A Study of Oral Nitrate in Adults With Pulmonary Hypertension With Heart Failure and Preserved Ejection Fraction

We will enroll 60 Group II PH (PH-HFpEF) or Group I PAH patients and 60 matched healthy
controls over three years. The Subjects will receive a single dose of one of the two study
drugs, determined by whether they will participate in one study visit or two: 15N nitrate
(1,000 mg) or 14N Sodium Nitrate: standard sodium nitrate, and all will receive one dose of
CLA 3g. Twenty of the PH or PAH subjects and 20 of the control subjects willing to return for
a follow up visit 24 hours after drug administration will receive 15N nitrate. All others
will receive standard sodium nitrate. CLA will be obtained from GNC (General Nutrition
Corporation) and given once.

Throughout the experiment, we will measure blood pressure, heart rate, and respiratory rate
as well as co-oximetry. Plasma samples are collected at approximate times 0, 2, and 6 hrs
post-drug administration. Urine will be collected at approximate times 0 and 6 hrs. We will
examine plasma and urine nitrate and nitrite. The 40 subjects who return for a second visit
24 hours post-drug administration will provide an additional plasma and urine sample.

INCLUSION:

- Male or female, 18 years of age or older

- Undergoing clinical right heart catheterization (RHC) or RHC in the past 5 years

- PAH group: WHO Group I PAH hemodynamically defined by a mean PAP ≥ 25 mm Hg, a PCWP <=
15 mm Hg, and have a TPG >= 12

- PH-HFpEF group: WHO Group II PH secondary to heart failure with preserved ejection
fraction (PH-HFpEF) hemodynamically defined by a mean PAP ≥ 25 mm Hg, a PCWP > 15 mm
Hg, and have TPG >= 12 at rest or during exercise

- Control group: Normal hemodynamics (mean PAP < 25 mm Hg, PCWP ≤ 15 mm Hg) on clinical
right heart catheterization

- Ability to provide written informed consent

EXCLUSION:

- Use of systemic antibiotics and/or chlorhexidine mouthwash, within the previous three
months

- Use of immune suppression (chemotherapy, oral prednisone greater than 20mg per day,
etc) with in the previous three months

- Use of phosphodiesterase-5 inhibitors (tadalafil, sildenafil, etc) within 7 days
before study drug administration

- Current pregnancy or lactation

- Uncontrolled systemic hypertension based on repeated measurement of sitting systolic
blood pressure >185 mm Hg or sitting diastolic blood pressure >110 mm Hg at screening

- Has chronic renal insufficiency as defined by serum creatinine >3 mg/dL at screening
or requires dialytic support

- Known history of left ventricular ejection fraction < 40% by multiple gated
acquisition scan (MUGA), angiography, or echocardiography

- History of atrial septostomy

- Repaired or unrepaired congenital heart disease

- Pericardial constriction

- Restrictive or constrictive cardiomyopathy

- Symptomatic coronary disease with demonstrable ischemia

- Addition or change in dosing of hormonal contraception medications (OCP, IUD,
Depo-Provera) in the past 4 weeks.

- Other severe acute or chronic medical or laboratory abnormality that may increase the
risk associated with study participation or investigational product administration,
that may interfere with the interpretation of study results and, in the judgment of
the investigator, would make the subject inappropriate for entry into this study or
would prevent completion of the study

- Active participation in other research studies with investigational drugs