Assessing Response to Inhaled Prostacyclin With Hyperpolarized Xe MRI

This study seeks to determine whether hyperpolarized 129Xenon MRI can detect improvements in
pulmonary gas exchange in patients with Group 1 and 3 PH treated with iTRE. We will associate
this with changes in serum concentrations of treprostinil and levels of peripheral
vasodilation. This work seeks to apply and test a novel non-invasive methodology,
hyperpolarized (HP) 129Xenon (Xe) magnetic resonance imaging (MRI), for the diagnosis of
Pulmonary Vascular Disease. Hyperpolarized 129Xe MRI has been under active development and
used in clinical research at Duke for over 7 years. If successful, 129Xe MRI could overcome
the current limitations of PVD diagnosis while conferring a number of potential benefits.
First, imaging the abnormalities in the lungs allows the diagnosis of PVD in the setting of
concomitant heart or lung disease. With HP 129Xe MRI, abnormalities in gas exchange secondary
to PVD can be directly visualized. Second, non-invasive diagnosis of PVD could remove the
need for an invasive RHC. While RHC is a relatively safe procedure, there are a number of
limitations to the interpretation of RHC, including arbitrary cutoffs for mPAP, PCWP, and
PVR. Third, the abnormalities on HP 129Xe MRI could be used to non-invasively monitor
response to therapy. If we are successful in demonstrating the applicability of HP 129Xe MRI,
this technology holds the promise of greatly improving the diagnosis and management of PVD.

This study will enroll ten patients with pulmonary hypertension (PH). The ten patients will
be World Health Organization (WHO) PH classification Group 1 or out-of-proportion Group 3,
with lung disease. These patient have been inhaled treprostinil (iTRE) as standard of care
for their PH. Inhaled treprostinil (iTRE) is an FDA approved medication under the brand name
of Tyvaso. The major pharmacologic actions of treprostinil are direct vasodilation of
pulmonary and systemic arterial vascular beds and inhibition of platelet aggregation. The
medication is delivered noninvasively, directly to the lungs using the approved ultrasonic
nebulizer delivery system. Patients will take the inhaled treatment four times a day, about
every four hours.

The iTRE will be used to characterize their 129Xe MRI imaging, peripheral vasodilation and
serum treprostinil concentration before and after treatment with iTRE. As iTRE has a plasma
concentration half-life of ~ 45 minutes and time-to-peak concentration of 15 minutes, imaging
done immediately before, 15 minutes after and 2-4 hours after drug treatment would
potentially allow the visualization of changes in gas diffusion and peripheral vasodilation
associated with iTRE. This is similar to changes seen in changes in ventilation in asthma
after treatment with bronchodilators. Monitoring a later time point would also allow us to
test whether vasodilation persists in the lung vasculature compared to the peripheral
circulation. This study seeks to deploy several forms of 129Xe MRI contrast as well as
emerging conventional proton MRI techniques for imaging lung structure and perfusion.
Specifically, the 129Xe MRI scans will provide 3D images of ventilation and gas exchange, and
spectroscopic indices will be evaluated to test gas exchange dynamics with high temporal
resolution. The conventional 1H MRI scans will include a free-breathing ultra-short echo time
(UTE) scan that provides images similar to that of a CT scan.

Inclusion Criteria:

Patients with known Pulmonary Hypertension on treatment with inhaled prostacyclin (iTRE)
that are followed in the Duke Pulmonary Vascular Disease Clinic. Inclusion criteria
includes: Group 1 PH (mPAP ≥ 25 mmHg, PCWP ≤ 15 mmHg in the absence of significant
concomitant left heart disease or lung disease), out-of-proportion Group 3 PH (mPAP ≥ 25
mmHg, PCWP ≤ 15 mmHg with PVR ≥ 5 WU and evidence of right heart failure in the setting of
lung disease), maintenance on a stable, well-tolerated treatment dose of iTRE (ideally ≥ 8
breaths QID).

Exclusion Criteria: