The role of the pulmonary vasculature in the Fontan circulation

The Fontan circulation is a definitive surgical palliation for patients with
congenital heart defects for whom a biventricular correction is not possible,
resulting in an non-physiologic pre- and afterload of the single ventricle,
chronically increased systemic venous pressures and a chronic non-pulsatile
flow in the pulmonary vascular bed. Since the Fontan procedure was introduced
in the 1970s1 improvement in patient selection, surgical strategies, operation
techniques and peri-operative care have led to improved short term survival of
these patients.2
However with a growing number of Fontan patients reaching adulthood and
longer follow-up time, it appears that a gradual attrition of the Fontan
circulation occurs, eventually resulting in the so-called failing Fontan
circulation. This situation may include protein-losing enteropathy, plastic
bronchitis, ascites, hepatic cirrhosis and hepatic malignancy, ventricular
dysfunction and a low cardiac output state. Multiple factors are suggested to
contribute to the attrition of the Fontan circulation. However recently it has
been hypothesized that the pulmonary vasculature, may form the common
denominator in these processes.3 To date medical or surgical treatment options
to reverse or even slow down the failing of the Fontan circulation are
extremely limited.
There are indications that the pulmonary circulation is of great importance
in the Fontan circulation. Because of the absence of a subpulmonary ventricle
to propel the blood through the pulmonary circulation a low pulmonary vascular
resistance is a requisite. It has been shown that over time the pulmonary
vascular resistance (PVR) gradually rises, the pathophysiological mechanism of
this phenomenon still has to be elucidated. When the pulmonary vascular
resistance rises, less blood returns to the single ventricle and a decreased
preload is the consequence. It has been proposed that diminished preload is the
controlling and limiting factor of cardiac output in Fontan patients.4 Fontan
patients have impaired exercise capacity.5 During exercise, the body demands an
increase in cardiac output and an increase in cardiac preload is required. In
the Fontan circulation this can only be achieved by lowering PVR, which might
be problematic in the Fontan patient.
Normally, pulsatile pulmonary blood flow is important for the release of
endothelium-derived compounds such as nitric oxide (NO), which induces
vasodilatation and lowers PVR. The non-pulsatile pulmonary flow in the Fontan
circulation is suggested to induce endothelial dysfunction, associated with
compromised vasodilatory capacity, adverse pulmonary vascular remodeling and
local prothrombotic environment over time. Structural changes of the pulmonary
vasculature and altered pulmonary vascular hemodynamics may play a role in the
limited exercise capacity of Fontan patients. However, its exact role remains
to be determined.
Optical Coherence Tomography (OCT) and pulmonary vasodilatation tests
during cardiac catheterization are tools to assess this role in vivo. OCT is a
catheter-based optical imaging modality which uses near-infrared light
(1300nm). It produces an image of the vessel wall by optical scattering. OCT
has a resolution 10-fold higher than intravascular ultrasound (IVUS) and allows
for in vivo diagnosing of vascular lesions and structural wall remodeling.6
Pulmonary OCT has been used to diagnose peripheral pulmonary thrombi 7 and to
asses pulmonary artery morphology.8 To date pulmonary vessel wall
characterization using OCT has not been reported in Fontan patients.
Pulmonary vasodilator testing using NO is common clinical practice in
pulmonary vascular diseases. 9 NO is frequently administered to Fontan patients
post-operatively. 10-12 However little is known about the effects of NO at mid
to long-term follow up in Fontan patients. Only one study has studied the
effects of inhaled NO during cardiac catheterization (N=15) at mid-term follow
up (under general anesthesia, median 12 years old, median 9 years after Fontan
operation) and reported that pulmonary vascular resistance dropped
significantly after administration of NO. 13 The possible beneficial effects of
iNO on cardiac output during (pharmacologically simulated) exercise (with
dobutamine) have not been reported in Fontan patients and should be subject of
study.
In summary determination of the structural and functional
characteristics of the pulmonary vasculature in the Fontan circulation would
identify the pulmonary circulation as a future treatment target in Fontan
patients and may provide clues for new therapeutic treatment strategies to
improve the long term outcome of these patients.

Primary Objectives:

- Determine the effect of pulmonary vasodilatation on indexed cardiac output
during simulated exercise.

- Characterization of structural properties of small pulmonary arteries.

Secondary Objectives:

- Investigate the effect of pulmonary vasodilatation during simulated exercise
on hemodynamic characteristics (e.g. pulmonary vascular resistance index,
end-diastolic pressure single ventricle).

- Investigate the effect of pulmonary vasodilatation during simulated exercise
on ventricular and valvular function (based on echocardiographic assessment)

- Investigate the relationship between hemodynamic characteristics (all three
conditions) and demographic (e.g. age, time since Fontan operation) and
clinical and functional characteristics (e.g. NYHA class, VO2max).

- Investigate differences in hemodynamic characteristics (all three conditions)
in sub-groups
(Based on e.g. NYHA class, presence of a fenestration)

- Investigate differences between the structural properties of small pulmonary
arteries between the Fontan group, the PAH group and the Control group.

- Investigate the relationship between structural properties of small pulmonary
arteries and demographic (e.g. age, time since Fontan operation) and clinical
and functional characteristics (e.g. NYHA class, VO2max).

It is a cross-sectional observational cohort single center study with 2 control
groups.

Fontan patients
The study protocol will be performed during a clinically indicated cardiac
catheterization. The procedure is under conscious sedation, if necessary. The
duration of the routine catheterization protocol for Fontan patients is 90
minutes. In the context of this study additional measurements will be done,
this will take an additional 25 minutes.

Control group
The study protocol will be performed at the end of a clinically indicated right
heart catheterization. The procedure is under conscious sedation, if necessary.
The duration of the routine right heart catheterization protocol for the
control group is 20 minutes. In the context of this study pulmonary OCT
measurements will be done at the end of the routine catheterization protocol,
this will take an additional 5 minutes. These measurements are necessary to
provide normal pulmonary OCT control data to discriminate between the pulmonary
OCT data from the Fontan group.

PAH group
The study protocol will be performed at the end of a clinically indicated right
heart catheterization. The procedure is under conscious sedation, if necessary.
The duration of the routine right heart catheterization protocol for the PAH
group is 45 minutes. In the context of this study pulmonary OCT measurements
will be done at the end of the routine catheterization protocol, this will take
an additional 5 minutes. These measurements are necessary to provide abnormal
pulmonary OCT control data to discriminate between the pulmonary OCT data from
the Fontan group.

Procedures that the subjects will undergo:

Fontan group (N=15)

patient care
Cardiac catheterization (includes dobutamine stress test)

Additional study procedures:
- pulmonary OCT analysis
- inhaled nitric oxide 40ppm for 10 minutes
- 40 ug/kg/min dobutamine stress for 10 minutes
- pressure measurements and oximetry (6ml) after inhaled NO
- trans-thoracic echocardiography

Control group (N=5)

patient care:
- right heart catheterization

Additional study procedures:
- pulmonary OCT analysis

PAH group (N=5)

patient care:
- right heart catheterization

Additional study procedures:
- pulmonary OCT analysis

Fontan group:

Group relatedness
The Fontan circulation is a unique pathophysiological condition. There have
been to date no long term experimental models designed to adequately study this
condition. To eventually improve the treatment for Fontan patients it is
necessary to investigate in vivo the mechanisms involved in the impaired
exercise capacity and the gradual attrition over time.

Benefits
The participating patients wil not directly benefit from the potential results
of this study. However It is possible that Fontan patients will benefit from
participation because this study could identify the pulmonary circulation as a
future treatment target in Fontan patients and may provide clues for new
therapeutic treatment strategies to improve the long term outcome of these
patients.*

Burden
- The catheterization protocol will be extended with 25 minutes. The duration
of the standard catheterization protocol is approximately 90 minutes.
- NO inhalation for 10 minutes
- 20-30ml of additional contrast fluid (Xenetix 300mg I/ml) is necessary for
pulmonary artery imaging using OCT.
- 1 minute of additional fluoroscopy is necessary for positioning of the OCT
catheter for pulmonary artery imaging. The calculated additional radiation
exposure is 0.1 - 0.16 mSv.
- 6ml of additional blood samples are necessary for oximetry.
- An additional amount of 40µg/kg/min dobutamine stress for 10 minutes.

Risks
Pulmonary vascular response tests using inhaled nitric oxide is a safe and a
potent vasodilatation test routinely used in patients with pulmonary vascular
disease such as pulmonary arterial hypertension in the cardiac catheterization
laboratory. No major risks are associated with inhalation of NO. An overdose of
nitric oxide (manifested in elevations of methaemoglobinaemia and NO2) is
unlikely because of the short period of administration (10 minutes).

Abrupt discontinuation of the administration of inhaled nitric oxide may cause
rebound reaction; decrease in oxygenation and increase in central pressure and
subsequent decrease in systemic blood pressure. Rebound reaction is the most
common side effect in association with the clinical use of NO. Because the
subject is gradually weaned from NO the occurrence of a rebound reaction is
unlikely.

The use of an optical coherence tomography catheter implies risks associated
with one additional catheter handling.

Control group:

Group relatedness
The control group is necessary to provide control values of the pulmonary
artery optical coherence tomography measurements. Patients with a clinical
indication for a right heart catheterization are included; therefore the
additional burden and risks associated with these additional measurements are
small.

Benefits
For the control subjects there are no benefits associated with the pulmonary
artery optical coherence tomography measurements.

Burden
- The catheterization protocol will be extended with 5 minutes. The duration of
a standard right heart catheterization protocol is approximately 20 minutes.
- 20-30ml of additional contrast fluid (Xenetix 300mg I/ml) is necessary for
pulmonary artery imaging using OCT.
- 1 minutes of additional fluoroscopy is necessary for pulmonary artery imaging
using OCT. The calculated additional radiation exposure is 0.1 - 0.16 mSv

Risks
The use of an optical coherence tomography catheter implies risks associated
with one additional catheter handling.

PAH group:

Group relatedness
The PAH group is necessary to provide 'abnormal/pathological' control values of
the pulmonary artery optical coherence tomography measurements. Patients with a
clinical indication for a right heart catheterization are included; therefore
the additional burden and risks associated with these additional measurements
are small.

Benefits
For the PAH subjects there are no benefits associated with the pulmonary artery
optical coherence tomography measurements.

Burden
- The catheterization protocol will be extended with 5 minutes. The duration of
a standard right heart catheterization protocol is approximately 45 minutes.
- 20-30ml of additional contrast fluid (Xenetix 300mg I/ml) is necessary for
pulmonary artery imaging using OCT.
- 1 minutes of additional fluoroscopy is necessary for pulmonary artery imaging
using OCT. The calculated additional radiation exposure is 0.1 - 0.16 mSv

Risks
The use of an optical coherence tomography catheter implies risks associated
with one additional catheter handling.