CASE REPORT

Selective pulmonary vasodilation improves ventriculovascular

coupling and gas exchange in a patient with unrepaired
single-ventricle physiology
F. Rischard,1 R. Vanderpool,2 I. Jenkins,3 M. Dalabih,1 J. Colombo,4 D. Lax,5 M. Seckeler5
1
Department of Pulmonary, Critical Care, Sleep, and Allergy Medicine, University of Arizona, Tucson, Arizona, USA; 2Pulmonary Vascular Disease Center,
University of Pittsburgh, Pittsburgh, Pennsylvania, USA; 3BIO5 Institute, University of Arizona, Tucson, Arizona, USA; 4Department of Pediatrics, University
of Arizona, Tucson, Arizona, USA; 5Department of Pediatric Cardiology, University of Arizona, Tucson, Arizona, USA

Abstract: We describe a 63-year-old patient with unrepaired tricuspid valve atresia and a hypoplastic right ventricle (single-ventricle physiology)
who presented with progressive symptomatic hypoxia. Her anatomy resulted in parallel pulmonary and systemic circulations, pulmonary arterial
hypertension, and uncoupling of the ventricle/pulmonary artery. Hemodynamic and coupling data were obtained before and after pulmonary
vasoactive treatment, rst inhaled nitric oxide and later inhaled treprostinil. The coupling ratio (ratio of ventricular to vascular elastance) shunt
fractions and dead space ventilation were calculated before and after treatment. Treatment resulted in improvement of the coupling ratio between
the ventricle and the vasculature with optimization of stroke work, equalization of pulmonary and systolic ows, a decrease in dead space ventilation from 75% to 55%, and a signicant increase in 6-minute walk distance and improved hypoxia. Inhaled treprostinil signicantly increased
6-minute walk distance and improved hypoxia. This is the rst report to show that pulmonary vasoactive treatment can be used in a patient with
unrepaired single-ventricle anatomy and describes the hemodynamic effects of inhaled therapy on ventriculovascular coupling and gas exchange
in the pulmonary circulation in this unique physiology.
Keywords: pulmonary hypertension, ventricular/vascular coupling hemodynamics, congenital heart disease, treatment effect.
Pulm Circ 2015;5(2):407-411. DOI: 10.1086/681269.

Pulmonary arterial hypertension (PAH) is a progressive disease dened by severe pulmonary vasculopathy resulting in high right ventricular (RV) afterload. Although treatment focus is often on the pulmonary vasculopathy, mortality in this disease is most specically
indicated by RV load adaptation.1 Therefore, there has been recent
research emphasis on methods directed toward recognition of early
pump dysfunction. One such method is ventriculovascular coupling,
a method that describes the hydraulic transfer of energy from the ventricle to the vasculature.2 This method is not generally thought of
in the context of the coupling of gas exchange. Functional improvements with therapy are attributed to a combination of improvements
in gas exchange and RV function. However, the extent to which each
component contributes is unknown.
Ventriculovascular coupling is most often described by the coupling ratio, the numeric ratio of ventricular elastance (Ees) to vascular elastance (Ea). Ees is often termed contractility and thought
of as a component that is independent of acute changes in preload
and afterload, or Ea. The RV increases contractility as an adaptation to sustained increases in afterload.3 The degree of adaptation
of the ventriculovascular unit is typically indicated by the coupling
ratio, Ees/Ea. While stroke work is optimized at a coupling ratio of
1.0,4 studies of experimental PAH indicate that the system is coupled
under normal conditions to maximum work for minimum energy
cost (efciency) at a coupling ratio of approximately 1.52.0.5

Pulmonary gas exchange in vascular disease can be characterized

: :
by increased inequality of ventilation-perfusion (V=Q ) unitslower
: :
: :
V=Q units nearing shunt and higher V=Q units nearing dead space
(VD/VT).6 Shunts may be intracardiac, such as a patent foramen ovale,
or intrapulmonary, due to relative overperfusion of nondiseased lung
segments. Dead space is due to poor perfusionfrom vasculopathy,
for exampleof well-ventilated segments. Thus, gas exchange abnormalities in PAH can be described by shunt and dead space analysis.7
We present an adult patient with complex, unrepaired congenital
heart disease with single-ventricle physiology. This represents a unique
clinical situation where a single pump, a morphologic left ventricle
(LV), distributes stroke volume to both the pulmonary and the systemic circulation, and the volume distribution is determined by afterload in parallel. In this situation, symptoms may result primarily from
gas exchange imbalance, early ventriculovascular uncoupling indicating pump dysfunction, or both. Therefore, this is a unique scenario
by which we can study the effects of coupling integrated with gas exchange under changing conditions as well as how this interaction
affects functional parameters.
CAS E DE S CR I PT I ON
A 63-year-old woman was referred for evaluation of treatment for
her pulmonary hypertension and possible embolization of aortopulmonary collateral arteries after suffering recurrent hemoptysis. She

Address correspondence to Dr. Franz P. Rischard, 1501 North Campbell Avenue, Tucson, AZ 85724, USA. E-mail: [email protected].
Submitted October 8, 2014; Accepted December 8, 2014; Electronically published April 29, 2015.
2015 by the Pulmonary Vascular Research Institute. All rights reserved. 2045-8932/2015/0502-0022. $15.00.

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atrium, across the atrial septal defect, and into the LV. The catheter
was then advanced to the pulmonary artery for hemodynamic measurements.
Ventricular (Ees), pulmonary arterial (Eapulm), and systemic arterial (Easys) systolic elastances were calculated using the single-beat
method, as described elsewhere.3 This method utilizes Piso, the isovolemic pressure of a nonejecting beat, determined by sine extrapolation of the RV waveform near maxima dP/dt and minima dP/dt
(Fig. 2). For clarication, contractility,
Ees Piso  sPAP=SVpulm and Piso  sAo=SVsys ;

resulted in nearly equivalent Ees (Fig. 2). For afterload,

Eapulm sPAP=SVpulm ;
Easys sAO=SVsys :

So the coupling ratio is

Ees=Eapulm or sys Piso  ESP=SV=ESP=SV

Piso =ESP  1;
where Piso is maximal nonejecting ventricular pressure, sAo is systolic aortic pressure, sPAP is systolic pulmonary arterial pressure,
SV is stroke volume, and ESP is end-systolic pressure (either pulmonary or systemic, as appropriate). SV for this calculation was estimated using time-averaged pulmonary and systemic ow from
the Fick principle, corrected for heart rate. Shunt ratios were also
calculated using the Fick principle with arterial and venous blood

Figure 1. Cardiac anatomy of the patient. A, Two-dimensional echocardiographic apical four-chamber view showing an atretic tricuspid valve (arrow), severely hypoplastic right ventricle, large secundum atrial septal defect, and normal-sized left atrium and ventricle.
B, Ventriculography with an angiographic catheter advanced antegrade up the inferior vena cava, across the atrial septal defect, and
into the apex of the ventricle (thick black arrow). The great arteries
are transposed, and the morphologic left ventricle gives rise to a calcied main pulmonary artery (blue arrow) and, through a nonpressure
restrictive ventricular septal defect, to the aorta (thin black arrow).

was diagnosed as a child with tricuspid valve atresia, a hypoplastic

RV, transposition of the great arteries (aorta arising from the hypoplastic RV and pulmonary artery arising from the LV), a ventricular
septal defect, and an atrial septal defect (Fig. 1). She had signicant
hypoxemia for years, was receiving chronic oxygen supplementation,
and had subjectively worsening dyspnea. She underwent diagnostic
cardiac catheterization with general anaesthesia. A 5F balloon-tipped
wedge catheter was advanced through the venous system to the right

Figure 2. Pressure-volume relationship of the single ventricle relative to pulmonary and systemic elastance before and after inhaled
nitric oxide (iNO) therapy. Maximal isovolemic pressure (Piso) is
denoted by asterisks. Shown are pulmonary effects of reduced afterload (Ea), reduced systolic pulmonary arterial pressure, and improved
pulmonary ow. Systemic coupling demonstrates a concurrent increase in afterload during therapy with only a slight change in ow.
Thus, treatment aided in restoring balance to the system, reducing
overall afterload and improving stroke work. Ees: ventricular elastance.

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and 20 ppm of inhaled nitric oxide (iNO). Metabolic cart analysis was used for direct measurement of oxygen consumption and
calculation of dead space. Since there was no outow pressure restriction, combined afterload in parallel of the ventricle represents
the harmonic mean of pulmonary and systemic vascular impedance.
Therefore, stroke work, the area bounded by the pressure-volume
loop, was taken as the numeric mean of both systolic pressure and
SV, giving the equation


SW sPAP sAo=2  EDP SVpulm SVsys =2 :

Figure 3. Pulmonary arterial and aortic pressure tracings. The pulmonary arterial waveform (PA; thin arrow) has taken a rounded peak
and rapid taper similar to the aortic waveform (Ao; thick arrow), indicating increased pulse-wave reection and reduced compliance. However, delay in dicrotic notching and reduced diastolic pressure indicate retention of some of the normal pulmonary arterial phenotype.
gas analysis and oximetry. Resistance-compliance (RC) time was calculated as the product of resistance and compliance corrected for
heart period. This metric is a constant that may be used to quantify the relative contribution of compliance/pulsatile components to
afterload.
The patient was studied with baseline measurements at 35%
FiO2 and repeat measurements under 100% FiO2 and 100% FiO2

After hemodynamics were obtained, the interventional cardiologist

(MS) proceeded with embolization of the aortopulmonary collateral arteries that were causing hemoptysis. After discharge, the patient underwent 6-minute walk distance (6MWD) testing before
and after inhaled treprostinil. Inhaled treprostinil was titrated to
effect, including tolerance, dyspnea relief, oxygenation, and walk
distance. Echocardiography, both before and after treatment, demonstrated normal ventricular systolic function (ejection fraction of
>60%). She has not had recurrence of hemoptysis.

Hemodynamics and gas exchange

Results during catheterization showed elevated pulmonary pressure, resistance, and elastance. Pulmonary arterial and aortic pressure tracings are shown in Figure 3. The pulmonary arterial waveform showed a hybrid contour (rounded peak similar to an aortic
tracing) but a rapid descent to a lower diastolic pressure and a dicrotic notch. Baseline hemodynamics demonstrated a right-to-left
shunt (Table 1). Dead space measured 75% at baseline. Measurements were unchanged with 100% FiO2. During iNO inhalation,
pulmonary pressure, resistance, and elastance all decreased. The
shunt equalized, and there was a small improvement in dead space
(Table 1).

Table 1. Hemodynamic and gas exchange data

Patient characteristics and hemodynamics

Body surface area, m2
Systolic pulmonary arterial pressure, mmHg
Diastolic pulmonary arterial pressure, mmHg
Mean pulmonary arterial pressure, mmHg
Systolic aortic pressure, mmHg
Ventricular end-diastolic pressure, mmHg
Pulmonary ow, L/min/m2
Systemic ow, L/min/m2
Right-to-left shunt, %
Ratio of dead space to tidal volume, %

Baseline

100% FiO2 +
20 ppm of iNOa

16-week
follow-up

1.46
123
29
66
93
11
2.4
3.4
62
75

110
30
64
115
9
3.3
3.1
51
70

...
...
...
...
...
...
...
55
55

Note: Selective pulmonary vasodilator treatment led to improvements in pulmonary pressure,

systemic pressure, ow, and gas exchange. iNO: inhaled nitric oxide.
a
There was no change in gas exchange or hemodynamics with 100% FiO2 alone; therefore,
these data are not presented.

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Table 2. Coupling and afterload data

Hemodynamics and pressure volume data

Baseline

100% FiO2 + 20 ppm of iNO

Pulmonary vascular resistance, iWU

Systemic vascular resistance, iWU
Pulmonary vascular compliance, mL/mmHg
Systemic vascular compliance, mL/mmHg
Pulmonary vascular elastance, mmHg/mL
Systemic vascular elastance, mmHg/mL
Pulmonary vascular RC time, s
Systemic vascular RC time, s
Ventricular systolic elastance, mmHg/mL
Systolic ventricular-pulmonary coupling ratio
Systolic ventricular-systemic coupling ratio
Stroke work, mL mmHga

23
21.1
0.47
0.89
2.73
1.45
0.43
0.90
1.48
0.54
1.02
5,335

16.7
22.6
0.81
0.92
1.77
1.95
0.52
0.92
1.88
1.06
0.96
6,231

Note: Pulmonary vasodilation led to improvement with a decrease in afterload and improved coupling and
optimization of stroke work. iWU: indexed Wood units; RC: resistance-compliance.
a
Stroke work was calculated as [(sPAP + sAo/2) EDP] (SVPA + SVAo/2), where sPAP is systolic
pulmonary arterial pressure, sAo is systolic aortic pressure, EDP is ventricular end-diastolic pressure, SVPA is
pulmonary arterial stroke volume, and SVAo is aortic stroke volume. Ventricular and vascular elastances are
calculated from the estimate of stroke volume derived from the Fick principle.

Ventriculovascular coupling
Baseline pulmonary afterload was very high and decreased considerably during iNO therapy (Table 2). Although contractility was high,
the pulmonary ventriculovascular interaction was uncoupled at baseline (0.54). As illustrated in Figure 2, the pulmonary ventriculovascular coupling ratio improved during iNO therapy (1.06), while
systemic ventriculovascular coupling was unchanged. This led to improvements in pulmonary stroke volume index, from a baseline of
31 to 43 mL/m2 during iNO therapy.

systemic perfusion, but such a balance is difcult to attain. Additionally, combined mean harmonic afterload may substantially increase
ventricular work as pulmonary vasculopathy progresses, leading to
eventual pump failure.

Decrease in pulmonary vascular afterload results

in improved gas exchange and distribution
of pulmonary blood flow
Although baseline pulmonary afterload was quite high, the pulmonary arterial pressure waveform morphology demonstrated re-

Long-term therapy and functional improvement

Given the physiological improvements, we attempted to treat the
patient similarly in the ambulatory setting. The patient was titrated
on inhaled treprostinil to ve inhalations four times daily. She had
sustained functional improvement measured during submaximal exercise, with a 6MWD increase of more than 100 m (Table 3). She
also had sustained benets in resting right-to-left shunt and large reductions (20%) in dead space relative to baseline (Table 1).
DISCUSSION
The results of the present case suggest that selective pulmonary vasodilator treatment aids in the coupling of the ventriculovascular
unit for gas exchange and optimization of stroke work. Although
animal models of single-ventricle physiology demonstrate similar
ndings,8 these ndings are unique in that they are the rst to show
combined physiological and functional benet in a patient.
Tricuspid valve atresia without outow obstruction allows a single ventricle to distribute stroke volume to the pulmonary and systemic circulations. Proper balance between pulmonary and systemic
afterload ensures adequate gas exchange while maintaining a normal

Table 3. Functional improvement in 6-minute walk distance

(6MWD) before and after treatment with inhaled treprostinil
4-week
follow-up

16-week
follow-up

Functional improvement

Baseline

6MWD, m
SpO2 nadir, %
Supplemental O2, LPM
Maximal heart rate, bpm
Maximal systolic blood
pressure, mmHg
Borga

169
76
4
85

218
76
3
96

271
85
3
85

126
2

122
0.5

138
1

Note: Signicant improvements with inhaled treprostinil in functional capacity, systemic oxygen saturation, and maximal systolic
blood pressure were observed.
a
Borg scale of dyspnea (110), where 10 indicates increased
dyspnea.

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tained phenotypic characteristics of the normal pulmonary circulation, and RC time remained approximately half that of the systemic circulation. In addition, the patients intrapulmonary ventilation
perfusion matching was likely near normal, as evidenced by the
lack of effect of 100% FiO2 on the degree of right-to-left shunting.
These two characteristics helped maintain a balance of volume distribution and gas exchange until the gradual onset of pulmonary vasculopathy.
In this context, iNO and treprostinil likely lead to restoration
of the optimal balance in gas exchange coupling. Initial improvements in pulmonary blood ow resulted from acute changes in vaso: :
reactivity or distribution to relatively normal V=Q units, given the
lack of change in dead space. Later, during chronic inhaled treprostinil
therapy, there was an improvement in dead space as well, indicating
an improvement in the vasculopathic process.

or predominantly intrapulmonary shunts. Furthermore, the effects

of selective pulmonary vasodilation on shunting in patients with
normal atrial-ventricular-vascular concordance may not be as impressive.
In summary, treatment-associated improvements in gas exchange
in this patient were associated with improvements in ventriculovascular coupling. This phenomenon may indicate a new link between
gas exchange and hydraulic work optimization. Additionally, this
case highlights a novel use of inhaled treprostinil to establish optimal gas exchange and functional status.

Pulmonary vasodilatation results in improvement

in ventricular dysfunction and optimization
of stroke work

Conict of Interest: None declared.

The patient presented with no signs or symptoms of ventricular

failure, and echocardiography demonstrated normal ejection fraction.
However, at baseline the ventriculovascular unit had likely reached
maximum contractile reserve. The ventricle was uncoupled from
the pulmonary circuit in the presence of systemic hypotension. Pulmonary vasoactive treatment led to a balance of coupling, optimization of stroke work, and equalization of ow. These relationships
are likely maintained during treatment with inhaled treprostinil.
Given maintained systemic blood pressure, shunt fraction, and oxygenation, both coupling and gas exchange were maintained amazingly under dynamic conditions, and signicant functional improvement resulted.
Although there was a drop in pulmonary vascular afterload during iNO therapy, the overall load of the ventricle remained relatively
unchanged (composite Ea before iNO, 2.09 mmHg/mL; composite
Ea after iNO, 1.9 mmHg/mL). This is explained by a compensatory
increase in systemic perfusion to a new equilibrium at the optimization of stroke work (coupling ratio, 1.0). This equilibrium was aided
by an increase in overall Ees. In experimental models, iNO had variable effects on the myocardium; however, the preponderance of scientic data indicate that its principal effects are on the vasculature.9-11
This suggests that the increase in systolic elastance may have resulted
from enhanced coronary perfusion pressure.
Although the coupling data in this case were acquired in the
acute setting, the same physiology was likely simulated chronically
with inhaled treprostinil. Dead space and shunt were preserved
and/or improved during treprostinil therapy, indicating probable
vascular remodeling and preserved Ees/Ea. In addition, exercise
oxygenation, systemic pressure, and functional status improved
during therapy, furthering this concept.
Ultimately, the clinical relevance of this case may perhaps be
limited to a select population. This patient suffered from a very
rare condition in which nearly all the shunt was intracardiac and
therefore improved signicantly with pulmonary vasodilation therapy alone. The results cannot be generalized to patients with mixed

REFER E NCES

Source of Support: There were no direct funding sources for this

project. FR is funded in other research projects by U01 grant
HL125208-01 from the National Heart, Lung, and Blood Institute
and by the United Therapeutics Corporation.

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