<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT01682356</url>
  </required_header>
  <id_info>
    <org_study_id>BRJ_201111134</org_study_id>
    <nct_id>NCT01682356</nct_id>
  </id_info>
  <brief_title>Dietary Nitrates for Heart Failure (HF)</brief_title>
  <official_title>Dietary Nitrates for Heart Failure</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Washington University School of Medicine</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>The Foundation for Barnes-Jewish Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Washington University School of Medicine</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this study is to determine if nitrates in a food, in this case - beetroot&#xD;
      juice (BRJ) - is efficacious in improving exercise tolerance and/or peak power in patients&#xD;
      with heart failure. The investigators will also determine if BRJ improves blood pressure,&#xD;
      exercise efficiency, vascular and muscle function, and whether blood levels of nitrates&#xD;
      increase hourly for a total of 4 hours after BRJ ingestion. A secondary aim is to determine&#xD;
      if BRJ-derived nitrates are still effective at 1, 2 and 4 weeks after starting treatment. A&#xD;
      tertiary aim is to determine the variation in the 6 minute walk test. Subjects will answer a&#xD;
      basic medical information sheet and undergo a 6-minute walk test. After at least a 48 hours&#xD;
      rest, subjects will be asked to repeat the 6 minutes' walk. The investigators will (1)&#xD;
      determine if BRJ (as compared to placebo) improves peak power output in heart failure&#xD;
      patients and controls (at ~ 1½ to 2 hours after ingestion); (2) compare the changes in&#xD;
      cardiac muscle (on average ~ 8-12 hours after) BRJ or placebo ingestion in patients who will&#xD;
      be undergoing an left ventricle (LV) assist device placement for clinical purposes. (a&#xD;
      cross-sectional study); (3) determine if BRJ decreases elevated pulmonary artery (PA)&#xD;
      pressures or improves vascular and/or microvascular function (at ~ 1½ - 2 hours after&#xD;
      ingestion) in patients who are already coming in for a PA catheter placement for clinical&#xD;
      purposes; (4) compare the physiological changes after BRJ ingestion in non-heart failure&#xD;
      control subjects with those of patients with heart failure. Endpoints measured at the same&#xD;
      time points after ingestion. The investigators hypothesize (1) that patients with heart&#xD;
      failure and controls will have improved exercise capacity and power at lower oxygen cost (and&#xD;
      thereby greater efficiency) ~ 1½- 2 hours after ingesting beet juice (BRJ) than after&#xD;
      ingesting placebo (beet juice without nitrates); (2) that patients with heart failure will&#xD;
      have a greater physiologic response to BRJ than non-heart failure controls since the former&#xD;
      have worse physiological function to start with; (3) that patients with high pulmonary artery&#xD;
      pressures will have an improvement in the pressures after ingestion with BRJ; (4) that&#xD;
      myocardial perfusion will be higher after BRJ ingestion than after placebo; (5) that cyclic&#xD;
      guanosine monophosphate (cGMP) levels will be increased in left ventricle assist device&#xD;
      (LVAD) samples after BRJ ingestion compared with placebo.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      For all studies and sub-studies:&#xD;
&#xD;
      A) All Subjects will be consented. B) All Subjects will give permission for the investigators&#xD;
      to review their medical records.&#xD;
&#xD;
      For the BRJ main study (acute dose BRJ intervention):&#xD;
&#xD;
        1. After consenting to participate, subjects will be instructed to refrain from spitting or&#xD;
           the use of an antibacterial mouthwash, antacids, proton pump inhibitors, or chewing gum&#xD;
           during the study.&#xD;
&#xD;
        2. Subjects will be asked to answer questionnaires regarding their medical health (basic&#xD;
           health questionnaire, Minnesota living with heart failure questionnaire, a magnetic&#xD;
           resonance safety -i.e., questions regarding implanted pacemakers, etc...) 2a)Subjects&#xD;
           will undergo a physical examination at one time during the study.&#xD;
&#xD;
        3. Subjects will be interviewed by a dietician with regards to their typical dietary intake&#xD;
           and instructed on a low nitrate diet.&#xD;
&#xD;
        4. In study visit #1 subjects will be randomized to receive either a &quot;shot&quot; of BRJ (James&#xD;
           White Drinks)or placebo (BRJ without nitrates).&#xD;
&#xD;
        5. Before and at 3 time points (~hourly) after receiving the BRJ or placebo, subjects will&#xD;
           undergo phlebotomy for plasma nutrient/hormone levels and will have their blood pressure&#xD;
           checked. They will also be asked to swish (5 minutes) and spit out a dilute ~ 4tbps&#xD;
           solution of nitrate,so we can quantify nitrate to nitrite conversion at ~ 1 1/4 hours&#xD;
           after ingestion 5A) Subjects will undergo an echocardiogram just after the swish and&#xD;
           spit.&#xD;
&#xD;
        6. ~ 1 3/4 hours after ingestion, subjects will undergo a 6 minute walk.&#xD;
&#xD;
        7. ~ 2 hours after ingestion, subjects will pedal an ergometer for 6 min at 15, 30, and 45&#xD;
           W (requiring ~50, ~60, and ~70% of oxygen consumption (VO2) peak, i.e., peak oxygen&#xD;
           consumption) while VO2 is measured using a ParvoMedics TrueOne (this is the brand)&#xD;
           metabolic cart. Five min of rest will be allowed between stages. The average VO2 during&#xD;
           the last 2 min of each stage will be used to calculate gross and delta efficiency using&#xD;
           stoichiometric equations as previously described. Following a 10 min rest period, peak&#xD;
           power and VO2 peak will determined during a continuous exercise test performed using a&#xD;
           10 W/min ramp protocol.&#xD;
&#xD;
        8. Subjects will then (immediately afterwards )undergo an Magnetic resonance (MR) study of&#xD;
           skeletal muscle (and if there is time cardiac performance) with mild exercise (pushing&#xD;
           one foot on a pedal for 6 min of submaximal isometric exercise (1 s contraction at 50%&#xD;
           of previously-determined maximal voluntary contraction - according to their VO2 peak&#xD;
           levels in their medical charts - every 9 s) with spectra acquired before, during, and&#xD;
           after exercise.&#xD;
&#xD;
           During exercise, subjects will have their heart rate, blood pressure and rhythm&#xD;
           monitored.&#xD;
&#xD;
        9. Subjects will be asked to undergo a mouth swab for bacterial DNA analyses (after the&#xD;
           swish and spit) 9A) Subjects will undergo a Dual-energy Xray absorptiometry (DXA) scan&#xD;
           for body composition analysis (either before or after BRJ ingestion - it is a&#xD;
           phenotyping measure - not an endpoint)&#xD;
&#xD;
       10. Subjects will undergo a 7 d wash-out period&#xD;
&#xD;
       11. Subjects will come in for study day 2 in which they will receive whichever treatment&#xD;
           (BRJ or placebo) that they did not receive at first and then repeat the studies listed&#xD;
           above 5)-9).&#xD;
&#xD;
      (The total time of the study is estimated to take 5 hours)&#xD;
&#xD;
      For the longer 2 (or 4) week BRJ substudy: (subjects include HF (heart failure) patients and&#xD;
      nonHF controls, i.e., those without heart failure)&#xD;
&#xD;
        1. Subjects will be asked to undergo steps 1-9 above, ingest 1 week of BRJ (1 &quot;shot&quot;/day)&#xD;
           and then undergo the studies listed 5)-9).&#xD;
&#xD;
        2. Subjects will be asked to ingest 1 more week of BRJ (1 &quot;shot&quot;/day for a total of 2&#xD;
           weeks) and then undergo a repeat of studies listed 5)-9)&#xD;
&#xD;
      For the BRJ neuromuscular function testing sub-study:&#xD;
&#xD;
        1. Subjects will be asked to undergo steps 1-6 above&#xD;
&#xD;
        2. Subjects will be asked to undergo a mouth swab for bacterial DNA analyses.&#xD;
&#xD;
        3. Subjects will undergo a test of neuromuscular function using an isokinetic dynamometer&#xD;
           (a device that measures voluntary muscle force production while controlling the speed of&#xD;
           movement) immediately after the echocardiogram at ~2 h after BRJ (or placebo ingestion).&#xD;
&#xD;
      3A) Subjects will be asked to undergo an optional skeletal muscle biopsy immediately after&#xD;
      the Biodex study.&#xD;
&#xD;
      3B) Subjects will undergo a dual-energy isokinetic dynamometry study for body composition&#xD;
      analysis (at any time point during the study day).&#xD;
&#xD;
      4) Subjects will undergo a 7 d washout period.&#xD;
&#xD;
      5) Subjects will come in for Study day 2 in which they will receive whichever treatment (BRJ&#xD;
      or placebo) they did not receive at first and then repeat the studies listed above 1-3.&#xD;
&#xD;
      For the Pulmonary artery (PA) pressure sub-study:&#xD;
&#xD;
      NOTE: This study will only be performed in patients who are undergoing a PA catheter&#xD;
      placement for clinical purposes (high PA pressures) anyway.&#xD;
&#xD;
        1. After consenting to participate, subjects will be instructed to refrain from spitting or&#xD;
           the use of an antibacterial mouthwash, antacids, proton pump inhibitors, or chewing gum&#xD;
           during the study.&#xD;
&#xD;
        2. Subjects will be asked to answer questionnaires regarding their medical health (basic&#xD;
           health questionnaire, Minnesota living with heart failure questionnaire, etc.) 2a)&#xD;
           Subjects will be asked to undergo a physical examination.&#xD;
&#xD;
        3. Before and at 3 (hourly) time points after receiving a &quot;shot&quot; of BRJ, subjects will&#xD;
           undergo phlebotomy for plasma nutrient/hormone levels and will have their blood pressure&#xD;
           checked and will blow into a tube connected to a small machine that will measure the&#xD;
           amount of nitric oxide in their breath. Subjects will also have cardiovascular&#xD;
           measurements (e.g., cardiac output, PA pressure, etc.) made before and at 3 ~ hourly&#xD;
           time points after receiving the BRJ. These measurements will be made using a PA catheter&#xD;
           that is being placed for clinical purposes.&#xD;
&#xD;
        4. If a subject is to undergo an LVAD placement he/she will be randomized to receive BRJ or&#xD;
           placebo the evening before surgery (anticipated average ~ 8-12 hours before), and then&#xD;
           the LV core will be harvested and immediately frozen for later analysis.&#xD;
&#xD;
        5. Subjects who will be undergoing myocardial perfusion studies will undergo the same basic&#xD;
           studies (breath NO, plasma nitrate/nitrite determination, as mentioned in the&#xD;
           neuromuscular aim, but subjects will also undergo a positron emission tomography (PET)&#xD;
           study in which they will receive O-15 water for quantification of myocardial blood flow&#xD;
           ~ 2 hours after consumption of BRJ or placebo. Then they will undergo a washout phase of&#xD;
           7 d and then repeat the PET study after the other treatment (BRJ or placebo).&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date>January 2012</start_date>
  <completion_date type="Anticipated">July 2024</completion_date>
  <primary_completion_date type="Anticipated">July 2024</primary_completion_date>
  <phase>Phase 1/Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Crossover Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Double (Participant, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Peak power</measure>
    <time_frame>each subject is tested at maximum over a 4 week period</time_frame>
    <description>Each subject performs a neuromuscular power test after ingesting BRJ or placebo. There is a 7 d washout period and then the test is repeated after the subject ingests the BRJ or placebo (whichever was not taken the first time).</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>VO2 peak</measure>
    <time_frame>each subject is tested over a maximum of a 2 week period</time_frame>
    <description>Each subject performs a VO2 test after ingesting BRJ or placebo. There is a 7 d washout period and then the test is repeated after the subject ingests the BRJ or placebo (whichever was not taken the first time).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>pulmonary artery pressure</measure>
    <time_frame>1 day intervention</time_frame>
    <description>Each patient who is going to have a PA catheter placed for clinical purposes will have their PA pressures measured before and after ingestion of BRJ.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cardiac function</measure>
    <time_frame>after ingestion of BRJ or placebo</time_frame>
    <description>Subjects undergoing MRI or echocardiography will have various measures of cardiac function made</description>
  </secondary_outcome>
  <other_outcome>
    <measure>blood pressure</measure>
    <time_frame>each subject is tested at a maximum of over a ~ 2week period</time_frame>
    <description>Each subject undergoes blood pressure checks after ingesting BRJ or placebo. There is a 10 d washout period and then the test is repeated after the subject ingests the BRJ or placebo (whichever was not taken the first time).</description>
  </other_outcome>
  <other_outcome>
    <measure>vascular function</measure>
    <time_frame>each patient will undergo a study for a maximum of ~ 2 weeks</time_frame>
    <description>Each subject undergoes a laser Doppler test and a brachial artery test after ingesting BRJ or placebo. There is a 10 d washout period and then the test is repeated after the subject ingests the BRJ or placebo (whichever was not taken the first time).</description>
  </other_outcome>
  <other_outcome>
    <measure>Nitric oxide and nitrate and nitrite</measure>
    <time_frame>before and after BRJ or placebo ingestion</time_frame>
    <description>We will measure nitric oxide, nitrate and nitrite before and after ingestion of BRJ or placebo</description>
  </other_outcome>
  <other_outcome>
    <measure>Myocardial perfusion</measure>
    <time_frame>before and after BRJ or placebo ingestion</time_frame>
    <description>We will measure perfusion using noninvasive PET imaging</description>
  </other_outcome>
  <other_outcome>
    <measure>Myocardial tissue changes</measure>
    <time_frame>after BRJ or placebo ingestion</time_frame>
    <description>We will measure cyclic GMP and nitrate in LV tissue after LVAD placement and after ingestion of either BRJ or placebo</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">126</enrollment>
  <condition>Heart Failure</condition>
  <condition>Hypertension, Pulmonary</condition>
  <arm_group>
    <arm_group_label>BRJ crossover to placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Beetroot Juice without nitrate.s Patients will be studied before and after ingestion of beetroot juice</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Beetroot Juice</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Beetroot Juice with nitrates. Patients will be studied before and after ingestion of beetroot juice with nitrates</description>
  </arm_group>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>Beetroot Juice (BRJ)</intervention_name>
    <description>double-blind placebo-controlled cross-over study</description>
    <arm_group_label>Beetroot Juice</arm_group_label>
    <other_name>Beetroot juice</other_name>
    <other_name>Beet It</other_name>
  </intervention>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>placebo</intervention_name>
    <description>double-blind placebo-controlled cross-over study</description>
    <arm_group_label>BRJ crossover to placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Men and women will have a history of heart failure (and/or pulmonary hypertension for&#xD;
             PA catheter substudy).&#xD;
&#xD;
          -  Age &gt; or = 18 y and controls of the same age range without heart failure.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Age &lt; 18 y.&#xD;
&#xD;
          -  Those taking phosphodiesterase inhibitors (e.g., Viagra) will be excluded, as these&#xD;
             can potentiate NO effects.&#xD;
&#xD;
          -  Those taking proton pump inhibitors, antacids, or xanthine oxidase inhibitors will be&#xD;
             excluded as these can affect reduction of nitrate (NO3-) and nitrite (NO2-) to nitric&#xD;
             oxide (NO).&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Linda R Peterson, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Washington University School of Medicine</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Andrew R Coggan, PhD</last_name>
    <role>Study Director</role>
    <affiliation>Indiana U -Purdue U- at Indianapolis (IUPUI)</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Indiana U. - Purdue U - at Indianapolis (IUPUI)</name>
      <address>
        <city>Indianapolis</city>
        <state>Indiana</state>
        <zip>46202</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Washington University School of Medicine</name>
      <address>
        <city>Saint Louis</city>
        <state>Missouri</state>
        <zip>63110</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <reference>
    <citation>Masschelein E, Van Thienen R, Wang X, Van Schepdael A, Thomis M, Hespel P. Dietary nitrate improves muscle but not cerebral oxygenation status during exercise in hypoxia. J Appl Physiol (1985). 2012 Sep 1;113(5):736-45. doi: 10.1152/japplphysiol.01253.2011. Epub 2012 Jul 5.</citation>
    <PMID>22773768</PMID>
  </reference>
  <reference>
    <citation>Hobbs DA, Kaffa N, George TW, Methven L, Lovegrove JA. Blood pressure-lowering effects of beetroot juice and novel beetroot-enriched bread products in normotensive male subjects. Br J Nutr. 2012 Dec 14;108(11):2066-74. doi: 10.1017/S0007114512000190. Epub 2012 Mar 14.</citation>
    <PMID>22414688</PMID>
  </reference>
  <reference>
    <citation>Cermak NM, Gibala MJ, van Loon LJ. Nitrate supplementation's improvement of 10-km time-trial performance in trained cyclists. Int J Sport Nutr Exerc Metab. 2012 Feb;22(1):64-71. doi: 10.1123/ijsnem.22.1.64.</citation>
    <PMID>22248502</PMID>
  </reference>
  <reference>
    <citation>Vanhatalo A, Fulford J, Bailey SJ, Blackwell JR, Winyard PG, Jones AM. Dietary nitrate reduces muscle metabolic perturbation and improves exercise tolerance in hypoxia. J Physiol. 2011 Nov 15;589(Pt 22):5517-28. doi: 10.1113/jphysiol.2011.216341. Epub 2011 Sep 12.</citation>
    <PMID>21911616</PMID>
  </reference>
  <reference>
    <citation>Kenjale AA, Ham KL, Stabler T, Robbins JL, Johnson JL, Vanbruggen M, Privette G, Yim E, Kraus WE, Allen JD. Dietary nitrate supplementation enhances exercise performance in peripheral arterial disease. J Appl Physiol (1985). 2011 Jun;110(6):1582-91. doi: 10.1152/japplphysiol.00071.2011. Epub 2011 Mar 31.</citation>
    <PMID>21454745</PMID>
  </reference>
  <reference>
    <citation>Ferreira LF, Behnke BJ. A toast to health and performance! Beetroot juice lowers blood pressure and the O2 cost of exercise. J Appl Physiol (1985). 2011 Mar;110(3):585-6. doi: 10.1152/japplphysiol.01457.2010. Epub 2010 Dec 23. No abstract available.</citation>
    <PMID>21183624</PMID>
  </reference>
  <reference>
    <citation>Vanhatalo A, Bailey SJ, Blackwell JR, DiMenna FJ, Pavey TG, Wilkerson DP, Benjamin N, Winyard PG, Jones AM. Acute and chronic effects of dietary nitrate supplementation on blood pressure and the physiological responses to moderate-intensity and incremental exercise. Am J Physiol Regul Integr Comp Physiol. 2010 Oct;299(4):R1121-31. doi: 10.1152/ajpregu.00206.2010. Epub 2010 Aug 11.</citation>
    <PMID>20702806</PMID>
  </reference>
  <reference>
    <citation>Wilkerson DP, Hayward GM, Bailey SJ, Vanhatalo A, Blackwell JR, Jones AM. Influence of acute dietary nitrate supplementation on 50 mile time trial performance in well-trained cyclists. Eur J Appl Physiol. 2012 Dec;112(12):4127-34. doi: 10.1007/s00421-012-2397-6. Epub 2012 Apr 20.</citation>
    <PMID>22526247</PMID>
  </reference>
  <reference>
    <citation>Bailey SJ, Winyard P, Vanhatalo A, Blackwell JR, Dimenna FJ, Wilkerson DP, Tarr J, Benjamin N, Jones AM. Dietary nitrate supplementation reduces the O2 cost of low-intensity exercise and enhances tolerance to high-intensity exercise in humans. J Appl Physiol (1985). 2009 Oct;107(4):1144-55. doi: 10.1152/japplphysiol.00722.2009. Epub 2009 Aug 6.</citation>
    <PMID>19661447</PMID>
  </reference>
  <verification_date>January 2023</verification_date>
  <study_first_submitted>September 5, 2012</study_first_submitted>
  <study_first_submitted_qc>September 7, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 10, 2012</study_first_posted>
  <last_update_submitted>January 30, 2023</last_update_submitted>
  <last_update_submitted_qc>January 30, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">January 31, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>heart failure</keyword>
  <keyword>hypertension, pulmonary</keyword>
  <keyword>oxygen consumption</keyword>
  <keyword>exercise tolerance</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Hypertension, Pulmonary</mesh_term>
    <mesh_term>Hypertension</mesh_term>
    <mesh_term>Heart Failure</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
    <ipd_description>Aggregate data that contains no HIPPA identifiers will be made available as required if the request complies with all federal and University policies for data sharing. IPD will not be shared since this is a small study at a single institution, so the likelihood of identifying subjects would be increased.</ipd_description>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT01682356
org study id: BRJ_201111134
nct id: NCT01682356
lead sponsor: 
collaborator: 
has dmc: Yes
The purpose of this study is to determine if nitrates in a food, in this case - beetroot
      juice (BRJ) - is efficacious in improving exercise tolerance and/or peak power in patients
      with heart failure. The investigators will also determine if BRJ improves blood pressure,
      exercise efficiency, vascular and muscle function, and whether blood levels of nitrates
      increase hourly for a total of 4 hours after BRJ ingestion. A secondary aim is to determine
      if BRJ-derived nitrates are still effective at 1, 2 and 4 weeks after starting treatment. A
      tertiary aim is to determine the variation in the 6 minute walk test. Subjects will answer a
      basic medical information sheet and undergo a 6-minute walk test. After at least a 48 hours
      rest, subjects will be asked to repeat the 6 minutes' walk. The investigators will (1)
      determine if BRJ (as compared to placebo) improves peak power output in heart failure
      patients and controls (at ~ 1½ to 2 hours after ingestion); (2) compare the changes in
      cardiac muscle (on average ~ 8-12 hours after) BRJ or placebo ingestion in patients who will
      be undergoing an left ventricle (LV) assist device placement for clinical purposes. (a
      cross-sectional study); (3) determine if BRJ decreases elevated pulmonary artery (PA)
      pressures or improves vascular and/or microvascular function (at ~ 1½ - 2 hours after
      ingestion) in patients who are already coming in for a PA catheter placement for clinical
      purposes; (4) compare the physiological changes after BRJ ingestion in non-heart failure
      control subjects with those of patients with heart failure. Endpoints measured at the same
      time points after ingestion. The investigators hypothesize (1) that patients with heart
      failure and controls will have improved exercise capacity and power at lower oxygen cost (and
      thereby greater efficiency) ~ 1½- 2 hours after ingesting beet juice (BRJ) than after
      ingesting placebo (beet juice without nitrates); (2) that patients with heart failure will
      have a greater physiologic response to BRJ than non-heart failure controls since the former
      have worse physiological function to start with; (3) that patients with high pulmonary artery
      pressures will have an improvement in the pressures after ingestion with BRJ; (4) that
      myocardial perfusion will be higher after BRJ ingestion than after placebo; (5) that cyclic
      guanosine monophosphate (cGMP) levels will be increased in left ventricle assist device
      (LVAD) samples after BRJ ingestion compared with placebo.
For all studies and sub-studies:

      A) All Subjects will be consented. B) All Subjects will give permission for the investigators
      to review their medical records.

      For the BRJ main study (acute dose BRJ intervention):

        1. After consenting to participate, subjects will be instructed to refrain from spitting or
           the use of an antibacterial mouthwash, antacids, proton pump inhibitors, or chewing gum
           during the study.

        2. Subjects will be asked to answer questionnaires regarding their medical health (basic
           health questionnaire, Minnesota living with heart failure questionnaire, a magnetic
           resonance safety -i.e., questions regarding implanted pacemakers, etc...) 2a)Subjects
           will undergo a physical examination at one time during the study.

        3. Subjects will be interviewed by a dietician with regards to their typical dietary intake
           and instructed on a low nitrate diet.

        4. In study visit #1 subjects will be randomized to receive either a "shot" of BRJ (James
           White Drinks)or placebo (BRJ without nitrates).

        5. Before and at 3 time points (~hourly) after receiving the BRJ or placebo, subjects will
           undergo phlebotomy for plasma nutrient/hormone levels and will have their blood pressure
           checked. They will also be asked to swish (5 minutes) and spit out a dilute ~ 4tbps
           solution of nitrate,so we can quantify nitrate to nitrite conversion at ~ 1 1/4 hours
           after ingestion 5A) Subjects will undergo an echocardiogram just after the swish and
           spit.

        6. ~ 1 3/4 hours after ingestion, subjects will undergo a 6 minute walk.

        7. ~ 2 hours after ingestion, subjects will pedal an ergometer for 6 min at 15, 30, and 45
           W (requiring ~50, ~60, and ~70% of oxygen consumption (VO2) peak, i.e., peak oxygen
           consumption) while VO2 is measured using a ParvoMedics TrueOne (this is the brand)
           metabolic cart. Five min of rest will be allowed between stages. The average VO2 during
           the last 2 min of each stage will be used to calculate gross and delta efficiency using
           stoichiometric equations as previously described. Following a 10 min rest period, peak
           power and VO2 peak will determined during a continuous exercise test performed using a
           10 W/min ramp protocol.

        8. Subjects will then (immediately afterwards )undergo an Magnetic resonance (MR) study of
           skeletal muscle (and if there is time cardiac performance) with mild exercise (pushing
           one foot on a pedal for 6 min of submaximal isometric exercise (1 s contraction at 50%
           of previously-determined maximal voluntary contraction - according to their VO2 peak
           levels in their medical charts - every 9 s) with spectra acquired before, during, and
           after exercise.

           During exercise, subjects will have their heart rate, blood pressure and rhythm
           monitored.

        9. Subjects will be asked to undergo a mouth swab for bacterial DNA analyses (after the
           swish and spit) 9A) Subjects will undergo a Dual-energy Xray absorptiometry (DXA) scan
           for body composition analysis (either before or after BRJ ingestion - it is a
           phenotyping measure - not an endpoint)

       10. Subjects will undergo a 7 d wash-out period

       11. Subjects will come in for study day 2 in which they will receive whichever treatment
           (BRJ or placebo) that they did not receive at first and then repeat the studies listed
           above 5)-9).

      (The total time of the study is estimated to take 5 hours)

      For the longer 2 (or 4) week BRJ substudy: (subjects include HF (heart failure) patients and
      nonHF controls, i.e., those without heart failure)

        1. Subjects will be asked to undergo steps 1-9 above, ingest 1 week of BRJ (1 "shot"/day)
           and then undergo the studies listed 5)-9).

        2. Subjects will be asked to ingest 1 more week of BRJ (1 "shot"/day for a total of 2
           weeks) and then undergo a repeat of studies listed 5)-9)

      For the BRJ neuromuscular function testing sub-study:

        1. Subjects will be asked to undergo steps 1-6 above

        2. Subjects will be asked to undergo a mouth swab for bacterial DNA analyses.

        3. Subjects will undergo a test of neuromuscular function using an isokinetic dynamometer
           (a device that measures voluntary muscle force production while controlling the speed of
           movement) immediately after the echocardiogram at ~2 h after BRJ (or placebo ingestion).

      3A) Subjects will be asked to undergo an optional skeletal muscle biopsy immediately after
      the Biodex study.

      3B) Subjects will undergo a dual-energy isokinetic dynamometry study for body composition
      analysis (at any time point during the study day).

      4) Subjects will undergo a 7 d washout period.

      5) Subjects will come in for Study day 2 in which they will receive whichever treatment (BRJ
      or placebo) they did not receive at first and then repeat the studies listed above 1-3.

      For the Pulmonary artery (PA) pressure sub-study:

      NOTE: This study will only be performed in patients who are undergoing a PA catheter
      placement for clinical purposes (high PA pressures) anyway.

        1. After consenting to participate, subjects will be instructed to refrain from spitting or
           the use of an antibacterial mouthwash, antacids, proton pump inhibitors, or chewing gum
           during the study.

        2. Subjects will be asked to answer questionnaires regarding their medical health (basic
           health questionnaire, Minnesota living with heart failure questionnaire, etc.) 2a)
           Subjects will be asked to undergo a physical examination.

        3. Before and at 3 (hourly) time points after receiving a "shot" of BRJ, subjects will
           undergo phlebotomy for plasma nutrient/hormone levels and will have their blood pressure
           checked and will blow into a tube connected to a small machine that will measure the
           amount of nitric oxide in their breath. Subjects will also have cardiovascular
           measurements (e.g., cardiac output, PA pressure, etc.) made before and at 3 ~ hourly
           time points after receiving the BRJ. These measurements will be made using a PA catheter
           that is being placed for clinical purposes.

        4. If a subject is to undergo an LVAD placement he/she will be randomized to receive BRJ or
           placebo the evening before surgery (anticipated average ~ 8-12 hours before), and then
           the LV core will be harvested and immediately frozen for later analysis.

        5. Subjects who will be undergoing myocardial perfusion studies will undergo the same basic
           studies (breath NO, plasma nitrate/nitrite determination, as mentioned in the
           neuromuscular aim, but subjects will also undergo a positron emission tomography (PET)
           study in which they will receive O-15 water for quantification of myocardial blood flow
           ~ 2 hours after consumption of BRJ or placebo. Then they will undergo a washout phase of
           7 d and then repeat the PET study after the other treatment (BRJ or placebo).
allocation: Randomized
intervention model: Crossover Assignment
primary purpose: Treatment
masking: Double (Participant, Investigator)
measure: Peak power
time frame: each subject is tested at maximum over a 4 week period
description: Each subject performs a neuromuscular power test after ingesting BRJ or placebo. There is a 7 d washout period and then the test is repeated after the subject ingests the BRJ or placebo (whichever was not taken the first time).
measure: VO2 peak
time frame: each subject is tested over a maximum of a 2 week period
description: Each subject performs a VO2 test after ingesting BRJ or placebo. There is a 7 d washout period and then the test is repeated after the subject ingests the BRJ or placebo (whichever was not taken the first time).
measure: pulmonary artery pressure
time frame: 1 day intervention
description: Each patient who is going to have a PA catheter placed for clinical purposes will have their PA pressures measured before and after ingestion of BRJ.
measure: Cardiac function
time frame: after ingestion of BRJ or placebo
description: Subjects undergoing MRI or echocardiography will have various measures of cardiac function made
measure: blood pressure
time frame: each subject is tested at a maximum of over a ~ 2week period
description: Each subject undergoes blood pressure checks after ingesting BRJ or placebo. There is a 10 d washout period and then the test is repeated after the subject ingests the BRJ or placebo (whichever was not taken the first time).
measure: vascular function
time frame: each patient will undergo a study for a maximum of ~ 2 weeks
description: Each subject undergoes a laser Doppler test and a brachial artery test after ingesting BRJ or placebo. There is a 10 d washout period and then the test is repeated after the subject ingests the BRJ or placebo (whichever was not taken the first time).
measure: Nitric oxide and nitrate and nitrite
time frame: before and after BRJ or placebo ingestion
description: We will measure nitric oxide, nitrate and nitrite before and after ingestion of BRJ or placebo
measure: Myocardial perfusion
time frame: before and after BRJ or placebo ingestion
description: We will measure perfusion using noninvasive PET imaging
measure: Myocardial tissue changes
time frame: after BRJ or placebo ingestion
description: We will measure cyclic GMP and nitrate in LV tissue after LVAD placement and after ingestion of either BRJ or placebo
arm group label: BRJ crossover to placebo
arm group type: Placebo Comparator
description: Beetroot Juice without nitrate.s Patients will be studied before and after ingestion of beetroot juice
arm group label: Beetroot Juice
arm group type: Active Comparator
description: Beetroot Juice with nitrates. Patients will be studied before and after ingestion of beetroot juice with nitrates
intervention type: Dietary Supplement
intervention name: Beetroot Juice (BRJ)
description: double-blind placebo-controlled cross-over study
arm group label: Beetroot Juice
other name: Beetroot juice
other name: Beet It
intervention type: Dietary Supplement
intervention name: placebo
description: double-blind placebo-controlled cross-over study
arm group label: BRJ crossover to placebo
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: Accepts Healthy Volunteers
last name: Linda R Peterson, MD
role: Principal Investigator
affiliation: Washington University School of Medicine
last name: Andrew R Coggan, PhD
role: Study Director
affiliation: Indiana U -Purdue U- at Indianapolis (IUPUI)
facility: 
facility: 
country: United States
citation: Masschelein E, Van Thienen R, Wang X, Van Schepdael A, Thomis M, Hespel P. Dietary nitrate improves muscle but not cerebral oxygenation status during exercise in hypoxia. J Appl Physiol (1985). 2012 Sep 1;113(5):736-45. doi: 10.1152/japplphysiol.01253.2011. Epub 2012 Jul 5.
PMID: 22773768
citation: Hobbs DA, Kaffa N, George TW, Methven L, Lovegrove JA. Blood pressure-lowering effects of beetroot juice and novel beetroot-enriched bread products in normotensive male subjects. Br J Nutr. 2012 Dec 14;108(11):2066-74. doi: 10.1017/S0007114512000190. Epub 2012 Mar 14.
PMID: 22414688
citation: Cermak NM, Gibala MJ, van Loon LJ. Nitrate supplementation's improvement of 10-km time-trial performance in trained cyclists. Int J Sport Nutr Exerc Metab. 2012 Feb;22(1):64-71. doi: 10.1123/ijsnem.22.1.64.
PMID: 22248502
citation: Vanhatalo A, Fulford J, Bailey SJ, Blackwell JR, Winyard PG, Jones AM. Dietary nitrate reduces muscle metabolic perturbation and improves exercise tolerance in hypoxia. J Physiol. 2011 Nov 15;589(Pt 22):5517-28. doi: 10.1113/jphysiol.2011.216341. Epub 2011 Sep 12.
PMID: 21911616
citation: Kenjale AA, Ham KL, Stabler T, Robbins JL, Johnson JL, Vanbruggen M, Privette G, Yim E, Kraus WE, Allen JD. Dietary nitrate supplementation enhances exercise performance in peripheral arterial disease. J Appl Physiol (1985). 2011 Jun;110(6):1582-91. doi: 10.1152/japplphysiol.00071.2011. Epub 2011 Mar 31.
PMID: 21454745
citation: Ferreira LF, Behnke BJ. A toast to health and performance! Beetroot juice lowers blood pressure and the O2 cost of exercise. J Appl Physiol (1985). 2011 Mar;110(3):585-6. doi: 10.1152/japplphysiol.01457.2010. Epub 2010 Dec 23. No abstract available.
PMID: 21183624
citation: Vanhatalo A, Bailey SJ, Blackwell JR, DiMenna FJ, Pavey TG, Wilkerson DP, Benjamin N, Winyard PG, Jones AM. Acute and chronic effects of dietary nitrate supplementation on blood pressure and the physiological responses to moderate-intensity and incremental exercise. Am J Physiol Regul Integr Comp Physiol. 2010 Oct;299(4):R1121-31. doi: 10.1152/ajpregu.00206.2010. Epub 2010 Aug 11.
PMID: 20702806
citation: Wilkerson DP, Hayward GM, Bailey SJ, Vanhatalo A, Blackwell JR, Jones AM. Influence of acute dietary nitrate supplementation on 50 mile time trial performance in well-trained cyclists. Eur J Appl Physiol. 2012 Dec;112(12):4127-34. doi: 10.1007/s00421-012-2397-6. Epub 2012 Apr 20.
PMID: 22526247
citation: Bailey SJ, Winyard P, Vanhatalo A, Blackwell JR, Dimenna FJ, Wilkerson DP, Tarr J, Benjamin N, Jones AM. Dietary nitrate supplementation reduces the O2 cost of low-intensity exercise and enhances tolerance to high-intensity exercise in humans. J Appl Physiol (1985). 2009 Oct;107(4):1144-55. doi: 10.1152/japplphysiol.00722.2009. Epub 2009 Aug 6.
PMID: 19661447
responsible party type: Sponsor
mesh term: Hypertension, Pulmonary
mesh term: Hypertension
mesh term: Heart Failure
sharing ipd: No
ipd description: Aggregate data that contains no HIPPA identifiers will be made available as required if the request complies with all federal and University policies for data sharing. IPD will not be shared since this is a small study at a single institution, so the likelihood of identifying subjects would be increased.