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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Nitrate rich beetroot juice | Active Comparator | Subjects with heart failure with preserved ejection fraction will receive 140 mL of Nitrate-rich concentrated beetroot juice (containing 12 mmol of NO-3). This will be a cross-over study. Therefore all subjects will receive both interventions, but the order of the interventions will be randomized. |
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| Nitrate depleted beetroot juice | Placebo Comparator | Subjects with heart failure with preserved ejection fraction will receive 140 mL of nitrate-depleted beetroot juice (containing <0.01 mmol of NO-3).This will be a cross-over study. Therefore all subjects will receive both interventions, but the order of the interventions will be randomized. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Nitrate rich beetroot juice | Dietary Supplement | Subjects will receive 140 mL of Nitrate-rich concentrated beetroot juice. |
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| Measure | Description | Time Frame |
|---|---|---|
| Change in Peak exercise efficiency during maximal effort supine-bicycle exercise and peak oxygen consumption (VO2) during a maximal effort supine-bicycle exercise test | We will assess the relationship between total power output and total O2 consumption (VO2, assessed via expired gas analysis) during a maximal-effort supine bicycle exercise test. | Baseline study, repeat study 4-7 days later |
| Measure | Description | Time Frame |
|---|---|---|
| Change in Arterial wave reflection magnitude | Reflection wave magnitude will be assessed using arterial tonometry to arrive at the augmentation index. The data will also be processed using custom designed software for wave separation analysis to quantify the magnitude and timing of the reflected waves. | Baseline study, repeat study 4-7 days later |
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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:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Julio A Chirinos, MD, PhD | Philadelphia VA Medical Center & University of Pennsylvania | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Philadelphia Veterans Affairs Medical Center | Philadelphia | Pennsylvania | 19104 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 12524257 | Background | American Thoracic Society; American College of Chest Physicians. ATS/ACCP Statement on cardiopulmonary exercise testing. Am J Respir Crit Care Med. 2003 Jan 15;167(2):211-77. doi: 10.1164/rccm.167.2.211. No abstract available. | |
| 21982360 | Background | Manetos C, Dimopoulos S, Tzanis G, Vakrou S, Tasoulis A, Kapelios C, Agapitou V, Ntalianis A, Terrovitis J, Nanas S. Skeletal muscle microcirculatory abnormalities are associated with exercise intolerance, ventilatory inefficiency, and impaired autonomic control in heart failure. J Heart Lung Transplant. 2011 Dec;30(12):1403-8. doi: 10.1016/j.healun.2011.08.020. Epub 2011 Oct 7. |
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| ID | Term |
|---|---|
| D006333 | Heart Failure |
| ID | Term |
|---|---|
| D006331 | Heart Diseases |
| D002318 | Cardiovascular Diseases |
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| Nitrate depleted beetroot juice | Dietary Supplement | Subjects will receive 140 mL of nitrate-depleted beetroot juice. |
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| Change in Peripheral vascular resistance, total arterial compliance and reflection magnitude during supine bicycle peak exercise | Baseline study, repeat study 4-7 days later |
| Change in lower extremity exercise vasodilator reserve (change in femoral vascular resistance between rest and maximal effort supine-bicycle exercise) | Baseline study, repeat study 4-7 days later |
| Change in lower extremity blood flow reserve (change in femoral artery blood flow between rest and maximal effort supine-bicycle exercise) | Baseline study, repeat study 4-7 days later |
| Change in submaximal exercise efficiency (O2 consumption per power output during submaximal exercise and standardized handgrip exercise) | Baseline study, repeat study 4-7 days later |
| Change in Skeletal Muscle Mitochondrial Oxidative Capacity | The investigators will assess the oxygen consumption recovery kinetics after moderate forearm exercise, using repeated cuff brachial artery occlusions and near-infrared spectroscopy. | Baseline study, repeat study 4-7 days later |
| Change in post-ischemic vasodilatory response | The investigators will assess the post-ischemic vasodilatory response in the forearm using brachial artery pulsed wave Doppler interrogations before and after inflation of a brachial cuff at 200 mmHg for 5 minutes. The investigators will also assess forearm microvascular skeletal muscle flow with near-infrared spectroscopy and forearm skin microvascular flow using laser Doppler. | Baseline study, repeat study 4-7 days later |
| 25533966 | Result | Zamani P, Rawat D, Shiva-Kumar P, Geraci S, Bhuva R, Konda P, Doulias PT, Ischiropoulos H, Townsend RR, Margulies KB, Cappola TP, Poole DC, Chirinos JA. Effect of inorganic nitrate on exercise capacity in heart failure with preserved ejection fraction. Circulation. 2015 Jan 27;131(4):371-80; discussion 380. doi: 10.1161/CIRCULATIONAHA.114.012957. Epub 2014 Dec 22. |