<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/NCT04506606</url>
  </required_header>
  <id_info>
    <org_study_id>E3343-R</org_study_id>
    <nct_id>NCT04506606</nct_id>
  </id_info>
  <brief_title>Cardiac Rehab Effects in HFpEF</brief_title>
  <official_title>Efficacy of Exercise Training in Patients With HFpEF</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>VA Office of Research and Development</agency>
      <agency_class>U.S. Fed</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>VA Office of Research and Development</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      This research in Veterans with heart failure with preserved ejection fraction (HFpEF) will&#xD;
      provide new information on the mechanisms determining the patients' exercise intolerance and&#xD;
      the efficacy of regular physical activity to improve this shortcoming by alleviating the&#xD;
      patients' neurocirculatory abnormalities. Specifically, the investigators will focus on the&#xD;
      role of nerves originating in working limb muscles in determining the patients' exercise&#xD;
      intolerance and compromised fatigue resistance before and after a chronic exercise&#xD;
      intervention. By focusing on a specific mechanism, this project will evaluate the validity of&#xD;
      exercise as an alternative treatment strategy with the overall purpose of improving the&#xD;
      quality of life of Veterans with HFpEF.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Patients with heart failure with preserved ejection fraction (HFpEF) are characterized by&#xD;
      exercise intolerance and premature fatigue during physical activity. An abnormal exercise&#xD;
      pressor reflex mediated by neural feedback from mechano- and/or metabosensitive group III and&#xD;
      IV muscle afferents may contribute to these debilitating symptoms. However, little is known&#xD;
      about the role and relative contribution of group III/IV afferents in circulatory control and&#xD;
      fatigue development in patients with HFpEF. By studying both patients with HFpEF and&#xD;
      well-matched controls, the investigators will evaluate the contribution of these muscle&#xD;
      afferents to circulatory control and fatigue development, factors recognized to be major&#xD;
      contributors to exercise intolerance. The investigators will use lumbar intrathecal fentanyl&#xD;
      to block the central projection of group III/IV muscle afferents during voluntary and passive&#xD;
      exercise (no concomitant effect on feedforward drive). This proven approach will enable us to&#xD;
      evaluate, and distinguish between, the effects of group III and IV muscle afferents on&#xD;
      central and peripheral hemodynamics during exercise, the exercise-induced development of&#xD;
      central and peripheral fatigue (femoral nerve stimulation techniques), and on exercise&#xD;
      tolerance. The investigators will also study muscle morphometry, baroreflex and chemoreflex&#xD;
      sensitivity, and investigate intramuscular metabolic changes of the quadriceps during&#xD;
      exercise using 31phosphorus magnetic resonance spectroscopy to evaluate disease-related&#xD;
      alterations in cardiovascular reflex sensitivity and intrinsic muscle characteristics as a&#xD;
      potential factor determining alterations in circulatory control and fatigue resistance in&#xD;
      patients with HFpEF. Finally, the investigators will repeat these studies after a supervised&#xD;
      12-week knee-extension exercise training program, allowing us to investigate the effect of&#xD;
      chronic exercise on the role of group III/IV muscle afferents in the hemodynamic response to&#xD;
      exercise, the development of fatigue, and, ultimately, exercise tolerance. If this project&#xD;
      confirms a significant contribution of group III/IV muscle afferents to the exercise&#xD;
      intolerance exhibited by patients with HFpEF, and that chronic exercise can alleviate these&#xD;
      impairments, the proposed work will provide the scientific basis for a paradigm shift in the&#xD;
      treatment of this growing population.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">May 2, 2022</start_date>
  <completion_date type="Anticipated">September 30, 2026</completion_date>
  <primary_completion_date type="Anticipated">September 30, 2025</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>femoral blood flow</measure>
    <time_frame>1 hour</time_frame>
    <description>Quantifying femoral blood flow during exercise with and without afferent blockade</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>femoral blood flow</measure>
    <time_frame>12 weeks</time_frame>
    <description>Impact of cardiac rehab on the influence of afferent blockade on femoral blood flow</description>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Anticipated">50</enrollment>
  <condition>Heart Failure With Preserved Ejection Fraction</condition>
  <arm_group>
    <arm_group_label>Afferent effect on hemodynamics</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Evaluate impact of group III/IV muscle afferents on femoral blood flow</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Afferent effect on fatigue</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Evaluate impact of group III/IV muscle afferents on exercise-induced changes in quadriceps twitch force</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Effect of cardiac rehab</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Evaluate effect of chronic exercise on influence of muscle afferents on limb blood flow</description>
  </arm_group>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Afferent block</intervention_name>
    <description>Block sensory feedback to evaluate hemodynamic and fatigue consequence of group III/IV muscle afferents</description>
    <arm_group_label>Afferent effect on fatigue</arm_group_label>
    <arm_group_label>Afferent effect on hemodynamics</arm_group_label>
    <arm_group_label>Effect of cardiac rehab</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  heart failure with preserved ejection fraction&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  heart failure with reduced ejection fraction&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>21 Years</minimum_age>
    <maximum_age>85 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Markus Amann, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>VA Salt Lake City Health Care System, Salt Lake City, UT</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Misti R Seppi, MBA BS AAS</last_name>
    <phone>(801) 582-1565</phone>
    <phone_ext>4860</phone_ext>
    <email>Misti.Seppi@va.gov</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Tabitha Randall, MS</last_name>
    <phone>(801) 582-1565</phone>
    <phone_ext>4855</phone_ext>
    <email>tabitha.randall@va.gov</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>VA Salt Lake City Health Care System, Salt Lake City, UT</name>
      <address>
        <city>Salt Lake City</city>
        <state>Utah</state>
        <zip>84148-0001</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Misti R Seppi, MBA BS AAS</last_name>
      <phone>801-582-1565</phone>
      <phone_ext>4860</phone_ext>
      <email>Misti.Seppi@va.gov</email>
    </contact>
    <contact_backup>
      <last_name>Tabitha Randall, MS</last_name>
      <phone>(801) 582-1565</phone>
      <phone_ext>4855</phone_ext>
      <email>tabitha.randall@va.gov</email>
    </contact_backup>
    <investigator>
      <last_name>Markus Amann, PhD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>June 2023</verification_date>
  <study_first_submitted>August 6, 2020</study_first_submitted>
  <study_first_submitted_qc>August 6, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">August 10, 2020</study_first_posted>
  <last_update_submitted>June 6, 2023</last_update_submitted>
  <last_update_submitted_qc>June 6, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">June 7, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Heart Failure</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </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/NCT04506606
org study id: E3343-R
nct id: NCT04506606
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
is us export: No
This research in Veterans with heart failure with preserved ejection fraction (HFpEF) will
      provide new information on the mechanisms determining the patients' exercise intolerance and
      the efficacy of regular physical activity to improve this shortcoming by alleviating the
      patients' neurocirculatory abnormalities. Specifically, the investigators will focus on the
      role of nerves originating in working limb muscles in determining the patients' exercise
      intolerance and compromised fatigue resistance before and after a chronic exercise
      intervention. By focusing on a specific mechanism, this project will evaluate the validity of
      exercise as an alternative treatment strategy with the overall purpose of improving the
      quality of life of Veterans with HFpEF.
Patients with heart failure with preserved ejection fraction (HFpEF) are characterized by
      exercise intolerance and premature fatigue during physical activity. An abnormal exercise
      pressor reflex mediated by neural feedback from mechano- and/or metabosensitive group III and
      IV muscle afferents may contribute to these debilitating symptoms. However, little is known
      about the role and relative contribution of group III/IV afferents in circulatory control and
      fatigue development in patients with HFpEF. By studying both patients with HFpEF and
      well-matched controls, the investigators will evaluate the contribution of these muscle
      afferents to circulatory control and fatigue development, factors recognized to be major
      contributors to exercise intolerance. The investigators will use lumbar intrathecal fentanyl
      to block the central projection of group III/IV muscle afferents during voluntary and passive
      exercise (no concomitant effect on feedforward drive). This proven approach will enable us to
      evaluate, and distinguish between, the effects of group III and IV muscle afferents on
      central and peripheral hemodynamics during exercise, the exercise-induced development of
      central and peripheral fatigue (femoral nerve stimulation techniques), and on exercise
      tolerance. The investigators will also study muscle morphometry, baroreflex and chemoreflex
      sensitivity, and investigate intramuscular metabolic changes of the quadriceps during
      exercise using 31phosphorus magnetic resonance spectroscopy to evaluate disease-related
      alterations in cardiovascular reflex sensitivity and intrinsic muscle characteristics as a
      potential factor determining alterations in circulatory control and fatigue resistance in
      patients with HFpEF. Finally, the investigators will repeat these studies after a supervised
      12-week knee-extension exercise training program, allowing us to investigate the effect of
      chronic exercise on the role of group III/IV muscle afferents in the hemodynamic response to
      exercise, the development of fatigue, and, ultimately, exercise tolerance. If this project
      confirms a significant contribution of group III/IV muscle afferents to the exercise
      intolerance exhibited by patients with HFpEF, and that chronic exercise can alleviate these
      impairments, the proposed work will provide the scientific basis for a paradigm shift in the
      treatment of this growing population.
allocation: Randomized
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: femoral blood flow
time frame: 1 hour
description: Quantifying femoral blood flow during exercise with and without afferent blockade
measure: femoral blood flow
time frame: 12 weeks
description: Impact of cardiac rehab on the influence of afferent blockade on femoral blood flow
arm group label: Afferent effect on hemodynamics
arm group type: Experimental
description: Evaluate impact of group III/IV muscle afferents on femoral blood flow
arm group label: Afferent effect on fatigue
arm group type: Experimental
description: Evaluate impact of group III/IV muscle afferents on exercise-induced changes in quadriceps twitch force
arm group label: Effect of cardiac rehab
arm group type: Experimental
description: Evaluate effect of chronic exercise on influence of muscle afferents on limb blood flow
intervention type: Procedure
intervention name: Afferent block
description: Block sensory feedback to evaluate hemodynamic and fatigue consequence of group III/IV muscle afferents
arm group label: Afferent effect on fatigue
arm group label: Afferent effect on hemodynamics
arm group label: Effect of cardiac rehab
criteria: 
gender: All
minimum age: 21 Years
maximum age: 85 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Markus Amann, PhD
role: Principal Investigator
affiliation: VA Salt Lake City Health Care System, Salt Lake City, UT
last name: Misti R Seppi, MBA BS AAS
phone: (801) 582-1565
phone ext: 4860
email: Misti.Seppi@va.gov
last name: Tabitha Randall, MS
phone: (801) 582-1565
phone ext: 4855
email: tabitha.randall@va.gov
facility: 
status: Recruiting
contact: 
contact backup: 
investigator: 
country: United States
responsible party type: Sponsor
mesh term: Heart Failure
sharing ipd: No