Effect of Inorganic Nitrates (Beetroot Juice) on Arterial Hemodynamics and Exercise Capacity

This represents a series of double-blind, controlled pilot randomized studies in which the
effects of nitrate-rich beetroot juice and nitrate-depleted beetroot juice will be assessed
in patients with heart failure and preserved ejection fraction (n=20), patients with heart
failure and reduced ejection fraction (n=20), normal volunteers (n=20), and patients with
hypertension (n=20). A total of 80 subjects will be enrolled over a 1.5 year period and
randomized in a cross-over design to a single dose of nitrate-rich beetroot juice and
nitrate-depleted beetroot juice. The order of the interventions will be randomized; thus,
all subjects will receive the nitrate-rich and nitrate-depleted juice, with a 4-7 day
washout period in-between studies.

Inclusion Criteria:

The investigators will enroll 80 subjects >18 years of age who are either: (1)
Normotensive and have no evidence of heart failure; (2) Have hypertension (defined by
JNC-7 criteria) but no heart failure; (3) Have a diagnosis of heart failure with reduced
ejection fraction (<50%) by 2d echocardiography and, current New York Heart Association
Class II-IV symptoms; (4) Have a diagnosis of heart failure with a preserved ejection
fraction (>50%) by 2d echocardiography, with current New York Heart Association Class
II-IV symptoms.

In addition, subjects with heart failure must meet the following inclusion criteria:

1. Chronic treatment with a loop diuretic for control of HF symptoms.

2. If EF is normal, subjects must demonstrate elevated filling pressures as evidenced by
at least one of the following: a) left atrial enlargement (LAVI > 32 mL/m2); b) at
least stage II diastolic dysfunction; c) Documentation of elevated NT-pro BNP levels
or other natriuretic peptide marker (BNP, ANP) according to the laboratory and assay
upper limit of normal in the previous year.

3. Stable medical therapy as defined by: (I) No addition or removal of ACE, ARB,
beta-blockers, or calcium channel blockers (CCBs) for 30 days. (II) No change in
dosage of ACE, ARBs, beta-blockers or CCBs of more than 100% for 30 days. (III) No
change in diuretic dose for 10 days.

Exclusion Criteria:

1. Rhythm other than sinus rhythm (i.e., atrial fibrillation).

2. Neuromuscular, orthopedic or other non-cardiac condition that prevents patient from
exercising.

3. Valve disease (> mild aortic or mitral stenosis; > moderate aortic or mitral
regurgitation).

4. Hypertrophic cardiomyopathy.

5. Known infiltrative or inflammatory myocardial disease (amyloid, sarcoid).

6. Pericardial disease.

7. Primary pulmonary arteriopathy.

8. Have experienced a myocardial infarction or unstable angina, or have undergone
percutaneous transluminal coronary angiography (PTCA) or coronary artery bypass
grafting (CABG) within 60 days prior to consent, or requires either PTCA or CABG at
the time of consent.

9. Other clinically important causes of dyspnea such as morbid obesity or significant
lung disease defined by clinical judgment or use of steroids or oxygen for lung
disease within the past 6 months.

10. Systolic blood pressure < 110 mmHg or > 180 mm Hg.

11. Diastolic blood pressure < 40 mmHg or > 100 mmHg.

12. Resting heart rate (HR) > 100 bpm.

13. Hemoglobin <10 g/dL.

14. Patients with known severe liver disease (AST > 3x normal, alkaline phosphatase or
bilirubin > 2x normal).

15. Patients with a clinically indicated stress test demonstrating significant ischemia
within a year of enrollment which was not followed by percutaneous or surgical
revascularization.

16. Current therapy with phosphodiesterase inhibitors, such as sildenafil, vardanafil or
tadalafil.

17. Known allergies to beetroot or lemon juice.

18. Current use of organic nitrates or phosphodiesterase inhibitors.

19. Pregnancy. Although beetroot juice has not knows teratogenic effects, we feel that
not enough data exist in this regard. Therefore, all females patients of reproductive
age will be required to undergo a pregnancy test prior to enrollment.