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Reduced Work Capacity in Individuals with Down Syndrome: A Consequence of Autonomic Dysfunction?

Fernhall, Bo1; Mendonca, Goncalo V.2; Baynard, Tracy1

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Exercise and Sport Sciences Reviews: July 2013 - Volume 41 - Issue 3 - p 138-147
doi: 10.1097/JES.0b013e318292f408
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INTRODUCTION TO DOWN SYNDROME

Down syndrome (DS), or trisomy 21, is the most common genetic cause of intellectual disability (ID) and more than 90% of the time is caused by an extra copy of chromosome 21 in every cell in the body. Other causes include mosaicism (affecting only some of the cells) and translocation (two chromosomes grown together as one but containing the genetic material of both) (40). These chromosomal abnormalities can lead to altered mitochondrial function, neuropathogenesis, growth disorders, generalized physiological malfunction, and atypical physical development. As a consequence, DS is typically characterized by delayed psychomotor, brain, and neurological development (most individuals with DS would be classified with mild ID). DS also is associated with an increased risk for various congenital and other organic disorders, including leukemia, congenital heart disease, hypothyroidism, Alzheimer’s disease and dementia, gastrointestinal disorders, muscle hypotonia, and pulmonary disorders (33,40).

The prevalence of DS is estimated at 1 per 700 to 1 per 1000 live births, and maternal age is the primary risk factor for DS. Although congenital heart disease used to be a major cause of early mortality in patients with DS, improvements in surgical procedures and early diagnosis have substantially improved the lifespan in this population (33,40). Life expectancy has been increasing rapidly in individuals with DS. Although still much lower than in the general population, life expectancy is now close to 60 yr, with some living into their 80s (38). This drastic change in life expectancy likely is caused by improved medical care, better living conditions, and the previously mentioned increased survival after corrective cardiac surgery. Individuals with DS have often been described as presenting with “accelerated biological aging,” with high rates of Alzheimer’s disease, dementia, leukemia, and infection-related conditions, contributing to overall morbidity and mortality (38). Considering that almost all individuals with DS need assisted living care, the financial cost of DS likely is substantial, but little or no information is available. As life expectancy for individuals with DS continues to increase and the ability for self-care decreases as a function of the aging process, the need for services and support will certainly rise. Thus, targeting areas that will promote participation, self-care, and quality of life is important. Mobility impairment and poor self-care are both associated with morbidity and mortality in persons with ID (33); therefore, maintaining and improving physical work capacity are important for individuals with DS.

LOW WORK CAPACITY IN INDIVIDUALS WITH DS

Individuals with DS have very low levels of work capacity (defined as peak oxygen consumption (V˙O2peak)) regardless of age and sex (Fig. 1), and this is a consistent finding in the available literature (4,12,15,33). The low work capacity is not a function of congenital heart disease because studies to date have included only individuals with DS without congenital heart disease. Traditionally, the low work capacity was often attributed to lack of motivation and understanding, coupled with high levels of obesity and a lack of physical activity. However, our laboratory has provided convincing evidence arguing against these purported reasons. First, individuals with DS can achieve objective criteria for treadmill maximal oxygen consumption when appropriate familiarization has been achieved before testing (13,16). Second, the reliability of maximal treadmill exercise testing in this population is very high, similar to populations without disability (13). Accordingly, it is unlikely that lack of understanding and motivation is the underlying cause of the low work capacity in persons with DS, provided appropriate testing and familiarization procedures are followed. Furthermore, obesity possibly may explain reduced work capacity in this population, yet this does not seem to be the case. For instance, nonobese individuals with DS have low work capacity as well (12,15), and nonobese men with DS who trained 8 to 10 h·wk−1 still exhibited much lower than expected work capacity (mean values ∼32 mL·kg−1·min−1 and mean age of ∼28 yr) (21). Moreover, obesity impacts maximal work capacity much less in persons with DS than in their peers without DS (4,12,15). As shown in Figure 1, body mass index (BMI) increases with age in DS (as in other populations), but physical work capacity does not change appreciably with age in DS (4). Last, individuals with DS are not physically active as a group, yet their levels of physical activity are not markedly different from the general population (33). Consequently, factors other than task understanding, motivation, obesity, or physical activity must contribute to their low physical work capacity.

Figure 1
Figure 1:
A. Peak oxygen consumption (V˙O2peak) across age in individuals with Down syndrome (DS), intellectual disability (ID), and individuals without disabilities. In the youngest age group, individuals with DS and ID exhibited lower work capacity than nondisabled individuals, but after age 16 yr, only individuals with DS exhibited reduced work capacity (P < 0.05). B. Body mass index (BMI) across age in individuals with DS, ID, and without disabilities. Individuals with DS exhibited significantly higher BMI than persons with ID without DS at all ages and higher than persons without disabilities in age groups 9 to 15 yr and 22 to 29 yr (P < 0.05). C. Peak heart rate across age in individuals with DS, ID without DS, and nondisabled persons. Individuals with DS exhibited lower peak heart rate values across all age groups (P < 0.05). [Adapted from (5). Copyright © 2008 Lippincott Williams & Wilkins. Used with permission.]

CHRONOTROPIC INCOMPETENCE IN DS — A MARKER OF AUTONOMIC DYSFUNCTION

Chronotropic incompetence, or reduced heart rate response to exercise, accompanying the low work capacity, is another common finding in persons with DS. Our laboratory, in the largest studies to date, consistently has shown that, regardless of age and sex, most individuals with DS exhibit chronotropic incompetence (4,12,15). Maximal heart rates are typically approximately 25 to 30 beats·min−1 below maximal heart in persons without disabilities (Fig. 1), and these low maximal heart rates may contribute to the low work capacity. Although a reduction in maximal heart rate per se may not affect work capacity because the reduced heart rate could be accompanied by increased stroke volume, thus maintaining cardiac output as shown in healthy young individuals (26), this does not seem to be the case in persons with DS. Stroke volume during exercise is similar between individuals with and without DS (39), and we have shown that the low maximal heart rate accounts for a large portion of the reduction in physical work capacity in this population (15). Chronotropic incompetence also is evident when using the chronotropic response index, which is independent of effort during graded exercise testing, physical fitness, and age (20). Consequently, chronotropic incompetence in persons with DS limits exercise performance, consistent with findings in other clinical populations where chronotropic incompetence is a significant contributor to exercise intolerance (5).

The question is: what causes the reduction in maximal heart rate in this population? Our laboratory has postulated that individuals with DS exhibit autonomic dysfunction and that this is the major cause of both the reduction in maximal heart rate and physical work capacity. However, there also is some evidence that intrinsic heart rate, evaluated after both sympathetic and parasympathetic blockade with atropine and propanolol, is lower in persons with DS (∼15 beats·min−1) compared with that in individuals without disabilities (37). Thus, it is possible that both autonomic dysfunction and lower intrinsic heart rate contribute to chronotropic incompetence and low work capacity in individuals with DS. An overview of the framework for our hypothesis and discussion is presented in Figure 2. In the following sections, we will discuss the evidence for autonomic dysfunction in DS and the evidence for our working hypothesis that autonomic dysfunction may cause a reduction in physical work capacity in this population. We also will discuss the possibility that altered autonomic dysfunction in individuals with DS may be consistent with the concept of accelerated or premature biological aging in this population. Finally, we will discuss the impact of exercise training on physical work capacity and autonomic function in persons with DS.

Figure 2
Figure 2:
Proposed model for the influence of altered autonomic function on work capacity in persons with Down syndrome (DS). Both a reduction in intrinsic heat rate and altered autonomic function contribute to chronotopic incompetence and ultimately reduced work capacity. The altered autonomic function is manifested by reductions in both sympathetic and parasympathetic control, contributing to both chronotropic incompetence and reduced hemodynamic control, leading to reduced work capacity.

DECREASED RESPONSE TO SYMPATHOEXCITATORY TASKS

There is consistent evidence showing that individuals with DS exhibit reduced responses to sympathoexcitatory tasks (i.e., orthostatic stress, isometric handgrip exercise, and cold pressor testing). Typically, standard heart rate and blood pressure (BP) responses have been evaluated, coupled with techniques such as heart rate variability (HRV) and baroreceptor sensitivity, providing an opportunity to understand the underpinnings of autonomic function in this unique population.

Orthostatic Responses

Orthostatic stress is a potent adrenergic stressor where heart rate and BP are regulated by the baroreceptor reflex in an effort to maintain the systemic BP. Both passive upright tilt and active standing have uncovered decrements in heart rate response and cardiac autonomic control in individuals with DS. Reduced changes in BP and heart rate have been reported during active standing (28,44) in individuals with DS compared with that seen in those without DS; however, these differences were not always statistically significant. Iellamo et al. (25) found similar BP but reduced heart rate delta [Δ] values between individuals with and without DS (DS: 8 beats·min−1 vs non-DS: 17 beats·min−1) in transition from supine to active standing. This led to the speculation that there were differences in baroreceptor sensitivity (BRS) and BP regulation between populations. However, individuals with DS had higher BRS during active standing (DS: 13.0 ms·mm Hg−1 vs non-DS: 8.1 ms·mm Hg−1), yet the Δ BRS was similar between groups (DS: 13 ms·mm Hg−1 vs non-DS: 11 ms·mm Hg−1), suggesting that change in BRS per se could not explain the lower chronotropic response in participants with DS. Nevertheless, as only the vagal contribution to BRS was evaluated, it remains possible that sympathetic portion of BRS may have been different between persons with and without DS. The reduced changes both in the normalized low frequency (LF) and high frequency (HF) power of HRV in participants with DS further support this notion. Taken together, these findings indicate that an attenuated heart rate response to active standing in persons with DS may result from a combination of blunted vagal withdrawal and reduced sympathetic activation.

Active standing involves the activation of central command, which may be different between individuals with and without DS; however, this has never been evaluated. Passive upright tilt removes most of the contribution of central command to heart rate and BP responses. Our group also observed a smaller heart rate change (DS: 9 beats·min−1 vs non-DS: 14 beats·min−1), coupled with nearly identical BP, in adults with DS during upright tilt (11). Moreover, this response was dependent on resting and maximal heart rate but not on differences in BMI or cardiovascular fitness. We also have observed lower BRS values during supine rest in persons with DS (14.5 ms·mm Hg−1) compared with that seen in those without DS (21 ms·mm Hg−1). The BRS change in response to 5 min of passive upright tilt also was reduced in individuals with DS (DS: Δ 6 ms·mm Hg−1 vs non-DS: Δ 13 ms·mm Hg−1) (2). Interestingly, we found very similar changes in HRV and heart rate complexity (1) during the 5-min upright passive tilt to those reported by Iellamo et al. (25) during active standing. Participants with DS exhibited reduced responses in HF and LF power and heart rate complexity (indices of vagal function) to upright tilt, coupled with substantial reductions in systolic BP variability (an index of sympathetic vascular control) (2), suggesting that both vagal and sympathetic control of heart rate were reduced in these individuals. Thus, taken together, these results indicate that individuals with DS clearly exhibit altered autonomic function probably caused by baroreflex dysfunction during orthostatic stress, producing both reduced vagal withdrawal and sympathetic activation. These data also suggest that neural cardiovascular regulation is altered in persons with DS, and that this is independent of central command or adrenal catecholamines in response to orthostatic stress (1).

It also is interesting to note that these alterations in cardiovascular control during orthostatic stress are consistent with aspects of premature aging in persons with DS. Normal “healthy aging,” up to age approximately 70 yr, is characterized by a reduced heart rate response to acute orthostatic stress, coupled with maintenance of BP likely caused by increased peripheral vascular resistance (27). The reduced heart rate response to orthostatic stress in aging has been attributed to decreased vagal withdrawal and reduced beta adrenergic response, coupled with reduced baroreceptor function (27). This is very similar to the response observed in young otherwise healthy individuals with DS, suggesting that cardiovascular control of heart rate during orthostatic stress may be influenced by “accelerated biologic aging” in this population.

Cold Pressor Testing

Cold pressor testing is used to evaluate sympathetic influence on autonomic control, and we are aware of only two articles that have investigated the effects of this provocative task (hand cooling) on autonomic control in individuals with DS. One of those studies had only five participants with DS and found no differences in heart rate or BP between individuals with and without DS at 1 or 5 min of testing using cold water at a temperature of 4°C (44). Nevertheless, the change in systolic BP was considerably lower in the group with DS. Similar results also were obtained for catecholamines, but without statistical significance. Conversely, we (14) observed reduced heart rate and BP responses in persons with DS during 2 min of hand cooling (10°C), suggesting blunted sympathetic activation in this population during cold pressor testing. Statistically controlling for BMI did not alter the original findings, also indicating that obesity does not influence autonomic control during hand cooling in persons with DS. However, it is important to note that these findings may have been influenced by reduced pain perception in persons with DS. Therefore, although the existent literature corroborates the notion of altered autonomic control during hand cooling in DS, considering the limited data available, definite conclusions should be avoided.

Isometric Handgrip

Isometric handgrip, at approximately 30% of maximal voluntary contraction, is a sympathoexcitatory task that elicits increases in heart rate and BP. Traditionally, these hemodynamic responses were thought to be caused by vagal withdrawal during the first minute of muscle contraction and followed by an increased sympathetic dominance until exercise cessation (41,42). However, recent data suggest a more complex interaction between central command, parasympathetic and sympathetic influences, arterial and cardiopulmonary baroreflex control, and the exercise pressor reflex (readers are referred to Fadel and Raven (9) and Matsukawa (30) for more complete reviews). Briefly, the arterial baroreflex is reset upward and rightward at the onset of exercise, and the amount of resetting is dependent on exercise intensity. Resetting of the baroreflex is necessary to allow for simultaneous increases in both heart rate and BP during exercise. Both central command (feed-forward mechanism) and the exercise pressor reflex (feedback mechanism) augment the resetting of the baroreflex (9). Recent data, in decerebrate animal models, suggest that central command increases cardiac sympathetic nerve activity with the initiation of exercise without affecting cardiac vagal nerve traffic, casting doubt on the traditional view explaining heart rate increases with isometric exercise (30). Support for this notion also is provided in humans with tetraplegia, who have intact vagal neural pathways to the sinus node but have lost supraspinal sympathetic control but have reduced initial heart rate responses compared with healthy controls during isometric handgrip (43). This provides support for the notion that sympathetic activation is needed for appropriate increases in both heart rate and BP at the initiation of isometric handgrip exercise.

We have demonstrated that persons with DS respond to isometric handgrip performed at 30% maximal voluntary contraction with a marked attenuation (less than ∼50% of the expected response) in both heart rate and BP compared with those without DS (14). It is interesting to note that these reduced responses were observed at both 30 and 120 s of isometric handgrip. In fact, BP actually decreased slightly at 30 s and did not increase until the 120-s time point of the isometric handgrip task. These findings suggest that individuals with DS exhibit reductions in both sympathetic activation and vagal withdrawal. However, the reduction in BP at 30 s of isometric handgrip exercise suggests that individuals with DS also may exhibit an inappropriate left ventricular response with initiation of the handgrip task, which is gradually corrected 2 min into the exercise. Furthermore, because the HF power of HRV remains unaltered during or following the handgrip exercise in DS (17), we speculate that autonomic dysfunction in these individuals may implicate a combination between reduced vagal withdrawal and vagal reactivation. In addition, despite demonstrating reduced resting BRS, persons with DS respond to isometric handgrip exercise with a similar decrease in BRS as those without DS (23). Participants with DS also exhibited reduced strength and they were considerably more obese than controls. However, controlling for differences in handgrip strength and obesity did not alter the findings, suggesting that neither muscle strength nor obesity influenced cardiovascular control during isometric handgrip exercise.

The data clearly suggest that individuals with DS exhibit both parasympathetic and sympathetic dysfunction in response to isometric handgrip exercise. An intriguing possibility is that the reduction in BP at exercise initiation may originate from an inability of central command to activate sympathetic nerve firing at exercise initiation, as expected (30) in persons with DS; however, this has not been investigated to date. In addition, greater vagal modulation during exercise likely contributes to the reduced exercise heart rate response and may even affect the BP response as well. Although the change in BRS, as measured through the sequence method, has been shown to be similar between persons with and without DS (23), individuals with DS still exhibit lower BRS during isometric exercise compared with controls. It also should be noted that the entire carotid-cardiac baroreflex function curve has never been elucidated in persons with DS. It is therefore possible that resetting of the baroreflex and thus the threshold, saturation, and operational point on the baroreflex curve may be altered in persons with DS; but this has never been investigated. Furthermore, it is likely that the exercise pressor reflex is altered in persons with DS. Although this has not been specifically investigated in persons with DS, individuals with ID typically exhibit a reduced BP response to postexercise circulatory occlusion, suggesting an attenuated metaboreflex in this population (7).

We suggest that the collective data at rest and during isometric handgrip exercise partially support the notion of premature physiologic aging in individuals with DS given reduced baroreflex control of cardiovagal drive. Normal aging also is associated with a reduced heart rate and cardiac response to isometric exercise and pressor stress (27), consistent with our findings in young healthy individuals with DS. However, in normal aging, one would not expect the reduction in BP seen in persons with DS. Thus, it is possible that individuals with DS also exhibit reduced left ventricular function or may exhibit signs of autonomic failure, which are not consistent with normal aging. We have provided further evidence for the notion of premature physiologic aging in individuals with DS, showing that the time-dependent structure of force output during isometric handgrip exercise is lower in persons with DS than that in age-matched controls but similar to that in older controls (24). The mean force output also was similar between young individuals with DS and older controls. The reduced complexity of force output corresponds to what is seen with aging and often is attributed to both structural functional changes in the central nervous system. Thus, well-documented alterations in brain anatomy of persons with DS (40) may contribute to a condition analogous to premature aging demonstrated by reductions in both muscle force and cardiovascular autonomic control.

The data presented show that sympathoexcitatory tasks such as orthostatic stress, cold stimulus, and isometric handgrip exercise seem to largely demonstrate altered autonomic control in individuals with DS. This is supported by consistent findings demonstrating smaller changes in heart rate and BP to these tasks, coupled with reduced changes in cardiovagal modulation and BRS. Clearly, decreased sympathetic drive also is involved; however, the relative degree of dysfunction between both divisions of the autonomic nervous system has never been quantified in persons with DS.

AUTONOMIC FUNCTION OF PERSONS WITH DS IN RESPONSE TO ACUTE ENDURANCE EXERCISE

Persons with DS have low physical work capacity and reduced exercise economy. Thus, acute exercise performance in persons with DS is characterized by an atypical physiological profile that ultimately leads to the premature onset of fatigue. Importantly, this contrasts with that seen in individuals of similar age and sex without DS (33). Among several possible explanations, there is compelling evidence that the etiological basis for lower exercise economy in individuals with DS is related to biomechanical factors (i.e., disturbed gait kinetics and kinematics). In contrast, there is general agreement that chronotropic incompetence likely is responsible for the low levels of V˙O2peak seen in this population (12,20).

Recently, we showed that catecholamine (i.e., epinephrine and norepinephrine) responsiveness to peak exercise virtually is absent in adults with DS (10) (Fig. 3). We also found positive correlations between catecholamine concentrations, peak heart rate (epinephrine: r = 0.48; norepinephrine: r = 0.57; P < 0.05) and V˙O2peak (epinephrine: r = 0.46; norepinephrine: r = 0.62; P < 0.05), which strongly corroborate that an attenuated adrenergic drive explains chronotropic incompetence in these individuals and, thus, their limited work capacity (Fig. 4). Importantly, both epinephrine and norepinephrine were unresponsive to peak exercise in persons with DS. This indicates that the physiological response of individuals with DS to intense endurance exercise is characterized by a combination of inadequate sympathetic nerve traffic and sympathetic hormonal drive. Because decreased adrenergic drive produces a reactive up-regulation of β-receptor density, these findings agree with past research showing that DS fibroblasts are hyperresponsive to β-adrenergic stimulation (31). Although the origin of sympathetic dysfunction remains largely unknown, there are major differences in the catecholamine metabolism of persons with DS. Dopamine β-hydroxylase activity, which catalyzes the production of norepinephrine, is decreased in DS plasma (28) and the activity of catechol-O-methyltransferase, which is responsible for degrading catecholamines, is increased (22). This would suggest that production of catcholamines is deceased and clearance is increased, leading to the reduced catecholamine response to exercise in this population. However, this needs further investigation. It also is possible that individuals with DS exhibit reduced activation of central sympathetic networks (i.e., rostral ventrolateral medulla) during exercise. Reflex circulatory control during exercise is dependent on muscle mechanoreflexes and chemoreflexes (together termed exercise pressor reflex), which convey Type III and IV nociceptive afferents to the sympathetic premotor neurons located in the brain stem (41). As muscle hypotonia is highly prevalent in persons with DS and they typically express an enhanced tolerance to noxious stimuli, it is possible that the ability to potentiate increased outflow from the central sympathetic networks via the exercise pressor reflex may be limited in persons with DS.

Figure 3
Figure 3:
Epinephrine and norepinephrine concentrations before and after peak exercise in individuals with and without Down syndrome (DS). No group differences existed for either catecholamine at baseline. Epinephrine increased only for the group without DS (P < 0.0001). Norepinephrine increased for the two groups after exercise (P < 0.0001), with the largest increase in those without DS (P < 0.0001). (Reprinted from (10). Copyright © 2009 Elsevier. Used with permission).
Figure 4
Figure 4:
Scatter plots showing the relation between the changes in epinephrine and norepinephrine from rest to maximal exercise, peak metabolic equivalent (MET) level (top), and peak heart rate (HR; bottom) in all subjects. The change in epinephrine was related significantly to peak MET level (r = 0.46; P < 0.05) and peak heart rate (HR) (r = 0.48; P < 0.05). The change in norepinephrine also was related significantly to peak MET level (r = 0.62; P < 0.05) and peak HR (r = 0.57, P < 0.05). (Reprinted from (10). Copyright © 2009 Elsevier. Used with permission).

At exercise onset, central command, originating in cortical brain centers, increases heart rate by vagal withdrawal and heightened cardiac sympathetic nerve traffic (30) in addition to resetting the baroreflex to operate at higher BP (41). Thus, although the primary cause of chronotropic incompetence is impaired, sympathetic activation (20), blunted vagal withdrawal, or baroreflex dysfunction also may play a role. However, to our knowledge, there are no studies examining the chronotropic response to endurance exercise in persons with DS using atropine administration to accomplish vagal blockade, considered the gold standard for measuring the contribution of vagal tone to control of heart rate. Consequently, information on vagal function during endurance exercise in persons with DS is provided by noninvasive measures of vagal modulation, such as HRV. The HF power of HRV, partially resulting from baroreflex buffering changes induced by the mechanical effect of breathing, is mediated by vagal modulation to the sinus node (8). Therefore, HRV can be used to track changes in vagal modulation in transition from rest to exercise conditions.

Our group (3) first observed similar vagal withdrawal (Δ HF power), in transition from rest to submaximal exercise, between adolescents with ID with and without DS, but the individuals with DS still exhibited chronotropic incompetence and lower work capacity. Unfortunately, the participants exercised at the same absolute work rate but at different relative intensities. Thus, because the individuals with DS had lower work capacity, these results are difficult to interpret. We have shown that adolescents with DS may have greater levels of resting HRV in the time domain compared with ID peers without DS in the sitting position (3), but we also have found reduced total HRV in the time domain in adults with DS compared with that in nondisabled individuals in the supine position (19). This discrepancy may be related to the different age of the participants, differences in body position during HRV measurements, or ID per se. Interestingly, Goulopoulou et al. (19) found no significant correlations between resting cardiac autonomic control and the V˙O2peak of participants with DS. This might suggest that cardiac autonomic dysfunction is not likely to contribute to the low levels of cardiorespiratory fitness typically seen in DS, and that exercise training may not be an effective strategy to improve cardiac autonomic control in this population.

We recently compared (34) vagal withdrawal, using HRV analyses, between adults with DS and nondisabled participants in response to treadmill exercise at a constant relative intensity below the ventilatory threshold (45% V˙O2peak). Similar to our previous results, using an absolute work rate during treadmill walking, we found that both individuals with and without DS exhibited a similar magnitude of vagal withdrawal (Δ HF power) in transition from rest to submaximal exercise. The available data therefore suggest that DS is not associated with blunted vagal withdrawal in transition from rest to submaximal endurance exercise. Conversely, in another study, we showed that adults with DS have reduced heart rate recovery after peak exercise compared with nondisabled peers, and that this is independent of chronotropic incompetence and obesity (32). As heart rate recovery depends on acetylcholine release at the sinus node and M2 muscarinic receptor sensitivity (vagal tone reactivation), these findings indicate that these individuals exhibit attenuated recovery of vagal tone after peak exercise. Our group also observed a fractal breakdown of scale-invariant (greater distance from the healthy value of 1.0 in the short-term scaling exponent (α1)) organization in heart rate dynamics toward Brownian noise at rest, during dynamic exercise at 50% V˙O2peak, and passive recovery in adults with DS (35). These findings provide further support for the contention of autonomic dysfunction in persons with DS during exercise. As this apparent loss of fractal behavior in heart rate dynamics may reflect the degradation and decoupling of physiological systems in DS and is similar to that described in healthy aging, it is likely that premature aging contributes to autonomic dysfunction in this population.

Theoretically, peak work capacity in persons with DS might be limited by an exacerbated resistance to change in cardiac autonomic function from rest to exercise conditions. To further explore this issue, using data from our previous study (35), we computed the age-adjusted correlation coefficients between peak work capacity, V˙O2peak, and delta HRV values (from standing rest to treadmill exercise at 45% V˙O2peak under steady-state conditions) in 13 participants with and 12 without DS aged 27 to 50 yr. We found that the change in total power, in the frequency domain of HRV (from rest to exercise), and time to exhaustion during graded exercise testing were significantly related. Moreover, as can be seen in Figure 5, these findings were restricted to participants with DS (r = −0.74; P < 0.05) as statistical significance was not attained in those without DS (r = −0.53; P > 0.05). This suggests that the changes in cardiac autonomic control from rest to exercise predict physical work capacity, consistent with our hypothesis. It also indicates that, among adults with DS, peak work capacity is higher in those showing greater vagal withdrawal from rest to exercise. Therefore, taken together, these data support the notion that cardiac autonomic dysfunction contributes to poor work capacity in persons with DS and that this is at least partially dependent on their inability to achieve an optimal balance between sympathetic activation and vagal modulation to the sinus node in response to dynamic exercise. Although some of these data support the concept that autonomic dysfunction in this population may be caused by premature aging (low maximal heart rate, reduced heart rate recovery, and fractal collapse of heart rate dynamics), the catecholamine response to maximal exercise is drastically different in persons with DS compared with the response expected in healthy aging. Healthy aging is characterized by increased levels of catecholamines, coupled with a reduction in adrenergic receptor sensitivity (27). This is exactly the opposite of what is observed in persons with DS, who exhibit a reduced catecholamine response to exercise, coupled with increased baseline adrenergic receptor sensitivity (10,31).

Figure 5
Figure 5:
Association between time to exhaustion during graded exercise testing (GXT) and the changes (Δ) in total power (TP) of spectral heart rate variability from standing rest to submaximal exercise at 45% V˙O2peak. TP is the natural logarithm (ln). Closed triangles represent participants with Down syndrome (DS); open circles represent participants without DS.

AUTONOMIC FUNCTION OF PERSONS WITH DS IN RESPONSE TO CHRONIC EXERCISE

Exercise training is considered an effective strategy for improving autonomic function in both healthy and diseased populations. Increased HRV, both in the frequency and time domain (HF power and SD of all normal R-R intervals, respectively), has been demonstrated in healthy persons (6,29). In contrast, only limited information on the effects of exercise training on cardiac autonomic function of persons with DS is available.

Our group (36) investigated whether cardiac autonomic function could be improved after combined endurance and resistance exercise training in persons with DS and compared the responses with those of a control group without DS. The exercise intervention included both aerobic (65%–85% V˙O2peak) and resistance training (12 repetition-maximum) for 12 wk at a frequency of 3 d·wk−1. Both groups of participants showed similar relative improvements in V˙O2peak and muscle strength after training. In addition, training increased the normalized power of HF and decreased the normalized power of LF in participants with and without DS under resting conditions. Giagkoudaki et al. (18) found similar changes in HRV after a 6-month endurance training program in persons with DS. These findings suggest that exercise training may be an effective intervention for improving cardiac autonomic function in persons with DS. We also showed that heart rate recovery (at 1 min), after a maximal treadmill test, was improved after training. This provides evidence for improved vagal reactivation in participants with DS after 12 wk of combined exercise training.

In healthy persons without disabilities, V˙O2peak may be improved without changes in resting cardiac autonomic function, and there is compelling evidence that the relationship between the exercise training stimulus and the responses in reflex control of heart rate displays a bell-shaped relation, with a maximal response at moderate volumes of training. Cardiovascular autonomic regulation also is an important determinant of the training response to physical exercise (6). It is possible that individuals with DS may enhance peak exercise performance after training through greater adjustments in cardiac autonomic function (i.e., greater vagal withdrawal and sympathetic activation) in transition from rest to exercise or between different exercise intensities; however, this has never been investigated.

Because the role of the autonomic nervous system in predicting the response to exercise training has never been explored in persons with DS, we decided to test this hypothesis using data from our previous study (36) in two groups of participants (13 DS; 12 non-DS) aged 27 to 50 yr. Age-adjusted correlation analysis was used to compare the association between the change in peak exercise performance from pretraining to posttraining (Δ V˙O2peak and Δ time to exhaustion) and the HRV-derived indexes obtained at baseline. For participants without DS, significant correlations were limited to the relationship between baseline square root of the mean squared differences of successive R-R intervals (RMSSD, a time domain HRV measure depicting vagal modulation) and the change in work capacity from pretraining to posttraining periods (r = −0.67; P < 0.05). For participants with DS, significant correlations were obtained between the change in V˙O2peak after training and the baseline levels of the normalized HRV power of LF and HF (r = 0.61 and r = −0.61, respectively; P < 0.05) (Fig. 6). Overall, these findings indicate that vagal cardiac autonomic function at baseline is inversely associated with the response to exercise training in both adults without disabilities and in individuals with DS. Interestingly, these data also suggest that the greatest V˙O2peak improvements induced by training were attained by the participants with lower levels of vagal modulation at baseline (i.e., higher normalized power of LF and lower normalized power of HF). For this reason, training may be particularly effective for improving the cardiorespiratory fitness of those with a greater degree of autonomic dysfunction.

Figure 6
Figure 6:
Partial correlations, controlling for age, between the pre-training low- (LF) and high-frequency (HF) normalized (nu) power of heart rate variability (HRV) and the change in peak oxygen consumption (V˙O2peak) in individuals with Down syndrome (DS) after 12 wk of exercise training.

CONCLUSIONS

The life expectancy of individuals with DS has increased dramatically during the past 50 yr, although it is still lower than that in the general population. Nevertheless, in the future, more individuals with DS will reach middle and older age than ever before. Because most persons with DS require some level of support, it is likely that the need for support for this population will increase substantially. Thus, finding strategies that enhance participation, independence, and quality of life in this population is important. Considering the importance of mobility and self-care for maintaining participation and independence, the very low levels of work capacity in persons with DS are disconcerting.

There is no question that physical work capacity is low in individuals with DS. The data are surprisingly uniform, showing that most young individuals (mid 20s) with DS exhibit a physical work capacity expected of someone in their 60s. This cannot be explained by congenital heart disease because the data available to date have all been collected on individuals with DS without congenital heart disease. Neither can the low work capacity be explained by the “usual suspects,” including poor motivation, a lack of task understanding, sedentary lifestyle and obesity. No doubt, a sedentary lifestyle and obesity contribute to the low work capacity but cannot explain most of the difference between individuals with and without DS. Therefore, low work capacity in persons with DS most certainly is caused by an alternative factor. We postulate, and provide evidence, that this “unidentified factor” is altered autonomic function leading to chronotropic incompetence and reduced work capacity.

It seems that altered autonomic function in individuals with DS involves both sympathetic and parasympathetic dysfunction. Individuals with DS do not increase circulating catecholamines in response to maximal exercise, suggesting a substantial deficit in sympathetic activation. This is supported by “functional” data, showing lower maximal heart rates and lower BP values in response to exercise and other sympathetic challenges. Furthermore, the cell surface receptors from individuals with DS exhibit characteristics consistent with a “catecholamine deficit.” Conversely, the evidence for altered parasympathetic function is more confusing, showing reduced vagal withdrawal to most adrenergic tasks, except endurance exercise in persons with DS. Nevertheless, vagal withdrawal is associated with work capacity in persons with DS, suggesting a role of altered parasympathetic, in addition to altered sympathetic, function in explaining the low work capacity in this population.

Exercise training improves both work capacity and autonomic function in individuals with DS, in a similar fashion to people without disabilities. Furthermore, we have demonstrated that low baseline resting parasympathetic modulation of heart rate is associated with greater improvements in work capacity for individuals with and without DS. This suggests that those with a low basal vagal function may have the most gain from exercise training. However, it is important to realize that, despite being an effective strategy for improving work capacity and autonomic function in persons with DS, exercise training does not “normalize” the chronotropic response to maximal exercise nor work capacity in this population. Consequently, exercise training cannot “correct” the altered autonomic function in this population. Thus, normalizing the chronotropic response to exercise in persons with DS is difficult. Rate-adaptive pacing has been used with some success in other populations with chronotropic incompetence (5), but there are no data on individuals with DS. It also is likely that using rate-adaptive pacing in populations without heart blocks is counterintuitive (5), thus providing a barrier for the possible use of this technique to treat chronotropic incompetence. Nevertheless, improving work capacity through exercise training is worthwhile, important, and an achievable goal for individuals with DS.

Finally, some of the changes in autonomic function exhibited by individuals with DS are consistent with accelerated aging. Accelerated aging is well documented in individuals with DS, including a very high incidence of Alzheimer’s disease in persons with DS older than 40 yr. However, there are some alterations in autonomic function that are inconsistent with the notion of accelerated aging, notably, the lack of catecholamine response to maximal exercise and enhanced adrenergic receptor sensitivity documented in persons with DS. Nevertheless, it is entirely possible that accelerated aging contributes to the low levels of work capacity in this population.

Acknowledgment

The work of the authors discussed in this article was partially funded by the American Heart Association (Grant-in-Aid 005028N) and the National Institute on Disability and Rehabilitation Research (H133G040323).

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Keywords:

V˙O2peak; intellectual disability; heart rate variability; catecholamine; vagal withdrawal; sympathetic activation

© 2013 American College of Sports Medicine