Abstract
Background: Aortic stiffness, quantified by carotid-femoral pulse wave velocity (PWV), is a strong predictor of cardiovascular disease events. In general, dynamic “aerobic” exercise training performed regularly for many years in middle and older age is associated with an attenuated or absence of an age-related increase in aortic stiffness without hypertension. However, cross-sectional studies can be confounded by physiological or lifestyle factors that may contribute in part to the lower aortic stiffness observed, and prospective interventions are often limited by short duration and inadequate exercise frequency to have clinical benefit. Therefore, this review will discuss the evidence for the de-stiffening effects of regular, dynamic aerobic exercise training on aortic stiffness in the presence or absence of hypertension with some discussion on high-intensity interval training (HIIT). Summary: Short-term (3–12 months) aerobic exercise interventions, 2–3 days per week initiated in middle age or older age without hypertension, result in small decreases in carotid-femoral PWV that is likely the result of reductions in distending pressure (i.e., mean arterial pressure) rather than an alteration in structural wall properties. However, cross-sectional data indicate that 4–5 days/week appears to be the minimal frequency that is obligatory for de-stiffening of the aorta among adults who perform regular exercise in middle age and continue into older age. Despite greater improvements in aerobic fitness by high-intensity interval training (HIIT), short-term HIIT 4 days/week does not provide any benefit over moderate-intensity continuous training for de-stiffening the aorta among older adults with or without hypertension. Key Messages: Short-term aerobic exercise interventions 2–3 days/week at moderate intensity initiated in middle age or older age have small or no favorable blood pressure-independent effect on aortic wall stiffness. In contrast, 4–5 days/week appears to be the minimal obligatory dose of aerobic exercise to have some de-stiffening effects if performed during middle age and continuing into older age. Short-term HIIT provides no greater de-stiffening effects on the aged aorta than continuous aerobic exercise training.
Introduction
The aorta stiffens with advancing age resulting in a loss of physiological damping of pulsatile pressure and flow (i.e., “Windkessel effect”) that leads to elevated pulse pressure as a result of a rise in systolic and decline in diastolic blood pressure beyond the 6th decade of life [1‒3]. Aortic stiffness, quantified by the reference standard measurement carotid-femoral pulse wave velocity (PWV), is a robust predictor of cardiovascular disease (CVD) events and death, even after adjusting for traditional CVD risk factors including the presence of hypertension [4, 5]. Indeed, a 1 m/s increase in carotid-femoral PWV is associated with a 14–15% higher relative risk of CVD events and CVD death and, importantly, reclassifies 10-year CVD risk in younger adults at intermediate risk [4, 6]. Consistent with the relation between age-related aortic stiffness and CVD risk, pulse pressure and systolic blood pressure are also robust predictors of CVD risk after age 60, while diastolic pressure is inversely related to CVD risk [1, 7]. In addition to CVD events, downstream consequences of raised pulse pressure in larger conduit arteries are that this augmented pressure energy is transmitted into the small microvasculature of high-flow, low-resistance organs such as the brain, kidney, heart, and retina [8‒10]. As such, both high aortic stiffness and/or pulse pressure are associated with end-organ clinical sequelae including impaired cognitive function [11‒14], greater subcortical white matter damage (hyperintensities on MRI), and cortical atrophy [12‒15]; lower renal glomerular filtration rate and higher incidence and progression of chronic kidney disease [16‒18]; and larger retinal arteriole narrowing and more flow pulsatility [19, 20]. Interestingly, end-organ microvascular damage and remodeling in turn have a reciprocal effect on raising mean arterial pressure (MAP) via increased vascular resistance that subsequently promotes accelerated aortic stiffening [10]. Although the origination of this bidirectional, feed-forward relation is unclear, aortic stiffness appears to precede the development of hypertension with older age [21, 22], suggesting that age-related aortic stiffening may be a cause of isolated systolic hypertension (characterized by high systolic and pulse pressure and low diastolic blood pressure) rather than a hemodynamic consequence.
In general, dynamic, large muscle group, “aerobic” or “endurance” type exercise training performed regularly for many years in middle and older age is associated with attenuated or absence of age-related aortic stiffness when hypertension is not present [23]. However, these cross-sectional studies can be confounded by non-exercise physiological (e.g., genetics, lower adiposity) or lifestyle (e.g., healthier diet, low sodium) factors that may explain part of the lower aortic stiffness observed among aerobically active older adults. The effectiveness of aerobic exercise intervention studies on de-stiffening the aorta in previously inactive older adults is mixed because of differences in frequency, intensity, and duration of exercise bouts employed, whether hypertension is present or not, if studies use continuous moderate- or high-intensity interval training (HIIT), and consideration (or lack thereof) of concomitant decreases in MAP or distending pressure. Therefore, this review will discuss the evidence for the de-stiffening effects of regular, dynamic large muscle group aerobic exercise training on aortic stiffness quantified by Doppler flow or arterial pressure waveforms acquired and calculated as aortic arch to femoral, or carotid to femoral, PWV among older adults. This review will not include brachial-ankle, CAVI, or other regional expressions of PWV, or local compliance, stiffness, or distensibility of the carotid artery. Additionally, the focus will include the modulating role of the presence or absence of hypertension, whether training-related changes in blood pressure are accounted for in interpreting aortic stiffness alterations in cross-sectional and intervention studies, and if the purported superior benefits of HIIT exercise over moderate-intensity continuous aerobic exercise training for aerobic fitness extend to de-stiffening the aorta in aged adults.
Aortic Stiffness and Regular Aerobic Exercise among Aged Adults without Hypertension
Most cross-sectional studies compare older adults without clinically diagnosed hypertension who have been carrying out moderate and/or vigorous regular aerobic exercise five or more days per week to aerobically inactive or sedentary age- and sex-matched adults. In general, these studies report a complete or some prevention of age-related aortic stiffness in both older men [24, 25] and postmenopausal women [26]. For example, Vaitkevicius et al. [24] reported that aortic PWV was significantly lower among older adults (men and women) who had been performing moderate and/or vigorous aerobic exercise for many years compared with aerobically inactive or sedentary adults of similar age. In addition, there was no difference in aortic PWV between the aerobically active older and younger adults, indicating that regular moderate-to-vigorous aerobic exercise and/or high aerobic fitness (quantified by rate of oxygen consumption at maximal exercise, VO2max) related in part to the regular exercise abolished the age-related increase in aortic stiffness among aerobically inactive older adults. Furthermore, higher aerobic fitness was inversely associated with lower aortic PWV. In a similar study of 53 postmenopausal women, Tanaka et al. [26] studied aerobically active postmenopausal women (average age 59 years) and young premenopausal women (average age 31 years) who ran on average 6 h/week and competed in competitive endurance races for at least 2 years or more (mean 13 years). They compared these active women to aerobically inactive age-matched postmenopausal and young women. They found that the age-related higher aortic stiffness observed among the older aerobically inactive women compared with young inactive women (despite no differences in MAP) was completely absent in the older aerobically active women. Interestingly, despite an 8 mm Hg higher MAP, greater body fat percentage, and lower exercise VO2max in the older aerobically active compared with the young aerobically active women, there was no difference in aortic stiffness between these groups. These data suggest a primary effect of aging on aortic stiffness in the absence of higher blood pressure and that regular aerobic exercise abolished the age-related higher aortic stiffness among postmenopausal women even in the presence of CVD risk factors and lower aerobic fitness. In summary, these data indicate that regular moderate-to-vigorous aerobic exercise in middle and older age prevents the age-related increase in aortic stiffness among older men and postmenopausal women who have no clinical hypertension. However, it cannot be ruled out that other accompanying physiological factors associated with high aerobic fitness (e.g., genetics, higher fat-free mass, lower adiposity) or healthy lifestyle behaviors (e.g., low sodium diet, better sleep habits) in older aerobically active adults may contribute in part to the de-stiffening effects associated with multiple years of regular aerobic exercise.
Because of the known limitations of cross-sectional studies, prospective, intervention studies (preferably randomized, controlled) among previously inactive older adults are needed to test the potential effects of regular exercise to reverse or decrease aortic stiffness. However, prospective intervention trials have been inconsistent likely because the studies differ in frequency, intensity, and exercise mode, have been limited by modest sample sizes, absence of control groups, lack of randomization, and/or consist of short-duration interventions (2–6 months) [27‒29] (see Fig. 1). Importantly, many studies do not adjust for decreases in distending pressure (e.g., MAP) as a result of the exercise intervention, making interpretation of changes in aortic wall stiffness properties difficult. For example, 4 months of walking or jogging reduced carotid-femoral PWV −0.5 m/s among middle-aged men without hypertension; however, the lack of adjustment for the small but significant decrease (−3 mm Hg) in MAP and lack of a randomized, attention-time control group make it challenging to conclude that the reported changes in carotid-femoral PWV were mediated by reductions in arterial wall stiffness rather than just as a result of reductions in distending pressure [27]. In another study, among thirty-five middle-aged women who were assigned to resistance exercise, aerobic exercise, or a non-exercise control group in a randomized design for 3 months, the women in the aerobic exercise reported a −0.4 m/s decrease in carotid-femoral PWV accompanied by a 9% increase in VO2max, while no changes in carotid-femoral PWV were observed in the resistance exercise or non-exercise time control group. Notably, the small reduction in carotid-femoral PWV was not adjusted for the −3 mm Hg lowering in MAP that, in turn, was quantitatively not more than the decrease in the resistance exercise group, indicating that the decrease in distending pressure rather than the aortic wall stiffness properties likely explains the findings [28]. Lastly, forty-eight aerobically inactive older adults were assigned to 12 months of aerobic exercise or a non-exercise control group in combination with or without the drug alagebrium (cross-link breaker) in a randomized, controlled trial [29]. Despite a 15% increase in aerobic fitness, carotid-femoral PWV did not change after 12 months of aerobic exercise alone or with alagebrium. Thus, it is plausible that the total dose of aerobic exercise required to increase aerobic fitness is lower than what is required to favorably de-stiffen the aorta, or that aortic stiffness may not be amenable to change among older adults without hypertension. Alternatively, more than three exercise sessions per week and/or a duration longer than 1 year may be necessary to cause clinically significant decreases in aortic stiffness among previously aerobically inactive aged adults. In summary, short-term (2–6 months) aerobic exercise interventions among older or middle-aged adults without clinical hypertension result in no changes or small decreases in carotid-femoral PWV that are likely in part because of decreases in distending pressure (i.e., MAP) leading to lower load-dependent aortic stiffness, and even longer (12 months) aerobic exercise at a frequency of 3 days/week has little effect (see Fig. 1). Considering the data for both cross-sectional and intervention studies, it is likely that a longer duration than 12 months with a frequency of more than 3 times per week of aerobic exercise is obligatory to de-stiffen the aorta among aged adults.
Summary of four short-term aerobic exercise interventions 3–12 months, 2–3 days/week on carotid-femoral PWV (aortic stiffness) among older adults without hypertension [27‒30].
Summary of four short-term aerobic exercise interventions 3–12 months, 2–3 days/week on carotid-femoral PWV (aortic stiffness) among older adults without hypertension [27‒30].
One cross-sectional study does provide some insight into the question of the frequency or “dose” of aerobic exercise per week required to de-stiffen the aorta in older adults [31]. While acknowledging the aforementioned limitations of cross-sectional studies, Shibata et al. [31] investigated the question of frequency of exercise per week in a cohort of older adults who had performed aerobic exercise training for at least the previous 20 years at a consistent frequency. Participants were stratified and named “sedentary,” “casual exercisers,” “committed exercisers,” or “Master’s athletes” based on self-reported frequency of performing moderate-to-vigorous aerobic exercise over at least the past 20 years: <2 days per week (“sedentary”), 2–3 days per week (“casual exercisers”), 4–5 days per week (“committed exercisers”), and 6–7 days per week (“Master’s athletes”). Results showed that carotid-femoral PWV was lower in the “Master’s athletes” and “committed exercisers” compared with “casual exercisers” and “sedentary” older adults, but the carotid-femoral PWV did not differ between “Master’s athletes” and “committed exercisers.” Thus, these data suggest that a frequency of at least 4–5 days per week was required to achieve some de-stiffening benefits on the aorta from regular aerobic exercise and that there was no additional de-stiffening benefits with 6–7 days per week.
Aortic Stiffness and Regular Aerobic Exercise among Aged Adults with Hypertension
Hypertension increases with advancing age, with isolated systolic hypertension becoming the predominant phenotype of hypertension beyond age 60 years compared with diastolic hypertension or systolic/diastolic hypertension before middle age [6]. Hypertension is associated with greater aortic stiffness [32], but somewhat underappreciated is that the presence of hypertension accelerates the rate of increase of stiffening of the aorta with aging even when statistically controlling for the use of antihypertensive therapy [33]. However, the presence of elevated aortic stiffness may precede the onset of hypertension, thus indicating that aortic stiffness may be causal in the development of hypertension rather than a consequence [21, 22]. Thus, the bidirectional nature of the relation between aortic stiffness and hypertension makes interpreting the cause and effect of exercise interventions difficult. As such, aerobic exercise initiated by inactive older adults with hypertension could theoretically lead to reductions in blood pressure that subsequently result in decreased aortic stiffness, or alternatively, direct effects of aerobic exercise that de-stiffen the aortic wall could subsequently reduce blood pressure. As such, prospective studies that initiate regular aerobic exercise training in older adults with hypertension, whether treatment naïve or on antihypertensive medications, have largely been ineffective in altering aortic stiffness with a few exceptions [23]. For example, ten older adults with stage I systolic hypertension (untreated) were assigned to 2 months of moderate-intensity cycling exercise or 8 weeks of sedentary activity in a randomized, cross-over design [34]. Compared with an age-matched control group of adults without hypertension, at baseline, the group with hypertension had significantly higher blood pressure, aortic characteristic impedance, carotid-femoral PWV, and lower systemic arterial compliance. In the hypertension group, cycling exercise training resulted in no change in aortic stiffness or aortic characteristic impedance despite a 13% increase in aerobic fitness (i.e.,VO2max), suggesting that aortic wall stiffness properties are resistant to change among older adults with diagnosed hypertension. In another study, thirty-five healthy postmenopausal women with systolic hypertension demonstrated no change in 24-h ambulatory systolic BP or carotid-femoral PWV after 12 weeks of moderate-intensity walking 5 days per week compared with moderate dietary sodium restriction (decrease in 1,200 mg/day sodium intake) [35]. In contrast, a significant decrease in carotid-femoral PWV was associated with a reduction in 24-h ambulatory systolic BP after 3 months of sodium restriction. These data suggest that among postmenopausal women with untreated pre- or stage I hypertension, 3 months of regular aerobic exercise, 5 days per week, has little or no effect on aortic wall stiffness, but moderate sodium restriction does appear to have some beneficial de-stiffening effect on age-related aortic stiffness.
In a similar but longer duration study, older adults with stage I systolic or diastolic hypertension who were not treated were randomized to either combined aerobic and resistance exercise training (n = 51) or usual care control (n = 53) 3 days/week for 6 months [36]. Despite a 16% increase in VO2max after 6 months of exercise compared with the control group, there was no significant change in aortic stiffness. Lastly, among twenty-one older women (one-half on antihypertensive medication) who completed a 6-month walking exercise program 2 sessions per week [37], carotid-femoral PWV was decreased −0.75 m/s, even after adjusting for reductions in MAP. Notably, the majority of the reduction was explained by the women with hypertension because they demonstrated a greater reduction in carotid-femoral PWV (−1.3 m/s) compared with the women with clinically normal BP (−0.4 m/s). However, the lack of information related to the timing of taking their antihypertensive medication, the absence of a randomized control group, unknown dosing of medication, and the small sample size make the interpretation of the overall effects of this aerobic exercise intervention challenging. Taken together, the majority of the randomized intervention studies suggest that regular aerobic exercise training (i.e., walking/jogging or cycling) has small or no favorable effects on de-stiffening the aorta among older adults with untreated or treated hypertension.
As noted, aerobic exercise intervention studies among older adults with hypertension frequently result in minor or no alterations in aerobic fitness indicating that a larger exercise stimulus may be required to increase VO2max to a greater extent to favorably alter aortic stiffness. Yet, a cross-sectional study [38] reported that aortic stiffness (via MRI-based measurements of PWV) was not different between a group of middle-aged adults with hypertension who were stratified by high and low aerobic fitness. In contrast, in the absence of hypertension the “high fitness” adults had lower aortic stiffness as expected compared with “low aerobic fitness” adults. In agreement with these results, aortic PWV was associated with VO2max only among the group without hypertension. Moreover, this finding remained for both younger (age <50 years) and middle-aged and older (age ≥50 years) adults indicating that aortic stiffness was not altered by the level of aerobic fitness in the presence of hypertension. Furthermore, the adults who were treated with antihypertensive therapy exhibited lower blood pressure compared with the adults not treated as expected, but the groups did not differ in aortic PWV. In summary, although a cross-sectional design, these findings indicate that lower blood pressure from ongoing antihypertensive treatment did not necessarily modify the wall stiffness of the aorta.
Aortic Stiffness and High-Intensity Interval Training among Aged Adults with and without Hypertension
Some studies in older adults with hypertension have employed HIIT in an attempt to raise aerobic fitness to a greater extent than continuous training interventions and potentially overcome the lack of effectiveness of continuous aerobic exercise training in modifying aortic stiffness in many studies (see Fig. 2). In a non-randomized, noncontrolled study, 71 older adults (mean age 64.6 years) with and without hypertension (38% hypertension; 8% diabetes) initiated 9 weeks of aerobic interval-type exercise training on the cycle ergometer (2 days per week; 30 min per session; six 5-min bouts: 4 min moderate/1 min 90% max) that resulted in ∼20% increase in VO2max and subsequently a −0.6 m/s decrease in carotid-femoral PWV [39]. However, after adjusting for a significant ∼7 mm Hg reduction in MAP, the decrease in carotid-femoral PWV was abolished suggesting that the small change in aortic stiffness was largely explained by the reductions in distending pressure (i.e., MAP).
Effects of 8 weeks of high-intensity interval training (HIIT), moderate-intensity isocaloric continuous training (MICT) at 70% peak heart rate, or control (CON) in a randomized, controlled intervention study in older adults on carotid-femoral pulse wave velocity (PWV). HIIT protocol was 4 × 4 at 90% peak heart rate, 3 × 3 active recovery at 70% peak heart rate. HIIT resulted in a 12% increase in VO2peak compared with no change in MICT or control. There were no changes in blood pressure in either MICT or HIIT groups. Caloric expenditure matched between MICT versus HIIT groups. MICT resulted in a small but significant decrease in carotid-femoral PWV, whereas HIIT and CON resulted in no change in carotid-femoral PWV after 8 weeks [40].
Effects of 8 weeks of high-intensity interval training (HIIT), moderate-intensity isocaloric continuous training (MICT) at 70% peak heart rate, or control (CON) in a randomized, controlled intervention study in older adults on carotid-femoral pulse wave velocity (PWV). HIIT protocol was 4 × 4 at 90% peak heart rate, 3 × 3 active recovery at 70% peak heart rate. HIIT resulted in a 12% increase in VO2peak compared with no change in MICT or control. There were no changes in blood pressure in either MICT or HIIT groups. Caloric expenditure matched between MICT versus HIIT groups. MICT resulted in a small but significant decrease in carotid-femoral PWV, whereas HIIT and CON resulted in no change in carotid-femoral PWV after 8 weeks [40].
In another study, Kim et al. [40] randomized 49 older adults (34% on antihypertensive medications) to 3 groups: (1) HIIT, (2) moderate-intensity continuous training, or (3) non-exercise control for 8 weeks. HIIT consisted of 4 days/week of 40 min of 4 min of 90% maximal heart rate (4 times) interspersed with 3 min active recovery at 70% maximal heart rate (3 times) while isocaloric moderate-intensity continuous training for 47 min at 70% maximal heart rate. Of note, both exercise groups performed all-extremity (arms and legs) seated upright cycle ergometry. Surprisingly, carotid-femoral PWV was reduced −0.5 m/s in the moderate-intensity continuous group after 8 weeks, in the absence of any changes in carotid-femoral PWV in the HIIT or control group. As expected, VO2max increased in the HIIT group to a greater extent than the other two groups. Because VO2max increased +16% in the HIIT group without any change in VO2max in the moderate-intensity continuous training group, this indicated that the change in aerobic fitness did not explain the divergent changes in carotid-femoral PWV between HITT and continuous training. Although blood pressure, adiposity, and other cardiometabolic risk factors did not change in either group, the duration of each moderate-intensity continuous training session was slightly longer than the HIIT group to match the high caloric expenditure of the HIIT sessions. Thus, one explanation of these results is that longer duration or greater acute increases in blood pressure and/or sympathetic tone during HIIT sessions counteracted any beneficial effects of the exercise on aortic stiffness, but this hypothesis could not be confirmed in this study. Nonetheless, these studies, especially the well-designed, controlled exercise intervention study by Kim et al. [40], indicate that short-term HIIT aerobic exercise interventions do not provide any obvious benefit over moderate-intensity continuous training for de-stiffening the aorta among older adults with and without hypertension. Additional studies of longer duration and other exercise modalities using HIIT versus continuous training might provide additional insight into whether HIIT provides any greater benefit than continuous training or not.
Overall Summary of Findings
The evidence for the de-stiffening effects of regular, dynamic large muscle group aerobic exercise training on aortic stiffness among older adults is mixed. Cross-sectional studies indicate that regular moderate-to-vigorous aerobic exercise in middle and older age prevents the age-related increase in aortic stiffness in older men and postmenopausal women in the absence of hypertension. However, other favorable physiological factors associated with regular aerobic exercise such as high aerobic fitness, genetics, body composition, and/or healthy lifestyle behaviors in older aerobically active adults possibly contribute in part to the direct de-stiffening effects associated with multiple years of regular aerobic exercise. Because short-duration (8 weeks–12 months) aerobic exercise intervention studies show minimal or no blood pressure-independent effects on aortic stiffness [27‒30], a longer duration than 12 months with a frequency of > 3 day per week frequency of exercise is likely necessary to de-stiffen the aorta among aged adults. This is supported by cross-sectional data of older adults who have performed regular moderate-to-vigorous aerobic exercise for the previous 25 years in that 4–5 days per week appears to be the minimal frequency that is required to achieve the de-stiffening benefits on the aorta with no added benefit of 6–7 days per week. Importantly, this assumes that this level of regular aerobic exercise training starts before middle age (<60 years of age) and continues into older age in the absence of the development of hypertension (see Fig. 3). When hypertension is present, the majority of the randomized intervention studies suggest that regular lower body, dynamic aerobic exercise training (i.e., walking/jogging or cycling) has no favorable effects on de-stiffening the aorta among older adults with hypertension whether they are untreated or treated with antihypertensive medications. Moreover, these data are supported by cross-sectional data that demonstrate older adults with hypertension and high aerobic fitness do not exhibit any favorable reduction in aortic stiffness. Lastly, moderate-intensity continuous aerobic exercise training appears to be slightly more beneficial than short-term HIIT aerobic exercise interventions for beneficially altering age-related aortic stiffness in the presence or absence of hypertension. In that HIIT resulted in greater improvements in VO2max than continuous training even when matched for caloric expenditure suggests a dissociation between the beneficial effects of aerobic exercise on aortic stiffness and aerobic fitness.
Theoretical trajectory based on the summary of regular aerobic/endurance exercise studies of the age-related increase in aortic stiffness through middle age and older age in the absence of hypertension (“normal BP”) or with hypertension. Dotted lines indicate the theoretical trajectory of aortic stiffness change when aerobic exercise intervention is initiated at middle age (between 50 and 60 years of age) or older age (>65 years of age) versus not initiating exercise (solid lines).
Theoretical trajectory based on the summary of regular aerobic/endurance exercise studies of the age-related increase in aortic stiffness through middle age and older age in the absence of hypertension (“normal BP”) or with hypertension. Dotted lines indicate the theoretical trajectory of aortic stiffness change when aerobic exercise intervention is initiated at middle age (between 50 and 60 years of age) or older age (>65 years of age) versus not initiating exercise (solid lines).
Conclusions
Short-term aerobic exercise interventions 2–3 days/week at moderate intensity initiated in middle age or older age have small or no favorable blood pressure-independent effect on aortic wall stiffness. In contrast, 4–5 days/week appears to be the minimal obligatory dose of aerobic exercise to have some de-stiffening effects if exercise is performed during middle age and continues into older age. Moreover, short-term HIIT provides no greater de-stiffening effects on the aged aorta than continuous aerobic exercise training. Future studies should include longer-duration studies that combine aerobic and resistance training or selective pharmacological agents. Alternatively, exercise combined with some nutraceutical compounds that have recently been purported to have de-stiffening effects in aged humans such as those that reduce mitochondrial oxidative stress [41], vascular inflammation [42], NAD+ bioavailability [43], or increase nitric oxide bioavailability [44]. Furthermore, recent novel non-exercise interventions such as inspiratory muscle training [45] and hot water immersion therapy [46] have also been reported to have beneficial effects on aortic stiffness in humans that need further exploration in combination with exercise that can be sustainable for the lifespan.
Conflict of Interest Statement
The authors have no conflicts of interest to declare.
Funding Sources
G.L.P. is supported by grants from the National Institutes of Health [AG063790] and the American Heart Association [969732] and is also supported by the Russell B. Day and Florence D. Day Endowed Chair in Liberal Arts and Sciences at the University of Iowa. The funders had no role in the design, data collection, data analysis, and reporting of this study.
Author Contributions
G.L.P. was responsible for the conception and design of the first draft and the development of the figures; edited and revised the manuscript; and approved the final version of the manuscript.