Article

Right ventricular assist device in end-stage pulmonary arterial hypertension: Insights from a computational model of the cardiovascular system

Division of Cardiology, Weill Cornell Medical College, New York, NY. Electronic address: .
Progress in cardiovascular diseases (Impact Factor: 4.25). 09/2012; 55(2):234-243.e2. DOI: 10.1016/j.pcad.2012.07.008
Source: PubMed

ABSTRACT

The high mortality rate of pulmonary arterial hypertension (PAH) mainly relates to progressive right ventricular (RV) failure. With limited efficacy of medical therapies, mechanical circulatory support for the RV has been considered. However, there is lack of understanding of the hemodynamic effects of mechanical support in this setting.
We modeled the cardiovascular system, simulated cases of PAH and RV dysfunction and assessed the theoretical effects of a continuous flow micro-pump as an RV assist device (RVAD). RVAD inflow was sourced either from the RV or RA and outflow was to the pulmonary artery. RVAD support was set at various flow rates and additional simulations were carried out in the presence of atrial septostomy (ASD) and tricuspid regurgitation (TR).
RVAD support increased LV filling, thus improving cardiac output and arterial pressure, unloading the RA and RV, while raising pulmonary arterial and capillary pressures in an RVAD flow-dependent manner. These effects diminished with increasing disease severity. The presence of TR did not significantly impact the hemodynamic effects of RVAD support. ASD reduced the efficacy of RVAD support, since right-to-left shunting decreased and ultimately reversed with increasing RVAD support due to the progressive drop in RA pressure.
The results of this theoretical analysis suggest that RVAD support can effectively increase cardiac output and decreases RA pressure with the consequence of increasing pulmonary artery and capillary pressures. Especially in advanced PAH, low RVAD flow rates may mitigate these potentially detrimental effects while effectively increasing systemic hemodynamics.

Full-text

Available from: Lynn Punnoose, Jan 26, 2015
Right ventricular assist device in end-stage pulmonary arterial
hypertension: insights from a computational model of the
cardiovascular system
Lynn Punnoose
a,
, Daniel Burkhoff
b
, Stuart Rich
c
, Evelyn M. Horn
a
a
Division of Cardiology, Weill Cornell Medical College, New York, NY
b
Division of Cardiology, Columbia University College of Physicians and Surgeons, New York, NY
c
University of Chicago, Chicago, IL
Abstract Background: The high mortality rate of pulmonary arterial hypertension (PAH) mainly relates
to progressive right ventricular (RV) failure. With limited efficacy of medical therapies,
mechanical circulatory support for the RV has been considered. However, there is lack of
understanding of the hemodynamic effects of mechanical support in this setting.
Methods: We modeled the cardiovascular system, simulated cases of PAH and RV dysfunction
and assessed the theoretical effects of a continuous flow micro-pump as an RV assist device
(RVAD). RVAD inflow was sourced either from the RV or RA and outflow was to the
pulmonary artery. RVAD support was set at various flow rates and additional simulations were
carried out in the presence of atrial septostomy (ASD) and tricuspid regurgitation (TR).
Results: RVAD support increased LV filling, thus improving cardiac output and arterial
pressure, unloading the RA and RV, while raising pulmonary arterial and capillary pressures in
an RVAD flow-dependent manner. These effects diminished with increasing disease severity.
The presence of TR did not significantly impact the hemodynamic effects of RVAD support.
ASD reduced the efficacy of RVAD support, since right-to-left shunting decreased and
ultimately reversed with increasing RVAD support due to the progressive drop in RA pressure.
Conclusions: The results of this theoretical analysis suggest that RVAD support can effectively
increase cardiac output and decreases RA pressure with the consequence of increasing
pulmonary artery and capillary pressures. Especially in advanced PAH, low RVAD flow rates
may mitigate these potentially detrimental effects while effectively increasing systemic
hemodynamics. (Prog Cardiovasc Dis 2012;55:234-243.e2)
© 2012 Elsevier Inc. All rights reserved.
Keywords: Pulmonary arterial hypertension; Right ventricular failure; Mechanical circulatory support
Multiple medical modalities have been introduced in
the last decade for the treatment of World Health
Organization (WHO) Group I pulmonary artery hyper-
tension (PAH), including intravenous prostacyclin,
1,2
subcutaneous treprostinil,
3
inhaled iloprost,
4
inhaled
treprostinil,
5
oral endothelin receptor antagonists
6
and
oral phosphodiesterase inhibitors.
7
Nevertheless and
despite these successes, mortality still ranges between
20% and 40% three years after diagnosis
8,9
predomi-
nantly due to progre ssive right ventricular (RV) failure.
Whereas the gradual onset of RV hypertrophy (RVH) in
congenital heart disease allows for a robust and long term
compensatory hypertrophic response, in most other WHO
Group I PAH patients, this initial well compensated RVH
more rapidly progresses to impaired RV contractility,
8
RV
chamber dilatation and leftward shift of the interventric ular
Progress in Cardiovascular Diseases 55 (2012) 234 243.e2
www.onlinepcd.com
Statement of Conict of Interest: See page 242.
Address reprint requests to Lynn Punnoose MD, 520 East 70th
Street, Starr 4, New York, NY 10021.
E-mail address: punnoosl@alum.mit.edu (L. Punnoose).
0033-0620/$ see front matter © 2012 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.pcad.2012.07.008 234
Page 1
septum.
10
This then leads
to under lling of the left
ventricle (LV), systemic
hypotension and a lethal
combination of RV is-
chemia, acidosis, pul-
monary hypertension
crisis and ultimately,
cardiog eni c s hoc k .
With the advent of
successful mechanical
circu latory sup port de-
vices (MCSD) for the
failing LV and their
more recent use for sup-
porting the RV in condi-
tions of biventricular
heart failure in some of
myocarditis, post-cardi-
otomy, post left ventricu-
lar assist device (LVAD)
and heart transplant
patients,
10,11
the use of
MCSD for cardiogenic
shock associated with
PAH and isolated RV
failure is being consid-
ered. However, the he-
modynamic effe cts of
RV support in the setting
of severely elevated pul-
monary vasc ular resis-
tance (PVR), in the
absence of concomitant
mechanical support of
the left ventricle or the
use of extracorporeal membrane oxygenation (ECMO),
have not been delineated. In the absence of clinical data
and the unlikelihood of such data becoming available in
the short term, it is reasonable and appropriate to turn to
computer simulations to provide insights into the
potential benets and hazards of isolated right ventricular
support in PAH. This topic is timely due to t he
availability of new, small mechanical circulatory assist
devices with low ow capabilities. The Synergy micro-
pump system
1214
is one such pump t hat can be
congured for right-sided support (Fig 1) and has been
proposed for use in this specic patient population.
Therefore, the purpose of this study was to employ a
previously validated computational model of the circula-
tory system to simulate varying degrees of PAH disease
severity and to predict the hemodynamic effects of varying
degrees of right ventricular support. Simulations were also
performed in the presence of a sim ulated atrial septostomy,
a form of therapy employe d in some centers for medically
refractory PAH.
15
Methods
Ventricular and atrial contractile properties were
modeled as time-varying elastances and the system ic
and pulmonary vascular beds were modeled by series of
resistance and capacitance elements as detailed
previously
16
and su mmari zed in the Appendix.Right-
sided mechanical circulatory support was modeled by
incorporating a pump with the pressure-o w character-
istics of the Sy nergy continuous o w micr o-pu mp
(CircuLite Inc, Saddle Brook, NJ), also detailed in the
Appendix. RVAD blood ow could be sourced from
either the right atrium or from the right ventricle and
was ejected into the proximal pulmonary artery. Atrial
septostomy was modeled by incorpor atin g a blood ow
path between the right and left atria with a resistance
determined by the equations governing ow through an
orice. Five sets of model parameter values were
established to simulate hemodynamic conditions of
varying degrees of PAH and RV dysf unctio n, yie ldin g
overall conditions ranging from mild right-sided failure
to severe right-sided failure with cardiogenic shock
(CGS). The he modynamic characteristics of the se
patients were determined from a review of the
literature
17,18
and are summarize d in Table 1. Parameter
values of the model were adjuste d by a custom designed
algorithm to t the hemodynamic conditi ons for each o f
these conditions. Parameters that were varied included
those that determine righ t and left ve ntri cular chamber
systolic and diastolic properties (E
es
and α , respec tively) ,
vascular r esis tance (Ra and Rc), vas cul ar compliance
(C) for both s ystemic and pulmonary be ds and stressed
Abbreviations and Acronyms
ASD = atrial septal defect
CGS = cardiogenic shock
CO = cardiac output
CVP = central venous
pressure
ECMO = extracorporeal
membrane oxygenation
LA = left atrium
LV = left ventricle
MCSD = mechanical
circulatory support devices
PA = pulmonary artery
PAH = pulmonary arterial
hypertension
PCWP = pulmonary capillary
wedge pressure
PV = pressure-volume
PVR = pulmonary vascular
resistance
RA = right atrium
RV = right ventricle
RVAD = right ventricular
assist device
RVH = right ventricular
hypertrophy
VAD = ventricular assist
device
Fig 1. Schematic of mechanical circulatory support device, with inow
cannula in the RA and outow in the PA.
235L. Punnoose et al. / Progress in Cardiovascular Diseases 55 (2012) 234243.e2
Page 2
blood volume (which correlates with patient overall
uid status). V alues of key pa rameter s are summa rized
in Table 2 and detailed further in Appendix Table A1.
Aortic, pulmonary arterial, ventricular and atrial
pressure waveforms, as well as RV and LV pressure
volume (PV) loops, were constructed for each disease
state. The effects of RVAD ow rate on these waveforms,
as well as on aortic and pulmonary arterial pressures,
central venous pressure (CVP), pulmonary capillary
wedge pressures (PCWP) and left-sided cardiac output
(CO) were determined. Total blood ow to the pulmonary
artery was the sum of VAD ow plus residual ow
generated directly by the RV. Additional calculations were
carried out for simulated patients with a 6 mm diameter
atrial septostomy, with and without an RVAD.
Results
Review of the literature indicates that with increasing disease
severity, there is progressive RV chamber dilation (correspond-
ing with decreasing diastolic stiffness constant, α)
17
and
hypertrophy with increases in contractile strength (corresponding
with increased E
es
).
10
RA and PA pressures rise, except in severe
end-stage disease with CGS where the RV fails (E
es
decreases)
and is unable to generate higher PA pressures (Tables 1 and 2).
On the other hand, with chronic LV underlling, mean arterial
pressures and CO decline. The reduction in LV chamber size
appears to be due to structural changes in the LV and shifts of the
interventricular septum that result in chamber sti ffening
(reected in the increase in the left ventricular diastolic stiffness
coefcient, α). Also note that in order to appropriately simulate
these cases, stressed blood volumes increased with disease
Table 1
Sample patient hemodynamics and chamber volumes for simulation.
Parameter
Severity of pulmonary hypertension
Normal Mild Moderate Severe CGS
HR (bpm) 60 60 75 85 95
LVEF (%) 55 55 55 55 55
CO (L/min) 5 4.75 4.4 3.5 2.5
CVP (mmHg) 7 12 18 25 25
PASP (mmHg) 20 60 80 100 80
PADP (mmHg) 12 30 35 50 44
mPAP (mmHg) 15 40 50 67 56
PCWP (mmHg) 8 10 10 8 8
Ao-S (mmHg) 130 130 110 90 75
Ao-D (mmHg) 70 70 60 60 52
MAP (mmHg) 87 87 76 70 61
RA volume (mL) 70 100 140 160 160
RV volume (mL) 150 150 200 250 250
LA volume (mL) 70 70 70 70 70
Stressed volume (mL) 1200 1980 2420 2560 2500
AO-D, diastolic aortic pressure; Ao-S, systolic aortic pressure; CGS,
cardiogenic shock; CO, cardiac output; CVP, central venous pressure;
HR, heart rate; LA, left atrium; LVEF, left ventricular ejection fraction;
MAP, mean arterial pressure; mPAP, mean pulmonary arterial pressure;
PADP, pulmonary artery diastolic pressure; PASP, pulmonary artery
systolic pressure; PCWP, pulmonary capillary wedge pressure; RA, right
atrium; RV, right ventricle.
Table 2
Values of model parameters determined to simulate patients with hemodynamic characteristics with different severities of PAH as summarized in Table 1.
Parameter
Severity of pulmonary arterial hypertension
Normal Mild Moderate Severe CGS
Heart rate (bpm) 60 60 75 85 95
AV delay 160 160 160 160 160
Stressed blood
Volume (mL) 1200 1980 2420 2560 2500
Systemic circulation
R
c
(mmHg.s/mL) 0.02 0.02 0.02 0.02 0.02
C
a
(mL/mmHg) 2.2 2.2 1.3 2.7 1.3
R
a
(mmHg.s/mL) 0.92 0.91 0.75 0.73 0.80
Pulmonary circulation
R
c
(mmHg.s/mL) 0.02 0.02 0.10 0.11 0.13
C
a
(mL/mmHg) 13 13 13 1.5 1.5
R
a
(mmHg.s/mL) 0.03 0.34 0.43 0.85 1.00
Left ventricle
E
es
(mmHg/mL) 1.8 1.5 2.1 2.5 4.0
α (mL
1
) 0.023 0.026 0.035 0.049 0.081
Right ventricle
E
es
(mmHg/mL) 0.35 0.61 0.52 0.43 0.32
α (mL
1
) 0.023 0.020 0.020 0.017 0.017
Left atrium
E
es
(mmHg/mL) 0.42 0.44 0.44 0.42 0.42
α (mL
1
) 0.050 0.050 0.050 0.050 0.050
Right atrium
E
es
(mmHg/mL) 0.41 0.31 0.24 0.22 0.22
α (mL
1
) 0.049 0.037 0.028 0.026 0.026
α, diastolic stiffness coefcient; Ca, arterial capacitance; Ees, end-systolic elastance; Rc, proximal resistance; Ra, arterial resistance.
236 L. Punnoose et al. / Progress in Cardiovascular Diseases 55 (2012) 234243.e2
Page 3
severity (Table 2) suggesting, consistent with clinical experience,
that these patients become increasingly volume overloaded as
their disease progresses.
RVADs could be congured to draw blood from either the
RA or RV. Fig 2A summarizes the hemodynamic effects of these
two congurations in the simulated patient with severe PAH. RV
sourcing results in a triangular shaped PV loop, with loss of
isovolumic contraction and relaxation periods, signicant in-
creases in PA diastolic and mean pressures, and slight increases
in PA systolic, LA and aortic pressures. When sourced from the
RA, the loop shifts only slightly leftward (lower RV lling) and
narrows (indicating a decrease in RV stroke volume). Despite the
signicantly different impact on the RV pressure-volume loop,
the impact on RA, pulmonary, left atrial and aortic pressures
achieved with the two congurations are very similar (Fig 2B).
The impact of varying RVAD speed on hemodynamic
parameters is summarized in Fig 3. First consider total pulmonary
blood ow, which is the sum of native RV output and ow from
the RVAD (Fig. 3A). As RVAD speed is increased, RVAD ow
increases and native RV output decreases due to the simultaneous
reduction in RV lling and increase in pulmonary afterload
pressure. In this example, total ow increases from the baseline
value of ~3.5 L/min to ~4.75 L/min at maximal RVAD speed. As
a result of the increased ow, and assuming pulmonary vascular
resistance is xed, there is a progressive increase in diastolic and
mean pulmonary pressures, but syst olic pressure does not
increase substantially (Fig. 3B). Since LV cardiac output equals
the total ow through the pulmonary circuit, this means RVAD
support increases LV lling (increased PCWP), resulting in
increased aortic pressures (Fig. 3C). Two factors contributing to
this rise in pulmonary capillary pressure are the increased
stressed blood volume (which predominantly resides in the
systemic circulation and is shifted to the pulmonary circulation
by the RVAD) and the LV diastolic dysfunction discussed above.
Finally, as RVAD ow is increased there is a progressive
decrease in CVP.
Figs 2 and 3 illustrate the impact of RVAD support in the
simulated case of severe PAH dened according to the data in
Table 1. There were qualitatively similar effects of RVAD
support on right and left ventricular pressure-volume loops at
each stage of PAH disease severity. RVAD support shifted the
LV pressure-volume loops rightward towards higher end-
diastolic volumes (i.e., increased LV lling), with resultant
increases in stroke volume and aortic pressures. Right ventricular
Fig 2. Model simulations of hemodynamic outcomes with RVAD implantation. A, Effects of RVAD implantation on pressure volume loops, with inow
cannula placed in the RA or RV. B, Effects of RVAD implantation on PA, RA, LA and Ao pressures. Abbreviations as per Table 1.
237L. Punnoose et al. / Progress in Cardiovascular Diseases 55 (2012) 234243.e2
Page 4
pressure-volume loops shift leftward (i.e., RV unloading),
become narrower with right atrial sourcing, became triangular
with right ventricular sourcing and resulted in higher diastolic
and mean pulmonary pressures.
However, the effects of RVAD support on hemodynamic
parameters varied with PAH disease severity, as summarized in
Table 3. Data in this table compare baseline hemodynamic
parameters to those simulated with RVAD speed set at 26 k rpm
with inow sourced from either the RA or the RV. Central
venous pressure decreased by 35 mmHg regardless of disease
severity or source of inow. The rise in mean pulmonary artery
pressure was similar for RA and RV sourcing of blood and for
different levels of PAH disease severity, except in the most
extreme case of PAH with cardiogenic shock where the increase
was signicantly greater with RV sourcing. This was mainly due
to the markedly increased pulmonary vascular resistance present
in severe PAH (Table 2). The rise in pulmonary capillary wedge
pressure was also signicantly greater in the end-stage disease
states, due to the severity of LV diastolic dysfunction and the
increased stressed blood volume.
Tricuspid regurgitation
Most patients with severe pulmonary hypertension have
signicant tricuspid regurgitation (TR). Therefore, a simulation
was performed to investigate the potential implications of TR on
the efcacy of right-sided mechanical circulatory support and to
address the potentia l bene ts of RVAD implantation in
combination with a p rocedure to eliminate TR. TR was
introduced into the model, as detailed in the Appendix,by
inclusion of a resistance to backward ow from the right ventricle
to the right atrium; the other model parameter values were set at
the values determined for severe PAH (Table 2). The value of the
resistance was adjusted to simulated moderate-to-severe TR with
a regurgitant fraction of 50% which, in this case corresponded to
a regurgitant volume of 39 mL/beat. As summarized in Table 4,
introduction of TR caused a slight reduction in cardiac output and
thus a decrease in pulmonary, pulmonary capillary and aortic
pressures, though no signicant impact on mean central venous
pressure. The overall efcacy of VAD support was not
signicantly impacted by the presence of TR. When RVAD
support was sourced from the right atrium, there was a 0.2 L/min
improvement in total cardiac output when TR was removed,
which correlated with corresponding increases in pulmonary and
systemic pressures. Interestingly, the regurgitant volume in-
creased slightly with this RVAD conguration, which was a
result of the decrease in right atrial pressure (especially during
RV systole which is not reected in the subtle change in mean
pressure shown in the Table) and an increased RV-RA systolic
pressure gradient. There was even less of an impact of TR on
overall hemodynamics when RVAD support was sourced from
the RV and there was also minimal impact of this form of RVAD
support on regurgitant volume.
Atrial septostomy with and without RVAD
In the simulated patient with severe PAH, the creation of an
atrial septostomy defect (ASD, 6 mm diameter, with resulting
Fig 3. Patient hemodynamics as a function of MCS in severe PAH (RA source). A, Total output compared to RV and device ows. B, PA systolic, diastolic
and mean pressures. C, Aortic systolic, diastolic and mean pressures. D, Wedge and central venous pressures.
238 L. Punnoose et al. / Progress in Cardiovascular Diseases 55 (2012) 234243.e2
Page 5
right-to-left shunt) resulted in leftward shifting of the RA PV
loop towards lower volumes and pressures with a minimal shift in
the RV PV loop. In contrast, LA and LV loops shift rightward,
reecting increased lling pressures and end-diastolic volumes
(Fig 4). These changes underlie a marked increase in LV CO
(Fig 5C) and pulmonary capillary pressure from 8 to 20mmHg
(Fig 5E) and only a modest decrease of 3mmHg in CVP
(Fig 5D). There was no signicant change in PA pressures caused
by the ASD. Shunt fraction (Qp/Qs) was 0.77 with a 6 mm ASD.
Under this condition, with an assumed mixed venous saturation
of 74% and pulmonary capillary saturati on of 100%, aortic
saturation is estimated to be 91% (by the Fick method for a
65 kg, 50 year old female patient with hemoglobin 13.3 g/dL). If
the ASD size was increas ed to 12 mm in diameter, the shunt
fraction decreased to only 0.75. Thus, increasing the size of the
ASD from 6 to 12 mm did not lead to a marked change i n CO or
arterial desaturation.
The overall impact of the septostomy on RVAD effects at
different speeds i n the simulate d case of severe PAH is
summarized in Fig. 5. The septostomy had no signicant impact
on RVAD ows (Fig 5B) or mean PA pressures (Fig 5F).
Compared to the simulated patient without an ASD, addition of
an RVAD at low speeds (24 kRPM) did not improve total
cardiac output (LV CO, Fig 5C) but, because of the reduction in
RA pressure, did decrease shunt ow. Pulmonary capillary
pressure was higher at low RVAD ows in the presence of the
ASD (Fig 5E). Notably, at higher RVAD ows (i.e., 26 kRPM)
the drop in RA pressure was sufcient to reverse the ow through
the ASD (Fig 5A); compared to the case without an ASD, this
lead to lower pulmonary capillary pressures (Fig 5E), but also to
lower LV CO (Fig 5C) and no improvement in CVP (Fig 5D).
Shunt ow reversal was observed even at low RVAD ows in
the patient with moderate disease and an ASD due to earlier
reversal of the interatrial pressure gradient.
Discussion
Mechanical support of the failing RV decreas es RA
pressures and RV stroke work, unloads the RV and
increases CO effectively in cases of inferior MI, sepsis and
post-cardiotomy RV failure
19
as well as in patients with
RV failure after LVAD implantation and orthotopic heart
transplantation.
10,11
By contrast, its efcacy in patients
with PAH has not been well described. A specic
challenge for RVAD use in PAH is how to safely augment
ow through a pulmonary vascular bed with signicantly
elevated resistance and impedance,
20,21
with concerns of
damaging the m icrocirculation leading to pulmonary
hemorrhage, as described in one case report.
22
To our
knowledge, only two case reports to date detail the use of
RVAD in severe PAH and cardiogenic shock.
22,23
In the
rst,
23
an RVAD was implanted for 56 hours, and it
generated higher PA pressures but also rises in CO and
aortic pressures
23
without evidence of pulmonary hemor-
rhage. The second
22
describes suprasystemic pulmonary
hypertension immediately after RVAD implantation, with
subsequent pulmonary hemorrhage necessitating a switch
from RVAD to ECMO for hemodynamic support.
Table 3
Hemodynamic effects of RVAD support set At 26 kRPM, with either RA or RV used as inow source.
PH
CVP mPAP PCWP MAP CO
Baseline RVADRA RVADRV Baseline RVADRA RVADRV Baseline RVADRA RVADRV Baseline RVADRA RVADRV Baseline RVADRA RVADRV
Mild 12 8 9 40 59 55 10 23 20 87 102 101 4.75 5.93 5.75
Moderate 18 13 14 50 73 70 10 24 22 76 86 86 4.4 5.5 5.4
Severe 25 18 18 67 80 79 8 26 25 70 79 79 3.5 4.78 4.74
CGS 25 20 20 56 105 115 8 37 44 61 71 73 2.53 3.63 3.78
239L. Punnoose et al. / Progress in Cardiovascular Diseases 55 (2012) 234243.e2
Page 6
The present simulations demonstrate that partial RV
circulatory support can signicantly augment cardiac
output and decrease RA pressures (Table 3) in patients
with PAH, RV dysfunction and heart failure. As illustrated
by pressure-volume analysis (Fig 2), this is true whether
sourcing inow is from the RA or the RV. RVAD support
decreases RV end-diastolic pressures and volumes and
increases LV lling, total cardiac output and arterial blood
pressure. These hemodynamic improvements are less
pronounced in the simulated pati ents with more severe
disease (Table 3), due to progres sive increases in
pulmonary vascular resistance and xed RV afterload.
Furthermore, with worsening disease, RVAD support
causes signicant increases in diastolic and mean
pulmonary pressures (Fig 3, Table 3), though not in
systolic pulmonary pressure. This is consistent with prior
reports of increased PA pressures with RVAD support
20,23
due to increased ows pumping into high resistance
vasculatures, particularly with decreasing vascular com-
pliance in more severe disease.
24
However, at present, our
model does not incorporate rheological abnormalities of
the diseased vasculature.
In addition to higher PA pressures, simulated RVAD
ows achieved at 26 kRPM (~3 L/min) also lead to rising
pulmonary capillary wedge pressures at every disease
severity (Table 3). The effects on pulmonary arterial and
venous pressures were markedly more dramatic in the
patient with cardiogenic shock, even as CO and RA
pressures improved. This result reects the effect of the
increased stressed volumes with increasing degrees of heart
failure (Table 1) that are now shifted to a previously
underlled pulmonary circuit and LV. The increased
Table 4
Hemodynamic impact of tricuspid regurgitation on RVAD support in different congurations.
TR
TR Volume RVAD Speed RVAD Flow RV CO Total CO CVP PAP PCP AoP
mL/beat kRPM L/min L/min L/min mmHg mmHg mmHg mmHg
Baseline No 0 0 0 3.55 3.55 25 101/50 (67) 8 90/62 (70)
Yes 37 0 0 3.25 3.25 25 89/45 (60) 6 86/59 (67)
RA-PA VAD Yes 45 26 3.95 0.44 4.34 22 97/86 (88) 18 101/68 (79)
No 0 26 3.82 0.77 4.54 21 109/92 (96) 22 103/69 (80)
RV-PA VAD Yes 39 26 4.2 0.09 4.39 22 92/86 (88) 19 102/69 (79)
No 0 26 4.19 0.31 4.5 22 102/91 (93) 21 103/69 (80)
TR, tricuspid regurgitation; RA-PA VAD, right atrial-to-pulmonary artery VAD conguration; RV-PA VAD, right ventricular-to-pulmonary artery VAD
conguration; RV, right ventricle; CO, cardiac output; CVP, central venous pressure; PAP, pulmonary artery systolic/diastolic (mean) pressure; PCP,
pulmonary capillary pressure; AoP, aortic systolic/diastolic (mean) pressure.
Fig 4. PV loops for each heart chamber generated in severe PAH, with and without atrial septostomy.
240 L. Punnoose et al. / Progress in Cardiovascular Diseases 55 (2012) 234243.e2
Page 7
stressed volumes correlate with clinical practice in that
patients with PAH become increasingly volume overloaded
due, at a minimum, to renal hypoperfusion and sympathetic
activation, which conspire to reduce renal function, the
same as in end-stage left-sided heart failure. From a clinical
perspective, this picture is also similar to unexpected LV
failure following lung transplantation or inhaled nitric
oxide
25
: augmented ows to the LV following a decrease in
PVR result in signicant and abrupt shifts of volume from
the peripheral vasculature to the pulmonary circulation.
Such abrup t redistribution of volume can result in
pulmonary edema, even in the setting of normal LV
systolic and diastolic function.
26
In addition, recent studies in animals
27,28
and
humans
29,30
with PAH have provided evidence of LV
diastolic dysfunction, manifest as reduced chamber size (i.e.,
leftward shifted end-diastolic pressure-volume relationship).
Indeed, our patient hemodynamic parameter tting algo-
rithm indicated that with increasing disease severity and
progressively lower cardiac outputs, LV diastolic stiffness
increased substantially (i.e., higher LV diastolic stiffness
coefcient, α, Table 2). Increased LV diastolic stiffness
would also be expected to contribute to the risk of increased
pulmonary capillary pressure in the setting of large volume
shifts from peripheral to pulmonary circulations.
An analysis of the potential impact of tricuspid
regurgitation on the effectiveness of RVAD was also
performed. The results showed that the presence of TR did
not impact signicantly on the hemodynamic effectiveness
of the RVAD, nor did the RVAD have a signicant effect
the degree of TR. This appears to be because as disease
severity increases, right atrial volume and compliance
increase substantially, which has the effect of increasingly
dampening the hemodynamic effects of TR. There is,
however, one potential advantage of the presence of TR
with the RVA D when it is used in a conguration that
sources blood from the right atrium. Specically, in severe
PAH, the RVAD has the potential to overtake the RV so
that there is no output from the native RV. If that happens,
there can be stagnation of blood within the RV which has
the potential to form intraventricular clots. When signif-
icant TR is present, blood continues to ow into and out of
the RV with each beat, independent of RVAD speed
which, along with standard VAD anticoagulation and
antiplatelet therapy, eliminates this possibility. When
blood is source d directly from the RV, this is not a factor.
The result of this analysis suggests that there would be no
signicant benet of surgically correcting TR at the time
of RVAD implantation.
Taken together, our ndings would argue for the
potential benets of partial RV support, for starting
RVADs at low ows (particularly based on severity of
disease) and, importantly, also addressing the higher
stressed volumes with diuresis or ultraltration if necessary.
Fig 5. Patient hemodynamics as a function of MCS, with and without atrial septostomy, showing shunt ow (A, positive values indicate right to left shunt),
device ows (B), total output (C), CVP (D), PCWP (E) and mPAP (F). Abbreviations as per Table 1.
241L. Punnoose et al. / Progress in Cardiovascular Diseases 55 (2012) 234243.e2
Page 8
Decreasing PVR with vasodilators would also be
helpful in the long run; however, patient selection for
RVAD support would undoubtedly require failed treat-
ment with vasodilators. It would therefore not be expected
that further vasodilation can be achieved in the patients
likely to undergo RVAD implantation. On the other hand,
preexisting vasodilator therapy should denitely not be
withdrawn. Furthermore, it is conceivable that pulmonary
capillary pressure could rise even further with additional
vasodilation. An earlier simulation of acute and chronic
PH showed, consistent with clinical case reports, that
higher pulmonary venous pressures and pulmonary edema
can result from vasodilation with nitric oxide.
25
As
discussed above, this was primarily due to the shift of
volume from the systemic to pulmonary vasculature in
response to the decrease d PVR.
In se lect patients with advanced PAH and RV
dysfunction, atrial septostomy can be performed as a
palliative procedure, reducing RA pressures, augmenting
ow to the left side, improving systemic output
15
and
survival.
31
We hypothesized that an atrial septostomy
could both augment CO and mitigate the higher PA
pressures produced by the RVAD ows. Indeed, in the
patient with severe PAH (PA systolic pressure of 100),
baseline RA pressures decreased and CO improved with
the addition of an ASD (Fig 5), but without much change
in PA pressures. However, the RVAD, by withdrawing
blood from either RA or RV, decreased interatrial pressure
gradients, diminished the right-to-left shunt ow and then
eventually reversed it (Fig 5A). For this reason, adding an
RVAD to a patient with an ASD would not appear to
produce a further increase in CO (Fig 5C) or decrease in
CVP ( Fig 5D). In fact, with outright shunt reversal at
RVAD speeds of 28 kRPM, LV CO decreases and ow
through the pulmonary vascular bed increases due to left-
to-right shunting.
Limitations
There are many important limitations inherent in any
theoretical simulation and the results should not be
considered in detailed quantitat ive terms. For the current
analysis, particular limitations relate to assumptions about
the hemodynamic properties of the pulmonary circulation
and effects of RVAD implantation. First, the model
reects the acute effects o f RVADs, assuming, for
example, that PVR, LV diastolic properties and stressed
blood volume all remain the same immediately before and
after RVA D implantation. However, in the hours or days
after RVAD implantation, improved CO and renal ow
may promote an augmented diuresis and effectively
decrease the stressed blood volumes. Similarly, reduction
of sympathetic tone could decrease venous tone and also
contribute to decreased stressed volumes. Furthermore,
with all of the many changes induced by RVAD support, it
is possible that pulmonary properties (and in particular,
PVR) may decrease following initiation of support. In
such a case, mean PAP may not rise as much as the model
predicts. Additionally, the model did not include inter-
ventricular interactions with RV unloading. Decreased RV
loading will normalize septal motion, improve LV
diastolic lling
30
and thereby decrease the effect of
stressed volumes; the immediate rise in pulmonary
capillary pressure would be reduced over time.
Conclusions
Heart failure in the setting of advanced PAH and RV
dysfunction represents a difcult therapeutic challenge.
Our hemodynamic model demonstrates that partial
circulatory support of the RV can effectively augment
CO and decrease RA pressures, but at the expense of
RVAD ow-dependent increases in mean PA pressure and
pulmonary capillary pressure. These effects were partic-
ularly prominent in our simulation of the most advanced
and decompensated right heart failure simulation. Thus,
the results suggest that low RVAD ows, especially early
after initiation of support, minimize these potential adverse
effects related to both the added stressed volume on the
previously under-lled LV and of the high blood ows
through a pulmonary bed with h igh vascular resistance
while effectively improving systemic hemodynamics. In
this regard, the Synergy device may be ideally suited
because of its small size and ability to be set at ows as
low as 1.5 L/min.
Statement of Conflict of Interest
This work was supported by a grant from the
Cardiovascular Medical Research and Education Fund
(Philadelphia, PA) awarded to DB. DB is also an
employee of CircuLite Inc, the manufacturer of the
Synergy micro-pump. The remaining authors have no
conicts of interest to disclose.
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243L. Punnoose et al. / Progress in Cardiovascular Diseases 55 (2012) 234243.e2
Page 10
Appendix
The cardiovascular system was modeled as shown by
the electrical analog in Figure A1. The details of this
model are provided elsewhere
26,32
and will be discussed
here in brief. Ventricular and atrial pumping characteris-
tics were represented by modications of the time-var ying
elastance [(E(t)] theory of chamber contraction which
relates instantaneous ventricular pressure [P(t)] to instan-
taneous ventricular volume [V(t)]. For each chamber:
PtðÞ=P
ed
VðÞ+etðÞP
es
VðÞP
ed
VðÞ½
In which:
P
ed
VðÞ= β e
α VVoðÞ
1

P
es
V
ðÞ
=E
es
VV
o
ðÞ
and
etðÞ=
1
2
sin π = T
max
ðÞtπ = 2½+1
fg
0bt3 = 2T
max
1
2
e
t3T
max
= 2ðÞ=
τ t N 3 = 2T
max
where P
ed
(V) is end-diastolic pressure as a function of
volume, P
es
(V) is end-systolic pressure as a function of
volume, E
es
is end-systolic elastance, V
o
is the volume axis
intercept of the end-systolic pressure-volume relationship
(ESPVR), α and β are parameters of the end-diastolic
pressure-volume relationship (EDPVR), T
max
is the point of
maximal chamber elastance, τ is the time constant of
relaxation and t is the time during the cardiac cycle.
The systemic and pulmonary circuits are each modeled
by lumped venous and arterial capacitances (C
v
and C
a
,
respectively), a proximal resistance (R
c
, also commonly
called characteristic impedance) which relates to the
stiffness of the proximal aorta or pulmonary artery, a
lumped arterial resistance ( R
a
), and a resistance to return of
blood from the venous capacitance to the heart (R
v
, which
is similar, though not identical, to Guyton's resistance to
venous return
33
). The heart valves permit ow in only one
direction through the circuit. Tricuspid regurgitation (TR)
was introduced by adding a second diode in the opposite
direction with a serial resistance that could be adjusted to
set the degree of tricuspid regurgitation.
The total blood volume (V
tot
) contained within each of
the capacitive compartments is divided functionally into
two pools: the unstressed blood volume (Vol
unstr
) and the
stressed blood volume (Vol
str
). Vol
unstr
is dened as the
maximum volume of blood that can be placed within a
vascular compartment without raising its pressure above
0 mmHg. The blood volume within the vascular compart-
ment in excess of Vol
unstr
is Vol
str
, so that V
tot
=V-
unstr
+V
str
. The unstressed volume of the entire vascul ar
system is equal to the sum of Vol
unstr
of all the capacitive
compartments; similarly, the total body stressed volume
equals the sum of Vol
str
for all compartments.
34
The
pressure within the compartment rises linearly with Vol
str
in relation to the compliance ( C): P =Vol
str
/C.
The RVAD was modeled as a continuous ow pump
with approximately linear pressure-ow characteristics
that varied with pump speed as shown in Figure A2. These
data were obtained from a real Synergy System
(including inow and outow grafts) interfaced with a
mock circulation lled with a water-glycerol solution
(viscosity 3.6 cp). This pump is currently in clinical trials
as a left ventricular assist device to provide partia l
circulatory support to patients with INTERMACS 4, 5
and 6 heart failure.
14,35
As illustrated, such a pump can
generate ows up to 4.25 L/min with its impeller spinning
at 28,000 rpm (pressure head between 100 and
150 mmHg). As indicated in Figure A1, it could be
specied during t he simulation w hether the R VAD
withdrew blood from the right atrium or from the right
ventricle. In either case, the blood was pumpe d to the
proximal portion of the arterial system.
The normal value of each parameter of the model was
set to be appropriate for a 7075 kg man (body surface
area 1.9 m
2
). These values, adapted from values in the
literature
32,3638
are listed in Table A1. Values used to
simulate patients with different degrees of PAH are
summarized in the main text, Table 2.
Finally, atrial septostomy was modeled by a connection
between right and left atria through which ow was
determined by the equation governing ow through an orice:
Flow = K:Area:
ffiffiffiffiffiffi
ΔP
p
Where A is the area (in cm
2
), ΔP is the pressure gradient
across the orice (in mmHg) and K =2.66.
Table A1
Normal parameter values.
Parameter
group/name Symbol Units Values
Common
parameters
Heart rate HR min
1
70
AV delay AVD msec 160
Total blood
volume
BV
tot
mL 5000
Stressed
blood
volume
BV
stress
mL 950
Unstressed
blood
volume
BV
unstress
mL 4050
Heart RA RV LA LV
End-systolic
elastance
E
es
mmHg/
mL
0.45 0.61 0.45 3
Volume axis
intercept
V
o
mL 10 5 10 5
Β mmHg 0.44 0.35 0.44 1.3
243.e1L. Punnoose et al. / Progress in Cardiovascular Diseases 55 (2012) 234243.e2
Page 11
Table A1 (continued)
Parameter
group/name Symbol Units Values
Scaling factor
for EDPVR
Exponent for
EDPVR
α mL
1
0.049 0.04 0.049 0.027
Time to
end-systole
T
max
msec 125 200 125 200
Time constant
of relaxation
Τ msec 25 30 25 30
AV valve
resistance
R
av
mmHg.s/
mL
0.0025 0.0025
Circulation Pulmonary Systemic
Characteristic
impedance
R
c
mmHg.s/
mL
0.03 0.04
Arterial
resistance
R
a
mmHg.s/
mL
0.03 1.1
Venous
Resistance
R
v
mmHg.s/
mL
0.025 0.025
Arterial
compliance
C
a
mL/
mmHg
13 1.5
Venous
compliance
C
v
mL/
mmHg
870
Fig A1. Electrical analog for modeling the cardiovascular system.
Fig A2. Pressure-ow characteristics of the RVAD.
243.e2 L. Punnoose et al. / Progress in Cardiovascular Diseases 55 (2012) 234243.e2
Page 12
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