MPO Inhibitor A_Zeneca for HFpEF

Enroll subjects with a normal ejection fraction referred to the catheterization laboratory
for evaluation of breathlessness or shortness of breath. During the catheterization
researchers will perform blood draws, assessment of endothelial function, assess baseline
exercise capacity at rest and during exercise. During the catheterization procedure
researchers will do an echocardiogram to take measurements of the heart. Subjects will be
randomized to one of two groups, Oral Myeloperoxidase Inhibitor or placebo group. Study drug
or placebo will be administered followed by a repeat of resting and exercise testing. During
that time blood measurements are taken. At the conclusion of the second exercise test the
subject will be moved to a room and monitored overnight for safety. Repeat blood draws,
echocardiogram, endothelial function test, and heart monitoring will be completed. The
subject will be asked to follow up with the researchers between 9-14 days after the study
drug dosage. The subjects history and blood work will be completed at that visit.

Inclusion Criteria:

1. Males and females of non-childbearing potential

2. Age ≥ 30 years

3. Symptoms of dyspnea (II-IV) at the time of screening

4. EF ≥ 50% as determined on imaging study within 12 months of enrollment

5. Catheterization documented elevated filling pressures at rest (PCWP ≥15) or with
exercise (PCWP ≥25)

Exclusion Criteria:

1. Use of nitrates, phosphodiesterase 5 inhibitors or other NO-providing therapy in the
past 24 hours of screening

2. Significant valvular disease (>moderate left-sided regurgitation, >mild stenosis)

3. Requirement of intravenous heparin at the start of case

4. Severe pulmonary parenchymal disease

5. Acute coronary syndrome or coronary disease requiring revascularization in the
judgement of investigators

6. Resting systolic blood pressure < 100 mmHg

7. Constrictive pericarditis

8. Infiltrative, restrictive, or hypertrophic obstructive cardiomyopathies

9. Previous anaphylaxis to any drug

10. Pregnancy or breastfeeding mothers

11. High Output heart failure

12. Active thyroid disease

13. Treatment with a new chemical entity (defined as a compound which has not been
approved for marketing) within the preceding 3 months