Oral Nitrite for Older Heart Failure Patients

Heart failure (HF) is epidemic with aging and prevalence of HF is steadily increasing as the
population of older adults expands. Despite the fact that age always stands out as a leading
risk factor for HF incidence as well as for poor HF prognosis, few HF trials focus
specifically on aging physiology as a key determinant of the disease, and/or on the utility
of targeting mechanisms associated with aging as beneficial therapeutic targets.
Consistently, HF trials have tended to focus primarily on central mechanisms of cardiac
pumping dysfunction despite the fact that HF-outcomes are strongly related to functional
decrements that are largely mediated by peripheral manifestations of the disease, and which
are particularly interrelated with aging physiology. HF-related skeletal muscle myopathy is a
manifestation of HF that diminishes physical function, and which is likely exacerbated by
sarcopenia, vascular stiffening, and other aspects of aging such that exercise intolerance is
disproportionate among older HF populations as well as its insidious clinical implications.
In a pilot investigation, the investigators will study older (age ≥70 years) adults,
including patients with HF with reduced ejection fraction (HFrEF) and HF with preserved
ejection fraction (HFpEF) and age-matched healthy controls, to study benefits of nitrite
therapy (in addition to established standards of HF care) to improve physical function. In
this pilot analysis the investigators will focus on the utility of daily nitrite supplements
to moderate aerobic (maximal and submaximal) and strength (maximal, endurance, and power)
indices as well as underlying skeletal muscle mechanisms (skeletal muscle mitochondrial
performance, gene expression, and capillarity).

Atrophy of type 1 skeletal muscle myocytes is associated with HFrEF and HFpEF. Multiple
studies of normal aging have also demonstrated typical atrophy of type 2 skeletal muscle
fibers. Consistently, older adults are compromised by cumulative atrophy risks, with studies
showing losses of lean body mass as well as intrinsic skeletal muscle weakening, increased
interstitial fat, and increased inflammation, with associated functional decrements and
fatigue. While aerobic and strength exercise training may be used to modify such HF-related
muscle patterns, deconditioning remains pervasive among older HF patients, and efforts to
promote exercise interventions are typically confounded by comorbidity (e.g. arthritis,
peripheral arterial disease, diabetes, depression), geriatric syndromes (e.g., falls,
frailty, incontinence, dementia, poor sleep, malnutrition, auditory and vision impairments),
as well as pain, anxiety, and logistic limitations. Even major exercise-training trials that
provided strong reinforcements to ensure requisite behavioral changes yielded only poor
exercise adherence. There is high conceptual rationale for a therapy that intrinsically
improves skeletal muscle performance in HF as a vital means to improve physical function and
moderate effects of disease itself as well as to frailties and enfeeblement associated with
the disease. This will potentially improve efficacy and quality of care, and also potentially
mitigate the skyrocketing costs associated with aggregate HF management.

Studies have demonstrated nitrate therapy increases adenosine triphospate (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-IND approved
sodium nitrite (10 mg) capsule, and its utility to upregulate the SIRT3-AMP pathway of
skeletal muscle of younger 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.

Overall aims:

1. To demonstrate that oral nitrite pills provide skeletal muscle physiological benefit in
old HFrEF and HFpEF patients:

- To show that oral supplements are manifest as increased plasma nitrite.

- To show that increased plasma nitrite is associated with improved skeletal muscle
(mitochondrial respirometry) and platelet (Seahorse XF) metabolism.

- To demonstrate that improved metabolism is associated with shifts in skeletal
muscle anabolic gene expression (Fibronectin type III domain-containing protein 5
[FNDC5], peroxisome proliferator-activated receptor-γ coactivator [PGC1α], Sirtuin
3) as well as reduced catabolic gene expression (ubiquitin, muscle RING-Finger
Protein [MuRF], Atrogin1]) and inflammation (Tumor necrosis factor alpha [TNFα],
Interleukin 1beta (IL-1β), Interleukin six (IL-6).

2. To demonstrate that improved skeletal physiology achieved using oral nitrate pills is
associated with improved clinical indices in old HFrEF and HFpEF patients:

- To show that oral nitrite supplements increase efficiency of work, i.e., reduced
oxygen uptake (VO2) required for the same work intensity.

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.