MODELING CARDIOVASCULAR AND RESPIRATORY DYNAMICS IN

CONGESTIVE HEART FAILURE

LAURA M. ELLWEIN
1
, SCOTT R. POPE
2
, ALIANG XIE
3
, JERRY J. BATZEL
4
, C.T. KELLEY
5
, METTE
S. OLUFSEN
5
1) Olin Engineering Center, Marquette University, 1515 West Wisconsin Av, Milwaukee, WI
2) SAS, 100 SAS Campus Drive, Cary, NC
3) Pulmonary Physiology Laboratory, William S. Middleton Veterans Hospital,
2500 Overlook Tarace, Madison, WI
4) Inst. for Math. and Scientic Computing, Univ. of Graz, Heinrichstrasse 36, Graz, Austria
5) Dept. of Mathematics, North Carolina State University, Campus Box 8205, Raleigh, NC
Abstract. This study develops a coupled cardiovascular-respiratory model that predicts cerebral
blood ow velocity (CBFV), arterial blood pressure, end-tidal CO
2
, and ejection fraction for a
patient with congestive heart failure. The model is a lumped parameter model giving rise to
a system of ordinary dierential equations. We use sensitivity analysis and subset selection to
identify a set of model parameters that can be estimated given the patient data. Gradient based
nonlinear optimization is used to estimate the subset of parameters. Optimization was caried out
rst for the cardiovascular submodel and subsequently for the respiratory model. Once a set of
optimal parameters were found, the coupled model was computed to conrm that the model is still
able to predict the observed data. Results showed that with the approach and methods presented
in this paper it is possible to examine and quantify identiability of model parameters. Using
this approach we identied 5 key cardiovascular parameters and 4 key respiratory parameters.
Nonlinear optimization techniques was used to estimate these parameters and we tested that values
for all parameters were physiologically reasonable for a patient with congestive heart failure.
1. Introduction. The strong pathophysiological links between sleep-related breathing disorders
and cardiovascular diseases have recently received raised attention among clinicians and researchers.
On one hand, sleep-related respiratory disorders, especially obstructive apneas, have been identied
as an independent risk factor for hypertension, myocardial infarction and stroke due to the associ-
ated recurrent upper airway vibration, intermittent hypoxia, surges of sympathetic neural activities,
and repetitive arousals and resulting sleep fragmention a (see for example [23, 16]). Central sleep
apnea has been considered a marker for congestive heart failure (CHF) and also been associated with
the deterioration of heart function in CHF [21]. On other hand, epidemiological data reveal that
about one-half of patients with CHF develop periodic breathing [17, 53]. CHF is characterized by a
reduction in cardiac output, elevation of left atrial pressure and pulmonary capillary wedge pressure,
accumulation of uid in the lung, reduced functional residual capacity (FRC), and prolongation of
circulation time. All of these factors may destabilize breathing. In fact, a greater central and pe-
ripheral chemosensitivity to CO
2
(i.e., controller gain) has been observed in CHF patients [54, 9] and
CHF animal models [57]. Respiratory changes duiring sleep combined with these cardiovascular and
control sensitivity changes can contribute to the occurrence of sleep apnea ([12, 37, 4]. Furthermore,
the low cardiac output also reduces brain perfusion [9, 36] and attenuates cerebrovascular chemosen-
sitivity [22, 63]. The combination of hypoperfusion and low cerebrovascular reactivity impairs the
CBF protective mechanism for breathing stability [64]. Finally, CHF and its concomitant cardiovas-
cular insuciency and potential for reduced cerebral perfusion has been associated with impaired
cognitive function [5], while syncope is an issue in patients with CHF [26]. In general, although the
Key words and phrases. Cardiovascular modeling, Respiratory modeling, Parameter estimation, Model validation,
Sensitivity analysis, Subset selection.
1
2 L.M. ELLWEIN, S.R. POPE, A. XIE, J. J. BATZEL, C.T. KELLEY, M.S. OLUFSEN
underlying mechanisms for the interaction between the respiratory disorders and cardiaovascular
disorders have not fully understood, the two disorders eventually exacerbate each other, creating a
vicious cycle.
Modeling and especially models that can be applied in the clinical setting can contribute to the
development of methods for assessment of respiratory function such as estimating central and periph-
eral control gain and CO
2
reactivity. Models can also provide insight into the control mechanisms
that govern respiratory function, respiratory interaction with cardiovascular control, and mutual
regulation between ventilation and cerebral blood ow (CBF) through partial pressure of arterial
CO
2
.
Recent models that address aspects of the above topics include work by Dong and Langford [13],
which developed a model to study factors aecting stable behavior of the cardiovascular-respiratory
system in heart failure and Bidini et al. [38, 39] who applied a combined cardiovascular-respiratory
model to study the Valsalva maneuver and factors aecting cerebral blood ow. Recent experimental
studies include work investigating the dierential role of partial pressures of CO
2
and sympathetic
response on vasoconstriction [1], and the role of cerebral vascular function in setting ventilatory
response via inuence on CO
2
[63].
Thus, mathematical models that integrate ventilatory and cardiovascular system dynamics and
control functions have the potential to be used as a diagnostic tool as well as to obtain more
detailed knowledge of the dynamics of the underlying complex systems including aspects related to
cardiovascular diseases. Furthermore, models that can be used to investigate the cardiovascular-
respiratory coupling both in health and disease has potential to help understanding and diagnosing
clinical conditions. To understand this complex dynamics models should be applicable for analyzing
dynamics during typical orthostatic and ventilatory tests such postural change, step changes in
inspiratory CO
2
concentrations, or rhythmic breathing at various rates. These requirements indicate
that models should include a fair degree of complexity. On the other hand, for a given model
to have an impact in clinical settings, it is essential that the model can predict patient specic
outcomes such as systemic and cerebrovascular resistances. The latter is often studied by solving
an inverse problem, using a model combined with experimental data to predict patient specic
parameters that minimize the dierence between observed and computed quantities such as arterial
blood pressure, cerebral blood ow velocity, or end-tidal CO
2
. However, estimating parameters
from complex nonlinear models is dicult, in particular since parameters may be correlated or not
sensitive to given observations. Developing better techniques for analyzing such complex data is the
main focus in this manuscript.
To achieve an eective compromise between model complexity and clinical application requires
a modular approach to model analysis. This entails several considerations. First, model reduction
should be applied to reect only the key functional elements under investigation. This simplies
the parameter estimation problem but care needs to be taken to avoid loss of the models predictive
power. Second, a given model must be analyzed with regard to available data so that key model pa-
rameters sensitive to the observed data can be eectively and reliably estimated within a reasonable
time frame. Other less sensitive parameters should be estimated using information from literature,
statistics, or allometric scaling. Conversely, sensitivity analysis can provide suggestions for exper-
imental design. However, sensitivity analysis alone does not fully enable estimation of all model
parameters. Therefore, this analysis must be coupled with a more advanced analysis investigating
correlations between model parameters, e.g., two correlated sensitive parameters should not both be
estimated.
This study develops a coupled pulsatile cardiovascular-respiratory model applicable to clinical
problems related to CHF. We use sensitivity analysis to rank model parameters from the most to
the least sensitive with respect to the available data. Furthermore, we study correlation of model
parameters using subset selection.
CARDIOVASCULAR & RESPIRATORY DYNAMICS IN CONGESTIVE HEART FAILURE 3
Right
Ventricle
Left
Ventricle
Lungs
Systemic Tissue
Cerebral Tissue
Body
Head
Ccv
pa,g
p
D1,g
p
D2,g
p
D3,g
VD
pI,g
pexp,CO2
qp Rp
Cpa Vpa
ppa
Vrv
Cpv
ppv
qpv
Vpv
Rmv Rpv
ca,g
Rc
qc
Rs
MS,g
cS,g
cB,g
qs
E
lv
V
lv
Erv
Rtv
qpa
Vsv Csv
qcv
psv
pcv
pca
Rcv Rca
qca
Rav
p
lv prv
psa
Vsa Csa
Vca Cca
qsa
Thorax
Vcv
MB,g
qsv
csv,g
Figure 1. Compartmental model of systemic and pulmonary circulations. Systemic (subscript s),
cerebral (subscript c), and pulmonary (subscript p) arteries (subscript a) and veins (subscript v);
Vessels carrying oxygenated blood (systemic arteries and pulmonary veins) are red, while vessels
carrying deoxygenated blood (systemic veins and pulmonary arteries) are blue. All vascular com-
partments represent a group of vessels with similar pressure p [mmHg]. Each vascular compartment
is characterized by its volume V [ml] and compliance C [ml/mmHg]. The left (dark red, subscript lv)
and right (dark blue, subscript rv) ventricles generate pulsatile pressure p
lv
, p
rv
[mmHg]. These two
compartments are dened using time-varying elastance E [mmHg/ml]. Flow q [ml/sec] between com-
partments are opposed by constant resistances R [mmHg sec/ml]. Tissue compartments (magenta)
account for exchange of gases (O
2
and CO
2
). Each vascular bed is characterized by a metabolic
rate M [ml
STPD
/sec], and the gas concentrations in the tissues are denoted by c [ml
STPD
/ml]. The
lungs are represented by three dead-space compartments each predicting the partial pressure of the
gases p
Di,g
[mmHg]. The partial pressure of the gases in the inspired air p
I,g
, and the end tidal
partial pressure of expiratory CO
2
p
exp,CO2
are marked separately.
2. Methods. The cardiorespiratory model depicted in Figure 1 is a lumped parameter compart-
mental model designed to predict systemic arterial blood pressure p
sa
, cerebral blood ow velocity
v
c
, and end tidal partial pressure of expiratory CO
2
p
exp,CO2
for a CHF patient resting in supine
position.
For the purposes of this paper, we are considering dynamic oscillatory variations in cardiovascular
and respiratory system quantities around a resting steady state. Hence, control mechanisms are not
responding to system stress and control responses are not directly invoked. For this reason we do
not consider control submodels in this study. Note also that H and

V
IE
are inputs to the model so
that variations in the controls of these quantities are implicitly included in the model.
4 L.M. ELLWEIN, S.R. POPE, A. XIE, J. J. BATZEL, C.T. KELLEY, M.S. OLUFSEN
2.1. Cardiovascular system. The cardiovascular system (see Figure 1) is represented by a closed
circuit with 3 arterial compartments, 3 venous compartments, and 2 ventricular compartments.
Vascular compartments represent systemic arteries and veins in the body and the brain, as well as
pulmonary arteries and veins. Each compartment lumps vessels with similar transmural pressure
p(t) [mmHg], volume V (t) [ml], and compliance C [ml/mmHg] (constant). For each compartment i,
the stressed volume V
i,str
(t) is given by
V
i,str
(t) = V
i
(t) V
i,unstr
= C
i
p
i
(t), (1)
where V
i
(t) [ml] is the time-dependent total volume and V
i,unstr
[ml] (constant) is the unstressed
volume, at zero transmural pressure.
Flow between adjacent compartments are characterized by a constant resistance R [mmHg sec/ml]
and volumetric ow rate q(t) [ml/sec]. Incorporating Ohms law, the net change in volume for each
compartment is given by
dV
i
(t)
dt
= q
in
(t) q
out
(t), q
in
(t) =
p
i1
(t) p
i
(t)
R
in
, q
out
(t) =
p
i
(t) p
i+1
(t)
R
out
. (2)
The subscripts i 1 and i + 1 refer to upstream and downstream compartments in relation to
compartment i, respectively. A system of dierential equations is obtained by dierentiating (1)
and equating with (2),
dp
i
(t)
dt
=
q
in
(t) q
out
(t)
C
i
. (3)
An equation of this form is associated with each vascular compartment.
The heart is represented by the left and right ventricles, modeled to generate the driving pressures
for the systemic and pulmonary systems. This is realized by imposing a time-varying pressure
predicted as a function of ventricular volume. Thus, for the ventricular compartments we obtain a
dierential equation by imposing volume conservation, i.e.,
dV
iv
(t)
dt
= q
in
(t) q
out
(t), i = l, r (4)
where the ows q are determined similarly to (2). We use a time-varying elastance model to predict
ventricular pressures p
iv
(t) [48, 51, 55, 60],
p
iv
(t) = E
iv
(t)[V
iv
(t) V
id
], i = l, r, (5)
where V
d
[ml] denotes the volume at zero end-systolic pressure [48, 52] and E
iv
(t) [mmHg/ml] denotes
the time-varying elastance. In the above equations subscript i denote the left and right ventricles,
respectively. For each ventricle, time-varying elastance E(t) is modeled using a piecewise sinusoidal
function of the form
E(t) =
_

_
(E
M
E
m
)
_
1 cos
_
t
T
M
__
/2 +E
m
0 t T
M
(E
M
E
m
)
_
cos
_
(t T
M
)
T
R
_
+ 1
_
/2 +E
m
T
M
t T
M
+T
R
E
m
T
M
+T
R
t T,
(6)
where T
M
and T
R
denote the time for maximum (systolic) elastance (T
M
) and the remaining time to
relaxation (T
R
). To account for varying heart rate, we express these times as fractions of the heart
period T, i.e., T
M,frac
= T
M
/T and T
R,frac
= T
R
/T. We assume that peak elastance occurs at the
same time for both left and right ventricles; thus we assume that the values of the two parameters
T
M
and T
R
remain the same between the two sides of the heart. E
m
and E
M
denote that minimum
and maximum elastance of each ventricle. The maximum and minimum elastance dier signicantly
between the right and the left ventricle, in particular for the CHF patient studied in this manuscript.
CARDIOVASCULAR & RESPIRATORY DYNAMICS IN CONGESTIVE HEART FAILURE 5
Thus we include four elastance parameters E
ml
, E
mr
and E
Ml
, E
Mr
and two timing parameters T
M
and T
R
.
Similar to previous studies [45, 14, 50], the ventricular valves are modeled using time-varying
resistances {R
mv
(t), R
av
(t), R
tv
(t), R
pv
(t)} dened as a function of the pressure drop across the
valves. A small baseline resistance is used to dene an open valve (subscript o) and a resistance
that is several orders of magnitude larger is used to dene the closed valve (subscript c). An
exponential function is applied to describe the degree of openness as a function of the pressure
gradient. The eective resistance of a valve is then dened by
R
valve
= min
_
R
valve,o
+e
k(pinpout)
, R
valve,c
_
. (7)
The parameter R
valve,o
is the small resistance allowing ow out of the ventricle, k describes the
speed of the transition from open to closed, and R
valve,c
is a value large enough to eectively shut
o the ow through the valve. Since this function is non-smooth at the junctions of the exponential
and R
valve,c
, a smoothing function [11]
min

(x) = log
_

i
exp(x
i
/)
_
,
where 0 < < 1 denotes the degree of smoothness (in this study we used = 0.5) and x denote the
vector to be minimized.
All equations and initial conditions for the cardiovascular model are given in the Appendix.
2.2. Respiratory system. The respiratory system is modeled using components allowing for gas
exchange, transport, and metabolism. We model the dynamics of the two metabolite gases, O
2
and
CO
2
, while we do not account for inert gases such as N
2
. As shown in Figure 1, a tissue compartment
connects each peripheral arterial compartment with each peripheral venous compartment. Dynamic
gas concentrations in each tissue compartment reect O
2
consumption and CO
2
production during
metabolism as well as convection via blood ow into and out of each compartment. The model
also includes two pulmonary components. The alveolar space has a dynamic volume, in which O
2
and CO
2
are exchanged between the lungs and the pulmonary vasculature. The lungs have been
modeled using rigid dead space compartments connecting the alveolar space with the atmosphere.
The rigid-walled dead space is divided into three compartments of the same size to account for some
of the eects of the pulmonary branching. Gas concentrations and partial pressures are predicted in
all compartments. The inputs to the model include HR and volumetric airow

V
IE
, which provides
information about tidal volume V
T
and ventilation frequency f
R
.
Standard material balance equations describe respiration in the tissue compartments. The fol-
lowing symbol convention will be used: c represents concentration, T represents a generic tissue
compartment which can be chosen to be systemic tissue S or brain tissue B. Generic gas quantity
is denoted by g and gas fractional amount by F. Venous outow is denoted by v and arterial inow
by a. Thus we denote the total amount of a gas in a tissue compartment by A
T,g
[ml] which is given
by
A
T,g
= V
T,g
c
T,g
.
This equation describes A
T,g
by the product of the eective tissue volume V [ml] (constant) available
for the gas and the concentration c [ml
gas
/ml
blood
] of the gas in the volume. The change in amount of
gas in a compartment is equal to the sum of the amount of gas produced or consumed by metabolism
M [ml/sec] and the amount added or removed by the bloodstream q
T
[ml/sec].
dA
T,g
dt
=
dV
T,g
dt
c
T,g
+V
T,g
dc
T,g
dt
= M
T,g
+q
T
(c
a,g
c
T,g
).
6 L.M. ELLWEIN, S.R. POPE, A. XIE, J. J. BATZEL, C.T. KELLEY, M.S. OLUFSEN
Note, the concentration in the systemic arteries (i.e., in the body and the brain) are the same, since
no metabolism has been accounted for on this side. Hence we denote the arterial concentration for
c
a
. Thus, Assuming dV
T,g
/dt = 0, this equation reduces to
V
T,g
dc
T,g
dt
= M
T,g
+q
T
(c
a,g
c
T,g
). (8)
The tissue compartments are considered well-mixed and equilibrated with exiting venous concentra-
tion. Note that the gas concentration c
sv,g
is calculated as a mixture of the concentrations from the
incoming systemic venous stream q
s
and cerebral stream q
cv
so that
c
sv,g
=
c
S,g
q
s
+c
B,g
q
cv
q
s
+q
cv
,
where c
S,g
and c
B,g
are the systemic and cerebral concentrations of each gas, respectively.
Let A denote the alveolar compartment; then the quantity of alveolar gas is given by
V
A,g
= V
A
F
A,g
,
which is the product of alveolar volume V
A
and gas fraction F
A,g
. The change in quantity of alveolar
gas is represented by a mass balance relation parallel to the one developed for the tissue compartment,
taking into account this time a time-varying alveolar volume, and with gas transport via uid owing
to and from the lungs via pulmonary capillaries, and gas exchange with environment via inspiration
and expiration. Let subscript p represent the pulmonary compartment. Thus we have,
dV
A,g
dt
= F
A,g
dV
A
dt
+V
A
F
A,g
dt
=
dV
A
dt
F
i,g
+q
p
(c
sv,g
c
a,g
).
In this representation F
i,g
denotes the fraction of gas in the air that is either being inspired or expired
into the alveolar compartment. Hence, i = D
3
during inspiration since inspired air is coming from
the adjacent dead space region and i = A during expiration since air leaving the alveoli is alveolar
air equilibrated with the pulmonary capillaries. Rearranging to express the rate of change of alveolar
gas fraction gives
V
A
dF
A,g
dt
=
_
_
_
dV
A
dt
(F
D3,g
F
A,g
) +q
p
(c
sv,g
c
a,g
), inspiration
q
p
(c
sv,g
c
a,g
), expiration.
Gas fractions are converted to partial pressures via the relationship
F
A,g
= p
A,g
/(p
amb
p
water
) = p
A,g
/713,
where p
amb
is the ambient air pressure of 760 mmHg and water vapor partial pressure p
water
equals
47 mmHg at body temperature of 37

, i.e.,
V
A
713
dp
A,g
dt
=
_
_
_
dV
A
dt
(p
D3,g
p
A,g
)
713
+q
p
(c
sv,g
c
a,g
), inspiration
q
p
(c
sv,g
c
a,g
), expiration.
Because blood gas concentrations are reported in [ml
STPD
/ml] (STPD is the Standard Temperature
(0

C), barometric Pressure at sea level and Dry gas), but alveolar volumes are in BTPS (standard-
ized to Body Temperature, barometric Pressure at sea level, Saturated with water vapor: body
temperature and pressure, saturated), we convert tissue concentrations to BTPS. Incoming air is
immediately humidied once it enters the nasal passages [7, 8] and expired air is a composition of
alveolar air and dead space air at BTPS, therefore terms with those quantities are not converted.
The nal equations are obtained by using the conversions and multiplying through by 713, i.e.,
V
A
dp
A,g
dt
=
_
_
_
dV
A
dt
(p
D3,g
p
A,g
) + 863 q
p
(c
sv,g
c
a,g
), inspiration
863 q
p
(c
sv,g
c
a,g
), expiration.
(9)
CARDIOVASCULAR & RESPIRATORY DYNAMICS IN CONGESTIVE HEART FAILURE 7
Additional modeling considerations concern the relationship between the pulmonary capillaries and
the systemic arteries. First, an anatomical shunt is present in the pulmonary circulation. This con-
sists of O
2
-decient blood that bypasses the alveoli for physiological or pathological reasons. Typical
shunt values range from 2-5%, with a larger shunt percentage possibly indicating a pathological con-
dition [8, 7]. The subject studied has no known pulmonary health issues so we assume a 2% shunt.
Therefore only 98% of the cardiac output becomes oxygenated, altering the alveolar equations to
read as
V
A
dp
A,g
dt
=
_
_
_
dV
A
dt
(p
D3,g
p
A,g
) + 0.98 863q
p
(c
v,g
c
a,g
), inspiration
0.98 863q
p
(c
v,g
c
a,g
), expiration.
(10)
Second, we note that the thin alveolar wall allows for almost immediate equilibration of gases between
the alveoli denoted by A and the pulmonary capillaries; thus we assume that the concentrations of
blood gases is the same in the pulmonary capillaries and in the systemic arteries. This concentration
is denoted by p
sa,g
, i.e., we assume p
A,g
= p
sa,g
as an auxiliary equation.
Connected to the alveolar compartment are three compartments of equal volume with a total vol-
ume representing anatomical dead space. Each dead space is considered a well-mixed compartment
with units V
BTPS
, in ml. Material balance equations for the dead space compartments reect change
in gas levels due to airow, with opposite directions of ow for inspiration versus expiration. The
relation F
A,g
= p
A,g
/713 holds, and equation units are all in BTPS. Thus following the derivation
of (10),
Inspiration: V
D1
dp
D1,g
dt
=
dV
A
dt
(p
I,g
p
D1,g
), (11)
V
Di
dp
Di,g
dt
=
dV
A
dt
(p
Di1,g
p
Di,g
), i=2,3.
Expiration: V
Di
dp
Di,g
dt
=
dV
A
dt
(p
Di,g
p
Di+1,g
), i=1,2, (12)
V
D3
dp
D3,g
dt
=
dV
A
dt
(p
D3,g
p
sa,g
).
Pressure p
I,g
is the partial pressure of the gas in the inspired air.
Note that dV
A
/dt is positive during inspiration and negative during expiration. The rate of change
of alveolar volume dV
A
/dt is equivalent to the ventilation airow

V
IE
. Thus, the alveolar volume
can be predicted as
V
A
=
_

V
IE
dt. (13)
To give a correct value for the alveolar volume, additional information is needed to oset the inte-
gration constant. We have chosen to adjust this assuming that the minimum alveolar volume should
match the FRC [ml], which we determine as a function of height H [cm] and weight W [kg], i.e., we
assume
min(V
A
) = FRC, FRC = (3.8 H/100 3.41 W/H 2.74) 1000
The above estimation for FRC is based on work by Stocks and Quanjer [56]. Furthermore, it should
be noted that the use of the dot notation in

V
IE
is a standard way to indicate a volumetric owrate
as opposed to a rate of change of volume. The airow

V
IE
is measured during experimentation and
is used as an input to the model to drive the gas concentration dynamics.
O
2
and CO
2
have dierent anities for hemoglobin, therefore behave dierently in the gas ver-
sus liquid phases. Gas dissociation laws are used to convert alveolar gas pressures to blood gas
concentrations.
8 L.M. ELLWEIN, S.R. POPE, A. XIE, J. J. BATZEL, C.T. KELLEY, M.S. OLUFSEN
In this study we use equations also used by Batzel et al. [4],
c
T,CO2
= K
CO2
p
T,CO2
+k
CO2
,
c
T,O2
= K
1
(1 e
K2pT,O
2
)
2
.
Note that the law for CO
2
is linear while the law for O
2
is exponential. This reects general behavior,
but does not account for the the dependencies of each gas on the other (Bohr and Haldane eects)
as well as factors such as pH and temperature.
All respiratory equations and initial values are listed in the Appendix.
3. Experimental Methods. The data analyzed in this study include continuous (sampled at
128 Hz) measurements of systemic arterial blood pressure (p
sa
), cerebral blood ow velocity v
c
measured from the middle cerebral artery (MCA), and end tidal partial pressure of CO
2
in expiratory
air. In addition we have a measure for left ventricular ejection fraction, as well as anthropometric
measurements of height, weight, and gender. These data are obtained from Dr. Skatruds group,
Department of Medicine, University of Wisconsin.
The subject is a male age 55, height 178 cm, weight 82.3 kg with CHF but no known sleep apnea
syndrome. Data used for this study were recorded while the subject was in semirecumbent position
during normal breathing (for 10 min). Experiments were started between 8.00 and 9.00 am, to
standardize the eect of diurnal variability of cerebral vasomotor reactivity [2].
A 2-MHz pulsed Doppler ultrasound system (Neurovision 500 M; Multigon Industries, Yonkers,
NY) was used to continuously measure cerebral blood ow velocity in the proximal segment of the
middle cerebral artery (MCA). The MCA was insonated through the right temporal bone window
using search techniques described in Otis and Ringelstein [46]. After detection and optimization of
the Doppler signal, the probe was mechanically secured using a headband device and probe holder
to provide a xed angle of insonation for the duration of the experiment. The subject, in the
semirecumbent position, was asked to keep his head still and eyes open throughout the experiment.
Heart rate was obtained from the electrocardiogram, and arterial pressure (p
sa
) was measured beat
by breat in the middle nger of the left hand by photoelectric plethysmography (Finapres, Ohmeda,
Louisville CO). Tidal volume (V
T
) and breathing frequency were measured with a pneumotachograph
Model 3700, Hans Rudolph, Kansas City, MO) that was attached to a leak-free nasal mask. End
tidal PETCO
2
tensions was sampled from the mask and measured by gas analyzers (#S-3A/I &
CD-3; Ametek, Pittsburgh PA). Detailed descriptions of the experimental protocol can be found
in [63].
4. Parameterization.
4.1. Cardiovascular parameters. Nominal parameter values and initial conditions for the cardio-
vascular model were estimated from the subjects anthropometric measurements. A complete list of
all initial parameter values can be found in Table 1. We start by setting up predictions for nominal
parameter values used to predict time-varying elastance. Parameters needed include maximum and
minimum elastance of the left ventricle (E
Mi
, E
mi
, i = l, r), as well as fractions predicting the timing
of the cardiac cycle (T
M,frac
, T
R,frac
).
Nominal parameter values for end diastolic elastance are obtained from estimated diastolic ven-
tricular pressure p
dia
, end diastolic volume EDV, and zero pressure volume V
d
as
E
mi
=
p
iv,dia
EDV
iv
V
id
, i = l, r.
Diastolic ventricular pressures are set using literature values [29]. The subject studied has CHF and
is thus expected to have an enlarged left ventricle, while the size of the right ventricle is closer to
normal. We estimate these volumes using results for CHF patients without sleep-apnea reported by
Tkacova et al. [59].
CARDIOVASCULAR & RESPIRATORY DYNAMICS IN CONGESTIVE HEART FAILURE 9
End systolic elastances are estimated using a similar relation, but as functions of systolic ven-
tricular pressure p
sys
, end systolic volume ESV, and zero pressure volume V
d
. Systolic ventricular
pressure is obtained from the maximum measured arterial pressure. End systolic volume is obtained
by subtracting stroke volume (SV) from the end diastolic volume: ESV = EDVSV. Stroke volume
is estimated from end left ventricular diastolic volume and ejection fraction (EF, measured 26% for
the subject studied): SV = EF EDV
lv
.
The timing fractions T
M,frac
and T
R,frac
were estimated from literature values suggested by
Ottesen and and Danielsen [47] and Heldt [30]. We assume that the ejection of the left and the right
sides of the heart are synchronous, thus we use the same values for both ventricles.
Initial values for blood pressures were obtained partly from the data and partly from literature
estimates. All arterial pressures were scaled relative to the measured arterial pressure, whereas
venous pressures were set using standard literature values. Initial blood pressures were used both
in computation of initial resistances and compliances and as initial conditions for the dierential
equations.
Initial ows were scaled to cardiac output, which was computed from stroke volume SV and mean
heart rate HR, i.e., CO = SV HR. Mean heart rate was obtained from the measurements. Flows
in the circuit was distributed to let 20% cardiac output go to the brain, while 80% was directed to
the systemic arteries.
Resistors were predicted using Ohms law as
R =
p
i
p
i+1
q
i
and compliances were predicted using the pressure volume relation (1). Estimates of total blood
volume was computed as a function of body surface area (BSA, m
2
), estimated from Mostellers
formula [42]
BSA =
_
(W H)/3600,
where W is the subjects weight in kg and H is the subjects height in cm. Total blood volume (ml)
was computed using Bakers formula [3] as
V
t
= (23.9 BSA 1.229) 1000.
Distributions of volume and prediction of unstressed volumes were obtained using values from
Beneken and DeWitt [6].
4.2. Respiratory parameters. Nominal values for metabolic rates and tissue volumes are given
in Table 2. As is standard practice, all tissue gas volumes and blood gas concentrations are given
in STPD, thus units are consistent. Metabolic rates were set using standard allometric scaling
proportional to body mass by the power of 3/4 [61, 62] using values in Table 2. We used metabolic
rates given in [4, 34, 27] for total systemic (including both the body and the brain) CO
2
(M
CO2
) and
O
2
(M
O2
) combined with a metabolic rate for the brain for CO
2
(M
B,CO2
). To compute metabolic
rates for oxygen in the brain M
B,O2
we assumed that the ratio of metabolism between oxygen and
carbon dioxide in the brain was approximately equal to one given that brain tissue burns primarily
carbohydrate (glucose) ([27]). Finally, we used these four metabolic rates to adjust metabolic rates
in the body. Similarly, for volumes of the gases we used total systemic volumes and brain volumes
to get the volumes in the body, based on values given by Batzel [4]. Alveolar volume was a dynamic
quantity as shown in (13). Dead space volume was set proportional to the body weight in pounds
(the subject weight 82.3 kg or 181.3 lbs). Finally, the coecients of the dissociation equations are
assumed to be independent of the size of the subject.
10 L.M. ELLWEIN, S.R. POPE, A. XIE, J. J. BATZEL, C.T. KELLEY, M.S. OLUFSEN
Table 1. Nominal values for all cardiovascular parameters.
Parameter Physiologic description Value Reference
EDV
lv
[ml] End diastolic volume (left ventricle) 312 [59]
EDVrv [ml] End diastolic volume (right ventricle) 100 [8, 29]
EF Ejection fraction 0.26 measured
SV [ml] Stroke volume EF EDV
l
ESV
l
End systolic volume (left ventricle) EDV
l
SV
ESVr End systolic volume (right ventricle) EDVr SV
HR [bpm] mean heart rate measured
CO [l/min] Cardiac output SV HR
p
d
sa
[mmHg] Measured arterial pressure measured
p
lv,sys
[mmHg] Systolic left ventricular pressure max(p
d
sa
) measured
prv,sys [mmHg] Systolic right ventricular pressure 30 [8, 29]
p
lv,dia
[mmHg] Diastolic left ventricular pressure 3 [8, 29]
p
lv,dia
[mmHg] Diastolic right ventricular pressure 6 [8, 29]
ppa [mmHg] Pulmonary arterial pressure 20 [8, 29]
ppv [mmHg] Pulmonary venous pressure 3.3 [8, 29]
psa [mmHg] Systemic arterial pressure p
d
sa
measured
psv [mmHg] Systemic venous pressure 6.6 [8, 29]
pca [mmHg] Cerebral arterial pressure psa 0.99 measured
pcv [mmHg] Cerebral venous pressure 7 [8, 29]
qs [ml/sec] Systemic ow 0.8 CO [8, 29]
qca, qc, qcv [ml/sec] Flow in cerebral circulation 0.2 CO [8, 29]
qpa, qpv [ml/sec] Flow in pulmonary circulation [8, 29]
Rmv, Rav [mmHg sec/ml] Mitral and aortic valve resistances 0.001 estimated
Rtv, Rpv [mmHg sec/ml] Tricuspid and pulmonary valve resistances 0.001 estimated
Rs [mmHg sec/ml] Systemic resistance (psa psv)/qs
Rca [mmHg sec/ml] Cerebral arterial resistance (psa pca)/qca
Rc [mmHg sec/ml] Cerebral resistance (pca pcv)/qc
Rcv[mmHg sec/ml] Cerebral venous resistance (pcv psv)/qcv
Rp [mmHg sec/ml] Pulmonary resistance (ppa ppv)/qp
Vsa [ml] Systemic artrial blood volume 0.1178 Vt [6]
Vsv [ml] Systemic venous blood volume 0.6091 Vt [6]
Vca [ml] cerebral arterial blood volume 0.237 Vt [6]
Vcv [ml] Cerebral venous blood volume 0.936 Vt [6]
Vpa [ml] Pulmonary arterial blood volume 0.0288 Vt [6]
Vpv [ml] Pulmonary arterial blood volume 0.1243 Vt [6]
Csa [ml/mmHg] Systemic arterial compliance 0.3 Vsa/psa [6]
Csv [ml/mmHg] Systemic venous compliance 0.08 Vsv/psv [6]
Cca [ml/mmHg] Cerebral arterial compliance 0.22 Vca/pca [6]
Ccv [ml/mmHg] Cerebral venous compliance 0.08 Vcv/pcv [6]
Cpa [ml/mmHg] Pulmonary arterial compliance 0.58 Vpa/ppa [6]
Cpv [ml/mmHg] Pulmonary venous compliance 0.11 Vpv/ppv [6]
Ac [cm
2
] Cerebral scaling factor 0.3 estimated
4.3. Parameter estimation. Model parameters discussed in the parameter above are obtained
using physiological considerations and allometric scaling, so even though they to some extend have
been adapted to the patient with CHF studied here, signicant variations from these standard
values is to be expected. Below we discuss how to estimate model parameters though the solu-
tion to the inverse problem: given data for cerebral blood ow velocity v
c
, arterial blood pressure
p
sa
, end tidal partial pressure of expiratory CO
2
p
exp,CO2
, and cardiac ejection fraction EF nd
the set of parameters that minimize the dierence between computed and measured values of the
observed quantities. The coupled model uses heart rate and airow as inputs to predict these quan-
tities. However, the model contains a large number of parameters (37) including 24 cardiovascular
parameters and 13 respiratory parameters. The cardiovascular parameters include 9 resistances
CARDIOVASCULAR & RESPIRATORY DYNAMICS IN CONGESTIVE HEART FAILURE 11
Table 2. Nominal values for metabolic rates, tissue volumes, and gas dissociation constants. All
values are adapted from [4, 34, 27].
Parameter Physiologic description Value
M
CO
2
[ml
STPD
/sec] Systemic tissue metabolic rate of CO
2
4.333
M
O
2
[ml
STPD
/sec] Systemic tissue metabolic rate of O
2
5.167
M
B,CO
2
[ml
STPD
/sec] Cerebral tissue metabolic rate of CO
2
0.875
M
B,O
2
[ml
STPD
/sec] Cerebral tissue metabolic rate of O
2
M
B,CO
2
M
S,CO
2
[ml
STPD
/sec] Systemic (body) tissue metabolic rate of CO
2
M
CO
2
M
B,CO
2
M
S,O
2
[ml
STPD
/sec] Systemic (body) tissue metabolic rate of O
2
M
O
2
M
B,O
2
V
T,CO
2
[ml
STPD
] Systemic tissue volume of CO
2
15000
V
T,O
2
[ml
STPD
] Systemic tissue volume of O
2
6000
V
B,CO
2
[ml
STPD
] Cerebral tissue volume of CO
2
900
V
B,O
2
[ml
STPD
] Cerebral tissue volume of O
2
1000
V
S,CO
2
[ml
STPD
] Systemic tissue volume of CO
2
V
T,CO
2
V
B,CO
2
V
S,O
2
[ml
STPD
] Systemic tissue volume of O
2
V
T,O
2
V
B,O
2
V
A,CO
2
[ml
BTPS
] Alveolar tissue volume of CO
2
3200
V
A,O
2
[ml
BTPS
] Alveolar tissue volume of O
2
2500
V
D
[ml
BTPS
] Total dead space volume 181.1
K
1
[ml
STPD
/ml] Dissociation coecient for O
2
0.200
K
2
[mmHg
1
] Dissociation coecient for O
2
0.046
K
CO
2
[ml
STPD
mmHg/ml] Dissociation coecient for CO
2
0.0065
k
CO
2
[ml
STPD
/ml] Dissociation coecient for CO
2
0.244
R = {R
s
,R
ca
,R
c
,R
cv
,R
p
,R
av,o
,R
mv,o
,R
pv,o
,R
tv,o
}, 6 compliances C = {C
sa
,C
ca
,C
cv
,C
sv
, C
pa
,C
pv
},
8 heart parameters
heart
= {V
rd
,V
ld
,E
mr
,E
ml
,E
Mr
,E
Ml
,T
M,frac
, T
R,frac
}, and a scaling factor A
c
.
The respiratory parameters include 3 metabolic rates M = {M
CO2
,M
O2
,M
B,CO2
}, 4 gas tissue vol-
umes V = {V
T,CO2
, V
T,O2
, V
B,CO2
, V
B,O2
}, the lung dead space volume V
D
, 4 dissociation constants
K = {K
1
,K
2
,K
CO2
,k
CO2
, }, and a fraction indicating alveolar air in the exiting air stream f
alv
.
Solving this inverse problem uniquely is not possible using this complex model, since it is likely that
many combinations of these parameters can give rise to the same solution. Thus, the goal here is
to identify a limited set of uncorrelated parameters that can be estimated reliably. To do so, we
use sensitivity analysis to rank parameters from the most to the least sensitive, and we use subset
selection to select a set of uncorrelated parameters. Subsequently, we use gradient based nonlinear
optimization to estimate this reduced set of parameters, while the remaining parameters will be
xed at their nominal values.
The data analyzed in this study comprise baseline values, thus it is essential that the solution
of the system allows all states to reach steady state (in this study steady state means that the
model should display steady oscillatory behavior). Timescales in the cardiovascular model are short,
and this model will reach steady state within a few cycles. However, the respiratory model operates
on much slower timescales. To analyze how long the model should run to reach steady state we
analyzed timescales for each of the two systems. Time constants in the cardiovascular model are all
of the same order of magnitude, while time constants in the respiratory model vary signicantly. The
largest time constant in the respiratory model is associated with the eective systemic tissue CO
2
volume, which is approximately 14.1 liter. To compare the two models, we look at time constants
related to cerebral arterial pressure p
ca
and concentration of systemic tissue CO
2
(c
S,CO2
). These
time constants appear in the equations
dp
ca
dt
=
1
C
ca
_
p
sa
p
ca
R
ca

p
ca
p
cv
R
c
_
,
dc
S,CO2
dt
=
M
S,CO2
+q
s
(c
a,CO2
c
S,CO2
)
V
S,CO2
.
12 L.M. ELLWEIN, S.R. POPE, A. XIE, J. J. BATZEL, C.T. KELLEY, M.S. OLUFSEN
0 1000 2000 3000 4000 5000 6000 7000
0.54
0.545
0.55
0.555
0.56
0.565
0.57
time [sec]
c
S
,
C
O
2

[
m
l
S
T
P
D
/
m
l
]
Figure 2. Dynamics of concentration of CO
2
in the systemic tissue computed using nominal pa-
rameter value, sequence between the two vertical lines denotes the last sequence of the data.
The time constant for these two equations are approximately (C
ca
R
ca
R
c
)/(R
ca
+ R
c
) 0.0167
seconds and V
S,CO2
/q
s
257 seconds, respectively. These estimates indicate that we need long
sequences of baseline data to reach steady state dynamics. In this study we analyze 172 seconds of
data, thus to ensure steady state dynamics we repeat the data-segment 40 times to reach an end
time of approximately 7000 seconds. Figure 2 show dynamics of the tissue CO
2
concentration.
Another important issue is that each respiratory cycle contain approximately 4-5 cardiac cycles,
requiring signicantly smaller time steps to resolve cardiovascular dynamics than respiratory dynam-
ics. Consequently, computation time for one simulation with the coupled cardiovascular-respiratory
model is approximately 23 min on a 3 GHz Mac Pro with 4 Dual-Core Intel processors and 12 GB
memory, rendering it computationally intensive to solve the parameter estimation problem using the
coupled model.
The cardiovascular and respiratory systems are weakly coupled. The respiratory model depends
on blood ow through the pulmonary, systemic and brain tissues, while as stated the cardiovascular
model does not depend on quantities from the respiratory model. Physiologically, the thoracic
arteries and veins depend on respiration since change of volume in the lungs imposes oscillation of
the external pressure in the tissue surrounding the thoracic arteries and veins. Such oscillations can
be observed in measurements of arterial pressure, even on the nger pressure measurements used
for analysis in this study. However, this slow oscillation is a secondary eect not included in the
present study. Furthermore, when control of the system is included respiration will impact cerebral
vascular resistance and compliance through autoregulation.
Based on the above observations, we decoupled the models. The parameter estimation problem
was solved by rst estimating parameters for the cardiovascular model. Using the optimized car-
diovascular parameters, systemic, pulmonary and cerebral mean blood ows were computed and
used as inputs to the respiratory model. Finally, respiratory model parameters were estimated. A
solution to the original coupled model was found using the optimized cardiovascular and respiratory
parameter values and this solution was compared with the experimental data. This was done to
ensure that the optimized parameters from the decoupled models could predict the dynamics of the
complete model.
4.4. Least squares cost. As mentioned earlier, model parameters are estimated by minimizing the
least squares error between computed and measured values of arterial pressure, cerebral blood ow
velocity, and left ventricular ejection fraction (for the cardiovascular model) and end tidal partial
CARDIOVASCULAR & RESPIRATORY DYNAMICS IN CONGESTIVE HEART FAILURE 13
pressure of expiratory CO
2
for the respiratory model. Similar to previous studies [50, 15] we note
that to accurately predict cardiovascular dynamics it is important to account for changes in systolic
and diastolic values of arterial pressure and cerebral blood ow velocity. For each timeseries, the
data are measured at a xed frequency (128 Hz); thus the quantities (pressure, velocity, partial
pressure of CO
2
) are observed at N equally spaced times, t
i
. The timeseries analyzed contain a
given number of cardiac cycles (M), thus for arterial pressure and cerebral blood ow velocity we
have M observations of systolic and diastolic values. In addition, we have an average value for
ejection fraction (EF). Since the study is done during steady state, we assume that the ejection
fraction should be the same for each of the M cardiac cycles. In summary, we have the following
observations:
Arterial blood pressure p
sa
(t
i
), i = 1 : N [mmHg]
Cerebral blood ow velocity v
c
(t
i
), i = 1 : N [cm/sec]
Systolic arterial blood pressure p
sa,sys,j
, j = 1 : M [mmHg]
Diastolic arterial blood pressure p
sa,dia,j
, j = 1 : M [mmHg]
Systolic cerebral blood ow velocity v
c,sys,j
, j = 1 : M [cm/sec]
Diastolic cerebral blood ow velocity v
c,dia,j
, j = 1 : M [cm/sec]
Left ventricular ejection fraction EF
j
, j = 1 : M = 0.26
End tidal partial pressure of expiratory CO
2
p
exp,CO2
(t
i
), i = 1 : N [mmHg].
Each of these data vectors has an associated predicted vector, which we denote by a superscript (p).
The predicted vectors are p
p
sa
, v
p
c
, p
p
sa,sys
, p
p
sa,dia
, v
p
c,sys
, v
p
c,dia
, EF
p
, and p
p
exp,CO2
.
Since the parameter estimation problem is solved separately for the cardiovascular and the respi-
ratory models, we dene two residual vectors R
car
and R
resp
, as
R
car
=
_
R
psa
, R
vc
, R
psa,sys
, R
p
sa,dia
, R
va,sys
, R
v
a,dia
, R
EF

T
,
R
resp
=
_
R
pexp,CO
2

T
.
where each component is scaled to account for the number of elements in the vector and relative to
the data, i.e.,
R
i
=
1

K
_
p
p
i
(t
1
) p
i
(t
1
)
p
i
(t
1
)
, ,
p
p
i
(t
N
) p
i
(t
N
)
p
i
(t
N
)
_
T
,
where i = p
sa
, v
c
, p
sa,sys
, p
sa,dia
, . . . , EF, and K = N, M, respectively.
Thus, the vector R
car
has 2N + 5M entries, while R
resp
has N entries. For each of the two
models, the least squares cost J is dened by
J = R
i

2
2
= R
T
i
R
i
, i = car, resp. (14)
Minimizing the cost function is a nonlinear least squares problem. Solutions were found using the
Levenberg-Marquardt variant of the Gauss-Newton optimization method [32]. Before solving the
least squares problem we used sensitivity analysis and subset selection to prune the set of parameters.
4.5. Sensitivity analysis. Sensitivity analysis gives a measure of how much the output of a model
is aected by changes in the model parameters. For the cardiovascular part of the model, sensitivities
were computed for arterial blood pressure, p
p
sa
, cerebral blood ow velocity v
p
c
, and ejection fraction
EF
p
. For each quantity x, the sensitivity to a parameter is a time-varying quantity, given by
dx
i
d

=0

0
x
i
for i = 1, . . . , N.
To remove the eects of poorly scaled parameters and output, each component of the derivative is
weighted by the parameter value and the reciprocal of predicted pressure. This gives sensitivities as
dimensionless quantities, allowing them to be compared amongst each other.
14 L.M. ELLWEIN, S.R. POPE, A. XIE, J. J. BATZEL, C.T. KELLEY, M.S. OLUFSEN
To rank parameters from the most to the least sensitive we use a weighted 2-norm to obtain a
sensitivity for each quantity. For the cardiovascular model, we compute sensitivities with respect to
three quantities (p
sa
, v
c
, and EF), then take the mean over the three quantities, i.e,
S
car,
= mean{S
p
p
sa
,

2
/

N, S
v
p
c
,

2
/

NS
EF
p
,

2
/

M}.
However, the respiratory model is only validated against one quantity (end tidal partial pressure of
expiratory CO
2
, i.e., the sensitivity is given by
S
resp,
= S
pexp,CO
2

2
/

N.
If the model is insensitive to a parameter, it should be not be considered during an optimization.
4.6. Subset Selection. Let be the vector of P model parameters. Let R be the model residual.
Subset selection looks at the Jacobian, dR/d, and attempts to nd a subset of columns that are
maximally independent. We employ a method from [24] which also appears in [25]. The method
was also used in [50, 15]. The method includes the following steps
Compute a Jacobian matrix at nominal parameter values, R

(
0
) = dR/d|
=0
, with error
estimate .
Find a singular value decomposition of R

(
0
) = UV
T
with
= diag(
1
, . . . ,
P
)
and singular values
1

2

P
.
Determine the number of columns, k, by counting the number of singular values larger than .
Use QR factorization with column pivoting [25] on V
T
k
where V
k
is the matrix consisting of
the rst k columns of V . The factorization is
V
T
k
P = QR.
The rst k components of
T
P = [
n1

nP
] should be used in the optimization.
Label the vector of k chosen parameters
k
and the vector of remaining parameters
Pk
. These steps
ensure that the condition number of the reduced Jacobian, (dR/d
k
) = dR/d
k

2
(dR/d
k
)

2
remains small, and that dR/d
k
does a good job of representing dR/d
Pk
[25].
5. Results. We rst present results from the sensitivity analysis, then we discuss the subset selec-
tion algorithm and present simulation results obtained from the nonlinear least squares optimization.
5.1. Sensitivity analysis. For both the cardiovascular and the respiratory models we computed
and ranked relative sensitives as described above. Figure 3 shows that both models contain both sen-
sitive and insensitive parameters, but no clear jump separates the two groups. For both models we de-
ned all parameters with a sensitivity greater than 10
2
as sensitive. This choice allows us to include
all parameters that we can account for using physiological arguments. For the cardiovascular model
this leaves 16 parameters including x
car,sens
= {V
ld
,E
mr
,R
c
,E
ml
,T
M,frac
,R
p
,C
sv
,C
sa
,C
pv
,E
Ml
,E
Mr
,
R
s
,V
rd
,R
ca
,R
cv
,C
ca
}. Note that all heart valve resistances are insensitive. From previous work [50,
15] we know that A
c
is correlated with R
c
, thus we keep this parameter constant and do not include
this parameter in our list of parameters that we seek to estimate using nonlinear optimization. For
the respiratory model, including parameters with sensitivity larger than 10
2
allows us to pick 6
parameters including x
resp,sens
= {M
CO2
,V
D
,K
CO2
,k
CO2
,V
T,CO2
,V
B,CO2
,M
B,CO2
}. Note, we do not
include any data predicting partial pressure of O
2
, thus all parameters related to prediction of O
2
partial pressures/concentrations are insensitive.
CARDIOVASCULAR & RESPIRATORY DYNAMICS IN CONGESTIVE HEART FAILURE 15
Figure 3. Ranked sensitivities, top graph shows ranking for the cardiovascular model and bottom
graph shows ranking for the respiratory model. For both graphs, blue squares denote sensitivities
computed using the initial (nominal) parameter values, and the red diamonds denote sensitivities
computed using the optimized parameters. Note, that the y-axis is a log scale.
5.2. Subset selection. For each subsystem, we investigated correlation between parameters using
subset selection. For the cardiovascular model, subset selection allowed us to extract ve uncorrelated
parameters including x
car,sub
= {R
c
, R
s
, C
a
,T
M,frac
, E
Ml
}. It should be noted that these are the
same cardiovascular parameters found to be uncorrelated in our previous studies [50, 15]. Estimation
of these ve parameters using nonlinear optimization did not allow us to accurately predict the
observed data. An analysis of the remaining parameters (not picked by subset selection) revealed
that including a sixth parameter C
ca
allowed us to better predict the data. We remind the reader
that subset selection was based on initial parameter values. We repeated the subset selection with
optimized parameter values, and at this stage C
ca
was included in the subset. Furthermore, it
should be noted, that if we ran the models using data from a young subject, the same cardiovascular
parameters were identied, but for the young subject it was not necessary to also estimate arterial
cerebral compliance.
Before predicting sensitivities for the respiratory model we used optimized cardiovascular pa-
rameters to compute the mean ow in the systemic q
s
, cerebral q
c
, and pulmonary q
p
circulations.
Along with airow data these ows were used as inputs to the model. These quantities were kept
xed during the subset selection. Results from subset selection allowed us to estimate 4 parame-
ters including x
resp,sub
= {K
CO2
, k
CO2
, M
S,CO2
, V
D
}. It should be noted that none of the selected
parameters were insensitive.
5.3. Nonlinear optimization. For both models parameters were estimated using the Levenberg-
Marquardt variant of the Gauss-Newton optimization method [32]. Optimized parameters are given
in Table 3. For the cardiovascular model data were subsampled at 64 Hz to speed up simulations,
and computations settled at steady state within the data analyzed. For the respiratory model data
were subsampled at 4.2667 Hz to speed up simulations, furthermore to ensure that steady state was
reached respiratory data were repeated 40 times. The comparison used to compute the least squares
error were done over the last repeat of the data. Results of optimizations are shown in Figures 4
16 L.M. ELLWEIN, S.R. POPE, A. XIE, J. J. BATZEL, C.T. KELLEY, M.S. OLUFSEN
Table 3. Optimized model parameters, note the value for T
M,frac
is the fraction relative to the
length of the cardiac cycle. Averaged model quantities include ejection fraction, cardiac output,
mean heart rate, as well as systemic, cerebral, and pulmonary ow.
Parameter Description Optimized Unit
Rs Systemic resistance 1.28 mmHg sec/ml
Rc Cerebral resistance 2.54 mmHg sec/ml
Csa Systemic arterial compliance 0.536 mmHg/ml
Cca Cerebral arterial compliance 2.96 mmHg/ml
E
Ml
Maximum left ventricular elastance 0.721 ml/mmHg
T
M,frac
Time for maximum ventricular elastance 0.139
EF Ejection fraction 0.262
CO Cardiac output 4.92 l/min
HR mean heart rate 62.5 beats/min
qs Mean systemic ow 55.0 ml/sec
qc Mean cerebral ow 26.9 ml/sec
qp Mean pulmonary ow 82.0 ml/sec
K
CO
2
Dissociation constant 0.00688 ml
STPD
mmHg/ml
k
CO
2
Dissociation constant 0.261 ml
STPD
mmHg/ml
M
S,CO
2
Metabolic rate systemic tissue 4.20 ml
STPD
mmHg/sec
V
D
Total deadspace volume 151 ml
and 5. The cardiovascular model used heart rate as an input, and the respiratory model used airow
and mean blood ows computed from the cardiovascular model with optimized parameters.
6. Discussion. Results from the cardiovascular and respiratory models (Figures 4, 5, and 6) showed
that the modular model approach used in this study enable prediction of both cardiovascular and
respiratory quantities. Results from the coupled model were indistinguishable from the results
obtained with each of the two models indicating that using mean values for ows do not impact the
respiratory model signicantly, which is to be expected since respiration occurs over a much slower
timescale as the cardiovascular oscillations.
In addition to estimating observed quantities, we also computed all internal states and most
of these were within physiological bounds as discussed below. It should be noted that techniques
used for parameter estimation do not guarantee that internal states cannot uctuate away from
physiological values, even though initial parameter estimates were within physiological bounds. This
is one of the main problems with the proposed method. Besides including bounds on all model
parameters, we did not impose additional constraints limiting the states within certain bounds.
Consequently some states did drift away from expected values.
In regards to cardiovascular characteristics as reected by the model for this subject with CHF,
we note that approximately 30% of cardiac output was utilized as cerebral blood ow. This is
large, however, cerebral blood ow velocity measured for this subject was signicantly larger than
mean velocities reported in the literature [28]. This could be due to poor circulation in the body
or exceptionally high values from the transcranial Doppler measurements. This subject exhibits
a severely enlarged left ventricle (consistent with left ventricular failure) and reduced pumping
eectiveness, with an ejection fraction of 26%. Neverless, the cardiac output (modeled) is close to
normal. This type of behavior is seen in approximately half the patients suering from CHF [43].
With optimized parameters the maximum left ventricular volume was approximately 317 ml,
which is close to initial volume chosen as 312 ml. The minimum ventricular volume was approxi-
mately 238 ml, yielding a stroke volume of 79 ml and with the mean heart rate of 62.5 beats/min
this gives an approximate CO of 4.9 computed from the ows in the model (see Table 3). Systemic
venous pressures were approximately 7.2 mmHg somewhat higher than normal, which is expected
for a patient with CHF (see Table 4). Pulmonary arterial pressures were approximately 23 mmHg
CARDIOVASCULAR & RESPIRATORY DYNAMICS IN CONGESTIVE HEART FAILURE 17
0 50 100 150
60
80
100
120
p
s
a

[
m
m
H
g
]


0 50 100 150
40
60
80
100
time [sec]
v
c

[
c
m
/
s
e
c
]


Data
Model
Data
Model
0 50 100 150
60
80
100
120
p
s
a

[
m
m
H
g
]


0 50 100 150
80
90
100
time [sec]
v
c

[
c
m
/
s
e
c
]


Data
Model
Data
Model
150 152 154 156 158 160
60
80
100
120
p
s
a

[
m
m
H
g
]


150 152 154 156 158 160
40
60
80
100
time [sec]
v
c

[
c
m
/
s
e
c
]


Data
Model
Data
Model
150 152 154 156 158 160
60
80
100
120
p
s
a

[
m
m
H
g
]


150 152 154 156 158 160
80
90
100
time [sec]
v
c

[
c
m
/
s
e
c
]


Data
Model
Data
Model
50 100 150
0.25
0.26
0.27
0.28
0.29
0.3
0.31
0.32
Heartbeat
E
j
e
c
t
i
o
n

F
r
a
c
t
i
o
n

(
E
F
)


Model
Data
50 100 150
0.25
0.255
0.26
0.265
0.27
0.275
0.28
Heartbeat
E
j
e
c
t
i
o
n

F
r
a
c
t
i
o
n

(
E
F
)


Model
Data
Figure 4. Simulation results cardiovascular model. Top panel shows arterial pressure and cerebral
blood ow velocity for the full dataset, second panel shows a zoom for 150 t 160 seconds.
Bottom panel shows computed and expected ejection fraction (set at 26%). Left graphs give results
with initial (nominal) parameter values, while the right graphs show results with the optimized
values.
18 L.M. ELLWEIN, S.R. POPE, A. XIE, J. J. BATZEL, C.T. KELLEY, M.S. OLUFSEN
0 50 100 150
0
5
10
15
20
25
30
35
40
time [sec]
p











[
m
m
H
g
]
e
x
p
,
C
O
2
0 50 100 150
0
5
10
15
20
25
30
35
40
time [sec]
p











[
m
m
H
g
]
e
x
p
,
C
O
2
100 110 120 130 140 150
0
5
10
15
20
25
30
35
40
time [sec]
p











[
m
m
H
g
]
e
x
p
,
C
O
2
100 110 120 130 140 150
0
5
10
15
20
25
30
35
40
time [sec]
p











[
m
m
H
g
]
e
x
p
,
C
O
2
Figure 5. Estimation of respiratory parameters minimizing dierence between measured and com-
puted values of partial pressure of CO
2
. Left graphs show computations with initial parameters and
right graphs show results with optimized parameters.
100 110 120 130 140 150
0
5
10
15
20
25
30
35
40
time [sec]
p
C
O
2

[
m
m
H
g
]


arterial
exp
Figure 6. Model simulation of p
sa,CO2
and p
exp,CO2
showing relation between these quantities
during inhalation and exhalation
CARDIOVASCULAR & RESPIRATORY DYNAMICS IN CONGESTIVE HEART FAILURE 19
and pulmonary venous pressures were approximately 5.5 mmHg. This is also to be expected for a
patient with left ventricular CHF (see Table 4). Heart rate (not modeled) was within normal range.
For this model both cerebral and systemic vascular resistance and compliance were kept constant.
The total resistance R
T
= (1/R
B
+ 1/R
s
) = 0.86, where R
B
= R
ca
+ R
c
+ R
cv
is fairly low, again
this is to be expected in CHF where CO is lower than normal, and for this subject in particular,
where a large quantity of the blood goes to the brain. Moreover, the somewhat large proportion of
ow to the brain could also be a result of the somewhat simplied modeling included for the cerebral
arteries. The blood ow velocity measured is from the middle cerebral arteries, this has then been
scaled (assuming constant area of the major cerebral arteries) to compute a total ow to the brain.
Without information about anatomical quantities for the size of the cerebral arteries, this scaling
factor cannot be computed accurately, and the magnitude of the scaling factor A
c
would impact the
optimized values for the cerebrovascular resistance R
c
since these two parameters are correlated as
stated earlier. However, if e.g., the area of all major cerebral vessels (PCA, MCA and ACA) were
measured e.g., with an angiogram, then this scaling parameter could be computed from data.
For the respiratory quantities values for dead space p
D,CO2
and p
D,O2
, arterial values p
a,CO2
and p
a,O2
, and systemic values p
S,CO2
and p
S,O2
(calculated from dissociation laws) are reasonable.
Dynamics of p
A,CO2
(equivalent with p
a,CO2
) are shown in Figures 5 and 6. Dead space values
for CO
2
oscillate between zero (inhaled air) and end-expiratory air approximately the same as
alveolar air. Oxygen values follow similar reasonable patterns. It should be noted that brain partial
pressures p
B,CO2
and p
B,O2
did not match typical values so well in the optimized case. Estimates
of the dissociation constants varied from the initial guesses which resulted in p
B,CO2
approximately
43 mmHg (too low) and p
B,O2
approximately 48 mmHg (too high). There are likely several reasons
for this. Firstly, the data for cerebral blood velocity for this subject was rather high, which would
tend to depress brain p
B,CO2
and raise p
B,O2
. Secondly, we did not have data on O
2
which might
impact the results. Further, research indicates that normal cerebral metabolism is distorted in CHF
and cerebral energy decits can exist in certain cerebral tissue [35]. This complicates the picture for
the estimation process.
These observations lead us to conclude that the proposed methodology and model can be used for
quantitative prediction of changes within several subjects with CHF. To use this model to compare
quantities from a larger population it should be emphasized that the model should be used with care.
It is important that nominal parameters reect known characteristics from a subject with CHF, in
particular since only a subset of the parameters will be estimated. Conclusions based on analysis of
parameters obtained from several subjects should all be interpreted related to the nominal parameter
values used. Furthermore, additional measurements that would increase predictability of the model
parameters include measurements of cardiac output and estimation of diameters of major cerebral
vessels. Knowing these quantities would allow better prediction of systemic and arterial ow as
well as help to get better estimation of the scaling factor needed, which would help in prediction of
the scaling factor relating MCA CBFV to CBF. Furthermore, if constants used in dissociation laws
(optimized with our respiratory model) are xed, subset selection allows estimation of the tissue and
brain CO
2
metabolic rates as well as the deadspace volume. The parameter values for deadspace
volume were identical to simulation reported here, while parameters for tissue metabolic rate went
down slightly (from 4.20 to 4.16) and the parameter for brain CO
2
metabolic rate was reduced
from its initial value (from 1.04 to 0.87). Furthermore, simulations with this set of parameters
leads to similar dynamics that were observed in results presented above. Again, it should be noted
that it is essential that caution is used when choosing parameters fed to the subset selection. Subset
selection will give a subset of uncorrelated parameters that can be estimated given particular nominal
parameter values and initial conditions for the dierential equations.
20 L.M. ELLWEIN, S.R. POPE, A. XIE, J. J. BATZEL, C.T. KELLEY, M.S. OLUFSEN
Table 4. Generic state changes in left systolic CHF.
State Value Source
Mean pap [mmHg] increase [44]
Mean pvp [mmHg] increase [40, 31]
Mean pas [mmHg] decrease or stable [49]
Mean pvs [mmHg] increase [31]
Mean p
lv
[mmHg] steady to increase [41]
Mean p
la
[mmHg] increase [49]
LVEDP [mmHg] increase [41]
LVESP [mmHg] steady or increase [41]
LVEDV [ml] increase [10, 49]
LVESV [ml] increase [10, 49]
LVEF [ml] decrease [10, 20]
CO [mlmin] decrease [49]
SV [ml] decrease [49]
HR [beat/min] increase [49, 20]
Systemic resistance [mmHg s /ml] increase [31]
Fluid retention [ml] increase [31, 19]
Acknowledgments. Olufsen and Ellwein were partially supported by National Science Founda-
tion under grant DMS-0616597 and OISE-524249, Batzel was suported in part by FWF (Austrian
Research Funds) project P18778-N13, Pope and Kelley was supported in part by National Science
Foundation under grant DMS-0707220, and Xie was supported in part by the American Lung As-
sociation of Wisconsin.
Appendix.
6.1. Cardiovascular model. Blood pressures, ventricular volumes, and intrathoracic pressure.
dp
pa
dt
=
_
p
rv
p
pa
R
pv

p
pa
p
pv
R
p
_
/C
pa
dp
pv
dt
=
_
p
pa
p
pv
R
p

p
pv
p
lv
R
mv
_
/C
pv
dp
sa
dt
=
_
p
lv
p
sa
R
av

p
sa
p
sv
R
s

p
sa
p
ca
R
ca
_
/C
sa
dp
sv
dt
=
_
p
sa
p
sv
R
s
+
p
cv
p
sv
R
cv

p
sv
p
rv
R
tv
_
/C
sv
dp
ca
dt
=
_
p
sa
p
ca
R
ca

p
ca
p
cv
R
c
_
/C
ca
dp
cv
dt
=
_
p
ca
p
cv
R
c

p
cv
p
sv
R
cv
_
/C
cv
dV
lv
dt
=
p
pv
p
lv
R
mv

p
lv
p
sa
R
av
dV
rv
dt
=
p
sv
p
rv
R
tv

p
rv
p
pa
R
pv
.
CARDIOVASCULAR & RESPIRATORY DYNAMICS IN CONGESTIVE HEART FAILURE 21
Table 5. Initial values for the cardiovascular model. Note initial values for the cardiovascular
system are set using the corresponding nominal parameter values given in Table 1.
Variable Physiologic description Value Reference
ppa [mmHg] Pulmonary arterial pressure 20 [8, 29]
ppv [mmHg] Pulmonary venous pressure 3.3 [8, 29]
p
d
sa
[mmHg] Systemic arterial pressure p
d
sa
measured
psv [mmHg] Systemic venous pressure 6.6 [8, 29]
pca [mmHg] Cerebral arterial pressure psa 0.99 measured
pcv [mmHg] Cerebral venous pressure 7 [8, 29]
V
lv
[ml] Left ventricular volume EDV
lv
= 312 [59]
Vrv [ml] Right ventricular volume EDVrv = 100 [8, 29]
Note the airow

V
IE
is dened below. Heart valves
R
av
= min
_
R
av,o
+e
2(p
lv
psa)
, R
av,c
_
R
mv
= min
_
R
mv,o
+e
2(ppvp
lv
)
, R
mv,c
_
R
pv
= min
_
R
pv,o
+e
2(prvppa)
, R
pv,c
_
R
tv
= min
_
R
tv,o
+e
2(psvprv)
, R
tv,c
_
.
Ventricular pressures
p
lv
(t) = E
lv
(t)[V
lv
(t) V
ld
]
p
rv
(t) = E
rv
(t)[V
rv
(t) V
rd
].
where
E
lv
(t) =
_

_
E
ml
+ (E
Ml
E
ml
)
_
1 cos
_
t
T
M
__
/2 0 t T
M
E
ml
+ (E
Ml
E
ml
)
_
cos
_
(t T
M
)
T
R
_
+ 1
_
/2 T
M
t T
M
+T
R
E
ml
T
M
+T
R
t T,
E
rv
(t) =
_

_
E
mr
+ (E
Mr
E
mr
)
_
1 cos
_
t
T
M
__
/2 0 t T
M
E
mr
+ (E
Mr
E
mr
)
_
cos
_
(t T
M
)
T
R
_
+ 1
_
/2 T
M
t T
M
+T
R
E
mr
T
M
+T
R
t T.
Note, the timing parameters T
M
and T
R
are the same for both the left and right ventricles. Input
to this model is heart rate HR. Output from the model is arterial blood pressure p
sa
(t) and cerebral
blood ow velocity v
c
= (p
ca
p
cv
)/R
c
. Initial values for these dierential equations are listed in
Table 5 (below), while nominal values for all model parameters are listed in Table 1 and optimized
values for estimated parameters are given in Table 3.
22 L.M. ELLWEIN, S.R. POPE, A. XIE, J. J. BATZEL, C.T. KELLEY, M.S. OLUFSEN
6.2. Respiratory model.
dc
S,CO2
dt
= M
S,CO2
+q
s
(c
a,CO2
c
S,CO2
)/V
S,CO2
dc
S,O2
dt
= M
S,O2
+ q
s
(c
a,O2
c
S,O2
)/V
S,O2
dc
B,CO2
dt
= M
B,CO2
+q
c
(c
a,CO2
c
B,CO2
)/V
B,CO2
dc
B,O2
dt
= M
B,O2
+q
c
(c
a,O2
c
B,O2
)/V
B,O2
.
Inspiration
dp
D1,CO2
dt
=

V
ie
(p
i,CO2
p
D1,CO2
)/V
D1
dp
D1,O2
dt
=

V
ie
(p
i,O2
p
D1,O2
)/V
D1
dp
D2,CO2
dt
=

V
ie
(p
D1,CO2
p
D2,CO2
)/V
D2
dp
D2,O2
dt
=

V
ie
(p
D1,O2
p
D2,O2
)/V
D2
dp
D3,CO2
dt
=

V
ie
(p
D2,CO2
p
D3,CO2
)/V
D3
dp
D3,O2
dt
=

V
ie
(p
D2,O2
p
D3,O2
)/V
D3
dp
a,CO2
dt
= 863 0.98 q
p
(c
v,CO2
c
a,CO2
) +

V
ie
(p
D3,CO2
p
a,CO2
)/V
A
dp
a,O2
dt
= 863 0.98 q
p
(c
v,O2
c
a,O2
) +

V
ie
(p
D3,O2
p
a,O2
)/V
A
.
Expiration
dp
D1,CO2
dt
=

V
ie
(p
D1,CO2
p
D2,CO2
)/V
D1
dp
D1,O2
dt
=

V
ie
(p
D1,O2
p
D2,O2
)/V
D1
dp
D2,CO2
dt
=

V
ie
(p
D2,CO2
p
D3,CO2
)/V
D2
dp
D2,O2
dt
=

V
ie
(p
D2,O2
p
D3,O2
)/V
D2
dp
D3,CO2
dt
=

V
ie
(p
D3,CO2
p
a,CO2
)/V
D3
dp
D3,O2
dt
=

V
ie
(p
D3,O2
p
a,O2
)/V
D3
dp
a,CO2
dt
= 863 0.98 q
p
(c
v,CO2
c
a,CO2
)/V
A
dp
a,O2
dt
= 863 0.98 q
p
(c
v,O2
c
a,O2
)/V
A
.
Note, instantaneous airow is obtained from integrating the air ow velocity data as described in
equation (13).
Inputs to the stand alone respiratory model are airow velocity, average systemic, pulmonary, and
cerebral blood ow obtained by solving the cardiovascular model. For the coupled model, these ows
CARDIOVASCULAR & RESPIRATORY DYNAMICS IN CONGESTIVE HEART FAILURE 23
are computed at any instant in time. Initial values for the respiratory model are given in Table 6,
while nominal parameters for all respiratory parameters are listed in Table 2, and optimized values
for estimated parameters are given in Table 3.
Table 6. Initial values for the respiratory model.
Variable Physiologic description Value Reference
p
D1,CO
2
[mmHg] CO
2
partial pressure lung deadspace 1 5 [27, 33]
p
D1,O
2
[mmHg] O
2
partial pressure lung deadspace 1 159 [27, 33]
p
D2,CO
2
[mmHg] CO
2
partial pressure lung deadspace 2 6 [27, 33]
p
D2,O
2
[mmHg] O
2
partial pressure lung deadspace 2 158 [27, 33]
p
D3,CO
2
[mmHg] CO
2
partial pressure lung deadspace 3 7 [27, 33]
p
D3,O
2
[mmHg] O
2
partial pressure lung deadspace 3 157 [27, 33]
p
a,CO
2
[mmHg] Systemic arterial CO
2
partial pressure 40 [58]
p
a,O
2
[mmHg] Systemic arterial O
2
partial pressure 100 [18]
c
S,CO
2
[ml
STPD
/ml] Systemic tissue CO
2
concentration 0.543 [18]
c
S,O
2
[ml
STPD
/ml] Systemic tissue O
2
concentration 0.128 [18]
c
B,CO
2
[ml
STPD
/ml] Cerebral tissue CO
2
concentration 0.569 [27, 33]
c
B,O
2
[ml
STPD
/ml] Cerebral tissue O
2
concentration 0.112 [27, 33]
REFERENCES
[1] P.N. Ainslie, J.C. Ashmead, K. Ide, B.J. Morgan, and M. J. Poulin, Dierential responses to CO
2
and sympathetic
stimulation in the cerebral and femoral circulations in humans, J Physiol, 566 (2005), 613624.
[2] S. F. Ameriso, J. G. Mohler, M. Suarez, and M. Fisher, Morning reduction of cerebral vasomotor reactivity,
Nerology, 44 (1994), 19071909.
[3] R. J. Baker, D. D. Kozoll, and K. A. Meyer, The use of surface area as a basis for establishing normal blood
volume, Surg Gynecol Obstet, 104 (1957), 183189.
[4] J. J. Batzel, F. Kappel, and S. Timischl-Teschl, A cardiovascular-respiratory control system model including
state delay with application to congestive heart failure in humans, J Math Biol, 50 (2005), 293-335.
[5] S. J. Bennett, M. J. Sauve, and R. M. Shaw, A conceptual model of cognitive decits in chronic heart failure, J
Nurs Scholarsh, 37 (2005), 222228.
[6] J. Beneken and B. DeWitt, A physical approach to hemodynamic aspects of the human cardiovascular system,
in Physical Bases of Circulatory Transport: Regulation and Exchange (eds. E. Reeve and A. Guyton), W. B.
Saunders, Philadelphia, PA, 1967, 145.
[7] R. M. Berne and M. N. Levy, Physiology, C. V. Mosby Company, Second edition, 1988.
[8] W. Boron and E. Boulpaep, Medical Physiology, W. B. Saunders, Philadelphia, PA, 2003.
[9] S. N. Caparas, M.J Clair, R. S. Krombach, J. W. Hendrick, W. V. Houck, S. B. Kribbs, R. Mukherjee, G. E.
Tempel, F. G. Spinale, Brain blood ow patterns after the development of congestive heart failure: eects of
treadmill exercise, Crit Care Med, 28 (2000), 209214.
[10] K. Chatterjee and B. Massie. Systolic and diastolic heart failure: dierences and similarities, J Card Fail, 13
(2007), 569576.
[11] X. Chen, L. Qi, and K-L. Teo, Smooth convex approximation to the maximum eigenvalue function, J Global Opt,
30 (2004), 253270.
[12] N. S. Cherniack, Apnea and periodic breathing during sleep, New England J Med, 341 (1999), 985987.
[13] F. Dong and W. F. Langford, Models of Cheyne-Stokes respiration with cardiovascular pathologies, J Math Biol,
57 (2008), 497519.
[14] L. Ellwein, H. T. Tran, C. Zapata, V. Novak, and M. S. Olufsen, Sensitivity analysis and model assessment:
mathematical models for arterial blood ow and blood pressure, J Cardiovasc Eng, 8 (2008), 94108.
[15] L. M. Ellwein, Cardiovascular and respiratory regulation, modeling and parameter estimation, Ph.D. Thesis,
Applied Mathematics, North Carolina State University, Raleigh, NC, 2008.
[16] G. E. Foster, M. J. Poulin, and P. J. Hanly, Intermittent hypoxia and vascular function: implications for ob-
structive sleep apnea, Exp Physiol, 92 (2007), 5165.
[17] S. Javaheri, T. J. Parker, J. D. Liming, W. S. Corbett, H. Nishiyama, L. Wexler, G. A. Roselle, Sleep apnea in 81
ambulatory male patients with stable heart failure. Types and their prevalences, consequences, and presentations,
Circulation, 97 (1998), 21542159, 1998.
[18] S. I. Fox, Human Physiology, Wm C Brown Publishers, Dubuque, IA, 1993.
24 L.M. ELLWEIN, S.R. POPE, A. XIE, J. J. BATZEL, C.T. KELLEY, M.S. OLUFSEN
[19] G. S. Francis. Pathophysiology of chronic heart failure, Am J Med, 110 (2001), 37S46S.
[20] N. Fukuda, H. Shinohara, K. Sakabe, S. Morishita, Y. Fukuda, and Y. Tamura, Evaluation of right ventricular
function in patients with congestive left heart failure by the Doppler derived total cardiac performance index (tei
index), J Echocard, 5 (2007), 1117.
[21] A. Garcia-Touchard, V. K. Somers, L. J. Olson, and S. M. Caples, Central sleep apnea: implications for congestive
heart failure, Chest, 133 (2008), 14951504.
[22] D. Georgiadis, M. Sievert, S. Cencetti Cerebrovascular reactivity is impaired in patients with cardiac failure, Eur
Heart J, 21 (2000), 407413.
[23] J. M. Golbin, V. K. Somers, and S. M. Caples, Obstructive Sleep Apnea, cardiovascular disease, and pulmonary
hypertension, Proc Am Thorac Soc, 5 (2008), 200206.
[24] G. H. Golub, V. Klema, and G. W. Stewart, Rank Degeneracy and the Least Squares Problem, Technical Report
TR-456, Department of Computer Science, University of Maryland, College Park, MD, 1976.
[25] G. Golub and C. Van Loan, Matrix Computations, The Johns Hopkins Univ Press, Baltimore, MD, 1989.
[26] R. Gopinathannair, A. Mazur, and B. Olshansky, Syncope in congestive heart failure, J Cardiol, 15 (2008),
303312.
[27] F. S. Grodins, J. Buell, and A. J. Bart, Mathematical analysis and digital simulation of the respiratory control
system, J Appl Physiol, 22 (1967), 260276.
[28] N. Gruhn, F. S. Larsen, S. Boesgaard, G. M. Knudsen, S. A. Mortensen, G. Thomsen, J. Aldershvile. Cerebral
blood ow in patients with chronic heart failure before and after heart transplantation, Stroke, 32 (2001), 2530
2533.
[29] A. Guyton and J. Hall, Textbook of Medical Physiology, W. B. Saunders, Philadelphia, PA, 1996.
[30] T. Heldt, Computational Models of Cardiovascular Response to Orthostatic Stress, Ph.D. Thesis, Harvard/MIT
Division of Health Science and Technology, MIT, 2004.
[31] A. M. Katz, Heart failure: a hemodynamic disorder complicated by maladaptive proliferative responses, J Cell
Mol Med, 7 (2003), 110.
[32] C. T. Kelley, Iterative methods for optimization, SIAM, Philadelphia, PA, 1999.
[33] M. C. K. Khoo, A model-based evaluation of the single breath CO
2
test, J Appl Physiol, 68 (1990), 393399.
[34] M. C. K. Khoo, A. Gottschalk, and A. I. Pack, Sleep-induced periodic breathing and apnea: A theoretical study,
J Appl Physiol, 70 (1991), 20142024.
[35] C. W. Lee, J. H. Lee, J. J. Kim, S. W. Park, M. K. Hong, S. T. Kim, T. H. Lim, and S. J. Park, Cerebral
metabolic abnormalities in congestive heart failure detected by proton magnetic resonance spectroscopy, J Am
Coll Cardiol, 33 (1999), 1196 1202.
[36] C. W. Lee, J. H. Lee, T. H. Lim, H. S. Yang, M. K. Hong, J. K. Song, S. W. Park, S. J. Park, J. J. Kim,
Prognostic signicance of cerebral metabolic abnormalities in patients with congestive heart failure, Circulation,
103 (2001), 27842787.
[37] G. S. Longobardo, N. S. Cherniack, and B. Gothe, Factors aecting respiratory system stability, Ann Biomed
Eng, 17 (1989), 377396.
[38] K. Lu, J. Clark, F. Ghorbel, D. Ware, and A. Bidani, A human cardiopulmonary system model applied to the
analysis of the Valsalva maneuver, Am J Physiol, 281 (2001), H2661H2679.
[39] K. Lu, W. Clark, F. H. Ghorbel, C. S. Robertson, D. L. Ware, J. B. Zwischenberger, and A. Bidani, Cerebral
autoregulation and gas exchange studied using a human cardiopulmonary model, Am J Physiol Heart Circ Physiol,
286 (2004), 584601.
[40] S. Magder, S. Veerassamy, and J. H. Bates. A further analysis of why pulmonary venous pressure rises after the
onset of lv dysfunction, J Appl Physiol, online rst Oct. 9, 2008.
[41] S. Mak, E. R. Azevedo, P. P. Liu, and G. E. Newton. Eect of hyperoxia on left ventricular function and lling
pressures in patients with and without congestive heart failure, Chest, 120 (2001), 467473.
[42] R. Mosteller, Simplied calculation of body surface area, N Engl J Med, 317 (1987), 1098.
[43] J. O. Mudd and D. A. Kass. Tackling heart failure in the twenty-rst century, Nature, 451 (2008), 919928.
[44] K. M. ODell, J. S. Kalus, S. Kucukarslan, and B. Czerska. Nesiritide for secondary pulmonary hypertension in
patients with end-stage heart failure, Am J Health Syst Pharm, 62 (2005), 606609.
[45] M. S. Olufsen, J. T. Ottesen, H. T. Tran, L. M. Ellwein, L. A. Lipsitz and V. Novak. Blood pressure and blood ow
variation during postural change from sitting to standing: model development and validation, J Appl Physiol, 99
(2005), 15231537.
[46] S. M. Otis and E. B. Ringelstein, The transcranial Doppler examination: principles and applications of transcra-
nial Doppler sonography, in Neurosonology, by C. H. Tegeler, V. L. Babikian, and C. R. Gomez (eds), Mosby,
St. Louis, MO,
[47] J. T. Ottesen and M. Danielsen, Modeling ventricular contraction with heart rate changes, J Theo Biol, 22 (2003),
337346.
CARDIOVASCULAR & RESPIRATORY DYNAMICS IN CONGESTIVE HEART FAILURE 25
[48] J. T. Ottesen, M. S. Olufsen and J. Larsen, Applied Mathematical Models in Human Physiology, SIAM, Philadel-
phia, PA, 2004.
[49] W. W. Parmley. Pathophysiology of congestive heart failure, Clin Cardiol, 15 (Suppl) (1992), I5I12.
[50] S. R. Pope, L. M. Ellwein, C. L. Zapata, V. Novak, C. T. Kelley, M. S. Olufsen, Estimation and identication of
parameters in a lumped cerebrovascular model, Math Biosci Eng, 6 (2009).
[51] V. Rideout Mathematical and computer modeling of physiological systems, Prentice Hall, Englewood Clis, NJ,
1991.
[52] G. S. Schro, J. S. Janicki, and K. T. Weber, Left ventricular systolic dynamics in terms of its chamber mechanical
properties, Am J Physiol Heart Circ Physiol, 14 (1983), H110H124.
[53] D. D. Sin, F. Fitzgerald, J. D. Parker, G. Newton, J.S. Floras, T.D Bradley, Risk factors for central and
obstructive sleep apnea in 450 men and women with congestive heart failure, Am J Respir Crit Care Med, 160
(1999), 1077-1078.
[54] P. Solin, T. Roebuck, D. P.Johns, E.H. Walters, M.T. Naughton, Peripheral and central ventilatory responses
in central sleep apnea with and without congestive heart failure, Am J Respir Crit Care Med, 162 (2000), ;
162(6):2194-2200.
[55] N. Stergiopoulos, J. Meister, and N. Westerhof, Determinants of stroke volume and systolic and diastolic aortic
pressure, Am J Physiol, 270 (1996), H2050H2059.
[56] J. Stocks and P. H. Quanjer, Reference values for residual volume, functional residual capacity and total lung
capacity, J Biomech Eng, 124 (2002), 920.
[57] S. Y. Sun, W. Wang, I. H. Zucker, H. D. Schultz, Enhanced peripheral chemoreex function in conscious rabbits
with pacing-induced heart failure, J Appl Physiol, 86 (1999), 12641272.
[58] V. Thomas, F. Costes, T. Busso, Estimation of arterial PCO
2
from a lung model during ramp exercise in healthy
young subjects, Resp Physiol Neurobiol, 156 (2007), 259265.
[59] R. Tkacova, M. J. Hall, P. P. Liu, F. S. Fitzgerald, and T. D. Bradley, Left ventricular volume in patients with
heart failure and cheyne-stokes respiration during sleep, Am J Respir Crit Care Med, 156 (1997), 15491555.
[60] M. Ursino Interaction between carotid baroregulation and the pulsating heart: a mathematical model, Am J
Physiol, 44 (1998), H1733H1747.
[61] G. B. West, J. H. Brown, and B. J. Enquist, A general model for the origin of allometric scaling laws in biology,
Science, 276 (1997), 122126.
[62] C. R. White and R. S. Seymour, Allometric scaling of mammalian metabolism, J Exp Biol, 208 (2008), 16111619.
[63] A. Xie, J. B. Skatrud, R. Khayat, J. Dempsey, B. Morgan, and D. Russell, Cerebrovascular response to carbon
dioxide in patients with congestive heart failure, Am J Resp Crit Care Med, 172 (2005), 371378.
[64] A. Xie, J. V. Skatrud, B. Morgan, B. Chenuel, R. Khayat, K. Reichmuth, J. Lin, J. A. Dempsey, Inuence of
cerebrovascular function on the hypercapnic ventilatory response in healthy humans, J Physiol, 577 (Pt 1) (2006),
31929.