Oral Nitrite for Older Heart Failure With Preserved Ejection Fraction

Age-related physiological changes predispose to heart failure with preserved ejection
fraction (HFpEF). Thus, HFpEF prevalence is escalating as the older population expands. High
mortality and morbidity, diminished quality of life, and spiraling healthcare costs are
typical consequences, and no effective HFpEF therapy is known. Therefore, several small
exercise training (ExT) trials for HFpEF stand out by showing that ExT result in improved
aerobic exercise capacity and infer that ExT constitutes novel substantive therapy.
Nonetheless, such benefit was evident only after months of moderate to high intensity ExT;
regimens that are unfeasible for most patients. In fact, poor compliance with ExT is typical
in most HFpEF patients. The investigators propose there are intrinsic physiological
components of HFpEF pathophysiology that predispose to "fatigability". The investigators
advance the concept of fatigability by quantifying it as a performance-based measure; i.e.,
subjective tiring during a standardized steady-state walking (perceived fatigability) and
deterioration of self-selected walking speed over time (performance fatigability). The
investigators assert that therapies to reduce fatigability will enhance HFpEF outcomes.
Ongoing studies reveal pleiotropic benefits of oral inorganic nitrite (NO2), including
enhanced performance of skeletal muscle (metabolism and bioenergetics) and vasomotor
responses (systemic and pulmonary). The investigators' pilot work shows safety and biological
efficacy of oral NO2 capsules. Thus, the investigators propose a randomized, controlled,
double-blinded trial to study oral NO2 therapy in older (≥70 years) HFpEF patients. Aim 1
explores the utility of NO2 capsules to reduce perceived and performance fatigability (rated
perceived exertion), improve aerobic capacity (peak oxygen uptake) and increase daily
activity (accelerometry). Aim 2 delineates the mediating processes by which NO2 benefits are
achieved. Skeletal muscle determinants are differentiated from the right and left heart
vasomotor dynamics by integrating assessments using 31Phosphorus magnetic resonance
spectroscopy and percutaneous needle muscle biopsies with those made using non-invasive and
invasive cardiopulmonary exercise testing, near infrared spectroscopy and other techniques.
The principal investigator is trained geriatrics and cardiology, and is solidly oriented to
the dynamics of aging and cardiovascular disease (clinically and mechanistically) with
particular expertise in functional assessment and skeletal muscle gene expression as
determinants of performance. The investigative team provides formidable synergies that are
well-suited to this translational investigation of systemic, cellular, and sub-cellular
physiological dynamics. Our proposal is significant in multiple respects: 1) HFpEF is endemic
with aging and constitutes a critical contemporary healthcare challenge today's growing
population of older adults. 2) Fatigability is rooted in HFpEF pathophysiology, but it has
not previously been addressed as a key part of management. 3) NO2 therapy is a novel and
compelling therapeutic strategy. 4) Mechanisms underlying fatigability are clarified; we
advance principles of patient-centered care by clarifying mechanisms that underlie a
patient's experience of fatigability.

Inclusion Criteria:

- Age ≥70 years

- Diagnosis of HFpEF [adapted from the 2016 European Society of Cardiology (ESC)
Guidelines to include:

1. Prior diagnosis of HF via one of these:

- medical record diagnosis by attending cardiologist

- verbal confirmation of HFpEF with attending cardiologist

- PI review of medical record to confirm HFpEF AND 2. Ejection Fraction % ≥40

- Clinically stable (euvolemic; baseline heart rate <100 bpm) and without
hospitalization or invasive cardiac procedure for 6 weeks

- Patients using 81 milligram (mg) aspirin (ASA) will be eligible, but will be asked to
hold the medication for 3 days 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 2 days 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.

Exclusion Criteria:

- Allergy to lidocaine

- BP >180/95 or <100/60

- Anemia: Hgb<11.0 (♂),10.0 (♀)

- Dementia or inability to give informed consent

- End-stage malignancy

- Severe orthopedic exercise limitation

- Use of chronic oral corticosteroids or other medications that affect muscle function.

- Chronic alcohol 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

- 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 uncorrected primary valvular heart disease (if valve replacement has been
performed, patients will not be eligible for at least 12 months)

- Mechanical valve replacement requiring warfarin

- Peripheral or pulmonary artery disease

- Currently taking clopidogrel for a recent stent placement and/or a complex
atherosclerotic lesion such that holding clopidogrel creates disproportionate risk.

- Current use of organic nitrates or phosphodiesterase type 5 inhibitors (PDE5s)

- Unable to hold warfarin or use bridging therapy, or to hold aspirin for 3 days (81
mg), 3 days (325 mg) prior to muscle biopsy or thienopyridine medications for 5 days
prior to muscle biopsy.

- Subjects with diabetes whose HgbA1c >10.0

- Other chronic unstable disease such as active neoplasm, end stage chronic kidney,
liver or other organ disease,