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

Participants with heart failure with preserved ejection fraction will undergo 12 weeks of cardiac rehabilitation for exercise training (ET) and be randomized to either sodium nitrite or placebo through the training period. Study drug is administered 3 times daily with one of these doses being 30 minutes prior to onset of ET sessions throughout the12 week trial. The objective is to determine if the sodium nitrite improves the clinical responses and tolerability of ET.


Eligibility Criteria:
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:

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

   * 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