS). Patients with MetS had higher PWV compared to patients without MetS (10.2 ± 1.9 vs 8.3 ± 1.5 m/s, p < 0.001). However, participants with MetS who were more sedentary showed significantly greater PWV than those who were more active and of people without MetS regardless of the level of physical activity [69].

The above cross-sectional data have been confirmed by intervention trials investigating the effects of exercise training in patients with MetS. The effect of 6 months of high-intensity aerobic interval training was explored by Mora-Rodriguez et al. [11••] in a group of patients with MetS having a high prevalence of hypertension. PWV declined in the training group from 8.5 ± 2.1 to 7.8 ± 2.3 m/s (p = 0.05), while it remained unchanged in a group of subjects of control. Similarly, AIx was reduced after training from 24.7 ± 11.6 to 21.9 ± 9.2% (p = 0.038), with no changes in the group that remained sedentary. These beneficial effects were partly explained by the reduction in BP and partly by the improvement of the endothelial function documented by a 20% significant increase in cutaneous microcirculation reactive flow after training [11••]. Similar results were obtained by Koskinen et al. [70] in a longitudinal analysis of the Young Finns Study. After 6 years of follow-up, participants with baseline MetS who performed regular physical activity and recovered from the MetS had higher carotid artery distensibility compared with MetS people who remained sedentary and still had the MetS at study end [70].

In summary, according to the evidence mentioned above, several mechanisms can explain the favorable effect of exercise on arterial distensibility in people with MetS (Fig. 3). Exercise can counterbalance many detrimental effects of MetS: one main mechanism is the reduction in heart rate. Opposite effects of exercise and MetS have been observed also on inflammatory cytokines. The same applies to humoral factors, such as nitric oxide, leptin, adiponectin, and reactive oxygen species, which have an important impact on the endothelial function and the arterial structure.

Fig. 3
figure 3

Mechanisms for the beneficial effect of regular aerobic exercise on arterial elasticity in the metabolic syndrome. For heart rate and inflammatory markers, the sign + indicates an increase and the sign − a decrease. For humoral factors and endothelial function, the sign + indicates a favorable effect and the sign − a detrimental effect

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Conclusions

Regular physical activity has shown beneficial effects in general populations and several clinical conditions and should thus be recommended to every subject for the prevention of CV disease. However, implementing a long-lasting program of physical training is a challenging task because of the low compliance to exercise shown by participants in long-term studies [11••, 70]. Thus, special attention should be paid by clinicians to people with MetS in whom the adverse effect of metabolic disturbances on the arteries can be offset by a program of physical activity. A number of studies have shown that in these patients, exercise can reduce body weight and BP and improve the metabolic profile with a beneficial effect on arterial elasticity. In addition, physical activity can counteract the pathogenetic mechanisms favoring the development of AS in MetS and thus represents one of the best tools for restoring arterial structure and function in patients with this clinical condition.