Transactions of the Institute of

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Modelling a complex biological system: the human cardiovascular system−−1. Methodology and
model description
M.S. Leaning, H.E. Pullen, E.R. Carson and L. Finkelstein
Transactions of the Institute of Measurement and Control 1983 5: 71
DOI: 10.1177/014233128300500202

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Modelling a complex biological
system: the human cardiovascular
system—1. Methodology and model
description
by M. S. Leaning*†, BA, MSc, PhD, H. E. Pullent, MSc, PhD, E. R. Carson†‡, MSc, PhD, CEng, MIEE,
FlnstMC, and L. Finkelstein §, MSc, CEng, FIEE, FInstP, FInstMC

Mathematical models are powerful tools for investigating u CNS variable (heart rate)
and understanding complex systems. Their use must be v velocity
guided by knowledge of their potentialities and limitations V volume
and a well-based approach to the modelling process. Such is x, y periodic elastance functions
embodied in an integrated methodology for model formula- a venous-collapse parameter
tion, identification and validation which has emerged from (3 venous-retrograde-flow parameter
practical modelling as well as historical studies. The À CNS parameter
methodology in operation is illustrated by application to x kinematic viscosity
the formulation of a model of the human cardiovascular p density
system, its neural control and the effect of drugs. The a drug effect variable or parameter
derivation of the model is described in depth and a com- ~r time constant
plete model listing is given. The companion paper develops
a validation methodology and applies it to the cardiovascular
List of subscripts
model.
Ccrr~partmental subscripts (after Beneken & De Wit, 1967):
L.~s~ of symbols AA Abdominal arteries
a elastance .4011 Ascending aorta
A area A~2 Aortic arch
b CNS variable (myocardial contractility r~C~3 Thoracic aorta
B baroreceptor output ~1 ~’ Abdominal veins
c compliance CA Leg arteries
CO cardiac output IA Intestinal arteries
d CNS variable (venous tone) cv Leg veins
ETSR estimated total systemic resistance IV Intestinal veins
f frequency IVC Inferior vena cava
F flow ~.A Left atrium
g gravitational acceleration Lt~ Left ventricle
i, j, k segmental subscripts PA Pulmonary arteries .

I length P~’ Pulmonary veins

1, inertance RA Right atrium
tra mass R ~’ Right ventricle
At injected drug mass SVC Superior vena cava
MAP mean arterial pressure H4 Head and arm arteries
n number of g acceleration UV Head and arm veins
p pressure
q CNS variable resistance)
R resistance Other subscripts
s CNS variable (baroreceptors) AO Aorta
SV stroke volume ~~4 Systemic arteries
t time sic Systemic circulation
t~c elapsed time within cardiac cycle ~.~’I~’ Systemic veins
T period ,
.
~1,~~ Abdomen
--- - -- -

B~x ~1~~’ Bronchial

*Academic Dept of Medical Physics, Royal Free Hospital School of cm Critical closure
Medicine, London. †Department of Systems Science, The City COR
University, London. ‡Academic Dept of Chemical Pathology, Royal Coronary
Free Hospital School for Medicine, London. § Department of D Diastofic
Physics, The City University, London. H Heart

71

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HEAD Head and arms magnitude and irreducibility that distributed array
INT Intestinal processing is essential.)
~’Y Thoracic veins The roles of models range from the indirect measure-
YC Vena cava ment of system parameters and variables, to predicting
ADT Aortic arch and thoracic aorta future system states, to the development and testing of
1,1’A Lower part arteries theories. In medicine, simple models are used to estimate
l,Pi~ Lower part veins parameters for diagnostic purposes (eg Carson et al, 1~83),
LEG Legs Models of more complex biological systems are, at present,
L UNG Lungs more suited as heuristic tools for advancing understanding
lt~Q.~ Maximum (eg Leaning, 1980). An advantage o adopting a mathe-
11tE11.IN Minimum matical formulation is that a formidable body of pure and
N Normal applied mathematics is made available, including dynamical
~5 Systolic systems theory, control theory, topology, information
TH Thorax theory, estimation theory, and identifiability analysis.
T Total These form an implicit backdrop for a model and often
u Unstressed provide major new research tools to a scientific field.
The understanding of a complex system may be
Units employed improved by reducing the perceived complexity of the
system. Many complex systems have structures which
Pressure torr permit them to be decomposed into quasi-independent sub-
Flow ml/s systems or levels. For example, biological and social
Volume ml systems exhibit both compartmental and hierarchical
Compliance ml/torr structures. These subsystems may then be more effectively
Elastance torr/ml studied independently, often as distinct disciplines. The
Resistance torr s/nl compartmentalisation of biological systems is reflected in
Inertance torr s2/ml stable subsystems, such as the cardiovascular system which
Length cm has a complete control system for blood pressures and
Area cm~’2 flows (ie, haemodynamics) even though its main function
is the removal and supply of substances at local sites. The
1. ~~tr~rodt~ctic~~ implications for developmental and evolutionary biology
are clear. Simon (1969) argues that complex systems owe
This is the first of two papers reporting the results of an their .existence to structural properties of this kind.
extensive programme of work into the development and As a tool for investigating complex systems, mathe-
validation of a dynamic mathematical model of the human matical models may, therefore, be used to study the effects
cardiovascular system (pollen, 1976; Rajkumar, 1978; Al of system structure, for example: compartmentalisation
Dahan et al, 1979; Leaning, 1980). The aims of the papers and control in biological systems. By examining subsystem
are to demonstrate the potentialities and limitations of dominance, it is often possible to show under what con-
mathematical modelling of the cardiovascular system (as an ditions a complex system can have simpler representations.
example of a class of biological systems), and to illustrate This may be regarded as a major aim of such modelling
a general approach towards the modelling of complex exercises.
systems. The latter aim is part of the general thesis that
mathematical models of the kind described here are power-
ful tools for the investigation, understanding, and
1.2 The cardiovascular system as a complex system
management of complex systems.
The cardiovascular system (CVS) comprises the heart
and blood vessels (and also some parts of the peripheral and
1.1 Complex systems and models
central nervous system). It is a general transport system in
An informal definition of a complex dynamic system is: which blood circulates through the body distributing to the
a system which has, structurally, a large number of elements tissues oxygen from the lungs, certain products of meta-
and a high interconnectedness and, functionally, a large bolism and substances absorbed from the digestive tract,
number of behaviour modes. Social systems, weather C02 to the lungs and other waste products to the kidneys,
systems, and living organisms are all examples of complex and also acts as a communication channel for hormonal
systems. control. It also plays a role in regulating body temperature.
Mathematical models of complex systems may be based The simplest haemodynamic (ie, dynamics of blood How)
oii established mathematical relationships (eg Newtonian model is that of two loops, with ths heart acting as a
mechanics and the laws of states in meteorological model- synchronised double-pump between them. The network of
ling ; Ivloa~ir~, 1972), on relationships derived from empirical blood vessels is, however, highly intricate, and their
data (eg compartmental biological modelling; Atkins, physical properties possess many essential non-linearities.
1969), or on hypothesised relationships (eg modelling bi- In addition, the optimal operation of the heart requires
communal political conflict; Bowers et al, 1981). Mathe- precise co-ordination of the flows into, and contraction of,
matical models allow the overall behaviour of the system to the four heart chambers.
be investigated in a complete sense, ~vhich’ls not possible In order to understand how the CVS copes with
with verbal models. Owing to system complexity, these changing bodily needs and environmental conditions, other
models generally, but not always, require solution or subsystems and modalities of behaviour must be considered.
simulation on a digital computer. (In the case of global The CVS is under tight neural and endocrine adaptive
meteorological models, the complexity is of such great control. Many drugs finding their way into the blood

72

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stream have a significant effect on the CVS (pharmaco-
dynamics). It is clear, therefore, that the cardiovascular
system is complex, both in terms of the number of
elements it contains and of the different behaviour modes
it possesses.
As a subject for mathematical modelling, the CVS serves
the aims of the papers well. It is reasonably well based on
data and theory, yet there are uncertainties. The model
presented in the paper is sufficiently well founded to
represent the major aspects of CVS behaviour, and to
investigate less certain areas (such as CVS control).
1.3 Uut~ine of the Paper
The next section outlines the methodology used in this
and other modelling programmes. Identification of model-
ling objectives is of great importance for complex systems,
and they are defined for the cardiovascular model in
Section 3. Section 4 describes the historical background to
cardiovascular modelling. The conceptual basis of the
model is introduced in Section 5, and details of the
mathematical formulation are covered in Section 6.
Solution, simulation and software aspects are considered in
Section 7. The paper is summarised in Section 8. A full
version of the mathematical model is contained in
Appendix A.
1.4 Outline of Paper 111
The second paper presents, in depth, the approach
adopted for model validation and the results of an extensive
validation programme on the cardiovascular model. The
possibilities for model reduction and development are also
considered. Finally, conclusions are made at two levels.
First, the success, or otherwise, of the cardiovascular model
in terms of its objectives; second, the applicability and
potential of our model-based approach to complex systems.
2. ~,~ outline of the modelling methodology
The integrated methodology presented here for model
formulation, identification and validation has evolved from
extensive application of dynamic systems analysis to a
range of complex problems in metabolism, endocrinology
and physiological organ processes (Leaning et alp 1982;
Carson et ctt,1983~. In addition, it is based on other studies
of the process of modelling in science and engineering
(Leaning, 1980). The methodology is depicted in Fig l .
2.1 9nterpretat~c~r~ of the methodology
Fig 1 shows the distinct stages and information required
in the modelling process. First, there is the perception that
a mathematical model will be useful or necessary. This may
from a practical proMem, &dquo;heoretical m
background knowledge, or simply the feeling that there
might be some scientific ’pay-off’, and leads to a clear
expression of the objects or purposes for which the model
is desired. Then follows the process of model formulation
(conceptualisation, realisation, synthesis and solution).
Finally, when the basic form of a model has been resolved,
identification may be used for some models to resolve
uncertainties, such as structural ambiguity or unknown
parameters.
Background knowledge relating to the model, in the
form of laws, theories, models and data, is important
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Fig 1 The modeling methodology
throughout the process. This knowledge, together with the
modelling objectives create this ’modelling environment’
without which modelling would be meaningless, and which
is omitted from conventional analyses (eg Mihram, 1972).
Perhaps the major feature of the methodology is the
distribution of model validation through each stage.
Furthermore, the concept of model validity has been con-
sidered (see Section 2.5). Model validation consists of
the application of a series of tests or critical assessments
underpinned by specific validity criteria. Failing these at
any stage often results in a step back to an earlier stage, and
hence the process of modelling is highly iterative. It is clear
that the subject of the methodology is not a single model,
but a series of models, which come every closer to meeting
the modelling objectives.
Successful models which achieve solution, identification,
and final validation tests may pass into the background
knowledge and become generally available. Regarding the
background knowledge as a kind of data base, the model-
ling methodology is, effectively, an adaptive control system
for expanding, updating or restructuring that data base.
In modelling complex systems, the expression of
modelling objectives is a particularly important stage.
Modelling makes large demands of time, intellectual, com-
puting and other resources. Choosing objectives which have
little or no chance of being achieved is easy for complex
systems, owing to their nature, and will result in much
wasted effort.
2.2 N9ode11ing objectives
The general categories of modelling objectives normally
identified are ~’~~~~~~~~~¢ and ~~~~~~~~~, to
which may be added the category of pragnwtic objectives.
The last refers to the practical use of models, independent
of satisfying the first three objectives (examples include
engineering, design and policy models). For an individual
model, more specific objectives define the actual system to
be modelled, including resolution, time scale, detail etc.
required. This may be referred to concisely as the blended
range of ~p~licralaerr~ of the model.
The intended range of application, together with the
general categories of modelling objective, largely determine
the structure and detail of a model, the processes of
73
formulation., and the appropriate validation tests for the
model.
2.3 6~locl~l formulation
The distinct stages of model formulation are: con-
ceptualisation ; mathematical realisation; synthesis; and
solution to give the required relations between variables of
interest. At any stage, additional data may be required. In
conceptualisation, the system is decomposed into identi-
fiable physical and functional subsystems, and assumptions
are made concerning aggregation and idealisation of the
model. The latter should be consistent with the modelling
objectives (ie intended range of application), and the model
should be tractable. The mathematical realisation consists
of formulating mathematical equations for each subsystem
based on existing mathematical relationships, those derived
from data, or hypothesised relationships. In synthesis, the
submodels are brought together and examined for
consistency and completeness.
Within the model, the relevant variables are commonly
connected through complex relations, eg differential
equations. Model solution involves obtaining the required
explicit relations between variables and/or parameters.
Ideally, this is by analytic or geometric techniques, but in
practice the complexity of most models requires computerr
solution or simulation.
2.4 ~tlor9el identification
Model identification is the determination of a model’s
structure and/or parameters by comparison of the response
of the model with that of the system under specified
experimental conditions. For models of complex systems,
identification is, necessarily, limited to subsets of model
parameters and possible structures, and it does not have the
mathematical vigour that is possible with simple models
(Carson et al, 1983; Leaning et al, 1982).
2.5 Model validation
In its broadest sense, model validation is the checking of
whether or not a model satisfies the objectives for which it
is intended. Validation is not performed solely as a final
step in modelling, but is part of the overall process (Section
2.1). The concept of validity is, therefore, a multidimensional
one, including: model consistency and algorithmic adequacy;
correspondence with empirical data; coherence with
accepted theories or models; heuristic potential as an
explanatory tool; and pragmatic usefulness. Each concept
can be expressed as a validity criterion which thereby
provides a basis for validation tests. Model validation is
considered in more depth in the following paper (in which
the results of validation of the cardiovascular model are
presented), and at length in Leaning (1980).
When modelling a complex system, it is unlikely that a
model will have high empirical validity as an accurate
representation of the intended range of application system.
It may be necessary, therefore, to consider heuristic aspects
to assess the validity and success of a model. In some cases
it is better to have a number of models each concentrating
on a particular aspect of the system.
~
3. (~bj~~~i~~~ c~~ modelling the human
cardiovascular system
The central objective of modelling the human cardio-
vascular system (CVS) was to produce a pulsatile mathe-
74
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matical model and computer simulation of the controlled
cardiovascular system of a normal, resting, conscious,
average human suitable for the study of short-term haemo-
dynamics. The aim was to make a mode sufficiently
detailed and comprehensive for the study of short-term
pharmacodynamics (ie, drug effects with the major
dynamics complete within 2 or 3 min) and to use the model
to study the overall effects of an injected drug assuming a
number of simultaneous actions of the circulating drug at
specific sites (Pullen, 1976).
The preceding paragraph is a clear description of the
intended range of application of the model. The general
categories of objective into which this fits are explanatory
and predictive. The former is associated with the develop-
ment of understanding of the CVS as a controlled system,
whereas the latter is concerned with the use of the model
to predict the effects of certain drugs.
4. ~listoric~l background
In
establishing the circulation of the blood, William
Harvey (1628) used quantitative reasoning (in addition to
physiological demonstration) based on a simple, though
implicit, compartmental model and the law of mass balance
(Leaning, 1980, Appendix 1). Heart muscle has a natural
rhythmicity and, given a supply of oxygenated blood, will
pump spontaneously and regularly. Starling’s ’Law of the
Heart’ states that the work done by the heart is propor-
tional to the volume of blood it contains prior to con-
traction (ie, the heart’s operational properties as a pump
guarantee that outflow will adjust to equal inflow). Thus,
the heart and circulatory system are a self-innervating
auto-controlled system, independent of other control
systems.
4.1 Models of the auto-controlled cardiovascular system
In I ~55, Guyton proposed a graphical method for the
determination of cardiac output based on cardiac and
systemic function curves. Dick and Rideout (1965)
developed a compartmental model which has four segments
representing the major divisions of the arterial tree and in
which the pumping of the heart is represented by time-
varying compliance of the left-ventricle compartment.
Beneken (1965) simulated a similar eight-segment model
on an analogue computer.
4.2 Models of the neural -controlled cardiovascular system
While the CVS is stable in a constant environment, its
stability from moment to moment depends upon rapid
neural control of the heart and blood vessels by the control
system, and De Wit (1967) produced a
19-segment model which includes neural control of heart
rate, myocardial contractility, peripheral resistance and
venous tone. The models of the baroreceptors (pressure
sensors) are based on Katona’s empirical dog studies (1967).
The model described in Sections 5,6 and 7 is based largely
on that of Beneken and De Wit with Hyndman’s ’bang-bang’
models of neural control (1970), and the ’multiple
modelling’ technique of Beneken and Rideout (1968) to
model drug transport. The method of modelling local drug
effects using non-dimensional multipliers was introduced
by Pullen (1976).
4.3 Models of long-term control of the cardiovascular
system
In order to cope with all bodily demands under various
environmental conditions, there are hormonal, fluid-
electrolyte and other control processes, in addition to
disease effects. Guyton’s models with Coleman (1967) and
Coleman and Granger (1972) are concerned with the overall
regulation of the cardiovascular system at this level.
4.4 Recent work
Recent work by our group includes that by Rajkumar
(1978), who investigated the possibility of model reduction
~4,1-Dahan (1979) has carried out extensive validation tests
and parameter sensitivity studies, has investigated control
loops based on volume receptors, and has used an
augmented version of a reduced model to appraise its
clinical applicability.
5 arteries, arterioles, capillaries, venules and
Conceptual model
Conceptualisation, the first stage of model formulation
(Section 2.3), involves identification of main subsystems
and choice of structural detail. The conceptual model
underlying the mathematical model can be very important
(eg, in assumptions about control, or aggregation) and may
change as the model develops. The conceptual model
presented here is that consistent with the model finalised
by Pullen (1976) and outlined in Section 6. Later versions
involve extra control loops and/or changes in aggregation
and mathematical idealisation.
5.1 Subsystems and main interactions
Fig 2 shows the division of the human cardiovascular
system (ie, that aspect defined as the intended range of
application in Section 3) into its main subsystems: un-
controlled haemodynamics; central nervous system (CNS)
control, and pharmacodynamics. It also shows the main
Downloaded from tim.sagepub.com at Information Links on November 27, 2012
variables affected by CNS control and drug effects. The
controlled cardiovascular system is a simple feedback
control system with the CNS monitoring blood pressure at
two sites (CS - carotid sinus, and AA a-- aortic arch) and
modifying heart and circulatory fluid mechanics parameters
to maintain stability. (The CNS controllers use negative
feedback. Their structures are based on empirical relation-
ships and shown in Figs 6, 7 and 8.) The pharmacokinetics
subsystem (dealing with distribution and disposal of the
drug) is driven by the blood flow rates in the circulatory
fluid mechanics, with a c~ne-to-one correspondence in
compartments (see Section 5.2). The physiological effect of
the drug (pharmacodynamics) is obtained by determining
the local drug effects on heart and circulatory parameters
and thereby modifying the controlled cardiovascular system.
5.2 Structure of the uncontrolled haemodynamics
subsystem
Blood circulates through a highly complex network of
veins. For the
purposes of studying cardiovascular control and haemo.
dynamics, only the main aspects of blood pressure and
flows need to be considered. In principle, blood flow at
every point in the system could be described by a set of
nonlinear partial differential equations, which would be
mathematically and computationally intractable. The
structure shown in Fig 3 has been found to be of sufficient
detail for the objectives of the model and consists of 19
elastic compartments, including the four heart chambers.
The pharmacokinetic subsystem has one compartment for
each drug corresponding to the same compartment for
blood (Fig 9). Movement of a drug between compartments
depends upon the blood flow rate between these
compartments.
f o ~n outline of the mathematical model
In this section, an outline is given of the mathematical
realisation of the model which, as indicated above, com-
Fig 2 Conceptual model - sub-
systems and main interactions
75
 transmural pressure (Pi) and volume ( fi) are related by the
equation:
~°j =t~ - ~uj~t~j, ~ ~ ~~~ .
where Vuj is the unstressed volume. The laminar Poisseuille
flow (Fj~) through the viscous resistance (R’jk) between the
two segments is

Fjk (~&dquo;i -~x)IR;x

=
...
(2)
From continuity considerations, it is necessary that
~F.
dt
dVj~~‘j= Fii~~~f~‘
-- Fj
k ...(3)

Equations for the 19 segments are derived using the above

general equations (1)--(~~.

6.1.2 A model of the heart

The heart is considered as a set of four separate uni-
directional pumps. Cardiac timing events are described by
linear approximations obtained by Beneken and De Wit
~I9~7):
7~=0.1+0.097~ ...(4)
~’’~ ~ = ~’~,~ °- O.U~ ...(5)
7~=0.16+0.27~ ...(6)
Fig 3 Structure of the uncontrolled haemodynamics where TA s is the duration of the arterial systole, TA v is
subsystem the time between the onset of arterial systole and the onset
of venticular systole, Ty~,~ is the duration of ventricular
systole, and 7~ is the heart period.
For a heart period, T~, of 0.8 s, corresponding to a heart
prises uncontrolled haemodynamics, central nervous system rate of 75 beats per minute, TAS = C~.l’7? s, ~&dquo;~~, ~ t3.i32 s
(CNS) control and pharmacodynamics. A full listing of the and Tvs 0.32 s. =
model equations together with the values adopted for all
the parameters is given in Appendix A. The pumping action of the heart is described by the
equation relating pressure and volume
6.1 Model of the uncontrolled haemodynamics ~’’~~t) ~~° ~~~ .
6.1.1 The basic structure and equations where tr (t) is the time-varying elastance function (reciprocal
Blood flow through the complex network of vessels in compliance).
the circulatory system may be described accurately by a The elastance functions for the four heart chambers are
given by equations derived using the time courses of the
very large set of simultaneous nonlinear partial differential
equations. As shown in Fig 3 above, however, a 19-segment four elastances shown in Fig 5
approximation is adopted to represent the fluid mechanics
where each segment is an elastic reservoir with lumped ~4 = ~ ~~~~,~ ‘- ORAD) + aRAD ...
(8)
hydrodynamic parameters representing the distributed ~~ v =Y ~~~ v~s -~ ~~ r~v ~ ~- ~~ v~r~ ...(9)
properties of the appropriate collection of blood vessels.
General equations characterising a typical segment are aLA -= ~ (~.~.~~s - ~‘~.~ r~ ~ ~- ~~.~ r~ ...
(10)
derived considering two typical segments connected together ~~~=.Y(~~~r ~~~z,~~~~~~v~ ... ( ’ I )
as shown in ~ig 4. The static pressure-volume curve of a

typical lumped parameter segment is approximated as being where

m the normal operating In passive -elements
~ /gt~ x
where the compliance Ci can be considered to be constant;
k TAS Jsm&horba ; L 0<~<~
< <
x=

sin
0
0
, tc0 t, s TA S
4~~
...~1~~
(12)

,1 t~ ~ ~’~ ~

Fig 4 Two typical adjoining lumped parameter segments

76
~ =
~’

~o~ sin

o
r ~
nTVs ~~~(fc - 7~~)J, ~ 9

,
,
7~~ < ~ <
~ ~ ~~~ ~ ~r~)~ ~
4 > ~~~.~
(T~ v +
~~~ ~r ~’ 7-~)

...(13)

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 inferior and superior venae cavae, represented in the model
by Eqns (21 ) and (22).
F$ F~>0
F9>0
~F9
’,

~,r~c’x ~ _ ... (21)

~.1F~, ~
f~ , Fto>0
Flo> 0

=
,~

FSVCRA ... (22)

0.1 FIO, .~’~o ~ ~
where F’g and Flo are the respective flows, assuming no
contraction.
In an analogous manner, equations can be written
describing the dynamics occurring in the left atrium, taking
into consideration the action of the mitral valve.
The ventricles. The basic equations for the right ventricle
are:

~‘x~=~~v~t)~~.~~- ~’~zv~ ... (23)

dVRV
df
~’~~~~ ~
*&dquo;&horbar;&dquo;-~R~~F’-~RFM.
--

~
F~~>0 (3 ..,(24)
..

In order to defme the outflow from this ventricle, use is

made of the equation developed by Beneken and De Wit
Fig 5 Elastances of the four heart chambers
(1967) to describe the pressure difference across the
pulmonary valve.
and the s~fficesD and for elastance values denote minimum dFRVpA
and maximum values given by
PRV-PPA =~r~r~~.~ ~j!!~4 +-~~ dtOf
2
= PD/(VD - ~~)~~s °~s/~~~ - Vu) .. (14) pP/Fo~p,iB~
aD

where t, is the elapsed time during each cardiac cycle

( RVPA) ,
2h~J’ ~°~rrp.~ ~ 0
~~~ ...~25)
...(25)

(0 4 t~ ~ TH). This then leads to the outflow equation:

The atria. The right atrium is modelled by the following set d F~v~p,~ p~ u~ - ~’~~ - ~.~ v~~ ~~~~~ - ~AI ~~ ~n~ ) ~’’~ ~~~
of equations
_

dt LRV
~’R~ = aRA (t) ~’~~ -- ~~~ ~] (15) ~’RV~~ ~ fl ... ~26~
Similar equations are developed for the left ventricle,
cidt~~~ ’~’n -F~.~tzrr~ ~~A ~ t~ ...~16) describing flow through the aortic valve.

’(~R~ - ~~)/~R~t~F, > ~4 > PRV 6.1.3 A model of the systemic arteries

~’~,~~~ ~:
~o , A < PRY
t0

~t = ~.S~CR.4 ~ ~fFC~~ ~ FBR ONC + FCOR

, PR ~ ~~ v
~’~~
...(17)

...(18)
~
For a typical arterial segment, inertia effects, wall
elasticity, geometric and elastic taper are taken into
account. The equations used by Beneken and De Wit
(1967) to describe a typical arterial segment are:

~ --~,~
~ =l~j~
~ ~&dquo;~~
~ +~ ~~ Lk
cl~’~~
visco-

...(27)
...
(27)
dt
Eqn (17) approximates the action of the tricuspid valve
with R-RAR v being the resistance of the fully opened valve. d Vi ..
Fi represents the total inflow of the right atrium. &horbar;
dt
~j =~~
=
I-, i~.;> 0
I

The basic flows through the coronary and bronchial

1 d V.
vascular beds are given by 4. R ~ li~
Pi
~J = -
_ V4)
~~<’V.--.- ~~~ -~-.F~~ dt
...
... ~2~~
Cj
FCOR ~~~ ~ ~--.. ~~~s ~/~c~~
=
...(19)
where R~
is equivalent to wall viscosity, the reciprocal of ~’’~
~~rza~vc ~ ~~’~ ~~ -~’~~~l~~~zorrc ’.
...
(20) is equivalent to wall elasticity and i~:Q4~. C¡ Rí =

The right atrial inlet contraction which assists the pumping

action introduces resistance to the inflow. While this is
negligible in the case of bronchial and coronary flow, it is
a significant effect in the case of blood flow from the
~.1.~ ~ model of the systemic vascular beds
The resistance of the vascular beds is represented by
lumped arterio-venous resistance. Thus the equations
77

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 derived for blood flow are typified by that given below for vena cava
flow through the bronchial vascular bed:
’ Fg>0

rO.667
,

FBRONC -‘, ~~Aa~a ~ ~’~.~~I~~~~re ...

(30) ~’trcfst~~ =
... (39)
(?.66’l Fs, F5
~’sx F’s <~ 0

6.1.5 A model of the systemic veins

Unlike the arteries, veins are highly compliant, collapsible, 6.1.6 A model of the pulmonary circulation
large-capacity vessels with low transmural pressures, and The pulmonary circulation is represented by two lumped
nonlinear modelling has to be applied. When a venous
parameter segments; pulmonary arteries and pulmonary
segment collapses and volume becomes less than the veins. The equations for the pulmonary arteries
unstressed volume ~’~&dquo; the compliance increases to 20 times (after
Beneken and De Wit, 1967) are:
its normal value ~’~.
Equations for a typical venous segment are: ~’~r~ ’ ~ ~’P~ °- VuPA)/CPA ...
(4fl)
pi 7-- (Vi - Vi)/Ci ..,~31~ d F~p~
=FRVPA FPAPV, ~ ~
~p.~ ~ 0~ ... (41)
~~
dt
dt
CiN fi Vii
>

~20 C~ N, ~.>~.
A

where CJ ~= ... 32) ~ (~4 &dquo; ~P~)/~L MVG’ ppv > < PCC
PPV

~’~~~~x ~
>

20 CJ~~ ~’~ ~ 1’’~i

i ..
’1
(PPA Pee )/RL UNG > ~’PV < Pcc
PCC
dK.
dt
d ~ y ~,z~ ~ ~,,xg
11 1 1
fi1 > 0 ... ~3~~ The flow in the pulmonary vascular bed is dependent on
the value of the pulmonary venous pressure relative to a
Owing to the increase in resistance as a result of a venous critical closing pressure {.~’~~.) which is approximately
segment collapsing, the flow is given by 7 torr.
The pulmonary veins are represented by a segment
Fik KA (Pj - Pk),4
=
...
(34) which has equations similar to those for the systemic veins
where 1~,~ is a constant and is the radius of the connecting
segment described in Section 6.1.5 with the addition of the
effect of artrial inlet contraction.
vessel. The volume Vi is given by:

~-=~2 ...~35~ 6.1.7 A model of orthostasis

where ~~ is a constant. Gravity effects on the columns of blood in the cardio-
vascular system are included in the model by employing the
~’i~ = ~~ ~~’i - ~’x) ~~ ... (36~ approach used by Snyder and Rideout (1969). Effective
where I~’~ hydrostatic pressure differences are represented by pressure
= ~,~ /I~B. generators included between various segments. The hydro-
If it is assumed that static pressure difference is given by:

G =ngpl sinrp ...(43)

~=&horbar;&h~iorbaRile
r-;&ho~’xrbar; where g is acceleration due to gravity, p is density of blood,
n is the number of g of acceleration (normally 1 ), l is the
when Vj = Vw then effective segment length for the lumped parameter repre-
1 sentation, and 0 is the angle between the axis of the
segment and a perpendicular to the direction of gravitational
a
Rix ~u/ force. These hydrostatic-pressure differences are introduced
into equations defining flow at the locations of the pressure
and
generators.
pli,
Fjk = ~~~ ~ ~~~- ... {37)
~~ Tl~i ~ i.~ Calculation of mean arterial pressure, stroke ~r~la~~rr~,
cardiac output, and total systemic resistance
Mean arterial pressure and stroke volume are obtained
Venous valves. The valve situated between the
venous
veins and abdominal veins
on a beat’by-beat basis by integration of the aortic pressure
segments representing leg and the left - ventricular outflow, respectively, over one
obstructs back flow completely. This valve is represented ’
cardiac cycle.
by the following equation:
1 TH
Fs, ~’s ~ 0 Mean arterial pressure, ~~1’.~.~ =
TH
T~_f
-~401 dt~c (44)

~0 ,
...

F8 < 0
’

~c~~ ~ ~ ... (38~ 0

0, F8 4 0 TH
where Fs is the flow, assuming no valve is present. Similarly,
for the valve between head and arm veins and the superior
Stroke volume, SV =
o
f FL VA odt~ ... (45)

78

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Cardiac output, CU =
SY’’/T~ ...
(46)
Estimated total systemic resistance, ESTR = MAP/CO
...(47)
6.2 Model of neural control
Fluid-mechanieal modelling is based, essentially, on
physical laws. However, modelling based on physical laws is
not applicable to the complete Central Nervous System
(CNS), and, therefore, empirical models have to be Fig 7 Linear combination of baroreceptor outputs to give
developed that represent neural control of the cardio- the CNS input function
vascular system. Such models, based on the data obtained
from physiological experiments, have been included for
baroreceptors (which monitor blood pressure in certain
main arteries and send information to the CNS) and CNS
control of heart rate, peripheral resistance, myocardial
dsC
d~1‘
_
~~A ~ ‘~G’~~~’2 .--(50)
..
<~°>
contractility and venous tone. These models are based upon.
the work of Katona et al (1967) and Hyndman (1970). Sp ’~Sg’~’~~SU-~D ...(51)
Further development of these models has resulted in the
incorporation of: (i) separate aortic arch and carotid sinus ~2=~D -..(52)
baroreceptors; (ii) pulsatile baroreceptor dynamics, and (iii)
adaptation of the controllers to the 19-segment circulatory where ~D is the threshold pressure below which firing does
fluid mechanics model. not occur and Kc is the average contribution of the positive-
The neural control model consists of 11 first order pressure derivative term over one cardiac cycle. Kc is
differential equations and 23 algebraic equations. Non- estimated by assuming that the average value of Kc sc over
linearities arise due to the unidirectional rate sensitivity of one cycle is 60, that is
the baroreceptors and the ’bang-bang’ action of the con-
trollers. The mathematical formulation is illustrated by con- 7M
TH
I1 60
60 TH
THf
sidering the baroreceptor model and that for the CNS -

K~ s~ dte ~ 6U Kc=
Kescdtc=60 ~ivin~ TH ... ~‘53)
..
(53)
,

control of heart rate. T~_ °

~
.

~ ~~ ~lt~
6.2.1 The baroreceptor system I’0
Baroreceptors, forming a part of short-term negative For normal heart rate and blood pressure, the value of Kc
feedback mechanisms, monitor blood pressure in certain thus calculated is approximately 1.0.
main arteries and transmit information to the CNS. The effective input for the central nervous system is
The relationship between response input and the baro- assumed to be a static function of the output of the aortic
receptor output fur~ctic~n,B~, is shown in Fi~ 6, where arch baroreceptor,BA 02, and the carotid sinus baroreceptor,
s,~ -s~ are dummy variables. Thus B2 is given by a linear 8~,,~ , (see Fig 7) and is given by
combination of a dynamic estimate (sc) of the positive
pressure derivative (sA ) and the dynamic mean pressure B-~U~F +~l &reg;~~~A(12 ...(54)
estimate (sB), together with a threshold pressure below
which firing of the baroreceptor does not occur. A further where a is assumed to be 0.7.
constraint is incorporated to ensure a positive firing rate.
The equations for each baroreceptor area are:

dP+ 6.2.2 Central nervous control of heart rate

s’~ dt
dt
...(48) A two-region dynamic model is adopted for the CNS
control of heart rate, one for blood pressures above normal
(ie, sA =
d~’/d~ for ~dP/r~~~ ~ 0 and sA =
0 otherwise) and the other for pressures below normal. For elevated
blood pressures, the CNS input function B is greater than a
dSB-
dSB
dt
dt =
(P - SB)IR 1 ...(49)
... ~4~~ threshold value KE and the dynamics of this region (region
A) are approximated by a first-order system, described by

Fig 6 Block diagram of an individual

baroreceptor model
79

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the following equations.
KE), B > K~
F>~
UA (B= -~0
UA
~0
d UA
, ~<~
,
, , , (55)

1 C -> 0
dt
U~ = , , , (56)
d UA
4.5, < 0
dt

dUc
dt
&horbar;&horbar;=(~-~c)/~ ...(57)
For the other region (region B), the dynamics are
approximated by a second-order system described by the Fig 9 Two typical segments for drug transport
following equations:
be combined with those of circulatory fluid mechanics and
KE, B > KE neural control.
UD =

d UE
~0 , B < K E
0 , F<~
...(58)
... (58)
6.3.1 Drug transport

&horbar;=(~-~)/~ ...(59) ’multiple modelling’ technique of Beneken & Ride-

The
di out (1968) is used to represent the transport of a chemical
substance in the blood stream. A slave 19-segment trans-
d~p. port model is coupled to the main 19-segment blood circu-
&horbar;=(~-~)/T....(60)
dt lation mode so that, for each segment, transport flow is
The overall response of the controller, which is a linear proportional to concentration in the transport model
combination of the outputs in regions A and B is given by: multiplied by volume flow in the circulation model.
Equations characterising a typical segment are derived,
...(61) from Fig 9, as follows. Concentration is mass per unit
~=~.(~+~-) volume and is given by
where UG represents a continuously varying estimate of
heart period for use in the next cardiac cycle, subject to the c..~ = rta/~’ ... 63)
following constraint (limiting the heart rate, fH, to a range The mass inflow to segment j is co ii F’~i and the mass
30 < fH < 200 beats per minute) outflow is Wik .F’f~ where

2,0 , UG > 2.0 wi, F~->0 tR3~, Fik> > 0

Fjk 0

~=~ -0
UH = UG,
.0.3,
0.3

UG
<

<
~< 2.0
0.3
...(62)
Cx3tj

The rate of
Wj, Ft~ ~ ti
Wjk- -
f:~~~
~ ~wj, ~’~x ~ 0
change of mass in segment is given by:
...(64)

d~M,
A block diagram of the heart rate controller is given in --1.= 0 ... (6 5)
dt
Wii Fii - w¡kF¡k, Mi >
Fig 8.

6.3 Model of pharmacodynamics 6.3.2 Drug injection

The model represents the injection, If the mass of drug contained in an injection is ~I, then
transport and action of a single drug. This model can thus injection into segment at t~rr~e ~~ may be modelled by a

Fig 8 Block diagram of the

heart rate controller based on
the model of Katona et al
(1967)
80

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 Dirac delta function, thus modifying Eqn (65) to become: + a~c.~~~ , bradycardia (slowness of heart beat)
d~L-
&horbar;’
dt
= l~I ~ (t ~- t~~ ~- c~~f F~~ - c~t~ Fak ... 66)
1 B1/(1 -~ ~~ c~~~ ~, tachycardia (abnormal rapidity of
heart beat)
Theinjected will be M = 70 A pg where A is the
mass ...(72)
dosage of drug (pg) per kg of bodyweight, and 70 kg is where cr2 is a constant which determines the sensitivity of
assumed to be the weight of an average human.
the heart period to changes in drug concentration.

6’.~.3 Drug breakdown and absorption
Assuming that the rate of change of mass due to break-
down is proportional to the remaining mass of drug in a
segment, and the time constant for breakdown (a-~) is
identical in all segments, the equation for drug transport
Drug effect c~n peripheral resistance. The drug action
variable, o~, multiplies the normal values of arterio-venous
resistance in the bronchial, intestinal, abdominal, leg and
head vascular beds in the model. For example:
1 -t cri c.~~~~ vasoconstriction

u$~~~~()NC ~ 1/(1
,

~65} is modified to: ’gBR

a1 crlc~a~~~), vasoconstriction
...(73)
~
(73)
.

d~
&horbar; W ij Fii - <~ Fik -m¡/rB
- m j/TB H.(67)
(67)
’

dt
=wi¡Fi¡-W¡k
=
...

where a1 determines the sensitivity of arterio-venous

resistances to changes in drug concentration.
fi~ depends upon the properties of the drug but is typically
of the order of 30 s.
Drug effect can myocardial contractility. The drug action
variable, a, multiplies the normal systolic elastances in all
6 3.4 Model of drug action four heart chambers. The multiplier, aRA, for the right
atrium is, for example, given by the following equation:
It is necessary to simulate the actions of the injected
drug at specific sites in the circulation. The selected para- I + v3 cJR A positive inotropy
i1~.otropy
cr~~ _
,

meters to be influenced by the circulating drugs are those

...(74)
already influenced by central nervous control. Thus the 1 /~ + 0~3 <u~), negative inotropy
relationship, representing the combined neural and humoral
influences on a general circulatory parameter ~~Z), is: where the empirical constant ff~ determines the sensitivity
of the individual systolic elastances to changes in drug con-
R aN (JD ...(68) centration and is assumed to be the same for each heart
where h’~ is the normal value of R, aN corresponds to chamber.
neural control action which is equal to 1.0 in the absence of
neural control and deviates from 1.0 when neural control is Drug effect on venous properties. Unstressed volumes and
present and aD corresponds to drug action which is equal compliances of venous segments are modified in the
to 1.0 in the absence of drug action and deviates from 1.0 following manner:
when drug action is present.
Tj~~ = 1~~~~’/cr~ ancl ~’ = ~/cr~ ...(75)
If (IN is regarded as constant and if~Z and drug concen-
tration (w) change in the same direction, then tr~ and ac represent the effects of the drug on the unstressed
volume and compliance, respectively, and depend on the
~~ =1 + I~c.~ ...(69)
drug concentration in the venous segments as follows:
This is a simple empirical approximation, in which l~ is a
1 + o~~ c~~ venoconstriction
positive constant (Pullen, 1976). (A similar approach has
(I /(I + a4
,

been adopted with regard to drug effects on heart rate, au- ...(/6)
peripheral resistance and myocardial contractility - see ~ 1 /(1 -~ cr~ c<aCO~~,, venoconstriction
venodilation
below.) If~2 and w change in opposite directions, then in
a like manner (Pullen, 1976) I + aswv venoconstriction

(I
I

ta~. ~
, ..
(77)
1 I /(IJ(I++ c~s
crs c.~ ~~,
m V), venodilation
~r~ = i ~ ~~ ... ~’7tJ)
1+j~ where rr~ md Cg 5 determine the sensitivity of the venous urn-
In this pharmacodynamic representation, it has been stressed volume and venous compliance, respectively, to
assumed that the receptor dynamics are extremely rapid in changes in drug concentration.
The total pharamacodynamics model consists of 19 first-
comparison to the dynamic effect and that the order differential equations and 53 algebraic equations and,
drug concentration is low. Where such assumptions are not in combination with the fluid mechanics and neural control
valid, a more complicated representation of the relationship
between plasma drug concentration and effect would be models, gives an overall model which is satisfactory for the
required (Hull, 1982). study of short term pharmacodynamics, (ie~ in which the
major dynamics are complete within 2 or 3 minutes).
Drug effect on heart rate. This is achieved by modifying the
rate controller output (Eqn (61)) to’become: 7. Model simulation
(71) Table 1 contains the number of first-order differential
~~ ’ ~~ n’~ +UF) ...

and algebraic equations in various subdivisions of the

where aH depends on drug concentration. mathematical model, which has 178 parameters in total.

81

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TABLE ’d : Equations in the mathematical model
TABLE 2: Simulation times for the model run on a
CDC 7600 computer
The model is amenable to very little analytic treatment, and
computer solution is necessary. A model simulation
program has been written in FORTRAN IV, in which the
differential equations are integrated using a first-order
Euler method with a fixed step length of 0.5 ms. Details of
simulation times for the model run on a CDC 7600
computer are given in Table II.
The program has been designed to produce a precis
report of the following variables at the end of each cardiac
cycle: systolic, diastolic and mean arterial pressures; stroke
volume; heart rate; cardiac output; and estimated total
systemic resistance. Parameter values in the model may be
simply varied (eg, for sensitivity analysis) and the simula-
tion details are easily changed (in a logical array) to
represent a variety of experimental conditions including:
rest (dynamic equilibrium); blood volume changes
(haemorrhage and infusion); passive tilting (orth~stasis~;
Valsalva manoeuvre; cardiac pacing; and the effect of
various drugs. The response of the model under these
different conditions is described and analysed in Paper 2
which deals with model validation.
The limitation of such a simulation technique is that,
whereas parameter changes are easy to make, modifications
of model structure, even small ones, are very difficult to
implement.
8.
Summary
The paper began by considering the ways in which
mathematical models may be used in the investigation of
complex systems. This led on to an outline of an integrated
methodology for model formulation, identification and
vaMatmn (Section 2) has evolved through modeYhng
studies in physiology and other work. The methodology is
more detailed than most, and its important features are:
recognition of the role of background knowledge; impor-
tance of modelling objectives; multidimensional concept of
model validity with validation occurring at every stage of
modelling; and the highly iterative nature of the modelling
process. , 13-46.
The methodology was then applied to modelling the
human cardiovascular system. The objectives of this work,
which has been carried out over the past decade, were to
study haemodynamic and drug effects in the controlled
82
Downloaded from tim.sagepub.com at Information Links on November 27, 2012
cardiovascular system over a time scale of 2 minutes
(Section 3). Section 4 outlined the historical background to
this area since the 1950s. The conceptual basis of the model
(Section 5) is fairly simple, contrasting with the complexity
of the mathematical realisation (Section 6). A complete
version of the mathematical model is presented in
Appendix A. Solution of the model is by digital computer
simulation described in Section 7.
In
Paper 2, the validation aspects of the modelling
methodology will be further developed: the concept of
model validity; programmes of model validation; and
validation problems for models of complex systems. Sub-
sequently, the results of an extensive programme of valida-
tion of the cardiovascular model will be presented and
analysed. Essentially, this programme determines the
validity of the model in terms of the extent to which it
satisfies the objects described above. As will be seen, the
results are not all satisfactory, and the limitations will be
discussed. In addition, the possibilities of model reduction
and development will be considered.
References
Al-Dahan, M., Rajkumar, N., Pullen, H. E., Finkelstein, L.,
Hill, D. W. and Carson, E. R. 1979. ’Mathematical
modelling of the human cardiovascular system’, Research
Memorandum DSS/MAD-NR-HEP-LF-DWH-ERC/188,
The City University, London.
Atkins, G. L. 1969. Multicompartmental models in bio-
logical systems, Methuen, London.
Beneken, J. E. W. 1975. ’A mathematical approach to
cardiovascular function’, Technical Report No 2-4-516,
Institute of Medical Physics, TNO, Utrecht, Netherlands.
Beneken, J. E. W. and De Wit
, B. 1967. ’A physical
approach to haemodynamic aspects of the human
cardiovascular system’, in Physical bases of circulatory
transport, E. B. Reeve and A. C. Guyton (eds), W. B.
Saunders, Philadelphia.
Beneken, J. E. W. and Rideout, V. C. 1968. ’The use of
multiple models in cardiovascular system studies: trans-
port and perturbation’, IEEE Trans Biomed Eng,
BME-15,
281-289.
Bowers, D. A., Mitchell, C. R. and Webb, K. 1981.
’Modelling bi-communal conflict: 3. Simulation and
validatican’, Futures, 13,115-127.
Carson, E. R., Cobelli, C. and Finkelstein. L. 1983. Mathe-
matical modeling of metabolic and endocrine systems,
John Wiley & Sons, Inc, New York.
Dick, D. E. and Rideout, V. C. 1965. ’Analog simulation of
left heart and arterial dynamics’, Proc 18th ACEMB,
Philadelphia.
Guyton, A. C. 1955. ’Determination of cardiac output by
equating venous return curves with cardiac output
curves’, Physiol Rev, 35,123-129.
, A. C. and Coleman; T. G. 1967. ’Long-term regu-
Guytom
lation of the circulation: interrelationships with body
fluid volume’ in Physical bases of circulatory transport,
E. B. Reeve and A. C. Guyton (eds), 170-201, W. B.
Saunders, Philadelphia.
Guyton, A. C.,Coleman, T. G. and Granger, H. J. 1972.
’Circulation: Overall regulation’, Am Rev Physiol, 34,
Harvey, W.1628. Excertatio de motu cordis et sanguinis in
animalibus, (translated by K. J. Franklin, Movement of
the heart and blood in animals, Blackwell Scientific
Publications, Oxford,1957).
Hull , C. J. 1982. Pharmacodynamics of non-depolarizing ~.PPENI3IX A
neuromuscular blocking agents’, Brit J Anaesthesia, 54,
169-182.
The complete mathematical model
Hyndman, P. W.1970. A digital simulation of the human The listing of the mathematical model has been made as
cardiovascular system and its use in the study of sinus concise as possible by using generic equations for the circu-
arrythmia. PhD Thesis, Imperial College, University of latory fluid mechanics and pharmacokinetic subsystems,
London. using the notation described in the paper and depicted in
and Jackson, W. D. 1967. ’Com-
Katona, P. G., Barnet, O. Fig 4. The specific equations and numerical parameter
puter simulation of the blood pressure control of heart values for each segment may be determined by using the
period’, in Baroreceptors and hypertension, P. Kezdi appropriate generic form, the table of segmental intercon-
(ed), Pergamon, Oxford, pp 191-199. nections (Table A I }, and the parameter tables.
Leaning, M. S. 1980. The validity and validation of mathe- The equations are written in first-order differential
matical models, PhD Thesis, The City University, form, which allows computer simulation by numerical
London. integration. The computer program which is written in
Learning, M. S., Uttamsingh, R. J., Carson, E. R., Cobelli, FORTRAN IV contains additional dummy variables not
C. and Finkelstein, L. 1982. ’Methodological aspects of shown below, and is available as source code on paper,
model validation: a model of the human renal - artificial papertape or cards from the authors.
kidney system’, in A general survey of systems
methodology, (Proc. 26th Annual Meeting of the SGSR), A.1 Circuiaxory fluid-mechanics subsystem
L. Troncale (ed), Society for General Systems Research,
Louisville, Kentucky, pp 508-516. Refer to Fig 3 and Table At.
Mihram, G. A. 1972. ’The modeling process’, IEEE Trans For all segments j:
Sys Man & Cybern, SMC-2, 621-629. dP-
Monin, A. S. 1972. Weather forecasting as a problem in
physics, MIT Press.
. 1976. Studies in the modelling and simulation
Pullen, H. E
dt ~ ~ ~~i ~ ~f~’
dt f
Fj
&
k, ~ ’’ 0,
Ví;;. ~’ Vi
Vj

of the human cardiovascular system with application to

the effect of drugs, PhD Thesis, The City University, A. 1. l..~e~terial segments
London.
Reduction of a mathematical model of
Rajkumar, N. 1978. dfik _ (~/ -~ - ~4~R/A~ - C~) ’
’~x
the human cardiovascular system, MSc Thesis, The City dtt Lk
University, London. - where
Simon, H. A. 1969. The sciences of the artificial, (2nd edn,
1981), MIT Press. ~rj~ = 7‘~g~l~ sin Oik
Snyder, M. F. and Rideout, V. C. 1969. ’Computer simula- 1 K- d ~
tion studies of the venous circulation’, IEEE Trans Bio- ~~ - V4) +&horbar;2
Pj =- (vi
-’;
_i
med Eng, BME-16,
325-334. C B ci dt
TABLE A 1: Interconnections in the haemodynamic subsystem also showing specific neural control actions and local drug
effects

No tes
f3 Where there is no entry for neural control or drug effect parameters in the ~~~&e, the appropriate parameters shotaici be set
to unity in the model equations.

83

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 Leaning, Pullen, Carson and Finkelstein
A.1..2 Heart segments ~.7.3 Venous segments
For all venous segments:
For all heart segments,/:i
d, V -~’ ’ ~’~~4
fí> V~,jld,~
~’ j’ ,=~coj
pi :--ci (-Vir/,&dquo;,),
-d4
-

~’~ = ~r ~t~ ~~ - ~’u~) &dquo;/ ~’

Timings for the cardiac cycle:i

~’ . cj ~C~
ci, ~-<~4
Vj < Vild,~

(pi - Pk) V2
-’&horbar;&Rik
horbar;&horbar;&hoVui
rbar;&horbar;&horbar;&horbar; , ~.>~>
pi B

P~
’

7~=~o+Xn ~f~l
Vk
Ffk
TAV ~AS ’~’ ~12 (p_ _ V2
~~-~)~
fl,
..
~.<P~
~~’S ’ ~ ~~ ~‘ ~ t4 ~‘~ B &horbar;&horb~~/
ar;&horbar;~&horbar;&horbar;&horbar;~ ;
U ~>~
(sin
,

x A ~.4 C9/cu/af/bnof~~P~V,COa~F7~/?
(?r~/~~). 4 < TAS 1 TH
0, tc < ~’AT~ Or t~ > ~’,,~y’~’ ~’t~S’ ~~o M4P=&horbar;~ P~d~
r ~sin ar(te - 7~4
sin 7T(fc ~’~ v)~~’vs~
For ventricle segments:
~)/~, ~’a r~ ~ t~ ~ TAV + 7’~
~4F<~2<’~4F+ Tvs
~=/ 0
TH
~01~

C<9=~F/7~
d F’~~ ~ ~ P -~ ~ ~ ~PI ‘~ ~ f ~ ~]
::
, ~f~ ~ 0
~~ ETSR =M4P/CO
dt Li
A.2 Neural control (CNS) subsystem
ai ~t) ~ Y (&2 ~a ~~s ~.- aiD) + aiD
A.2.1 Aortic-arch baroreceptors
For atrial segments:
~ _~4Q2 -.!l
F¡k = -P&dquo;
~J7~
, ~~0 dt 71

~_(dP4Q2/d~-~
af ~ ~ (b ~l ~I~, ~.. ~7~~ -~- ~D dt 7’2

TABLE A2: Parameter and initial state variable values for the circulatory fluid mechanics subsystem

84

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 TABLE A3: Parameter and initial state variable values for the neural control (CNS) subsystem

A.2.5 CNS control of peripheral resistance

N~3: ~~’~02~+= ~~oz if ~,~o~ ~ 0
B dt / dt ’ dt Xis, B>À.
B> X6

dt~d~)+)+ =0 if ~~ 0
B df /
==
0, if
dt
df
< 0
~=
(ÀIS>
X,6, F<X6

~ 02 ° ~ ~ ~ ~ ~’ ~asz -° ?t~)~ dq2 q, -q2

dt rs
A.2.2 Carotid-sinus ~raror~c~ptcrr~
dS3 _~ -~3 dq3=ql-q3
dt _ 71 dt T6

ds4 == (dPUA/dtt - S4 ~4=~t7~3+(~ -~17)~22

dt 7-2
*
BUA = [XI(S3+ X2S4-X3)1+
A.2.6 CNS control of myocardial contractility
~<~.~ CNS input function
X22, jB>X6
~ ~ ~~ ~- ~~~~o~ ~’ ~~~r,~ &t=
bl=
( ÀZ2’ B>
X23, F<X~ X~
d4..~.~ CNS control of heart rate d&2 b, - b2
Ui - [h5 (B - X6)1+ dt Tg
dy
dUl
X7,7,
~~’ &horbar;>0
~t ~ ~0
i

H2=’
;;;.

~
À&dquo;
x~,
~
U2 =
du
< 0
&horbar;<0
~t ~ ~
A.2.7 CNS control of venous tone

dt
X 18,
( À 18,
À19’
B >

EB< 6
Xs

X6
À6
_~~ ‘

dt U2 d~2 d, -d2
B> dt 7*7
~6, X6

M4=
dus U4 u5
~I3, .8B << X6
À6 ~3=1+~20(~2-1)
~=!+X~(~-1)
dt
dz~~ t~s -- t~~ TABLE A4: Parameter and initial variable values
for the pharmacokinetic subsystem
~t _ T4

~~a=~t~~~s~&dquo;~~~ ~~
2.0, M?>2.0 <

~’’~ -- r~~,,
~ t~.3 .
B0.3,
Trans Inst M C Vol 5, PJo 2, Api-Jun 1983
U.3 ~ r~.~

r~~ ~ °~.~
M~<03
< 2.0

85

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Leaning, Pullen, Carson and Finkelstein
A.3 Pharmacokinetic subsystem A.3.2 Drug effect
-A,3. 1 Drug distribution and disposal On heart rate:

For all segments,/:e 1 bradycardia

j
,

mi ~H = ( 1 -~ ~~ c,oR~ ) ~y l=
<~,=&horbar;
~.’i -1 , tachycardia
~
wi, F,;>0 On peripheral resistance
U)ii =
~ w~ ,
wi, ~’~ < ~ 0U
F, For all arterio&horbar;venous resistance (see Table A.1):
- I ci ii Fii - Y wi~ F~~. ~. m~Ti-~ ~ ~r~ ~t~
dt i k f1 vasoconstriction

~&horbar;1,
,

(NB: M5 (f) is for UV segment only) 0~=(l+Ct~, 1=

-1, vasodilatation
TABLE A5: Other
parameter values
On myocardial contractility:
Parameter Value
positive inotropy
I i ~t 1
,
p (1.C~0£~796
n 1 Jjt1¡~ ( (ll ~ J3 &dquo;j)
= +
t13&dquo;-’¡Y,~ , ~=t &horbar;1,I ,
-

negative inotro
inotropy
py

Transaction Papers
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on development,
application and education - and from any discipline.

Guide Notes for intending contributors to the Transactions are available from:

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86

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