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The role of the autonomic nervous system in hypertension: a bond graph model study

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2008 Physiol. Meas. 29 473

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IOP PUBLISHING PHYSIOLOGICAL MEASUREMENT

Physiol. Meas. 29 (2008) 473–495 doi:10.1088/0967-3334/29/4/005

The role of the autonomic nervous system in

hypertension: a bond graph model study

Shuzhen Chen1, Shaowen Zhang2, Yuexian Gong1, Kaiyong Dai1,

Meirong Sui1,3, Yi Yu1 and Gangmin Ning1
1 Department of Biomedical Engineering, Zhejiang University (Yuquan Campus),

Zheda Road 38, 310027 Hangzhou, People’s Republic of China

2 Clinic of Zhejiang University, Hangzhou, People’s Republic of China
3 Xuzhou Medical College, People’s Republic of China

E-mail: gmning@zju.edu.cn

Received 19 September 2007, accepted for publication 17 March 2008

Published 9 April 2008
Online at stacks.iop.org/PM/29/473

Abstract
A bond graph model of the cardiovascular system with embedded autonomic
nervous regulation was developed for a better understanding of the role of the
autonomic nervous system (ANS) in hypertension. The model is described
by a pump model of the heart and a detailed representation of the head and
neck, pulmonary, coronary, abdomen and extremity circulation. It responds to
sympathetic and parasympathetic activities by modifying systemic peripheral
vascular resistance, heart rate, ventricular end-systolic elastance and venous
unstressed volumes. The impairment of ANS is represented by an elevation
of the baroreflex set point. The simulation results show that, compared
with normotensive, in hypertension the systolic and diastolic blood pressure
(SBP/DBP) rose from 112/77 mmHg to 144/94 mmHg and the left ventricular
wall thickness (LVWT) increased from 10 mm to 12.74 mm. In the case
that ANS regulation was absent, both the SBP and DBP further increased by
8 mmHg and the LVWT increased to 13.22 mm. The results also demonstrate
that when ANS regulation is not severely damaged, e.g. the baroreflex set point
is 97 mmHg, it still has an effect in preventing the rapid rise of blood pressure
in hypertension; however, with the worsening of ANS regulation, its protective
role weakens. The results agree with human physiological and pathological
features in hemodynamic parameters and carotid baroreflex function curves,
and indicate the role of ANS in blood pressure regulation and heart protection.
In conclusion, the present model may provide a valid approach to study the
pathophysiological conditions of the cardiovascular system and the mechanism
of ANS regulation.

Keywords: cardiovascular system model, bond graph, hypertension,

autonomic nervous system, carotid baroreflex
0967-3334/08/040473+23$30.00 © 2008 Institute of Physics and Engineering in Medicine Printed in the UK 473
474 S Chen et al

1. Introduction

The autonomic nervous system (ANS) is involved in regulating various pathophysiological

cardiovascular conditions and its behavior in hypertension has been extensively investigated
(Gonzalez et al 1983, Grassi et al 1998, Guyenet 2006, Pagani and Lucini 2001). Recent studies
have shown that ANS may play an important protective role in hypertension (Li et al 2002).
Disturbance of ANS was observed in hypertension, which was characterized as an increased
sympathetic and reduced vagal cardiac drive coupling with an enhancement of vasomotor
sympathetic modulation in long-term hypertension (Guyenet 2006, Pagani and Lucini 2001).
Also, the changes in baroreflex sensitivity and increased sympathetic activity were associated
with left ventricular morphology in hypertensive patients (Milan et al 2007, Schlaich et al
2003). However, at present, fully understanding the role of ANS in a hypertensive situation
remains a problem. For instance, the baroreflex resetting was observed in chronic hypertension
(Ashton 2007, Gonzalez et al 1983), but the exact level of the baroreflex reset point is still
unclear. Furthermore, the specific role of ANS and its regulation on both hemodynamics and
heart morphology in hypertension require quantitative investigation.
For ANS mechanism study, clinical experiments including the measurement of an end-
organ response to a physiological provocation, prolonged tilt-table testing and some other
autonomic maneuvers (Freeman 2006, Zollei et al 2003) were usually taken. However,
the interpretation of the results can be very difficult due to the fact that the cardiovascular
control mechanisms are multifactorial (Le Rolle et al 2005). Furthermore, some hypothetical
conditions are actually impossible to control in a living body (Le Rolle et al 2005). Fortunately,
mathematical models can be of great help in this field and thus receive more and more attention.
Some circulation system models containing autonomic nervous regulation have been reported
(Ursino 1998, Ursino and Magosso 2003). However, little work was done for analyzing the
ANS influence in chronic hypertension.
The aim of this work is to construct an extendable cardiovascular model to investigate
the role of ANS in hypertension. It is based on the bond graph technique which has been
demonstrated as a powerful tool to describe a multi-energy system by capturing the common
energy structure of systems with unified elements (Diaz-insua and Delgado 1996). The carotid
baroreflex regulation is embedded in the model. Thus, the designed model consists of two
submodels: blood circulation system model and autonomic nervous regulation model. The
heart and vascular network in the model are represented by an elastance variable description
and segment description, respectively (Diaz-insua and Delgado 1996, Goldstein et al 1988),
while their interaction with carotid baroreflex is accomplished by adjusting the systemic
peripheral resistance, ventricular end-systolic elastance, venous unstressed volume and heart
rate (Ursino 1998).

2. Methods

In this section, the blood circulation system and autonomic nervous regulation submodels are
introduced in detail and the methods of calculating oxygen consumption per heart beat and
left ventricular wall thickness are presented.

2.1. Blood circulation system model

Heart and vascular system model. In the heart model, the inlet and outlet valves are emulated
by modifying the resistance corresponding to the blood flow direction (Goldstein et al 1988).
The left and right atria are described as linear capacities characterized by constant values of
A bond graph model for ANS in hypertension 475

ith segment

Qi-1 Qi
(i-1)th segment (i+1)th segment
Pi Pi+1

Figure 1. Bond graph for the ith vessel segment.

compliance and unstressed volume, i.e. the contractile activity of the atria is neglected (Ursino
1998), while the left and right ventricles are simulated by an improved pressure–volume
relationship model (Guarini et al 1998, Hunter 1989, Shroff et al 1989, Suga and Sagawa
1974, Ursino 1998). More details about the heart model are given in appendix A.
The vascular system is described by a detailed tree structure accounting for the head,
neck, pulmonary, coronary, abdomen and extremity circulation. Each circulation structure is
further divided into several vessel segments representing arteries, arterioles, capillaries and
veins, thus in total 30 vessel segments (see appendix C.1 for the notation of the segments) are
constructed in the vascular model. Each segment is regarded as a modified Windkessel model,
which is composed of capacitance (C), resistance (R) and inertial (I) elements.
To represent the changes in peripheral vascular resistance (PVR) and capacitance of large
arteries, two gain factors Kr and Kc are introduced. For the ith segment of peripheral vessels,
its resistance is described as
Ri = Kr Ri0 , (1)
where Ri0 is the initial resistance, Kr is an index (Kr
1) representing the change in PVR,
and it is set to be 1.0 for normal state.
Similarly, for the ith segment of large arteries, its capacitance is described as
Ci = Kc Ci0 , (2)
where Ci0 is the initial capacitance, Kc is an index (0 < Kc  1) representing the change in
vessel compliance, and it is set to be 1.0 for normal state.
Using the bond graph technique, a vessel segment is expressed in figure 1. The coupling
of vessel segments is accomplished by the pressure–volume relationship of adjacent segments.
For the ith segment, the flow is provided by the (i − 1)th segment, which is denoted as Qi-1,
and the pressure is provided by the (i + 1)th segment, which is denoted as Pi+1. Meanwhile,
the output of the ith segment is the flow to the (i + 1)th segment and the pressure for the
(i − 1)th segment, which are denoted as Qi and Pi, respectively. Concretely, the mathematical
equations of the ith segment are deduced by
dVi
= Qi−1 − Qi (3)
dt
dλi
= Pi − Pi+1 − Ri × Qi , (4)
dt
476 S Chen et al

where
Qi = λi /Ii (5)
Pi = (Vi − Vi0 )/Ci , (6)
dλi
Vi is the volume on Ci, λi is the pressure momentum of Ii, dt
denotes the pressure difference
on Ii, and Vi0 is the unstressed volume of the ith segment.

Integration of the heart and vascular system model. A complete bond graph model for the
blood circulation system is illustrated in figure 2. For the integration of the heart and vascular
system, the cardiac cycle is divided into three phases, i.e. the ventricular ejection period,
isovolumic contraction–relaxation period and the filling period. In each phase the coupling
of the heart and vascular system is performed by their inner pressure–flow relationship.
Equations (7) are the mathematical expressions for the ventricular ejection period. In this
period, the flows through the left ventricle and aortic valve are assigned to be equal, since the
aortic valve is opened, and the flow into the left ventricle through the mitral valve is assigned
to be zero: ⎧
⎪
⎪
dVlat
= Qpvn
⎪
⎪
⎪
⎪ dt
⎪
⎪
⎪
⎪ dλmvv
⎨ =0
dt (7)
⎪
⎪ dVtat
⎪
⎪ = Q − Q − Q − Q − Q − Q
⎪
⎪ dt
avv lsa rsa eca cor aat
⎪
⎪
⎪
⎪ dλavv
⎩ = Plvt − Ptat − Pavv
dt
Likewise, for the isovolumic contraction relaxation and filling period, the corresponding
model expression can also be defined. Consequently, an extendable circulation system model
is constructed of a total of 54 ordinary differential equations (appendix B).

2.2. Autonomic nervous regulation model

The autonomic regulation mechanism includes baroreflex, chemoreflex and pulmonary stretch
reflex. Among them carotid baroreflex plays the main role in the modulation of blood pressure.
Thus this study centered on it. As shown in figure 2, the carotid baroreflex regulation loop
consists of three parts: the afferent pathway, the efferent pathway and the effectors. More
descriptions of the carotid baroreflex regulation model are given in appendix A.
In the present model, the input of the afferent pathway is the pressure of carotid artery
Pcca , which is calculated by dVdtcca (Vcca is the blood volume of the carotid artery). The efferent
pathway accepts the signal from the afferent pathway and acts on the effectors. The effectors
are classified into four categories: systemic peripheral vascular resistance (SPVR), ventricular
end-systolic elastance, venous unstressed volumes and heart rate (HR). As depicted in figure 2,
SPVR includes the vessel resistance of left arm (Rlac ), right arm (Rrac ), abdomen (Racl ), left
leg (Rlgc ) and right leg (Rrgc ). Ventricular end-systolic elastance includes both left- and right-
ventricle elastances (Clvt and Crvt ). Venous unstressed volumes contain the unstressed volume
of the ventral vena cave (Vavc0 ), internal abdomen circulation (Vacl0 ), thoracic vena cave (Vtvc0 ),
external jugular vein (Vejv0 ) and veins in the left arm (Vlav0 ), right arm (Vrav0 ), left crura (Vlgv0 )
and right crura (Vrgv0 ). Parameter values which are different from those of Ursino are given
in appendix C.4. These values are deduced by estimating the change of systemic peripheral
vascular resistance and ventricular end-systolic elastance due to carotid baroreflex regulation.
A bond graph model for ANS in hypertension 477

Carotid
Baroreceptor

Afferent
Pathway

Efferent
Pathway

Peripheral
Resistance

Heart

Ventricular Elastance

Effectors

Heart
Rate

Venous
Volumes

Figure 2. Bond graph model for the cardiovascular circulation system.

478 S Chen et al

2.3. Implementation of the integral model

The establishment and simulation of the integral model of the blood circulation system and
autonomic nervous regulation were accomplished using MATLAB 7.01 (Mathworks, Inc.).
Numerical integration of the differential equations was performed using the fourth-order
Runge–Kutta method with a step length of 0.001 s. It starts with an initial state and ultimately
reaches a steady state. The simulation results are given by averaging the corresponding
parameters over 20 cardiac periods.

2.4. Oxygen consumption per heart beat and left ventricular wall thickness calculation
Calculation of oxygen consumption per heart
 beat.
 In order to investigate the function of the
heart, oxygen consumption per heart beat VO2 is computed and presented in the simulation
results. According to Suga (Suga et al 1981)
VO2 = A × PVA + B, (8)
where
 T
1
PVA = P (t) × Q(t) dt + (LVESV − Vd ) × SBP, (9)
0 2
where T is the cardiac period, LVESV is the end-systolic volume of the left ventricle, SBP
is the systolic blood pressure, Vd is the unstressed volume of the ventricle, A = 1.6 ×
10−5 ml · O2 /(mmHg ml) and B = 0.015 ml · O2 /beat.

Calculation of the left ventricular wall thickness. Sustained pressure overload induced by
hypertension may lead to self-adaptation of the left ventricle, which causes left ventricle
hypertrophy (LVH). Thus, the left ventricular wall thickness (LVWT) under various states was
computed for a better understanding of the effect of ANS on LVH.
According to the literature (Segers et al 2000, 2001), the maximal myocardial tension of
the left ventricle during systolic phase is maintained at normal levels despite chronic pressure
overload such as hypertension. The left ventricle is assumed to be a thick-walled prolate
spheroid (Mirsky 1969); thus the myocardial tension in the ventricle can be represented by
Laplace’s law:
σs = P · r 2 / h · (2r + h), (10)
where σs is the maximal myocardial tension of the left ventricle in the systolic period, P is
the systolic blood pressure, h is the wall thickness ranging from 9 to 12 mm in a normal case,
r is the radius of the left ventricle and is obtained by the hemisphere volume formula:
 1
3Vs 3
r= , (11)
2π
where Vs is the volume of the left ventricle when the myocardial tension of the left ventricle
reaches its maximum in the systolic period. It is affected by both systolic elastance and
diastolic stiffness.
Thus, the left ventricle wall thickness h is calculated as
 1
 1 
3Vs 3 P + σs 2
h= −1 . (12)
2π σs
A bond graph model for ANS in hypertension 479

180 600
(a) (b)
160
500
140
Blood pressure of aorta/mmHg

Flow of left ventricle/mL.s –1

120 400

100
300
80

60 200

40
100
20

0 0
175 176 177 178 179 180 181 182 183 175 176 177 178 179 180 181 182 183
t/s t/s

140 180
(c) (d )
130 160

120
140

Blood pressure of left arm/mmHg

Volume of left ventricle/mL

110
120
100
100
90
80
80
60
70
40
60

50 20

40 0
175 176 177 178 179 180 181 182 183 175 176 177 178 179 180 181 182 183
t/s t/s

Figure 3. The simulation results under normal physiological condition: (a) blood pressure in aorta;
(b) outflow wave of the left ventricle; (c) volume of the left ventricle; (d) blood pressure in the left
arm.

3. Results

3.1. Normal physiological state

To verify the validity of the present model, the simulation results under normal physiological
state and the baroreflex function curve were obtained.

Hemodynamic status. A group of initial parameters was selected and adjusted to

represent a normal physiological condition (see appendix C for the values). About 100 s
after simulation, the perturbation of the dynamic response was exhausted and pulsatile
hemodynamic parameter curves were obtained. The typical parameter curves are shown
in figure 3. Small fluctuations in these curves were observed due to the effect of baroreflex
modulation. The corresponding numerical values of systolic and diastolic blood pressure
(SBP and DBP), cardiac output (CO), VO2 , eject fraction (EF), end-systolic volume (LVESV)
and end-diastolic volume (LVEDV) of the left ventricle were achieved and are given in
table 1.

Baroreflex function. To validate the appropriateness of the ANS regulation model, two kinds
of simulation addressed in the literature (Ursino 1998) were respectively repeated.
(i) Carotid baroreflex in open-loop nonpulsatile conditions. To analyze the function of
carotid baroreflex, the close-loop baroreflex regulation was removed, i.e. the input of the
480 S Chen et al

160

140

Arterial pressure/mmHg
120

100

80

60

40
40 60 80 100 120 140 160
Intrasinus pressure/mmHg

Figure 4. Baroreflex function curve under the open-loop condition with static loading of carotid
sinuses. The abscissa is the intrasinus pressure and the ordinate is the change in the systemic
arterial pressure.

Table 1. The numerical results under normal condition and hypertension.

SBP/DBP CO VO2 EF LVESV LVEDV

(mmHg) (L min−1) (ml · O2 /beat) (%) (ml) (ml)
Normotension 112/77 5.69 0.17 60.77 51 130
Hypertension with autonomic regulation 144/94 5.61 0.23 54.20 66 144
Hypertension without autonomic regulation 152/102 5.69 0.25 54.01 67 146

SBP: systolic blood pressure, DBP: diastolic blood pressure, CO: cardiac output, VO2 : oxygen consumption per heart
beat, EF: eject fraction, LVESV: end-systolic volume of left ventricle, LVEDV: end-diastolic volume of left ventricle.

afferent pathway was not obtained from the carotid artery pressure, but was given by
adjusting the pressure from 50 mmHg to 150 mmHg with a step of 10 mmHg. The mean
systemic arterial pressure (MAP) was computed and the function curve (MAP versus
mean intrasinus pressure) is illustrated in figure 4. As shown in the figure, MAP changes
from 146 mmHg to 55 mmHg with the alteration of the mean intrasinus pressure.
(ii) Effect of intrasinus pressure pulsatility. The effect of intrasinus pressure pulsatility on
the carotid baroreflex control was investigated. The mean intrasinus pressure varies from
50 mmHg to 150 mmHg with a step of 10 mmHg. And a 2 Hz pulsatile fluctuation
with varying peak-to-peak amplitudes (0 mmHg, 20 mmHg, 30 mmHg and 40 mmHg,
respectively) is superposed on the mean intrasinus pressure. Figure 5 demonstrates
that the pulsating pressure at the carotid sinuses decreases the sensitivity of the carotid
baroreflex.

3.2. The role of autonomic nervous regulation in hypertension

Abnormality of the main hemodynamic parameters and LVH is frequently observed in
hypertension. Hence, ANS regulation in hypertension is assessed by investigating its effect
on these two aspects. In hypertension simulation, by setting Kc = 0.75 and Kr = 1.4 (Segers
et al 2001) the compliance of arteries was reduced by 25% and the total peripheral resistance
A bond graph model for ANS in hypertension 481

160
0mmHg
20mmHg
30mmHg
140
40mmHg

Arterial pressure/mmHg
120

100

80

60

40
40 60 80 100 120 140 160
Intrasinus pressure/mmHg

Figure 5. Effect of pressure-pulse amplitude at carotid sinuses on the overall open-loop

characteristic of the baroreflex. The abscissa is the mean intrasinus pressure and the ordinate
is the change in the systemic arterial pressure. Asterisk: 0 mmHg fluctuation, circle: 20 mmHg
fluctuation, triangle: 30 mmHg fluctuation, diamond: 40 mmHg fluctuation.

Table 2. Blood pressures under different set points under hypertensive condition.

Pn (mmHg) 87 97 102 107 112 117

SBP 134 139 141 144 147 149
DBP 84 89 91 94 96 99
MAP 101 106 108 111 113 116
Pn : Set point in the afferent pathway of the carotid baroreflex regulation model.

was increased by 40%, respectively. The assessment is processed in two cases:

(i) ANS regulation is intact or slightly impaired. The imbalance of the ANS is considered
by resetting the baroreflex set point from 87 mmHg (the normal SBP/DBP are assumed
as 110/75 mmHg) to higher levels.
(ii) ANS regulation is completely damaged. In this case the baroreflex regulation pathway in
the model is disabled.

Resetting of the baroreflex set point in hypertension. Simulation results under different
carotid baroreflex set points are given in table 2. As indicated in the results, the blood pressure
increased as the baroreflex set point rose. Referring to the classification of hypertension
(JNC7 2003), it developed from prehypertension (set points are 87 and 97 mmHg) to stage 1
hypertension (set points are 102, 107, 112 and 117 mmHg).
The following simulation results were under stage 1 hypertension condition in which the
baroreflex set point was reset to 107 mmHg (SBP/DBP were assumed as 140/90 mmHg).

ANS regulation on hemodynamic parameters. Figure 6 illustrates the aorta blood pressure
and the left ventricle pressure–volume loop for normal and hypertensive states. It is shown that
under hypertension the blood pressure is higher than that in normal (figure 6(a)) and the left
ventricle pressure–volume loop shifts toward right, i.e. both LVESV and LVEDV are increased
(figure 6(b)). Additionally, it is observed that if the ANS function is damaged completely,
SBP/DBP under hypertension increase more and the left ventricle pressure–volume loop shifts
482 S Chen et al

170
(a) normal with baroreflex 200 (b)
160 normal with baroreflex
hypertension with baroreflex
180 hypertension with baroreflex
hypertension absent of baroreflex
150 hypertension absent of baroreflex
160
140
140
130
Pressure/mmHg

Pressure/mmHg
120
120
100
110
80
100

90 60

80 40

70 20

60 0
0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 0 20 40 60 80 100 120 140 160 180 200
t/s Volume/mL

Figure 6. Hemodynamic state in normotension and hypertension. Solid line, normotension;

dashed line, hypertension with intact baroreflex; dot line, hypertension lacking baroflex. (a) Blood
pressure in aorta. (b) Left ventricle pressure–volume loops.

50
hypertension with
intact regulation
40 of all effectors
no SPVR
30
Percent of changes(%)

20 no elastance

10
no venous volume
VO2
0
no HR
-10
SBP DBP CO EF VO2 LVESV LVEDV
-20

Figure 7. Sensitivity analysis of SPVR, elastance, venous volume and HR. The abscissa indicates
parameters and the ordinate is their percentage change.

further right. As shown in table 1, when hypertension occurs, the blood pressure rises from
112/77 mmHg to 144/94 mmHg. If autonomic nervous regulation is absent in hypertension,
SBP and DBP both increase further by 8 mmHg, while EF decreases by 0.19% and VO2
increases by 20 × 10−3 ml · O2 /beat.
SPVR, ventricular end-systolic elastance, venous unstressed volumes and HR are four
different categories of effectors in ANS regulation. To clarify their roles in hemodynamic
regulation, a sensitivity analysis was carried out in the hypertension simulation. This was
done by isolating SPVR, ventricular end-systolic elastance, venous unstressed volumes and
HR one by one from the efferent pathway, and thus a total of four tests were processed.
The corresponding changes of the main hemodynamic parameters in the tests were obtained
and are illustrated in figure 7. It shows that when SPVR is not modified by the efferent
pathway, the changes in blood pressure are the largest (SBP: 33.04%, DBP: 29.87%). The
effect of the venous unstressed volume is the second largest; when it is absent the changes in
SBP and DBP are 31.25% and 24.68%, respectively. It is also observed that CO decreases
the least (−0.356%) when the venous unstressed volume is neglected. This suggests that
A bond graph model for ANS in hypertension 483

Table 3. The left ventricle wall thickness under hypertensive condition.

Hypertension with Hypertension without

State Normal autonomic regulation autonomic regulation
Thickness (mm) 10 12.74 13.22

the venous unstressed volume contributes much to the modulation of the cardiac output and
then indirectly affects the blood pressure. Thus evidently, it indicates that SPVR and venous
unstressed volume play critical roles in blood pressure regulation, while ventricle elastance
and HR contribute less.

ANS regulation on LVH. To elucidate the effect of autonomic nervous system regulation on
LVH in hypertension, LVWT was calculated in the hypertensive state. In the simulation, the
initial ventricle wall thickness is assigned to be 10 mm under normal physiological condition.
The left ventricle end-systolic volume and systolic pressure were obtained by the simulation
and LVWT under hypertension was computed by equation (12).
Table 3 gives the simulation results for LVWT. It reveals that the occurrence of
hypertension induces the thickening of LVWT from 10 mm to 12.74 mm. If autonomic
regulation is absent in hypertension, the LVWT visibly increases to 13.22 mm.

4. Discussion

Various mathematical models have been recently proposed for physiological study (Heldt
et al 2001, Li et al 2002, Segers et al 2000, 2001, Ursino 1998, Ursino and Magosso 2003,
Van Roon et al 2004). Most of them were constructed based on electrical analog theory
and the model equations are usually difficult to deduce. In the present model, the bond
graph technique is applied. It describes different energy domains by unified elements, and
has a single form in deducing model equations. Meanwhile, a number of software tools are
available for bond graph modeling, such as 20-sim (www.20sim.com), CAMP-G (Granda and
Reus 1997) etc. Thus the complexity in model solving is not so huge as it looks like. The
graphical characteristic of the bond graph makes the interpretation of the model easy as its
design approaches the anatomy structure (Le Rolle et al 2005). In this sense, the bond graph
technique is more convenient for understanding and extending the model in contrast with the
electrical analog method.
Another benefit of the current model is the detailed description of the vascular system.
Each part of the vascular system is lumped as a modified Windkessel model and can be further
divided into much more detailed segments to satisfy intensive research purposes. For instance,
the cerebral arteries which are represented by a lumped segment in the present model can be
further depicted by a Willis circle. Such a clear distinction of the vascular network may
improve the understanding of the role of a specific vessel segment under physiological and
pathological conditions.

4.1. Validation of the model

The validation of the model was investigated under two aspects. First, according to the
simulation results under normal physiological state, the typical values of SBP/DBP, EF and
VO2 were achieved as 112/77 mmHg, 60.77% and 0.17 ml · O2 /beat, respectively. The
blood pressure in the left ventricle and aorta, wave flow and volume in the left ventricle, and
484 S Chen et al

blood pressure in the left arm were obtained (figure 3). It also shows that the systolic blood
pressure in the left arm is higher than that in the aorta, while the diastolic blood pressure is
lower. These simulation results are in good agreement with human physiological features
(Fung 1996, Guyton and Hall 2000) where the normal ranges of the main parameters are
SBP < 120 mmHg, DBP < 80 mmHg, EF: 55%–65%. Thus, our model provides the
availability of a tool for the study of main cardiovascular characteristics. Second, the baroreflex
function simulation results from the present model are accordant with the results obtained by
Ursino and other observations (Angell James and Daly 1971, Chen and Chang 1991, Guyton
and Hall 2000, Schmidt et al 1972, Ursino 1998). The carotid baroreflex function curve
illustrated in figure 4 demonstrates a sigmoid shape. A mean intrasinus pressure alteration from
50 mmHg to 150 mmHg results in a MAP change from 146 mmHg to 55 mmHg. It agrees
well with the autonomic nervous regulation mechanism in normal physiological state (Chen
and Chang 1991, Guyton and Hall 2000). The curves in figure 5 indicate that the sensitivity
of the carotid baroreflex decreases when the intrasinus pressure shifts from nonpulsatile to
pulsatile conditions. These results are consistent with other simulation studies (Angell James
and Daly 1971, Ursino 1998, Schmidt et al 1972); thus, the ANS regulation model in our work
is appropriate. Furthermore, a small fluctuation on the parameter curves in figure 3 indicates
the tone of baroreflex, which disappears in the models without autonomic regulation. These
facts confirm the validity of the autonomic nervous regulation model.

4.2. The role of autonomic regulation in hypertension

Simulation of hypertension and baroreflex resetting. The simulation of hypertension is
reasonable considering both the methodology and the results. First, parameter setting of
the hypertension condition (Kc = 0.75, Kr = 1.4) is referred to clinical data employed in
the literature (Segers et al 2001). If one focuses on severe hypertension, relevant parameters,
e.g. Kc and Kr , should be adjusted to be smaller or larger. The baroreflex resetting in chronic
hypertension has been verified in early study (Gonzalez et al 1983). Second, the simulation
outcome well reflects the cardiovascular state and change in hemodynamic parameters in
hypertension. These results are in accordance with clinical observations. Accordingly, we
can conclude that the hypertension simulation by our model is effective.
As a symbol of ANS disturbance, the baroreflex resetting is frequently observed in chronic
hypertension (Gonzalez et al 1983). The disturbances in ANS regulation even appear preceding
overt arterial hypertension, which may result in the increased risk of prehypertensive condition
(Lucini et al 2002). However, simulation of baroreflex resetting was rarely considered in the
previous studies (Li et al 2002, Segers et al 2000, 2001). In our work, the model is able to
simulate the shifting of baroreflex resetting and makes quantitative investigation possible.
Results in table 2 indicate that if the ANS is somewhat but not heavily destroyed, e.g. the
baroreflex set point is 97 mmHg, despite the abnormality of vascular capacitance and SPVR,
the blood pressure is well controlled at prehypertension. With the aggravation of impairment
of ANS, e.g. the baroreflex set point is 102, 107, 112 and 117 mmHg, the blood pressure is
elevated to hypertension. As an extreme case, if ANS is completely destroyed, the elevation
in blood pressure is more severe than that under intact ANS. Thus, it can be concluded that
ANS plays a role of alleviation and protection in hypertension by preventing the rise of blood
pressure in hypertension. With the development of ANS damage, the protective role becomes
weaker.

ANS regulation on hemodynamic parameters and LVH. LVH is often observed in

hypertension. Baroreflex sensitivity and increased sympathetic activity are associated with
A bond graph model for ANS in hypertension 485

LVH in hypertensive patients (Milan et al 2007, Schlaich et al 2003). The complex interaction
mechanisms of LVH, arterial system and ANS are not well understood (Guyenet 2006). LVH
is considered to compensate for the increased systolic wall stress induced by the chronic
elevation of blood pressure (Segers et al 2001). It was investigated by a simple model which
comprises a heart model and a 4-element lumped parameter Windkessel model (Segers et al
2000, 2001). However, the role of ANS in LVH was not mentioned.
The present work aimed at a better understanding of the role of ANS in hypertension,
in particular its regulation on both hemodynamics and LVH. The results demonstrate that
autonomic regulation is crucial in the protection of hypertension. It is found that despite
ANS being partially impaired in the hypertensive situation, the status of both hemodynamics
and LVH is less serious than the case without baroreflex regulation. If the ANS regulation
is lacking, the blood pressure increases notably. Consequently, the elevated pressure results
in an increase of the left ventricle wall stress (Segers et al 2000); thus LVWT is increased
to maintain the wall stress at normal levels and correspondingly more oxygen is needed.
Such straightforward adaptive compensation preserves the cardiac output at the cost of
fundamentally impairing the heart.

The effectors of ANS regulation. The sensitivity analysis helps to clarify the effectors of
ANS regulation. The results demonstrate that the most important effector of ANS regulation
on the hypertension is SPVR, followed by venous unstressed volume. From the results,
one can deduce that ANS regulation on the hypertension performs mainly by a remarkable
reduction of SPVR and increase of venous unstressed volume. The reduction of SPVR
decreases the overloading of the heart. This reduction in the load of the heart may prevent
it from being damaged. The increase of venous unstressed volume reduces the end-diastolic
volume and causes the decrease of cardiac output, which leads to the reduction of blood
pressure. Therefore, the present work gives more insight into the protective effect of ANS in
hypertension.
Being a mathematical model of the intricate human system, the present study inevitably
has some limitations. Other regulations such as humoral factors, chemoreflex and pulmonary
stretch reflex are not taken into account in the model. The humoral factor is important in
the regulation of blood pressure. A long-term regulation of the blood pressure is achieved
through the combined actions of a number of hormones, which influence the kidney and the
regulation of extracellular fluid volume. The maintenance of blood volume is achieved by the
renin-angiotensin system, aldosterone and vasopressin (antidiuretic hormone) which act on
the kidney to promote the retention of sodium and water. Also, atrial natriuretic peptide causes
diuresis and natriuresis to reduce the blood volume (Ashton 2007, Schroeder et al 1996). In
addition to direct regulation on blood pressure, some receptor-mediated humoral factors affect
the blood pressure indirectly by modulating the reflex sensitivity of the receptors distributing
on the baroreflex arc (Schlaich et al 2003, 2004). Further, the simplification of the heart model
may be another shortcoming. In a simplified pump model, specific details related to myocardial
contraction, such as the influence of calcium concentration during the contraction process, are
not accounted for. Also, the Windkessel model components R, C, and I are simplified to be
constant during simulation; thus the model is unable to represent some nonlinear characteristics
such as nonlinear pressure–volume relationship in some vessel segments. Besides, neglecting
atrial contraction may impact some of the hemodynamic parameters. Early studies show
that atrial contraction results in about 10% increase in aortic pressure and left ventricular
systolic pressure; it also contributes to stroke volume (Korakianitis and Shi 2006). Lastly, the
whole model is a zero-dimensional lumped-parameter model without geometrical information.
Lumped-parameter methods can be used to represent a single-vessel segment or a collection
486 S Chen et al

of vessels and have been applied to model blood flow in large portions of the human arterial
system. However, since the geometry is not explicitly defined, the model is not able to simulate
wave propagation and reflection effects. Based upon the considerations above, more effort
should be taken in future work to improve these aspects.

5. Conclusion

In this paper, a conveniently extendable cardiovascular model is constructed and numerous

simulations were performed. The simulation results are within reasonable physiological ranges
and agree with human physiological features. Results indicate that the ANS has a valuable
protective effect on hypertensive subjects when it is not severely damaged, i.e. when the set
point of baroreflex regulation is not extremely elevated. According to the sensitivity analysis,
it mainly works by the tone of SPVR and venous unstressed volume.
In conclusion, the present work provides a useful model to study the laws of the
cardiovascular system as well as the mechanism of ANS regulation. Moreover, due to the
identical structure design of functional components by the bond graph technique, the model is
flexible and can be extended if necessary. Therefore, the model has the potential to be further
developed for educational, research and clinical purposes.

Acknowledgments

This work is supported by the National Nature Science Foundation of China (Grant 30570483),
the Science & Technology Department of Zhejiang Province, China (Grant 2006C13018). The
authors would like to thank Professor Mauro Ursino (University of Bologna, Italy) for the
helpful discussions and suggestions.

Appendix A

A.1. Heart model

In the diastolic phase of the heart, the ventricular pressure is assumed to rise as an exponential
function of the ventricular volume, which increases from the end-systolic volume to the
end-diastolic volume (Tsuruta et al 1994):
P (t) = a · [exp(Ds · V (t)) − 1] + Po (A.1)
where P(t) and V(t) are ventricular pressure and volume respectively, Ds is the ventricular
diastolic stiffness, P0 is the minimum diastolic ventricular pressure and a is constant.
While in the systolic phase, the relationship between the ventricular pressure and the
volume is assumed as
dV
P (t) = E(t) · [V (t) − Vd ] + R(t) , (A.2)
dt
where Vd is the unstressed volume of the ventricle. R(t) is the source resistance, which is
defined by
R(t) = k · E(t) · (Ved − Vd ), (A.3)
−1
where k = 0.0015 s mL .
E(t) is ventricular systolic elastance; the expression of E(t) which was brought forward
by Ursino (1998) is used in the model:
E(t) = Emax · sin2 (π · T · u(t)/Tsys ). (A.4)
A bond graph model for ANS in hypertension 487

A.2. Carotid baroreflex regulation model

The model consists of afferent pathway, efferent pathway and regulation effectors. The
efferent pathway has separated the sympathetic and vagal path. These processes are described
by vital parameter equations. Following is a brief introduction to these parameters. A detailed
description of the equations and definition of the variables can be found in the literature (Ursino
1998).

Afferent pathway. It is characterized byfcs , the frequency of spikes in the afferent fibers:
    
P̃ − Pn P̃ − Pn
fcs = fmin + fmax exp 1 + exp . (A.5)
ka ka

Efferent sympathetic pathway. It is characterized by fes , the frequency of spikes in the

efferent sympathetic nerves:
fes = fes,∞ + (fes,0 − fes,∞ ) · e−kes ·fcs . (A.6)

Efferent vagal pathway. It is characterized by fev , the frequency of spikes in the efferent
vagal fibers:
    
fcs − fcs,0 fcs − fcs,0
fev = fev,0 + fev,∞ exp 1 + exp . (A.7)
kev kev

Regulation effectors. It is characterized by θ and heart period T. θ is a generic controlled

parameter regulating the response of resistances, unstressed volumes and cardiac elastance.
It is deduced by

Gθ · ln[fes (t − Dθ ) − fes,min + 1] if fes
fes,min
σθ (t) = (A.8)
0 if fes < fes,min
dθ 1
(t) = (−θ (t) + σθ (t)) (A.9)
dt τθ
θ (t) = θ (t) + θ0 . (A.10)

T is regulated by

GT ,s · ln[fes (t − DT ,s ) − fes,min + 1] if fes
fes,min
σT ,s (t) = (A.11)
0 if fes < fes,min
dTs (t) 1
= · (−Ts (t) + σT ,s (t)) (A.12)
dt τT ,s
σT ,v (t) = GT ,v · fev (t − DT ,v ) (A.13)
dTv (t) 1
= · (−Tv (t) + σT ,v (t)) (A.14)
dt τT ,v
T = Ts + Tv + T0 . (A.15)
488 S Chen et al

Appendix B

Fifty four ordinary differential equations of the circulation system sub-model:

dλrsa Vtat − Vtat0 Vrsa − Vrsa0 Rrsa · λrsa
= − − (B.1)
dt Ctat Crsa Irsa
dλraa Vrsa − Vrsa0 Vraa − Vraa0 Rrsa · λraa
= − − (B.2)
dt Crsa Craa Iraa
dλrra Vraa − Vraa0 Vrra − Vrra0 Rrra · λrra
= − − (B.3)
dt Craa Crra Irra
dλrav Vrav − Vrav0 Vtvc+rat − Vtvc0+rat0 Rrav · λrav
= − − (B.4)
dt Crav Ctvc+rat Irav
dλlsa Vtat − Vtat0 VClsa − VClsa0 Rlsa · λlsa
= − − (B.5)
dt Ctat Clsa Ilsa
dλlaa Vlsa − Vlsa0 Vlaa − Vlaa0 Rlaa · λlaa
= − − (B.6)
dt Clsa Claa Ilaa
dλlra Vlaa − Vlaa0 Vlra − Vlra0 Rlra · λlra
= − − (B.7)
dt Claa Clra Ilra
dλlav Vlav − Vlav0 Vtvc+rat − Vtvc0+rat0 Rlav · λlav
= − − (B.8)
dt Clav Ctvc+rat Ilav
dλcca Vtat − Vtat0 Vcca − Vcca0 Rcca · λcca
= − − (B.9)
dt Ctat Ccca Icca
dλici Vcca − Vcca0 Vici − Vici0 Rici · λici
= − − (B.10)
dt Ccca Cici Iici
dλbrn Vici − Vici0 Vivn − Vivn0 Rbrn · λbrn
= − − (B.11)
dt Cici Civn Ibrn
dλivn Vivn − Vivn0 Vejv − Vejv0 Rivn · λivn
= − − (B.12)
dt Civn Cejv Iivn
dλejv Vejv − Vejv0 Vtvc+rat − Vtvc0+rat0 Rejv · λejv
= − − (B.13)
dt Cejv Ctvc+rat Iejv
dλtvv Vtvc+rat − Vtvc0+rat0 (Rrat + Rtvv ) · λtvv
= − PRV − (B.14)
dt Ctvc+rat Itvv
dλpvv Vpar − Vpar0 Rpar · λpar
= PRV − − (B.15)
dt Cpar Ipar
dλpar Vpar − Vpar0 Vpvn − Vpvn0 (Rpar + Rpcl ) · λpar
= − − (B.16)
dt Cpar Cpvn Ipar
dλpvn Vpvn − Vpvn0 Vlat − Vlat0 Rpvn · λpvn
= − − (B.17)
dt Cpvn Clat Ipvn
dλmvv Vlat − Vlat0 (Rlat + Rmvv ) · λmvv
= − PLV − (B.18)
dt Clat Imvv
dλavv Vtat − Vtat0 Ravv · λavv
= PLV − − (B.19)
dt Ctat Iavv
A bond graph model for ANS in hypertension 489

dλcor Vtat − Vtat0 Vtvc+rat − Vtvc0+rat0 Rcor · λcor

= − − (B.20)
dt Ctat Ctvc+rat Icor
dλtat Vtat − Vtat0 Vaat − Vaat0 Rtat · λtat
= − − (B.21)
dt Ctat Caat Itat
dλacl Vaat − Vaat0 Vavc − Vavc0 Racl · λacl
= − − (B.22)
dt Caat Cavc Iacl
dλaat Vaat − Vaat0 Vlga − Vlga0 Raat · λaat Rlga · λlga dλlga
= − − − − (B.23)
dt Caat Clga Iaat Ilga dt
dλrga Vaat − Vaat0 Vrga − Vrga0 Raat · λaat Rrga · λrga dλaat
= − − − − (B.24)
dt Caat Crga Iaat Irga dt
dλrgv Vrgv − Vrgv0 Vavc − Vavc0 Ravc · λavc Rrgv · λlrv dλavc
= − − − − (B.25)
dt Crgv Cavc Iavc Ilrv dt
dλlga Vaat − Vaat0 Vlga − Vlga0 Raat · λaat Rlga · λlga dλaat
= − − − − (B.26)
dt Caat Clga Iaat Ilga dt
dλlgv Vlgv − Vlgv0 Vavc − Vavc0 Ravc · λavc Rlgv · λlgv dλavc
= − − − − (B.27)
dt Clgv Cavc Iavc Ilgv dt
dλavc Vlgv − Vlgv0 Vavc − Vavc0 Ravc · λavc Rlgv · λlgv dλlgv
= − − − − (B.28)
dt Clgv Cavc Iavc Ilgv dt
dλtvc Vavc − Vavc0 Vtvc+rat − Vtvc0+rat0 Rtvc · λtvc
= − − (B.29)
dt Cavc Ctvc+rat Itvc
dVrsa λrsa λraa
= − (B.30)
dt Irsa Iraa
dVraa λraa λrra
= − (B.31)
dt Iraa Irra
Vrra −Vrra0 Vrav −Vrav0
dVrra λrra Crra
− Crav
= − (B.32)
dt Irra Rrac
Vrra −Vrra0
dVrav Crra
− VravC−V rav0
λrav
= rav
− (B.33)
dt Rrac Irav
dVlsa λlsa λlaa
= − (B.34)
dt Ilsa Ilaa
dVlaa λlaa λlra
= − (B.35)
dt Ilaa Ilra
Vlra −Vlra0 Vlav −Vlav0
dVlra λlra Clra
− Clav
= − (B.36)
dt Ilra Rlac
Vlra −Vlra0
dVlav Clra
− VlavC−V lav0
λlav
= lav
− (B.37)
dt Rlac Ilav
dVcca λcca λici
= − (B.38)
dt Icca Iici
dVici λici λbrn
= − (B.39)
dt Iici Ibrn
490 S Chen et al

dVivn λbrn λivn

= − (B.40)
dt Ibrn Iivn
dVejv λivn λejv
= − (B.41)
dt Iivn Iejv
dVtvc+rat λejv λlav λrav λtvc λtvv λcor
= + + + − + (B.42)
dt Iejv Ilav Irav Itvc Itvv Icor
dVrvt λtvv λpvv
= − (B.43)
dt Itvv Ipvv
dVpar λpvv λpar
= − (B.44)
dt Ipvv Ipar
dVpvn λpar λpvn
= − (B.45)
dt Ipar Ipvn
dVlat λpvn λmvv
= − (B.46)
dt Ipvn Imvv
dVlvt λmvv λavv
= − (B.47)
dt Imvv Iavv
dVtat λavv λlsa λrsa λcca λcor λtat
= − − − − − (B.48)
dt Iavv Ilsa Irsa Icca Icor Itat
dVaat λtat λaat λacl
= − − (B.49)
dt Itat Iaat Iacl
Vrga −Vrga0 Vrgv −Vrgv0
dVrga λrga Crga
− Crgv
= − (B.50)
dt Irga Rrgc
Vrga −Vrga0 Vrgv −Vrgv0
dVrgv Crga
− Crgv λrgv
= − (B.51)
dt Rrgc Irgv
Vlga −Vlga0 Vlgv −Vlgv0
dVlga λlga Clga
− Clgv
= − (B.52)
dt Ilga Rlgc
Vlga −Vlga0 Vlgv −Vlgv0
dVlgv Clga
− Clgv λlgv
= − (B.53)
dt Rlgc Ilgv
dVavc λavc λacl λtvc
= + − , (B.54)
dt Iavc Iacl Itvc

where PLV and PRV are the left and right ventricular pressures which are calculated by the
heart model, Ctvc+rat is the sum of the capacitances of the thoracic vena cava and left atrium.

Appendix C

C.1. Parameters of the vascular system

 A bond graph model for ANS in hypertension
Circulation Vascular segment Notation R (mmHg s mL−1 × 10−3) C (mmHg−1 mL) I (mmHg s2 mL−1× 10−3) V0 (ml) Source
Head and neck External carotid artery eca 12.45 0.15 7.75 0 a

Internal carotid artery and arteries in brain ici 31.23 0.15 15.51 0 a

Veins in the brain ivn 1.95 14.80 3.88 157.98 a

External jugular vein ejv 0.77 7.38 1.94 78.85 a

Impedance of the brain brn 3 300.28 — 0.38 0 a

Pulmonary Pulmonary vein pvn 15.00 7.99 0.33 120 a

Pulmonary artery par 15.00 3.99 1.32 0 a

Pulmonary circulation pcl 90.01 — — 123 a

Coronary Coronary circulation cor 15 001.28 — 1.50 0 a

Abdomen Abdominal aorta aat 7.05 0.13 16.60 0 a

Ventral vena cava avc 0.62 21.67 5.00 1121 a

Thoracic vena cava tvc 0.56 18.98 2.84 202.68 a

Thoracic aorta tat 0.81 0.38 9.43 0 a

Internal abdomen circulation acl 2 194.31 — 5.10 274.4 a

491
 492
(Continued.)

Circulation Vascular segment Notation R (mmHg s mL−1 × 10−3) C (mmHg−1 mL) I (mmHg s2 mL−1× 10−3) V0 (ml) Source
Extremity Left subclavian artery lsa 12.45 0.14 7.76 0
Arteries in the left arm laa 31.23 0.11 15.51 0
Left radial artery lra 37.00 0.08 20.00 0 a,b

Resistance of the left arm lac 2 850.00 — — 0

Veins in the left arm lav 29.78 7.0 1.70 318.02
Right subclavian artery rsa 12.45 0.14 7.76 0
Arteries in the right arm raa 31.23 0.11 15.51 0
Right radial artery rra 37.00 0.08 20.00 0 a,b

Resistance of the right arm rac 2 850.00 — — 0

Veins in the right arm rav 29.78 7.0 1.7 318.02
Arteries in left crura lga 54.35 0.14 20.51 0
Veins in left crura lgv 3.38 15.78 8.50 318.02
Resistance of left crura lgc 2 850.00 — — 0
Arteries in right crura rga 54.35 0.14 20.51 0
Veins in right crura rgv 3.38 15.78 8.50 318.02
Resistance in right crura rgc 2 850.00 — — 0
The parameters without given source are estimated as follows. R, C and I are concerned with blood density (D), pulse wave velocity (V), blood viscosity (µ), cross-sectional area (A)
and length (L) of the vessel segment. D, V and µ are assumed as constant, while A and L vary in different vessel segments. ‘—’ indicates the parameter not applied in the model.
a Goldstein et al (1988).
b Guyton and Hall (2000).

S Chen et al
A bond graph model for ANS in hypertension 493

C.2. Parameters of heart and valves

Notation R (mmHg s mL−1 × 10−3) C (mmHg−1 mL) I (mmHg s2 mL−1 × 10−3) Source

Left atrium lat 2.5 3.80 — a,b

Aortic valve avv 0.015 — 0.045 a

Mitral valve mvv 205.53 — 0.23 a

Right atrium rat 2.5 9.70 — a,b

Pulmonary valve pvv 0.066 — 0.045 a

Tricuspid valve tvv 195.53 — 0.23 a

‘—’ indicates the parameter not applied in the model.

a Goldstein et al (1988).
b Tsuruta et al (1994).

C.3. Parameters of the ventricle

Emax (mmHg mL−1) Vd (mL) a (mmHg) Ds (mL−1) P0 (mmHg)

Left ventricle 4.2a 16.77b 1.5b 0.014b 0c

Right ventricle 2.75a 40.8b 1.5b 0.011d 0c
Emax : maximum elastance of ventricle, Vd: unstressed volume of ventricle, Ds : ventricular
diastolic stiffness, P0 : minimum diastolic ventricular pressure and a is constant.
a Wu et al (1999).
b Goldstein et al (1988).
c Tsuruta et al (1994).
d Ursino (1998).

C.4. Parameters of autonomic regulation

Some initial values of effectors. Others refer to Ursino (1998).

Maximum elastance Left ventricle Emax,lv0 = 3.5696 mmHg ml−1

Right ventricle Emax,rv0 = 2.3376 mmHg ml−1

Peripheral vascular resistance Abdomen Racl0 = 1.4068 mmHg s ml−1

Left arm Rlac0 = 1.1969 mmHg s ml−1
Right arm Rrac0 = 1.1969 mmHg s ml−1
Left leg Rlgc0 = 1.1969 mmHg s ml−1
Right leg Rrgc0 = 1.1969 mmHg s ml−1

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