Non-Invasive Diagnosis of Pulmonary Vascular Disease Using Inhaled 129Xe Magnetic Resonance Imaging

This study seeks to deploy several forms of 129Xe MRI contrast as well as emerging
conventional proton MRI technqiues 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. In addition, to characterize perfusion and
vascular dimensions directly, patients will undergo a gadolinium-enhanced perfusion scan. The
overall aims of the study are as follows:

Aim 1. Perform 129Xe MRI scans in cohorts of patients with PVD, isolated left sided heart
failure and isolated lung disease:

1.1 Deploy and optimize 129Xe gas exchange MR spectroscopy and imaging, 129Xe ventilation
MRI, structural 1H UTE MRI, and breath-hold 1H perfusion MRI.

1.2 Conduct comprehensive 1H-129Xe MRI in 10 patients with pure pulmonary arterial
hypertension (PAH) 1.3 Conduct comprehensive MRI in 10 patients with pure left heart failure
1.4 Conduct comprehensive MRI in 10 patients with pure lung disease but no pulmonary
hypertension

Aim 2. Develop diagnostic criteria for optimizing the sensitivity and specificity of 129Xe
MRI for the diagnosis of PVD:

2.1 Develop quantification/scoring methods based on PAH, left heart disease, and lung disease
MRI 2.2 Develop reader training materials and train 3 expert readers 2.3 Begin prospective
recruitment of 92 patients being evaluated for PAH for MRI scans

Aim 3. Perform a larger, single-blind study testing the diagnostic accuracy of 129Xe MRI for
diagnosis of PVD:

3.1 Trained readers will evaluate 129Xe MRI, while blinded to the subject's disease state and
will determine the presence and severity of PVD 3.2 Diagnostic accuracy of 129Xe MRI will be
compared to the gold standard of hemodynamic and clinical criteria of PAH

This will be an single-blinded, open-label study enrolling volunteers and patients with pure
PAH (10 subjects), pure left heart disease (10 subjects) and pure lung disease (10 subjects)
[Aim 1] followed by a larger cohort of 92 subjects being evaluated for PAH [Aim 2]. The
investigators plan to consent 122 subjects.

The sample size calculation is based on testing whether the proposed diagnostic test based on
Xe MRI has accuracy comparable to imaging diagnostic procedures in clinical practice, such as
mammography. To this end, the investigator proposes to test the hypotheses H0: AUC = 0.72 vs.
H1: AUC > 0.85, where area under the curve (AUC) is a summary measure of diagnostic accuracy
obtained as the the area under the receiver operating characteristic (ROC) curve which
displays the tradeoff between sensitivity and specificity for our proposed Xe MRI based
diagnostic test. Here AUC = 0.72 represents a moderately accurate test while AUC = 0.85
represents accuracy comparable to clinical mammography. Based on a one sided, one sample test
with variances approximated using the binormal model, the investigator estimates a minimum
sample size of 46 normals and 46 with disease will be required to test the above hypotheses
at a significance level of 5% with 80% power.

Inclusion criteria

- Outpatients of either gender, age > 18

- Willing and able to give informed consent and adhere to visit/protocol schedules.
(Consent must be given before any study procedures are performed)

- Women of childbearing potential must have a negative serum pregnancy test. This will
be confirmed before participation in this investigational protocol

- Either have a diagnosis of PAH, isolated left heart disease or lung disease (chronic
obstructive pul-monary disease or interstitial lung disease) or recently evaluated for
PAH using established clinical criteria

Exclusion criteria

- Medical or psychological conditions which, in the opinion of the investigator, might
create undue risk to the subject or interfere with the subject's ability to comply
with the protocol requirements

- Conditions that will prohibit MRI scanning (metal in eye, claustrophobia, inability to
lie supine)

- Subjects with renal insufficiency (eGFR < 30 mL/min/1.73 m2) will be excluded.