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Autonomic response to upright tilt in people with and without Down syndrome
Research in Developmental Disabilities 31 (2010) 857–863
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Research in Developmental Disabilities
Autonomic response to upright tilt in people with and without Down syndrome Stamatis Agiovlasitis a,*, Scott R. Collier b, Tracy Baynard c, George H. Echols d, Styliani Goulopoulou e, Arturo Figueroa f, Michael W. Beets g, Kenneth H. Pitetti h, Bo Fernhall i a
Department of Kinesiology, Mississippi State University, 233 McCarthy Gym, P.O. Box 6186, Mississippi State, MS 39762, USA Department of Health, Leisure, and Exercise Science, Appalachian State University, 054 Holmes Convention Center, 111 Rivers Street, Boone, NC 28608, USA Department of Kinesiology & Community Health, University of Illinois at Urbana-Champaign, 906 South Goodwin Avenue, MC-056, Urbana, IL 61801, USA d Department of Kinesiology & Community Health, University of Illinois at Urbana-Champaign, Rehabilitation Education Center, 1207 S. Oak St., Urbana, IL 61820, USA e Department of Exercise Science, Syracuse University, 820 Comstock Ave, Syracuse, NY 13244, USA f Department of Nutrition, Food and Exercise Sciences, Florida State University, 120 Convocation Way, Tallahassee, FL 32306-1493, USA g Department of Exercise Science, University of South Carolina, 921 Assembly St, RM 131, Columbia, SC 29208, USA h Department of Physical Therapy, Wichita State University, 417 Ahlberg Hall, Wichita, KS 67260, USA i Department of Kinesiology and Community Health, University of Illinois at Urbana-Champaign, 227 Freer Hall, 906 South Goodwin Avenue, Urbana, IL 61801, USA b c
A R T I C L E I N F O
A B S T R A C T
Article history: Received 10 February 2010 Accepted 1 March 2010
This study examined whether the autonomic response to passive upright tilt as evidenced by changes in measures of heart rate and blood pressure variability differs between individuals with DS and without DS. Beat-to-beat blood pressure was measured in 26 individuals with Down syndrome (DS) and 11 individuals without DS during 5 min of rest and 5 min of upright tilt. Dependent variables included heart rate, blood pressure, frequency component measures of heart rate and blood pressure variability, and baroreflex sensitivity. The normalized high frequency (HF) power, normalized low frequency (LF) power, and LF/HF of heart rate variability, as well as the LF of blood pressure variability were reduced in persons with DS in response to upright tilt (p < 0.05). This was accompanied by smaller change in baroreflex sensitivity (p < 0.05) in individuals with DS. Blood pressure responses to upright tilt were also reduced in individuals with DS (p < 0.05), but the heart rate response did not differ between groups. Individuals with DS show less vagal withdrawal and sympatho-excitation in response to passive upright tilt. These effects may be partially mediated by smaller change in baroreflex sensitivity in individuals with DS. The results support the hypothesis of altered autonomic modulation in people with DS. ß 2010 Elsevier Ltd. All rights reserved.
Keywords: Down syndrome Autonomic function Heart rate Blood pressure
1. Introduction Individuals with Down syndrome (DS) are at high risk for cardiovascular morbidity and mortality (Day, Strauss, Shavelle, & Reynolds, 2005; Esbensen, Seltzer, & Greenberg, 2007), and have low levels of cardiovascular fitness (Fernhall et al., 1996; Pitetti, Climstein, Campbell, Barrett, & Jackson, 1992). These findings may be partially related to their altered cardiovascular
* Corresponding author. Tel.: +1 662 325 4772; fax: +1 662 325 4525. E-mail addresses: [email protected] (S. Agiovlasitis), [email protected] (S.R. Collier), [email protected] (T. Baynard), [email protected] (G.H. Echols), [email protected] (S. Goulopoulou), afi[email protected] (A. Figueroa), [email protected] (M.W. Beets), [email protected] (K.H. Pitetti), [email protected] (B. Fernhall). 0891-4222/$ – see front matter ß 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.ridd.2010.03.002
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autonomic function which has been evidenced in response to sympatho-excitatory tasks (Bricout et al., 2008; Fernhall et al., 2009; Fernhall et al., 2005; Fernhall & Otterstetter, 2003; Figueroa et al., 2005; Guerra, Llorens, & Fernhall, 2003; Iellamo et al., 2005). For instance, individuals with DS exhibit less vagal withdrawal than controls without disabilities during isometric hand-grip exercise (Figueroa et al., 2005). Similar findings have also been shown following active standing (Iellamo et al., 2005), but not during low level endurance exercise (Baynard, Pitetti, Guerra, & Fernhall, 2004). These findings suggest that different types of sympatho-stimulatory tasks provoke differential changes in autonomic regulation in persons with DS. However, there is little information regarding the sympathetic response to sympatho-stimulatory tasks in individuals with DS. Individuals with DS show blunted heart rate or blood pressure responses to a variety of adrenergic perturbations (Fernhall et al., 2005; Fernhall & Otterstetter, 2003; Fernhall et al., 1996; Figueroa et al., 2005; Guerra et al., 2003; Pitetti et al., 1992) which have been interpreted as blunted adrenergic responses. However, these data provide only indirect evidence for blunted adrenergic responses, since sympathetic modulation of heart rate and blood pressure was not measured. Although it is now well established that individuals with DS exhibit reduced catecholamine response to high intensity aerobic exercise (Bricout et al., 2008; Fernhall et al., 2009), this does not provide insight regarding neural autonomic regulation during low intensity tasks such as isometric or low intensity aerobic exercise, or maintenance of posture. Furthermore, in order to understand autonomic regulation of heart rate and blood pressure in persons with DS, it may be important to avoid procedures influenced by central command (Olufsen, Alston, Tran, Ottesen, & Novak, 2007), since differences in voluntary cortical activation between persons with and without DS may influence the results. Consequently, studies evaluating autonomic regulation while minimizing central command and measuring the contribution of both the parasympathetic and sympathetic systems are needed in persons with DS. Because no studies to date in persons with DS have investigated the neural sympathetic modulation during sympathostimulatory tasks, and almost all studies to date have used procedures involving central command, the purpose of the present study was to examine whether the autonomic response to upright tilt differs between individuals with DS and without DS. We chose passive upright tilt as a sympatho-stimulatory task, because central command is minimized during this procedure. We specifically examined potential differences in the responses of heart rate, blood pressure, frequency components of heart rate and blood pressure variability, as well as baroreflex sensitivity (BRS), between individuals with DS and individuals without disabilities. We hypothesized that individuals with DS will show less vagal withdrawal and lower sympathetic response to upright tilt.
2. Methods 2.1. Participants Twenty-six individuals with DS (8 women and 18 men; age range 16–40 years) and 11 individuals without DS or any other disability (6 women and 5 men; age range 17–39 years) participated in this study. The two groups of participants did not differ in age or body mass, but those with DS were shorter and had greater body mass index than participants without DS (Table 1). The parents or direct caregivers of participants with DS reported that these individuals had mild-to-moderate intellectual disability. All of the participants with and without DS were free of pulmonary or cardiovascular disorders. None of the participants smoked, took any medications that could affect the hemodynamic responses, or engaged in regular exercise training. The study was approved by the Institutional Review Board. Written informed consent was obtained from participants with and without DS as well as from the legal guardians of participants with DS. 2.2. Procedures All participants were familiarized with the protocol prior to data collection. Participants refrained from food for at least 4 h and from caffeine and exercise for 24 h prior to a data collection session. The session commenced with a 5-min supine period to bring physiologic functions to resting levels. Beat-to-beat blood pressure was then measured at a frequency of 200 Hz during 5 min of supine rest and 5 min of head-up tilt at an angle of 808, using finger photo-plethysmography (Portapres, TNO Biomedical Instrumentation, Amsterdam, The Netherlands). The cuff was applied to the middle finger of the non-dominant hand which was secured at heart level on the chest of participants. Table 1 Mean SD age and anthropometric characteristics of individuals with Down syndrome (DS) and individuals without Down syndrome (Non-DS). Group
Age (years) Height (m)* Body mass (kg) Body mass index (kg/m2)* *
DS (n = 26)
Non-DS (n = 11)
26.5 7.6 1.55 0.72 72.1 16.3 29.9 6.0
25.5 7.3 1.68 0.77 74.6 14.0 26.3 3.4
Difference between DS and Non-DS statistically significant (p < 0.05) in independent-samples t-test.
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2.3. Measures Vagal and sympathetic cardiovascular autonomic modulations were examined non-invasively using heart rate and blood pressure variability. The high frequency power (HF) of the heart rate variability spectrum reflects vagal cardiac modulation, its low frequency power (LF) offers information on both sympathetic and vagal outflows, and the ratio of LF/HF is considered an index of sympatho-vagal dominance (Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology, 1996). While these measures of heart rate variability provide information primarily on the vagal system, the LF power of the blood pressure variability spectrum is thought to provide information on vascular sympathetic modulation (Malliani, Pagani, Lombardi, & Cerutti, 1991). Additional information on cardiovascular regulation may be offered by examining the sensitivity of arterial baroreceptors which partially mediate the activity of the nucleus tractus solitarius in the medulla oblongata (Klabunde, 2004). These measures collectively offer clinically significant information on cardiovascular autonomic modulation involving both the sympathetic and parasympathetic systems (Tank et al., 2000; Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology, 1996; Taylor, Hayano, & Seals, 1995). All data were free of ectopy and artifact as confirmed by visual inspection. The data were subsequently processed and all variables were obtained with the WinCPRS software (Absolute Aliens, Turku, Finland) in accordance with widely accepted standards (Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology, 1996). The beat-to-beat blood pressure waveforms were utilized to generate blood pressure and heart rate variability variables. Specifically, the software generated the beat-to-beat systolic blood pressure time series and determined, with autoregressive modeling, the LF (power in 0.04–0.15 Hz) of blood pressure variability. From the blood pressure waves, the software also generated the time series of the R–R intervals which was autoregressively analyzed to obtain the spectral components of heart rate variability; total power, the normalized LF and HF (power in 0.04–0.15 and 0.15–0.4 Hz, respectively, normalized to total power from which the very low frequency power had been subtracted), and the LF/HF ratio. BRS was determined in the time domain using the sequence method (Bertinieri et al., 1985) which evaluates the vagal portion of the baroreflex (Cooke & Carter, 2005; Parlow, Viale, Annat, Hughson, & Quintin, 1995). Specifically, the software identified any occurrence of at least three consecutive beats in which both R–R interval and the corresponding systolic blood pressure (with a one beat lag) changed either negatively (Down-Down) or positively (Up-Up) for at least 4 ms and with a correlation of >0.8. Subsequently, the mean slopes of the Down-Down and the Up-Up sequences were calculated and pooled together, providing an index of BRS. In addition, the means of systolic and diastolic blood pressures, mean arterial pressure, pulse pressure, and heart rate across the resting and tilt periods were calculated. 2.4. Statistical analyses The dependent variables statistically evaluated included total power for heart rate variability, the normalized LF and HF, and the LF/HF of heart rate variability, the LF of blood pressure variability, BRS, the systolic and diastolic blood pressures, the mean arterial pressure, the pulse pressure, and the heart rate. The effects of DS and of the testing condition (rest vs. tilt) on each dependent variable were analyzed with 2 2 repeated-measures analysis of variance (ANOVA). When the interaction was significant, between-group differences at each level were evaluated with independent t-tests, whereas the responses to tilt were examined with paired t-tests within each group. For all analyses, the alpha level was set at 0.05. Statistical analyses were performed with SPSS 15.0 (SPSS Inc., Chicago, IL, USA). 3. Results The responses to upright tilt of the normalized HF, normalized LF, and LF/HF of heart rate variability, as well as the LF of blood pressure variability were significantly reduced in persons with DS than persons without DS (significant interactions p < 0.007; Fig. 1). For heart rate variability measures, follow-up analyses demonstrated that the normalized HF decreased (p 0.013), whereas the normalized LF (p 0.02) and the LF/HF increased (p 0.029) in response to tilt in both groups of participants. In addition, the LF of blood pressure variability increased with tilt in both groups (p = 0.019). There were no between-group differences in these four variables at rest. During tilt, however, the normalized HF was higher (p = 0.007), whereas the normalized LF, the LF/HF, and the LF of blood pressure variability were lower (p 0.039) in individuals with DS than those without DS. Total power did not differ between groups and decreased similarly in response to tilt in individuals with and without DS as shown by a significant condition effect (p = 0.004) without significant group effect or interaction. There was also a significant group-by-condition interaction for BRS (p < 0.05; Fig. 2). In response to tilt, BRS decreased (p = 0.001) in adults with and without DS, but, as indicated by the interaction the change was reduced in individuals with DS. This was because BRS was lower at rest (p < 0.05) in adults with DS, whereas it did not differ between groups during the tilt. The blood pressure responses to upright tilt were reduced in individuals with DS (significant interactions p 0.027; Fig. 3), but the heart rate response did not differ between groups. For both groups, systolic, diastolic, and mean arterial pressure increased in response to tilt (p 0.004). Individuals with DS had lower systolic blood pressure at rest and during tilt (p = 0.039 and 0.002, respectively) and lower diastolic and mean arterial pressure only during tilt (p 0.003) than adults
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Fig. 1. Spectral components of heart rate and blood pressure variability at rest and during upright tilt in individuals with Down syndrome (DS) and individuals without Down syndrome (Non-DS). (a) Normalized high frequency (HF) power; (b) normalized low frequency (LF) power; (c) LF/HF ratio; (d) total power of heart rate variability; (e) low frequency power of blood pressure variability (LF BPV). Normalized HF and LF are expressed as a fraction of total power, excluding its very low frequency component. The responses to tilt were reduced in individuals with DS (significant interactions) for all variables except total power. *p < 0.05 between groups; yp < 0.05 for main effect of condition (rest vs. tilt) without interaction; ôp < 0.05 between rest and tilt for DS group; §p < 0.05 between rest and tilt for Non-DS group.
without DS; there were no group differences in diastolic or mean arterial pressure at rest. Pulse pressure decreased similarly in the two groups of participants and was lower both at rest and during tilt in participants with DS as shown by significant condition and group effects (p = 0.005 and 0.028, respectively) without interaction. Heart rate increased similarly in both groups as shown by a significant condition effect (p < 0.001) without significant group effect or interaction.
Fig. 2. Baroreflex sensitivity (BRS) at rest and during upright tilt in individuals with Down syndrome (DS) and individuals without Down syndrome (NonDS). The response to tilt was reduced in individuals with DS (significant interaction). *p < 0.05 between groups; ôp < 0.05 between rest and tilt for DS group; § p < 0.05 between rest and tilt for Non-DS group.
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Fig. 3. Blood pressure and heart rate at rest and during upright tilt in individuals with Down syndrome (DS) and individuals without Down syndrome (NonDS). (a) Systolic blood pressure; (b) mean arterial pressure; (c) heart rate; (d) diastolic blood pressure; (e) pulse pressure. The response to tilt was reduced in individuals with DS (significant interaction) for all variables except heart rate. BP, blood pressure; *p < 0.05 between groups; yp < 0.05 for main effect of condition (rest vs. tilt) without interaction; zp < 0.05 for main effect of group (DS vs. Non-DS) across conditions; ôp < 0.05 between rest and tilt for DS group; § p < 0.05 between rest and tilt for Non-DS group.
4. Discussion This study examined whether cardiovascular responses to passive upright tilt, a procedure that minimizes the influence of central command, differ between individuals with and without DS. The main findings were that, compared to individuals without DS, persons with DS showed reduced vagal withdrawal and reduced vascular sympathetic modulation in response to upright tilt. These effects may be partially mediated by a smaller change in BRS in response to tilt in participants with DS. At rest, the lack of between-group differences in heart rate or any of the spectral components of heart rate or blood pressure variability suggests similar resting parasympathetic and sympathetic modulation in persons with and without DS. These findings support the results of previous studies (Figueroa et al., 2005; Goulopoulou et al., 2006; Iellamo et al., 2005). However, one study found greater resting parasympathetic modulation in people with DS (Baynard et al., 2004). Although such possibility has not been examined rigorously, a state of parasympathetic dominance in the present participants with DS may be reflected in their lower systolic blood pressure at rest. However, resting BRS as measured by the sequence method, which measures primarily the vagal portion of the baroreflex (Cooke & Carter, 2005; Parlow et al., 1995), was lower in participants with DS, suggesting lower vagal influence in persons with DS. Among the two previous studies that examined resting BRS in persons with and without DS, one found no difference between groups (Iellamo et al., 2005), whereas the other provided results similar to the ones in the present investigation (Heffernan et al., 2005). Although it is difficult to determine the reasons for this disparity, it may partially be due to differences in participant populations, since DS is a diverse condition with great inter-individual differences. However, lower baroreflex control of cardiac vagal drive may be due to the reportedly faster biological aging of persons with DS (Monahan et al., 2001; Roth, Sun, Greensite, Lott, & Dietrich, 1996). Alternately, the lower BRS may be the outcome of the lower resting pulse pressure of participants with DS which may decrease baroreceptor firing rate and sensitivity especially since mean arterial pressure did not differ between groups (Klabunde, 2004). Reduced pulse pressure among persons with DS may be related to greater peripheral vasodilation, increased systemic arterial compliance, or lower stroke volume; however, this has not been investigated in persons with DS.
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In response to upright tilt, persons with DS showed reduced vagal withdrawal and a smaller increase in sympathetic modulation than persons without DS, confirming our hypotheses. Reduced vagal withdrawal in response to standing (Iellamo et al., 2005) and hand-grip exercise (Figueroa et al., 2005) has been reported previously in persons with DS and may be partially mediated by the smaller change in BRS. Others have shown that the response of BRS to hand-grip exercise is similar in persons with and without DS (Heffernan et al., 2005). This disparity with the present result may be due to the different sympatho-excitatory stimuli. In the only previous study involving orthostatic stress (Iellamo et al., 2005), the BRS response to standing of people with and without DS was not evaluated statistically, and the prolonged standing (10 min) used in that study likely invoked considerable input from central command. In contrast, we provided evidence that the BRS response to passive upright tilt was reduced in persons with DS, potentially explaining their reduced vagal withdrawal. Nevertheless, the present findings and those of previous studies are consistent with a state of altered autonomic function in individuals with DS. During the tilt, the absolute BRS did not differ between groups, even though individuals with DS exhibited lower mean arterial pressure. Notably, the mean arterial pressure of participants without DS was near the ‘‘set-point’’ of 95 mmHg at which maximal baroreceptor sensitivity occurs in healthy individuals (Klabunde, 2004). The finding that individuals with DS had similar BRS, but lower mean arterial pressure may suggest a resetting of maximal sensitivity to a lower pressure in persons with DS. The validity of this argument should be tested empirically. It should be noted that past findings on BRS during perturbations in persons with DS have provided contradictory results. Specifically, persons with DS exhibited lower BRS than persons without DS during hand-grip exercise (Heffernan et al., 2005), whereas they showed higher BRS during standing (Iellamo et al., 2005). The reasons for these differing results between studies may partially relate to the different methodological approaches or to sample-size issues. Since the supine to stand test did not affect blood pressure (Iellamo et al., 2005), but upright tilt (our present data) increased blood pressure, it is possible that BRS is differentially affected by these procedures, which may be partially affected by differences in central command. Collectively, however, the present results and those of others suggest that, besides a reduced BRS response to upright tilt, additional factors may contribute to the higher parasympathetic modulation during tilt in participants with DS. One such potential factor is reduced afferent activity by chemoreceptors. In support of this argument, persons with DS show reduced catecholamine responsiveness to maximal exercise, another sympatho-excitatory activity (Bricout et al., 2008; Fernhall et al., 2009). Greater parasympathetic and reduced sympathetic modulation during tilt in persons with DS suggests a state of greater parasympathetic dominance which was also reflected in their lower LF/HF response. Furthermore, since the LF power of blood pressure variability, a measure of sympathetic modulation on blood vessels, increased less in persons with DS, this provides evidence for reduced sympathetic activation during tilt in individuals with DS. This is also consistent with the lower absolute blood pressure during tilt in participants with DS. Reduced blood pressure responses during sympatho-excitatory conditions in persons with DS have previously been documented (Fernhall & Otterstetter, 2003; Figueroa et al., 2005; Heffernan et al., 2005). Parasympathetic dominance during tilt, however, was not reflected in heart rate which did not differ between groups. This is in contrast to a past report of lower heart rates during sympatho-excitatory tests in persons with DS than persons without DS (Fernhall & Otterstetter, 2003; Figueroa et al., 2005; Guerra et al., 2003; Iellamo et al., 2005). This disparity may be related to different methodologies between studies. In the only previous examination that used upright tilt (Fernhall et al., 2005), persons with DS showed lower heart rates only after controlling for resting and peak heart rates. In the present study, such statistical control was not used because resting heart rates did not differ between groups and peak heart rates were not available. The causes of the differing effects on heart rate and blood pressure during tilt are difficult to discern from the present data. The lower blood pressure during tilt in persons with DS is likely, at least partially, due to their lower sympathetic response. This suggestion is supported by previous research showing that the blood pressure response to tilt is primarily sympathetically mediated (Cooke et al., 1999). Alternately, structural factors such as muscle hypotonia, which is common in persons with DS (American Academy of Pediatrics, 2001), may also affect the smooth muscle of their resistance vessels, potentially lowering vascular tone and peripheral resistance and resulting in lower blood pressure; however, there are presently no data to support this hypothesis. It is possible that this lower blood pressure during tilt of individuals with DS may have provided a greater baroreceptor-induced stimulus to increase their heart rate to the level of participants without DS. Several limitations of the present study warrant consideration. The use of indirect methods may have introduced some error in the assessment of autonomic function. These methods, however, are considered valid (Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology, 1996). Moreover, any measurement error should apply equally to both groups without systematically affecting between-group comparisons. A second limitation relates to the method employed to measure BRS; this method does not offer information on sympathetic contributions to the baroreflex. In addition, resting heart rate variability measures may have been partially affected by breathing rate which was not controlled in this study; however, pilot work indicated that controlling breathing rate was not feasible for individuals with DS. Finally, it should be considered that the differences between individuals with and without DS may also reflect possible effects of differences in body surface area and aerobic fitness. Future research should examine whether the differences in autonomic responses between individuals with and without DS are progressively increased with aging and whether they lead to further impairment in persons with DS. Furthermore, the possibility of resetting of maximal baroreceptor sensitivity in persons with DS and the ways in which such potential effect may alter autonomic function should be examined.
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Contents lists available at ScienceDirect
Research in Developmental Disabilities
Autonomic response to upright tilt in people with and without Down syndrome Stamatis Agiovlasitis a,*, Scott R. Collier b, Tracy Baynard c, George H. Echols d, Styliani Goulopoulou e, Arturo Figueroa f, Michael W. Beets g, Kenneth H. Pitetti h, Bo Fernhall i a
Department of Kinesiology, Mississippi State University, 233 McCarthy Gym, P.O. Box 6186, Mississippi State, MS 39762, USA Department of Health, Leisure, and Exercise Science, Appalachian State University, 054 Holmes Convention Center, 111 Rivers Street, Boone, NC 28608, USA Department of Kinesiology & Community Health, University of Illinois at Urbana-Champaign, 906 South Goodwin Avenue, MC-056, Urbana, IL 61801, USA d Department of Kinesiology & Community Health, University of Illinois at Urbana-Champaign, Rehabilitation Education Center, 1207 S. Oak St., Urbana, IL 61820, USA e Department of Exercise Science, Syracuse University, 820 Comstock Ave, Syracuse, NY 13244, USA f Department of Nutrition, Food and Exercise Sciences, Florida State University, 120 Convocation Way, Tallahassee, FL 32306-1493, USA g Department of Exercise Science, University of South Carolina, 921 Assembly St, RM 131, Columbia, SC 29208, USA h Department of Physical Therapy, Wichita State University, 417 Ahlberg Hall, Wichita, KS 67260, USA i Department of Kinesiology and Community Health, University of Illinois at Urbana-Champaign, 227 Freer Hall, 906 South Goodwin Avenue, Urbana, IL 61801, USA b c
A R T I C L E I N F O
A B S T R A C T
Article history: Received 10 February 2010 Accepted 1 March 2010
This study examined whether the autonomic response to passive upright tilt as evidenced by changes in measures of heart rate and blood pressure variability differs between individuals with DS and without DS. Beat-to-beat blood pressure was measured in 26 individuals with Down syndrome (DS) and 11 individuals without DS during 5 min of rest and 5 min of upright tilt. Dependent variables included heart rate, blood pressure, frequency component measures of heart rate and blood pressure variability, and baroreflex sensitivity. The normalized high frequency (HF) power, normalized low frequency (LF) power, and LF/HF of heart rate variability, as well as the LF of blood pressure variability were reduced in persons with DS in response to upright tilt (p < 0.05). This was accompanied by smaller change in baroreflex sensitivity (p < 0.05) in individuals with DS. Blood pressure responses to upright tilt were also reduced in individuals with DS (p < 0.05), but the heart rate response did not differ between groups. Individuals with DS show less vagal withdrawal and sympatho-excitation in response to passive upright tilt. These effects may be partially mediated by smaller change in baroreflex sensitivity in individuals with DS. The results support the hypothesis of altered autonomic modulation in people with DS. ß 2010 Elsevier Ltd. All rights reserved.
Keywords: Down syndrome Autonomic function Heart rate Blood pressure
1. Introduction Individuals with Down syndrome (DS) are at high risk for cardiovascular morbidity and mortality (Day, Strauss, Shavelle, & Reynolds, 2005; Esbensen, Seltzer, & Greenberg, 2007), and have low levels of cardiovascular fitness (Fernhall et al., 1996; Pitetti, Climstein, Campbell, Barrett, & Jackson, 1992). These findings may be partially related to their altered cardiovascular
* Corresponding author. Tel.: +1 662 325 4772; fax: +1 662 325 4525. E-mail addresses: [email protected] (S. Agiovlasitis), [email protected] (S.R. Collier), [email protected] (T. Baynard), [email protected] (G.H. Echols), [email protected] (S. Goulopoulou), afi[email protected] (A. Figueroa), [email protected] (M.W. Beets), [email protected] (K.H. Pitetti), [email protected] (B. Fernhall). 0891-4222/$ – see front matter ß 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.ridd.2010.03.002
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autonomic function which has been evidenced in response to sympatho-excitatory tasks (Bricout et al., 2008; Fernhall et al., 2009; Fernhall et al., 2005; Fernhall & Otterstetter, 2003; Figueroa et al., 2005; Guerra, Llorens, & Fernhall, 2003; Iellamo et al., 2005). For instance, individuals with DS exhibit less vagal withdrawal than controls without disabilities during isometric hand-grip exercise (Figueroa et al., 2005). Similar findings have also been shown following active standing (Iellamo et al., 2005), but not during low level endurance exercise (Baynard, Pitetti, Guerra, & Fernhall, 2004). These findings suggest that different types of sympatho-stimulatory tasks provoke differential changes in autonomic regulation in persons with DS. However, there is little information regarding the sympathetic response to sympatho-stimulatory tasks in individuals with DS. Individuals with DS show blunted heart rate or blood pressure responses to a variety of adrenergic perturbations (Fernhall et al., 2005; Fernhall & Otterstetter, 2003; Fernhall et al., 1996; Figueroa et al., 2005; Guerra et al., 2003; Pitetti et al., 1992) which have been interpreted as blunted adrenergic responses. However, these data provide only indirect evidence for blunted adrenergic responses, since sympathetic modulation of heart rate and blood pressure was not measured. Although it is now well established that individuals with DS exhibit reduced catecholamine response to high intensity aerobic exercise (Bricout et al., 2008; Fernhall et al., 2009), this does not provide insight regarding neural autonomic regulation during low intensity tasks such as isometric or low intensity aerobic exercise, or maintenance of posture. Furthermore, in order to understand autonomic regulation of heart rate and blood pressure in persons with DS, it may be important to avoid procedures influenced by central command (Olufsen, Alston, Tran, Ottesen, & Novak, 2007), since differences in voluntary cortical activation between persons with and without DS may influence the results. Consequently, studies evaluating autonomic regulation while minimizing central command and measuring the contribution of both the parasympathetic and sympathetic systems are needed in persons with DS. Because no studies to date in persons with DS have investigated the neural sympathetic modulation during sympathostimulatory tasks, and almost all studies to date have used procedures involving central command, the purpose of the present study was to examine whether the autonomic response to upright tilt differs between individuals with DS and without DS. We chose passive upright tilt as a sympatho-stimulatory task, because central command is minimized during this procedure. We specifically examined potential differences in the responses of heart rate, blood pressure, frequency components of heart rate and blood pressure variability, as well as baroreflex sensitivity (BRS), between individuals with DS and individuals without disabilities. We hypothesized that individuals with DS will show less vagal withdrawal and lower sympathetic response to upright tilt.
2. Methods 2.1. Participants Twenty-six individuals with DS (8 women and 18 men; age range 16–40 years) and 11 individuals without DS or any other disability (6 women and 5 men; age range 17–39 years) participated in this study. The two groups of participants did not differ in age or body mass, but those with DS were shorter and had greater body mass index than participants without DS (Table 1). The parents or direct caregivers of participants with DS reported that these individuals had mild-to-moderate intellectual disability. All of the participants with and without DS were free of pulmonary or cardiovascular disorders. None of the participants smoked, took any medications that could affect the hemodynamic responses, or engaged in regular exercise training. The study was approved by the Institutional Review Board. Written informed consent was obtained from participants with and without DS as well as from the legal guardians of participants with DS. 2.2. Procedures All participants were familiarized with the protocol prior to data collection. Participants refrained from food for at least 4 h and from caffeine and exercise for 24 h prior to a data collection session. The session commenced with a 5-min supine period to bring physiologic functions to resting levels. Beat-to-beat blood pressure was then measured at a frequency of 200 Hz during 5 min of supine rest and 5 min of head-up tilt at an angle of 808, using finger photo-plethysmography (Portapres, TNO Biomedical Instrumentation, Amsterdam, The Netherlands). The cuff was applied to the middle finger of the non-dominant hand which was secured at heart level on the chest of participants. Table 1 Mean SD age and anthropometric characteristics of individuals with Down syndrome (DS) and individuals without Down syndrome (Non-DS). Group
Age (years) Height (m)* Body mass (kg) Body mass index (kg/m2)* *
DS (n = 26)
Non-DS (n = 11)
26.5 7.6 1.55 0.72 72.1 16.3 29.9 6.0
25.5 7.3 1.68 0.77 74.6 14.0 26.3 3.4
Difference between DS and Non-DS statistically significant (p < 0.05) in independent-samples t-test.
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2.3. Measures Vagal and sympathetic cardiovascular autonomic modulations were examined non-invasively using heart rate and blood pressure variability. The high frequency power (HF) of the heart rate variability spectrum reflects vagal cardiac modulation, its low frequency power (LF) offers information on both sympathetic and vagal outflows, and the ratio of LF/HF is considered an index of sympatho-vagal dominance (Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology, 1996). While these measures of heart rate variability provide information primarily on the vagal system, the LF power of the blood pressure variability spectrum is thought to provide information on vascular sympathetic modulation (Malliani, Pagani, Lombardi, & Cerutti, 1991). Additional information on cardiovascular regulation may be offered by examining the sensitivity of arterial baroreceptors which partially mediate the activity of the nucleus tractus solitarius in the medulla oblongata (Klabunde, 2004). These measures collectively offer clinically significant information on cardiovascular autonomic modulation involving both the sympathetic and parasympathetic systems (Tank et al., 2000; Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology, 1996; Taylor, Hayano, & Seals, 1995). All data were free of ectopy and artifact as confirmed by visual inspection. The data were subsequently processed and all variables were obtained with the WinCPRS software (Absolute Aliens, Turku, Finland) in accordance with widely accepted standards (Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology, 1996). The beat-to-beat blood pressure waveforms were utilized to generate blood pressure and heart rate variability variables. Specifically, the software generated the beat-to-beat systolic blood pressure time series and determined, with autoregressive modeling, the LF (power in 0.04–0.15 Hz) of blood pressure variability. From the blood pressure waves, the software also generated the time series of the R–R intervals which was autoregressively analyzed to obtain the spectral components of heart rate variability; total power, the normalized LF and HF (power in 0.04–0.15 and 0.15–0.4 Hz, respectively, normalized to total power from which the very low frequency power had been subtracted), and the LF/HF ratio. BRS was determined in the time domain using the sequence method (Bertinieri et al., 1985) which evaluates the vagal portion of the baroreflex (Cooke & Carter, 2005; Parlow, Viale, Annat, Hughson, & Quintin, 1995). Specifically, the software identified any occurrence of at least three consecutive beats in which both R–R interval and the corresponding systolic blood pressure (with a one beat lag) changed either negatively (Down-Down) or positively (Up-Up) for at least 4 ms and with a correlation of >0.8. Subsequently, the mean slopes of the Down-Down and the Up-Up sequences were calculated and pooled together, providing an index of BRS. In addition, the means of systolic and diastolic blood pressures, mean arterial pressure, pulse pressure, and heart rate across the resting and tilt periods were calculated. 2.4. Statistical analyses The dependent variables statistically evaluated included total power for heart rate variability, the normalized LF and HF, and the LF/HF of heart rate variability, the LF of blood pressure variability, BRS, the systolic and diastolic blood pressures, the mean arterial pressure, the pulse pressure, and the heart rate. The effects of DS and of the testing condition (rest vs. tilt) on each dependent variable were analyzed with 2 2 repeated-measures analysis of variance (ANOVA). When the interaction was significant, between-group differences at each level were evaluated with independent t-tests, whereas the responses to tilt were examined with paired t-tests within each group. For all analyses, the alpha level was set at 0.05. Statistical analyses were performed with SPSS 15.0 (SPSS Inc., Chicago, IL, USA). 3. Results The responses to upright tilt of the normalized HF, normalized LF, and LF/HF of heart rate variability, as well as the LF of blood pressure variability were significantly reduced in persons with DS than persons without DS (significant interactions p < 0.007; Fig. 1). For heart rate variability measures, follow-up analyses demonstrated that the normalized HF decreased (p 0.013), whereas the normalized LF (p 0.02) and the LF/HF increased (p 0.029) in response to tilt in both groups of participants. In addition, the LF of blood pressure variability increased with tilt in both groups (p = 0.019). There were no between-group differences in these four variables at rest. During tilt, however, the normalized HF was higher (p = 0.007), whereas the normalized LF, the LF/HF, and the LF of blood pressure variability were lower (p 0.039) in individuals with DS than those without DS. Total power did not differ between groups and decreased similarly in response to tilt in individuals with and without DS as shown by a significant condition effect (p = 0.004) without significant group effect or interaction. There was also a significant group-by-condition interaction for BRS (p < 0.05; Fig. 2). In response to tilt, BRS decreased (p = 0.001) in adults with and without DS, but, as indicated by the interaction the change was reduced in individuals with DS. This was because BRS was lower at rest (p < 0.05) in adults with DS, whereas it did not differ between groups during the tilt. The blood pressure responses to upright tilt were reduced in individuals with DS (significant interactions p 0.027; Fig. 3), but the heart rate response did not differ between groups. For both groups, systolic, diastolic, and mean arterial pressure increased in response to tilt (p 0.004). Individuals with DS had lower systolic blood pressure at rest and during tilt (p = 0.039 and 0.002, respectively) and lower diastolic and mean arterial pressure only during tilt (p 0.003) than adults
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Fig. 1. Spectral components of heart rate and blood pressure variability at rest and during upright tilt in individuals with Down syndrome (DS) and individuals without Down syndrome (Non-DS). (a) Normalized high frequency (HF) power; (b) normalized low frequency (LF) power; (c) LF/HF ratio; (d) total power of heart rate variability; (e) low frequency power of blood pressure variability (LF BPV). Normalized HF and LF are expressed as a fraction of total power, excluding its very low frequency component. The responses to tilt were reduced in individuals with DS (significant interactions) for all variables except total power. *p < 0.05 between groups; yp < 0.05 for main effect of condition (rest vs. tilt) without interaction; ôp < 0.05 between rest and tilt for DS group; §p < 0.05 between rest and tilt for Non-DS group.
without DS; there were no group differences in diastolic or mean arterial pressure at rest. Pulse pressure decreased similarly in the two groups of participants and was lower both at rest and during tilt in participants with DS as shown by significant condition and group effects (p = 0.005 and 0.028, respectively) without interaction. Heart rate increased similarly in both groups as shown by a significant condition effect (p < 0.001) without significant group effect or interaction.
Fig. 2. Baroreflex sensitivity (BRS) at rest and during upright tilt in individuals with Down syndrome (DS) and individuals without Down syndrome (NonDS). The response to tilt was reduced in individuals with DS (significant interaction). *p < 0.05 between groups; ôp < 0.05 between rest and tilt for DS group; § p < 0.05 between rest and tilt for Non-DS group.
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Fig. 3. Blood pressure and heart rate at rest and during upright tilt in individuals with Down syndrome (DS) and individuals without Down syndrome (NonDS). (a) Systolic blood pressure; (b) mean arterial pressure; (c) heart rate; (d) diastolic blood pressure; (e) pulse pressure. The response to tilt was reduced in individuals with DS (significant interaction) for all variables except heart rate. BP, blood pressure; *p < 0.05 between groups; yp < 0.05 for main effect of condition (rest vs. tilt) without interaction; zp < 0.05 for main effect of group (DS vs. Non-DS) across conditions; ôp < 0.05 between rest and tilt for DS group; § p < 0.05 between rest and tilt for Non-DS group.
4. Discussion This study examined whether cardiovascular responses to passive upright tilt, a procedure that minimizes the influence of central command, differ between individuals with and without DS. The main findings were that, compared to individuals without DS, persons with DS showed reduced vagal withdrawal and reduced vascular sympathetic modulation in response to upright tilt. These effects may be partially mediated by a smaller change in BRS in response to tilt in participants with DS. At rest, the lack of between-group differences in heart rate or any of the spectral components of heart rate or blood pressure variability suggests similar resting parasympathetic and sympathetic modulation in persons with and without DS. These findings support the results of previous studies (Figueroa et al., 2005; Goulopoulou et al., 2006; Iellamo et al., 2005). However, one study found greater resting parasympathetic modulation in people with DS (Baynard et al., 2004). Although such possibility has not been examined rigorously, a state of parasympathetic dominance in the present participants with DS may be reflected in their lower systolic blood pressure at rest. However, resting BRS as measured by the sequence method, which measures primarily the vagal portion of the baroreflex (Cooke & Carter, 2005; Parlow et al., 1995), was lower in participants with DS, suggesting lower vagal influence in persons with DS. Among the two previous studies that examined resting BRS in persons with and without DS, one found no difference between groups (Iellamo et al., 2005), whereas the other provided results similar to the ones in the present investigation (Heffernan et al., 2005). Although it is difficult to determine the reasons for this disparity, it may partially be due to differences in participant populations, since DS is a diverse condition with great inter-individual differences. However, lower baroreflex control of cardiac vagal drive may be due to the reportedly faster biological aging of persons with DS (Monahan et al., 2001; Roth, Sun, Greensite, Lott, & Dietrich, 1996). Alternately, the lower BRS may be the outcome of the lower resting pulse pressure of participants with DS which may decrease baroreceptor firing rate and sensitivity especially since mean arterial pressure did not differ between groups (Klabunde, 2004). Reduced pulse pressure among persons with DS may be related to greater peripheral vasodilation, increased systemic arterial compliance, or lower stroke volume; however, this has not been investigated in persons with DS.
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In response to upright tilt, persons with DS showed reduced vagal withdrawal and a smaller increase in sympathetic modulation than persons without DS, confirming our hypotheses. Reduced vagal withdrawal in response to standing (Iellamo et al., 2005) and hand-grip exercise (Figueroa et al., 2005) has been reported previously in persons with DS and may be partially mediated by the smaller change in BRS. Others have shown that the response of BRS to hand-grip exercise is similar in persons with and without DS (Heffernan et al., 2005). This disparity with the present result may be due to the different sympatho-excitatory stimuli. In the only previous study involving orthostatic stress (Iellamo et al., 2005), the BRS response to standing of people with and without DS was not evaluated statistically, and the prolonged standing (10 min) used in that study likely invoked considerable input from central command. In contrast, we provided evidence that the BRS response to passive upright tilt was reduced in persons with DS, potentially explaining their reduced vagal withdrawal. Nevertheless, the present findings and those of previous studies are consistent with a state of altered autonomic function in individuals with DS. During the tilt, the absolute BRS did not differ between groups, even though individuals with DS exhibited lower mean arterial pressure. Notably, the mean arterial pressure of participants without DS was near the ‘‘set-point’’ of 95 mmHg at which maximal baroreceptor sensitivity occurs in healthy individuals (Klabunde, 2004). The finding that individuals with DS had similar BRS, but lower mean arterial pressure may suggest a resetting of maximal sensitivity to a lower pressure in persons with DS. The validity of this argument should be tested empirically. It should be noted that past findings on BRS during perturbations in persons with DS have provided contradictory results. Specifically, persons with DS exhibited lower BRS than persons without DS during hand-grip exercise (Heffernan et al., 2005), whereas they showed higher BRS during standing (Iellamo et al., 2005). The reasons for these differing results between studies may partially relate to the different methodological approaches or to sample-size issues. Since the supine to stand test did not affect blood pressure (Iellamo et al., 2005), but upright tilt (our present data) increased blood pressure, it is possible that BRS is differentially affected by these procedures, which may be partially affected by differences in central command. Collectively, however, the present results and those of others suggest that, besides a reduced BRS response to upright tilt, additional factors may contribute to the higher parasympathetic modulation during tilt in participants with DS. One such potential factor is reduced afferent activity by chemoreceptors. In support of this argument, persons with DS show reduced catecholamine responsiveness to maximal exercise, another sympatho-excitatory activity (Bricout et al., 2008; Fernhall et al., 2009). Greater parasympathetic and reduced sympathetic modulation during tilt in persons with DS suggests a state of greater parasympathetic dominance which was also reflected in their lower LF/HF response. Furthermore, since the LF power of blood pressure variability, a measure of sympathetic modulation on blood vessels, increased less in persons with DS, this provides evidence for reduced sympathetic activation during tilt in individuals with DS. This is also consistent with the lower absolute blood pressure during tilt in participants with DS. Reduced blood pressure responses during sympatho-excitatory conditions in persons with DS have previously been documented (Fernhall & Otterstetter, 2003; Figueroa et al., 2005; Heffernan et al., 2005). Parasympathetic dominance during tilt, however, was not reflected in heart rate which did not differ between groups. This is in contrast to a past report of lower heart rates during sympatho-excitatory tests in persons with DS than persons without DS (Fernhall & Otterstetter, 2003; Figueroa et al., 2005; Guerra et al., 2003; Iellamo et al., 2005). This disparity may be related to different methodologies between studies. In the only previous examination that used upright tilt (Fernhall et al., 2005), persons with DS showed lower heart rates only after controlling for resting and peak heart rates. In the present study, such statistical control was not used because resting heart rates did not differ between groups and peak heart rates were not available. The causes of the differing effects on heart rate and blood pressure during tilt are difficult to discern from the present data. The lower blood pressure during tilt in persons with DS is likely, at least partially, due to their lower sympathetic response. This suggestion is supported by previous research showing that the blood pressure response to tilt is primarily sympathetically mediated (Cooke et al., 1999). Alternately, structural factors such as muscle hypotonia, which is common in persons with DS (American Academy of Pediatrics, 2001), may also affect the smooth muscle of their resistance vessels, potentially lowering vascular tone and peripheral resistance and resulting in lower blood pressure; however, there are presently no data to support this hypothesis. It is possible that this lower blood pressure during tilt of individuals with DS may have provided a greater baroreceptor-induced stimulus to increase their heart rate to the level of participants without DS. Several limitations of the present study warrant consideration. The use of indirect methods may have introduced some error in the assessment of autonomic function. These methods, however, are considered valid (Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology, 1996). Moreover, any measurement error should apply equally to both groups without systematically affecting between-group comparisons. A second limitation relates to the method employed to measure BRS; this method does not offer information on sympathetic contributions to the baroreflex. In addition, resting heart rate variability measures may have been partially affected by breathing rate which was not controlled in this study; however, pilot work indicated that controlling breathing rate was not feasible for individuals with DS. Finally, it should be considered that the differences between individuals with and without DS may also reflect possible effects of differences in body surface area and aerobic fitness. Future research should examine whether the differences in autonomic responses between individuals with and without DS are progressively increased with aging and whether they lead to further impairment in persons with DS. Furthermore, the possibility of resetting of maximal baroreceptor sensitivity in persons with DS and the ways in which such potential effect may alter autonomic function should be examined.
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