<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/NCT03262753</url>
  </required_header>
  <id_info>
    <org_study_id>CHLC.CI.69.2012</org_study_id>
    <nct_id>NCT03262753</nct_id>
  </id_info>
  <brief_title>Long-term Outcomes and Vascular Evaluation After Coarctation of the Aorta Treatment</brief_title>
  <acronym>LOVE-COARCT</acronym>
  <official_title>LOVE-COARCT Study: Long-term Outcomes and Vascular Evaluation After Coarctation of the Aorta Treatment</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Centro Hospitalar de Lisboa Central</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Centro de Estudos de Doenças Crónicas</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Baylor College of Medicine</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Lucile Packard Children's Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Children's Hospital Colorado</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of Nebraska</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Boston Children's Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Instituto Superior Técnico de Lisboa</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Caselas, Ressonância Magnética, S.A.</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Centro Hospitalar de Lisboa Central</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>
      Background: Coarctation of the aorta (CoA) can be treated using surgery, balloon angioplasty&#xD;
      or stent implantation. Although short-term results are excellent with all three treatment&#xD;
      modalities, long term cardiovascular (CV) morbidity and mortality remain high, likely due to&#xD;
      persistently abnormal vascular function. The effects of treatment modality on long term&#xD;
      vascular function remain uncharacterized. The goal of this study is to assess vascular&#xD;
      function in this patient population for comparison among the treatment modalities. Methods:&#xD;
      Vascular function in large and small arteries will be prospectively assessed fusing multiple&#xD;
      non-invasive modalities, and the results will be compared among the three groups of CoA&#xD;
      patients previously treated using surgery, balloon angioplasty or stent implantation after&#xD;
      frequency matching for confounding variables. A comprehensive vascular function assessment&#xD;
      protocol was created to be used in 7 centers. The primary outcome is arterial stiffness&#xD;
      measured by arterial tonometry. Inclusion and exclusion criteria were carefully established&#xD;
      after consideration of several potential confounders. Sample size was calculated for the&#xD;
      primary outcome variable. Conclusions: Treatment modalities for CoA may have distinct impact&#xD;
      on large and small arterial vascular function. The results of this study will help identify&#xD;
      the treatment modality that is associated with the most optimal level of vascular function,&#xD;
      which, in the long term may reduce CV risk.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Study overview. This cross-sectional prospective observational study of patients with CoA&#xD;
      previously treated using one of three treatment modalities assesses if treatment type is&#xD;
      associated with differences in vascular function. The three treatment groups will be&#xD;
      frequency-matched for key confounding variables.&#xD;
&#xD;
      Study feasibility. The investigators assembled a multi-disciplinary team with proven&#xD;
      expertise in epidemiology, clinical trial design, congenital heart disease, non-invasive&#xD;
      imaging, interventional cardiology, vascular function assessment, preventive cardiology and&#xD;
      statistical analysis. A multicenter design is used to ensure sufficient statistical power in&#xD;
      evaluating the hypothesis.&#xD;
&#xD;
      Participating centers and study core laboratories. Patients are recruited at six large&#xD;
      pediatric cardiac centers from Portugal and USA.&#xD;
&#xD;
      Screening procedures. The medical records of potentially eligible patients are screened by a&#xD;
      local study investigator using a pre-specified screening form to ensure that they satisfy our&#xD;
      selection criteria.&#xD;
&#xD;
      Overview of the study workflow. Study procedures will occur in a one- or two-day visit. Upon&#xD;
      arrival for testing, formal consent for participation will be obtained. Assessment of&#xD;
      arterial stiffness, endothelial function, and blood sampling for biomarkers will be done&#xD;
      while fasting. Cardiopulmonary stress test will be performed on the same day. CMR and&#xD;
      ambulatory blood pressure monitoring (ABMP) will be arranged for the same or for the&#xD;
      following day. When the study tests cannot be completed at the first visit, they will be&#xD;
      completed within 3 months of the first visit. The study protocol was approved by the&#xD;
      Institutional Review Board or Institutional Ethics Committee at each participating center,&#xD;
      and informed consent and assent will be obtained, depending on age, from patients and their&#xD;
      parents/legal guardians before trial enrollment.&#xD;
&#xD;
      Recruitment. A review of the patient database at each participating institution will be&#xD;
      performed to assemble a cohort of patients with CoA who have previously undergone treatment&#xD;
      with balloon dilation, surgery or stenting. Study data will be collected and managed using&#xD;
      REDCap electronic data capture tools hosted at Boston Children's Hospital.&#xD;
&#xD;
      Data collection. A retrospective chart review will be performed to collect demographic and&#xD;
      clinical data including severity of coarctation, type and details of CoA treatment and&#xD;
      presence of associated conditions.&#xD;
&#xD;
      Diagnostic procedures.&#xD;
&#xD;
      Arterial Stiffness Plan &amp; Rationale:&#xD;
&#xD;
      Measurements: Carotid-femoral PWV (cfPWV) will be measured using applanation tonometry.&#xD;
      Segmental PWV is measured using CMR. Segmental measures of arterial distensibility will be&#xD;
      measured using CMR. Other parameters that describe arterial stiffness reflect the&#xD;
      relationship of arterial change in diameter to change in pressure and include aortic strain&#xD;
      (relative change in diameter), compliance (absolute change in diameter in response to a&#xD;
      change in pressure), distensibility (relative change in diameter in response to a change in&#xD;
      pressure), and the aortic stiffness β index (distensibility using the logarithmic conversion&#xD;
      of the relative pressure). Applanation tonometry, which uses a probe or tonometer to record&#xD;
      the pulse wave with a transducer, is the most widely accepted method for estimating PWV and&#xD;
      both the NIHem (Cardiovascular Engineering, Inc., Norwood, MA USA) and the SphygmoCor (AtCor&#xD;
      Medical, West Ryde, NSW, Australia) devices have been validated in large cohort trials. Both&#xD;
      devices will be used, based on local availability.&#xD;
&#xD;
      Endothelial Function Measurements: Endothelium-dependent reactive hyperaemia index and&#xD;
      augmentation index will be measured using the EndoPAT 2000 system (Itamar Medical, Caesarea,&#xD;
      Israel). The protocol includes measures to minimize the influence of the autonomic nervous&#xD;
      system.&#xD;
&#xD;
      Pulse Waveform Analysis: Central aortic pressure and pulse pressure will be measured using&#xD;
      applanation tonometry). Augmentation index will be measured using applanation tonometry and&#xD;
      Endo-PAT. CAP, PP and AIx can be measured non-invasively using radial or carotid applanation&#xD;
      tonometry (and Endo-PAT for AIx), calibrated by the peripheral diastolic and mean arterial&#xD;
      pressure. Both the NIHem system and the SphygmoCor device were used.&#xD;
&#xD;
      Blood Pressure Phenotype will be measured using conventional standard techniques including&#xD;
      auscultatory right arm BP measurement, measurement of BP gradient between arm and leg, BP&#xD;
      response during treadmill exercise stress testing (ET) and ABPM. Based on the auscultatory BP&#xD;
      and ABPM results, the appropriate children and adult guidelines will be used to classify&#xD;
      patients. Patients currently on antihypertensive medication will be classified as&#xD;
      hypertensive.&#xD;
&#xD;
      Biomarkers: The researchers will measure biomarkers of endothelial function (total oxides of&#xD;
      nitrogen- NOx and ADMA), inflammation (hs-CRP), vascular wall function (VCAM-1 and IL-1β) and&#xD;
      vascular remodeling (MMP-2; MMP-9 and TGF-beta1). NOx will be determined by chemiluminescence&#xD;
      (Sievers NOAnalyzer 280i) and all remaining measurements will be performed with appropriate&#xD;
      enzyme-linked immunosorbent assay (ELISA) kits: ADMA (Sunred Biological Technology, Shanghai,&#xD;
      China); hs-CRP (BoosterBio, Pleasanton, USA); VCAM-1; IL-1β; MMP-9; MMP-2 and TGFβ-1&#xD;
      (RayBiotech, Inc. Norcross, USA).&#xD;
&#xD;
      Left Ventricular Mass Assessment by CMR. The altered blood pressure phenotype that persists&#xD;
      after CoA treatment represents an increase in afterload that leads to LV hypertrophy. Our CMR&#xD;
      protocol will include sequences that allow this quantification.&#xD;
&#xD;
      Cardiovascular Health Assessment: The researchers will assess health factors (blood pressure,&#xD;
      total cholesterol, plasma glucose), behaviors (smoking, body mass index BMI, physical&#xD;
      activity and diet) and family history of cardiovascular disease and risk factors. A&#xD;
      questionnaire was implemented to assess family history of CV disease and ICVH according to&#xD;
      the procedures and recommendations of the American Heart Association.&#xD;
&#xD;
      Statistical Considerations. The treatment groups will be frequency-matched for documented&#xD;
      confounders. The confounding variables will include: (a) Age at treatment; (b) Current age;&#xD;
      (c) Bicuspid aortic valve as it is associated with impaired aortic elasticity. Because of the&#xD;
      relatively large number of matching variables and three treatment groups, matching individual&#xD;
      subjects was not feasible. During analysis, the treatment groups will be compared for each of&#xD;
      these confounding variables and appropriate adjustments made, if needed. Differences in the&#xD;
      confounding variables across the three treatment groups will be evaluated using Fisher's&#xD;
      exact test for severity of coarctation and the Kruskal-Wallis test for age at treatment,&#xD;
      current age and bicuspid aortic valve. The primary outcome variable will be carotid-femoral&#xD;
      PWV assessed by tonometry. Differences in cfPVW across groups will be explored using one-way&#xD;
      analysis of variance. If differences in matching variables are detected among the groups,&#xD;
      adjustment will be made using analysis of covariance. Post-hoc analyses will be performed as&#xD;
      necessary.&#xD;
&#xD;
      Sample size estimates were obtained based on prior data that show that ascending- descending&#xD;
      PWV measured by CMR is 3.3±0.6 m/s in normal subjects and 4.7±1.1 m/sec after CoA surgery.22,&#xD;
      70 Sample size estimates for comparison of PVW between three equal sized treatment groups&#xD;
      (assuming overall significance level=0.05 and power=0.8) are shown in table 2. The&#xD;
      investigators plan on recruiting 24 to 30 patients in each group for a total sample size of&#xD;
      72 to 90.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">June 1, 2013</start_date>
  <completion_date type="Anticipated">December 30, 2017</completion_date>
  <primary_completion_date type="Anticipated">September 30, 2017</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>Vascular function</measure>
    <time_frame>6 months to 35 years after primary treatment</time_frame>
    <description>Arterial stiffness assessed with carotid-femoral PWV measurements by tonometry</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Cardiac Magnetic Resonance functional indexes</measure>
    <time_frame>6 months to 35 years after primary treatment</time_frame>
    <description>Ascending-descending aorta PWV and aorta strain, distensibility, compliance and aortic stiffness β index measured by CMR</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Endothelial function</measure>
    <time_frame>6 months to 35 years after primary treatment</time_frame>
    <description>Endothelial function determined by endothelial pulse amplitude testing</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pulse wave form</measure>
    <time_frame>6 months to 35 years after primary treatment</time_frame>
    <description>Pulse wave form analysis using arterial tonometry</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Blood pressure phenotype</measure>
    <time_frame>6 months to 35 years after primary treatment</time_frame>
    <description>Blood pressure phenotype at rest, during ambulatory measurement, and at peak exercise</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Left ventricular mass</measure>
    <time_frame>6 months to 35 years after primary treatment</time_frame>
    <description>Left ventricular mass assessed by Cardiac Magnetic Resonance</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Left ventricular systolic function</measure>
    <time_frame>6 months to 35 years after primary treatment</time_frame>
    <description>Left ventricular systolic function assessed by Cardiac Magnetic Resonance</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Biomarkers of endothelial function</measure>
    <time_frame>6 months to 35 years after primary treatment</time_frame>
    <description>biomarkers of endothelial function (total oxides of nitrogen- NOx and ADMA),</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Biomarkers of vascular inflammation</measure>
    <time_frame>6 months to 35 years after primary treatment</time_frame>
    <description>biomarkers of inflammation (hs-CRP).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Biomarkers of vascular wall function</measure>
    <time_frame>6 months to 35 years after primary treatment</time_frame>
    <description>biomarkers of vascular wall function (VCAM-1 and IL-1β)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Biomarkers of vascular remodeling</measure>
    <time_frame>6 months to 35 years after primary treatment</time_frame>
    <description>biomarkers of vascular remodeling (MMP-2; MMP-9 and TGF-beta1).</description>
  </secondary_outcome>
  <number_of_groups>3</number_of_groups>
  <enrollment type="Anticipated">90</enrollment>
  <condition>Aortic Coarctation</condition>
  <condition>Arterial Stiffness</condition>
  <condition>PULSE WAVE VELOCITY</condition>
  <condition>Functional Magnetic Resonance Imaging</condition>
  <condition>Vascular Endothelium</condition>
  <arm_group>
    <arm_group_label>surgery</arm_group_label>
    <description>Primary end-to-end surgical treatment of coarctation of the aorta</description>
  </arm_group>
  <arm_group>
    <arm_group_label>balloon dilation</arm_group_label>
    <description>Primary balloon dilation treatment of coarctation of the aorta</description>
  </arm_group>
  <arm_group>
    <arm_group_label>stent</arm_group_label>
    <description>Primary stent dilation treatment of coarctation of the aorta</description>
  </arm_group>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Surgery</intervention_name>
    <description>Primary end-to-end surgical treatment of coarctation of the aorta</description>
    <arm_group_label>surgery</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Balloon dilation</intervention_name>
    <description>Primary balloon dilation treatment of coarctation of the aorta</description>
    <arm_group_label>balloon dilation</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Stent</intervention_name>
    <description>Primary stent dilation treatment of coarctation of the aorta</description>
    <arm_group_label>stent</arm_group_label>
  </intervention>
  <eligibility>
    <study_pop>
      <textblock>
        Patients with isthmic coarctation of the aorta, treated after 1994, submitted to only one&#xD;
        of either of the three procedures described above.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Diagnosis of isthmic coarctation of the aorta;&#xD;
&#xD;
          -  Current age between 8 (to allow cooperation with study procedures) and 35 years (to&#xD;
             avoid confounding by aging-related vascular dysfunction); and&#xD;
&#xD;
          -  Treatment for CoA after 1994, after which all three modalities were in clinical use.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Residual CoA defined by a systolic upper-to-lower extremity BP gradient&gt; 20mmHg;&#xD;
&#xD;
          -  Co-morbidities that may independently affect vascular function, including associated&#xD;
             significant congenital heart disease, history of known vasculopathy, genetic syndromes&#xD;
             or other cardiovascular risk factors;&#xD;
&#xD;
          -  History of two treatment types for CoA; and&#xD;
&#xD;
          -  CoA types likely representing a different entity or patients amenable to one single&#xD;
             treatment type (surgery), including atypical CoA site (such as mid-thoracic or&#xD;
             abdominal), severe hypoplasia of the aortic arch, and an age of treatment &lt;1 year of&#xD;
             age.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>8 Years</minimum_age>
    <maximum_age>35 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>José D Martins, MD MSc</last_name>
    <role>Principal Investigator</role>
    <affiliation>Centro Hospitalar de Lisboa Central</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Miguel Mota Carmo, MD PhD</last_name>
    <role>Study Chair</role>
    <affiliation>Centro de Estudos de Doenças Crónicas da Faculdade de Ciências Médicas da Universidade Nova de Lisboa</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>José D Martins, MD, MSc</last_name>
    <phone>+351918338690</phone>
    <email>jose.martins@chlc.min-saude.pt</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Centro de Investigação Centro Hospitalar de Lisboa Central</last_name>
    <phone>+351213596481</phone>
    <email>centro.investigacao@chlc.min-saude.pt</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Department of Pediatric Cardiology, Hospital de Santa Marta, Centro Hospitalar de Lisboa Central</name>
      <address>
        <city>Lisboa</city>
        <zip>1169-024</zip>
        <country>Portugal</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>José D Martins, MD MSc</last_name>
      <phone>+351918338690</phone>
      <email>jose.martins@chlc.min-saude.pt</email>
    </contact>
  </location>
  <location_countries>
    <country>Portugal</country>
  </location_countries>
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  <verification_date>August 2017</verification_date>
  <study_first_submitted>August 8, 2017</study_first_submitted>
  <study_first_submitted_qc>August 24, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 25, 2017</study_first_posted>
  <last_update_submitted>August 24, 2017</last_update_submitted>
  <last_update_submitted_qc>August 24, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">August 25, 2017</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>Aortic Coarctation</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/NCT03262753
org study id: CHLC.CI.69.2012
nct id: NCT03262753
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Background: Coarctation of the aorta (CoA) can be treated using surgery, balloon angioplasty
      or stent implantation. Although short-term results are excellent with all three treatment
      modalities, long term cardiovascular (CV) morbidity and mortality remain high, likely due to
      persistently abnormal vascular function. The effects of treatment modality on long term
      vascular function remain uncharacterized. The goal of this study is to assess vascular
      function in this patient population for comparison among the treatment modalities. Methods:
      Vascular function in large and small arteries will be prospectively assessed fusing multiple
      non-invasive modalities, and the results will be compared among the three groups of CoA
      patients previously treated using surgery, balloon angioplasty or stent implantation after
      frequency matching for confounding variables. A comprehensive vascular function assessment
      protocol was created to be used in 7 centers. The primary outcome is arterial stiffness
      measured by arterial tonometry. Inclusion and exclusion criteria were carefully established
      after consideration of several potential confounders. Sample size was calculated for the
      primary outcome variable. Conclusions: Treatment modalities for CoA may have distinct impact
      on large and small arterial vascular function. The results of this study will help identify
      the treatment modality that is associated with the most optimal level of vascular function,
      which, in the long term may reduce CV risk.
Study overview. This cross-sectional prospective observational study of patients with CoA
      previously treated using one of three treatment modalities assesses if treatment type is
      associated with differences in vascular function. The three treatment groups will be
      frequency-matched for key confounding variables.

      Study feasibility. The investigators assembled a multi-disciplinary team with proven
      expertise in epidemiology, clinical trial design, congenital heart disease, non-invasive
      imaging, interventional cardiology, vascular function assessment, preventive cardiology and
      statistical analysis. A multicenter design is used to ensure sufficient statistical power in
      evaluating the hypothesis.

      Participating centers and study core laboratories. Patients are recruited at six large
      pediatric cardiac centers from Portugal and USA.

      Screening procedures. The medical records of potentially eligible patients are screened by a
      local study investigator using a pre-specified screening form to ensure that they satisfy our
      selection criteria.

      Overview of the study workflow. Study procedures will occur in a one- or two-day visit. Upon
      arrival for testing, formal consent for participation will be obtained. Assessment of
      arterial stiffness, endothelial function, and blood sampling for biomarkers will be done
      while fasting. Cardiopulmonary stress test will be performed on the same day. CMR and
      ambulatory blood pressure monitoring (ABMP) will be arranged for the same or for the
      following day. When the study tests cannot be completed at the first visit, they will be
      completed within 3 months of the first visit. The study protocol was approved by the
      Institutional Review Board or Institutional Ethics Committee at each participating center,
      and informed consent and assent will be obtained, depending on age, from patients and their
      parents/legal guardians before trial enrollment.

      Recruitment. A review of the patient database at each participating institution will be
      performed to assemble a cohort of patients with CoA who have previously undergone treatment
      with balloon dilation, surgery or stenting. Study data will be collected and managed using
      REDCap electronic data capture tools hosted at Boston Children's Hospital.

      Data collection. A retrospective chart review will be performed to collect demographic and
      clinical data including severity of coarctation, type and details of CoA treatment and
      presence of associated conditions.

      Diagnostic procedures.

      Arterial Stiffness Plan & Rationale:

      Measurements: Carotid-femoral PWV (cfPWV) will be measured using applanation tonometry.
      Segmental PWV is measured using CMR. Segmental measures of arterial distensibility will be
      measured using CMR. Other parameters that describe arterial stiffness reflect the
      relationship of arterial change in diameter to change in pressure and include aortic strain
      (relative change in diameter), compliance (absolute change in diameter in response to a
      change in pressure), distensibility (relative change in diameter in response to a change in
      pressure), and the aortic stiffness β index (distensibility using the logarithmic conversion
      of the relative pressure). Applanation tonometry, which uses a probe or tonometer to record
      the pulse wave with a transducer, is the most widely accepted method for estimating PWV and
      both the NIHem (Cardiovascular Engineering, Inc., Norwood, MA USA) and the SphygmoCor (AtCor
      Medical, West Ryde, NSW, Australia) devices have been validated in large cohort trials. Both
      devices will be used, based on local availability.

      Endothelial Function Measurements: Endothelium-dependent reactive hyperaemia index and
      augmentation index will be measured using the EndoPAT 2000 system (Itamar Medical, Caesarea,
      Israel). The protocol includes measures to minimize the influence of the autonomic nervous
      system.

      Pulse Waveform Analysis: Central aortic pressure and pulse pressure will be measured using
      applanation tonometry). Augmentation index will be measured using applanation tonometry and
      Endo-PAT. CAP, PP and AIx can be measured non-invasively using radial or carotid applanation
      tonometry (and Endo-PAT for AIx), calibrated by the peripheral diastolic and mean arterial
      pressure. Both the NIHem system and the SphygmoCor device were used.

      Blood Pressure Phenotype will be measured using conventional standard techniques including
      auscultatory right arm BP measurement, measurement of BP gradient between arm and leg, BP
      response during treadmill exercise stress testing (ET) and ABPM. Based on the auscultatory BP
      and ABPM results, the appropriate children and adult guidelines will be used to classify
      patients. Patients currently on antihypertensive medication will be classified as
      hypertensive.

      Biomarkers: The researchers will measure biomarkers of endothelial function (total oxides of
      nitrogen- NOx and ADMA), inflammation (hs-CRP), vascular wall function (VCAM-1 and IL-1β) and
      vascular remodeling (MMP-2; MMP-9 and TGF-beta1). NOx will be determined by chemiluminescence
      (Sievers NOAnalyzer 280i) and all remaining measurements will be performed with appropriate
      enzyme-linked immunosorbent assay (ELISA) kits: ADMA (Sunred Biological Technology, Shanghai,
      China); hs-CRP (BoosterBio, Pleasanton, USA); VCAM-1; IL-1β; MMP-9; MMP-2 and TGFβ-1
      (RayBiotech, Inc. Norcross, USA).

      Left Ventricular Mass Assessment by CMR. The altered blood pressure phenotype that persists
      after CoA treatment represents an increase in afterload that leads to LV hypertrophy. Our CMR
      protocol will include sequences that allow this quantification.

      Cardiovascular Health Assessment: The researchers will assess health factors (blood pressure,
      total cholesterol, plasma glucose), behaviors (smoking, body mass index BMI, physical
      activity and diet) and family history of cardiovascular disease and risk factors. A
      questionnaire was implemented to assess family history of CV disease and ICVH according to
      the procedures and recommendations of the American Heart Association.

      Statistical Considerations. The treatment groups will be frequency-matched for documented
      confounders. The confounding variables will include: (a) Age at treatment; (b) Current age;
      (c) Bicuspid aortic valve as it is associated with impaired aortic elasticity. Because of the
      relatively large number of matching variables and three treatment groups, matching individual
      subjects was not feasible. During analysis, the treatment groups will be compared for each of
      these confounding variables and appropriate adjustments made, if needed. Differences in the
      confounding variables across the three treatment groups will be evaluated using Fisher's
      exact test for severity of coarctation and the Kruskal-Wallis test for age at treatment,
      current age and bicuspid aortic valve. The primary outcome variable will be carotid-femoral
      PWV assessed by tonometry. Differences in cfPVW across groups will be explored using one-way
      analysis of variance. If differences in matching variables are detected among the groups,
      adjustment will be made using analysis of covariance. Post-hoc analyses will be performed as
      necessary.

      Sample size estimates were obtained based on prior data that show that ascending- descending
      PWV measured by CMR is 3.3±0.6 m/s in normal subjects and 4.7±1.1 m/sec after CoA surgery.22,
      70 Sample size estimates for comparison of PVW between three equal sized treatment groups
      (assuming overall significance level=0.05 and power=0.8) are shown in table 2. The
      investigators plan on recruiting 24 to 30 patients in each group for a total sample size of
      72 to 90.
observational model: Cohort
time perspective: Prospective
measure: Vascular function
time frame: 6 months to 35 years after primary treatment
description: Arterial stiffness assessed with carotid-femoral PWV measurements by tonometry
measure: Cardiac Magnetic Resonance functional indexes
time frame: 6 months to 35 years after primary treatment
description: Ascending-descending aorta PWV and aorta strain, distensibility, compliance and aortic stiffness β index measured by CMR
measure: Endothelial function
time frame: 6 months to 35 years after primary treatment
description: Endothelial function determined by endothelial pulse amplitude testing
measure: Pulse wave form
time frame: 6 months to 35 years after primary treatment
description: Pulse wave form analysis using arterial tonometry
measure: Blood pressure phenotype
time frame: 6 months to 35 years after primary treatment
description: Blood pressure phenotype at rest, during ambulatory measurement, and at peak exercise
measure: Left ventricular mass
time frame: 6 months to 35 years after primary treatment
description: Left ventricular mass assessed by Cardiac Magnetic Resonance
measure: Left ventricular systolic function
time frame: 6 months to 35 years after primary treatment
description: Left ventricular systolic function assessed by Cardiac Magnetic Resonance
measure: Biomarkers of endothelial function
time frame: 6 months to 35 years after primary treatment
description: biomarkers of endothelial function (total oxides of nitrogen- NOx and ADMA),
measure: Biomarkers of vascular inflammation
time frame: 6 months to 35 years after primary treatment
description: biomarkers of inflammation (hs-CRP).
measure: Biomarkers of vascular wall function
time frame: 6 months to 35 years after primary treatment
description: biomarkers of vascular wall function (VCAM-1 and IL-1β)
measure: Biomarkers of vascular remodeling
time frame: 6 months to 35 years after primary treatment
description: biomarkers of vascular remodeling (MMP-2; MMP-9 and TGF-beta1).
arm group label: surgery
description: Primary end-to-end surgical treatment of coarctation of the aorta
arm group label: balloon dilation
description: Primary balloon dilation treatment of coarctation of the aorta
arm group label: stent
description: Primary stent dilation treatment of coarctation of the aorta
intervention type: Procedure
intervention name: Surgery
description: Primary end-to-end surgical treatment of coarctation of the aorta
arm group label: surgery
intervention type: Procedure
intervention name: Balloon dilation
description: Primary balloon dilation treatment of coarctation of the aorta
arm group label: balloon dilation
intervention type: Procedure
intervention name: Stent
description: Primary stent dilation treatment of coarctation of the aorta
arm group label: stent
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 8 Years
maximum age: 35 Years
healthy volunteers: No
last name: José D Martins, MD MSc
role: Principal Investigator
affiliation: Centro Hospitalar de Lisboa Central
last name: Miguel Mota Carmo, MD PhD
role: Study Chair
affiliation: Centro de Estudos de Doenças Crónicas da Faculdade de Ciências Médicas da Universidade Nova de Lisboa
last name: José D Martins, MD, MSc
phone: +351918338690
email: jose.martins@chlc.min-saude.pt
last name: Centro de Investigação Centro Hospitalar de Lisboa Central
phone: +351213596481
email: centro.investigacao@chlc.min-saude.pt
facility: 
status: Recruiting
contact: 
country: Portugal
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responsible party type: Sponsor
mesh term: Aortic Coarctation
sharing ipd: No