Spironolactone for Pulmonary Arterial Hypertension

• INCLUSION CRITERIA:

1. WHO Group 1 PH patients on either no medical therapy or stable medical therapyfor at least the past 4 weeks (defined as no new PAH-specific therapy, nochange in the dose of current PAH-specific therapy and no change in NYHA/WHOfunctional classification within the past 4 weeks) are eligible. The followingparameters on RHC are required to meet the hemodynamic definition of PAH:

2. mean pulmonary artery pressure of > 25 mmHg at rest,

3. pulmonary capillary wedge pressure of less than or equal to 15 mmHg (or a leftventricular end-diastolic pressure of less than or equal to 12 mmHg) and

4. pulmonary vascular resistance of > 3 Wood units (240 dyn.s.cm^-5).

If clinically indicated at the time of enrollment, then a RHC will be performed at the NIH Clinical Center upon study entry under a procedural consent.

2. Females who are able to become pregnant (i.e., are not postmenopausal, have notundergone surgical sterilization, and are sexually active with men) must agree touse adequate contraception (hormonal or barrier method of birth control; abstinence)prior to and for the duration of study participation.

EXCLUSION CRITERIA:

1. Patients with WHO Group 1 PH and evidence of right heart failure as defined by:

2. NYHA/WHO class IV symptoms and

3. Echocardiographic evidence of severe RV dysfunction and

4. Clinical evidence of right heart failure which may include, but is not limitedto elevated jugular venous pressure, ascites, and lower extremity edema

5. Patients with WHO Group 1 pulmonary hypertension and a prior diagnosis of cirrhosiswith portal hypertension as evidenced by a history of ascites, hepaticencephalopathy and/or varices prior to enrollment

6. Patients with WHO Group 1 pulmonary hypertension and evidence of active infection, (HIV patients with two consecutive viral loads of < 500 on their most recentdeterminations within the past 12 months will be considered to have inactiveinfection)

7. Patients with WHO Group 1 pulmonary hypertension who have taken spironolactone oreplerenone within the last 30 days

8. Known or suspected allergy to spironolactone

9. Pregnant or breastfeeding women (all women of childbearing potential will berequired to have a screening urine or blood pregnancy test)

10. Age <18 years

11. Inability to provide informed written consent for participation in the study

12. Chronic kidney disease (an estimated glomerular filtration rate of < 35mL/min/1.73m^2 of body surface area)

13. Serum potassium at the time of enrollment of > 5 mEq/L

14. Concurrent use of an ACE inhibitor and angiotensin II receptor blocker OR Patients currently taking the maximum recommended dose of an ACE inhibitor or anangiotensin II receptor blocker [For patients taking one of these medicines (ACE-Inhibitors or ARBs), the investigators agree to do due diligence by consultinga clinical center pharmacist and/or a standard pharmacy reference (i.e. Micromedex)to certify whether or not the patient is on a maximum dose of the drug.]

15. Women currently taking drospirenone-containing oral contraceptives

The estimated glomerular filtration rate (eGFR) will be calculated using the IDMS-traceable Modification of Diet in Renal Disease (MDRD) equation and corrected for body surface area.

eGFR = 175 x (serum creatinine in mg/dL)^-1.154 x (age in years)^-0.203 x [1.212 if African-American] x [0.742 if female]

Exclusion Criteria for MRI

These contraindications include but are not limited to the following devices or conditions:

1. Implanted cardiac pacemaker or defibrillator

2. Cochlear Implants

3. Ocular foreign body (e.g. metal shavings)

4. Embedded shrapnel fragments

5. Central nervous system aneurysm clips

6. Implanted neural stimulator

7. Any implanted device that is incompatible with MRI

8. Unsatisfactory performance status as judged by the referring physician such that thesubject could not tolerate an MRI scan. Examples of medical conditions that wouldnot be accepted would include unstable angina and severe dyspnea at rest

9. Subjects requiring monitored sedation for MRI studies

10. Subjects with a condition precluding entry into the scanner (e.g. morbid obesity,claustrophobia, etc.)

11. Subjects with severe back-pain or motion disorders who will be unable to toleratesupine positioning within the MRI scanner and hold still for the duration of theexamination.

EXCLUSION CRITERIA FOR GADOLINIUM BASED MRI STUDIES ONLY:

1. History of severe allergic reaction to gadolinium contrast agents despite pre-medication with diphenhydramine and prednisone

2. Chronic kidney disease (an estimated glomerular filtration rate of < 60mL/min/1.73m^2 of body surface area)