Download Effects of Epoprostenol on Right Ventricular Hypertrophy and

Effects of Epoprostenol on Right
Ventricular Hypertrophy and Dilatation
in Pulmonary Hypertension*
Roald J. Roeleveld, MD; Anton Vonk-Noordegraaf, MD, PhD;
J. Tim Marcus, PhD; Jean G. F. Bronzwaer, MD; Koen M. J. Marques, MD;
Pieter E. Postmus, MD, PhD; and Anco Boonstra, MD, PhD, FCCP
Objectives: To gain more knowledge of changes in main pulmonary artery flow and right
ventricular mass and volumes in patients with pulmonary hypertension during epoprostenol
therapy.
Methods: Eleven patients (9 women) were evaluated before the start of therapy and every 4
months thereafter. Right and left ventricular volumes and masses were measured by cine MRI.
Flow was measured with MRI velocity quantification. At the same times, 6-min walking tests were
performed. Right-heart catheterizations were performed at baseline and after 1 year.
Results: Right ventricular mass in the patient group was significantly higher from that in a control
group of healthy volunteers (95 ⴞ 26 g vs 42 ⴞ 10 g, p < 0.05 [mean ⴞ SD]), whereas the stroke
volume was lower (34 ⴞ 11 mL vs 81 ⴞ 11 mL, p < 0.05). The greatest improvement in right
ventricular stroke volume (to 41 ⴞ 11 mL, p < 0.05) took place in the first 4 months. During the
1-year follow-up, right ventricular end-diastolic volume and mass did not change, and mean
pulmonary artery pressure remained nearly stable at 55 mm Hg at baseline and 53 mm Hg after
1 year. Pulmonary vascular resistance decreased by 12.5% (p ⴝ 0.06).
Conclusions: From these data we conclude that epoprostenol lowers pulmonary vascular resistance,
leading to an increase in pulmonary artery flow. This increase in pulmonary artery flow corresponds
well with the increase in 6-min walking distance and can be noninvasively monitored by MRI (flow
quantification). Right ventricular dilatation and hypertrophy are not reversed by epoprostenol
therapy, but do not progress either.
(CHEST 2004; 125:572–579)
Key words: MRI; pulmonary hypertension; right ventricular function
Abbreviations: COfick ⫽ cardiac output measured invasively using the Fick method; COmri ⫽ cardiac output measured
by MRI velocity mapping; ED ⫽ end diastole; EDV ⫽ end-diastolic volume; EF ⫽ ejection fraction; ES ⫽ end systole;
ESV ⫽ end-systolic volume; LV ⫽ left ventricle; mPAP ⫽ mean pulmonary artery pressure; NYHA ⫽ New York Heart
Association; PAP ⫽ pulmonary artery pressure; PPH ⫽ primary pulmonary hypertension; RV ⫽ right ventricle;
RVEDP ⫽ right ventricular end-diastolic pressure; RVSP ⫽ right ventricular systolic pressure; RVSV ⫽ right ventricular
stroke volume; SA ⫽ short axis; 6MWD ⫽ 6-min walking distance; TPVR ⫽ total pulmonary vascular resistance
rimary pulmonary hypertension (PPH) is a rare,
P progressive,
and fatal disease. Continuous administration of epoprostenol improves survival and
exercise tolerance in patients with PPH.1–3 Clinical
*From the Departments of Pulmonology (Drs. Roeleveld, VonkNoordegraaf, Postmus, and Boonstra), Physics and Medical
Technology (Dr. Marcus), and Cardiology (Drs. Bronzwaer and
Marques), VU University Medical Center, Amsterdam, The
Netherlands.
This study was financially supported by GlaxoSmithKline Netherlands BV.
Manuscript received March 19, 2003; revision accepted September 1, 2003.
Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (e-mail:
[email protected]).
Correspondence to: R. J. Roeleveld, MD, Department of Pulmonology, VU University Medical Center, De Boelelaan 1117,
1081 HV Amsterdam, The Netherlands; e-mail: [email protected]
experience shows that most of the improvement
takes place in the first few months of treatment. The
mechanism underlying this improvement is not yet
fully understood.
As reported by Barst et al,4 the clinical improvement induced by epoprostenol in patients with PPH
is correlated to an increase in pulmonary blood flow
and not to pulmonary artery pressures (PAPs). The
increase in flow may be caused by a decreased
afterload or an increased preload of the right ventricle (RV). Positive inotropic effects of epoprostenol
must not be excluded.
Measurement of blood flow in the pulmonary
artery to obtain right ventricular stroke volume
(RVSV) may therefore be a valid way of monitoring
the hemodynamic effects of epoprostenol in patients
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Clinical Investigations
with PPH. Such measurements can be performed
noninvasively using MRI velocity quantification.
Cine MRI also yields information on the origin of
changes in stroke volume by measuring end-diastolic
and end-systolic ventricular volumes, and changes in
ventricular mass during treatment. The aim of the
study was to examine the effects of epoprostenol on
RVSV, as well as the structure and function of the
heart in a 1-year follow-up of 11 patients with PPH.
then performed. For the cine imaging, a gradient-echo pulse
sequence was applied with segmented k space, 7 Ky lines per
heartbeat, and a data-acquisition window of 80 ms. Echo sharing
(or “view sharing”) was used, yielding a temporal frame at every
40 ms. Slice thickness was 6 mm and interslice gap 4 mm,
yielding a slice distance of 10 mm. The full protocol has been
described in earlier studies6 – 8 and has proven its feasibility even
in severely dyspneic patients. MRI scans were made in the same
week as the first catheterizations, and after 4 months, 8 months,
and 1 year of treatment.
MRI Postprocessing
Patients and Methods
Study Subjects and Functional Status
The study protocol was approved by the institutional ethics
review commission. Eleven consecutive patients (9 women; aged
31 to 74 years) with PPH gave informed consent to be included
in our study. Multiple investigations, including transthoracic and
transesophageal echocardiography, were performed to rule out
any causes for a secondary pulmonary hypertension in these
patients, following the algorithm of Gaine and Rubin.5
The functional status of the patients was assessed by the
consulting pulmonologist using the New York Heart Association
(NYHA) classification every 4 months. The unencouraged 6-min
walking test was administered by a pulmonary function technician, and was performed just before the start of epoprostenol
therapy and repeated every 4 months thereafter. MRI measurements were performed in 11 healthy age- and sex-matched
control subjects to obtain reference values.
MRI Acquisition
A Siemens 1.5 T ‘Vision’ whole-body scanner (Siemens Medical Systems; Erlangen, Germany) was used, using a quadruple
phased-array circularly polarized body coil with two receiver
antennas locally applied on the anterior chest wall, and two on the
posterior chest wall. RVSV was quantified by MRI velocity
mapping in the main pulmonary artery. An image plane was
positioned perpendicular to the main pulmonary artery. A twodimensional, gradient-echo pulse sequence was used with excitation angle of 25° and echo time of 5 ms. One-dimensional
velocity encoding was perpendicular to the image plane (and thus
parallel to the flow in the main pulmonary artery). The phase
encoding steps of two different acquisitions (repetition time of 12
ms) were interleaved, one with velocity encoding of phase and
one without. Subtracting of the resulting phase maps compensated for phase changes caused by inhomogeneity of the magnetic field, leaving only phase changes related to velocity. The
temporal resolution within the cardiac cycle was thus 2 ⫻ 12
ms ⫽ 24 ms. The velocity sensitivity was set at 150 cm/s, by
proper adjustment of the amplitude of the velocity-encoding
gradients. Field of view was 225 ⫻ 360 mm, and matrix size was
140 ⫻ 256. The R-R interval and heart rate were registered
during the MRI acquisition of this flow map.
Additionally, short-axis (SA) cines were acquired covering the
whole left ventricle (LV) and RV for volume and mass measurements. By using the end-diastolic cine frame of a four-chamber
view, a series of parallel SA image planes was defined starting at
the base of the LV and RV, and encompassing the entire LV and
RV from base to apex. The most basal image plane was positioned
close to the transition of ventricular myocardium to the atria,
ensuring that also the most basal part of the ventricles was
covered. At every SA plane, a breathhold cine acquisition was
RVSV was calculated as follows: in each time frame of the
velocity images, the cross-sectional area of the artery was delineated by hand in order to account for translations of the artery
with respect to the image plane. No aliasing due to high peak
systolic velocities was encountered. Volumetric flow (in milliliters
per second) was obtained in each time frame by multiplying the
spatial mean velocity (in centimeters per second) with the
cross-sectional area (centimeters squared). Finally, integrating
the volumetric flow curve over systole yielded the RVSV (stroke
volume in milliliters). Cardiac output measured by MRI velocity
mapping (COmri) is heart rate times stroke volume.
The SA images were processed using the MASS software
package (Department of Radiology, Leiden University Medical
Center; Leiden, the Netherlands). End diastole (ED) was defined as the first temporal frame directly after the R-wave of the
ECG. End systole (ES) was defined as the temporal frame at
which the image showed the smallest LV cavity area, usually 240
to 320 ms after the R-wave. Epicardial and endocardial contours
were traced, and the papillary muscles were excluded from the
ventricular volume and included with the ventricular mass.
Because of the ventricular shortening, at least one more image
slice at the base was needed at ED than at ES to encompass the
complete ventricles. If the most basal image at ES was difficult to
interpret (due to eg, partial volume effects), then this most basal
plane was projected on the ES frame of the four-chamber cine
images. The resulting projection line on this four-chamber image
then provided the decisive clue, on whether or not to include the
ES SA image as a part of the LV or RV.
For both ventricles, the end-diastolic volume (EDV) and
end-systolic volume (ESV) were calculated by summation of
the product of area ⫻ slice distance for all slices. Ejection
fraction (EF) was calculated as follows: EF ⫽ (EDV ⫺ ESV)/
EDV ⫻ 100%. The LV and RV end-diastolic mass were obtained
from the volume of the ventricular muscle tissue, multiplied with
the specific weight of muscle tissue, which is 1.05 g/cm3. The
septum was included with the LV mass, and thus RV mass refers
to the mass of the RV free wall.
Invasive Measurements
All patients underwent right-heart catheterization to obtain the
right ventricular EDP (RVEDP) and right ventricular systolic
pressure (RVSP) and PAP. Cardiac output was measured invasively using the Fick method (COfick). Oxygen consumption
was measured within 24 h before or after the catheterization,
using an on-line analyzer (V̇max 6200; SensorMedics; Yorba
Linda, CA) connected to a mouthpiece. Sampling took place over
a period of 5 min, preceded by 10 min of absolute rest in a quiet
room. During the measurement, the patients were wearing a
nose clamp, and supplemental oxygen was temporarily discontinued. Blood samples were taken during the catheterization from
the pulmonary and femoral arteries and saturation analyzed with
a whole-blood oximeter (Oxicom 2000; Waters Instruments;
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573
Plymouth, MA) Total pulmonary vascular resistance (TPVR) was
calculated from the COfick and PAP.
Directly after the right-heart catheterization, all patients underwent acute vasodilator testing. The vasodilators used were
oxygen (100%) and epoprostenol, in a dose-escalation scheme of
5-min periods with 2, 4, 6, 8, 10, and 12 ng/kg/min. At each step,
PAP and systemic BP were recorded as well as COfick and
TPVR calculated. A drop in mean PAP of ⬎ 20% was considered
reversible pulmonary hypertension. After 1 year (range, 11 to 15
months) of treatment, a second right-heart catheterization was
performed.
Data Analysis
All analyses were performed using the SPSS statistical software
package (Release 9.0.1; SPSS; Chicago, IL). Unless mentioned
otherwise, all data were summarized as mean ⫾ SD. The Wilcoxon signed rank test was used to compare baseline data with
data obtained after 4, 8, and 12 months of treatment. MannWhitney U tests were used to compare study results with
reference values; p ⬍ 0.05 was considered statistically significant.
Results
Clinical Status and Treatment
The baseline characteristics of the 11 patients are
summarized in Table 1. During the vasodilator test,
none of the patients showed a ⱖ 20% fall in PAP on
epoprostenol. At the start of treatment, after the first
catheterization and MRI scan, all patients received 4
ng/kg/min of epoprostenol. Additional therapy consisted of oral anticoagulation with a vitamin K antagonist, diuretics and, if required, oxygen to maintain
an arterial Po2 ⬎ 60 mm Hg. The epoprostenol dose
was adapted during the study period using a regime
of linear increase in time, based on earlier studies9
and previous clinical experience. This lead to an
average increase of 1.6 ng/kg/min/mo, which is a
common regime.9,10 For the continuous IV drug
delivery, permanently implanted port systems and
cassette pumps were used (Port-a-Cath and
CADD-1; SIMS-Deltec; St. Paul, MN).
One patient died unexpectedly, shortly before
completing the 1-year follow-up period. In a postmortem examination, a cerebral hemorrhage was
considered the most likely cause of death. This
patient was included in the study up to the 8-month
follow-up measurements. The remaining 10 patients
completed the 1-year follow-up period of this study.
At the start of the study, seven patients were
NYHA class III and four were NYHA class IV. After
4 months, seven of the patients had improved one
NYHA class, and the remaining four patients remained stable. Between 4 months and 8 months,
three patients improved by one class. Between 8
months and 1 year, no further improvement was
found. The distances covered during the 6-min
walking test showed significant improvement in the
first 4 months of treatment, with only minor changes
thereafter (Table 1).
Pulmonary Artery Flow
In total, 43 MRI scans were made. In two patients,
the scans after 4 months and 8 months of follow-up
could not be performed because of logistical reasons.
Figure 1 shows the flow patterns in the main
pulmonary artery measured in one patient during
1-year follow-up. In all subjects, a biphasic flow
pattern during systole was observed. At baseline, the
mean RVSV was 34 ⫾ 11 mL, considerably lower
than the reference value of 70 mL (Fig 2). The
Table 1—Clinical Status, Invasive Hemodynamics, and MRI Velocity Quantification-Based Pulmonary
Artery Flow (n ⴝ 11)*
Variables
Clinical status
NYHA I/II/III/IV class, No.
6MWD, m
Invasive measurements
Mean right atrial pressure
RVEDP, mm Hg
RVSP, mm Hg
mPAP, mm Hg
Cardiac output, L/min
TPVR, dyne䡠s䡠cm5
Pulmonary artery flow
RVSV, mL
Heart rate, beats/min
Baseline
4 mo
8 mo
1 yr†
0/0/7/4
318 ⫾ 123
0/6/3/2
383 ⫾ 118㛳
0/9/0/1
451 ⫾ 100㛳
3/6/0/1
427 ⫾ 62
8⫾5
16 ⫾ 5
87 ⫾ 20
54 ⫾ 7
4.1 ⫾ 0.9
1121 ⫾ 373
34 ⫾ 11§
88 ⫾ 15§
Reference Values‡
11 ⫾ 5
16 ⫾ 10
83 ⫾ 20
53 ⫾ 9
4.7 ⫾ 1.5㛳
981 ⫾ 401
41 ⫾ 11㛳
88 ⫾ 15
45 ⫾ 14㛳
86 ⫾ 16
46 ⫾ 14㛳
87 ⫾ 11
81 ⫾ 11
*Data are presented as mean ⫾ SD unless otherwise indicated. A p value ⬍ 0.05 was considered statistically significant.
†Data of 10 surviving patients only.
‡Obtained in group of 11 healthy age- and sex-matched control subjects.
§Baseline measurement significantly different from reference value.
㛳Significantly different from baseline value.
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Clinical Investigations
Figure 1. Changes in flow by MRI flow quantification in the main pulmonary artery during
epoprostenol therapy in one patient. Each curve represents one cardiac cycle, and is an average of 140
heartbeats. The flow curve after 8 months of therapy was almost identical to the one after 1 year, and
is therefore not shown.
stroke volume increased to 41 ⫾ 11 mL (p ⬍ 0.05)
within the first 4 months, to 45 ⫾ 14 mL (p ⬍ 0.05)
after 8 months, and 46 ⫾ 14 mL (p ⬍ 0.05) after 1
year (significances when comparing each of the
follow-up measurements with baseline; differences
between the three follow-up measurements were not
significant).
Without any significant change of mean heart rate
throughout the study (Fig 3, bottom left), this increase in stroke volume lead to an equal increase in
COmri. Within the first 4 months, COmri increased
from an average of 3.0 to 3.5 L/min (p ⬍ 0.05).
COmri increased further to 3.7 L/min after 8
months and 4.0 L/min after 1 year (both p ⬍ 0.05
compared to baseline). Again, there were no significant differences between the follow-up measurements.
Ventricular Masses and Volumes
Table 2 shows that the LV wall mass of 133 g was
close to the normal value. The average RV wall mass
of 95 g was significantly higher than the normal value
of 41 g in healthy subjects (p ⬍ 0.05). The masses of
both ventricles did not change during the follow-up
period. Compared to the reference value, the LV
showed a substantially decreased average EDV,
whereas the average ESV was normal (Table 2). In
comparison to the reference values, the RV had a
substantially increased EDV and ESV. An example
of the large EDV is shown in Figure 4. During the
1-year follow-up, RVEDV did not change significantly. Figure 3 shows the change in RVEDV (Fig 3,
top left) as well as RVSV (Fig 3, top right).
Invasive Measurements
At the initial catheterizations, mean PAP (mPAP)
ranged from 46 to 64 mm Hg (average, 55 ⫾ 7 mm
Hg). At the second catheterization, average mPAP
was 53 ⫾ 9 mm Hg (p ⫽ not significant). However,
changes in both directions were observed in individual patients (Fig 3, bottom right).
COfick at baseline was 4.1 ⫾ 0.9 L/min, and
4.7 ⫾ 1.5 L/min after 1 year (p ⬍ 0.05). Although
COfick was significantly higher than COmri
(p ⬍ 0.05), the correlation between both measurements was good (R ⫽ 0.81). Average TPVR was
1121 ⫾ 373 dyne䡠s䡠cm⫺5 at baseline and 981 ⫾ 401
dyne䡠s䡠cm⫺5 at the end of our study (p ⫽ 0.06).
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575
Figure 2. Relationship between RVSV, by MRI velocity quantification, and 6MWD. Displayed are the
mean values, the SEMs (error bars), and the correlation line (dotted). The error bars at the 8-month
point are not drawn for reasons of legibility.
Discussion
The performance of the heart per time unit is
determined by four factors: heart rate, preload,
afterload, and contractility. In patients with pulmonary hypertension, malperformance of the RV is the
main cause of death, and improvement of this performance leads to a longer life expectancy. In our
study population at baseline, heart rate, PAP, and
TPVR were elevated, and RVSV was below normal.
After 1 year of therapy with epoprostenol, heart rate
and PAP had not changed, and TPVR showed a
decrease of 12.5%, consistent with earlier studies.3,4,11 The increase of RVSV took place without
increasing the RV EDV or RVEDP. In terms of
cardiac performance, our findings imply that the
increase in stroke volume cannot be explained by a
change in preload.
In our patients, we found a significant increase in
6-min walking distance (6MWD) during the first 4
months of treatment. After the first 4 months, the
clinical and hemodynamic status seemed to stabilize.
Castelain et al12 showed that a decrease in incremental pulmonary vascular resistance during exercise,
which is not automatically reflected by a decrease in
TPVR measured during rest, might also contribute to
the improved exercise tolerance during the first
months of treatment. Although we did not measure
the PAP/cardiac index relation during exercise in our
patients, the significant increase in RVSV that appeared to be closely related to the improvement of
the 6MWD indicate that RVSV measured during
resting conditions reflects these changes in the pulmonary vascular bed.
Direct measurement of RVSV by MRI velocity
quantification is a sensitive, noninvasive method of
detecting hemodynamic changes in these patients.
Pulmonary and tricuspid valve insufficiencies may
result in a certain overestimation of the cardiac
output when using invasive techniques13,14 or volumetric calculations by deducting ESV from EDV.
These latter measurements are also complicated by
the fact that placement of the most basal slice of the
SA images has a large influence on the calculated
volumes. Furthermore, the postprocessing steps of
selecting the correct ES time frame and tracing the
inner contours of the ventricles was done manually
for each individual image, undoubtedly introducing
some measurement error. Therefore, it is our opinion that the difference between RV EDV and RV
ESV, calculated using the SA images, may not be
seen as a reliable measurement of changes in stroke
volume.
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Clinical Investigations
Figure 3. Hemodynamic data. Each dot represents an individual patient; the horizontal lines represent
the mean. Top left: RV-EDV changes during the study. Top right: RVSV by flow mapping changes in
time. Bottom left: Heart rate as recorded during the acquisition of the RVSV flow maps. Bottom right:
mPAP as found at the baseline catheterization and after 1 year of therapy.
MRI velocity mapping in the main pulmonary
artery yields the forward flow to the lungs, irrespective of tricuspid valve insufficiency, and can be
corrected for any back flow due to pulmonary valve
insufficiency. Because of the high accuracy both in
vitro as in vivo, MRI velocity mapping has been
proposed as the “gold standard” to quantify blood
flow.15 The high reproducibility also enables studies
to be performed on small patient groups,16 a great
advantage in a rare disease as PPH.
The biphasic systolic flow patterns in the main
pulmonary artery found in the PPH patients have
Table 2—Calculations of Ventricular Volumes and Masses Based on the SA MRI Scans of the 10 Patients Who
Completed the Study*
Volumetric Calculations
LV EDV, mL
LV ESV, mL
LV EF, %
LV mass, g
RV EDV, mL
RV ESV, mL
RV EF, %
RV mass, g
Baseline
76 ⫾ 26‡
32 ⫾ 10
56 ⫾ 11‡
133 ⫾ 34
156 ⫾ 46‡
105 ⫾ 40‡
34 ⫾ 10‡
95 ⫾ 26‡
4 mo
8 mo
82 ⫾ 31
32 ⫾ 13
61 ⫾ 12§
137 ⫾ 31
144 ⫾ 45
96 ⫾ 43
36 ⫾ 10
95 ⫾ 20
86 ⫾ 32
33 ⫾ 15
61 ⫾ 13
139 ⫾ 35
144 ⫾ 45
91 ⫾ 42
38 ⫾ 17
93 ⫾ 23
1 yr
84 ⫾ 29
35 ⫾ 15
58 ⫾ 12§
133 ⫾ 32
148 ⫾ 46
97 ⫾ 49.0
38 ⫾ 15
90 ⫾ 24
Reference Values†
117 ⫾ 19
33 ⫾ 10
72 ⫾ 6
134 ⫾ 27
120 ⫾ 17
38 ⫾ 10
69 ⫾ 6
42 ⫾ 10
*Data are presented as mean ⫾ SD. A p value ⬍ 0.05 was considered statistically significant.
†Obtained in a group of 11 healthy age, and sex-matched control subjects.
‡Baseline measurement significantly different from reference value.
§Significant change from baseline value.
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Figure 4. MRIs of the heart in SA orientation at ED. The images were made at baseline (top left) as
well as 4 months (top right), 8 months (bottom left), and 1 year (bottom right) of therapy. At baseline,
note the enlarged RV and the disturbed geometry of the interventricular septum. At 1 year of therapy,
the septum shows a more normal shape with bowing to the right.
earlier been identified by Bogren et al,17 and other
studies18,19 state that abnormal flow patterns may be
indicative for PH. The cause of this phenomenon is
uncertain, but it may be related to a lack of compliance of the pulmonary vascular bed. Although pressure-wave analysis has been found to be of clinical
value in pulmonary hypertension patients,15,17–20 extensive flow-wave analysis has not been performed in
these patients until now. The clinical implications of
the flow patterns in patients with pulmonary hypertension require further investigation.
RV EDV as well as RV ESV in our patients are
significantly larger than the reference values, and do
not change during 1 year of therapy; RV mass was
found to be over twice the reference value. Neither
RV EDV nor RV mass did increase further, as would
have been expected in untreated patients. However,
there are no historical data available on untreated
patients followed over a 1-year period, based on the
same methods.
The LV EDV is substantially decreased. LV ESV is
within a normal range, indicating insufficient filling
of the LV due to the small RVSV found in these
patients. The left ventricular EF increased slightly,
but the underlying mechanism remains unclear.
Possible mechanisms are improved pump function
by increased contractility, or complex systolic rightleft ventricular interactions leading to an altered left
systolic function.21
In conclusion, during 1 year of epoprostenol therapy in patients with pulmonary hypertension, the
PAP as well as RV dilatation and hypertrophy did not
change, whereas RVSV (measured by means of MRI
velocity quantification) increased. Most improvement in RVSV, NYHA classification, and 6MWD
took place in the first 4 months of therapy. The
increase in RVSV corresponded well with the functional improvement, and was consistent with decreased pulmonary vascular resistance at 1-year
follow-up.
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Clinical Investigations
ACKNOWLEDGMENT: The authors thank Th. J. C. Faes, J-W.
Lankhaar, and N. Westerhof for their valuable comments.
12
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