Clinical Trials

Inclusion Criteria:

1. Age ≥ 40 years
2. Symptoms of dyspnea (NYHA class II-IV) without evidence of a non-cardiac or ischemic explanation for dyspnea
3. EF ≥ 50% as determined on imaging study within 12 months of enrollment with no change in clinical status suggesting potential for deterioration in systolic function
4. One of the following within the last 12 months:
   1. Previous hospitalization for HF with radiographic evidence (pulmonary venous hypertension, vascular congestion, interstitial edema, pleural effusion) of pulmonary congestion or
   2. Catheterization documented elevated filling pressures at rest (PCWP ≥15 or LVEDP ≥18) or with exercise (PCWP ≥25) or
   3. Elevated NT-proBNP (>400 pg/ml) or BNP(>200 pg/ml) or
   4. Echo evidence of diastolic dysfunction/elevated filling pressures manifest by medial E/e' ratio≥15 and/or left atrial enlargement and chronic treatment with a loop diuretic for signs or symptoms of heart failure
5. Heart failure is primary factor limiting activity as indicated by answering # 2 to the following question:
   1. My ability to be active is most limited by:
      1. Joint, foot, leg, hip or back pain
      2. Shortness of breath and/or fatigue and/or chest pain
      3. Unsteadiness or dizziness
      4. Lifestyle, weather, or I just don't like to be active
6.  Peak VO2 ≤75% predicted with peak respiratory exchange ratio≥1.0 CPET Normal Values for Peak VO2* Criteria (ml/kg/min)
7. No chronic nitrate therapy or not using intermittent sublingual nitroglycerin (requirement for >1 SL nitroglycerin per week) within last 1 week
8. No daily use of phosphodiesterase 5 inhibitors or soluble guanylyl cyclase activators and willing to withhold prn use of phosphodiesterase 5 inhibitors for duration of study
9. Ambulatory (not wheelchair / scooter dependent)
10. Body size allows wearing of the accelerometer belt as confirmed by ability to comfortably fasten the test belt provided for the screening process (belt designed to fit persons with BMI 20-40 kg/m2 but belt may fit some persons outside this range)
11. Willingness to wear the accelerometer belt for the duration of the trial
12. Willingness to provide informed consent

Exclusion Criteria:

1. Recent (< 1 month) hospitalization for heart failure
2. Ongoing requirement for PDE5 inhibitor, organic nitrate or soluble guanylyl cyclase activators
3. Hemoglobin (Hgb) < 8.0 g/dl within 30 days prior to randomization
4. GFR < 20 ml/min/1.73 m2 within 30 days prior to randomization
5. Systolic blood pressure < 115 mmHg seated or < 90 mmHg standing just prior to test dose
6. Resting HR > 110 just prior to test dose
7. Previous adverse reaction to the study drug which necessitated withdrawal of therapy
8. Significant chronic obstructive pulmonary disease thought to contribute to dyspnea
9. Ischemia thought to contribute to dyspnea
10. Documentation of previous EF < 45%
11. Acute coronary syndrome within 3 months defined by electrocardiographic (ECG) changes and biomarkers of myocardial necrosis (e.g., troponin) in an appropriate clinical setting (chest discomfort or anginal equivalent)
12. PCI, coronary artery bypass grafting, or new biventricular pacing within past 3 months
13. Primary hypertrophic cardiomyopathy
14. Infiltrative cardiomyopathy (amyloid)
15. Constrictive pericarditis or tamponade
16. Active myocarditis
17. Complex congenital heart disease
18. Active collagen vascular disease
19. More than mild aortic or mitral stenosis
20. Intrinsic (prolapse, rheumatic) valve disease with moderate to severe or severe mitral, tricuspid or aortic regurgitation
21. Acute or chronic severe liver disease as evidenced by any of the following: encephalopathy, variceal bleeding, INR > 1.7 in the absence of anticoagulation treatment
22. Terminal illness (other than HF) with expected survival of less than 1 year
23. Regularly (> 1x per week) swims or does water aerobics
24. Enrollment or planned enrollment in another therapeutic clinical trial in next 3 months.
25. Inability to comply with planned study procedures
26. Pregnancy or breastfeeding mothers