Introduction
Aortic augmentation pressure (AP) represents a manifestation that presents in mid-systole due to the interaction between forward and backward travelling pressure waves, aortic stiffness (i.e. aortic pulse wave velocity, aPWV), and aortic reservoir pressure (O'Rourke and Mancia
1999; Mynard et al.
2020). Notably, AP and aPWV increase with age (McEniery et al.
2005) and contribute to the increase aortic systolic blood pressure (aSBP), which is predictive of future cardiovascular events in the general population (Lamarche et al.
2020). Whether lifestyle factors, such as habitual endurance exercise, influence AP, aPWV, and aSBP similarly is currently unclear.
As recently highlighted by Van Bortel et al. (
2020), erroneous conclusions can be made when comparing aortic stiffness between individuals without the appropriate statistical adjustment of aPWV for mean arterial pressure (MAP). Furthermore, it is well known that habitual endurance exercise lowers heart rate (Katona et al.
1982) and that heart rate influences both AP and aPWV (Wilkinson et al.
2000,
2002; Tan et al.
2016). Therefore, in the presence of between-group differences in MAP and/or heart rate, statistical adjustments for these confounders should be made (Stoner et al.
2014). In the studies conducted to date comparing aPWV between endurance-trained and untrained individuals, the majority have not adjusted for MAP and/or heart rate when necessary and have reported lower aPWV in well-trained individuals (Vaitkevicius et al.
1993; McDonnell et al.
2013; Tarumi et al.
2013; Pierce et al.
2013,
2016). However, Shibata et al. (
2018) reported no effects of lifelong exercise “dose” on aortic stiffness in middle-aged/older individuals. Unlike aPWV, AP, or more commonly reported augmentation index (AIx), is always adjusted for heart rate and is found to be lower in well-trained individuals (Vaitkevicius et al.
1993; McDonnell et al.
2013; Tarumi et al.
2013; Pierce et al.
2013,
2016; Shibata et al.
2018). Furthermore, not all studies include height or MAP (Stoner et al.
2014) as covariates when comparing AP or AIx between groups. Thus, to the best of our knowledge, no study has reported on the effects of habitual endurance exercise on aPWV and AP, with appropriate statistical adjustments for potential confounders.
As well as habitual exercise, sympathetic vasomotor outflow to the skeletal muscle (i.e. muscle sympathetic nerve activity [MSNA]) could also influence aortic haemodynamics. MSNA is well known to play a pivotal role in the dynamic beat-by-beat control of peripheral vascular tone, and therefore peripheral blood pressure (Charkoudian and Wallin
2014; Shoemaker et al.
2015; Dampney
2017). However, less is known about whether MSNA also influences aortic haemodynamics. Previously, basal MSNA burst frequency and incidence have been shown to positively correlate with AP in normotensive young men (Casey et al.
2011; Smith et al.
2015), postmenopausal women with elevated blood pressure (i.e. [pre]hypertension) (Hart et al.
2013) and normotensive heart failure patients with reduced ejection fraction (Millar et al.
2019). In contrast, MSNA and AP were not correlated in a mixed-sex sample of healthy normotensive middle-aged individuals (Millar et al.
2019). Casey et al. (
2011) suggested that MSNA likely influences AP via alterations in peripheral vascular tone, and subsequent increases in the magnitude of backward travelling pressure waves, as well as increases in aortic stiffness. Importantly, in young normotensive men, there is often no mid-systolic rise in aortic pressure (McEniery et al.
2005) and therefore AP is either zero or negative (Fig.
1A), unlike older normotensive men (Fig.
1B). Thus, in young men AP does not contribute to aSBP and therefore is not physiologically meaningful in the context of effecting increases in aSBP. Furthermore, inclusion of negative AP values can exaggerate relationships between variables (e.g. between AP and age), whereby this relationship does not exist following the removal of these values (Hughes et al.
2013). In the two aforementioned studies of young men, both negative and positive AP values were included in analyses (Casey et al.
2011; Smith et al.
2015); accordingly, the reported positive correlation between MSNA and AP may be exaggerated.
Herein, we aimed to (1) establish whether appropriate statistical adjustment influences the findings as to the effects of habitual endurance exercise on aortic haemodynamics, and, (2) assess the relationship between MSNA burst frequency and AP in normotensive young and middle-aged men. For aim 1, we hypothesised that adjusted aPWV and AP would not be different between groups due to training-mediated effects on heart rate and/or blood pressure, and that the age-related differences in aortic haemodynamics would be smaller in runners compared to nonrunners. To address aim 2, we merged the endurance-trained and recreationally active groups as MSNA burst frequency is not influenced by habitual exercise in either age group (Wakeham et al.
2019). Furthermore, we performed separate analyses for each age group due to higher MSNA and positive AP values in middle age (Matsukawa et al.
1998; McEniery et al.
2005). We hypothesised that there would be no significant correlation between MSNA and AP in either age group.
Discussion
The principal findings from this study are as follows. First, the statistical adjustment of aPWV and AP for aMAP and heart rate changed the conclusions as to the effects of habitual endurance; adjusted aPWV and AP were not different between trained and untrained men, which contrasts the lower unadjusted values of Converted aPWV and AP. Second, there was an age-dependent effect of habitual exercise on aSBP, whereby aSBP was lower in young runners compared to nonrunners only. Accordingly, the magnitude of difference in aSBP was greater with age in runners compared to nonrunners, with a similar age-related difference for aPWV and AP. Third, we report no significant relationship between MSNA burst frequency, in other words sympathetic vasomotor outflow, and AP in young or middle-aged men, with negative and positive AP, respectively. These data suggest that habitual exercise is associated with a different aortic haemodynamic profile in young compared to middle-aged men and habitual endurance exercise does not influence aortic stiffness or augmentation pressure when adjusted for the physiological effects of heart rate and blood pressure. Furthermore, the data presented here show that aortic systolic pressure augmentation does not correlate with the level of sympathetic vasoconstrictor drive to skeletal muscle in groups of active young or middle-aged normotensive men.
Effects of habitual exercise on aortic haemodynamics in young and middle-aged men
In the present study, HR and aMAP adjusted aPWV was not influenced by habitual exercise in either young or middle-aged men. In the studies conducted to date aPWV has not been adjusted for HR and aMAP (Vaitkevicius et al.
1993; Tanaka et al.
1998; McDonnell et al.
2013; Pierce et al.
2013,
2016; Tarumi et al.
2013,
2021). Notably, the adjustment of aPWV markedly changed our study findings. Converted aPWV (i.e. unadjusted) was lower with habitual exercise in both young and middle-aged men, as reported in most (Vaitkevicius et al.
1993; Tanaka et al.
1998; McDonnell et al.
2013; Pierce et al.
2013,
2016; Tarumi et al.
2013,
2021; Otsuki et al.
2007a,
b), but not all (Bjarnegard et al.
2018; McDonnell et al.
2013; Shibata et al.
2018) previous studies. Our findings suggest that habitual exercise may not directly influence
intrinsic aortic stiffness (i.e. aPWV independent of confounders) per se, rather that habitual exercise influences
operating aortic stiffness (i.e. measured aPWV) due to training-related effects on heart rate and arterial pressure. Thus, future studies should also determine adjusted aPWV when appropriate, dependent on differences in heart rate and/or arterial pressure, to avoid reporting erroneous conclusions (Van Bortel et al.
2020) regarding the effects of habitual exercise on
intrinsic aortic stiffness. These data suggest that habitual exercise does not change
intrinsic aortic stiffness in healthy normotensive men.
Alongside aortic stiffness, aortic systolic pressure augmentation is an important determinant of aortic blood pressure, which independently increases cardiovascular risk (Wang et al.
2010). When adjusted for heart rate and aMAP, there were no significant effects of habitual exercise on AP (or AIx) in young or middle-aged men. Again, these findings differ when these variables are unadjusted, as AP was not different in young men, but AP was higher in middle-aged runners compared to nonrunners. AP@75 was, however, lower in young runners compared to nonrunners, whereas the normalisation to a heart rate of 75 bpm removed the difference between middle-aged groups. Thus, the adjustment of AP for heart rate and aMAP highlights the importance of including aMAP as a covariate when comparing AP between the trained and untrained men here, as adjusted AP was not effected by habitual exercise in either age group. The use of ANCOVA for the adjustment of AP or AIx for heart rate, as opposed to the automated adjusted to 75 bpm within the SphygmoCor, is beneficial as this statistical method adjusts the dependent variable according to the group means and not based upon an arbitrary calculation from previous data, as highlighted previously (Stoner et al.
2014). Furthermore, the adjustment to 75 bpm is limited to heart rates between 40 and 110; thus, it is not possible to generate these data in endurance athletes who present with heart rates below 40 bpm, as was the case for four runners included here. Previous studies have reported that systolic pressure augmentation (AP, AIx or AIx@75) is either lower (Edwards and Lang
2005; Denham et al.
2016; McDonnell et al.
2013; Bjarnegard et al.
2018) or not different (Knez et al.
2008; McDonnell et al.
2013; Shibata et al.
2018) with habitual exercise. The mechanism(s) mediating the higher raw AP in middle-aged runners compared to nonrunners are unclear; future studies are required to determine the influence of habitual exercise across the lifespan on forward, backward and reservoir pressures. The disparity in findings is likely due to the differences in the measure (AP vs AIx), or equipment used, whether, or not, heart rate and aMAP were adjusted for, as well as the magnitude of differences in cardiorespiratory fitness and/or participant age. Together, the data presented here suggest that the habitual endurance exercise related difference in aortic systolic pressure augmentation is mediated by heart rate and aMAP.
The effects of habitual exercise on aSBP were age-dependent; whereby, aSBP was only lower in young runners compared to nonrunners, despite no significant differences in adjusted aPWV or AP in either age group. This age-dependent effect is likely due to the greater magnitude of difference in non-augmented aSBP (i.e. P1) in young runners compared to nonrunners (-6 mmHg); the mean difference was smaller (− 2 mmHg) between middle-aged groups. As P1 is determined by the interaction between the left ventricular ejection wave and ascending aortic stiffness, the greater ascending aortic compliance in young endurance-trained men (Tarumi et al.
2021) likely contributes to this difference in non-augmented aSBP. The effects of habitual exercise on ascending aortic stiffness in middle/older age are currently unclear. It is important to note that our data do contradict a previous study which reported the inverse, with effects of habitual exercise on aSBP in middle-aged but not young individuals (McDonnell et al.
2013). However, this discrepancy is likely related to the study of only normotensive men in both age groups here, unlike the previous study. Therefore, in terms of cardiovascular risk as determined by aSBP (Stamatelopoulos et al.
2006; Vlachopoulos et al.
2010; Lamarche et al.
2020), the benefit of habitual endurance exercise is apparent in young but not middle-aged normotensive men.
Effect of age in runners and nonrunners
With advancing age aortic stiffness, systolic pressure augmentation, and aortic blood pressure increase (McEniery et al.
2005). Many studies have suggested that lifelong habitual exercise can slow age-related aortic stiffening (Vaitkevicius et al.
1993; Tanaka et al.
1998; Gates et al.
2003; Pierce et al.
2013,
2016; McDonnell et al.
2013), which could also influence AP. However, some of these previous studies compared middle/older aged endurance-trained individuals with young sedentary, but not young endurance-trained, individuals (Vaitkevicius et al.
1993; Pierce et al.
2013,
2016), which could underestimate the age-related difference with the middle/older aged endurance-trained groups. Indeed, we report that the age-related differences in aPWV are similar for chronically endurance-trained runners and recreationally-active nonrunners. Importantly, the middle-aged runners here had been training for ~ 30 years, which is similar to the age difference between our young and middle-aged groups (~ 32 years). This finding opposes the view that habitual endurance exercise has “anti-ageing” effects on aortic stiffness, as reviewed recently (Nowak et al.
2018; Rossman et al.
2018; Seals et al.
2018; Tanaka
2019; Seals et al.
2019; Parry-Williams and Sharma
2020). The age-related difference in AP was greater (larger effect size) in runners compared to nonrunners. This also contradicts a previous report of no effect of habitual exercise on the age-related difference in AP has been reported previously (McDonnell et al.
2013); however, as mentioned previously, the older groups studied by McDonnell and colleagues were prehypertensive and hypertensive, unlike the present study, and the active group were likely not as homogenous as the sample studied here. Thus, more studies are warranted to provide further insight into whether habitual endurance exercise influences “aortic ageing”, utilising a similar four-group study design as utilised here, with appropriate adjustments of aPWV and AP.
In the present study, the age-related difference in aSBP was greater in runners compared to nonrunners. Despite this, the middle-aged runners did not present with higher aSBP or adjusted AP when compared to their recreationally active age-matched counterparts (Table
2). This is of importance for their cardiovascular risk profile, as absolute aSBP is predictive of cardiovascular morbidity and mortality (Stamatelopoulos et al.
2006; Vlachopoulos et al.
2010; Lamarche et al.
2020).
Relationship between MSNA and AP
In the current study, we found no relationship between MSNA burst frequency and AP, in young or middle-aged normotensive men. Specifically, we observed this in a sample of young men where AP did not contribute to aSBP in 91% of individuals, but did contribute to aSBP in 96% of middle-aged men, due to the return of the backward pressure wave occurring in diastole and systole in young and middle-aged men, respectively. MSNA and AP (or AIx) have been shown to positively correlate in young men (Casey et al.
2011; Smith et al.
2015); however, 44% (Casey et al.
2011) and 53% (Smith et al.
2015) of the samples studied previously had positive AP values. Whether these previously reported correlations between MSNA and AP in young men would remain when assessed for positive and negative AP values separately, is unclear. The previous studies in middle/older age report disparate findings. Millar et al. (
2019) reported no correlation between MSNA and AP in healthy normotensive individuals (75% male), where AP contributed to aSBP in 88% of participants studied. The discordance in findings between this study and those conducted previously likely reflects differences in the distribution of AP values and/or levels of aortic pressure. Indeed, higher arterial pressure is associated with higher AP (Mitchell
2014). Positive relationships between MSNA and AP may only exist in individuals with elevated arterial pressure and AP, as shown previously in prehypertensive and hypertensive postmenopausal women (Hart et al.
2013) and heart failure patients with reduced ejection fraction (Millar et al.
2019). Together, in normotensive young or middle-aged men, without and with pressure raising AP values respectively, resting peripheral sympathetic vasomotor outflow does not correlate with AP (or AIx).
Casey et al. (
2011) suggested that MSNA likely contributes to AP in young men via alterations in peripheral vascular tone, and subsequent increases in backward travelling pressure waves, as well as increases in aortic stiffness (Casey et al.
2011). However, the authors made this conclusion despite reporting no significant correlation between total peripheral resistance and AP in young men (Casey et al.
2011). Regarding the influence of MSNA on aortic stiffness, and subsequently AP, it has been shown that MSNA significantly correlates with aPWV at rest (Swierblewska et al.
2010; Holwerda et al.
2019) and there are pressure-independent increases in aPWV during acute sympathoexcitation (Nardone et al.
2018; Holwerda et al.
2019). Notably, we observe no significant correlation between MSNA and aPWV in either age group studied here (young:
r = 0.162,
P = 0.461; middle-aged:
r = − 0.367,
P = 0.085), which may contribute to the lack of relationships between MSNA and AP in this study. Thus, a positive relationship between MSNA and aortic stiffness may underlie the previously reported positive correlations between MSNA and AP (Casey et al.
2011; Smith et al.
2015; Hart et al.
2013; Millar et al.
2019); an effect likely due to the pressure-raising effect higher aortic stiffness has upon aortic reservoir pressure, and subsequently AP (Davies et al.
2010). This may especially be the case in the presence of high blood pressure and/or cardiovascular disease where AP raises aSBP (Mitchell
2014).
Methodological considerations
There are some limitations which warrant discussion. First, as we only studied Caucasian men here it is not possible to determine if there are similar or divergent effects of habitual exercise and/or ageing on aortic haemodynamics between the sexes or different racial groups. The effects of habitual exercise on central haemodynamics have been studied in women previous, with reports of no differences between trained and untrained women in either young (Bjarnegard et al.
2018) or middle/older age (Tanaka et al.
1998). Further, there are no effects of sex on aortic pressure in either African American or Caucasian individuals, despite lower aPWV in women (Yan et al.
2014). Future studies are required to understand the interaction between the effects of habitual exercise, age, sex, and other socio-cultural factors on aortic haemodynamics. Second, as a cross-sectional study design was utilised, it is not possible to truly determine the effects of habitual exercise on the age-related changes in aortic haemodynamics. Future studies should complete longitudinal follow-up studies in endurance-trained and untrained men and women to discern the effects of age, sex and habitual exercise on aortic haemodynamics. Furthermore, as we did not record objective measures of physical activity here, we cannot determine the effects of different physical activity and/or sedentary time on aortic haemodynamics. This was by design, as we studied healthy but untrained men who were meeting the current physical activity guidelines. Third, we assessed the relationships between resting MSNA and aortic AP which were recorded on separate days. However, the measurement of MSNA is repeatable within individuals over the short, medium and long-term (Fagius and Wallin
1993; Kimmerly et al.
2004; Notay et al.
2016; Grassi et al.
1997; Fonkoue and Carter
2015). Finally, it is not possible to directly record sympathetic outflow to the aorta in humans. Nevertheless, the main aim of the correlational analyses performed here was to determine whether peripheral sympathetic vasomotor outflow (i.e. MSNA) is correlated to AP with consideration of the effect of negative and positive AP values.
Conclusion
We report an age-dependent effect of habitual endurance exercise on aortic haemodynamics in normotensive men; whereby, aSBP is lower in young, but not middle-aged, runners compared to nonrunners, with no difference in adjusted aPWV or AP in either age-group. The difference in findings between the raw and adjusted aPWV and AP data highlight that the appropriate adjustments of aortic stiffness and systolic pressure augmentation are important when studying the effects of habitual exercise between groups of young and middle-aged men to avoid reporting erroneous conclusions (Van Bortel et al.
2020). However, the differences in unadjusted aPWV and AP with habitual exercise reported here are the functionally relevant
operating aortic stiffness and augmentation pressure values, which are of clear physiological and potential clinical relevance. Nevertheless, our study highlights that
intrinsic aortic stiffness and adjusted systolic augmentation pressure are not influenced by habitual exercise. Thus, the habitual exercise related differences in
operating aortic stiffness and systolic augmentation pressure appear to be mediated by differences in other hemodynamic indices, namely heart rate and blood pressure. In addition, we report no significant correlation between peripheral sympathetic vasomotor outflow and systolic pressure augmentation in either young or middle-aged normotensive men. Future studies should consider performing separate correlational analyses with positive and negative AP values, as only positive AP values represent clinically relevant physiological effects on aSBP.
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