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

The main objective is to test the hypothesis that inorganic nitrate supplementation will: (1) Improve exercise efficiency and performance; (2) Enhance the systemic vasodilator reserve during exercise and specifically, the vasodilator response in exercising muscle; (3) Reduce arterial wave reflections and arterial load; (4) Improve skeletal muscle mitochondrial function in subjects with heart failure with preserved ejection fraction.

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). A total of 20 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.

Eligibility Criteria:
Inclusion Criteria:

The investigators will enroll 20 subjects \>18 years of age who have a diagnosis of heart failure with 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.