Reduced aerobic capacity is common in persons with Down syndrome (DS), even in the absence of congenital heart defects (4,14,18,28,33). One of the primary contributors to this lower work capacity is reduced peak HR in response to aerobic exercise (11,20). It has been suggested that cardiac autonomic dysfunction may partially explain the blunted HR response in this population (12,13). Indeed, several studies investigating cardiac autonomic function using HR variability (HRV) analysis have reported altered autonomic function in persons with DS (3,15,19,34). Persons with DS exhibit reduced changes in parasympathetic modulation, coupled with lower sympathetic modulation in response to sympathoexcitatory perturbations, such as isometric handgrip exercise and submaximal exercise (13,16,29). However, such perturbations are largely influenced by central command, which could mask intrinsic levels of autonomic function. Other perturbations that lead to less stimulation via central command, such as passive upright tilt, may yield insightful information regarding underlying autonomic control in this population.
Passive upright tilt is a procedure that minimizes central command (32) and adrenal catecholamines (5) when assessing autonomic regulation of HR. Only a few studies have investigated cardiac autonomic function during passive upright tilt in persons with DS (1,2,10). During passive upright tilt, a blunted HR response, another indicator of autonomic dysfunction, was reported in persons with DS, suggesting reduced sympathoexcitation (10). Using HRV analyses, attenuated parasympathetic withdrawal and sympathoexcitation have been reported in persons with DS when compared with persons without DS during passive upright tilt (2,3). However, it is not clear whether autonomic dysfunction is present in all persons with DS and whether this autonomic dysfunction is the cause of the lower HR response to passive upright tilt in this population. It is also unclear whether there is a subset of persons with DS who have normal changes in HR and who do not exhibit autonomic dysfunction. To date, there are no studies that have compared the HR responses to passive upright tilt in a DS population, which groups them into the responders and nonresponders. Because underlying autonomic dysfunction is associated with reduced work capacity and quality of life in persons with DS (12), it would be important to understand whether a subset of persons with DS who have normal HR responses to sympathetic stressor also have normal autonomic function. This is especially important in the population with DS because autonomic function affects functional capacity, activity levels, and quality of life (12). It is still unclear whether persons with DS who exhibit normal HR responses to sympathoexcitation have normal autonomic function or whether DS per se causes autonomic dysfunction regardless of the HR response to a sympathoexcitatory task. This warrants further investigation that compares autonomic function with a task that removes most of the influence of central command (e.g., tilt), whereby HR responses are matched between groups with and without DS.
Therefore, the purpose of this study was to compare cardiac autonomic modulation during passive upright tilt using HRV analysis in persons with and without DS matched for the change in HR. Our design included three different groups: persons with DS matched on HR response to passive upright tilt (DS-matched) with controls without DS, persons without DS matched on HR response (control), and persons with DS that were not matched on the HR response (DS-not matched). It was hypothesized that DS-matched would not exhibit altered cardiac modulation when compared with control. In contrast, we hypothesized that the DS-not matched group would exhibit reduced parasympathetic withdrawal and sympathoexcitation versus the two matched groups.
A total of 49 persons age 16–40 yr participated in the study, 34 persons with DS and 15 without DS. Eight persons with DS were excluded because of missing HRV data; therefore, data on 41 persons (26 persons with DS and 15 without DS) were used for analysis. Fifteen persons with and 15 without DS (total of 30, control) were matched for HR change (mean of 16 bpm) in passive head-up tilt. The participants with DS matched for HR were individually matched with the controls. The group with DS-not matched consisted of 11 persons. Participants with DS were recruited from local organizations and community support groups. Participants without DS were recruited from the local and university communities. All participants were in sinus rhythm and had a normal ECG. All participants with DS were sedentary, and the participants without DS were either sedentary or recreationally active (e.g., participating in less than 1.5 h·wk-1 of regular exercise). None of the participants had evidence or history of cardiovascular disease based on medical history. Participants were excluded from the study if they exhibited any form of cardiovascular disease including congenital heart disease, as were those with any medication that may alter cardiovascular responses. Other exclusion criteria included smoking, severe or profound intellectual disability, any pulmonary disorders, hypertension, and diabetes. All participants as well as the parent(s) and/or guardian(s) of the participants with DS signed informed consent forms before study participation. The protocol was approved by the institutional review board.
All participants were familiarized with tests (treadmill exercise test and passive upright tilt) before data collection. One to two additional familiarization sessions were conducted for participants with DS to ensure satisfactory performance. Participants were in the postprandial state for 4 h and refrained from caffeine and exercise for 24 h before data collection on each testing day, more than 1 but less than 21 d apart. The first day of testing consisted of a maximal exercise test on a motorized treadmill (Quinton, Bothell, WA) to confirm the presence of chronotropic incompetence in participants with and without DS. The passive upright tilt was performed on the second day in the morning at ambient temperature (22°C–24°C) and consisted of a 10-min supine rest, followed by a 5-min head-up tilt at 80°. Body mass index (BMI) was calculated (kg·m-2).
Peak aerobic capacity.
Detailed information on the protocols can be found elsewhere (4). In brief, participants with DS underwent an individualized graded protocol and participants without DS underwent the same protocol except at higher speeds. The initial stage consisted of comfortable walking for 3 min, followed by a 2-min stage of fast walking. From this point, treadmill grade was increased by 2.5% every 2 min until 12.5% grade was reached. Thereafter, the speed was increased every minute until exhaustion. Oxygen uptake (V·O2) was measured using an online breath-by-breath system (Quark B2; Cosmed, Rome, Italy), and the data were expressed in 20-s averages.
Passive upright tilt.
After being secured on an electrically controlled tilt table with straps located at the torso and thighs, participants rested in a supine position for 10 min before head-up tilt was initiated. Resting data were collected during the last 5 min of the 10-min period. Participants were then tilted to 80° for 5 min. HR was collected using a single-lead electrocardiogram (modified CM5) interfaced with a computer data collection system (BIOPAC, Santa Barbara, CA) at a sampling rate of 1000 Hz. HRV was analyzed offline.
HRV was analyzed in the frequency and time domains. As previously described (2,3), the ECG data were automatically and visually analyzed and edited for arrhythmias and artifacts and converted to a tachogram of the R-R interval. The harmonic components of R-R interval variability were evaluated from segments of 500 beats by the autoregressive method (model order 10) using the Heart Signal software (Oulu, Finland). The two primary components of the frequency domain analysis included low-frequency (LF, 0.04–0.15 Hz) and high-frequency (HF, 0.15–0.40 Hz) spectra (35). LF reflects both sympathetic and parasympathetic influences, although LF may be indicative of baroreflex sensitivity (17,35). HF is a marker of parasympathetic modulation of HR; thus, the LF/HF ratio is indicative of sympathovagal balance (35). The root mean square of successive differences (RMSSD), an additional indicator of parasympathetic modulation of HR (35), was analyzed in the time domain.
Descriptive characteristics and treadmill exercise responses were compared between groups using one-way ANOVA. Data were checked for normality of distribution using Shapiro–Wilk tests. Data that were skewed were either analyzed using a nonparametric test or were normalized using natural log–transformed (Ln) and analyzed using parametric tests. A 3 × 2 ANOVA with repeated measures (group (DS-not matched, DS-matched, and control) × condition (rest vs tilt)) was conducted on all dependent variables to compare differences between groups in response to tilt. When a significant group by condition interaction was detected, between-group differences at each level were examined using appropriate post hoc analyses. To examine potential group differences in the change in HR with passive upright tilt, we used Kolmogorov–Smirnov test of distributions between groups because the change in HR was not normally distributed. To examine the effect of differences in BMI and V·O2peak between groups, we repeated the analyses using BMI or V·O2peak as a covariate. Values are mean ± SE. The alpha level was set at 0.05. All data analyses were carried out using the Statistical Package for the Social Sciences (SPSS version 19.0; IBM, SPSS, Inc., Armonk, NY).
Descriptive characteristics and treadmill exercise responses are shown in Table 1. Height, V·O2peak, and HRpeak were higher, whereas BMI was lower in the control group when compared with those in DS-matched and DS-not matched groups (P < 0.05). No differences were found between groups in age and weight.
Resting HR was 70 ± 3 bpm in the DS-not matched, 68 ± 2 bpm in the DS-matched, and 62 ± 3 bpm in the control groups, respectively, with no group differences (P = 0.06). HR change data are presented in Figure 1. HR change was lower in the DS-not matched group when compared with that in the DS-matched and control groups (P < 0.05).
Raw HRV data in the frequency domain are shown in Table 2. No group differences at rest were found in any variable. In response to passive upright tilt, HF decreased similarly in all groups (P < 0.05). A significant interaction was found for LF/HF (P < 0.05). LF/HF increased during tilt in the DS-matched and control groups. In Figure 2, the change in LF/HF was greater in the control group when compared with that in the DS-not matched group (P < 0.05) but not when compared with that in the DS-matched group (P = 0.075). No difference in LF/HF changes was found between the two DS groups.
Log transformations of HRV data in the frequency domain are shown in Figure 3. No group differences at rest were found in any of the frequency domain log-transformed data or for RMSSD (Fig. 4). In response to passive upright tilt, LnHF (Fig. 3) and RMSSD (Fig. 4) decreased in all groups (P < 0.05). A tilt effect was also observed for LnTP (P < 0.05), with an overall decrease in LnTP. There was a group by condition interaction for LnLF (P < 0.05), in that only the DS-matched group exhibited reduced LnLF (P < 0.05) (Fig. 3). The power calculated for this interaction equals 0.74. No effect of tilt was observed in the control group, whereas the reduction in LnLF for the DS-not matched group approached significance (P = 0.075). Controlling for BMI or V·O2peak did not change the results of the present study.
This study examined whether cardiac autonomic modulation during passive upright tilt differs between persons with and without DS, when persons with DS were matched for the change in HR to persons without DS. The main finding was that despite similar HR responses, persons with DS that were matched for changes in HR exhibited similar alterations in HRV during passive upright tilt compared with persons with DS with significantly lower HR responses. Furthermore, the changes in HRV in individuals with DS matched for HR response with controls were still significantly different from those in controls. This reduction in LnLF was comparable with that in persons with DS whose HR response was not matched. Furthermore, the change in LF/HF was reduced in persons with DS whether or not the change in HR was matched. These results are consistent with the notion of altered HRV to perturbations in persons with DS, suggestive of autonomic dysfunction, regardless of the HR response (2,13,22).
Resting autonomic function.
HRV analysis provides information largely on the parasympathetic modulation of the sinoatrial (SA) node at rest and during steady-state tasks (3,25,26,35), with some parameters inferring a combination of parasympathetic and sympathetic (e.g., LF) modulation. At rest, several studies have found similar HR and cardiac autonomic modulation between persons with and without DS (2,16). Mendonca et al. (30) compared HRV in adults with and without DS and found that both groups exhibited similar resting HR and HRV parameters. Consistent with previous data, we also observed no differences in resting HRV measures and HR between groups, suggesting similar resting autonomic control of HR in persons with DS. In persons with intellectual disabilities with or without DS, Baynard et al. (3) reported greater parasympathetic modulation at rest only in persons with intellectual disabilities with DS, suggesting that DS is associated with increased parasympathetic modulation of the SA node at rest. In support of our data, Figueroa et al. (16) also observed similar resting HR and HRV in persons with DS when compared with those in persons without DS. Our results are supported by previous data that have shown that DS did not seem to be associated with altered autonomic modulation of HR at rest (2,16,30).
Chronotropic incompetence, characterized by inappropriate HR response to sympathoexcitatory perturbations, has been reported in persons with DS (13,20). In the present study, HR increased similarly in response to passive upright tilt in persons without DS and persons with DS whose HR change was matched. However, the HR increase was approximately 30% lower in the nonmatched group, suggesting abnormal HR response to passive upright tilt in this group of persons with DS (20). Consistent with our data, Agiovlasitis et al. (2) also reported that despite similar HR responses to passive upright tilt, persons with DS exhibited depressed sympathetic modulation in response to passive upright tilt when compared with that exhibited by persons without DS. In the present study, we observed altered autonomic modulation to passive upright tilt, evidenced by the reduced LnLF power and LF/HF ratio, in both groups of persons with DS. Fernhall et al. (10) reported blunted HR response to passive upright tilt in persons with DS, consistent with reduced sympathoexcitation. Together, those studies and ours are consistent in reporting reduced sympathetic dominance in persons with DS irrespective of their HR response to a perturbation with little central command such as passive upright tilt.
Consistent with passive upright tilt studies, altered cardiac autonomic dysfunction in persons with DS has been demonstrated during other sympathoexcitatory perturbations (16,19). Fernhall and Otterstetter (13) have shown attenuated rise in HR in response to isometric handgrip exercise and cold pressor testing in persons with DS, suggesting attenuated response to sympathoexcitation. In contrast, one study reported similar parasympathetic withdrawal but heightened sympathetic modulation during submaximal treadmill exercise in persons with DS (29). These studies used perturbations that largely involve central command, which could contribute to inconclusive findings in sympathoexcitatory studies. These perturbations could potentially mask intrinsic levels of autonomic function. Hence, in this study, we used passive upright tilt, which minimizes central command (32) and adrenal catecholamines (5), although some degree of central command may be involved in the autonomic modulation of HR possibly because of increased muscle tension and mental trepidation in anticipation of and during passive upright tilt (36); however, we still found altered cardiac autonomic function in persons with DS, despite normal HR changes.
Mechanisms explaining cardiac autonomic dysfunction in persons with DS are unclear. The interpretation of LF is controversial, with evidence suggesting that LF represents sympathetic outflow and a combination of both sympathetic and parasympathetic modulations (8,27,35). Several studies suggest that altered autonomic function could result from lower baroreflex sensitivity (21) or a blunted metaboreflex-induced pressor response (6) in persons with DS. Recently, a review study by Goldstein et al. (17) and a study by Moak et al. (31) reported that LF reflects baroreflex sensitivity instead of sympathetic modulation. It is possible that persons with DS exhibit reduced baroreceptor sensitivity; however, this was not assessed in the present study. Obesity is associated with autonomic dysfunction and reduced baroreflex sensitivity (23,24). Our persons with DS were obese (BMI of >30 kg·m-2); however, controlling for BMI did not change the results of the present study. Our finding is consistent with other studies that report altered autonomic function in persons with DS that was independent of obesity (13,16). Cardiorespiratory fitness is associated with autonomic function (12), but there was no difference in V·O2peak between the two groups with DS. Furthermore, controlling for V·O2peak did not alter our findings. Thus, differences between the two groups with DS cannot be explained by differences in cardiorespiratory fitness. Two studies have reported reduced catecholamine responses to exercise perturbations in persons with DS (7,9). Even though this was not measured in the present study, altered autonomic function may partially be mediated by the attenuated catecholamine concentrations in persons with DS.
Our findings may have substantial clinical implications for persons with DS. Our data suggest that even in normal HR response to sympathetic stressor, like passive upright tilt, this does not indicate that persons with DS have normal autonomic function. In fact, both groups with DS exhibited similar V·O2peak and HRpeak. This suggests that HR responses to sympathetic tasks, other than maximal exercise, do not necessarily provide useful information regarding autonomic function or functional capacity in this population.
Limitations of the present study warrant consideration. First, the present study is a retrospective study that matched persons with DS on changes in HR response to tilt, which led to a smaller sample size. Second, we did not control breathing rate, which can potentially affect measures of HRV (35); however, controlled breathing is not feasible in persons with DS. In addition, it is possible that some degree of central command may be involved because of possible muscle tension and mental trepidation in anticipation of and during passive upright tilt (36); however, persons with and without DS underwent the same challenge in the current study, yet autonomic dysfunction is still present in persons with DS despite normal HR changes and each person with DS was familiarized with testing several times. It is also plausible that autonomic dysfunction in the DS-matched group may be partly due to sex differences within this group; however, this aspect cannot be explored in the current study because of the small sample size. Finally, we used HRV, which is an indirect method, to assess cardiac autonomic function; however, this method has been validated (35).
We investigated cardiac autonomic function in persons with and without DS when matched for HR change to passive upright tilt and observed reduced sympathetic dominance in response to passive upright tilt in persons with DS despite similar HR responses.
We would like to thank all participants in our study.
This study was partly supported by the American Heart Association.
No conflicts of interest are reported. We do not have any professional relationships with companies or manufacturers who will benefit from the results of the present study to disclose.
The results of the present study do not constitute endorsement by the American College of Sports Medicine.
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Keywords:© 2015 American College of Sports Medicine
HEART RATE; AUTONOMIC FUNCTION; UPRIGHT TILT; DOWN SYNDROME