Study to Evaluate Sex Differences in the Acute Effects of PL-3994 in Heart Failure Subjects

Inclusion Criteria:

1. The subject has provided written informed consent.

2. Pre- or post-menopausal female or male age > 21 years

3. LVEF ≥ 45% by echocardiography within prior 6 months

4. Symptoms of HF requiring treatment with diuretics for ≥ 30 days prior to enrollment

5. Current symptoms of HF (NYHA class II-IV) at time of enrollment

6. 6. The subject has clinical indication for right heart catheterization forevaluation of HFpEF

7. Negative pregnancy test in a female of childbearing potential

Exclusion Criteria:

• A subject who meets ANY of the following exclusion criteria must not be enrolled.

1. Orthostatic hypotension, systolic blood pressure <100 mm Hg, diastolic bloodpressure < 50 mmHg.

2. Any prior echocardiogram with LVEF < 40%

3. Hemoglobin < 9 g/dl

4. eGFR < 30 mL/min/1.73 m2

5. Hemodynamically significant arrhythmias within prior 4 weeks

6. Acute coronary syndrome, cardiac surgery, or percutaneous coronary interventionwithin prior 3 months

7. Any of the following cardiac diagnoses: active myocarditis, hypertrophiccardiomyopathy, > moderate regurgitant valvular disease, any valvular stenosis,restrictive cardiomyopathy (including amyloid, sarcoid, or hemochromatosis),constrictive pericarditis, complex congenital heart disease, or pulmonaryarterial hypertension

8. Current need for IV inotropic medication

9. Currently taking nitrates or having stopped nitrates within 24 hours of visit

10. Currently taking antihistamines, antipsychotics, tri-cyclic antidepressants,catecholamines/related compounds, monoamine oxidase inhibitors, stimulants (including caffeine and nicotine), sympathomimetics, dopamine agonists.Additionally, medications that inhibit PDE activity will be prohibited duringthe study and for 5 half- lives prior to Day 1 so that cGMP measurements willnot be affected

11. Currently hospitalized for HF

12. Any prior need for mechanical circulatory support

13. Previous adverse reaction to the study drug

14. Inability to comply with planned study procedures

15. Pregnant or nursing mothers

16. Participation in another study with an investigational drug or device within 30days or a biologic study within 90 days prior to signing consent.

17. Study participants must use method of birth control that has been approved bythe Study Doctor and males must not donate sperm during the study and for 30days after the last dose of study drug.