The 2015 Biomedical Engineering International Conference (BMEiCON-2015)
Markers of Altered Cardiovascular Autonomic
Function in Overweight Children
Patjanaporn Chalacheva, Ph.D.
Department of Biomedical Engineering
University of Southern California
Los Angeles, CA, USA
chalache@usc.edu
Abstract-Autonomic dysfunction is known to be associated
with sleep apnea and insulin resistance. With the growing
prevalence of obesity, the common factor among subjects with
sleep apnea and insulin resistance, we sought to determine how
autonomic cardiovascular function is affected by the independent
and combined effects of sleep apnea and insulin resistance at the
early stage of these syndromes. In this study, we investigated the
autonomic function of overweight-to-obese children with either
sleep apnea or insulin resistance or both during supine and
standing postures. Using computational models of heart rate and
peripheral vascular resistance variability, we found that children
with sleep apnea, regardless of the presence of insulin resistance,
had higher peripheral vascular baroreflex gain. Furthermore,
children with insulin resistance, regardless of the presence of
sleep apnea, had decreased heart rate baroreflex gain from
supine to standing, which was opposite to those without insulin
resistance. In conclusion, we were able to detect altered
autonomic function by sleep apnea and insulin resistance using
markers derived from our computational models that based only
on non-invasive measurements.
Keywords-Autonomic dysfunction, insulin resistance, sleep
apnea, minimal model
I. INTRODUCTION
Global prevalence of obesity has rapidly increased,
becoming one of the most serious public health challenges.
Obesity is associated with increased risks of several adverse
health outcomes such as sleep-related breathing disorder, Type
2 diabetes mellitus, cardiovascular diseases and even premature
death [1]. Impairment in autonomic function has been reported
to be associated with obstructive sleep apnea syndrome
(OSAS), the most common form of sleep-related breathing
disorder, and cardiovascular diseases [2]. At the same time,
OSAS has been found to also be associated with insulin
resistance, one of the features of metabolic syndrome (MetS),
which predisposes to type 2 diabetes [3]. Because the
underlying interaction among the three disorders (autonomic
function impairment, MetS and OSAS) is still not clearly
understood, it would be beneficial to investigate the effects of
MetS and OSAS on autonomic function at the developmental
stage of these syndromes, such as in children, to delineate other
factors that may arise as a result of complications from other
diseases.
This work was supported in part by U.S. National Institute of Healtb
grants HL090451 and EB001978.
978-1-4673-9158-0/15/$31.00 ©20 15 IEEE
Michael C.K. Khoo, Ph.D.
Department of Biomedical Engineering
University of Southern California
Los Angeles, CA, USA
khoo@bmsr.usc.edu
In this study, we investigated how MetS and OSAS
affected autonomic function in overweight-to-obese children.
We focused on two components of autonomic cardiovascular
control: the regulation of heart rate and the control of
peripheral vascular resistance. Through computational
modeling, we sought to determine whether MetS and OSAS
would have more adverse effect on the autonomic function or
that the combination of both syndromes would have stronger
negative effect on autonomic function.
II. METHODS
A. Protocols and Data Processing
Data analyzed in this paper were obtained from 26 male
and 8 female overweight-to-obese pediatric subjects (mean ±
SE: age = l3.0 ± 0.4 years and BMI = 33.l ± 1.2 kg/m2) who
underwent autonomic function tests, metabolic tests and sleep
studies (standard polysomnography). The autonomic function
tests involved having the subject lying in supine position for 10
minutes then actively standing up for another 10 minutes.
During each posture, non-invasive measurements of respiratory
airflow, ECG, continuous blood pressure and peripheral arterial
tonometer (PAT) were recording. The metabolic tests involved
collection of morning fasting blood samples, followed by a
frequently sampled intravenous glucose tolerance test.
Recordings from the autonomic function tests were
processed as follows: 1) breath-to-breath tidal volume (Vt) was
calculated by integrating airflow and extracting the peak
volume from each breath; 2) beat-to-beat R-R intervals (RRI)
were extracted from the ECG; 3) beat-to-beat systolic blood
pressure (SBP) was extracted from the peak of each blood
pressure pulse waveform; 5) beat-to-beat beat-averaged blood
pressure (MAP) was the average blood pressure within one
cardiac cycle; and 5) beat-to-beat PAT amplitude (PATamp)
was extracted from PAT pulse waveform. The breath-to-breath
and beat-to-beat data were interpolated in order to obtain
continuous signals. These interpolated signals were then down-
sampled to 2 Hz and subjected to linear trend removal before
being used for further analyses. Homeostatic model assessment
(HOMA) index, one of the metabolic function indices obtained
in this study, was chosen to represent the subject's metabolic
function. It reflects the degrees of insulin resistance and beta
cell function [4]. Obstructive apnea hypopnea index (OAHI),
the number of apneas or hypopneas per hour of sleep [5], was
used to quantify the degrees of severity of the subject's
obstructive sleep apnea syndrome (OSAS).
To investigate the effect of MetS and OSAS on autonomic
function due to orthostatic stress, the subjects were classified
into 4 groups by their HOMA index and OAHl (Fig. 1):
1) Controls (HOMA index :s 2 and OAHI :s 2.5),
2) MetS (HOMA index> 2 and OAHl :s 2.5),
3) OSAS (HOMA index:S 2 and OAHI > 2.5),
4) MetS + OSAS (HOMA index> 2 and OAHI > 2.5).
Figure 1. Scatter plot oflog(OAHI) and HOMA index, showing how subjects
were classified into 4 groups.
B. Linear Minimal Models
In this paper, we employed two minimal models: 1) model
of heart rate variability and 2) model of peripheral vascular
conductance variability. The model of heart rate variability
consists of two main functional mechanisms: the arterial
baroreflex control of heart rate (ABR), which relates changes
in t1SBP to changes in heart rate (t1RRI), and the respiratory-
cardiac coupling (RCC), which relates changes in Vt (t1Vt) to
t1RRI. The model of peripheral vascular conductance also
consists of two mechanisms. The first mechanism is the
baroreflex control of peripheral vascular conductance (BPC),
which relates changes in MAP (t1MAP) to changes in PATamp
(t1PATamp) where PATamp is taken as a surrogate measure of
peripheral vascular conductance (the inverse of peripheral
vascular resistance). Another mechanism is the respiratory-
peripheral vascular conductance coupling (RPC), which relates
t1Vt to t1PATamp. The linear model can be represented
mathematically as
M-J M-J
y(t} = Lhx(i}x(t-i-Tx }+ Lhu(i}u(t-i-T.)+8(t}.
i=O i=O
hx and hu represent the impulse responses of the functional
mechanisms that relate the output, y, to the input x and u,
respectively. For the model of heart rate variability, y is t1RRI,
x is t1SBP and u is t1Vt; thus hx represents ABR and hu
represents RCC. For the model of peripheral vascular
conductance, y is M ATamp, x is t1MAP and u is t1Vt; thus hx
represents BPC and hu represents RPC. Tx and Tu represents the
latency of each mechanism. M represents the memory of the
system - the time it takes a response to a brief and abrupt input
to die out. Lastly, [; represents the extraneous influence in the
output that cannot be explained by the model.
C. Nonlinear Minimal Models
To explore the nonlinearity in the mechanisms that govern
heart rate and periIJheral vascular conductance variability, we
also employed a 2nd-order nonlinear Volterra model to include
the quadratic nonlinear component of each mechanism as well
as the interaction effect between the two inputs on the output.
The nonlinear model can be represented mathematically as
M-J M-J
y(t} = Lhx(i}x(t-i-Tx } + Lhu(i}u(t-i-T.)
i=O i=O
M-JM-J
+ LLhxx(i,j}x(t-i-TJx(t-i-TJ
i=O j=O
(2)
i=O j=O
M-JM-J
+ LLhxu(i,j}x(t-i-TJu(t-i-T,J
i=O j=O
+ 8(t}.
hxx and huu represent the 2nd-order effect of input on the output
while hxu represents the interaction effect between the inputs
and the output. For example, for the model of heart rate
variability, hxx; represents the 2nd-order effect of blood pressure
on heart rate and hxu represents the interaction between SBP
and Vt on RRI.
D. Model Estimation and Optimization
The linear kernels (impulse responses in case of the linear
models) and the nonlinear kernels are estimated using basis
function expansion technique as described in [6]. In brief, each
kernel can be represented as a sum of weighted basis functions.
In this study, Meixner functions were chosen because of its
exponential decaying characteristic, making it suitable for
representing physiological mechanisms which tend to die out
after certain time [7]. Then the weight of each basis function
was estimated using least-squares minimization. The main
advantage of this basis function expansion technique is that it
greatly reduces the number of parameters needed to be
estimated as the number of basis functions required to represent
the dynamics of an impulse response is generally much smaller
than the system memory (M).
The least-squares minimization was repeated for different
combinations of model parameters: model order, order of
(1)
generalization and delays. The model order (number of basis
functions) was allowed to vary between 2-8 and the order of
generalization was allowed to vary between 2-8. The delay
ranges for ABR, RCC, BPC and RPC were: 0-3, -3-0, 3-8 and
0-3 seconds, respectively [8, 9]. For each combination, the
minimum description length (MDL) was computed. MDL
gives a measure of a balance between goodness of fit and the
complexity of the model [10]. Thus, the parameter set that gave
the lowest MDL was selected as the optimal model parameters.
E. Feature Extraction and Statistical Tests
Compact descriptors were derived from the estimated linear
and nonlinear kernels. To do this, we applied fast Fourier
transform on the estimated kernels. Therefore, for the linear
models, the impulse responses were essentially transformed
into transfer functions. Then the low-frequency (LF) and high-
frequency (HF) gains were calculated by averaging the
magnitude of the transfer function within the frequency range.
The LF and HF ranges were 0.04-0.15 Hz and 0.15-0.4 Hz,
respectively. The gain of each mechanism was taken as the
indices reflecting sympathetic and parasympathetic modulation
during supine and standing. The ratio of the gain during supine
and standing (standing/supine) was taken as the measure of
reactivity - how one's autonomic nervous system reacts to
postural change.
Two-way Analysis of Variance (ANOVA) was employed
to test for the autonomic function and reactivity. The two
factors were HOMA index (HOMA index :'S 2 vs. HOMA
index > 2) and OARI (OAHI :'S 2.5 vs. OARI > 2.5).
Interaction was also included in the ANOVA model.
Significant level for statistical test was set to 0.05. Log
transformation was applied to the variable being tested to
satisfy the assumption of normality in ANOVA.
III. RESULTS
During supine, the LF gain of the BPC mechanism
(denoted as HBPC,LF), reflecting the sensitivity of the baroreflex
control of peripheral conductance, was similar between
controls and MetS subjects while the other two groups had
higher HBPC,LF (Fig. 2). Two-way ANOVA confirmed that the
high OARI groups (OSAS and MetS + OSAS) had statistically
significantly higher HBPC,LF (P = 0.017), suggesting higher
sensitivity in the baroreflex control of peripheral vascular
conductance in subjects with higher degrees of OS AS severity.
Figure 2. Log transfonned of the low-frequency gain of barore flex control of
peripheral vascular conductance (HBPC.LF) during supine in 4 groups. Subjects
with higher degrees of OSAS severity (higher OAHI) had higher HBPc.LF (P =
0.017). Error bars show mean ± SE.
Figure 3 shows how LF gain of heart rate baroreflex
(denoted as HABR,LF) changed with orthostatic stress. Both
controls and OSAS subjects showed increased HABR,LF from
supine to standing, reflected by the stand/supine ratio being> 1
(> 0 for the log transformed values). However, subjects with
higher HOMA index showed the opposite response. Their
HABR,LF became smaller in standing compared to supine,
resulting in the stand/supine ratio being < 1 « 0 for log
transformed values). Two-way ANOVA showed that subjects
with higher HOMA index (MetS and MetS + OSAS groups)
had marginally statistically significantly higher reactivity in
arterial baroreflex (p = 0.05). This suggests that insulin
resistance, indicated by higher HOMA index, reduces
orthostatic reactivity of the heart rate baroreflex.
Figure 3. Log transfonned of the ratio of the low-frequency gain of heart rate
baroreflex (HABR,LF) between standing and supine in 4 groups. The ratio reflects
the reactivity in heart rate baroreflex to postural change. Subjects with higher
insulin resistance (higher HOMA index) had decreased HABR.LF gain from
supine to standing (P = 0.050), Error bars show mean ± SE.
IV. DISCUSSION
In this study, we investigated the early stage of MetS and
OSAS and their independent or combined effects on autonomic
function in overweight-to-obese pediatric subjects. We found
that subjects with higher degrees of OSAS severity, regardless
of their insulin resistance level, had higher sensitivity in
baroreflex control of peripheral vascular conductance during
supine. The higher peripheral vascular baroreflex gain that we
found in subjects with OSAS, regardless of metabolic function,
is consistent with previous studies that demonstrated higher
blood pressure variability in patients with sleep-disordered
breathing [11], which has been thought to reflect sympathetic
overactivity.
Additionally, we found that subjects with insulin resistance,
regardless of their degrees of OSAS severity, had decreased
baroreflex sensitivity as they changed their posture from supine
to standing while the control and OSAS subjects without
insulin resistance tended to have increased heart rate baroreflex
sensitivity as they stood up. This is consistent with a previous
study that subjects with impaired glucose metabolism,
regardless of the presence of OSAS, had suppressed heart rate
baroreflex [12]. This suggests that insulin resistance has
stronger negative impact on the cardiac autonomic function [12] W. Wang, S. Redline, and M. C. Khoo, "Autonomic markers of
thanOSAS. impaired glucose metabolism: effects of sleep-disordered breathing," J
Diabetes Sci Technol, vol. 6, no. 5, pp. 1159-71, Sep, 2012.
Lastly, we demonstrated that by means of computational
modeling, we were able to extract compact descriptors of
autonomic cardiovascular control. These compact descriptors
can be employed as the markers of altered autonomic function
in different diseases/disorders. Furthermore, this method only
requires non-invasive measurements and simple intervention
such as orthostatic stress, making it readily feasible to be
applied in disease screening and detection process.

ACKNOWLEDGMENT
We thank W.H. Tran, F.M. Oliveira R. Bhatia and S.L
Davidson Ward for providing the experimental data used in
this paper.

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