Treatment of HFpEF With Nitrate Supplement

Heart failure (HF) is the most common principal diagnosis for hospital admission in patients
over 65 years old. There are two types of HF, those with reduced ejection fraction (HFrEF)
and those with preserved ejection fraction (HFpEF). Approximately half of patients with the
clinical syndrome of HF have preserved systolic function. HEpEF is becoming more prevalent
with aging of the population and obesity. There are only two class I recommendations for the
treatment of HFpEF, which are controlling blood pressure and the use of diuretics to relieve
symptoms. Exercise training is another approach to improving symptoms, however it may be
poorly tolerated.

Nitrate supplement in the form of concentrated beetroot juice was recently shown to improve
exercise tolerance in patients with HFpEF. (1) Beetroot juice contains high concentration of
nitrate (NO3). This is metabolized to nitrite (NO2). It enters the blood stream, where it is
further reduced to nitric oxide (NO) resulting in intense vasodilation.

Patients with diastolic dysfunction are often asymptomatic at rest but complain of dyspnea
with exertion. Increase in heart rate with exercise causes reduced diastolic filling time and
increases left sided filling pressure. Borloug, et al demonstrated this with right heart
catheterization and supine exercise in patients with diastolic dysfunction. Infusion of NO2
resulted in decreased filling pressures and increased cardiac output. (2)

Neo40 is a new product made from concentrated beetroot juice in the form of a lozenge
designed to dissolve on the tongue. NO3 supplement causes vasodilatation only in the setting
of hypoxia and acidosis resulting in targeted vasodilatation.

Inclusion Criteria:

1. Diagnosis of HFpEF, defined as:

- symptomatic with one of more of the following: orthopnea, paroxysmal nocturnal
dyspnea, lower-extremity edema, dyspnea on exertion; AND

- ejection fraction >50%

- ratio of early mitral inflow velocity to septal tissue dopler velocity >8; AND

- one or more of the following: left atrium measurement >34 mL/m2, elevated
N-terminal pro-brain natriuretic peptide level within the past 12 months, long
term loop diuretic use for control of symptoms or elevated filling pressures on
prior cardiac catheterization

2. Stable medical therapy, defined as: no change in cardiac medications within 30 days

3. Willing to comply with the protocol and provide written informed consent

Exclusion Criteria:

1. Non-cardiac condition causing limitation of exercise tolerance

2. Acute coronary syndrome, myocardial infarction or cardiac revascularization within 60
days

3. Clinically significant valvular disease, defined as moderate-severe or severe stenosis
or insufficiency

4. Significant ischemia seen on stress testing within the past 12 months that was not
revascularized

5. Subject has taken and investigational medication within the past 30 days

6. History of allergy to beets

7. Systolic blood pressure of <100 at screening

8. Significant medical condition that would interfere with treatment, safety or
compliance with the protocol