Download 5 rIGHt VentrIcular PacInG ImProVes rIGHt Heart FunctIon In

5
Right Ventricular
Pacing Improves Right
Heart Function in
Experimental Pulmonary
Arterial Hypertension:
A Study in the Isolated
Heart
M.L. Handoko1,2, R.R. Lamberts1,3, E.M. Redout1,
F.S. de Man2, C. Boer3, W.S. Simonides1, W.J.
Paulus1, N. Westerhof1,2, C.P. Allaart4, A. VonkNoordegraaf2
Departments of 1Physiology, 2Pulmonology,
3
Anesthesiology and 4Cardiology, VU University
Medical Center / Institute for Cardiovascular
Research, Amsterdam, The Netherlands
Am J Physiol Heart Circ Physiol 2009; 297:
H1752-H1759
Louis BW.indd 83
06-05-10 11:21
RV-pacing
ABSTRACT
Right heart failure in pulmonary arterial hypertension (PH) is associated with mechanical ventricular dyssynchrony, which leads to impaired right ventricular (RV) function, and - by adverse
diastolic interaction - to impaired left ventricular (LV) function as well. However, therapies aiming to restore synchrony by pacing are currently not available. In this proof-of-principle study, we
determined the acute effects of RV-pacing on ventricular dyssynchrony in PH.
Chronic PH with right heart failure was induced in rats by injection of monocrotaline (80 mg/
kg). To validate for PH-related ventricular dyssynchrony, rats (6 PH, 6 controls) were examined
by cardiac magnetic resonance imaging (9.4 Tesla), twenty-three days after monocrotaline- or
sham-injection. In a second group (10 PH, 4 controls), the effects of RV-pacing were studied in
detail, using Langendorff-perfused heart preparations.
In PH, septum bulging was observed, coinciding with a reversal of the trans-septal pressure
gradient, as observed in clinical PH. RV-pacing improved RV systolic function, compared to
unpaced condition (RV dP/dtmax: +8.5 ±1.3 %, p < 0.001). In addition, RV-pacing markedly decreased PTIRVP>LVP, an index of adverse diastolic interaction (-24 ±9 %, p < 0.01), and RV-pacing
was able to resynchronize time of RV and LV peak-pressure (Δtpeak, unpaced: 9.8 ±1.2 ms vs.
paced: 1.7 ±2.0 ms, p < 0.001). Finally, RV-pacing had no detrimental effects on LV function or
coronary perfusion, and no LV pre-excitation occurred.
Taken together, we demonstrate that in experimental PH, RV-pacing improves RV function and
diminishes adverse diastolic interaction. These findings provide a strong rationale for further in
vivo explorations.
84
Louis BW.indd 84
06-05-10 11:21
INTRODUCTION
Pulmonary arterial hypertension (PH) is characterized by progressive pulmonary vascular
remodeling. During the progression of the disease, right ventricular (RV) afterload continues to
rise and eventually right heart failure develops in the majority of patients.
In PH-patients, signs of mechanical RV dyssynchrony along with signs of adverse interventricular diastolic interaction are often observed.1-3 This results in inefficient pumping of the heart.4-6
In essence, the duration of RV contraction is lengthened due to increased RV afterload.7 As
a consequence, time-to-peak shortening of the RV free wall is delayed, even beyond closure
of the pulmonary valves.5,6,8 Loss of a coordinated ventricular contraction results in impaired
RV systolic function.8,9 In addition, the prolonged RV contraction in early left ventricular (LV)
diastole causes the already relaxing interventricular septum to bulge into the left ventricle. This
negatively influences early LV filling, eventually contributing to the impairment of LV diastolic
function as well.10,11
To this date, no specific treatment is available for the failing right ventricle.12 Cardiac resynchronization therapy is a well-established treatment for LV dyssynchrony related to left heart
failure,13 and might be an interesting therapeutic option for right heart failure as well. However,
our research group recently demonstrated that the origin of PH-related ventricular dyssynchrony
lies in regional differences in the duration of the contraction, rather than regional differences in
onset of the contraction (e.g. due to a conductance delay).6 For this reason, PH-related ventricular dyssynchrony is essentially different from dyssynchrony associated with left heart failure.13
In the present proof-of-principle study, we tested whether RV-pacing could synchronize presa reduction of adverse diastolic interaction. First, we validated the monocrotaline rat model,
a well-established model for chronic PH, for the presence of ventricular dyssynchrony. Subsequently, we evaluated the acute effects of RV-pacing on cardiac performance and PH-related
ventricular dyssynchrony in isolated Langendorff-perfused heart preparations. This approach
Chapter 5
sure generation across the septum, resulting in an improvement of RV systolic function and
allows relatively easy manipulation and offers a high degree of preparation stability in which LV
and RV load can be varied independently, with derivation of cardiac-specific functional data.14
METHODS
All experiments were approved by the Institutional Animal Care and Use Committee of the VU
University Amsterdam.
Experimental model of pulmonary arterial hypertension
In total, 26 male Wistar rats were included in the study (150-175g; Harlan, Horst, the Netherlands). PH was induced (n = 16) by a single subcutaneous injection of monocrotaline (80 mg/
85
Louis BW.indd 85
06-05-10 11:21
RV-pacing
kg dissolved in sterile saline; Sigma-Aldrich, Zwijndrecht, The Netherlands). This resulted in
a PH-phenotype, followed by right heart failure approximately 23 days after injection.15,16 The
control group was injected with saline only (n = 10).
Cardiac magnetic resonance imaging
Twenty-three days after monocrotaline-injection, the presence of ventricular dyssynchrony in
vivo was assessed in PH-rats and compared to controls (6 for each group), by measuring cardiac
function and the behavior of the interventricular septum with cardiac magnetic resonance imaging (CMR; 9.4 Tesla; Varian Medical Systems, Palo Alto CA), as previously described.17 After
CMR-scanning, all rats were euthanized and their organs weighed.
Images were analyzed off-line using Segment (version 1.698; http://segment.heiberg.se).18
Endocardial borders of both ventricles were automatically detected for all slices of the heart and
for each frame in the heart cycle. LV and RV volume curves were constructed using the modified Simpson’s rule, from which end-diastolic and end-systolic volume, peak filling rate, stroke
volume, heart rate, cardiac output, and ejection fraction were derived.10,19 Septum curvature was
calculated as previously described.2 In short, the anterior, middle and posterior positions of the
interventricular septum at mid-ventricular level were determined, through which a circle was
fitted. The reciprocal of the radius of this circle was used to quantify septum curvature (1/R), and
was defined positive if the septum bowed toward the right ventricle.
Isolated Langendorff–perfused heart preparation
To characterize the hearts of PH-rats and controls (10 PH-rats, 4 controls; no CMR performed),
and to study ventricular dyssynchrony in detail, a Langendorff-setup was used as previously
described, with balloons in left and right ventricle (Figure 1).14 The heart was perfused (at 35-37°
C) using a modified Krebs-Henseleit solution (composition in mM: 118.5 NaCl, 4.7 KCl, 1.4
CaCl2, 25 NaHCO3, 1.2 MgCl2, 1.2 KH2PO4, and 11 glucose) that was continuously gassed with
95% O2 / 5% CO2 (pH 7.4). Coronary perfusion pressure was set at a constant value of 80 mmHg
to minimize edema formation.20,21 Electrodes were placed at the right atrium, and at a vessel-free
area of the LV and RV free wall (LV: posterolateral - midventricular; RV: RV “anterolateral”,
opposite to the LV electrode), after which normal atrial and subsequent ventricular activation
were checked to verify that the intrinsic conductance system was intact. In addition, signals of
LV and RV electrodes were compared to detect potential differences in electrical activation of left
and right ventricle. Atrial and ventricular threshold stimuli were determined, and the heart was
atrial-paced at 4.0 Hz (pulse duration 1.0 ms, at twice the threshold). During the whole experiment, electrical activity and stimuli, LV and RV pressures, and coronary flow were continuously
recorded with a sample rate of 2.0 kHz.
After stabilization (10 min), the volumes at maximal developed pressure (Vmax) of both ventricles were determined by small stepwise increases and decreases in balloon volume (in analogy
to Lmax, used in isolated muscle studies22), subsequently the pressure-volume relationship of the
86
Louis BW.indd 86
06-05-10 11:21
Figure 1
atrial pacing
SET
AV-time
monitoring electrogram
right
atrium
second pulse
generator
PRV
PLV
RV free wall
The Langendorff / RV-pacing setup. Ventricular balloons were inserted into both ventricles, volumes were set, and
isovolumic LV and RV pressures measured (PLV, PRV). Epicardial electrodes were placed at the right atrium, LV and RV free
wall. RV-pacing was performed by shortening atrioventricular delay (AV-shortening) with the use of a second (coupled)
pulse generator. AV-time = time-interval between atrial (A) and ventricular (V) electrical activation.
left ventricle was determined (in the physiological range of 70 to 100% Vmax), with the RV volume
set at 75% Vmax, and this was repeated for the right ventricle, now with the LV volume set at 75%
Vmax.14
RV-pacing protocol
RV-pacing was only performed in PH-hearts; RV-pacing experiments in normal hearts were
not performed, since it is known that this results in loss of synchrony and worsening of cardiac
function.23 LV volume was set at 75 %Vmax and RV volume was set at 95 %Vmax. These volumes
as observed in PH-patients,19 and in monocrotaline-treated rats in vivo.16 The intrinsic atrioventricular delay (AV-time) was defined as the time-interval between atrial and (right) ventricular
activation (Figure 1).
RV-pacing was performed by direct stimulation of the RV free wall (using the RV electrode),
Chapter 5
correspond with LV and RV end-diastolic pressures of 5 and 10 mmHg respectively (Figure 2),
triggered from atrial activation, starting with an AV-time equal to the intrinsic AV-time.
Subsequently, AV-time was shortened in steps of 10 ms (AV-shortening). Effects of RV-pacing
stabilized within 5 seconds. After the experiment, all hearts were dissected in left (including
interventricular septum) and right ventricle, and weighed.
Functional assessment of RV-pacing
The isovolumic pressure recordings were evaluated off-line using MATLAB (version R2007b, The
MathWorks, Natick MA). Signals were averaged over approximately hundred beats (25 seconds).
The effects of RV-pacing on both intra- as well as inter-ventricular aspects of PH-related dyssynchrony were evaluated.24 Intra-ventricular dyssynchrony was measured by RV dP/dtmax and
RV systolic pressure (RV SP). The time difference between RV and LV peak-pressure was used as
an index for inter-ventricular dyssynchrony (Δtpeak).
87
Louis BW.indd 87
06-05-10 11:21
RV-pacing
Figure 2
A
B
C
D
LV and RV pressure-volume relationships of PH-hearts and control hearts. A,C) Compared to control, a significant upward
shift in PV-relationship of the right ventricle was found for both systole (RV SP) and diastole (RV DP) in PH-hearts,
indicating PH-induced RV remodeling (LV volume set at 75% Vmax). B,D) No differences in PV-relationship were observed
for the left ventricle (RV volume set at 75% Vmax).
Data are presented as mean ±SEM; PH: n = 10, control: n = 4. %Vmax = volume percentage of the ventricular volume at
maximal developed pressure.
PTIRVP>LVP was used to quantify the interventricular diastolic interaction in isolated hearts. It
measures the degree as well as the duration of reversed pressure differences across the interventricular septum (i.e. RV pressure > LV pressure) during a heartbeat, which is considered the
driving force that causes the septum to bulge into the left ventricle,2 impairing LV filling.10,11 This
parameter is especially sensitive (it decreases) for improvements in synchronic pressure generation across the septum (due to RV-pacing). PTIRVP>LVP expresses the pressure-time integral of the
trans-septal pressure gradient when RV pressure exceeds LV pressure, and was calculated by:
PTIRVP>LVP =, ∫ (RV pressure — LV pressure)dt when RV pressure – LV pressure > 0
1 beat
The onset of LV and RV contraction was defined as the time-point at which pressure rose to 5%
of developed pressure above diastolic pressure. The difference between the onset in RV and LV
contraction was used to identify presence of LV pre-excitation (Δtonset). LV pre-excitation refers
88
Louis BW.indd 88
06-05-10 11:21
to depolarization of the LV myocardium that is earlier than would occur by conduction of an impulse through the AV node (in this case LV depolarization triggered by artificial pacing of the RV
free wall), and is known to be detrimental for LV function in the long-term.23 This phenomenon
can be recognized from pressure recordings, when the difference in onset no longer changes at
larger AV-shortening intervals (see Figure 1, Figure 5D); in that case RV-pacing no longer solely
advances RV contraction, but prematurely activates the left ventricle as well.
The duration of RV and LV contraction was defined as the time-interval between 5% rise and
95% fall in developed pressure. Coronary perfusion was measured by average total coronary flow.
Statistical analysis
All data were verified for normal distribution, and values were expressed as mean±SEM, unless
stated otherwise. A p-value < 0.05 was considered significant. Group differences were analyzed
by unpaired Student T-test. Septum curvature, ventricular volume curves and pressure-volume
relationships were analyzed by two-way ANOVA for repeated measurements. Paired Student
T-test was performed to evaluate the effect of RV-pacing.
RESULTS
General characteristics of PH-rats vs. controls
In PH-rats, CMR revealed significantly smaller cardiac output, stroke volume, lower heart rate
and RV ejection fraction, and significantly larger RV end-diastolic volumes, compared to control
(Table 1). An upward shift in systolic and diastolic pressure-volume relationships for the right
ventricle in PH was observed; The pressure-volume relationships for the left ventricle were not
different between PH and control (Figure 2). These results indicate PH-induced RV remodeling
and RV dysfunction in monocrotaline-treated rats.
Chapter 5
(Table 1). Autopsy showed a significant increase in (wet) lung mass and RV / (LV+S) mass ratio
Septum bulging and PH-related ventricular dyssynchrony in vivo
In PH-rats, CMR revealed that the interventricular septum at the midventricular level was less
curved throughout the cardiac cycle, compared to controls (Figure 3A,B; average 1/R, PH: 0.50
±0.15 cm-1 vs. control: 2.07 ±0.05 cm-1, p < 0.001). In addition, solely in PH-hearts septum bulging was observed. At early LV diastole, the septum temporarily protruded into the left ventricle
(negative 1/R; Figure 3A,B). Furthermore, we found significantly smaller LV end-diastolic volumes and lower LV peak filling rates for PH (Table 1).
89
Louis BW.indd 89
06-05-10 11:21
RV-pacing
Table 1 General characteristics of PH-rats vs. controls
PH
control
(n = 6)
(n = 6)
p-value
CMR
Cardiac output (ml/min)
66 ±9
119 ±5
<0.001
0.14 ±0.02
0.25 ±0.01
<0.01
404 ±30
487 ±19
<0.05
35 ±2
66 ±3
<0.001
RV end-diastolic volume (ml)
0.47 ±0.02
0.35 ±0.02
<0.01
LV end-diastolic volume (ml)
0.18 ±0.02
0.36 ±0.02
<0.001
LV peak filling rate (ml/min)
0.25 ±0.02
0.41 ±0.05
<0.01
Lung mass (g)
2.14 ±0.12
1.06 ±0.09
<0.001
Heart mass (g)
1.38 ±0.04
1.21 ±0.04
<0.01
RV mass (g)
0.42 ±0.02
0.23 ±0.02
<0.001
RV / (LV + S)
0.65 ±0.03
0.30 ±0.03
<0.001
Liver (g)
11.7 ±0.4
10.3 ±0.2
<0.01
262 ±5
305 ±6
<0.001
37.6 ±0.0
37.6 ±0.0
n.s.
Stroke volume (ml)
Heart rate (bpm)
RV ejection fraction (%)
Autopsy
Body mass (g)
Tibia length (mm)
Data are presented as mean ±SEM. RV / (LV +S), RV over LV (including septum) mass ratio.
Reversed trans-septal pressure gradient and ventricular dyssynchrony in isolated
hearts
Pressure measurements revealed no differences in the onset between RV and LV contraction in
PH-hearts (onset delay RV-to-LV, PH: 5.1 ±0.6 ms vs. control: 5.5 ±0.4 ms, n.s.). This finding
was confirmed by the lack of a difference in electrical activation between right and left ventricle
(activation delay RV-to-LV, PH: 0.1 ±0.8 ms vs. control: 0.7 ±1.0 ms, n.s.). In contrast, we found a
prolonged duration of RV contraction in PH-hearts (Figure 3C; duration of RV contraction, PH:
197 ±3 ms vs. control: 168 ±4 ms, p < 0.001). As a consequence, only in PH-hearts RV pressures
were found to exceed LV pressures during late systole in the heart cycle, resulting in a temporary
reversal of the trans-septal pressure gradient (Figure 3D).
When comparing in vivo septum measurements (Figure 3B) with the pressure measurements
obtained in isolated hearts (Figure 3D), it was found that time of peak negative trans-septal
pressure gradient (t = 66 ±2 %RR-interval) coincided with the occurrence of maximal septum
bulging in PH (t = 64 ±2 %RR-interval).
In addition, we found that in PH-hearts, PTIRVP>LVP (an index of diastolic interaction) was RVvolume dependent, whereas this relationship was not observed in controls (Figure 4).
Effects of RV-pacing
The effects of RV-pacing in PH-remodeled hearts were studied at different AV-shortening intervals. The intrinsic AV-time at baseline (no pacing of the RV free wall) was 89 ±3 ms (AV-time,
control: 92 ±3 ms). At maximal RV dP/dtmax, AV-shortening was found to be 15 ±2 ms (p <
0.001), which was considered as the optimal pacing interval (Fig 5B). At this interval, there
90
Louis BW.indd 90
06-05-10 11:21
Figure 3
CMR (in vivo)
A
A
t = 0.0 * RR-interval
septum
t = 0.65* RR-interval
B
B
3.0
1/R (mm-1)
control
LV
R
RV
control
2.0
p<0.001
1.0
PH
0.0
-1.0
P
PH
0
50
75
100
septum
bulging
Langendorff (isolated heart)
D
D
LV
100
LV
50
RV
RV
0
50
100
time (%RR-interval)
0
50
100
time (%RR-interval)
100
50
control
0
p<0 001
p<0.001
PH
reversal trans-septal
pressure gradient
-50
0
25
50
75
time (%RR-interval)
100
PH-related ventricular dyssynchrony in monocrotaline-treated rats. A) Examples of short-axis CMR-images at the
midventricular level of control- and PH-hearts at time points t = 0, and t = 65 %RR-interval. Epi- and endocardial borders
are indicated by the thin lines. The interventricular septum is highlighted by the dotted line. Crosses indicate anterior,
middle and posterior positions of the interventricular septum that were used to calculate septum curvature (1/R). B)
Septum curvature was less pronounced in PH vs. control throughout the heart cycle, and septum bulging (negative 1/R,
arrow) was observed in all PH-hearts (mean ±SEM, both groups: n = 6). C) Examples of LV and RV pressure recordings
in isolated Langendorff–perfused hearts of control and PH, used to construct the trans-septal pressure gradient. D) In
PH, RV contraction is prolonged and as a consequence RV pressure exceeds LV pressure at early LV diastole, causing a
momentary reversal of the trans-septal pressure gradient (arrow). No reversal was observed in control hearts
Data are presented as mean ±SEM, PH: n = 10, control: n = 4.
Chapter 5
PH
control
sure (mmHg)
 Press
C
C
Pressu
ure (mmHg)
25
time (%RR-interval)
(%
)
2.0 mm
0
septum bulging
was no evidence for LV pre-excitation (Figure 5D), as LV pre-excitation only occurred at longer
AV-shortening intervals (AV-shortening at the transition point to LV pre-excitation: 32 ±2 ms; p
< 0.001 vs. optimal pacing interval).
Compared to baseline, pacing at optimal interval improved RV systolic function in all experiments; RV dP/dtmax (baseline PH: 1.75 ±0.04 *103 mmHg/s, control: 0.88 ±0.08 *103 mmHg/s)
increased by 8.5 ±1.3 % (p < 0.001; Figure 6A), and peak RV systolic pressure increased by 2.7
±0.6 % (p < 0.01; Figure 6B). Pacing also decreased the time-difference between RV and LV
peak-pressure (Δtpeak, PH baseline: 9.8 ±1.2 ms vs. paced: 1.7 ±2.0 ms, p < 0.001; Δtpeak control:
-3.5 ±0.6 ms; Figure 6C). In addition, RV-pacing positively influenced the diastolic interaction,
as PTIRVP>LVP decreased by 24 ±9 % (p < 0.01; Figure 6D). Furthermore, RV-pacing shortened
91
Louis BW.indd 91
06-05-10 11:21
RV-pacing
Figure 4
A
B
Relationship between RV volume and interventricular diastolic interaction in PH. A) Examples of LV and RV pressure
measurements in a PH-heart for different RV volume settings: RV70, RV95 = RV pressure curves at 70 or 95 %Vmax (thick
red lines; thin red lines represent RV pressure curves at intermediate RV volume settings). LV pressure was minimally
affected, and for the sake of clarity only one LV pressure curve is shown. B) Only in isolated PH-hearts, interventricular
dyssynchrony (quantified by PTIRVP>LVP; gray area) increased with increasing RV volume.
Data are presented as mean ±SEM, PH: n = 10, control: n = 4. Abbbreviations: PTIRVP>LVP, pressure-time integral, when RV
pressure exceeds LV pressure.
Figure 5
A
B
C
D
Determining the optimal RV-pacing setting. A) Example of a RV pressure curve at baseline (dashed line) and when
optimally paced (solid line). For every experiment, the same series of AV-shortening were tested. Notice that pacing
implies earlier start of RV contraction. B) RV dP/dtmax as function of AV-shortening. Optimal pacing interval was defined
when RV dP/dtmax was highest. Notice the initial rise in RV dP/dtmax at short AV-shortening intervals and the subsequent
fall at longer AV-shortening intervals. C) Diastolic interaction (PTIRVP>LVP) decreased precipitously with AV-shortening.
Optimal RV dP/dtmax was found at relatively low values of AV-shortening. D) Difference in onset of RV vs. LV contraction
(∆tonset) as function of AV-shortening (overall, ∆tonset at LV-pre-excitation was -6.3 ±1.2 ms, ranging from -0.5 to -13.0 ms).
LV pre-excitation only occurred at higher AV-shortening interval than when optimally paced.
92
Louis BW.indd 92
06-05-10 11:21
the duration of RV as well as LV contraction (RV duration at baseline: 197 ±2 ms, change in RV
duration after pacing: -1.0 ±0.4 %, p < 0.05; LV duration at baseline: 191 ±2 ms, after pacing: -1.3
±0.3 %, p < 0.001).
No significant effects of RV-pacing were observed on RV diastolic function (RV DP, baseline:
8.5 ±1.2 mmHg, paced 0.9 ±1.2 %; RV dP/dtmin, baseline: -819 ±28 mmHg/s, paced: -2.0 ±2.2 %;
both n.s.). Also, no effects of RV-pacing were observed, either on LV function (LV SP, baseline: 95
±2.2 mmHg, paced: 0.2 ±0.3 %; LV DP, baseline: 2.4 ±0.4 mmHg, paced: -3.2 ±2.6 %; both n.s.),
or on coronary perfusion (mean Qcor, baseline: 15 ±1 ml/min, paced: 0.3 ±0.3 %; n.s.).
The minimal rundown of the functional properties (decline in developed pressure: < 5%/hr,
increase in diastolic pressure: < 5%/hr), during our short-lasting experiment ( < 30 min), suggest
minimal effect of edema formation.
Figure 6
B
C
D
Chapter 5
A
RV-pacing improved RV function and reduced interventricular diastolic interaction. A,B) At optimal pacing interval, RVpacing significantly improved RV dP/dtmax and RV systolic pressure (RV SP), compared to baseline, and (partially) restored
intra-ventricular synchrony. C) RV-pacing significantly reduced the time-difference between RV and LV peak (∆tpeak), and
restored inter-ventricular synchrony. D) RV-pacing markedly decreased PTIRVP>LVP, an index of adverse diastolic interaction.
Data are shown as mean ±SEM (aside) and as paired individual observations (center)
N = 10 (all PH). Baseline, paced: before pacing, and when optimally RV-paced (AV-shortening = 15 ±2 ms).
DISCUSSION
After validation of the monocrotaline-rat model for PH-related ventricular dyssynchrony, we
demonstrated that in chronic PH:
93
Louis BW.indd 93
06-05-10 11:21
RV-pacing
1) RV-pacing improved RV systolic function, characterized by enhanced RV dP/dtmax and peak
RV systolic pressure.
2) RV-pacing diminished adverse interventricular diastolic interaction, by resynchronizing
time between RV and LV peak-pressure (Δtpeak), and reducing PTIRVP>LVP.
In addition, RV-pacing slightly shortened the duration of RV as well as LV contraction; No
(detrimental) effects on LV function or coronary perfusion were observed, and there was no
evidence for LV pre-excitation.
By providing this proof-of-principle, the findings may give support for the potential role of RVpacing as a novel treatment for PH-induced right heart failure.
Validation of the monocrotaline rat model for ventricular dyssynchrony
The monocrotaline rat model is a well-established model for chronic PH in general,25 but so far
this model has not specifically been validated for PH-related ventricular dyssynchrony. Therefore, we first investigated whether signs of ventricular dyssynchrony were present in vivo.
We used sophisticated CMR-techniques to accurately quantify septum curvature and LV and
RV function in the monocrotaline rat model. CMR offers superior imaging quality and allows
generation of cross-sectional images in virtually any plane, both of major advantage, especially
when visualizing septum bulging.26 Our CMR measurements confirmed the pulmonary hypertensive state of the monocrotaline-treated rats, with clear signs of right heart failure. Moreover,
CMR demonstrated the presence of septum bulging, low LV end-diastolic volumes and low LV
peak filling rates, comparable to the clinical situation.4,6 As observed in clinical PH, ventricular
dyssynchrony in monocrotaline-induced PH was explained by regional differences in duration,
rather than in onset of contraction (as measured by ECG and pressure recordings). Prolonged RV
contractions and reversal of trans-septal pressure gradients in our PH-model were demonstrated
by biventricular pressure measurements in isolated Langendorff-perfused heart preparations,
which is in line with what was previously shown by Boissiere et al.27 It is important to note that
the expected coincidence in time of septum bulging and peak reversed trans-septal pressure
gradient (RV pressure exceeds LV pressure; Figure 3) was also found in the isolated hearts.
These observations demonstrate that the monocrotaline rat model is an appropriate model to
study PH-related ventricular dyssynchrony, and in addition, that ventricular dyssynchrony can
be studied in detail in a Langendorff-setup with balloons in both ventricles. This approach has
major advantages. It allows relatively easy manipulation with a high degree of preparation stability. Furthermore, it allows derivation of robust functional data with cardiac-specific parameters.
Finally, in the Langendorff-setup LV and RV load can be varied independently, by changing
ventricular volumes, which enabled us to reveal the relationship between ventricular dyssynchrony and RV load.
94
Louis BW.indd 94
06-05-10 11:21
Beneficial effects of RV-pacing
To the best of our knowledge, our study is the first that explored the effects of RV-pacing on
intra- and inter-ventricular dyssynchrony in chronic PH. We found a modest, but highly significant improvement in RV systolic function. Moreover, we observed an important reduction
in interventricular diastolic interaction, without detrimental effects on LV function or coronary
perfusion. At the optimal RV-pacing interval, there was no evidence for LV pre-excitation, which
is known to be detrimental for LV function at the long-term.23
The early activation of the RV free wall probably compensated for the longer RV contraction
period and therefore the delay in time-to-peak-shortening of the RV free wall relative to the
interventricular septum and LV free wall.6,27 Pacing helped to restore synchrony of the left and
right ventricle, and as a result RV systolic function improved. The time of activation is critical: if
the RV free wall is activated too early synchrony is lost again, which explains the initial rise and
then fall in RV dP/dtmax with increasing AV-shortening (Figure 5B).
Another beneficial effect of pacing was the reduction in interventricular diastolic interaction,
expressed by PTIRVP>LVP. Pacing-induced earlier activation of the RV free wall and the shortened
RV contraction resulted in an earlier start of RV relaxation. The partially restored synchrony
in the relaxation of both ventricles explains the observed reduction of the PTIRVP>LVP. Although
isovolumic pressure measurements in our Langendorff-setup cannot directly provide this information, a marked decrease in PTIRVP>LVP together with a shortened duration of LV contraction
would predict less septum bulging and improvement in early LV filling.10,11
Recently, Quinn et al. also reported positive effects of pacing in a different model of RV pressure
overload.28 However, their findings are only partially applicable to the PH-patient group, because
damaged by ethanol injection. A few clinical studies have explored the effect of RV-pacing on
RV dysfunction secondary to congenital heart disease (studies on systemic right ventricles are
not discussed here).29,30 These studies aimed to restore RV electromechanical dyssynchrony
related to a complete right bundle branch block, a late complication of surgical repair. However
Chapter 5
they applied an acute pressure overload in a pig-model with the conductance system artificially
as mentioned earlier, ventricular dyssynchrony in PH is based on prolonged contraction, rather
than disturbances in the electrical conductance system.6
Limitations – the isolated heart vs. in vivo
This study supports the potential role of RV-pacing for the treatment of PH-related ventricular
dyssynchrony and right heart failure. However the results cannot be translated directly to the in
vivo situation yet; Future studies in a large animal model or (acute) RV-pacing experiments in
PH-patients are necessary.
In the Langendorff preparation the mediating role of RV afterload remains unknown, which
limits the prediction of the effects of RV-pacing and improved RV contractility on stroke volume
and cardiac output. Nonetheless, related studies reported an improvement of cardiac output after
RV-pacing to the same extent as the improvement in RV contractility.28,30 RV-pacing could also
95
Louis BW.indd 95
06-05-10 11:21
RV-pacing
potentially worsen tricuspid regurgitation through elevation of RV systolic pressures. On the
other hand, it was recently shown that resynchronization therapy in left heart failure actually
reduced pre-existing mitral regurgitation.31
Another important issue is the role of the pericardium. In our isolated Langendorff-perfused
hearts, the pericardium was removed, which is known to reduce the interventricular diastolic
interaction in the case of RV pressure overload.32 This might explain why we did not observe
a significant reduction in LV diastolic pressures / LV filling pressures by RV-pacing (that were
already low at baseline) in our isolated heart preparations.33 The effects of RV-pacing will probably be more pronounced in vivo with the pericardium intact.
Crystalloid based Langendorff-perfused hearts are prone to edema formation, which could
affect diastolic properties. However, with a coronary perfusion pressure of 80 mmHg, this
was reduced to a minimum.20,21 In addition, edema formation was found to have only limited
functional effects during our experiments, as we observed a minimal rundown of the functional
properties during our short-lasting experiments and, we were also able to detect clear differences
in diastolic properties between control and PH-heart.
We found longer PR-intervals than are reported for (PH-)rats in vivo (~90 vs. ~60 ms).34
However, no differences were observed between PR-intervals of isolated PH- and control hearts.
We therefore conclude that the prolonged PR-interval, compared to the in vivo situation, is
most likely to be attributed to the Langendorff set-up in general and unlikely to be related to
differences in cardiac condition between PH-hearts and controls. Furthermore, the apparently
prolonged PR-interval is of little relevance for the interpretation of our finding, as the intervention studied involves ventricular activation, which follows after the PR-interval.
As a last point, clinical effective medical therapies, such as epoprostenol, are known to have
a relatively small impact on hemodynamic measures, which nonetheless translate to improved
survival.35 Therefore, the small acute improvements in RV function found here, may in the longterm translate into substantial benefit.
Conclusions
In our experimental PH-model, RV-pacing improved cardiac performance through alleviation of
PH-related ventricular dyssynchrony. The promising results of this study identify RV-pacing as a
potential novel treatment for right heart failure in PH, and provide a strong rationale for future
investigations evaluating the effects of RV-pacing in vivo.
ACKNOWLEDGEMENT
We would like to thank T. Kind and I. Schalij (Pulmonology, VU University Medical Center) for
their assistance.
96
Louis BW.indd 96
06-05-10 11:21
Sources of funding
This work was supported by the Netherlands Organization for Scientific Research (NWO), The
Hague, The Netherlands (M.L.Handoko, A.Vonk-Noordegraaf).
Disclosures
None
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
Kingma I, Tyberg JV, Smith ER. Effects of diastolic transseptal pressure gradient on ventricular septal
position and motion. Circulation 1983;68:1304-1314.
Roeleveld RJ, Marcus JT, Faes TJ, Gan TJ, Boonstra A, Postmus PE, Vonk-Noordegraaf A. Interventricular septal configuration at MR imaging and pulmonary arterial pressure in pulmonary hypertension. Radiology 2005;234:710-717.
Tanaka H, Tei C, Nakao S, Tahara M, Sakurai S, Kashima T, Kanehisa T. Diastolic bulging of the
interventricular septum toward the left ventricle. An echocardiographic manifestation of negative
interventricular pressure gradient between left and right ventricles during diastole. Circulation
1980;62:558-563.
Beyar R. Heart inefficiency in pulmonary hypertension: a double jeopardy. J Am Coll Cardiol
2008;51:758-759.
Dohi K, Onishi K, Gorcsan J, III, Lopez-Candales A, Takamura T, Ota S, Yamada N, Ito M. Role of
radial strain and displacement imaging to quantify wall motion dyssynchrony in patients with left
ventricular mechanical dyssynchrony and chronic right ventricular pressure overload. Am J Cardiol
2008;101:1206-1212.
Marcus JT, Gan CT, Zwanenburg JJ, Boonstra A, Allaart CP, Gotte MJ, Vonk-Noordegraaf A. Interventricular mechanical asynchrony in pulmonary arterial hypertension: left-to-right delay in peak
shortening is related to right ventricular overload and left ventricular underfilling. J Am Coll Cardiol
2008;51:750-757.
Gillebert TC, Sys SU, Brutsaert DL. Influence of loading patterns on peak length-tension relation and
on relaxation in cardiac muscle. J Am Coll Cardiol 1989;13:483-490.
Lopez-Candales A, Dohi K, Rajagopalan N, Suffoletto M, Murali S, Gorcsan J, Edelman K. Right
ventricular dyssynchrony in patients with pulmonary hypertension is associated with disease severity
and functional class. Cardiovasc Ultrasound 2005;3:23.
Kalogeropoulos AP, Georgiopoulou VV, Howell S, Pernetz MA, Fisher MR, Lerakis S, Martin RP.
Evaluation of right intraventricular dyssynchrony by two-dimensional strain echocardiography in
patients with pulmonary arterial hypertension. J Am Soc Echocardiogr 2008;21:1028-1034.
Gan CT, Lankhaar JW, Marcus JT, Westerhof N, Marques KM, Bronzwaer JG, Boonstra A, Postmus
PE, Vonk-Noordegraaf A. Impaired left ventricular filling due to right-to-left ventricular interaction
in patients with pulmonary arterial hypertension. Am J Physiol Heart Circ Physiol 2006;290:H1528H1533.
Stojnic BB, Brecker SJ, Xiao HB, Helmy SM, Mbaissouroum M, Gibson DG. Left ventricular filling characteristics in pulmonary hypertension: a new mode of ventricular interaction. Br Heart J
1992;68:16-20.
Chapter 5
REFERENCES
97
Louis BW.indd 97
06-05-10 11:21
RV-pacing
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
Voelkel NF, Quaife RA, Leinwand LA, Barst RJ, McGoon MD, Meldrum DR, Dupuis J, Long CS,
Rubin LJ, Smart FW, Suzuki YJ, Gladwin M, Denholm EM, Gail DB. Right ventricular function
and failure: report of a National Heart, Lung, and Blood Institute working group on cellular and
molecular mechanisms of right heart failure. Circulation 2006;114:1883-1891.
McAlister FA, Ezekowitz J, Hooton N, Vandermeer B, Spooner C, Dryden DM, Page RL, Hlatky MA,
Rowe BH. Cardiac resynchronization therapy for patients with left ventricular systolic dysfunction: a
systematic review. JAMA 2007;297:2502-2514.
Lamberts RR, Vaessen RJ, Westerhof N, Stienen GJ. Right ventricular hypertrophy causes impairment of left ventricular diastolic function in the rat. Basic Res Cardiol 2007;102:19-27.
Buermans HP, Redout EM, Schiel AE, Musters RJ, Zuidwijk M, Eijk PP, van Hardeveld C, Kasanmoentalib S, Visser FC, Ylstra B, Simonides WS. Microarray analysis reveals pivotal divergent mRNA
expression profiles early in the development of either compensated ventricular hypertrophy or heart
failure. Physiol Genomics 2005;21:314-323.
Handoko ML, Schalij I, Kramer K, Sebkhi A, Postmus PE, van der Laarse WJ, Paulus WJ, VonkNoordegraaf A. A refined radio-telemetry technique to monitor right ventricle or pulmonary artery
pressures in rats: a useful tool in pulmonary hypertension research. Pflugers Arch 2008;455:951-959.
Schneider JE, Lanz T, Barnes H, Medway D, Stork LA, Lygate CA, Smart S, Griswold MA, Neubauer
S. Ultra-fast and accurate assessment of cardiac function in rats using accelerated MRI at 9.4 Tesla.
Magn Reson Med 2008;59:636-641.
Heiberg E, Wigström L, Carlsson M, Bolger AF, Karlsson M. Time Resolved Three-dimensional
Automated Segmentation of the Left Ventricle. Proc IEEE Comput Cardiol 2005;32:599-602.
Gan CT, Holverda S, Marcus JT, Paulus WJ, Marques KM, Bronzwaer JG, Twisk JW, Boonstra A,
Postmus PE, Vonk-Noordegraaf A. Right ventricular diastolic dysfunction and the acute effects of
sildenafil in pulmonary hypertension patients. Chest 2007;132:11-17.
Skrzypiec-Spring M, Grotthus B, Szelag A, Schulz R. Isolated heart perfusion according to Langendorff---still viable in the new millennium. J Pharmacol Toxicol Methods 2007;55:113-126.
Sutherland FJ, Hearse DJ. The isolated blood and perfusion fluid perfused heart. Pharmacol Res
2000;41:613-627.
Sys SU, De Keulenaer GW, Brutsaert DL. Physiopharmacological evaluation of myocardial performance: how to study modulation by cardiac endothelium and related humoral factors? Cardiovasc
Res 1998;39:136-147.
Sweeney MO, Prinzen FW. A new paradigm for physiologic ventricular pacing. J Am Coll Cardiol
2006;47:282-288.
Ghio S, Constantin C, Klersy C, Serio A, Fontana A, Campana C, Tavazzi L. Interventricular and
intraventricular dyssynchrony are common in heart failure patients, regardless of QRS duration. Eur
Heart J 2004;25:571-578.
Wilson DW, Segall HJ, Pan LC, Lame MW, Estep JE, Morin D. Mechanisms and pathology of monocrotaline pulmonary toxicity. Crit Rev Toxicol 1992;22:307-325.
Benza R, Biederman R, Murali S, Gupta H. Role of cardiac magnetic resonance imaging in the management of patients with pulmonary arterial hypertension. J Am Coll Cardiol 2008;52:1683-1692.
Boissiere J, Gautier M, Machet MC, Hanton G, Bonnet P, Eder V. Doppler tissue imaging in assessment of pulmonary hypertension-induced right ventricle dysfunction. Am J Physiol Heart Circ
Physiol 2005;289:H2450-H2455.
Quinn TA, Berberian G, Cabreriza SE, Maskin LJ, Weinberg AD, Holmes JW, Spotnitz HM. Effects of
sequential biventricular pacing during acute right ventricular pressure overload. Am J Physiol Heart
Circ Physiol 2006;291:H2380-H2387.
98
Louis BW.indd 98
06-05-10 11:21
29.
30.
31.
32.
33.
34.
Chapter 5
35.
Bordachar P, Iriart X, Chabaneix J, Sacher F, Lafitte S, Jais P, Haissaguerre M, Clementy J, Dos SP, Thambo JB. Presence of ventricular dyssynchrony and haemodynamic impact of right ventricular pacing
in adults with repaired Tetralogy of Fallot and right bundle branch block. Europace 2008;10:967-971.
Dubin AM, Feinstein JA, Reddy VM, Hanley FL, Van Hare GF, Rosenthal DN. Electrical resynchronization: a novel therapy for the failing right ventricle. Circulation 2003;107:2287-2289.
Ypenburg C, Lancellotti P, Tops LF, Boersma E, Bleeker GB, Holman ER, Thomas JD, Schalij MJ,
Pierard LA, Bax JJ. Mechanism of improvement in mitral regurgitation after cardiac resynchronization therapy. Eur Heart J 2008;29:757-765.
Beyar R, Dong SJ, Smith ER, Belenkie I, Tyberg JV. Ventricular interaction and septal deformation: a
model compared with experimental data. Am J Physiol 1993;265:H2044-H2056.
Bleasdale RA, Turner MS, Mumford CE, Steendijk P, Paul V, Tyberg JV, Morris-Thurgood JA, Frenneaux MP. Left ventricular pacing minimizes diastolic ventricular interaction, allowing improved
preload-dependent systolic performance. Circulation 2004;%19;110:2395-2400.
Henkens IR, Mouchaers KT, Vliegen HW, van der Laarse WJ, Swenne CA, Maan AC, Draisma HH,
Schalij I, van der Wall EE, Schalij MJ, Vonk-Noordegraaf A. Early changes in rat hearts with developing pulmonary arterial hypertension can be detected with three-dimensional electrocardiography.
Am J Physiol Heart Circ Physiol 2007;293:H1300-H1307.
Barst RJ, Rubin LJ, Long WA, McGoon MD, Rich S, Badesch DB, Groves BM, Tapson VF, Bourge
RC, Brundage BH, Koerner SK, Langleben D, Keller CA, Murali S, Uretsky BF, Clayton LM, Jöbsis
MM, Blackburn SD, Jr., Shortino D, Crow JW. A comparison of continuous intravenous epoprostenol
(prostacyclin) with conventional therapy for primary pulmonary hypertension. The Primary Pulmonary Hypertension Study Group. N Engl J Med 1996;334:296-302.
99
Louis BW.indd 99
06-05-10 11:21
Louis BW.indd 100
06-05-10 11:21
6
General Discussion
Perspectives on Novel
Therapeutic Strategies
for Right Heart Failure
in Pulmonary Arterial
Hypertension:
Lessons from the Left
Heart
M.L. Handoko1,2, F.S. de Man2, C.P. Allaart3, W.J.
Paulus1, N. Westerhof1,2, A. Vonk-Noordegraaf1,2
Departments of 1Physiology, 2Pulmonology and
3
Cardiology, VU University Medical Center / Institute
for Cardiovascular Research, Amsterdam, the
Netherlands
Eur Respir Rev 2010; 19: 72-82 (with editorial
comment)
Louis BW.indd 101
06-05-10 11:21
General discussion
ABSTRACT
Right heart function is the main determinant of prognosis in pulmonary arterial hypertension
(PH). Yet, no treatments are currently available that directly target the right ventricle, as we
demonstrate in this perspective; Meta-analysis of clinical trials in PH revealed that current PHmedication seems to have limited cardiac-specific effects, when analyzed by the pump-function
graph. Driven by the hypothesis that “left” and right heart failure might share important underlying pathophysiological mechanisms, we evaluated the clinical potential of left heart failure (LHF)
therapies for PH, based on currently available literature.
Like in LHF, the sympathetic nervous system and the renin-angiotension-aldosterone system
are highly activated in PH. From LHF we know that intervening in this process - by e.g. ACE
inhibition or beta-blockade - is beneficial in the long run. Therefore, these medications could
be also beneficial in PH. Furthermore, the incidence of sudden cardiac death in PH could be
reduced by implantable cardioverter-defibrillators. Finally, pilot studies have demonstrated that
interventricular dyssynchrony, present at end-stage PH, responded favorably to cardiac resynchronization therapy as well.
To conclude, therapies for LHF might be relevant for PH. However before they can be implemented in PH-management, safety and efficacy should be evaluated first, in well-designed clinical trials.
102
Louis BW.indd 102
06-05-10 11:21
INTRODUCTION
Pulmonary arterial hypertension (PH) is characterized by excessive pulmonary vascular remodeling, resulting in a marked increase in right ventricular (RV) afterload. The thin-walled,
crescent-shaped right ventricle in the normal situation needs to remodel to a thick-walled, more
spherical-shaped high-pressure pump, to overcome the often four-fold (!) increase in pressure
in the case of PH. Eventually, the right ventricle is not able to cope with the increase in load and
right heart failure develops.1,2 Despite the successful introduction of several new pulmonaryselective vasodilating therapies in the last decade, the prognosis of PH-patients remains poor.3,4
The relationship between RV afterload (mainly determined by pulmonary vascular resistance or
PVR, and pulmonary arterial compliance5) and RV dysfunction is not straightforward. Patients
with systemic sclerosis associated PH (relatively low load / low pressure) have a worse prognosis,
compared to patients with idiopathic PH, whereas patients with PH associated with congenital
heart disease (high load / high pressure) have a relative good prognosis.6 Also in PH, mean
pulmonary artery pressure (mPAP) and PVR are of limited prognostic value, while the strongest
predictors of survival are reflections of RV (mal)adaptation to its increased load (cardiac index,
right atrial pressure, tricuspid annular plane systolic excursion or TAPSE, NT-proBNP plasma
levels; Figure 1).7-9 Thus, it is not the load per se, but the failing right ventricle itself that leads to
death.
Current PH-medication (prostacyclines, endothelin receptor blockers, PDE-5 inhibitors,
calcium-antagonists) focuses on controlling the excessive vascular remodeling typical for PH,
resulting in a reduction in RV load.10 Their cardiac-specific effects on RV adaptation and remodeling have hardly been studied yet, but they are most likely of limited clinical relevance, as we
will demonstrate later (see ‘Cardiac effects of current PH-medication’). Therefore, there is still
unexploited potential for therapies that directly target the right ventricle.11
In left heart failure (LHF), it is well accepted that the process of cardiac remodeling itself,
regardless the initial cardiac event, is - although compensatory at first - detrimental in the long
run.12 There is now convincing evidence that intervening in the process of remodeling imporremodeling observed in PH-patients, shares important pathophysiological mechanisms with
the cardiac remodeling observed in LHF-patients. This implies that the adverse RV remodeling
could possibly be treated with the same well-established therapies for LHF.
To get better insight into the processes involved, it is essential to clinically distinguish cardiac-
Chapter 6
tantly reduces morbidity and mortality in patients with LHF.13,14 We hypothesize that the RV
specific effects of treatment from their effects on load (pulmonary vasodilation), which also indirectly affect the heart. In the first part of this review, we therefore discuss how this separation of
effects can be studied, and we will evaluate the cardiac-specific effects of current PH-treatments.
In the second part of the review, we explore the potential relevance of current evidence-based
LHF-therapy (Table 1) for right heart failure secondary to PH.
103
Louis BW.indd 103
06-05-10 11:21
General discussion
Figure 1
normal
fully compensated
decompensating
“concentric”
failing heart
“eccentric” RV hypertrophy
(specific RV-therapy)
relative
change
mPAP
(ssc-PAH)
RAP
reference
CI
progression of PAH
PVR
Hemodynamic changes during the progression of pulmonary arterial hypertension (PAH). The continuous rise in
pulmonary vascular resistance (PVR) during the progression of the disease is initially compensated by concentric
remodeling of the right ventricle; right atrial pressure (RAP) remains at normal levels, and there is a steep increase in
mean pulmonary artery pressure (mPAP) as cardiac index at rest (CI) is preserved. In the next stage, the right ventricle
is not able to fully compensate for the further increase of PVR, it starts to decompensate and eccentric RV remodeling
is observed; there is a modest rise in mPAP as CI is starting to fall as well, at this stage RAP remain at near-normal levels.
In the final stage of overt right heart failure, there is a severe drop in CI, a steep rise in RAP, and even though PVR still
increases, mPAP drops because of the low-output state.
Changes in RV function very well fits to the different disease stages in PAH, and explain the prognostic importance of CI
and RAP over mPAP. In systemic sclerosis associated (ssc-) PAH, the ability for the right ventricle to adapt to the increasing
PVR seems to be limited, and therefore the heart fails at lower PVR.26 The aim of specific RV-therapies is to improve the
ability of the heart to adapt to its afterload.
Table 1 Summary of current left (systolic) heart failure therapy*, data taken from 13,14
1. Treat underlying cause when possible (e.g. coronary artery disease, arterial hypertension)
2. General measurements (self-care management, avoid drugs that adversely affect the clinical status whenever possible)
3. Diuretics (and moderate salt restriction)
4. Beta-blockers (initiated in very low doses, followed by gradual increment)
5. Angiotension-converting enzyme inhibitors (or angiotensin II receptor blockers, if intolerant for ACE inhibitors)
6. Aldosterone antagonists (only when renal function is preserved and closely monitored)
7. Exercise training (adjunct to optimal medical therapy)
8. Implantable cardioverter-defibrillator (patients at high-risk for life-threatening arrhythmic disorders)
9. Cardiac resynchronization therapy (symptomatic heart failure patients despite optimal medical treatment, with signs of
cardiac dyssynchrony)
(10.) Digoxin, hydrazaline / nitrate, LV assist devices, heart transplantation
* Therapies marked in bold are not standard in current PAH-management
104
Louis BW.indd 104
06-05-10 11:21
How can we distinguish the cardiac-specific effects of PH-therapy from the
pulmonary vasodilating effects in patients?
The right ventricle and the pulmonary vascular bed are functionally coupled.1,2 As a consequence,
it is difficult to distinguish cardiac-specific from pulmonary-specific effects of an intervention
with the use of standard diagnostic tools (i.e. right heart catheterization, echocardiography).
For example, bosentan treatment has been shown to partially restore cardiac dimensions and
function (compared to placebo, bosentan-treatment improved cardiac output: 0.4 L/min/m2, p <
0.01; and RV:LV diastolic area ratio: -0.64, p < 0.01),15 but these effects are most likely the result
of the decrease in RV load (difference in PVR reduction, bosentan-treatment vs. placebo: -415
±99 dyn.s.cm-5, p < 0.001),16 and are therefore not cardiac-specific. Similar observations have
been reported for epoprostenol, sildenafil, and after successful pulmonary endarterectomy or
lung transplantation.
In an experimental setting, this problem can be circumvented by using models with a fixed
RV afterload (e.g. pulmonary arterial banding). Herein, we describe two methods that are also
applicable in a clinical setting.
Pressure-volume relationship
It is well accepted that from combined ventricular pressure and volume measurements, parameters of cardiac function and contractility can be derived that are independent of the arterial
load. An example of a load-independent parameter of systolic function is the end systolic elastance (‘Ees’ or ‘Emax’), which is measured by the slope of the fitted line connecting end-systolic
pressure volume points (Figure 2B); Also, load-independent parameters of diastolic function
can be derived.17,18 This method has been used successfully in describing LV performance in
multiple disease conditions,19 and more recently its use has been validated in PH-patients for
the right ventricle as well.20 The construction of PV-loops requires simultaneous measurements
of instantaneous pressure- and volume-signals (Figure 2A,B), which can only be obtained using
specialized equipment (e.g. conductance catheters). Moreover, to accurately determine Ees, it is
necessary to vary cardiac load (usually by a temporary partial occlusion the inferior vena cava),
tients. Fortunately, mathematical techniques (e.g. ‘single-beat estimation’) have been developed
that allow reasonable estimation of Ees and only requires a high-quality RV pressure curve and
a reliable stroke volume measurement during steady-state.21,22 Recent studies that compared the
separate cardiac and pulmonary effects of norepinephrine, dobutamine and levosimendan in an
Chapter 6
which might be unacceptable in patients that are hemodynamically compromised, like PH-pa-
experimental model for right heart failure, are examples of the usefulness of pressure-volume
relation (including single-beat estimation).23,24
Pump-function graph
An interesting alternative for studying cardiac-specific vs. pulmonary-specific effects is the
pump-function graphs.18,25 A major advantage of this method is that only instantaneous pres105
Louis BW.indd 105
06-05-10 11:21
General discussion
sure and average flow measurements suffice, and that its analysis does not require instantaneous
volume-signals. Average RV pressure is plotted against stroke volume (the ‘working point’),
and using the same single-beat estimation as discussed above, a pump-function graph can be
_
constructed (Figure 2C,D). An increase in ‘P iso’ while ‘SVmax’ remains unchanged (abbreviations:
see legend Figure 2), indicates improved cardiac contractility: in this case the new working point
moves to the upper right (Figure 2C). A change in cardiac load has a different effect: when load
decreases by pulmonary vasodilation (and cardiac contractility remains unchanged) the working point moves to the lower right (Figure 2D). With the use of the pump-function graph, we
Figure 2
B
B
Piso
Ventricular pressure
Sine wave fit
A
A
Piso
PAP
PRV
Pes
SV
Volume
D
D
Piso
Mean pressure
Mean pressure
C
C
Ees
1
P
SV
Piso
P
SVmax
Increase in Contractility (1):
SV & Pressure
2
SV
SVmax
Decrease in PVR (2):
SV & Pressure
Distinguishing cardiac- from pulmonary-specific effects in PAH-patients. A) Pressure curves of the right ventricle and
the main pulmonary artery are shown; by sine wave fit, maximal isovolumic pressure is estimated (Piso).22 B) Pressurevolume loops can be constructed from instantaneous pressure (y-axis) and volume (x-axis) measurements by use of e.g.
conductance catheters. End-systolic elastance (Ees) is considered a load-independent measure of RV contractility and is
measured from the slope of the connecting line between end-systolic pressure (Pes) and Piso.21
C,D) An alternative approach for describing heart function is the pump-function graph.25 Here, average RV
_ pressure vs.
stroke volume at steady-state are plotted (the ‘working point’) and by the same single-beat estimation (P iso) , a pumpfunction graph is constructed (black curved line). The slope of the line from the origin through the working point is a
measure for pulmonary vascular resistance divided by heart period (PVR/T) and therefore a measure
for RV afterload.
_
When RV contractility increases (2C), this is observed in the pump-function graph by increased P iso while SVmax remains
unchanged; the new working point has moves to the upper right (‘1’). When RV afterload is reduced (PVR/T decreases;
2D), the pump-function graph remains unchanged, while the new working point moves to the lower right (‘2’).
106
Louis BW.indd 106
06-05-10 11:21
recently demonstrated lower cardiac contractility in systemic sclerosis associated PH compared
to idiopathic PH, that could well explain their worse prognosis despite lower PVR.26
When studying chronic (as opposed to acute) effects of an intervention, both methods (PVloops or pump-function graph) may be insufficient due to RV remodeling. However, they can be
further refined, by incorporating measures of RV remodeling (RV wall thickness; RV diameter)
in the analysis, in which case RV wall stress (σ; estimated by Laplace’s law) is used instead of
RV pressure.18 We conclude that by an integral approach, it is well-possible to distinguish the
cardiac-specific from the pulmonary-specific effects of an intervention in PH-patients.18
Perspective – Often, it is very difficult in patients to distinguish the cardiac- from the pulmonary-specific effects of PH-therapy. For this purpose, the pressure-volume relation and
the pump-function graph have been developed. We propose the use of the pump-function
graph over the pressure-volume relation, as it is more easily obtained in patients, using
routine RV catheterization.
Cardiac effects of current PH-medication
The cardiac-specific effects of current PH-therapies, in contrast to their pulmonary vasodilating
effects, have only been studied in a small number of papers. The few relevant experimental studies are discussed first.
Experimental studies
Zierer et al. investigated the effects of diltiazem (a calcium-channel blocker) on RV function in
a chronic model of RV pressure overload, using pressure-volume analysis. Administration of
diltiazem during constant RV afterload acutely depressed cardiac output, and this was mainly
related to depressed right atrial function and RV filling.27 Kerbaul et al. investigated the effects of
prostacyclines in an acute model of RV pressure overload, also using pressure-volume analysis.
Epoprostenol improved cardiac output, and this was explained by a marked decrease in RV afterload without detectable changes in RV contractility.28 These observations have been confirmed
where RV pressure overload was induced by pulmonary artery banding.30,31 Both studies reported
an increase in RV hypertrophy and/or improvement of RV function, which implies that there is
a direct effect of sildenafil on the heart. Earlier, Nagendran et al. reported upregulation of PDE-5
in hypertrophied, but not in normal, rat and human RV myocardium, and also demonstrated
Chapter 6
by others29. Two recent papers studied the effects of chronic treatment of sildenafil, in a model
acute inotropic effects of sildenafil in the isolated Langendorff-perfused heart.32 In summary,
experimental data suggest acute detrimental effects of calcium-channel blockers, a neutral effect
of prostacyclines, and possibly beneficial cardiac-specific effects of sildenafil on RV function and
RV remodeling. Currently, no (experimental) data is available on the cardiac-specific effects of
endothelin receptor blockers on the right ventricle in the setting of PH; So far these substances
have only been evaluated in models, in which RV afterload was not fixed.
107
Louis BW.indd 107
06-05-10 11:21
General discussion
Meta-analysis of clinical studies
To the best of our knowledge, no clinical studies exist that specifically separated the cardiac from
pulmonary effects of current PH-therapies. We therefore re-evaluated all placebo-controlled
randomized clinical trials in PH that included serial invasive hemodynamic data, recently summarized by Galie et al.33, by use of the pump-function graph (Figure 3). MPAP was used as a
surrogate measure for mean RV pressure, stroke volume indexed for body surface area (SVi) was
recalculated by dividing cardiac output by heart rate and body surface area (estimated 1.82 m2
if not reported). Concomitant evaluation of the hemodynamic changes in mPAP and SVi by the
pump-function graph, during a typical study period of 12 weeks (range 8 weeks – 12 months),
suggests that current PH-therapies have predominantly pulmonary vasodilating effects. (compare Figure 3 with the situation 2 in Figure 2D). Although future clinical studies are necessary
that are specifically designed to address this issue, this observation demonstrates that there is a
strong rationale for developing novel PH-therapies, which specifically target the right ventricle.11
Figure 3
Meta-analysis of PAH-trials by the pump-function graph. Each individual arrow shows the general absolute change
in indexed stroke volume (ΔSVi) and mean pulmonary artery (ΔmPAP; as a surrogate measure for mean RV pressure)
per study group (red, placebo / control group; blue, intervention group) of all placebo controlled randomized clinical
trials in PAH that have reported serial hemodynamic measurements.33 During the study period, a decrease in SVi was
always accompanied by an increase in mPAP in the placebo groups, implying increase in PVR without relevant changes
in cardiac contractility. For the intervention groups, an increase in SVi was always accompanied by a decrease in mPAP,
implying reduction in PVR without important changes in cardiac contractility. Therefore, current PAH-medications have
predominantly pulmonary vasodilating effects, with only limited cardiac-specific effects.
108
Louis BW.indd 108
06-05-10 11:21
Perspective - Right heart function is the main determinant of prognosis in PH. Current
medication (endothelin receptor blockers, PDE-5 inhibitors, and prostacyclines) seems to
have limited cardiac-specific effects (when analysed by RV pump-function graph). Novel
therapies that specifically improve right heart function in PH are needed.
Relevance of left heart failure therapies for PH-related
right heart failure?
The cornerstones of current (systolic) LHF-therapy are: (loop)diuretics; a beta-blocker; angiotensin-converting enzyme (ACE) inhibitors, or angiotensin II receptor blockers if ACE inhibitors are not tolerated (Table 1). In case of persisting symptoms, an aldosterone antagonist or an
angiotensin blocker is added, if the patient’s renal function permits. Exercise training is regarded
an adjuvant therapy. For selected LHF–patients, an implantable cardioverter-defibrillator and/
or cardiac resynchronization therapy can be considered. These therapies are well-established,
and are based on numerous well-designed randomized controlled trials (more details on current
LHF-therapy can be found in current guidelines13,14). Of note, clinical benefit in these trials was
demonstrated irrespective of the aetiology of LHF. This supports the current idea that the process
of cardiac remodeling, after the initial hit, is similar and independent of its cause (e.g. ischaemia
or hypertension).12 However, it has been argued that therapy efficacy might be different in systolic vs. diastolic heart failure (different LHF-phenotype).34 Therefore, as the cardiac remodeling
observed in PH-patients with right heart failure is comparable to that of systolic LHF (reduced
ejection fraction, ventricular dilatation),9 only these recommendations will be discussed in this
perspective.
It is tempting to extrapolate the LHF-recommendations to right heart failure, even though
there are important structural, functional and developmental differences between the left and
right ventricle.1,2 Nevertheless, there is already some overlap in recommendations between the
LHF- and PH-guidelines,3,4,13,14 which suggests that, at least from a therapeutic perspective, there
symptomatic relieve, both in PH as well as in LHF. Also, moderate exercise training is nowadays
accepted as an adjuvant therapy for PH-patients that are clinically stable and under optimal
medical treatment.35-37
Since loopdiuretics and exercise training are already part of the recommendations of current
Chapter 6
might be some interesting similarities. For example, loopdiuretics are widely used to achieve fast
PH-guidelines, we shall not discuss these therapeutic modalities any further here. We will also
not discuss therapies for LHF that are still experimental. Instead, this perspective focuses on the
clinical potential of: 1) beta-blockers as modulators of the sympathetic nervous system; ACE
inhibitors, 2) angiotensin blockers and aldosterone antagonists as modulators of the reninangiotensin-aldosterone system (RAAS); and 3) the potential of electrical cardiac interventions,
like implantable cardioverter-defibrillators and cardiac resynchronization therapy, as novel
109
Louis BW.indd 109
06-05-10 11:21
General discussion
add-on therapies for PH (Figure 4). Because there are hardly any prospective controlled data
available that investigated the relevance of these LHF-therapies in PH, we will mainly focus on
the relevance of the underlying pathophysiological mechanisms for PH that are affected by these
interventions.
Figure 4
ETRAs
PDE-5 inhibitors
Prostacyclines
Diuretics
PAH:
RV afterload
Overfilling
Dyssynchrony
CRT
RV function
Cardiac output
Beta-blockers
Digoxin
SNS
Norepinephrine ; MSNA
123I-MIBG ; HRV
RV AR downregulation
RAAS
ACEIs
ARBs
Aldost. ant.
Renin ;Angiotensin II
Hyponatriaemie
RV AT1R downregulation
RV remodeling
Progression of RHF
Ventr. arrhythmias
ICD
Yet unexplored pathophysiological mechanisms in PAH.
Abbreviations (in alphabetical order): ACEIs, angiotensin-converting enzyme inhibitors; aldost. ant., aldosterone
antagonists; ARBs, angiotension receptor blockers; AT1R, cardiomyocyte angiotensin type 1 receptor; βAR, cardiomyocyte
beta1-adrenergic receptor; CRT, cardiac resynchronization therapy; ETRAs, endothelin receptor antagonists; HRV, heart
rate variability; ICD, implantable cardioverter-defibrillator; MSNA, muscle sympathetic nervous activity; PAH, pulmonary
arterial hypertension; PDE-5 inhibitors, phosphodiesterase-5 inhibitors; RAAS, renin-angiotensin-aldosterone system;
RHF, right heart failure; RV (afterload), right ventricular ; SNS, sympathetic nervous system; ventr. arrhythmias, ventricular
arrhythmias.
Neurohumoral activation and PH
The combined use of a beta-blocker (more specifically bisoprolol, carvedilol, or sustained released
metoprolol) with either an ACE inhibitor, angiotensin blocker, and/or an aldosterone antagonist,
in addition to symptomatic treatment by loopdiuretics, significantly reduces morbidity and mortality in LHF.13,14 These medications modulate the underlying “neurohumoral activation”, which
is nowadays considered pathological in the long run, as they promote cardiac remodeling and
progression of the disease.12,38 Neurohumoral activation in LHF can be seen as a state, in which
neural and hormonal systems, designed to maintain adequate organ perfusion, are increased to
110
Louis BW.indd 110
06-05-10 11:21
excessively high levels. This activation includes many components, of which the sympathetic
nervous system and RAAS are, from a therapeutic perspective, the most relevant.13,14,38
Sympathetic nervous system
Autonomic dysbalance with dominance of the sympathetic system already occurs at early stages of
LHF,39 and is mainly attributed to reduced baroreceptor discharge. Baroreceptors, mainly located
in the aortic arch, carotid arteries and in the left ventricle, are normally triggered by mechanical
stretch and respond by tonically inhibiting the central sympathetic neural outflow. In case of LHF,
both systemic arterial pressures and baroreceptor sensitivity are reduced. Sympathetic overdrive
leads to chronically elevated levels of norepinephrine, resulting in overstimulation and selective downregulation of the cardiac-specific beta1-adrenergic receptors in the left ventricle. This
stimulus not only leads to increased cardiac mechanical stress (by inotropic, chronotropic and
vasoconstrictive effects), but also has direct cardiotoxic effects.40 As a consequence, LV remodeling progresses with further functional deterioration.38 Beta-blockers are able to stop this vicious
circle of heart failure, by antagonizing the beta-adrenergic receptor.41 Of interest, the therapeutic
effects of digoxin are nowadays no longer solely attributed to its weak inotropic effects, but also
to its modest neurohumoral effects: digoxin indirectly sensitizes the cardiac baroreceptor, and in
this way reduces sympathetic outflow of the central nervous system.42
Although sympathetic activity is difficult to measure in the clinical setting, several methods
have been developed to demonstrate sympathetic overdrive in LHF-patients.39 Of these, measurements of regional norepinephrine spillover or microneurography (which directly measures
post-ganglionic muscle sympathetic nerve activity, often abbreviated as MSNA) quantify sympathetic activity best. A sophisticated non-invasive alternative is the use of
123
I-MIBG tracers
(heart-to-mediastinum ratio falls when the sympathetic nervous system is chronically activated).
A more crude but easy method is the assessment of heart rate variability (which is reduced when
the sympathetic nervous system is over-activated).
Renin-angiotensin-aldosterone system
is the RAAS.43 This system is triggered by impaired renal perfusion due to reduced cardiac output. In that case, the juxtaglomular cells in the kidneys react by secreting renin. Renin increases
angiotensin I levels, from which angiotensin II is formed by angiotensin-converting enzyme
(abundantly present in the lung endothelium). Angiotensin II mediates multiple processes: it is
Chapter 6
Another relevant system in this context, closely interrelated with the sympathetic nervous system,
a potent vasoconstrictor, and it has inotropic, natriuretic and antidiuretic properties; in the setting of LHF, all impose cardiac stress and are detrimental in the long run. Like norepinephrine,
elevated levels of angiotensin II overstimulate and selectively downregulate its angiotensin II
type 1 (AT1)-receptor in the left ventricle, directly promoting cardiac remodeling. Furthermore,
angiotensin II stimulates the secretion of aldosterone as well as vasopressin (also called antidiuretic hormone). Both have natriuretic and antidiuretic effects and also directly promote cardiac
111
Louis BW.indd 111
06-05-10 11:21
General discussion
remodeling. ACE inhibitors, angiotensin blockers, and aldosterone antagonists interfere in this
process by suppressing specific components of the RAAS.13,14
RAAS activity is relatively easily quantified by directly measuring renin or angiotensin II activity in plasma; A simple but indirect alternative to measure chronically activated RAAS is the
assessment of hyponatremia.38
Over-activation of the sympathetic nervous system in PH
Since the primary trigger of neurohumoral activation in LHF (reduction in cardiac output) is
also an important clinical feature in PH, one would expect that the sympathetic nervous system
and RAAS be highly activated in PH as well. Indeed, measurements of the sympathetic and
RAAS activation in PH are comparable to those in LHF.44,45
Measurements in PH-patients, as in LHF, revealed elevated levels of norepinephrine in
plasma,46,47 although this was not consistently found in other studies.48 Furthermore, increased
MSNA,48 reduced cardiac uptake of
123
I-MIBG,49 reduced heart rate variability,50 and selective
downregulation the beta1-adrenergic receptors in the right (but not left) ventricle have been
observed in PH-patients,51 which are all indicators of increased sympathetic activity affecting the
right ventricle. Moreover, these findings were correlated with disease severity.
The RAAS is also involved in PH-induced right heart failure. Forfia et al. recently identified
hyponatremia, which indirectly indicates RAAS activation, as an important independent prognostic factor in PH.52 Parameters that more directly measure RAAS activation (increased renin
activity, elevated levels of angiotensin II, aldosterone, and/or vasopressin) have not been systematically investigated in PH-patients yet. Nevertheless, increased renin activity and elevated
aldosterone levels in plasma have been demonstrated in patients with right heart failure due to
hypoxic pulmonary hypertension (“cor pulmonale”),53 and in different experimental models of
PH-induced right heart failure.54 Also, selective downregulation of the AT1-receptor in the right
ventricle has been observed in PH-patients.55
Together, these studies suggest that the sympathetic nervous system and RAAS are highly
activated in PH. But in contrast to LHF, there are only a few clinical studies that explored the
therapeutic potential of neurohumoral modulation. Rich et al. investigated the effect of i.v.
administration of digoxin in PH-patients, and found acute improvement in cardiac output with
concomitant reduction in norepinephrine levels, comparable to digoxin-effect in LHF.56
Interestingly, no clinical trial exists in PH-induced right heart failure on the effects of betablockers, which have more potent effects on the sympathetic nervous system than digoxin. By
common clinical consensus, beta-blocker use is even contra-indicated. Often this is substantiated
by the study of Provencher et al.57 They reported significant functional improvement, two months
after beta-blocker withdrawal in a small series of patients with porto-pulmonary hypertension.
However, all patients (treated for prophylaxis of variceal bleeding) were on high-dose propanolol
or atenolol. These old beta-blockers are also contraindicated for LHF, because of their profound
myocardial depressive and vasoconstrictive effects, in comparison to newer beta-blockers.41
112
Louis BW.indd 112
06-05-10 11:21
Moreover, it is well-known from LHF, that acute functional improvements do not invariably
lead to favourable changes at long-term, and that overall beneficial effects of beta-blockers can
typically be expected after chronic use of three months or more.41
Another (related) argument against beta-blocker use in PH, is the importance of maintenance
of RV systolic function. Acute administration of a beta-blocker is known to exacerbates dyspnea,
most likely due to its negative inotropic effects, leading to instant ventriculo-arterial uncoupling.22
However, this temporary effect might be better tolerated by careful use of selective beta-blockers
(“start low, go slow”), as is successfully demonstrated in LHF-patients.13,14
Although this is against present consensus, we would like to argue that, like in LHF, the sympathetic nervous system is activated to pathological levels in PH, and that this could be normalized
by careful beta-blocker use. Further (preclinical) research is necessary to investigate whether a
low-dose of a newer selective beta-blocker might be a tolerable option to abolish the detrimental
effects of sympathetic overdrive in PH.
Activation of the renin-angiotensin-aldosterone system in PH
The RAAS has long been recognized to have an important role in pulmonary vascular remodeling
and pulmonary vasoconstriction.58,59 Therefore, when captopril (the first ACE inhibitor) became
commercially available, this new drug was eagerly tested in PH-patients, for whom no effective
treatment existed at that time. In the 1980s, 4 small case-series (26 patients in total) reported
on the hemodynamic effects of captopril in PH; Three of the studies were positive and found
a significant increase in cardiac output,60,61 and exercise capacity.62 One study however, did not
observe any hemodynamic changes, neither positive nor negative.63 Surprisingly, no additional
clinical studies have appeared ever since. Currently, there is a renewed interest in the RAAS, since
the discovery of ACE2, an isoform of the angiotensin-converting enzyme with counteractive
(protective) actions.64,65 The theoretical beneficial effects of ACE inhibitors, angiotensin blockers,
and/or aldosteron antagonists on the heart in PH have not been addressed in patients yet.
Preclinical studies using different models of PH and right heart failure, however confirmed
that the use of ACE inhibitors or angiotensin blockers significantly reduces RV remodeling
interference in the RAAS could (partially) reverse pulmonary and cardiac remodeling, which
warrants a prospective controlled clinical study of the effects of ACE inhibitors, angiotensin
blockers, and/or aldosterone antagonists.
Chapter 6
and improves cardiac function and/or survival.66-69 We conclude that in PH, pharmacological
Perspective – There is convincing evidence that, like in left heart failure, the sympathetic
nervous system and the renin-angiotensin-aldosterone system in PH are highly activated.
Well-established pharmacological interventions for left heart failure could therefore be
relevant for PH as well. However, ACE inhibitors, angiotensin II blockers and selective betablockade have not been explored in PH, and clinical investigations of the potential of these
drugs are urgently needed. Nevertheless, routine use of these neurohumoral modulators, and
113
Louis BW.indd 113
06-05-10 11:21
General discussion
in particular the use of beta-blockers, are currently not recommended in PH, unless future
studies can prove that their use is safe and beneficial in PH.
Electrical remodeling and PH
Implantable cardioverter-defibrillators and cardiac resynchronization therapy are relatively new
therapeutic modalities in LHF-management. Major heart failure guidelines contain recommendations on implantable cardioverter-defibrillator use since 2001, and recommendations on
resynchronization therapy have only been incorporated since 2005. For selected LHF-patient
groups, it is nowadays well-accepted that resynchronization therapy significantly reduce morbidity, and both cardioverter-defibrillators and resynchronization therapy significantly reduce
mortality, in addition to the beneficial effect of optimal pharmacological LHF-treatment.13,14
Implantable cardioverter-defibrillator
A cardioverter-defibrillator detects and prematurely terminates malignant and life-threatening
ventricular arrhythmias, preventing sudden cardiac death. The incidence of ventricular arrhythmias increases with the progression of LHF. Therefore, implantable cardioverter-defibrillator use
is currently recommended as secondary prevention for sudden cardiac death in LHF-patients
with a (presumed) history of ventricular arrhythmia, or as primary prevention in LHF-patients
with a severely reduced LVEF. In both cases LHF-patients must have a reasonable expectation of
survival with acceptable functional status of more than one year.13,14 The clinical trials, on which
these recommendations are based, reported a relative reduction of all-cause mortality after 24
months of approximately 30% and an absolute risk reduction of approximately 5%,70,71 which
implies a number-needed-to-treat of about 20 patients.
Also in PH, sudden cardiac death, presumably due to malignant ventricular arrhythmias, has
been recognised as an important clinical risk for these patients,72 Like in LHF, markers for an
“electrically instable heart”, such as: prolonged QTc-intervals and increased QT dispersion derived
by ECG,73 neurohumoral disturbances (as discussed above), and increase in cardiac fibrosis,74
have been demonstrated in PH-patients. But, in contrast to LHF, the actual incidence of events
related to ventricular arrhythmias in PH is considered low. However, the reported percentages of
deaths in PH attributed to ventricular arrhythmias vary widely, from 8 to 26%,7,75 and the actual
numbers might importantly differ for the different PH-subgroups (e.g. higher for PH associated
with congenital heart disease, which might be related to the presence of surgical cardiac scars76).
Moreover, these numbers are based on retrospective studies and were partially obtained before
the introduction of PH-specific medications. Systematic prospective clinical studies are necessary
to accurately determine the current incidence of sudden cardiac deaths in different subgroups of
PH. These data will allow a crude estimation of the clinical potential of cardioverter-defibrillators
in PH, by calculation of the number-needed-to-treat (extrapolating the effect of cardioverterdefibrillators in LHF). Until then, implantable cardioverter-defibrillators (or pharmacological
114
Louis BW.indd 114
06-05-10 11:21
anti-arrhythmic agents) are in general not recommended as an (primary) preventive measure for
sudden cardiac death in PH-patients.4,72
Supraventricular tachyarrhythmias
In contrast to ventricular arrhythmias, the incidence of supraventricular arrhythmias seems to be
much higher, and they are considered an important cause of clinical deterioration in PH-patients.
In a retrospective analysis,77 an annual incidence of supraventricular tachyarrhythmias in PH
was found of around 3%: atrial fibrillation and atrial flutter were equally common. In this study,
persistent atrial fibrillation was associated with a very poor prognosis (9 out of 11 PH-patients
died within 24 months), which may be explained by worsening of RV function due to the loss of
atrial “kick” to ventricular filling. Maintenance of sinus rhythm is therefore currently considered
an important treatment goal in PH.4 This is however in contrast to the clinical experience in
LHF. The treatment strategy of rhythm-control, compared to rate-control (which is: acceptance
of atrium fibrillation, lowering of the ventricular response-rate in combination with adequate
anticoagulation), had no superior effect on survival, whereas it required more hospitalization
because of the need for repeated cardioversion.78,79 We fully support current recommendations
to restore and maintain sinus rhythm in PH-patients if possible, by lack of prospective and
controlled data. Future trials however, are necessary to test the validity of this treatment strategy.
Cardiac resynchronization therapy
Cardiac dyssynchrony in LHF is characterized by regional differences in electrical and/or
mechanical activation of the left ventricle (usually a delay in activation of the LV free wall in
relation to the interventricular septum). Dyssynchrony results in inefficient pumping of the
left ventricle, and further clinical deterioration. Cardiac resynchronization therapy can acutely
restore synchrony of LV contraction, thereby improving overall LV (systolic) performance. In the
long run, resynchronization therapy leads to reversed cardiac remodeling, resulting in an even
further improvement of LV performance. Although the current clinical selection criteria for resynchronization therapy (wide QRS-complex on ECG) sub-optimally predict clinical benefit for
morbidity and mortality, and is nowadays a well-established treatment modality in LHF.13,14
Ventricular dyssynchrony is often observed in progressive stages of PH-induced right heart
failure as well.80,81 Mechanical interventricular dyssynchrony in PH (which is clinically easily
recognised by the paradoxical bulging of the interventricular septum) is associated with im-
Chapter 6
the individual LHF-patient, resynchronization therapy has been shown to significantly reduce
paired RV systolic function. Furthermore, through septum bulging, ventricular dyssynchrony
is thought to impair LV diastolic function as well.82,83 Resynchronization of the right ventricle
could therefore be of clinical benefit in PH. However, we recently demonstrated that LV and RV
dyssynchrony are essentially different: the origin of PH-related ventricular dyssynchrony lies in
regional differences in the duration of the contraction, rather than regional differences in onset of
the contraction (e.g. due to a conductance delay); and is highly afterload dependent.83,84
115
Louis BW.indd 115
06-05-10 11:21
General discussion
Previously, successful application of cardiac resynchronization therapy has been demonstrated
in patients with PH associated with congenital heart disease.85 However, these patients display a
“LHF-like” dyssynchrony due to a complete right bundle branch block as a (late) complication
of cardiac surgery, and are therefore not representative for the PH-population in general. We
recently explored the clinical potential of resynchronization therapy in an experimental model
of PH-induced right heart failure, in the absence of conduction disturbances.84 We found that
pre-excitation of the RV free wall resulted in improved RV systolic function and reduced adverse LV diastolic interaction. Interestingly, these findings very recently have been confirmed
by Hardziyenka et al. in a study with patients suffering from right heart failure and ventricular
dyssynchrony secondary to chronic thromboembolic pulmonary hypertension.86 A cohort of 67
patients was preoperatively screened by standard tissue-Doppler echocardiography, and seven
patients were selected for a temporary pacing protocol, based on the presence of large diastolic
interventricular delay (as a quantification of PH-related ventricular dyssynchrony). Resynchronization therapy acutely reduced ventricular dyssynchrony, enhanced RV contractility and LV
diastolic filling, and this resulted in an improvement of stroke volume of more than 10%. These
promising results warrant further investigations of cardiac resynchronization therapy as a novel
treatment for right heart failure secondary to PH,11 that should focus on its long-term effects,
and on the identification of robust selection criteria for PH-patients that could profit most from
cardiac resynchronization therapy.
Perspective – In PH, the incidence of malignant ventricular arrhythmias is considered
low, but this observation needs prospective validation. For now, the use of implantable
cardioverter-defibrillators is not recommended for PH-patients. Supraventricular tachyarrhythmias often lead to clinical deterioration. Based on retrospective data, maintenance
of sinus rhythm is an important treatment goal, but this preference of rhythm- over ratecontrol needs be confirmed in prospective controlled studies, especially because this is opposite to the experiences in left heart failure. Cardiac resynchronization therapy emerges as
a promising new treatment modality. Prospective controlled trials are necessary to study its
long-term effects and to identify robust selection criteria.
Conclusions and future directions
In this perspective, we investigated the potential applicability of current LHF therapy for the
treatment of PH-induced right heart failure. Based on available literature, we conclude that:
1) Left and right heart failure share important underlying pathophysiological mechanisms that
are amenable for treatment (Figure 4), however;
2) Clinical experience with current LHF treatments in the setting of PH is very limited.
116
Louis BW.indd 116
06-05-10 11:21
This discrepancy is intriguing, and we can only speculate about its reasons. Firstly, it is difficult
to separate cardiac- from pulmonary-specific effects of therapeutic interventions in PH-patients.
As a solution, we propose the use of the pump function graph. Secondly, PH remains a rare
disease where many other clinical trials have been undertaken in the last two decades.33 Thirdly,
until recently right heart failure was regarded as an inevitable final consequence of PH, whereas
nowadays the right ventricle is considered a potential therapeutic target.11
So, how do we move forward? Solid clinical evidence is essential, before LHF-therapy can be
implemented in clinical PH-management. Therefore, phase I/II-trials need to be conducted first,
which must provide insights in safety, tolerability and efficacy of LHF-therapy in PH. Subsequently, randomized clinical trials should be performed that compare current PH-therapy with
and without add-on LHF-therapy. An important aspect is sufficient duration of the trial: the
experiences in LHF would predict that reversal of cardiac remodeling requires more than the
typical 12-week trial duration. In addition, the question remains which endpoint to choose in
these types of studies: classical endpoints in PH-trials, such as 6-minute walking distance, might
not be sensitive enough, and direct measures for RV remodeling and function are possibly more
appropriate. On the other hand, the most ideal endpoint, mortality, might be too stringent, and
will require inclusion of unrealistic high numbers of patients.87
To conclude, well-designed clinical studies are warranted, as they might us provide supporting
evidence for use of novel therapeutic modalities that are relatively easy at hand, to treat this
devastating disease. Future will reveal whether going “left” is a step in the “right” direction.
ACKNOWLEDGEMENT
Sources of funding
M.L.Handoko (Mozaïek 017.002.122) and A.Vonk-Noordegraaf (Vidi 917.96.306), were supported by the Netherlands Organisation for Scientific Research (NWO), The Hague, The Neth-
Disclosures
C.P. Allaart received a consulting fee from Biotronik, and has attended several cardiology conferences that were partly funded by several major pacemaker- / ICD-companies.
Chapter 6
erlands.
REFERENCES
1.
Haddad F, Hunt SA, Rosenthal DN, Murphy DJ. Right ventricular function in cardiovascular disease,
part I: Anatomy, physiology, aging, and functional assessment of the right ventricle. Circulation
2008;117:1436-1448.
117
Louis BW.indd 117
06-05-10 11:21
General discussion
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
Haddad F, Doyle R, Murphy DJ, Hunt SA. Right ventricular function in cardiovascular disease, part
II: pathophysiology, clinical importance, and management of right ventricular failure. Circulation
2008;117:1717-1731.
McLaughlin VV, Archer SL, Badesch DB, Barst RJ, Farber HW, Lindner JR, Mathier MA, McGoon
MD, Park MH, Rosenson RS, Rubin LJ, Tapson VF, Varga J. ACCF/AHA 2009 expert consensus
document on pulmonary hypertension a report of the American College of Cardiology Foundation
Task Force on Expert Consensus Documents and the American Heart Association developed in collaboration with the American College of Chest Physicians; American Thoracic Society, Inc.; and the
Pulmonary Hypertension Association. J Am Coll Cardiol 2009;53:1573-1619.
Galie N, Hoeper MM, Humbert M, Torbicki A, Vachiery JL, Barbera JA, Beghetti M, Corris P, Gaine
S, Gibbs JS, Gomez-Sanchez MA, Jondeau G, Klepetko W, Opitz C, Peacock A, Rubin L, Zellweger M,
Simonneau G. Guidelines for the diagnosis and treatment of pulmonary hypertension. The task force
for the diagnosis and treatment of pulmonary hypertension of the European Society of Cardiology
(ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart
and Lung Transplantation (ISHLT). Eur Respir J 2009.
Lankhaar JW, Westerhof N, Faes TJ, Marques KM, Marcus JT, Postmus PE, Vonk-Noordegraaf A.
Quantification of right ventricular afterload in patients with and without pulmonary hypertension.
Am J Physiol Heart Circ Physiol 2006.
McLaughlin VV, McGoon MD. Pulmonary arterial hypertension. Circulation 2006;114:1417-1431.
D’Alonzo GE, Barst RJ, Ayres SM, Bergofsky EH, Brundage BH, Detre KM, Fishman AP, Goldring
RM, Groves BM, Kernis JT, . Survival in patients with primary pulmonary hypertension. Results from
a national prospective registry. Ann Intern Med 1991;115:343-349.
Sandoval J, Bauerle O, Palomar A, Gomez A, Martinez-Guerra ML, Beltran M, Guerrero ML. Survival
in primary pulmonary hypertension. Validation of a prognostic equation. Circulation 1994;89:17331744.
van Wolferen SA, Marcus JT, Boonstra A, Marques KM, Bronzwaer JG, Spreeuwenberg MD, Postmus
PE, Vonk-Noordegraaf A. Prognostic value of right ventricular mass, volume, and function in idiopathic pulmonary arterial hypertension. Eur Heart J 2007;28:1250-1257.
Humbert M, Sitbon O, Simonneau G. Treatment of pulmonary arterial hypertension. N Engl J Med
2004;351:1425-1436.
Ghofrani HA, Barst RJ, Benza RL, Champion HC, Fagan KA, Grimminger F, Humbert M, Simonneau
G, Stewart DJ, Ventura C, Rubin LJ. Future perspectives for the treatment of pulmonary arterial
hypertension. J Am Coll Cardiol 2009;54:S108-S117.
Cohn JN, Ferrari R, Sharpe N. Cardiac remodeling--concepts and clinical implications: a consensus
paper from an international forum on cardiac remodeling. Behalf of an International Forum on
Cardiac Remodeling. J Am Coll Cardiol 2000;35:569-582.
Hunt SA, Abraham WT, Chin MH, Feldman AM, Francis GS, Ganiats TG, Jessup M, Konstam MA,
Mancini DM, Michl K, Oates JA, Rahko PS, Silver MA, Stevenson LW, Yancy CW. 2009 focused
update incorporated into the ACC/AHA 2005 Guidelines for the Diagnosis and Management of
Heart Failure in Adults: a report of the American College of Cardiology Foundation/American Heart
Association Task Force on Practice Guidelines: developed in collaboration with the International
Society for Heart and Lung Transplantation. Circulation 2009;119:e391-e479.
Dickstein K, Cohen-Solal A, Filippatos G, McMurray JJ, Ponikowski P, Poole-Wilson PA, Stromberg
A, van Veldhuisen DJ, Atar D, Hoes AW, Keren A, Mebazaa A, Nieminen M, Priori SG, Swedberg
K, Vahanian A, Camm J, De CR, Dean V, Dickstein K, Filippatos G, Funck-Brentano C, Hellemans
I, Kristensen SD, McGregor K, Sechtem U, Silber S, Tendera M, Widimsky P, Zamorano JL. ESC
118
Louis BW.indd 118
06-05-10 11:21
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
Chapter 6
15.
Guidelines for the diagnosis and treatment of acute and chronic heart failure 2008: the Task Force
for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2008 of the European Society
of Cardiology. Developed in collaboration with the Heart Failure Association of the ESC (HFA) and
endorsed by the European Society of Intensive Care Medicine (ESICM). Eur Heart J 2008;29:23882442.
Galie N, Hinderliter AL, Torbicki A, Fourme T, Simonneau G, Pulido T, Espinola-Zavaleta N, Rocchi G, Manes A, Frantz R, Kurzyna M, Nagueh SF, Barst R, Channick R, Dujardin K, Kronenberg
A, Leconte I, Rainisio M, Rubin L. Effects of the oral endothelin-receptor antagonist bosentan on
echocardiographic and doppler measures in patients with pulmonary arterial hypertension. J Am
Coll Cardiol 2003;41:1380-1386.
Channick RN, Simonneau G, Sitbon O, Robbins IM, Frost A, Tapson VF, Badesch DB, Roux S, Rainisio M, Bodin F, Rubin LJ. Effects of the dual endothelin-receptor antagonist bosentan in patients with
pulmonary hypertension: a randomised placebo-controlled study. Lancet 2001;358:1119-1123.
Suga H, Sagawa K, Shoukas AA. Load independence of the instantaneous pressure-volume ratio of
the canine left ventricle and effects of epinephrine and heart rate on the ratio. Circ Res 1973;32:314322.
Westerhof N, Stergiopulos N, Noble MIM. Snapshots of Hemdynamics: An aid for Clinical Research
and Graduate Education. New York (NY): Springer; 2005.
Burkhoff D, Mirsky I, Suga H. Assessment of systolic and diastolic ventricular properties via
pressure-volume analysis: a guide for clinical, translational, and basic researchers. Am J Physiol Heart
Circ Physiol 2005;289:H501-H512.
Kuehne T, Yilmaz S, Steendijk P, Moore P, Groenink M, Saaed M, Weber O, Higgins CB, Ewert P,
Fleck E, Nagel E, Schulze-Neick I, Lange P. Magnetic resonance imaging analysis of right ventricular
pressure-volume loops: in vivo validation and clinical application in patients with pulmonary hypertension. Circulation 2004;110:2010-2016.
Sunagawa K, Yamada A, Senda Y, Kikuchi Y, Nakamura M, Shibahara T, Nose Y. Estimation of
the hydromotive source pressure from ejecting beats of the left ventricle. IEEE Trans Biomed Eng
1980;27:299-305.
Brimioulle S, Wauthy P, Ewalenko P, Rondelet B, Vermeulen F, Kerbaul F, Naeije R. Single-beat
estimation of right ventricular end-systolic pressure-volume relationship. Am J Physiol Heart Circ
Physiol 2003;284:H1625-H1630.
Kerbaul F, Rondelet B, Demester JP, Fesler P, Huez S, Naeije R, Brimioulle S. Effects of levosimendan
versus dobutamine on pressure load-induced right ventricular failure. Crit Care Med 2006;34:28142819.
Kerbaul F, Rondelet B, Motte S, Fesler P, Hubloue I, Ewalenko P, Naeije R, Brimioulle S. Effects of
norepinephrine and dobutamine on pressure load-induced right ventricular failure. Crit Care Med
2004;32:1035-1040.
Elzinga G, Westerhof N. How to quantify pump function of the heart. The value of variables derived
from measurements on isolated muscle. Circ Res 1979;44:303-308.
Overbeek MJ, Lankhaar JW, Westerhof N, Voskuyl AE, Boonstra A, Bronzwaer JG, Marques KM,
Smit EF, Dijkmans BA, Vonk-Noordegraaf A. Right ventricular contractility in systemic sclerosisassociated and idiopathic pulmonary arterial hypertension. Eur Respir J 2008;31:1160-1166.
Zierer A, Voeller RK, Melby SJ, Steendijk P, Moon MR. Impact of calcium-channel blockers on
right heart function in a controlled model of chronic pulmonary hypertension. Eur J Anaesthesiol
2009;26:253-259.
119
Louis BW.indd 119
06-05-10 11:21
General discussion
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
Kerbaul F, Brimioulle S, Rondelet B, Dewachter C, Hubloue I, Naeije R. How prostacyclin improves
cardiac output in right heart failure in conjunction with pulmonary hypertension. Am J Respir Crit
Care Med 2007;175:846-850.
Rex S, Missant C, Segers P, Rossaint R, Wouters PF. Epoprostenol treatment of acute pulmonary
hypertension is associated with a paradoxical decrease in right ventricular contractility. Intensive
Care Med 2008;34:179-189.
Schafer S, Ellinghaus P, Janssen W, Kramer F, Lustig K, Milting H, Kast R, Klein M. Chronic inhibition
of phosphodiesterase 5 does not prevent pressure-overload-induced right-ventricular remodelling.
Cardiovasc Res 2009;82:30-39.
Andersen A, Nielsen JM, Peters CD, Schou UK, Sloth E, Nielsen-Kudsk JE. Effects of phosphodiesterase-5 inhibition by sildenafil in the pressure overloaded right heart. Eur J Heart Fail 2008;10:11581165.
Nagendran J, Archer SL, Soliman D, Gurtu V, Moudgil R, Haromy A, St AC, Webster L, Rebeyka
IM, Ross DB, Light PE, Dyck JR, Michelakis ED. Phosphodiesterase type 5 is highly expressed in
the hypertrophied human right ventricle, and acute inhibition of phosphodiesterase type 5 improves
contractility. Circulation 2007;116:238-248.
Galie N, Manes A, Negro L, Palazzini M, Bacchi-Reggiani ML, Branzi A. A meta-analysis of randomized controlled trials in pulmonary arterial hypertension. Eur Heart J 2009;30:394-403.
Paulus WJ, van Ballegoij JJM. Treatment of heart failure with normal ejection fraction: an inconvenient truth! J Am Coll Cardiol 2010;5:526-537.
Mereles D, Ehlken N, Kreuscher S, Ghofrani S, Hoeper MM, Halank M, Meyer FJ, Karger G, Buss J,
Juenger J, Holzapfel N, Opitz C, Winkler J, Herth FF, Wilkens H, Katus HA, Olschewski H, Grunig E.
Exercise and respiratory training improve exercise capacity and quality of life in patients with severe
chronic pulmonary hypertension. Circulation 2006;114:1482-1489.
de Man FS, Handoko ML, Groepenhoff H, van ‘t Hul AJ, Abbink J, Koppers RJ, Grotjohan HP, Twisk
JW, Bogaard HJ, Boonstra A, Postmus PE, Westerhof N, van der Laarse WJ, Vonk-Noordegraaf A.
Effects of exercise training in patients with idiopathic pulmonary arterial hypertension. Eur Respir J
2009;34:669-675.
Handoko ML, de Man FS, Happe CM, Schalij I, Musters RJ, Westerhof N, Postmus PE, Paulus WJ,
van der Laarse WJ, Vonk-Noordegraaf A. Opposite effects of training in rats with stable and progressive pulmonary hypertension. Circulation 2009;120:42-49.
Packer M. The neurohormonal hypothesis: a theory to explain the mechanism of disease progression
in heart failure. J Am Coll Cardiol 1992;20:248-254.
Triposkiadis F, Karayannis G, Giamouzis G, Skoularigis J, Louridas G, Butler J. The sympathetic
nervous system in heart failure physiology, pathophysiology, and clinical implications. J Am Coll
Cardiol 2009;54:1747-1762.
Engelhardt S, Hein L, Wiesmann F, Lohse MJ. Progressive hypertrophy and heart failure in beta1adrenergic receptor transgenic mice. Proc Natl Acad Sci U S A 1999;96:7059-7064.
Bristow MR. beta-adrenergic receptor blockade in chronic heart failure. Circulation 2000;101:558569.
Gheorghiade M, Ferguson D. Digoxin. A neurohormonal modulator in heart failure? Circulation
1991;84:2181-2186.
Baker KM, Booz GW, Dostal DE. Cardiac actions of angiotensin II: Role of an intracardiac reninangiotensin system. Annu Rev Physiol 1992;54:227-41.:227-241.
Kurzyna M, Torbicki A. Neurohormonal modulation in right ventricular failure. Eur Heart J (Suppl)
2007;9:H35-H40.
120
Louis BW.indd 120
06-05-10 11:21
46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
Schrier RW, Bansal S. Pulmonary hypertension, right ventricular failure, and kidney: different from
left ventricular failure? Clin J Am Soc Nephrol 2008;3:1232-1237.
Nootens M, Kaufmann E, Rector T, Toher C, Judd D, Francis GS, Rich S. Neurohormonal activation
in patients with right ventricular failure from pulmonary hypertension: relation to hemodynamic
variables and endothelin levels. J Am Coll Cardiol 1995;26:1581-1585.
Nagaya N, Nishikimi T, Uematsu M, Satoh T, Kyotani S, Sakamaki F, Kakishita M, Fukushima K,
Okano Y, Nakanishi N, Miyatake K, Kangawa K. Plasma brain natriuretic peptide as a prognostic
indicator in patients with primary pulmonary hypertension. Circulation 2000;102:865-870.
Velez-Roa S, Ciarka A, Najem B, Vachiery JL, Naeije R, van de BP. Increased sympathetic nerve
activity in pulmonary artery hypertension. Circulation 2004;110:1308-1312.
Morimitsu T, Miyahara Y, Sinboku H, Ikeda S, Naito T, Nishijima K, Takao M. Iodine-123-metaiodobenzylguanidine myocardial imaging in patients with right ventricular pressure overload. J Nucl Med
1996;37:1343-1346.
Wensel R, Jilek C, Dorr M, Francis DP, Stadler H, Lange T, Blumberg F, Opitz C, Pfeifer M, Ewert R.
Impaired cardiac autonomic control relates to disease severity in pulmonary hypertension. Eur Respir
J 2009;34:895-901.
Bristow MR, Minobe W, Rasmussen R, Larrabee P, Skerl L, Klein JW, Anderson FL, Murray J, Mestroni L, Karwande SV, . Beta-adrenergic neuroeffector abnormalities in the failing human heart are
produced by local rather than systemic mechanisms. J Clin Invest 1992;89:803-815.
Forfia PR, Mathai SC, Fisher MR, Housten-Harris T, Hemnes AR, Champion HC, Girgis RE, Hassoun
PM. Hyponatremia predicts right heart failure and poor survival in pulmonary arterial hypertension.
Am J Respir Crit Care Med 2008;177:1364-1369.
Anand IS, Chandrashekhar Y, Ferrari R, Sarma R, Guleria R, Jindal SK, Wahi PL, Poole-Wilson PA,
Harris P. Pathogenesis of congestive state in chronic obstructive pulmonary disease. Studies of body
water and sodium, renal function, hemodynamics, and plasma hormones during edema and after
recovery. Circulation 1992;86:12-21.
Watkins L, Jr., Burton JA, Haber E, Cant JR, Smith FW, Barger AC. The renin-angiotensin-aldosterone
system in congestive failure in conscious dogs. J Clin Invest 1976;57:1606-1617.
Asano K, Dutcher DL, Port JD, Minobe WA, Tremmel KD, Roden RL, Bohlmeyer TJ, Bush EW, Jenkin
MJ, Abraham WT, Raynolds MV, Zisman LS, Perryman MB, Bristow MR. Selective downregulation
of the angiotensin II AT1-receptor subtype in failing human ventricular myocardium. Circulation
1997;95:1193-1200.
Rich S, Seidlitz M, Dodin E, Osimani D, Judd D, Genthner D, McLaughlin V, Francis G. The shortterm effects of digoxin in patients with right ventricular dysfunction from pulmonary hypertension.
Chest 1998;114:787-792.
Provencher S, Herve P, Jais X, Lebrec D, Humbert M, Simonneau G, Sitbon O. Deleterious effects of
beta-blockers on exercise capacity and hemodynamics in patients with portopulmonary hypertension. Gastroenterology 2006;130:120-126.
Cargill RI, Lipworth BJ. The role of the renin-angiotensin and natriuretic peptide systems in the
pulmonary vasculature. Br J Clin Pharmacol 1995;40:11-18.
Qing F, McCarthy TJ, Markham J, Schuster DP. Pulmonary angiotensin-converting enzyme (ACE)
binding and inhibition in humans. A positron emission tomography study. Am J Respir Crit Care Med
2000;161:2019-2025.
Niarchos AP, Whitman HH, Goldstein JE, Laragh JH. Hemodynamic effects of captopril in pulmonary hypertension of collagen vascular disease. Am Heart J 1982;104:834-838.
Chapter 6
45.
121
Louis BW.indd 121
06-05-10 11:21
General discussion
61.
62.
63.
64.
65.
66.
67.
68.
69.
70.
71.
72.
73.
Alpert MA, Pressly TA, Mukerji V, Lambert CR, Mukerji B. Short- and long-term hemodynamic
effects of captopril in patients with pulmonary hypertension and selected connective tissue disease.
Chest 1992;102:1407-1412.
Ikram H, Maslowski AH, Nicholls MG, Espiner EA, Hull FT. Haemodynamic and hormonal effects
of captopril in primary pulmonary hypertension. Br Heart J 1982;48:541-545.
Leier CV, Bambach D, Nelson S, Hermiller JB, Huss P, Magorien RD, Unverferth DV. Captopril in
primary pulmonary hypertension. Circulation 1983;67:155-161.
Kuba K, Imai Y, Penninger JM. Angiotensin-converting enzyme 2 in lung diseases. Curr Opin Pharmacol 2006;6:271-276.
Ferreira AJ, Shenoy V, Yamazato Y, Sriramula S, Francis J, Yuan L, Castellano RK, Ostrov DA, Oh SP,
Katovich MJ, Raizada MK. Evidence for angiotensin-converting enzyme 2 as a therapeutic target for
the prevention of pulmonary hypertension. Am J Respir Crit Care Med 2009;179:1048-1054.
Okada M, Kikuzuki R, Harada T, Hori Y, Yamawaki H, Hara Y. Captopril attenuates matrix metalloproteinase-2 and -9 in monocrotaline-induced right ventricular hypertrophy in rats. J Pharmacol
Sci 2008;108:487-494.
Okada M, Harada T, Kikuzuki R, Yamawaki H, Hara Y. Effects of telmisartan on right ventricular
remodeling induced by monocrotaline in rats. J Pharmacol Sci 2009;111:193-200.
Rouleau JL, Kapuku G, Pelletier S, Gosselin H, Adam A, Gagnon C, Lambert C, Meloche S. Cardioprotective effects of ramipril and losartan in right ventricular pressure overload in the rabbit:
importance of kinins and influence on angiotensin II type 1 receptor signaling pathway. Circulation
2001;104:939-944.
Morrell NW, Atochina EN, Morris KG, Danilov SM, Stenmark KR. Angiotensin converting enzyme
expression is increased in small pulmonary arteries of rats with hypoxia-induced pulmonary hypertension. J Clin Invest 1995;96:1823-1833.
Moss AJ, Zareba W, Hall WJ, Klein H, Wilber DJ, Cannom DS, Daubert JP, Higgins SL, Brown MW,
Andrews ML. Prophylactic implantation of a defibrillator in patients with myocardial infarction and
reduced ejection fraction. N Engl J Med 2002;346:877-883.
Bardy GH, Lee KL, Mark DB, Poole JE, Packer DL, Boineau R, Domanski M, Troutman C, Anderson
J, Johnson G, McNulty SE, Clapp-Channing N, vidson-Ray LD, Fraulo ES, Fishbein DP, Luceri RM,
Ip JH. Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. N Engl J
Med 2005;20;352:225-237.
Zipes DP, Camm AJ, Borggrefe M, Buxton AE, Chaitman B, Fromer M, Gregoratos G, Klein G, Moss
AJ, Myerburg RJ, Priori SG, Quinones MA, Roden DM, Silka MJ, Tracy C, Smith SC, Jr., Jacobs AK,
Adams CD, Antman EM, Anderson JL, Hunt SA, Halperin JL, Nishimura R, Ornato JP, Page RL,
Riegel B, Blanc JJ, Budaj A, Dean V, Deckers JW, Despres C, Dickstein K, Lekakis J, McGregor K,
Metra M, Morais J, Osterspey A, Tamargo JL, Zamorano JL. ACC/AHA/ESC 2006 Guidelines for
Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death:
a report of the American College of Cardiology/American Heart Association Task Force and the
European Society of Cardiology Committee for Practice Guidelines (writing committee to develop
Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden
Cardiac Death): developed in collaboration with the European Heart Rhythm Association and the
Heart Rhythm Society. Circulation 2006;114:e385-e484.
Hong-liang Z, Qin L, Zhi-hong L, Zhi-hui Z, Chang-ming X, Xin-hai N, Jian-guo H, Ying-jie W, Shu
Z. Heart rate-corrected QT interval and QT dispersion in patients with pulmonary hypertension.
Wien Klin Wochenschr 2009;121:330-333.
122
Louis BW.indd 122
06-05-10 11:21
75.
76.
77.
78.
79.
80.
81.
82.
83.
84.
Lowes BD, Minobe W, Abraham WT, Rizeq MN, Bohlmeyer TJ, Quaife RA, Roden RL, Dutcher DL,
Robertson AD, Voelkel NF, Badesch DB, Groves BM, Gilbert EM, Bristow MR. Changes in gene expression in the intact human heart. Downregulation of alpha-myosin heavy chain in hypertrophied,
failing ventricular myocardium. J Clin Invest 1997;100:2315-2324.
Hoeper MM, Galie N, Murali S, Olschewski H, Rubenfire M, Robbins IM, Farber HW, McLaughlin
V, Shapiro S, Pepke-Zaba J, Winkler J, Ewert R, Opitz C, Westerkamp V, Vachiery JL, Torbicki A,
Behr J, Barst RJ. Outcome after cardiopulmonary resuscitation in patients with pulmonary arterial
hypertension. Am J Respir Crit Care Med 2002;165:341-344.
Walsh EP, Cecchin F. Arrhythmias in adult patients with congenital heart disease. Circulation
2007;115:534-545.
Tongers J, Schwerdtfeger B, Klein G, Kempf T, Schaefer A, Knapp JM, Niehaus M, Korte T, Hoeper
MM. Incidence and clinical relevance of supraventricular tachyarrhythmias in pulmonary hypertension. Am Heart J 2007;153:127-132.
Roy D, Talajic M, Nattel S, Wyse DG, Dorian P, Lee KL, Bourassa MG, Arnold JM, Buxton AE,
Camm AJ, Connolly SJ, Dubuc M, Ducharme A, Guerra PG, Hohnloser SH, Lambert J, Le Heuzey
JY, O’Hara G, Pedersen OD, Rouleau JL, Singh BN, Stevenson LW, Stevenson WG, Thibault B,
Waldo AL. Rhythm control versus rate control for atrial fibrillation and heart failure. N Engl J Med
2008;19;358:2667-2677.
Fuster V, Ryden LE, Cannom DS, Crijns HJ, Curtis AB, Ellenbogen KA, Halperin JL, Le Heuzey JY,
Kay GN, Lowe JE, Olsson SB, Prystowsky EN, Tamargo JL, Wann S, Smith SC, Jr., Jacobs AK, Adams
CD, Anderson JL, Antman EM, Halperin JL, Hunt SA, Nishimura R, Ornato JP, Page RL, Riegel
B, Priori SG, Blanc JJ, Budaj A, Camm AJ, Dean V, Deckers JW, Despres C, Dickstein K, Lekakis
J, McGregor K, Metra M, Morais J, Osterspey A, Tamargo JL, Zamorano JL. ACC/AHA/ESC 2006
Guidelines for the Management of Patients with Atrial Fibrillation: a report of the American College
of Cardiology/American Heart Association Task Force on Practice Guidelines and the European
Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001
Guidelines for the Management of Patients With Atrial Fibrillation): developed in collaboration with
the European Heart Rhythm Association and the Heart Rhythm Society. Circulation 2006;114:e257e354.
Roeleveld RJ, Marcus JT, Faes TJ, Gan TJ, Boonstra A, Postmus PE, Vonk-Noordegraaf A. Interventricular septal configuration at MR imaging and pulmonary arterial pressure in pulmonary hypertension. Radiology 2005;234:710-717.
Tanaka H, Tei C, Nakao S, Tahara M, Sakurai S, Kashima T, Kanehisa T. Diastolic bulging of the
interventricular septum toward the left ventricle. An echocardiographic manifestation of negative
interventricular pressure gradient between left and right ventricles during diastole. Circulation
1980;62:558-563.
Dohi K, Onishi K, Gorcsan J, III, Lopez-Candales A, Takamura T, Ota S, Yamada N, Ito M. Role of
radial strain and displacement imaging to quantify wall motion dyssynchrony in patients with left
ventricular mechanical dyssynchrony and chronic right ventricular pressure overload. Am J Cardiol
2008;101:1206-1212.
Marcus JT, Gan CT, Zwanenburg JJ, Boonstra A, Allaart CP, Gotte MJ, Vonk-Noordegraaf A. Interventricular mechanical asynchrony in pulmonary arterial hypertension: left-to-right delay in peak
shortening is related to right ventricular overload and left ventricular underfilling. J Am Coll Cardiol
2008;51:750-757.
Handoko ML, Lamberts RR, Redout EM, de Man FS, Boer C, Simonides WS, Paulus WJ, Westerhof
N, Allaart CP, Vonk-Noordegraaf A. Right ventricular pacing improves right heart function in
Chapter 6
74.
123
Louis BW.indd 123
06-05-10 11:21
General discussion
85.
86.
87.
experimental pulmonary arterial hypertension: a study in the isolated heart. Am J Physiol Heart Circ
Physiol 2009;297:H1752-H1759.
Dubin AM, Feinstein JA, Reddy VM, Hanley FL, Van Hare GF, Rosenthal DN. Electrical resynchronization: a novel therapy for the failing right ventricle. Circulation 2003;107:2287-2289.
Hardziyenka M, Surie S, de Groot J, de Bruin-Bon HA, Conrath C, Remmelink M, Yong ZY, Baan
J Jr., Bouma BJ, Bresser P, Tan HL. Interventricular resynchronization therapy in right ventricular
failure: a proof-of-concept study in patients with chronic thromboembolic pulmonary hypertension.
Heart failure secondary to chronic pulmonary arterial hypertension: cardiac imaging and electrophysiologic characteristics (thesis).Amsterdam (The Netherlands): 2009. p. 119-44.
Peacock AJ, Naeije R, Galie N, Rubin L. End-points and clinical trial design in pulmonary arterial
hypertension: have we made progress? Eur Respir J 2009;34:231-242.
124
Louis BW.indd 124
06-05-10 11:21