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Pulmonary Vascular Resistance, Collateral Flow and Ventricular Function in Fontan
Patients at Rest and During Dobutamine Stress
Running Title: Schmitt et al: Fontan Hemodynamic at Rest and During Stress
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Boris Schmitt, MD, Department of Congenital Heart Disease and Pediatric Cardiology,
Deutsches Herzzentrum Berlin, Berlin, Germany
Paul Steendijk, PhD, Departments of Cardiology and Cardiothoracic Surgery, Leiden
University Medical Center, Leiden, the Netherlands
Stanislav Ovroutski, MD, Department of Congenital Heart Disease and Pediatric Cardiology,
Deutsches Herzzentrum Berlin, Berlin, Germany
Karsten Lunze, MD, MPH, Department of Congenital Heart Disease and Pediatric
Cardiology, Deutsches Herzzentrum Berlin, Berlin, Germany
Pedram Rahmanzadeh, MD, Department of Congenital Heart Disease and Pediatric
Cardiology, Deutsches Herzzentrum Berlin, Berlin, Germany
Nizar Maarouf, MD, Department of Congenital Heart Diseasee an
Pediatric
Cardiology,
and
d Pe
Pedi
diat
di
atri
at
ricc C
ri
Deutsches Herzzentrum Berlin, Berlin, Germany
erm
man
any
y
Peter Ewert, MD, Department of Congenital Heart Disease and Pe
Pediatric
Pedi
d at
di
atri
ricc Cardiology,
ri
C r
Ca
Deutsches Herzzentrum Berlin, Berlin, Germany
Felix Berger, MD,
M PhD, Department of Congenital Heart Disease and Pediatric Cardiology,
Deutsches Herzzentrum Berlin, Berlin, Germany
Titus Kuehne, MD, PhD, Unit of Cardiovascular Imaging, Department of Cong
Congenital Heart
Disease and
Germany
d Pediatric Cardiology, Deutsches Herzzentrum Berlin, Berlin, G
Correspondence to:
Titus Kuehne
Unit of Cardiovascular Imaging
Department of Congenital Heart Disease and Pediatric Cardiology
Deutsches Herzzentrum Berlin
Augustenburger Platz 1
13353 Berlin
Germany
Telephone: +49 30 4593-2846/-2078
Fax: +49 30 450 576 983;
Email: [email protected]
Subject Codes: 41 (Congenital Heart Disease), 11 (heart failure), 18 (pulmonary circulation),
30 (MRI)
ABSTRACT
Background: The role, interplay, and relative importance of the multifactorial hemodynamic
and myocardial mechanisms causing dysfunction of the Fontan circulation remain
incompletely understood.
Methods and Results: Using a MRI catheterization technique, we performed a differential
analysis of pulmonary vascular resistance (PVR) and aorto-pulmonary collateral blood flow in
conjunction with global ventricular pump function, myocontractility (ESPVR), and diastolic
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compliance (EDPVR) in 10 Fontan patients at rest and during dobutamine stress. Pulmonary
ro
oni
n ze
zed
d wi
with
th vvelocity
elo
el
o
and ventricular pressures were measured invasively and synchronized
encoded
MRII de
deri
rive
ri
v ventricular
(VEC) MRI derived pulmonary and aortic blood flows and cine MR
derived
ressur volumes. PVR, ESPVR and EDPVR were determined from these pressurepressure-volume
data.
Aorto-pulmonary
y collateral flow was calculated as the difference between
betwe n aortic and
Co ared to rest, dobutamine caused a small increase in mean
mea pulmonary
pulmonary flow. Compared
pressures (p<0.05). Collateral flow was significantly augmented (p<0.001) and contributed
importantly to an increase in pulmonary flow (p<0.01). PVR decreased significantly (p<0.01).
Dobutamine failed to increase significantly stroke volumes despite slightly enhanced
contractility (ESPVR). Active early relaxation (Tau, dP/dtMin) was inconspicuous but the
EDPVR shifted upwards indicating reduced compliance.
Conclusions: In Fontan patients, aorto-pulmonary collateral flow contributes substantially to
enhanced pulmonary flow during stress. Our data indicate that pulmonary vascular response
to augmented cardiac output was adequate but decreased diastolic compliance was identified
as an important component of ventricular dysfunction.
Key Words: heart defects/congenital, pulmonary heart disease, heart failure, magnetic
resonance imaging
INTRODUCTION
Ventricular function and pulmonary vascular resistance (PVR) are important variables that
determine the outcome of patients with a Fontan circulation. Impaired growth of the
pulmonary arteries failing to match somatic growth was described in recent studies.1, 2 Other
authors report significant left-to-right shunting through aorto-pulmonary collaterals.3, 4 Both
factors may have a direct impact on the PVR that, however, can not be measured in the
Fontan circulation by conventional techniques such as thermodilution or oxymetry.
In addition to pulmonary vascular factors, heart failure was identified as an important cause of
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morbidity and the right-type systemic ventricle seems to have higher risk to develop heart
failure than the left-type ventricle.5, 6 However, the onset, coursee an
and
d th
thee pr
pred
predominant
edom
ed
om
form of
heart failure varies and remains unpredictable. Systolic dysfunction
was
tion w
as described
des
escr
crib
cr
i e but the role
ib
and mechanisms of diastolic dysfunction are less known.7-10 Diastolic filling is considered to
be impaired due to low preload that by itself is, at least in part, controlled bby pulmonary
nce. In addition, ventricular compliance
co liance is likely
like to be alt
aaltered because
vascular resistance.
congenital abnormalities as well as prolonged cyanosis and volume load may have impact on
the fibrous matrix of the myocardium.7, 11
In this study we performed a differential analysis of PVR and aorto-pulmonary collateral
blood flow in conjunction with global ventricular pump function, ventricular contractility and
diastolic compliance. Measurements were obtained at rest and during dobutamine stress using
a MRI catheterization technique. We hypothesized that exposure to dobutamine stress would
have a specific impact on PVR and aorto-pulmonary collateral flow as well as systolic and
diastolic ventricular function and hence improve our understanding of cardiovascular
pathophysiology in Fontan patients.
METHODS
Study design
The study was conducted in 10 preselected Fontan patients. The patients were referred to our
institution for cardiac catheterisation and MRI because of decreasing exercise capacity at
routine follow-up and therefore to determine ventricular systolic and diastolic function and
cardiovascular anatomy. The assessment of exercise capacity was based on NYHA
classification and ergometry. Only patients with extracardiac total cavopulmonary connection
that had no fenestration of the tunnel were included. Exclusion criteria were the presence of
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pulmonary artery stenosis, atrio-ventricular valve insufficiency, arrythmias, protein-loss
syndrome, thromboembolism, effusion or oedema. In addition,
n, patients
pati
pa
t en
ti
ents
ts with
wit
ith
h beta-blocker
medication were not included because this would have impacted
effect
cted th
thee ef
effe
fect
fe
ct oof dobutamine
infusion. All patients
that was
ients and/or their guardians
ardians gave
ve informed consent for the study
stt
approved by the responsible
r
institutional review board and ethic committee.
Atrio-ventricular valvar function and ventricular inflow profiles (E/A-wavee ratio) were
evaluated by Doppler-echocardiography. Exercise capacity was quantified by oxygen uptake
during ergometry. During catheterization, ventricular pressures were measured with 4-5F
fluid-filled pigtail catheters (Cordis, Warren, USA) and pulmonary pressures with 5F wedge
catheters (Arrow, USA). Catheters were advanced over a femoral artery and femoral or
cubital vein approach, respectively. At the end of the study a 24-36 mm sizing-balloon (AGA
Medical, Plymouth, USA) was placed at the level of the tunnel-to-pulmonary artery
connection. Then, patients were transferred to the neighbouring MRI laboratory keeping all
catheters in place. Details about the use of the catheters during MRI are given below.
MRI assessment of blood flow and pulmonary vascular resistance
All MRI studies were performed at a 1.5 Tesla scanner (Philips Intera, release 2.6.1, Best,
The Netherlands), maximum gradient performance 30 mT/m, slew rate 150 T/m/s. A 5-
element cardiac phased arrayed coil was used for signal acquisition (Philips, Best, The
Netherlands). In all patients, MRI was performed without sedation. Quantitative blood flow
was measured using VEC MRI orthogonal to the dominating flow direction in the superior
and inferior vena cave, left and right pulmonary artery and the ascending aorta as reported
elsewhehre.12,
13, 14
In the ascending aorta, flow was measured just distal to the coronary
arteries and the semilunar valves. In the inferior and superior vena cava, flow was measured
in a segment approximately 5-10 mm below or above its connection to the pulmonary artery,
respectively. Pulmonary flow was measured simultaneously with invasive pulmonary
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pressure. Technical details for pressure recording are given below. All measurements were
μg/k
μg
/kg/
/k
g/mi
g/
min
mi
n dobutamine.
performed free-breathing at rest and during continuous infusion of 1100 μg/kg/min
sin
ing
g fr
from
om tthe
h concomitant
he
Automated correction was performed for potential phase errors aris
arising
magnetic field. Sequence
e ence parameters
equence
arameters were: TR and TE shortest, acquired
ac ired spatial
s ti l resolution of
2x2x6 mm, 2 numbers
umbers of excitation, phase encoding velocity 70 cm/sec for
f r venous and
a 150 cm/sec for aortic flow, 35 reconstructed phases per card
d cycle.
pulmonary flow and
cardiac
Data analysis was done with View Forum software (release 6.1, Philips, Best, The
Netherlands). Antegrade and retrograde flows were measured as described elsewhere.12, 15
Aorto-pulmonary collateral flow (mL) was defined as the difference between effective
antegrade aortic flow and the sum of antegrade right and left pulmonary blood flow as
measured with VEC MRI in the right and left pulmonary artery.
Pulmonary vascular resistance was the quotient between transpulmonary gradient and
effective antegrade pulmonary flow.16, 17 The transpulmonary gradient was calculated as the
difference between mean pulmonary and ventricular enddiastolic pressures. Total effective
pulmonary flow was defined as the sum of antegrade flow as measured with VEC MRI in the
right and left pulmonary artery plus collateral blood flow.
The Nakata index was calculated as the sum of the crosssectional areas of the left and right
pulmonary artery divided by body surface area.18 The areas were obtained from the magnitude
images of the right and left pulmonary VEC MRI measurements.
MRI assessment of global ventricular function
Ventricular chamber volumes and myocardial mass were determined from axial stacks of
multislice-multiphase steady state free precession cine-MRI covering the entire heart.12, 19, 20
Sequence parameters were: TR/TE 3.4/1.7 msec, slice thickness 6 mm, no gap, in-plane
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resolution 1.9x1.3 mm2, 45 phases per cardiac cycle, number of averages 1, SENSE-reduction
ellea
ease
se 66.1,
.1,, Philips,
.1
Phil
Ph
ilip
il
ip Best, The
factor 2. Analysis was done using View Forum software (release
manuual
ally
ly traced
tra
race
ced
ce
d for
f computing
Netherlands). Biventricular endo- and epicardial borders were manually
mes and myocardial
ocardial mass where the septum
se um was accounted as left
lee ventricular
ventricular volumes
mass. Papillary muscles
and prominent right ventricular trabeculation were excluded for
m
ments. Stroke volume was calculated as the difference between the diastolic
volume measurements.
and systolic volumes. Ejection fraction was calculated as the ratio of stroke volume to enddiastolic volumes.
MRI assessment of myocontractile and diastolic function
Parameters of myocontractile and diastolic function were derived from pressure-volume loops
that were measured by a MRI catheterization technique. This MRI method was previously
validated in animal experiments and is described in detail in a recent report.21 Briefly,
ventricular volumes of the single ventricle were acquired over several cardiac beats with cine
MRI. During MRI invasive ventricular pressures were measured and averaged. At postprocessing, volumes and pressures were synchronized in time using a trigger signal. From
these measures apressure-volume loop under steady-state conditions was constructed. The
endsystolic pressure-volume relation (ESPVR) was estimated from this loop using a single-
beat approach as previously described.22-24 Emax, the slope of the ESPVR was defined as a
measure of contractility and was indexed to 100 mg myocardial muscle mass (Emax,i).
Effective arterial elastance (Ea) was calculated as end-systolic pressure divided by stroke
volume. Ventricular-arterial coupling was determined as the ratio of Emax to Ea.23, 25.
In a second step, instantaneous blood flows were measured using real-time VEC MRI in the
ascending aorta just distal to the orifices of the coronary arteries.13,
21
The sequence
parameters were: TR/TE 23/6.5 msec, matrix 128x256, FOV 400 mm, slice thickness 8 mm,
encoding velocity 150 cm/sec, SENSE reduction factor 3, halfscan factor 0.6, EPI factor 41.
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The scan time was 31 msec for the acquisition of one phase-contrast image. During flow
allo
al
loon
lo
on oocclusion
cclu
cc
lusi
lu
sion
si
on of the vena
measurements, ventricular preload was reduced by transient bballoon
each
ch uunloaded
nloa
nl
o
cava. The balloon was inflated with isotonic saline solution. Forr ea
beat, we
icular chamber volumes and ssynchronized
chronized them with ventricular
ventricula
ventricu a pressures to
determined ventricular
generate a set off pressure-volume loops, as previous described.21 The absolutee enddiastolic
etermined by matchin
volumes were determined
matching the VEC MRI derived volumes with th
the intercept of
the ESPVR. The resulting enddiastolic pressure-volume points were used to determine the
enddiastolic pressure-volume relation (EDPVR). The stiffness constant ß, a load-independent
measure of ventricular compliance, was calculated from the EDPVR with an exponential
regression: EDP=Aeß·EDV with EDP=enddiastolic pressure, EDV=enddiastolic volume and
A=curve fitting constant. ß was indexed to ventricular volumes to create a dimensionless
index (ß,i). From pressure measurements we derived relaxation time constant Tau as a
parameter of early diastolic relaxation.
Pressure recordings and catheter visualization during MRI
The fluid-filled catheters (details were provided above) were connected to pressure
transducers (Becton-Dickinson, Franklin Lakes, USA) and pressures were amplified, recorded
and analyzed with Ponemah software (DSI, St. Paul, USA). An additional pressure transducer
was positioned within the bore of the scanner to obtain a trigger signal for synchronizing
measured pressures with cine and VEC MRI derived ventricular and blood flow volumes.21
The position of the catheters was visualized on cine MR images (Figure 1). Appropriate
inflation of the balloon catheter with saline solution was confirmed on interactive-real time
MRI (Figure 1).26
Statistical analysis
Measurements at rest and during dobutamine were analyzed with paired Student’s t-test and
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Bonforroni-Holm correction for multiple comparisons of n=20 parameters. Data are expressed
as mean ± SD. The correlation was determined between ventricular
iccul
u ar vvolumes,
olum
ol
umes
um
es,, cardiac index
es
and aorto-pulmonary collateral flow. In addition, correlation
determined
between
on wa
wass de
dete
term
te
rmi
rm
measurements off collateral flow, pulmonary
ergometry
derived
ulmona vascular resistance and ergom
e m
parameters of functional
nctional capacity. The agreement between pulmonary and caval flow volumes
was assessed using
n the Bland-Altman test.
ng
RESULTS
General characteristics
We investigated 10 Fontan patients; n=5 with a right- and n=5 with a left-type single
ventricle. Eight patients were Caucasian, two of Arabic ethnicity. All patients were compliant
to the study. The duration of dobutamine exposure ranged between 15 and 25 minutes. There
were no side effects to dobutamine. Due to the length of the study protocol, flow
measurements in the inferior and superior vena cava were not performed in n=2 patients at
rest and in n=4 patients during dobutamine.
All patients were at NYHA I-II. Ergometry showed decreased functional capacity as
compared to published reference levels (Table).27 Angiograms revealed no obstruction within
the Fontan circulation and either no or only visibly small veno-venous or aorto-pulmonary
collaterals. Oxygen saturation at rest ranged between 91 and 97% and did not decrease
significantly during dobutamine.
There were no statistically significant differences between parameters as measured for the left
versus right type single ventricle. This comprises also the function parameters as given below.
Blood flow and pulmonary vascular resistance
The Nakata index of the pulmonary arteries was 150±45 mm2/m2 and thus substantially below
published reference values of healthy controls.1, 18 Quantitative flow volumes measured in the
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inferior and superior vena cava were similar to those measured in the left and right pulmonary
blle)
e).. In all
all ppatients,
atie
at
ien
ie
n there was
artery and they all increased during dobutamine (p<0.05) (Table).
elll as dduring
urin
ur
ing
in
g stress (Figure
only trivial retrograde flow in the pulmonary arteries, at rest ass wel
well
tman analysis showed good
ood agreement
reement between flow measurem
2). The Bland-Altman
measurements obtained
ure 3).. During augmented pul
ppulmonary flow,
in the vena cava and the pulmonary arteries (Figure
y artery
arter pressure
essure and trans
transpulmonary
lmonar pressure
essure gradient
radient did only change
mean pulmonary
slightly and, consequently, vascular resistance was decreased (Table). Blood flow volumes
were significantly larger when measured in the aorta compared to the pulmonary arteries and,
compared to rest, this difference increased during stress (Table). Thus, the calculated
collateral blood flow increased significantly during dobutamine (p<0.01). There was no
significant correlation between collateral blood flow and ventricular enddiastolic volumes (r=0.072 at rest and r=-0.062 during dobutamine) or between collateral blood flow and cardiac
index (r=-0.072 at rest and r=-0.062 during dobutamine). However, there were statistically
significant inverse correlations between collateral blood flow (APC) and both PVR and
ergometry derived peak oxygen uptake (r=-0.6, p=0.03 and r=-0.7, p=0.01). Blood flow
patterns in the pulmonary arteries were similar at rest and during dobutamine (Figure 2). The
profiles showed, in concordance to other reports, some degree of inter-individual
variability.28, 29
Global pump and myocontractile function
During dobutamine, heart rate and cardiac output increased significantly, but stroke volume
did not (Table). Differences in ejection fraction just failed of being significant when using
Bonferroni-Holm adjustments for multiple comparisons (p=0.009, Table).
Myocontractile and diastolic function
During dobutamine there was increase of Emax,I that however failed of being significant
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when adjusting for multiple comparisons (p=0.026, Table). Ventricular-arterial coupling
omi
m ta
tant
nt increase
inc
ncre
reeas
asee in Ea.25 By
(Emax/Ea) did not improve during dobutamine due to concomitant
echocardiography, the ratio of the E and A wave was above 0.7
patients.
7 in
n al
alll pa
pati
tien
ti
ents
en
ts During MRI
catheterization, att rest, the relaxation time constant Tau was at published referen
reference
n levels for
healthy controls and shortened significantly
the same time,
s nificant during dobutamine (Table).
Tabl . At th
there was a decrease
Enddiastolic
pressure
c
crease
of enddiastolic volumes (Table, Figure 4) Enddiast
t
increased slightly, but not significantly. There were no significant changes of the stiffness
constant ß, but the pressure-volume loops shifted towards the left in the pressure-volume
diagram in all patients (Table, Figure 4).
DISCUSSION
A progressive decrease of exercise capacity is commonly observed in patients with Fontan
circulation and, at late follow-up, heart failure contributes importantly to morbidity.5 The
pathophysiologic causes for failure seem to be multifactorial. In this study, MRI
catheterization was used to obtain, at rest and during dobutamine, information about
pulmonary vascular resistance, global ventricular pump function, myocardial contractility and
diastolic function. The major findings are that left-to-right shunt through aorto-pulmonary
collaterals increased during dobutamine but pulmonary vascular resistance decreased. In
addition, during stress the single ventricle had signs for abnormal diastolic compliance.
Blood flow and pulmonary vascular resistance
Several authors reported a diminished growth of the pulmonary arteries despite somatic
growth and assume that this might have an impact on pulmonary vascular resistance.1,
2
However, only sparse data is available about the functional status of the pulmonary arteries at
rest and during stress. This is partly due to the fact that vascular properties like PVR can not
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be evaluated in the Fontan patients with conventional techniques such as thermodilution or
ue tool by combining
com
mbi
b
Fick method. In this setting, MRI catheterization forms a unique
invasive
oll
llat
ater
at
erral aaorto-pulmonary
o
or
pressures and VEC MRI derived flow data that also accounts for co
collateral
blood flow.3, 16, 288 For reliable assessment of the PVR in the Fontan circulation, which is very
anges in volume load, pulmonary pressures and blood flow we
weree measured in
susceptible to changes
a
aneously
this study simultaneously
and not sequentially.
The MRI method used in this study for measuring collateral blood flow was adopted from the
work published by Whitehead and Grosse-Wortmann.3, 14 In these studies, collateral flow was
estimated by two approaches. Simplified, collateral flow was defined as the differences
between (i) flow volumes measured in the ascending aorta and the four pulmonary veines or,
alternatively as the difference between (ii) flow volumes in the ascending aorta and the
systemic venous return. The latter was determined in the descending aorta (GrosseWortmann) or the inferior and superior vena cava (Whitehead). In both studies, the different
methods had overall good agreement. In our study, we modified the approach of Whitehead
and colleagues slightly by measuring directly pulmonary arterial flow instead of caval flow.
Comparing pulmonary with caval flow volumes showed good agreement (Figure 3).
In concordance with the study by Whitehead and Grosse-Wortmann, we noted important
contribution of aorto-pulmonary collateral flow to total effective pulmonary blood flow.3, 14
The latter is considered being the amount of blood that passes through the pulmonary arteriole
level, thus the sum of antegrade pulmonary and collateral flow. Recirculating blood through
collaterals contributed about 13% to total effective pulmonary flow at rest and this percentage
increased substantially to over 25% during dobutamine. Interestingly, there was statistically
significant inverse correlation between the amount of collateral flow and peak oxygen uptake
during ergometry. Collateral flow also correlated inversely with PVR. However, the relatively
small sample size in this study limits the clinical interpretation of this finding. This issue must
be addressed systematically in future research.
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In the studied patients, PVR at rest was slightly above published control values that were
etter
eter
eriz
izat
iz
a io
at
ion
n method.
meth
me
th 16 During
determined in a former study using the same MRI catheterization
dobutamine, mean pulmonary pressures increased, but transpulmonary
lmona
nary
na
ry ggradient
radi
ra
dieen did not and
di
thus PVR decreased
ased in the presence
esence of augmented
au ented pulmonary
lmonar throughput.
thro hput. PVR is generally
considered being
resistive
g a valid indicator of structural changes at the small resistiv
v pulmonary
arteriole level. Hence we concluded that in the studied patients
least
tients there is at lea
l a a partially
functioning pulmonary vasculature regulation to variation in pulmonary perfusion. However,
one must keep in mind, when interpreting these data, that dobutamine was shown to increase
pulmonary blood flow but does not affect the pulmonary vascular tone.30,
31
In addition,
Hjortdal and colleagues demonstrated that in Fontan patients with total-cavo pulmonary
connection blood flow through the lung is driven by cardiac, respiratory and peripheral
muscular mechanisms.32 The relative contributions of these pumping mechanisms are
influenced by many factors that include cardiac performance, physical exercise, body position
and respiratory patterns. These different mechanisms can not be simulated in the MRI
environment realistically.
Global ventricular, myocontractile and distolic function
Similar to earlier studies, we noted no substantial stroke volume augmentation under
dobutamine stress in the Fontan patients.10, 33 Myocardial contractility increased only slightly
and not significantly during inotropic stimulation and thus the increase in cardiac output was
mainly regulated by heart rate. This is again in line with earlier studies.33 In conjunction with
slightly improved parameters of contractility, endsystolic volumes decreased adequately
suggesting that systolic dysfunction is not the predominant cause of the abnormal response to
stress. At the same time, enddiastolic volumes decreased, again similar to previous
observations, and Emax/Ea, a parameter for the efficiency of ventriculo-arterial coupling
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remained at a low level.10,
23
These findings suggest an abnormal diastolic function of the
ill
llin
ing
in
g is thought
tho
houg
ught
ug
ht to
t be affected
single ventricle during dobutamine stress. In Fontan, diastolic filling
entric
icle
ic
le aactively
ctiv
ct
ivel
iv
e y pumping an
el
by a limited preload reserve as there is no subpulmonary ventricle
u of blood through the pulmonary system.6, 10, 32 One might aalso speculate
unt
appropriate amount
that, in the presence
dysfunction
ence of diminished preload recruitment, diastolic dysfunctio
o is induced
tricle is “not trained” to be ful
elderl patien
ti n with atrial
because the ventricle
fully loaded. From elderly
patients
septal defect it is known, that chronic underloading can lead to a small and stiff left ventricle.
In these patients, pharmacological priming before defect closure mostly improved diastolic
function.34 On the contrary, recirculating blood through aorto-pulmonary collaterals
contributes increasingly to ventricular filling under stress and thus would attenuate a deficient
preload reserve. Other authors even discussed that collateral flow can impose a volume load
on the single ventricle.3, 35, 36 Overall, one should consider that there is important individual
variation in the presence of collaterals and the resulting amount of collateral flow.37
In our study, active early diastolic relaxation appeared to be normal, as indicated by a
decrease of tau during dobutamine.38 However, there was evidence of abnormal diastolic
compliance. During dobutamine, the stiffness constant ß remained at similar levels as
measured at rest, but, the EDPVR shifted towards the upper-left in the pressure-volume
diagram. Such a shift of the EDPVR was not observed in recent studies that were performed
in healthy pig left and right ventricles.21, 39 In addition, these studies showed that dobutamine
has no major impact on the stiffness constant ß. It seems that chamber properties for filling do
not improve during dobutamine stress but rather filling must be accomplished in a system
with increased stiffness. In our study we exposed the patients to moderate dobutamine stress
that caused no substantial increase in enddiastolic pressures. In more severe stress situations,
diastolic dysfunction might unmask even further which could go along with more increased
enddiastolic pressures. An abnormal ventricular stiffness could be explained by several
reasons. The geometry of the single ventricle has a direct impact on its mechanical pump
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function and thus on its systolic and diastolic properties.40 In addition, prolonged cyanosis and
caard
card
rdia
iall fi
ia
fibr
bros
br
osis
os
is..66,
is
volume load during infancy are thought to induce myocardial
fibrosis.
41
Finally,
histopathologic studies in tricuspid atresia showed abnormal form
formation
mat
atio
ion
io
n an
and
d ar
aarrangement of
the fibrous matrix
x and the aggregation of myocyte chains.11 Thus, the potential ccauses for the
development of heart and pulmonary vascular dysfunction are multifactoria
multifactorial
a as are the
function. This implies
i lies that it is essential to investigate
investi te tthese patients
resulting forms of ddysfunction.
with methods that give a differential insight into the predominant form of failure which in turn
will allow optimizing treatment concepts.
In summary, the findings of this study indicate that during dobutamine stress blood flow
through aorto-pulmonary collaterals contributes progressively to pulmonary perfusion. The
pulmonary arteries had abnormal growth index but vascular regulation appeared to be
unsuspicious. Pulmonary vascular resistance decreased during stress and thus did not
contribute to impaired diastolic filling in the studied patients. In contrast we noted, in the
presence of normal early relaxation, alteration of ventricular compliance during stress.
Limitations
There is no established animal model for studying the Fontan circulation. Also extrapolating
findings from healthy human controls to a univentricular physiology must be made with great
care. Therefore, this patient study has a descriptive nature and findings must be related to
parameters that were obtained in other research. Care must be taken when comparing changes
of ventricular and pulmonary vascular function induced by physical exercise with dobutamine
stress.30,
42, 43, 32
Therefore, it would be inappropriate to directly translate our findings to
exercise conditions. In addition, heart rate effects must be considered when interpreting our
data of diastolic compliance. Collateral flow through intrapulmonary shunts and veno-venous
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collaterals was not determined in our study. However, arterial oxygen saturation did not
at flow
fllow through
thr
hrou
ough
ou
gh these
t
decrease significantly during stress and thus one can assume that
types of
surin
ng bl
bloo
ood
oo
d fl
fflow
o in all four
shunt was relatively constant during the study protocol. Measuring
blood
uantifyi
the amount of veno
pulmonary veinss would have allowed quantifying
veno-venous and
protoco
proto o which was
intrapulmonary flow but at the expense of a substantially lengthened protocol
n
nding.
flo
o sequences
judged too demanding.
In general velocity-encoded (VEC) phase-contrast MR flow
must be used with great care when measuring quantitative flow.
Finally, there is a broad range of varieties in Fontan regarding anatomical conditions and the
onset and time-course of cardiovascular dysfunction. Therefore, one can not extrapolate our
data of preselected patients to other forms of Fontan. However, the method used in this study
allows differentiating between pulmonary, systolic and/or diastolic dysfunction which will
potentially improve the planning of individual treatment strategies.
Sources of Funding
This work was supported by the German Science Association (DFG) and the German Federal
Ministry of Education and Research, grant 01EV0704. Responsibility for the contents rests
with the authors.
Disclosures
None.
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Table: Patient characteristics and parameters of ventricular and pulmonary function
Patient
number
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1
2
3
4
5
6
7
8
9
10
Mean±SD
Patient
number
1
2
3
4
5
6
7
8
9
10
mean±SD
p-value
Patient
number
1
2
3
4
5
6
7
8
9
10
mean±SD
p-value
Leading
diagnosis
Mitral Atresia, TGA
Tricuspid Atresia
Pulmonary Atresia
Unbalanced AV canal
Tricuspid Atresia, TGA
DILV, TGA
Univentricular heart
Tricuspid Atresia
DORV, TGA
DORV, Heterotaxia
Systemic
Ventricle
(left/right)
RV
LV
LV
LV
LV
RV
RV
LV
RV
RV
Age
(years)
Body
weight
(kg)
14
16
40
14
39
13
26
21
18
18
22±10
24
27
59
29
69
29
86
57
39
56
48±20
BSI
(m2)
0.9
1.0
1.6
1.1
1.9
1.0
1.9
1.6
1.3
1.5
1.4±0.4
Myocardial
MM
(g)
44
61
101
56
103
54
97
55
76
88
73±21
73±2
73
±211
±2
NYHA
(I-IV)
I
I
I
I
II
I
I
II
II
I
VE/VCO2
slope
(ml/min/kg)
21.8
22.4
20.5
15.1
16.9
18
21.6
22.2
20.1
14.9
19.4±2.9
Heart rate
Contractility
(beats/min)
Emax (mmHg/mL/100 g)
Rest
Dobu
obu
Rest
Dobu
1
83
149
1.5
2.6
107
143
1.9
3.2
76
134
3.1
4.6
89
136
2.3
4.2
73
87
3.4
3.5
52
87
3.6
4.8
98
142
4.0
4.2
91
113
4.1
5.5
81
129
3.5
3.9
88
141
4.2
6.8
84±14
126.1±21.6 3.2±0.9
4.3±1.1
0.00002*
0.0264
Coupling
Emax/Ea
Rest
0.4
0.3
0.6
0.7
0.7
0.8
0.6
0.8
0.2
0.9
0.6±0.2
0.2171
Ventricular volumes
EDV (mL/m2)
ESV (mL/m2)
Rest
Dobu
Rest
Dobu
86.4
77.8
49.5
48.7
83.9
77.2
48.2
41.5
72.3
66.1
49.4
43.3
45.3
36.3
22.3
13.4
77.9
69.3
53.3
43.7
46.3
37.6
20.1
12.9
38.0
38.2
19.5
9.2
71.5
61.7
43.4
31.2
89.9
71.5
54.1
40.0
48.6
43.8
25.7
18.0
66±18.5 57.9±16.2 38.6±14
30.2±14.5
0.0004*
0.0001*
SV (mL/m2)
EF (%)
CI (L/min/m2)
Rest
Dobu
Rest
Dobu
Rest
36.9
29.1
42.7
37.4
2.9
35.7
35.7
42.5
46.3
3.8
22.9
22.9
31.6
34.6
1.7
23.0
22.9
50.7
63.1
2.0
24.5
25.6
31.5
36.9
1.8
26.3
24.6
56.7
65.6
1.4
18.5
22.6
48.6
71.0
1.8
28.1
30.5
39.3
49.5
2.6
28.0
31.5
39.8
44.1
2.3
22.9
25.9
47.1
59.0
2.0
26.7±5.5 27.1±4.2 43.1±7.6 50.7±12.4 2.2±0.7
0.6877
0.0092
0.0002*
Dobu
0.5
0.3
0.5
0.4
0.7
0.5
0.6
0.9
0.2
0.8
0.5±0.2
Distolic compliance
ß (1/mL/100 ml EDV)
Rest
Dobu
0.7
0.5
1.2
0.9
1.8
2.1
1.4
1.3
0.9
1.4
1.1
1.0
1.6
1.7
1.2
1.3
1.8
1.9
1.7
1.8
1.3±0.4
1.4±0.5
0.5212
VO2max
47
36
27
40
28
30
29
28
34
33
33.3±6.3
Early distolic relaxation
Tau
Rest
Dobu
48.2
28.4
27.3
25.0
31.5
25.3
33.8
22.6
32.4
27.5
40.1
36.0
23.5
18.0
49.2
23.0
57.6
43.0
23.1
15.0
36.7±11.1
26.4±7.8
0.0023*
Dobu
2.9
5.1
3.1
3.1
2.2
2.1
3.2
3.5
4.1
3.6
3.3±0.8
Patient
number
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1
2
3
4
5
6
7
8
9
10
mean±SD
p-value
Patient
number
1
2
3
4
5
6
7
8
9
10
mean±SD
p-value
Blood flow volumes
SVC+IVC (L/min/m2)
Rest
Dobu
na
na
1.4
na
na
na
3.0
4.4
2.0
2.6
1.9
3.3
1.5
2.4
1.9
2.3
1.8
na
1.8
3.1
1.9±0.4
3.0±0.7
0.0022*
LPA+RPA (L/min/m2)
Rest
Dobu
1.9
2.6
1.3
2.1
2.8
5.3
2.8
4.0
2.1
2.6
1.7
3.1
1.5
2.3
1.7
1.9
2.0
3.4
2.0
3.2
2.0±0.5
3.1±1.0
0.0004*
Aorta (L/min/m2)
Rest
Dobu
2.1
3.2
1.4
2.8
3.4
6.7
3.2
5.6
2.3
3.3
1.9
3.4
1.6
2.7
1.9
2.6
2.2
4.0
2.3
4.1
2.2±0.6
3.8±1.3
0.0001*
Ventricular pressures
EDP (mmHg)
Rest
Dobu
2.2
4.1
6.0
8.2
7.7
7.9
4.6
5.6
4.0
6.2
5.8
5.9
5.5
8.3
5.6
7.1
71
6.3
7.0
8.3
9.0
5.6±1.7
6.9±1.4
0.084
ESP (mmHg)
Rest
Dobu
90.0
110.0
98.0
104.0
82.1
101.0
80.0
97.0
105.0
103.0
91.6
85.0
78.0
97.0
96.0
96 0
111.0
111 0
91.0
117.0
93.1
119.0
90.5±8.0
104.4±9.7
0.0034*
Pulomonary pressures aand
nd rres
resistance
e is
es
ista
tanc
ta
ncee
Mean PAP (mmHg)
TPG
TPG (mmHg)
(mmH
(m
mHg)
mH
g)
Rest
Dobu
Rest
Reest
Dobu
Dob
obuu
9.7
11.7
7.5
7.6
10.6
12.8
4.6
4.6
11.3
12.9
3.6
4.2
9.0
13.3
4.4
7.7
10.1
11.7
6.1
5.5
10.0
13.2
4.2
6.4
12.7
12.9
7.2
4.3
12.2
12 2
13.3
13 3
6.6
66
5.8
58
12.5
12.0
6.2
5.0
12.4
12.9
4.1
3.5
11.1±1.3 12.7±0.6
5.5±1.3
5.5±1.4
0.0057*
0.986
APC (L/min/m2)
Rest
Dobu
0.2
0.6
0.1
0.7
0.6
1.4
0.4
1.5
0.3
0.7
0.2
0.3
0.2
0.4
0.2
0.6
0.2
0.6
0.3
0.9
0.3±0.1
0.8±0.4
0.0004*
APC contribution to Qp (%)
Rest
Dobu
13.3
24.2
8.5
33.3
21.7
26.6
14.4
37.5
13.4
26.8
12.0
8.1
10.3
19.4
12.6
33.6
9.7
17.6
14.7
28.7
13.1±3.5
25.6±8.3
0.0015*
PVR (wood units/BSI)
Rest
Dobu
3.6
2.4
3.2
1.7
1.0
0.6
1.4
1.4
2.6
1.7
2.2
1.9
4.5
1.6
3.5
2.3
2.9
1.2
1.8
0.8
2.7±1.0
1.6±0.5
0.0022*
TGA=Transposition of the Great Arteries, RV=right ventricle, LV=left ventricle, BSI=body surface
index, AV=atrioventricular, DORV=double outlet right ventricle, DILV=double inlet left ventricle,
MM=muscle mass, VO2max=peak oxygen uptake, VE/VCO2-slope=minute ventilation to carbon
dioxide production relationship, Dobu=Dobutamine, Emax=slope of the endsystolic pressure volume
relationship indexed to 100g muscle mass, Ea= arterial elastance, Emax/Ea=efficiency of ventriculararterial coupling, ß=stiffness constant indexed to 100 mL of enddiastolic volume, EDV=enddiastolic
volume, ESV=endsystolic volume, SV=stroke volume, EF=ejection fraction, CI=cardiac index,
SVC=superior vena cava, IVC=inferior vena cava, LPA=left pulmonary artery, RPA=right pulmonary
artery, APC=aorto-pulmonary collateral, EDP=end diastolic pressure, ESP=end systolic pressure,
PAP=pulmonary arterial pressure. TPG=transpulmonary gradient, PVR=pulmonary vascular
resistance, Qp=pulmonary blood flow. Significance levels of p-values were adjusted by BonferroniHolm correction for multiple comparisons. In the table uncorrected p-values derived from paired
Student´s t-test are given for differences between rest and dobutamine. Significant differences after
Bonferroni-Holm correction are indicated by *.
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FIGURE LEGENDS
Figure 1: Cine MR images of catheters as used for ventricular and pulmonary pressure
measurements (arrows, panels A and B). The catheters are visible due to small local signal
voids. Panel C shows an interactive real-time MR image of a balloon catheter in the inferior
vena cave during inflation with isotonic saline solution. Panel D illustrates the position of the
catheters in the pulmonary artery, the single ventricle and the inferior vena cava.
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Figure 2: Representative flow volumes and pressures of a patient with Fontan measured at
um ooff th
thee fl
flow
ow measured in
rest and during dobutamine. The pulmonary flow is shown as thee ssum
ta that
at w
as measured
mea
easu
s
the left and right pulmonary artery. For illustration purposes, data
was
at two
different heart rates
t (rest and dobutamine) were scaled to 35 heart phases.
tes
Figure 3: Bland-Altman
Altman plot
lot of pulmonary
ulmona and caval blood flow volumes (mL) ffor
measurements obtained at rest and during dobutamine.
Figure 4: Pressure-volumes loops (left panel) and enddiastolic pressure-volume points with
regression line (right panel) in a representative patient at rest and during dobutamine. Note the
left shift of the loops and enddiastolic pressure-volume points during dobutamine.
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Pulmonary Vascular Resistance, Collateral Flow and Ventricular Function in Fontan Patients
at Rest and During Dobutamine Stress
Boris Schmitt, Paul Steendijk, Stanislav Ovroutski, Karsten Lunze, Pedram Rahmanzadeh, Nizar
Maarouf, Peter Ewert, Felix Berger and Titus Kuehne
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Circ Cardiovasc Imaging. published online July 14, 2010;
Circulation: Cardiovascular Imaging is published by the American Heart Association, 7272 Greenville Avenue, Dallas,
TX 75231
Copyright © 2010 American Heart Association, Inc. All rights reserved.
Print ISSN: 1941-9651. Online ISSN: 1942-0080
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http://circimaging.ahajournals.org/content/early/2010/07/14/CIRCIMAGING.109.931592
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