Oral Nitrite for Older Heart Failure Patients
Condition: Heart Failure
MeSH terms: Heart Failure
Intervention: 14 N Sodium Nitrite
Intervention description: oral formulation of sodium nitrite 40 mg three times daily for 4 weeks
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Intervention model description: Healthy Controls vs Heart Failure with reduced Ejection Fraction (HFrEF) vs Heart Failure with preserved Ejection Fraction (HFpEF) on four weeks of nitrite treatment tid.
Masking: None (Open Label)
Enrollment: 21.0
Sex: All
Minimum age: 70 Years
Healthy volunteers: Accepts Healthy Volunteers

Summary:

      Studies have demonstrated nitrite therapy increases adenosine triphosphate (ATP) synthesis in
      skeletal muscle mitochondria concomitant with reduced whole-body oxygen cost during steady
      state exercise. Our own work has demonstrated safety and efficacy of an FDA investigational
      new drug (IND) approved sodium nitrite (10 milligram [mg]) capsule, and its utility to
      upregulate the sirtuin 3 adenosine monophosphate protein kinase (SIRT3-AMP) pathway of
      skeletal muscle of younger heart failure (HF) patients. It now seems exceptionally logical
      and opportune to apply these insights to older HF patients and to delineate mechanisms of
      disease and aging that respond to nitrite therapy.
    

Eligibility criteria:

        Inclusion Criteria:

        Inclusion Criteria HF Population

          -  New York Heart Association (NYHA) class II or III for the previous three months
             despite a minimum of 6 weeks of treatment. Echo criteria will be confirmed as part of
             the initial study assessment.

          -  Age ≥70 years

          -  HFrEF patients left ventricular ejection fraction (LVEF) ≤40%

          -  HFpEF patients LVEF>40%, may include E/E' >8, left atrial size>40 mL/m2

          -  Optimal therapy according to American Heart Association (AHA)/American College of
             Cardiology(ACC) and Heart Failure Society of America (HFSa) HFrEF guidelines,
             including treatment with angiotensin-converting enzyme inhibitor (ACEI) and
             beta-blocker therapy (for at least 6 weeks), or have documented reason for variation,
             including medication intolerance, contraindication, patient preference, or personal
             physician's judgment.

          -  Patients using aspirin (ASA) will be eligible, but asked to hold the medication for 48
             hours prior to biopsy. This technique has previously been used with consistent safety.
             Patients will also be asked to avoid non-steroidal anti-inflammatory medications
             (NSAIDs) for 48 hours prior to the biopsy.

          -  Patients using anti-thrombin and anti-platelet therapy will plan to modify prior to
             muscle biopsies individually in coordination with the participant's primary
             cardiologist.

        Inclusion Criteria Age-Matched Control Population

          -  Age ≥70 years

          -  Absence of any type of cardiovascular disease.

          -  Absence of diabetes or other chronic disease processes

        Exclusion Criteria:

        Exclusion Criteria for All participants

          -  Allergy to lidocaine

          -  Dementia

          -  End-stage malignancy

          -  Orthopedic exercise limitation

          -  Chronic use of oral corticosteroids or other medications that affect muscle function.

          -  Chronic ethyl alcohol (ETOH) or drug dependency.

          -  Any bleeding disorder that would contraindicate biopsy such as history of clinically
             significant bleeding diathesis (e.g., Hemophilia A or B, Von Willebrand's Disease or
             congenital Factor VII deficiency).

          -  Psychiatric hospitalization within the last 3 months

        Exclusion Criteria HF Population

          -  Major cardiovascular event or procedure within the prior 6 weeks.

          -  HF secondary to significant uncorrected primary valvular disease (except mitral
             regurgitation secondary to left ventricular dysfunction). If valve replacement has
             been performed, patient may not be enrolled for 12 months after this procedure.

          -  Severe valvular heart disease

          -  Mechanical valve replacement requiring warfarin

          -  Currently taking clopidogrel for a recent stent placement and/or a complex
             atherosclerotic lesion such that holding clopidogrel creates disproportionate risk.

          -  ICD (Internal cardiodefibrillator) device with heart rate limits that prohibit
             exercise assessments. Referring physicians will be provided with an opportunity to
             reprogram devices so that patients can participate.