xml: <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/NCT06015776</url>
    </required_header>
    <id_info>
      <org_study_id>2008P000151/13</org_study_id>
      <nct_id>NCT06015776</nct_id>
    </id_info>
    <brief_title>Purinergic Signaling and the Postmenopausal Heart</brief_title>
    <official_title>PGC-1, Purines and the Postmenopausal Heart</official_title>
    <sponsors>
      <lead_sponsor>
        <agency>Beth Israel Deaconess Medical Center</agency>
        <agency_class>Other</agency_class>
      </lead_sponsor>
    </sponsors>
    <source>Beth Israel Deaconess Medical Center</source>
    <oversight_info>
      <has_dmc>No</has_dmc>
      <is_fda_regulated_drug>No</is_fda_regulated_drug>
      <is_fda_regulated_device>No</is_fda_regulated_device>
    </oversight_info>
    <brief_summary>
      <textblock>
        There is an increased risk of diastolic heart failure in post menopausal women. Estrogen&#xD;
        plays a positive role in regulating molecular pathways in heart remodeling. Such pathways may&#xD;
        work through purinergic signaling and its downstream effects on the heart's mitochondrial&#xD;
        metabolism and angiogenic response to stress. Loss of estrogen functionality in post&#xD;
        menopausal women may account for the increased risk of diastolic heart failure. The&#xD;
        investigators will explore said pathways using cardiac tissue obtained from patients&#xD;
        undergoing cardiac surgery.&#xD;
      </textblock>
    </brief_summary>
    <detailed_description>
      <textblock>
        Cardiovascular disease (CVD) is the leading cause of death of women in the United States,&#xD;
        accounting for around 1 of every 3 deaths. Estrogen deficiency, as seen in aging women or&#xD;
        after oophorectomy, has been linked to loss of cardiovascular protection, typically seen&#xD;
        during reproductive life. Up to half of women evaluated for myocardial ischemia have normal&#xD;
        appearing coronary arteries. These women can develop heart failure with a preserved ejection&#xD;
        fraction (termed HFpEF) for which the etiology is unclear. Hormonal replacement therapy (HRT)&#xD;
        after menopause remains controversial but current evidence cannot support this for either&#xD;
        primary or secondary prevention of CVD. There are clearly modulatory influences on estrogenic&#xD;
        signaling, that could well influence cardiovascular health in later life. Previous studies&#xD;
        have demonstrated that estrogen improves energy production within the heart by increasing 5'&#xD;
        adenosine monophosphate-activated protein (AMPK) and mitochondrial biogenesis via&#xD;
        upregulation of peroxisome proliferator-activated receptor gamma coactivator 1-alpha&#xD;
        (PGC-1α); a master switch of mitochondrial function, linked to vascular integrity and&#xD;
        angiogenesis. Estrogen has been also found to modulate purinergic signaling by boosting&#xD;
        expression of adenosine receptors and of CD39, the dominant endothelial ecto-ADPase that&#xD;
        generates adenosine. There are also close relationships between purinergic signaling and&#xD;
        dipeptidyl peptidase-4 (DPP-4; otherwise known as adenosine deaminase complexing protein 2 or&#xD;
        CD26), possibly mediated by adenosine deaminase bioactivity. Decreased PGC-1α and aberrant&#xD;
        purinergic signaling in metabolic syndrome may lead to impaired mitochondrial function,&#xD;
        provoking diastolic dysfunction, and also result in impaired angiogenesis. The investigators&#xD;
        hypothesize there are central roles of PGC-1α, purines and DPP-4 linked neuropeptide pathways&#xD;
        in the control of angiogenesis and mitochondrial activity. These become increasingly&#xD;
        disordered in setting of estrogen loss provoking development of metabolic syndrome, thereby&#xD;
        exacerbating HFpEF and microvascular disease. Specific Aim 1: To determine how ischemia and&#xD;
        cardiometabolic dysfunction in women's heart disease are exacerbated by the loss of&#xD;
        puringeric pathways from estrogen deficiency. The investigators expect to determine that&#xD;
        diastolic dysfunction is a functional consequence of this microvascular loss and&#xD;
        cardiometabolic dessynchrony. Specific Aim 2: To evaluate the role of adenosingergic receptor&#xD;
        activation and DPPIV inhibition on angiogenesis in a ovariectomized swine model of chronic&#xD;
        myocardial ischemia and metabolic syndrome. Here, the investigators will explore&#xD;
        relationships between the regulated and linkages in the exocytosis of nucleotides and&#xD;
        neuropeptides, formation of nucleosides (adenosine) and alterations in angiogenic activity&#xD;
        secondary to these. Summary: The investigators will study fundamental mechanisms in heart&#xD;
        disease underpinning biological differences in women. The investigators will also offer new&#xD;
        therapeutic strategies that target cardiac metabolism.&#xD;
      </textblock>
    </detailed_description>
    <overall_status>Recruiting</overall_status>
    <start_date type="Actual">July 1, 2019</start_date>
    <completion_date type="Anticipated">June 2024</completion_date>
    <primary_completion_date type="Anticipated">June 2024</primary_completion_date>
    <study_type>Observational</study_type>
    <has_expanded_access>No</has_expanded_access>
    <study_design_info>
      <observational_model>Cohort</observational_model>
      <time_perspective>Prospective</time_perspective>
    </study_design_info>
    <primary_outcome>
      <measure>Comparative quantification of expression of CD39 and adenosinergic receptors</measure>
      <time_frame>6 months</time_frame>
      <description>Expression of CD39, ADORA2A and ADORA2B in cardiac tissue measured using Western blotting</description>
    </primary_outcome>
    <primary_outcome>
      <measure>Comparative quantification of expression of PGC-1 alpha, mitochondrial markers</measure>
      <time_frame>6 months</time_frame>
      <description>Expression of PGC-1 alpha, AMPK and mitochondrial markers using Western blot</description>
    </primary_outcome>
    <primary_outcome>
      <measure>Comparative quantification of expression of angiogenic markers</measure>
      <time_frame>6 months</time_frame>
      <description>Expression of angiogenic markers (PDGF, VEGF, Angiostatin)</description>
    </primary_outcome>
    <number_of_groups>2</number_of_groups>
    <enrollment type="Anticipated">100</enrollment>
    <condition>Diastolic Heart Failure</condition>
    <condition>Heart Failure With Preserved Ejection Fraction</condition>
    <arm_group>
      <arm_group_label>Men</arm_group_label>
      <description>Men who are undergoing cardiac surgery</description>
    </arm_group>
    <arm_group>
      <arm_group_label>Women</arm_group_label>
      <description>Women who are undergoing cardiac surgery</description>
    </arm_group>
    <intervention>
      <intervention_type>Other</intervention_type>
      <intervention_name>Gender</intervention_name>
      <description>Differences between men and women will be observed</description>
      <arm_group_label>Men</arm_group_label>
      <arm_group_label>Women</arm_group_label>
    </intervention>
    <biospec_retention>Samples With DNA</biospec_retention>
    <biospec_descr>
      <textblock>
        Atrial tissue containing atrial myocytes is snap frozen in liquid nitrogen and stored.&#xD;
  &#xD;
        Serum samples are also collected.&#xD;
      </textblock>
    </biospec_descr>
    <eligibility>
      <study_pop>
        <textblock>
          Patients presenting for elective cardiac surgery. Patients will be enrolled and consented&#xD;
          during hospital admission for surgery.&#xD;
        </textblock>
      </study_pop>
      <sampling_method>Non-Probability Sample</sampling_method>
      <criteria>
        <textblock>
          Inclusion Criteria:&#xD;
  &#xD;
            -  Patients undergoing cardiac surgery under cardiopulmonary bypass.&#xD;
  &#xD;
          Exclusion Criteria:&#xD;
  &#xD;
            -  Refusal to participate&#xD;
  &#xD;
            -  Emergency surgery&#xD;
  &#xD;
            -  Pre-existing heart block&#xD;
  &#xD;
            -  Preexisting atrial fibrillation&#xD;
  &#xD;
            -  Redo surgery&#xD;
  &#xD;
            -  Estrogen or hormone replacement therapy&#xD;
  &#xD;
            -  History of chronic heart failure&#xD;
  &#xD;
            -  History of major kidney disease&#xD;
        </textblock>
      </criteria>
      <gender>All</gender>
      <minimum_age>30 Years</minimum_age>
      <maximum_age>88 Years</maximum_age>
      <healthy_volunteers>No</healthy_volunteers>
    </eligibility>
    <overall_official>
      <last_name>Robina Matyal, MD</last_name>
      <role>Principal Investigator</role>
      <affiliation>Beth Israel Deaconess Medical Center, Professor of Anesthesia</affiliation>
    </overall_official>
    <overall_official>
      <last_name>Simon Robson, MD, PhD</last_name>
      <role>Principal Investigator</role>
      <affiliation>Beth Israel Deaconess Medical Center,Vice Chair Research</affiliation>
    </overall_official>
    <overall_contact>
      <last_name>Robina Matyal, MD</last_name>
      <phone>6176401208</phone>
      <email>rmatyal1@bidmc.harvard.edu</email>
    </overall_contact>
    <location>
      <facility>
        <name>Beth Israel Deaconess Medical Center</name>
        <address>
          <city>Boston</city>
          <state>Massachusetts</state>
          <zip>02215</zip>
          <country>United States</country>
        </address>
      </facility>
      <status>Recruiting</status>
      <contact>
        <last_name>Robina Matyal, MD</last_name>
        <phone>617-640-1208</phone>
        <email>rmatyal1@bidmc.harvard.edu</email>
      </contact>
    </location>
    <location_countries>
      <country>United States</country>
    </location_countries>
    <verification_date>August 2023</verification_date>
    <study_first_submitted>August 23, 2023</study_first_submitted>
    <study_first_submitted_qc>August 28, 2023</study_first_submitted_qc>
    <study_first_posted type="Actual">August 29, 2023</study_first_posted>
    <last_update_submitted>August 28, 2023</last_update_submitted>
    <last_update_submitted_qc>August 28, 2023</last_update_submitted_qc>
    <last_update_posted type="Actual">August 29, 2023</last_update_posted>
    <responsible_party>
      <responsible_party_type>Principal Investigator</responsible_party_type>
      <investigator_affiliation>Beth Israel Deaconess Medical Center</investigator_affiliation>
      <investigator_full_name>Robina Matyal</investigator_full_name>
      <investigator_title>Professor of Anesthesia</investigator_title>
    </responsible_party>
    <condition_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Heart Failure</mesh_term>
      <mesh_term>Heart Failure, Diastolic</mesh_term>
    </condition_browse>
    <patient_data>
      <sharing_ipd>No</sharing_ipd>
    </patient_data>
    <!-- Results have not yet been posted for this study                                          -->
  </clinical_study>
  
  
text: 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/NCT06015776
  org study id: 2008P000151/13
  nct id: NCT06015776
  lead sponsor: 
  has dmc: No
  is fda regulated drug: No
  is fda regulated device: No
  There is an increased risk of diastolic heart failure in post menopausal women. Estrogen
        plays a positive role in regulating molecular pathways in heart remodeling. Such pathways may
        work through purinergic signaling and its downstream effects on the heart's mitochondrial
        metabolism and angiogenic response to stress. Loss of estrogen functionality in post
        menopausal women may account for the increased risk of diastolic heart failure. The
        investigators will explore said pathways using cardiac tissue obtained from patients
        undergoing cardiac surgery.
  Cardiovascular disease (CVD) is the leading cause of death of women in the United States,
        accounting for around 1 of every 3 deaths. Estrogen deficiency, as seen in aging women or
        after oophorectomy, has been linked to loss of cardiovascular protection, typically seen
        during reproductive life. Up to half of women evaluated for myocardial ischemia have normal
        appearing coronary arteries. These women can develop heart failure with a preserved ejection
        fraction (termed HFpEF) for which the etiology is unclear. Hormonal replacement therapy (HRT)
        after menopause remains controversial but current evidence cannot support this for either
        primary or secondary prevention of CVD. There are clearly modulatory influences on estrogenic
        signaling, that could well influence cardiovascular health in later life. Previous studies
        have demonstrated that estrogen improves energy production within the heart by increasing 5'
        adenosine monophosphate-activated protein (AMPK) and mitochondrial biogenesis via
        upregulation of peroxisome proliferator-activated receptor gamma coactivator 1-alpha
        (PGC-1α); a master switch of mitochondrial function, linked to vascular integrity and
        angiogenesis. Estrogen has been also found to modulate purinergic signaling by boosting
        expression of adenosine receptors and of CD39, the dominant endothelial ecto-ADPase that
        generates adenosine. There are also close relationships between purinergic signaling and
        dipeptidyl peptidase-4 (DPP-4; otherwise known as adenosine deaminase complexing protein 2 or
        CD26), possibly mediated by adenosine deaminase bioactivity. Decreased PGC-1α and aberrant
        purinergic signaling in metabolic syndrome may lead to impaired mitochondrial function,
        provoking diastolic dysfunction, and also result in impaired angiogenesis. The investigators
        hypothesize there are central roles of PGC-1α, purines and DPP-4 linked neuropeptide pathways
        in the control of angiogenesis and mitochondrial activity. These become increasingly
        disordered in setting of estrogen loss provoking development of metabolic syndrome, thereby
        exacerbating HFpEF and microvascular disease. Specific Aim 1: To determine how ischemia and
        cardiometabolic dysfunction in women's heart disease are exacerbated by the loss of
        puringeric pathways from estrogen deficiency. The investigators expect to determine that
        diastolic dysfunction is a functional consequence of this microvascular loss and
        cardiometabolic dessynchrony. Specific Aim 2: To evaluate the role of adenosingergic receptor
        activation and DPPIV inhibition on angiogenesis in a ovariectomized swine model of chronic
        myocardial ischemia and metabolic syndrome. Here, the investigators will explore
        relationships between the regulated and linkages in the exocytosis of nucleotides and
        neuropeptides, formation of nucleosides (adenosine) and alterations in angiogenic activity
        secondary to these. Summary: The investigators will study fundamental mechanisms in heart
        disease underpinning biological differences in women. The investigators will also offer new
        therapeutic strategies that target cardiac metabolism.
  observational model: Cohort
  time perspective: Prospective
  measure: Comparative quantification of expression of CD39 and adenosinergic receptors
  time frame: 6 months
  description: Expression of CD39, ADORA2A and ADORA2B in cardiac tissue measured using Western blotting
  measure: Comparative quantification of expression of PGC-1 alpha, mitochondrial markers
  time frame: 6 months
  description: Expression of PGC-1 alpha, AMPK and mitochondrial markers using Western blot
  measure: Comparative quantification of expression of angiogenic markers
  time frame: 6 months
  description: Expression of angiogenic markers (PDGF, VEGF, Angiostatin)
  arm group label: Men
  description: Men who are undergoing cardiac surgery
  arm group label: Women
  description: Women who are undergoing cardiac surgery
  intervention type: Other
  intervention name: Gender
  description: Differences between men and women will be observed
  arm group label: Men
  arm group label: Women
  Atrial tissue containing atrial myocytes is snap frozen in liquid nitrogen and stored.
  
        Serum samples are also collected.
  study pop: 
  sampling method: Non-Probability Sample
  criteria: 
  gender: All
  minimum age: 30 Years
  maximum age: 88 Years
  healthy volunteers: No
  last name: Robina Matyal, MD
  role: Principal Investigator
  affiliation: Beth Israel Deaconess Medical Center, Professor of Anesthesia
  last name: Simon Robson, MD, PhD
  role: Principal Investigator
  affiliation: Beth Israel Deaconess Medical Center,Vice Chair Research
  last name: Robina Matyal, MD
  phone: 6176401208
  email: rmatyal1@bidmc.harvard.edu
  facility: 
  status: Recruiting
  contact: 
  country: United States
  responsible party type: Principal Investigator
  investigator affiliation: Beth Israel Deaconess Medical Center
  investigator full name: Robina Matyal
  investigator title: Professor of Anesthesia
  mesh term: Heart Failure
  mesh term: Heart Failure, Diastolic
  sharing ipd: No