Myeloperoxidase (MPO) Inhibitor A_Zeneca for Heart Failure With Preserved Ejection Fraction (HFpEF)

Enroll subjects with a normal ejection fraction referred to the catheterization laboratory for evaluation of breathlessness or shortness of breath. Perform safety lab sampling, echocardiography, arterial tonometry for pulse wave analysis, and assessment of endothelial function prior to administration of study drug. During the catheterization researchers will perform blood draws, assess baseline exercise capacity at rest and during exercise. Researchers will also 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 the baseline catheterization assessments. 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

• Males and females of non-childbearing potential
• Age ≥ 30 years
• Symptoms of dyspnea (II-IV) at the time of screening
• Ejection Fraction (EF) ≥ 50% as determined on imaging study within 12 months of enrollment
• Catheterization documented elevated filling pressures at rest (PCWP ≥15) or with exercise (PCWP ≥25)

Exclusion criteria

• Use of nitrates, phosphodiesterase 5 inhibitors or other NO-providing therapy in the past 24 hours of screening
• Significant valvular disease (>moderate left-sided regurgitation, >mild stenosis)
• Requirement of intravenous heparin at the start of case
• Severe pulmonary parenchymal disease
• Acute coronary syndrome or coronary disease requiring revascularization in the judgement of investigators
• Resting systolic blood pressure < 100 mmHg
• Constrictive pericarditis
• Infiltrative, restrictive, or hypertrophic obstructive cardiomyopathies
• Previous anaphylaxis to any drug
• Pregnancy or breastfeeding mothers
• High Output heart failure
• Active thyroid disease
• Treatment with a new chemical entity (defined as a compound which has not been approved for marketing) within the preceding 3 months
• Patients with any prior allergy to propylthiouracil