Pediatr Cardiol (2015) 36:344–349 DOI 10.1007/s00246-014-1012-5
ORIGINAL ARTICLE
Cardiac Autonomic Modulation of Children with Down Syndrome Tatiana Dias de Carvalho • Luiz Carlos de Abreu • Zan Mustacchi • Luiz Carlos Marques Vanderlei • Moacir Fernandes Godoy • Rodrigo Daminello Raimundo Celso Ferreira Filho • Talita Dias da Silva • Laura Guilhoto • Viviane Perico • Vivian Ribeiro Finotti • Celso Ferreira
•
Received: 26 May 2014 / Accepted: 20 August 2014 / Published online: 28 August 2014 Ó Springer Science+Business Media New York 2014
Abstract The aim of this study is to analyze the autonomic modulation in children with Down syndrome (DS). The study was conducted with a convenience sample of children with DS and without heart disease, from the Genetics Clinic of the Hospital Infantil Darcy Vargas and APAE Sa˜o Paulo, Sa˜o Paulo, SP, Brazil. The control group was matched for sex and age. The analysis of autonomic modulation was performed using the indices of heart rate variability (HRV). The children remained in the supine position with spontaneous breathing for 20 min. Heart rate was recorded beat-to-beat. HRV analysis was performed in time and frequency domain. For data analysis, we used Student’s t test: unpaired and Mann–Whitney. It was considered statistically significant at p \ 0.05. From 75 children with DS, 50 were excluded, a total of 25 children [16 boys, 8.6 (1.4) years] participated in this study, and the
control group also consisted of 25 children [16 boys, 9.0 (1.2) years] without the syndrome. The BMI of the volunteers with DS was higher than the controls [19.1 (2.9) vs. 15.8 (1.2), p \ 0.0001]. There were differences between groups in the indices in frequency domain: LFms2 [1242.1 (788.25) vs. 786.44 (481.90), p = 0.040], LFun [69.104 (11.247) vs. 57.348 (11.683), p = 0.0004], HFun [30.896 (11.247) vs. 42.520 (11.634), p = 0.0004] and LF/HF [2.594 (1.104) vs. 1.579 (0.9982), p = 0.0004]. No differences were observed in time domain indices. The results indicate increased indices representing the sympathetic branch of the autonomic nervous system and those that indicate the overall modulation in children with DS.
T. D. de Carvalho (&) T. D. da Silva V. R. Finotti C. Ferreira Departamento de Medicina, Disciplina de Cardiologia, Universidade Federal de Sa˜o Paulo (UNIFESP), Rua Napolea˜o de Barros, 715 Te´rreo Vila Clementino, Sa˜o Paulo, SP, Brazil e-mail: [email protected]
L. C. M. Vanderlei Departamento de Fisioterapia da Faculdade de Cieˆncias e Tecnologia, Universidade Estadual Paulista (UNESP), Presidente Prudente, SP, Brazil
T. D. de Carvalho L. C. de Abreu R. D. Raimundo T. D. da Silva Laborato´rio de Escrita Cientı´fica da Faculdade de Medicina do ABC (FMABC), Santo Andre´, SP, Brazil L. C. de Abreu Departamento de Sau´de Materno-infantil da Faculdade de Sau´de Pu´blica, Universidade de Sa˜o Paulo (USP), Sa˜o Paulo, SP, Brazil Z. Mustacchi Ambulato´rio de Gene´tica do Hospital Infantil Darcy Vargas, Sa˜o Paulo, SP, Brazil
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Keywords Autonomic nervous system Children Heart rate variability Down syndrome
M. F. Godoy Nu´cleo Transdisciplinar de Estudos do Caos e da Complexidade, Faculdade de Medicina de Sa˜o Jose´ de Rio Preto (FAMERP), Sa˜o Jose´ do Rio Preto, SP, Brazil C. Ferreira Filho Departamento de Medicina, Disciplina de Clı´nica Me´dica, Universidade Federal de Sa˜o Paulo (UNIFESP), Sa˜o Paulo, SP, Brazil L. Guilhoto V. Perico ˜ O PAULO (Association of Parents and Friends of APAE SA People With Intellectual Disability of Sa˜o Paulo), Sa˜o Paulo, SP, Brazil
Pediatr Cardiol (2015) 36:344–349
Introduction Down syndrome (DS) is typically characterized by delayed psychomotor, brain, and neurological development (it is the most common genetic cause of intellectual disability), and it is associated with an increased risk for various congenital and other organic disorders such as muscle hypotonia, hypothyroidism, gastrointestinal and pulmonary disorders, leukemia, Alzheimer’s disease and dementia, and congenital heart disease [8, 31]. It has recently been suggested that subjects with DS not suffering from concomitant congenital heart disease may exhibit a dysfunction in autonomic cardiac modulation [16]. Autonomic function can be assessed using heart rate variability (HRV) analysis, which is a noninvasive measure of the balance between sympathetic and parasympathetic mediators of heart rate [17], since it describes the oscillation of the intervals between consecutive heart beats (RR intervals), which are related to the influences of the ANS on the sinus node [29, 34]. Preliminary data show that individuals with DS have low physical work capacity, chronotropic incompetence, and significantly reduced heart rate and blood pressure responses to autonomic tasks compared with nondisabled control subjects [8, 16]. This could be related to both depressed sympathetic tone and response as incomplete vagal withdrawal [6]. Alterations in the sympathetic and parasympathetic modulation of heart rate are indicative of autonomic dysfunction and are important because these changes are associated with increased risk of early mortality and morbidity [2, 3, 6, 29]. Given the longer life expectancy in this population [4, 31] a more thorough understanding of autonomic cardiac regulation in children with DS might have important clinical implications. Thus, the aim of the present study is to analyze the cardiac autonomic modulation in children with DS.
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central nervous system malformations and/or neurological syndromes; (3) Absence of metabolic disorders; (4) Absence of respiratory disorders; (5) Absence of medication that influences the cardiac autonomic modulation or any other medication that alters metabolic responses. None of the children were participating in a formal exercise training program. Ethics Statement The study protocol was approved by the Ethics Committee of Universidade Federal de Sa˜o Paulo (Federal University of Sa˜o Paulo—protocol number 1773/11) and followed the guidelines and rules for research involving human subjects, contained in Resolution number 466/12 of the Conselho Nacional de Sau´de (National Health Council). The volunteers and their parents or legal guardian were informed about the procedures and objectives of the study and, after both agreed to participate, the parents/guardians signed terms of informed consent because children in the age group of this research are not considered legally able to sign such an agreement. Procedure
Methods
Data were collected under controlled temperature (21–23 °C) and humidity (40–60 %). Participants went to the laboratory between 8:00 am and 11:00 am. They were instructed to avoid consuming caffeine for 24 h before evaluation. Parents/guardian of the children stayed in the room, during all protocol. Body weight and height were measured to calculate body mass index, following the standard recommendations proposed by Lohman et al. [20]. The heart rate receiver (Polar RS800 CX monitor, Polar Electro OY, Kempele, Finland) was placed on the chest over the distal third of the sternum. This type of equipment was validated for beat-bybeat measurements and for HRV analysis [11, 18, 33]. Children rested in supine position with spontaneous breathing for 20 min and were instructed to avoid talking during data collection.
Subjects
Heart Rate Variability
Individuals with DS were recruited from the Hospital Infantil Darcy Vargas (Darcy Vargas Children Hospital) and the ˜ O PAULO (Association of Parents and Friends of APAE SA People with Intellectual Disability of Sa˜o Paulo), Sa˜o Paulo, Brazil. The control group was composed of age- and gendermatched healthy children without DS from schools. All volunteers in this study met the following inclusion criteria: (1) Absence of congenital anomalies such as congenital heart disease and pulmonary malformations; (2) Absence of
For HRV analysis, the data series was first digitally filtered using Polar Precision Performance SW software (version 4.01.029; Polar), in which only series with more than 95 % sinus rhythm beats were included. It was then manually complemented, and the visual inspection of the time series on the computer showed absence of artifacts. Finally, 1000 consecutive RR intervals were selected for data analysis [13]. HRV analysis was performed with linear methods in the domains of time and frequency [29, 34].
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Pediatr Cardiol (2015) 36:344–349
Table 1 Average values and standard deviations for age, weight, height and body mass index in children with DS and controls. Sa˜o Paulo, Brazil, 2014 Variables
DS average (SD) [CI]
Controls average (SD) [CI]
Age (years)
8.600 (1.414)
9.080 (1.222)
Table 2 Heart rate variability analysis in time domain of children with DS and controls. Sa˜o Paulo, Brazil, 2014 Variables
p MeanRR (ms)
[8.016–9.184]
[8.576–9.584]
Weight (kg)
29.343 (7.124)
31.348 (3.824)
[26.402–32.284]
[29.769–32.927]
Height (m)
1.235 (0.09823)
1.406 (0.07304)
[1.195–1.276]
[1.376–1.436]
19.104 (2.997)
15.835 (1.215)
[17.867–20.341]
[15.333–16.337]
2
BMI (kg/m )
0.2053 SDNN (ms) 0.2230 RMSSD (ms) \0.0001* NN50 (ms) \0.0001* pNN50 (ms)
BMI body mass index, SD standard deviation, CI confidence interval * p \ 0.05
In the time domain were used the root mean square of successive differences (RMSSD), the percentage of differences between adjacent normal-to-normal intervals greater than 50 ms (pNN50) and the differences between adjacent normal-to-normal intervals greater than 50 ms (NN50) that indicate isolated parasympathetic activity; and the standard deviation of normal-to-normal intervals (SDNN) which represents global variability [29, 34]. In the frequency domain, the spectral components of low frequency (LF: 0.04–0.15 Hz) which indicates global variability and high frequency (HF: 0.15–0.40 Hz) that indicates parasympathetic activity in normalized units (LFun and HFun, respectively) and in milliseconds squared were used, as well as the ratio between these components (LF/HF). Spectral analysis was performed using the fast Fourier transform algorithm [29, 34]. For analysis of indexes of HRV, we used the software program Kubios (Biosignal Analysis and Medical Image Group, Department of Physics, University of Kuopio, Finland) [24].
Statistical Analysis Each variable was checked for normality of distribution by the Shapiro-Wilks test. Comparisons between groups were performed using the independent Student’s t test for parametric sample distribution (MeanRR, SDNN, RMSSD, NN50, pNN50) or Mann–Whitney U-test for nonparametric (LFms, LFun, HFms, HFun, LF/HF). Descriptive statistics with estimates of mean, standard deviation were used, and differences were considered statistically significant when the probability of a Type I error was lower than 5 % (p \ 0.05). The statistical program was InStat3 (GraphPad Software Inc., La Jolla, CA, USA).
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DS median (SD) [CI]
Controls median (SD) [CI]
p
0.4688
645.26 (83.472)
661.41 (72.473)
[610.81–679.72]
[631.49–691.32]
57.832 (17.136) [50.758–64.906]
48.732 (15.264) [42.431–55.033]
0.0531
39.056 (13.467)
33.988 (13.294)
0.1869
[33.497–44.615]
[28.500–39.476]
198.72 (125.41)
138.40 (109.93)
[146.95–250.49]
[93.022–183.78]
19.872 (12.541)
13.840 (10.993)
[14.695–25.049]
[9.302–18.378]
0.0768 0.0768
SD standard deviation, CI confidence interval, ms milliseconds, RRi RR intervals, SDNN standard deviation normal-to-normal intervals, RMSSD root mean square of successive differences, NN50 adjacent normal-to-normal intervals that are greater than 50 ms, pNN50 percentage of differences between adjacent normal-to-normal intervals that are greater than 50 ms * p \ 0.05
Table 3 Heart rate variability analysis in frequency domain of children with DS and controls. Sa˜o Paulo, Brazil, 2014 Variables
DS median (SD) [CI]
Controls median (SD) [CI]
p
LF (ms2)
1242.1 (788.25)
786.44 (481.90)
0.0417*
{1218.0}
{644.00}
HF (ms2)
LF (un)
HF (un)
LF/HF
[916.69–1567.5]
[587.51–985.37]
553.00 (346.76)
589.24 (423.04)
{502.00}
{514.00}
[409.86–696.14]
[414.61–763.87]
69.104 (11.247)
57.348 (11.683)
{71.400}
{59.200}
[64.461–73.747] 30.896 (11.247)
[52.525–62.171] 42.520 (11.634)
{28.600}
{40.600}
[26.253–35.539]
[37.717–47.323]
2.594 (1.104)
1.579 (0.9982)
{2.502}
{1.457}
[2.138–3.050]
[1.167–1.991]
0.9923
0.0004*
0.0004*
0.0004*
SD standard deviation, CI confidence interval, LF low frequency, HF high frequency, ms milliseconds, un normalized units * p \ 0.05
Results We selected 75 children with DS of whom 50 were excluded for the following criteria: history of congenital heart disease or other cardiac problems (10), presence of metabolic diseases (10), current use of medications that
Pediatr Cardiol (2015) 36:344–349
would alter the cardiac autonomic modulation (20), and series with less than 95 % sinus rhythm beats (10). 25 children participated in this study (16 boys) and the control group comprised 25 children (16 boys) without the syndrome. Table 1 shows average values for age and anthropometric characteristics of DS children and controls. There were significant differences in height and BMI. Table 2 depicts the values for the RR interval and the SDNN, RMSSD, NN50, and pNN50 indices. There were no significant differences in these indices. Table 3 displays the values obtained for LF and HF indices and the LF/HF ratio in children with DS and controls. There were significant differences in the following indices: LFms2, LFun, HFun and LF/HF.
Discussion The novel finding of the current investigation is increasing HRV indices representing the sympathetic branch of the ANS and those that indicate the overall modulation. Regarding to anthropometric characteristics, no differences were observed between groups for age or body weight; however, the participants with DS were significantly shorter and had a larger BMI. Children with DS are at high risk of many disorders known to influence growth and the short stature is a characteristic of the syndrome [31]. Also, overweight and overfeeding require attention in caring for children with DS [21, 25], the prevalence of obesity in these individuals is around 31–47 % [21]. Although overweight causes alterations in cardiac autonomic function [28, 35], the observed difference in BMI values did not influence our results with respect to HRV and that is consistent with others searches [10, 12, 14]. The study of Figueroa et al. [10] evaluated this issue, and the authors suggested that autonomic dysfunction of DS may be independent of obesity. Similarly, Gouloupolou et al. [14] found no significant correlations between BMI and cardiac autonomic control at rest. And Giodaki et al. [12] reported that their results were not influenced either by weight alone or by BMI, emphasizing that dysfunction is independent of obesity in DS. Regarding HRV analysis in the time domain, no significant differences between groups were observed (Table 2). This is consistent with data from several studies that also reported no differences in HRV indices during rest [1, 2, 9, 10]. In the study of Ferri et al. [9], the abnormal imbalance between the sympathetic (increased) and vagal (decreased) systems in persons with DS was not identified during rest. Figueroa et al. [10] did not report differences between groups during rest, when investigated the
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modulation of HR and BP during isometric handgrip test. In other autonomic test, Agiovlasitis et al. [1, 2] found no differences in HRV in persons with DS in the rest period before the postural change. Iellamo et al. [16], evaluating the heart rate response to the active postural change, did not find differences between RR intervals during rest. In the frequency domain analysis, LFms2 index was higher in children with DS and no differences were found between groups for HFms2 index. The LF index is the combined action of branches of the ANS, with sympathetic predominance, and HF index represents the action of the isolated parasympathetic activity [29, 34]. Suggesting, therefore, that children with DS have an increased sympathetic activity and parasympathetic modulation similar to control group. When we analyzed in normalized units, LF index showed to be significantly higher in children with DS, whereas the HF index was lower. These changes, apparently contradictory in relation to that described above, are related to method for calculating these indexes. The indices in normalized units represent the relative value of each spectral component (LF and HF) in relation to total power minus the component of very low frequency (VLF) [29, 34]. Thus, with the increase in LF component area with no change in HF area, as observed in DS children, when these data are normalized, we found higher values for the LF and lower values for HF (Table 3). Also in frequency domain, the LF/HF ratio which indicates the balance sympathovagal [17, 29] was higher in children with DS, since the LF component was higher and HF component was lower, and this also indicates sympathetic predominance compared to controls. Differences in spectral indices have been found in several studies [1, 9, 16]. Iellamo et al. [16] investigated the spectral analysis and the HR response to active standing of subjects with DS and healthy volunteers. During standing, significant increase in LFun and decrease in HFun were observed in control subjects but not in DS subjects. In another autonomic task, Agiovlasitis et al. [1] examined whether the autonomic response to upright tilt differs between individuals with DS and without DS. Heart rate response did not differ between groups, and HF, LF, and LF/HF ratios were reduced in persons with DS in response to upright tilt. For some authors [1, 10], the reduced response may be explained by an attenuated vagal modulation. This statement corroborates our hypothesis that sympathetic predominance would be responsible for destabilizing the autonomic responses in DS, since some works mentioned above [9, 16], which conducted the analysis in the frequency domain, also found an increase in LF and decrease in HF.
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It is known that, during low to moderate intensity exercise, neural signals from the central command and muscle metaboreceptors evoke a decrease in vagal outflow, which in turn mediates the increase in HR. Concurrently with vagal withdrawal, exercise induces increases in muscle nerve sympathetic activity [7, 9, 10, 16]. Even though individuals with DS respond this way [22], such response is lower than that of controls, which could be explained by sympathetic predominance of these individuals, which hinder or delay the initial action of the vagus front of excitatory tasks. Collectively, these results offer additional evidence for altered autonomic function in individuals with DS independently of the presence of cardiopathy. However, the exact mechanism leading to this dysfunction is not well established. Some hypotheses are considered, such as muscular hypotonia [21, 25], pathological abnormalities in areas of the DS brain [5, 26, 32], and in neurotransmitters [19, 23, 30]. Given the longer life expectancy in this population, further studies are needed to evaluate the impact of impaired autonomic cardiac regulation on health outcome in children with DS. To the best of our knowledge, this is the first study of HRV in children with DS not suffering from concomitant congenital heart disease, conducted with a specific age group, from six to eleven years old. Our research presents a couple of points that should be addressed. First, we do not investigate the influence of gender on the HRV indices. Although some studies describe differences in HRV between men and women [27], none of the studies with DS [1, 2, 8, 10, 15, 16] assessed this topic. Furthermore, when searches are conducted with children, this is rarely mentioned, independently of condition evaluated. For this reason, our control group was sex- and age-matched and we do not believe that gender differences have influenced our findings. Second, the physical activity of groups was not investigated. It is known that the level of physical activity can influence the autonomic behavior, increasing the indexes which represent the modulation vagal [3, 6, 8, 10]. But we can say that none of the children of this study were participating in a formal exercise training program. In conclusion, our results indicate increasing indices representing the sympathetic branch of the ANS and those that indicate the overall modulation. Acknowledgments This study received financial support from FAPESP (Fundac¸a˜o de Amparo a` Pesquisa do Estado de Sa˜o Paulo. Process number: 2010/18005-0). The authors thank the staff of the Genetics Clinic of the Hospital Infantil Darcy Vargas and APAE Sa˜o Paulo for their co-operation in providing data. Also we would like to thank the group from Associac¸a˜o das Volunta´rias of the Hospital Infantil Darcy Vargas for their help in contacting volunteers.
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ORIGINAL ARTICLE
Cardiac Autonomic Modulation of Children with Down Syndrome Tatiana Dias de Carvalho • Luiz Carlos de Abreu • Zan Mustacchi • Luiz Carlos Marques Vanderlei • Moacir Fernandes Godoy • Rodrigo Daminello Raimundo Celso Ferreira Filho • Talita Dias da Silva • Laura Guilhoto • Viviane Perico • Vivian Ribeiro Finotti • Celso Ferreira
•
Received: 26 May 2014 / Accepted: 20 August 2014 / Published online: 28 August 2014 Ó Springer Science+Business Media New York 2014
Abstract The aim of this study is to analyze the autonomic modulation in children with Down syndrome (DS). The study was conducted with a convenience sample of children with DS and without heart disease, from the Genetics Clinic of the Hospital Infantil Darcy Vargas and APAE Sa˜o Paulo, Sa˜o Paulo, SP, Brazil. The control group was matched for sex and age. The analysis of autonomic modulation was performed using the indices of heart rate variability (HRV). The children remained in the supine position with spontaneous breathing for 20 min. Heart rate was recorded beat-to-beat. HRV analysis was performed in time and frequency domain. For data analysis, we used Student’s t test: unpaired and Mann–Whitney. It was considered statistically significant at p \ 0.05. From 75 children with DS, 50 were excluded, a total of 25 children [16 boys, 8.6 (1.4) years] participated in this study, and the
control group also consisted of 25 children [16 boys, 9.0 (1.2) years] without the syndrome. The BMI of the volunteers with DS was higher than the controls [19.1 (2.9) vs. 15.8 (1.2), p \ 0.0001]. There were differences between groups in the indices in frequency domain: LFms2 [1242.1 (788.25) vs. 786.44 (481.90), p = 0.040], LFun [69.104 (11.247) vs. 57.348 (11.683), p = 0.0004], HFun [30.896 (11.247) vs. 42.520 (11.634), p = 0.0004] and LF/HF [2.594 (1.104) vs. 1.579 (0.9982), p = 0.0004]. No differences were observed in time domain indices. The results indicate increased indices representing the sympathetic branch of the autonomic nervous system and those that indicate the overall modulation in children with DS.
T. D. de Carvalho (&) T. D. da Silva V. R. Finotti C. Ferreira Departamento de Medicina, Disciplina de Cardiologia, Universidade Federal de Sa˜o Paulo (UNIFESP), Rua Napolea˜o de Barros, 715 Te´rreo Vila Clementino, Sa˜o Paulo, SP, Brazil e-mail: [email protected]
L. C. M. Vanderlei Departamento de Fisioterapia da Faculdade de Cieˆncias e Tecnologia, Universidade Estadual Paulista (UNESP), Presidente Prudente, SP, Brazil
T. D. de Carvalho L. C. de Abreu R. D. Raimundo T. D. da Silva Laborato´rio de Escrita Cientı´fica da Faculdade de Medicina do ABC (FMABC), Santo Andre´, SP, Brazil L. C. de Abreu Departamento de Sau´de Materno-infantil da Faculdade de Sau´de Pu´blica, Universidade de Sa˜o Paulo (USP), Sa˜o Paulo, SP, Brazil Z. Mustacchi Ambulato´rio de Gene´tica do Hospital Infantil Darcy Vargas, Sa˜o Paulo, SP, Brazil
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Keywords Autonomic nervous system Children Heart rate variability Down syndrome
M. F. Godoy Nu´cleo Transdisciplinar de Estudos do Caos e da Complexidade, Faculdade de Medicina de Sa˜o Jose´ de Rio Preto (FAMERP), Sa˜o Jose´ do Rio Preto, SP, Brazil C. Ferreira Filho Departamento de Medicina, Disciplina de Clı´nica Me´dica, Universidade Federal de Sa˜o Paulo (UNIFESP), Sa˜o Paulo, SP, Brazil L. Guilhoto V. Perico ˜ O PAULO (Association of Parents and Friends of APAE SA People With Intellectual Disability of Sa˜o Paulo), Sa˜o Paulo, SP, Brazil
Pediatr Cardiol (2015) 36:344–349
Introduction Down syndrome (DS) is typically characterized by delayed psychomotor, brain, and neurological development (it is the most common genetic cause of intellectual disability), and it is associated with an increased risk for various congenital and other organic disorders such as muscle hypotonia, hypothyroidism, gastrointestinal and pulmonary disorders, leukemia, Alzheimer’s disease and dementia, and congenital heart disease [8, 31]. It has recently been suggested that subjects with DS not suffering from concomitant congenital heart disease may exhibit a dysfunction in autonomic cardiac modulation [16]. Autonomic function can be assessed using heart rate variability (HRV) analysis, which is a noninvasive measure of the balance between sympathetic and parasympathetic mediators of heart rate [17], since it describes the oscillation of the intervals between consecutive heart beats (RR intervals), which are related to the influences of the ANS on the sinus node [29, 34]. Preliminary data show that individuals with DS have low physical work capacity, chronotropic incompetence, and significantly reduced heart rate and blood pressure responses to autonomic tasks compared with nondisabled control subjects [8, 16]. This could be related to both depressed sympathetic tone and response as incomplete vagal withdrawal [6]. Alterations in the sympathetic and parasympathetic modulation of heart rate are indicative of autonomic dysfunction and are important because these changes are associated with increased risk of early mortality and morbidity [2, 3, 6, 29]. Given the longer life expectancy in this population [4, 31] a more thorough understanding of autonomic cardiac regulation in children with DS might have important clinical implications. Thus, the aim of the present study is to analyze the cardiac autonomic modulation in children with DS.
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central nervous system malformations and/or neurological syndromes; (3) Absence of metabolic disorders; (4) Absence of respiratory disorders; (5) Absence of medication that influences the cardiac autonomic modulation or any other medication that alters metabolic responses. None of the children were participating in a formal exercise training program. Ethics Statement The study protocol was approved by the Ethics Committee of Universidade Federal de Sa˜o Paulo (Federal University of Sa˜o Paulo—protocol number 1773/11) and followed the guidelines and rules for research involving human subjects, contained in Resolution number 466/12 of the Conselho Nacional de Sau´de (National Health Council). The volunteers and their parents or legal guardian were informed about the procedures and objectives of the study and, after both agreed to participate, the parents/guardians signed terms of informed consent because children in the age group of this research are not considered legally able to sign such an agreement. Procedure
Methods
Data were collected under controlled temperature (21–23 °C) and humidity (40–60 %). Participants went to the laboratory between 8:00 am and 11:00 am. They were instructed to avoid consuming caffeine for 24 h before evaluation. Parents/guardian of the children stayed in the room, during all protocol. Body weight and height were measured to calculate body mass index, following the standard recommendations proposed by Lohman et al. [20]. The heart rate receiver (Polar RS800 CX monitor, Polar Electro OY, Kempele, Finland) was placed on the chest over the distal third of the sternum. This type of equipment was validated for beat-bybeat measurements and for HRV analysis [11, 18, 33]. Children rested in supine position with spontaneous breathing for 20 min and were instructed to avoid talking during data collection.
Subjects
Heart Rate Variability
Individuals with DS were recruited from the Hospital Infantil Darcy Vargas (Darcy Vargas Children Hospital) and the ˜ O PAULO (Association of Parents and Friends of APAE SA People with Intellectual Disability of Sa˜o Paulo), Sa˜o Paulo, Brazil. The control group was composed of age- and gendermatched healthy children without DS from schools. All volunteers in this study met the following inclusion criteria: (1) Absence of congenital anomalies such as congenital heart disease and pulmonary malformations; (2) Absence of
For HRV analysis, the data series was first digitally filtered using Polar Precision Performance SW software (version 4.01.029; Polar), in which only series with more than 95 % sinus rhythm beats were included. It was then manually complemented, and the visual inspection of the time series on the computer showed absence of artifacts. Finally, 1000 consecutive RR intervals were selected for data analysis [13]. HRV analysis was performed with linear methods in the domains of time and frequency [29, 34].
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Table 1 Average values and standard deviations for age, weight, height and body mass index in children with DS and controls. Sa˜o Paulo, Brazil, 2014 Variables
DS average (SD) [CI]
Controls average (SD) [CI]
Age (years)
8.600 (1.414)
9.080 (1.222)
Table 2 Heart rate variability analysis in time domain of children with DS and controls. Sa˜o Paulo, Brazil, 2014 Variables
p MeanRR (ms)
[8.016–9.184]
[8.576–9.584]
Weight (kg)
29.343 (7.124)
31.348 (3.824)
[26.402–32.284]
[29.769–32.927]
Height (m)
1.235 (0.09823)
1.406 (0.07304)
[1.195–1.276]
[1.376–1.436]
19.104 (2.997)
15.835 (1.215)
[17.867–20.341]
[15.333–16.337]
2
BMI (kg/m )
0.2053 SDNN (ms) 0.2230 RMSSD (ms) \0.0001* NN50 (ms) \0.0001* pNN50 (ms)
BMI body mass index, SD standard deviation, CI confidence interval * p \ 0.05
In the time domain were used the root mean square of successive differences (RMSSD), the percentage of differences between adjacent normal-to-normal intervals greater than 50 ms (pNN50) and the differences between adjacent normal-to-normal intervals greater than 50 ms (NN50) that indicate isolated parasympathetic activity; and the standard deviation of normal-to-normal intervals (SDNN) which represents global variability [29, 34]. In the frequency domain, the spectral components of low frequency (LF: 0.04–0.15 Hz) which indicates global variability and high frequency (HF: 0.15–0.40 Hz) that indicates parasympathetic activity in normalized units (LFun and HFun, respectively) and in milliseconds squared were used, as well as the ratio between these components (LF/HF). Spectral analysis was performed using the fast Fourier transform algorithm [29, 34]. For analysis of indexes of HRV, we used the software program Kubios (Biosignal Analysis and Medical Image Group, Department of Physics, University of Kuopio, Finland) [24].
Statistical Analysis Each variable was checked for normality of distribution by the Shapiro-Wilks test. Comparisons between groups were performed using the independent Student’s t test for parametric sample distribution (MeanRR, SDNN, RMSSD, NN50, pNN50) or Mann–Whitney U-test for nonparametric (LFms, LFun, HFms, HFun, LF/HF). Descriptive statistics with estimates of mean, standard deviation were used, and differences were considered statistically significant when the probability of a Type I error was lower than 5 % (p \ 0.05). The statistical program was InStat3 (GraphPad Software Inc., La Jolla, CA, USA).
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DS median (SD) [CI]
Controls median (SD) [CI]
p
0.4688
645.26 (83.472)
661.41 (72.473)
[610.81–679.72]
[631.49–691.32]
57.832 (17.136) [50.758–64.906]
48.732 (15.264) [42.431–55.033]
0.0531
39.056 (13.467)
33.988 (13.294)
0.1869
[33.497–44.615]
[28.500–39.476]
198.72 (125.41)
138.40 (109.93)
[146.95–250.49]
[93.022–183.78]
19.872 (12.541)
13.840 (10.993)
[14.695–25.049]
[9.302–18.378]
0.0768 0.0768
SD standard deviation, CI confidence interval, ms milliseconds, RRi RR intervals, SDNN standard deviation normal-to-normal intervals, RMSSD root mean square of successive differences, NN50 adjacent normal-to-normal intervals that are greater than 50 ms, pNN50 percentage of differences between adjacent normal-to-normal intervals that are greater than 50 ms * p \ 0.05
Table 3 Heart rate variability analysis in frequency domain of children with DS and controls. Sa˜o Paulo, Brazil, 2014 Variables
DS median (SD) [CI]
Controls median (SD) [CI]
p
LF (ms2)
1242.1 (788.25)
786.44 (481.90)
0.0417*
{1218.0}
{644.00}
HF (ms2)
LF (un)
HF (un)
LF/HF
[916.69–1567.5]
[587.51–985.37]
553.00 (346.76)
589.24 (423.04)
{502.00}
{514.00}
[409.86–696.14]
[414.61–763.87]
69.104 (11.247)
57.348 (11.683)
{71.400}
{59.200}
[64.461–73.747] 30.896 (11.247)
[52.525–62.171] 42.520 (11.634)
{28.600}
{40.600}
[26.253–35.539]
[37.717–47.323]
2.594 (1.104)
1.579 (0.9982)
{2.502}
{1.457}
[2.138–3.050]
[1.167–1.991]
0.9923
0.0004*
0.0004*
0.0004*
SD standard deviation, CI confidence interval, LF low frequency, HF high frequency, ms milliseconds, un normalized units * p \ 0.05
Results We selected 75 children with DS of whom 50 were excluded for the following criteria: history of congenital heart disease or other cardiac problems (10), presence of metabolic diseases (10), current use of medications that
Pediatr Cardiol (2015) 36:344–349
would alter the cardiac autonomic modulation (20), and series with less than 95 % sinus rhythm beats (10). 25 children participated in this study (16 boys) and the control group comprised 25 children (16 boys) without the syndrome. Table 1 shows average values for age and anthropometric characteristics of DS children and controls. There were significant differences in height and BMI. Table 2 depicts the values for the RR interval and the SDNN, RMSSD, NN50, and pNN50 indices. There were no significant differences in these indices. Table 3 displays the values obtained for LF and HF indices and the LF/HF ratio in children with DS and controls. There were significant differences in the following indices: LFms2, LFun, HFun and LF/HF.
Discussion The novel finding of the current investigation is increasing HRV indices representing the sympathetic branch of the ANS and those that indicate the overall modulation. Regarding to anthropometric characteristics, no differences were observed between groups for age or body weight; however, the participants with DS were significantly shorter and had a larger BMI. Children with DS are at high risk of many disorders known to influence growth and the short stature is a characteristic of the syndrome [31]. Also, overweight and overfeeding require attention in caring for children with DS [21, 25], the prevalence of obesity in these individuals is around 31–47 % [21]. Although overweight causes alterations in cardiac autonomic function [28, 35], the observed difference in BMI values did not influence our results with respect to HRV and that is consistent with others searches [10, 12, 14]. The study of Figueroa et al. [10] evaluated this issue, and the authors suggested that autonomic dysfunction of DS may be independent of obesity. Similarly, Gouloupolou et al. [14] found no significant correlations between BMI and cardiac autonomic control at rest. And Giodaki et al. [12] reported that their results were not influenced either by weight alone or by BMI, emphasizing that dysfunction is independent of obesity in DS. Regarding HRV analysis in the time domain, no significant differences between groups were observed (Table 2). This is consistent with data from several studies that also reported no differences in HRV indices during rest [1, 2, 9, 10]. In the study of Ferri et al. [9], the abnormal imbalance between the sympathetic (increased) and vagal (decreased) systems in persons with DS was not identified during rest. Figueroa et al. [10] did not report differences between groups during rest, when investigated the
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modulation of HR and BP during isometric handgrip test. In other autonomic test, Agiovlasitis et al. [1, 2] found no differences in HRV in persons with DS in the rest period before the postural change. Iellamo et al. [16], evaluating the heart rate response to the active postural change, did not find differences between RR intervals during rest. In the frequency domain analysis, LFms2 index was higher in children with DS and no differences were found between groups for HFms2 index. The LF index is the combined action of branches of the ANS, with sympathetic predominance, and HF index represents the action of the isolated parasympathetic activity [29, 34]. Suggesting, therefore, that children with DS have an increased sympathetic activity and parasympathetic modulation similar to control group. When we analyzed in normalized units, LF index showed to be significantly higher in children with DS, whereas the HF index was lower. These changes, apparently contradictory in relation to that described above, are related to method for calculating these indexes. The indices in normalized units represent the relative value of each spectral component (LF and HF) in relation to total power minus the component of very low frequency (VLF) [29, 34]. Thus, with the increase in LF component area with no change in HF area, as observed in DS children, when these data are normalized, we found higher values for the LF and lower values for HF (Table 3). Also in frequency domain, the LF/HF ratio which indicates the balance sympathovagal [17, 29] was higher in children with DS, since the LF component was higher and HF component was lower, and this also indicates sympathetic predominance compared to controls. Differences in spectral indices have been found in several studies [1, 9, 16]. Iellamo et al. [16] investigated the spectral analysis and the HR response to active standing of subjects with DS and healthy volunteers. During standing, significant increase in LFun and decrease in HFun were observed in control subjects but not in DS subjects. In another autonomic task, Agiovlasitis et al. [1] examined whether the autonomic response to upright tilt differs between individuals with DS and without DS. Heart rate response did not differ between groups, and HF, LF, and LF/HF ratios were reduced in persons with DS in response to upright tilt. For some authors [1, 10], the reduced response may be explained by an attenuated vagal modulation. This statement corroborates our hypothesis that sympathetic predominance would be responsible for destabilizing the autonomic responses in DS, since some works mentioned above [9, 16], which conducted the analysis in the frequency domain, also found an increase in LF and decrease in HF.
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It is known that, during low to moderate intensity exercise, neural signals from the central command and muscle metaboreceptors evoke a decrease in vagal outflow, which in turn mediates the increase in HR. Concurrently with vagal withdrawal, exercise induces increases in muscle nerve sympathetic activity [7, 9, 10, 16]. Even though individuals with DS respond this way [22], such response is lower than that of controls, which could be explained by sympathetic predominance of these individuals, which hinder or delay the initial action of the vagus front of excitatory tasks. Collectively, these results offer additional evidence for altered autonomic function in individuals with DS independently of the presence of cardiopathy. However, the exact mechanism leading to this dysfunction is not well established. Some hypotheses are considered, such as muscular hypotonia [21, 25], pathological abnormalities in areas of the DS brain [5, 26, 32], and in neurotransmitters [19, 23, 30]. Given the longer life expectancy in this population, further studies are needed to evaluate the impact of impaired autonomic cardiac regulation on health outcome in children with DS. To the best of our knowledge, this is the first study of HRV in children with DS not suffering from concomitant congenital heart disease, conducted with a specific age group, from six to eleven years old. Our research presents a couple of points that should be addressed. First, we do not investigate the influence of gender on the HRV indices. Although some studies describe differences in HRV between men and women [27], none of the studies with DS [1, 2, 8, 10, 15, 16] assessed this topic. Furthermore, when searches are conducted with children, this is rarely mentioned, independently of condition evaluated. For this reason, our control group was sex- and age-matched and we do not believe that gender differences have influenced our findings. Second, the physical activity of groups was not investigated. It is known that the level of physical activity can influence the autonomic behavior, increasing the indexes which represent the modulation vagal [3, 6, 8, 10]. But we can say that none of the children of this study were participating in a formal exercise training program. In conclusion, our results indicate increasing indices representing the sympathetic branch of the ANS and those that indicate the overall modulation. Acknowledgments This study received financial support from FAPESP (Fundac¸a˜o de Amparo a` Pesquisa do Estado de Sa˜o Paulo. Process number: 2010/18005-0). The authors thank the staff of the Genetics Clinic of the Hospital Infantil Darcy Vargas and APAE Sa˜o Paulo for their co-operation in providing data. Also we would like to thank the group from Associac¸a˜o das Volunta´rias of the Hospital Infantil Darcy Vargas for their help in contacting volunteers.
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