Aortic Stiffness in Aging and Hypertension: Prevention and Treatment with Habitual Aerobic Exercise

Abstract

Purpose of review:

Habitual aerobic exercise is associated with lower aortic stiffness, as measured by carotid-femoral pulse wave velocity (CFPWV), in middle-aged/older adults without hypertension but beneficial effects of aerobic exercise on CFPWV in hypertension remain unclear. Therefore, the focus of this review will discuss the evidence for and against the beneficial effects of aerobic exercise on aortic stiffness in middle-aged and older adults with hypertension, possible limitations in these studies, and highlight novel directions for future research.

Recent findings:

Most randomized, controlled intervention studies (4–26 weeks duration) demonstrate that short-term aerobic exercise results in no reductions in CFPWV in middle aged and/or older adults with treated or treatment-naïve hypertension. Higher aerobic fitness is not associated with lower aortic stiffness among older adults with treated hypertension.

Summary:

Aortic stiffness appears to be resistant to clinically relevant reductions in response to habitual aerobic exercise in the presence of hypertension.

INTRODUCTION

Arterial stiffness is a robust predictor of cardiovascular disease (CVD) events in adults independent of blood pressure (BP) and other CVD risk factors [1]. Specifically, aortic stiffness, as measured by the ‘reference standard’ carotid-femoral pulse wave velocity (CFPWV), predicts CVD events and mortality in healthy community-dwelling middle-aged and older adults [2–4], as well as in persons with hypertension [5–7] and chronic kidney disease [8]. Furthermore, recent evidence suggests that carotid artery stiffness also predicts total CVD events particularly incident stroke rather than coronary heart disease morbidity [9]. As a result, treating or preventing aging-related stiffening of the large elastic arteries (aorta and carotid arteries) have emerged as a novel target for both pharmacological and lifestyle interventions/modifications.

A major component of lifestyle interventions/modifications is aerobic exercise training or total daily physical activity. Habitual aerobic exercise and greater amounts of physical activity are associated with a plethora of cardiometabolic benefits that contribute in part to the reduced risk of CVD mortality observed compared with sedentary behavior [10]. However, improvement in conventional CVD risk factors such as lipids, adiposity and BP as well as hemostatic/inflammatory risk factors only account for ~60% of the CVD risk reduction observed as a result of greater levels of physical activity [11]. As such, almost 40% of the risk reduction must be attributed to other physiological mechanisms or unaccounted for lifestyle behaviors. One such physiological mechanism that is thought be involved is repeated bouts of elevated hemodynamic laminar blood flow and shear stress on the vascular wall as a result of elevations in cardiac output and blood pressure from frequent habitual exercise that leads to enhanced arterial endothelial function [12] and expansive arterial remodeling [13]. Indeed, self-report of higher amounts of ‘light’ daily physical activity is associated with lower CFPWV compared with lower amounts of ‘light’ physical activity in middle-aged adults, although the differences in CFPWV in this cohort might be explained by lower BP and lack of elevated cardiorespiratory fitness in the higher physical activity group [14]. Additionally, a large cross-sectional study demonstrated clearly that each additional hour/week of moderate/vigorous physical activity at baseline was associated with a smaller increase in CFPWV over the subsequent 5 years in the cross sectional study. In the same report, participants who increased their level of moderate/vigorous physical activity over 5 years from age 65 to 70 years had a significantly attenuated rise in CFPWV over that span in a longitudinal study [15]. Importantly, those persons who decreased their physical activity over the 5 years exhibited larger increases in CFPWV during the 5 year follow up, suggesting that becoming sedentary may promote aortic stiffening. Furthermore, the mean 5 year increase in CFPWV was less in those performing moderate/vigorous intensity physical activity (e.g., sports or cycling), whereas persons engaging in only mild physical activity (e.g., gardening, housework) did not demonstrate this effect. An unexpected finding was that persons sitting for leisure demonstrated slightly accelerated increase in 5 year CFPWV, in contrast to those sitting for their occupation or commuting surprisingly exhibited an attenuation of the 5 year increase in CFPWV perhaps. This authors suggested that the latter was possibly associated with more breaks and less unhealthy snacking compared with former (Figure 1).

Figure 1.

Five‐year change in carotid-femoral pulse wave velocity (CFPWV) between 2008/2009 and 2012/2013 for total and intensity (per 1 MET hr/week) of physical activity (per 1 hr/week) (Left panel) and sedentary time in 1997/1999 (per 1 hr/week) (Right panel). Model 1 values are adjusted for age, sex, ethnicity, and mean arterial pressure. Model 2 values are additionally adjusted for heart rate, body mass index, waist circumference, smoking, alcohol intake, total cholesterol concentrations, history of cardiovascular disease, diabetes mellitus and hypertension medication. Data are mean difference compared with average 5 year increase in CFPWV of 0.76 m/sec (95% CI 0.69, 0.83). (Adapted and modified from [15]).

These data are consistent with smaller cross-sectional and some prospective studies indicate that habitual aerobic exercise prevents the age-associated increase in large elastic artery stiffness in normotensive middle-aged and older adults [16–22]. In contrast, in middle-aged and older adults with treated or untreated hypertension data are less clear with some reporting modest changes [23–25] and others reporting no effect [22,26–28] of aerobic exercise training or higher fitness on aortic stiffness. Therefore, the focus of this review will discuss the evidence for and against the beneficial effects of exercise on aortic stiffness as measured by CFPWV in adults with hypertension. Because the dearth of studies over the past 2–3 years on this topic, the emphasis will first be on important epidemiology studies that characterize the relation between aortic stiffness and aging in the presence or absence of hypertension. Then, cross-sectional and prospective studies focused on effects of habitual aerobic exercise on aortic stiffness, with a few references to seminal studies using carotid stiffness and compliance as the primary outcomes. The review will limit studies to primarily aerobic exercise with a few references to resistance exercise in middle-aged and/or older persons without hypertension and then cohorts with treatment-naïve or treated hypertension.

Arterial Stiffness with Aging and Hypertension

Although the concept of aortic stiffening with advancing age had been known for decades, a seminal study in 1983 by Avolio et al. using Doppler acquired flow waveforms to compute aortic-femoral PWV in urban-dwelling adults in Beijing, China, a population known to have low cholesterol and low rates of atherosclerosis. The study sought to distinguish whether the age-related increase in aortic stiffness was a result of vascular wall medial degeneration from ‘natural aging’ or from age-associated atherosclerosis [29]. They reported that aortic stiffness increased 134% between birth and age 90 years despite the cohort having low cholesterol and low rates of atherosclerosis, but that aortic PWV was higher and increased at a greater rate than similar cohorts from Western countries with higher rates of atherosclerosis. The study was the first to argue against atherosclerosis as the primary mediator of aortic stiffening with advancing age, and suggested that age-related alterations in vascular media were a contributing mechanism and that higher aortic PWV values compared with Western cohorts is likely attributed to some dietary or environmental factor.

A follow up study in rural Chinese living in Guangzhou, a group with much lower rates of hypertension than urban Chinese in Beijing, demonstrated a marked attenuation in the age-related increase in aortic PWV compared with urban dwellers (83% vs. 135% from birth to age 90) and as well as blunted increase in limb arterial stiffness. Interestingly, even when matched for age and BP, rural Chinese had lower aortic stiffness than the urban cohort suggesting that additional factors other than just higher BP explained the elevated aortic PWV. Indeed, urban Chinese in Beijing had significantly higher rates of urinary sodium excretion consistent with the idea that higher dietary sodium consumption was likely not only contributing to higher rates of hypertension in urban dwellers despite the absence of atherosclerosis, but also possibly accelerated age-related changes in vascular media of the aorta either directly or indirectly [30]. Taken together, these two seminal studies established the basis that 1) arterial wall stiffening occurred more steeply in the aorta than in the limb arteries with advancing age, 2) stiffening of the aortic wall occurs with aging even in the absence of atherosclerosis and/or hypercholesterolemia, and 3) the age-related increase in aortic PWV is attenuated in populations with lower dietary sodium intake compared with urban dwellers independent of BP, suggesting that dietary and/or other lifestyle factors have profound effects on aortic aging in humans.

More recent studies using contemporary assessments of CFPWV by applanation tonometry extended the earlier studies revealing that the relation between advancing age and aortic stiffness was not linear across the lifespan as inferred by Avolio et al.[31–33]. Indeed, CFPWV increases monotonically up until age 50–60 years but then increases exponentially thereafter until into the 70’s and 80’s [32,34,35]. However, one of the limitations of these studies is that they are cross-sectional studies of individuals at a single point in time at different ages with no follow up. Fortunately, data from the Baltimore Longitudinal Study on Aging (BLAS) and the SardiNia longitudinal studies have provided much needed insight into the complicated relation between the longitudinal change in BP and aortic stiffness and aging [36,37]. The BLAS has elucidated several important findings related to the temporal changes in arterial stiffness with advancing age. First, the rate of increase in CFPWV rise monotonically up until age 50–60 and accelerates exponentially thereafter as previously described in Framingham, however, the BLAS revealed that the longitudinal rate of change in CFPWV after mid-life is steeper in men than women. Second, the rate of increase in CFPWV after age 60 for men with pre-hypertension (systolic BP 120–139 mmHg) or hypertension (systolic BP ≥140 mmHg) is steeper compared with men with normal systolic BP (systolic BP< 120 mmHg) in a dose response manner even after adjusting for use of antihypertensive medications [36]. In contrast, women with prehypertension and hypertension demonstrate similarly higher rate of change in CFPWV compared with women with normal systolic BP, but do not demonstrate the accelerated increase in CFPWV in the decades after midlife [36]. Taken together, these data reveal important influences of pre-hypertension and hypertension not only on the absolute levels of aortic stiffness but also on the accelerated age-related stiffening of the aorta at each level of clinical hypertension (normal, prehypertension, and hypertension) and important sex-differences that may have clinical implications for treatment of hypertension in older men and women.

However, the SardiNia longitudinal study revealed that the relation between aortic stiffness, BP and aging is more complicated than previously described. They found that there is a dissociation between the longitudinal rise in CFPWV and systolic BP and pulse pressure with aging in men. Interestingly, they revealed that the rate of increase in systolic BP and pulse pressure plateaus in the 7^th and 8^th decade despite continued rise in CFPWV in men. In contrast, the rate of increase in systolic BP and pulse pressure paralleled the rate of increase in CFPWV in women into the later decades without plateau suggesting a clear sex difference in the relation between stiffness and BP in older adults [37]. As such, these divergent findings underscore likely sex-differences in aortic remodeling with advancing age whereby accelerated aortic dilation occurs to a greater extent in men than women with aging that subsequently offsets the age-related wall stiffening leading to the observed plateau in systolic BP and pulse pressure in men but not women.

Exercise and Arterial Stiffness with Aging in Normotensive Adults

Vaitkevicius et al. (1993) was the first to report that aortic stiffness, measured by aortic PWV, was 26% lower in middle-aged/older normotensive men who had been performing vigorous aerobic exercise for multiple years (i.e., running) compared with sedentary age-matched peers despite no difference in systolic BP between groups [18]. Interestingly, aortic PWV among the endurance trained middle-aged/older men did not significantly differ from the young adults, suggesting that aerobic fitness (or habitual aerobic exercise to maintain fitness) blunted the age-related increase in aortic stiffness observed in sedentary adults. Moreover, the rate of oxygen consumption at maximal exercise (VO₂max), a physiological index of recent habitual aerobic exercise as well as genetic factors, was inversely related with aortic PWV in this cohort. In particular, the relation was strongest among the oldest participants (>70 years of age) implying that higher aerobic exercise capacity, or other factors associated with higher fitness, attenuates the age-related rise in aortic stiffness in normotensive men. Alternatively, lower aortic stiffness in the endurance trained men could be a physiologically or genetic determinant of higher aerobic fitness in select older men. Nevertheless, additional cross-sectional studies have verified that normotensive middle-aged/older men and women who engage in frequent moderate to vigorous aerobic exercise over multiple years (usually 5 or more) clearly exhibit lower stiffness of the aorta and carotid arteries compared with their age-matched sedentary peers [19–21,38–40]. Furthermore, these favorable alterations on stiffness are independent BP or other CVD risk factors that are also modified by habitual aerobic exercise suggesting direct beneficial effects of repetitive exercise bouts on the vascular wall.

Given the limitation with cross-sectional studies, an important question is whether aerobic exercise or physical activity initiated in previously sedentary middle-aged and older adults can modify the arterial stiffness without hypertension. Tanaka et al. (2000) first reported that a 3 month intervention of aerobic exercise (moderate to vigorous walking) in middle-aged men (mean 53 ± 2 years), 4–6 days a week for 45 minutes/day at 70–75% of maximal heart rate resulted in ~25% improvement in carotid artery compliance and 20% reduction in carotid β-stiffness, and that compliance and stiffness were no longer different from age-matched middle-aged/older endurance athletes but not back to levels of young adults [39]. Importantly, these improvements in carotid compliance occurred in the absence of changes in adiposity, BP, cholesterol or VO₂max suggesting that alterations in risk factors and fitness did not explain the improvements in carotid compliance/stiffness. Using a similar 3 month aerobic exercise intervention, carotid compliance was increased ~40% and β-stiffness reduced ~25% after 12 weeks in previously sedentary postmenopausal women back to levels of young premenopausal women [21]. Taken together, these studies support the idea the habitual aerobic exercise prevents the acceleration of age-associated reduction in carotid artery compliance (increase in stiffness) and moderate to vigorous aerobic exercise initiated in middle-aged/older adults can improve carotid compliance in men without hypertension and restore to young levels in women. The clinical significance of these data have become more relevant recently given a meta-analysis demonstrating that carotid artery stiffening is a significant predictor of CVD events including incident stroke [9]. Thus, interventions that can modify carotid artery stiffness may be a novel strategy to reduce stroke risk, however this has not been studied to date.

In contrast to studies on carotid compliance/stiffness, investigations on whether aerobic exercise initiated in middle-aged/older normotensive adults can modulate aortic stiffness remain controversial in part because of the small sample sizes, short duration of studies, and non-randomized designs of some of the studies. For example, Hayashi et al. reported that 4 months of walking 3–4 days/week at 75% heart rate reserve (moderate to vigorous intensity) for 45 min/day reduced CFPWV ~0.5 m/sec in normotensive middle-aged men (age 50 ± 3 years), in the absence of any change in leg PWV [41]. However, there was no time-control group and mean BP decreased ~3 mmHg in this study so it is unclear whether the small change in CFPWV is a true change in wall stiffness or simply a result of reduced distending BP. Similarly, a non-randomized study of 9 weeks of intermittent aerobic cycling (30 min including six 5 minute bouts of high/moderate intensity) 2 days/week in older men and women (age 66 ± 7 years), demonstrated a 0.6 m/sec reduction in CFPWV, but there was no control group and this change was abolished after adjusting for the concomitant decrease in BP [42]. Yoshizawa et al. randomized 35 middle-aged women (mean age ~47 years) to aerobic exercise, resistance exercise or control for 12 weeks [43]. Although the primary aim of the study was to determine if resistance exercise increased arterial stiffness, they found that CFPWV decreased ~0.4 m/sec after 12 weeks in the aerobic exercise group. However, this was not different than the resistance exercise or combination groups and not adjusted for the 3 mmHg decrease in mean BP. Thus, although the magnitude of change is similar to the non-randomized studies, the changes are small and not clearly different than control or independent of BP. Finally, Donley et al. found that 8 weeks of cycling exercise 3 days/week in middle-aged adults (mean age ~43 yrs) with obesity/metabolic syndrome resulted in a significant ~0.7 m/sec reduction in CFPWV compared with non-exercise metabolic syndrome controls that remained significant after adjustments for MAP. However, this reduction in CFPWV was not significantly different than non-metabolic syndrome/obese controls who also exercised and exhibited a 0.3 m/sec reduction in CFPWV [44]. Taken together, these studies reveal that short-term exercise interventions (e.g., 8–12 weeks) initiated in previously sedentary middle-aged and older adults without hypertension appear to have small or minimal effects in modulating aortic stiffness independent of changes in BP and that longer duration (> 3 months) interventions may be necessary to alter aortic stiffness.

In this regard, Oudegeest-Sander et al. (2013) performed one of the longest exercise interventions to date on aortic stiffness, which was a 12 month randomized-controlled study of aerobic exercise (cycling 3 days/week at 70–85% heart rate reserve) or control in combination with or without the advanced-glycation end product (AGE) cross-link breaker alagebrium of previously sedentary normotensive older adults (mean age 70 years) [45]. Surprisingly, a one year intervention of moderate/vigorous intensity cycling resulted in no change in CFPWV with or without the presence of the AGE-cross-link breaker (Figure 2) Although the 3 day exercise frequency or the actual intensity achieved (as opposed to greater frequency or intensity) may have contributed to the negative results, the exercise training group significantly increased VO₂max by 15% suggesting that the exercise stimulus was sufficient to improve cardiorespiratory fitness. Nevertheless, these data suggest that a prolonged aerobic exercise intervention up to 1 year in older normotensive men and women has no appreciable effect on aortic stiffness. In summary, the preponderance of the existing data suggest that small changes in aortic stiffness are possible (< 1 m/sec) after short-term aerobic exercise in middle-aged normotensive adults (age 40–60 yrs), but that aortic stiffness may become resistant to change in older adults (age >65 yrs) even up to one year of aerobic exercise. Future studies are still needed to determine whether longer (>1 year) aerobic exercise can lead to clinically relevant reductions in CFPWV (>1 m/sec) in middle-aged adults, and in older adults what the duration of training is (e.g. 2, 3 or 4 years) that starts to reverse aortic stiffness beyond 65–70 years of age. Furthermore, use of novel training strategies (e.g., interval training; combination aerobic/resistance exercise) or a combination of exercise and other lifestyle or dietary interventions that might act synergistically to alter stiffness of the aged aorta are also needed.

Figure 2.

Aortic stiffness measured by carotid-femoral pulse wave velocity (CFPWV) before and after 12 months of aerobic exercise training or sedentary time control in the presence of absence of the advanced glycation cross-linked breaker alagebrium (ALT711) or placebo in older normotensive healthy adults. There was no change in CFPWV after 12 months of exercise in presence of absence of alagebrium despite a 15% increase in cardiorespiratory fitness. (Adapted and modified from [45]).

Exercise for Treatment of Arterial Stiffness with Hypertension and Aging

Although several studies suggest that aortic stiffness precedes the development of hypertension [46,47], aortic stiffening is accelerated in the presence of hypertension consistent with a bidirectional relation between BP and stiffness [48]. Thus, whether initiating habitual aerobic exercise in middle-aged and/or older adults with hypertension will reduce BP subsequently leading to decreased aortic stiffness, or whether aortic stiffness can be decreased directly by exercise training resulting in lower BP is difficult to tease out. Nevertheless, results from studies on the effectiveness of aerobic exercise on aortic stiffness initiated in previously sedentary middle-aged or older adults with prehypertension or stage 1 hypertension have been disappointing [25–28,49](Table 1). For example, middle-aged older adults with stage 1 isolated systolic hypertension performed 8 weeks of moderate intensity (65% of heart rate reserve) cycling 3 days/week for 40 minutes per session in a small randomized, controlled cross-over study [27]. Despite a 13% increase in VO₂max after the exercise training, neither CFPWV, characteristic impedance nor BP were altered after this 2 month exercise program (Table 1). Similarly, Seals et al. (2001) randomized postmenopausal women with systolic prehypertension or stage I hypertension to moderate intensity aerobic exercise (walking 5–6 days/week for 40 minutes/day at 70% maximal heart rate) or dietary sodium intake restriction (~1200 mg/day reduction) for 12 weeks [26]. They found that the exercise intervention had no effect on aortic PWV and 24-hour ambulatory BP despite small but significant decreases in casual systolic BP (e.g., −5 mmHg). Interestingly, moderate sodium restriction in the control group for 3 months significantly lowered aortic PWV by ~1.2 m/sec which was strongly correlated with a significant reduction in casual (−16 mmHg) and ambulatory (−7 mmHg) systolic BP. Thus, these data suggested that modest sodium restriction was a more potent stimulus for lowering aortic stiffness than daily aerobic exercise in older women (Table 1). Lastly, in a randomized, controlled trial of middle-aged and older adults with treatment-naïve stage I systolic or diastolic hypertension, 6 months of combined aerobic and resistance exercise (3 days/week; 45 min aerobic and 15 min resistance exercise) had no appreciable effect on aortic stiffness compared with usual care controls, despite a small decrease in diastolic BP in the exercise group [28](Table 1). Taken together, these small but well-designed randomized, controlled studies confirm that aortic stiffness appears to be resistant to change in response to short-term aerobic exercise interventions among middle-aged and older adults with pre- or stage 1 hypertension. Additional studies are needed using aerobic exercise in combination with select antihypertensive drugs that might act synergistically to modify aortic stiffness in older adults with hypertension. Moreover, length of exposure to hypertension (or time since diagnosis) and duration of anti-hypertensive treatment (if treated) in these studies should be considered as these might be critical factors that influence any effectiveness of exercise and medications on aortic stiffness.

Table 1:

Randomized, controlled studies of effects of continuous aerobic exercise training in middle-aged and/or older adults with pre-hypertension and hypertension on carotid-femoral pulse wave velocity

						Aerobic exercise program					Pre-CFPWV (m/sec)	Post-CFPWV (m/sec)
Study (year)	n (male/female)	Age	Pre HTN or HTN	Anti-HTN meds?	Control group	Frequency (days/week)	Duration/session (min	Intensity	Duration (weeks)	%ΔV02max			ΔCFPWV	P<0.05
Ferrier et al. (2001)	20 (10/10)	64 ± 7	Stage 1 HTN	No	Sedentary (n=20)	3	40	65% HRR	8	13%	11.5 ± 2.8	11.5 ± 1.9	0	No
Seals et al. (2001)	14 (14/0)	62 ± 9	PreHTN/Stage 1 HTN	No	Na+ restriction (n=11)	5.8 ± 1.1	40 ± 4	70% HRmax	12	5.2%	8.8 ± 2.9	8.7± 1.9	−0.15	No
Stewart et al. (2005)	40 (21/19)	63 (62, 65)	PreHTN/Stage 1 HTN	No	Sedentary (n=53)	3	45	60–90% HRmax	26	16.4%	9.0 (8.2, 9.9)	10.1 (7.9, 12.6)	1.1	No
Collier et al. (2008)	15 (10/5)	50 ± 2	PreHTN/Stage 1 HTN	No	RT (n=15)	3	30	65%V02peak	4	n/a	12.1±3.1	11.1 ± 3.1	−1.0	Yes
Guimaraes et al. (2010)	16 (9/7)	50 ± 8	Stage 1 HTN controlled	Yes	Interval (n=26), Sed (n=13)	3	40	60% HRR	16	n/a	10.2 ± 1.2	n/a	~0	No
Madden et al. (2013)	25 (13/12)	69 ± 5	HTN (+T2DM & dyslipidemia)	Yes	Sedentary (n=27)	3	40	60–75% HRR	24	14.0%	13.4 ± 3.5	12.2 ± 3.6	−1.2	No

Data are mean ± SD or (95% CI); HTN, hypertension; Hrmax, heart rate maximum; HRR, heart rate reserve; CFPWV, carotid-femoral pulse wave velocity; RT, resistance training

One unresolved question is whether the lack of improvements in aortic stiffness with aerobic exercise in middle-aged and/or older adults with hypertension related to the short intervention duration or perhaps the small increase in aerobic fitness (e.g., VO₂max). In this regard, Kraft et al. [22] investigated whether higher VO₂max was associated with lower aortic stiffness among healthy adults with hypertension in a cross-sectional study. As expected, they found that aortic PWV measured by MRI of the descending thoracic aorta was higher in adults with hypertension compared with clinically normal BP, but surprisingly that aortic PWV in the hypertensive adults did not differ between high and low fit patients. In contrast, aortic PWV was lower in the high fit compared with low fit normotensive adults, thus suggesting that higher aerobic fitness only modified aortic stiffness when hypertension was not present (Figure 3). Consistent with this, VO₂max was only inversely correlated with aortic PWV in the normotensive and not the hypertensive participants, and this was the same in both young and older (age >50 years) persons. Furthermore, although treated hypertensives had lower systolic and diastolic BPs than treatment naive participants matched for age and body mass index, there was no difference in aortic PWV (Figure 3). These data suggest that the BP reductions in the treated adults were not as a result from lower aortic stiffness, which is not surprising given that current antihypertensive drugs do not target wall stiffness of large arteries.

Figure 3.

Aortic pulse wave velocity (PWV) in normotensive and hypertensive adults stratified by cardiorespiratory fitness status (unfit vs. fit) indicate that high maximal aerobic capacity does not attenuate aortic stiffness in middle-aged adults with hypertension (Left panel). Aortic PWV between antihypertensive medication-treated and untreated adults suggest that there is no difference in aortic stiffness despite lower blood pressure in the treated group (Right panel). (Adapted from and modified from [22]).

In contrast to individuals with hypertension only, in older adults (mean age 69 years) with hypertension plus multiple cardiometabolic risk factors including type 2 diabetes and hyperlipidemia, short-term interventions (3 months) appear to be beneficial in reducing CFPWV [49,50], but longer training appears to result in a loss of the aortic benefits in these high risk persons [49]. Madden et al. found that 3 months of vigorous aerobic exercise (60–75% heart rate reserve, 3 days/week for 60 min) resulted in a large ~23% reduction in CFPWV (~3 m/sec), however, these robust reductions were not sustained after 6 months of training [49] (Table 1). The 10 mmHg decrease in systolic BP in the exercise group that accompanied the change in CFPWV in the first 3 months was not adjusted for so this could have explained at least part of the decrease in stiffness. Surprisingly, with an additional 4 mmHg reduction in systolic BP at 6 months CFPWV improvements were lost despite the further decrease in BP and sustained increases in cardiorespiratory fitness (i.e., VO₂max) at 6 months. Thus, these data suggest that alterations in aortic stiffness in response to prolonged aerobic exercise in older adults with multiple cardiometabolic risk factors may be resistant to change and dissociated with improvements in aerobic fitness and reductions in BP.

Several groups have used alternative exercise strategies and modalities such as interval aerobic training or resistance exercise training in middle-aged adults with treated or non-treated hypertension effective to evaluate for effectiveness in lowering aortic stiffness. Guimarães et al. randomized middle-aged adults (average age ~48 years) with treated hypertension to 40 minutes of interval training (alternating 50% for 2 min and 80% heart rate reserve for 1 min), continuous training (60% of heart rate reserve) or non-exercise control of treadmill walking/jogging for 16 weeks (Table 1). They found that 16 weeks of interval training resulted in small but significant reductions in CFPWV (−0.4 m/sec) compared with no change in CFPWV in the continuous or control groups. This occurred in the absence of any significant reductions in 24-hour ambulatory BP in the interval training group. Thus, it appears that the short bursts of higher intensity achieved by interval exercise training may have modified aortic stiffness more than the continuous training. However, the lack of reporting on the actual exercise volume achieved (e.g., average intensity, duration per session) between groups makes it difficult to compare whether the groups were matched in this respect but this study still provides motivation to further explore interval training as a possible novel strategy for treatment-resistant aortic stiffness.

Related to resistance exercise, Collier et al. found that 4 weeks of aerobic exercise reduced CFPWV by ~1 m/sec (3 days/week; 65% VO₂max) in middle-aged adults (mean age 48 years) with pre-hypertension or untreated stage I hypertension (Table 1). This was accompanied by a concomitant 5 mmHg decrease in systolic BP and increase in peak vasodilation in peripheral forearm arteries [24]. In contrast, persons randomized to 4 weeks of resistance exercise appeared to have a 1 m/sec increase in CFPWV, despite a similar 4 mmHg reduction in systolic BP and increase in peripheral vasodilation as in the aerobic exercise group. Therefore, this study suggests that both moderate intensity aerobic and resistance exercise effectively reduce BP, but only aerobic exercise (not resistance exercise) may have beneficial effects on aortic stiffness in middle-aged adults with treatment naïve pre- and stage 1 hypertension. The reasons for this divergent effects on BP and aortic stiffness with resistance exercise are unclear but may be related to enhanced sympathetic nerve activity from resistance exercise [51] leading to enhanced α-adrenergic vasoconstrictor tone of the aorta and large muscular arteries because there is evidence that sympathetic nerve activity and CFPWW are associated [52]. In turn, vasodilatory mechanisms in the small resistance arteries (e.g., nitric oxide bioavailability) that regulate BP may have “lysed” the α-adrenergic vasoconstrictor tone leading to reduced BP. This is important because several earlier studies reported that high intensity resistance exercise training for 3–4 months increased aortic stiffness and reduced carotid compliance in young normotensive men and women [53,54]. However, more recent studies demonstrate that 12 weeks of moderate intensity resistance exercise 3 days/week does not negatively alter aortic stiffness in young [55] or older normotensive adults [56]. Nonetheless, further research is needed on the effects of resistance exercise on aortic stiffness in middle-aged and/or older adults with hypertension so that the numerous health benefits of resistance exercise for older adults can be safely attained.

Conclusions

Aerobic exercise training and physical activity are associated with a plethora of cardiometabolic benefits that contribute at least in part to the reduction in CVD events in middle-aged and older adults. However, other mechanisms likely contribute to the decreased CVD risk beyond conventional CVD risk factors. Middle-aged and older adults who have been engaging in moderate/vigorous aerobic exercise/physical activity for more than one year (and more than 5 years in many studies) and have not developed hypertension clearly demonstrate an attenuation in the age-related rise in aortic stiffness. It is possible that the habitual exercise has starved off the development of isolated systolic hypertension in these persons as a result of tempering age-related aortic stiffening, or alternatively that the lack of hypertension from exercise for other reasons permitted potentiated the exercise-associated attenuation of elevated aortic stiffness with advancing age. However, initiating aerobic exercise in middle-aged and older adults results in only modest or minimal reductions in aortic stiffness, and is more likely to occur if BP is reduced concomitantly. In contrast, when hypertension is present most short term studies (4–26 weeks) suggest that aortic stiffness is resistant to change. Therefore, future studies of aerobic exercise training studies >6–12 months in duration in middle-aged and older adults with hypertension to determine if aortic stiffness is indeed modifiable at 1 year and beyond. However, given the challenges in completing such long studies in humans, shorter term studies combining exercise with select anti-hypertensive drugs or with novel anti-inflammatory drugs [57] and nutraceutical compounds [58–60] that have appear to modify aortic stiffness in aging animal models might be a novel approach to fight the a potential future epidemic of aortic stiffness-related hypertensive diseases in our aging population.