Inorganic Nitrite to Amplify the Benefits and Tolerability of Exercise Training in Heart Failure With Preserved Ejection Fraction (HFpEF) (INABLE-Training)

Inclusion Criteria:

Age ≥ 40 years
Symptoms of dyspnea (II-IV) without evidence of a non-cardiac or ischemic explanation for dyspnea
Ejection Fraction (EF) of > or = 50% determined on most recent imaging study within the preceding 5 years, with no change in clinical status suggesting potential for deterioration in systolic function

One of the following:

Previous hospitalization for Heart Failure (HF) with radiographic evidence (pulmonary venous hypertension, vascular congestion, interstitial edema, pleural effusion) of pulmonary congestion or
Catheterization documented elevated filling pressures at rest (Pulmonary Capillary Wedge Pressure (PCWP)= ≥15 or Left Ventricular End-Diastolic Pressure (LVEDP) ≥18) or with exercise (PCWP ≥25) or
Elevated Natruretic Peptide-proBNP (>400 pg/ml) or B-Type Natriuretic Peptide (BNP)(>200 pg/ml) or
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 diuretic for signs or symptoms of heart failure
Heart failure is primary factor limiting activity as indicated by answering # 2 to the following question:

My ability to be active is most limited by:

Joint, foot, leg, hip or back pain
Shortness of breath and/or fatigue and/or chest pain
Unsteadiness or dizziness

Lifestyle, weather, or I just don't like to be active

No chronic nitrate therapy or not using intermittent sublingual nitroglycerin (requirement for >1 sublingual nitroglycerin per week).
No daily use of phosphodiesterase 5 (PDE5) inhibitors or soluble guanylyl cyclase activators and willing to withhold as needed use of PDE5 inhibitors for duration of study
Ambulatory (not wheelchair / scooter dependent)
Body size allows wearing of the accelerometer belt as confirmed by ability to comfortably fasten the test belt provided for the screening process.
Willingness to wear the accelerometer belt for the duration of the trial

Exclusion Criteria:

Recent (< 1 month) hospitalization for heart failure
Ongoing requirement for PDE5 inhibitor, organic nitrate or soluble guanylyl cyclase activators
Hemoglobin (Hgb) < 8.0 g/dl within 30 days prior to randomization
Glomerular Filtration Rate (GFR) < 20 ml/min/1.73 m2 within 30 days prior to randomization
Systolic blood pressure < 115 mmHg seated or < 90 mmHg standing
Resting Heart Rate > 110
Previous adverse reaction to the study drug which necessitated withdrawal of therapy
Significant chronic obstructive pulmonary disease that is a primary contributor to symptoms, in the opinion of the Investigator.
Ischemia thought to contribute to dyspnea, in the opinion of the Investigator.
Documentation of previous Ejection Fraction < 40%
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)
Percutaneous Coronary Intervention, coronary artery bypass grafting, or new biventricular pacing within past 3 months
Obstructive hypertrophic cardiomyopathy
Known infiltrative cardiomyopathy (amyloid)
Constrictive pericarditis or tamponade
Active myocarditis
Complex congenital heart disease
Active collagen vascular disease
More than mild aortic or mitral stenosis
Intrinsic (prolapse, rheumatic) valve disease with more than moderate mitral, tricuspid or aortic regurgitation
Acute or chronic severe liver disease as evidenced by any of the following: encephalopathy, variceal bleeding, International Normalized Ratio (INR) > 1.7 in the absence of anticoagulation treatment
Terminal illness (other than HF) with expected survival of less than 1 year
Enrollment or planned enrollment in another therapeutic clinical trial in next 3 months.
Inability to comply with planned study procedures
Pregnancy or breastfeeding mothers