The GRAFT Study: Evaluation of Graft Function, Rejection and Cardiac Allograft Vasculopathy in First Heart Transplant Recipients.
Condition: Heart Transplant Recipients
MeSH terms: Vascular Diseases
Study type: Observational [Patient Registry]

Summary: 
      Objective:

        -  To assess the relationship between coronary allograft vasculopathy (CAV) and graft
           function, and to evaluate non-invasive methods for CAV diagnosis.

        -  To assess left ventricular (LV) and right ventricular (RV) function in the acute phase
           and serially during the first year after transplantation.

        -  To evaluate the impact of acute and repetitive rejection on the longitudinal myocardial
           function Hypothesis

             1. Timing of development and degree of CAV can be measured non-invasively combining
                myocardial longitudinal deformation (by advanced echocardiography) and coronary
                flow velocity reserve (CFVR) (by echocardiography and PET). This combination of
                methods can detect CAV before it is angiographically visual and gives supplementary
                information of the impact on myocardial graft function.

             2. Longitudinal deformation, 3D echocardiography, cardiac magnetic resonance imaging
                (CMRI) and PET can be used for RV and LV myocardial function assessment and
                represent more valid markers of the function than standard echocardiography in
                heart transplant (HTX) patients.

             3. Myocardial longitudinal deformation is a better marker of acute rejections than
                conventional ejection fraction (EF).

      Background The most frequent heart related death causes after HTX are CAV, acute graft
      failure and rejection.

      CAV is characterized by diffuse concentric intima thickening involving both epicardial
      vessels and the coronary microvascular system. In our clinical approach HTX-patients are
      followed with annual CAG and standard echocardiography with estimation of LV systolic
      function by EF. Standard echocardiography has not proven benefit in the diagnosis of CAV. CAG
      often misses CAV in early phases.

      In various cardiac diseases it is well known that ischemia and fibrosis often affect the
      endocardial longitudinal oriented layers. Longitudinal deformation by advanced
      echocardiography has shown to be better markers for systolic function in HTX patients
      compared to standard EF. Longitudinal LV systolic function is dependent of endocardial
      perfusion. CFVR represents the capacity of the coronary circulation to dilate due to
      metabolic demands and has been shown to correlate with longitudinal deformation in myocardial
      infarction. CFVR measurements in HTX patients with advanced echocardiography and PET scan
      have shown a significant correlation to CAV.

      RV failure is an early, potentially fatal, complication to HTX. The function and change over
      time of RV have not been fully studied using modern echocardiographic techniques or
      assessment by CMRI.

      Acute rejection is an inflammatory response often diagnosed by routine biopsies (gold
      standard). These are expensive, time consuming and inconvenient for the patient. The role of
      conventional echocardiography has not yet found a significant role in the diagnostics of
      acute rejections and furthermore how repeated rejections influence on graft function is not
      well described.

      Study 1 A cross sectional study consisting of 50 stabile HTX patients. These will be selected
      with 25 patients with no or light CAV and 25 patients with moderate or severe CAV.

      Severity of CAV will be evaluated by:

        -  CAG

        -  CFVR measurement by advanced echocardiography and PET.

      Graft function will be evaluated by:

        -  Advanced echocardiography at rest end during bicycle exercise.

        -  CMRI including assessment of LV and RV EF, strain and mass.

        -  During rest and bicycle exercise echocardiography simultaneously right heart
           catheterization are performed for hemodynamic measurement

      Study 2 A prospective cohort study with 20-25 newly transplanted patients over a period of 12
      months.

      LV and RV function will be measured by:

        -  Advanced echocardiography

        -  CFVR measurement (echocardiography and PET)

        -  CMRI for LV and RV EF, strain and mass

        -  Right heart catheterization

      Study 3 Prospective examination of correlation between graft function, CAV and rejection.
      Information of former episodes of acute rejection is collected retrospective. Study
      objectives are all living HTX patients (approx. 200) in the period of 2011-2013.

      Advanced echocardiography (including longitudinal deformation), biopsies (rejection
      evaluation) and CAG (CAV evaluation).
    

Detailed description: 
      Objective

        1. To assess the relationship between myocardial perfusion, coronary anatomy and
           longitudinal myocardial function in heart transplanted (HTX) patients with and without
           coronary allograft vasculopathy (CAV).

        2. Evaluation of systolic and diastolic capacity during exercise in HTX patients with and
           without CAV.

        3. Evaluation of non-invasive methods for CAV diagnosis.

        4. To assess left ventricular (LV) and right ventricular (RV) function in the acute phase
           and during follow-up (5 times) the first year after transplantation and furthermore to
           compare advanced echocardiographic evaluation of graft function with cardiac magnetic
           resonance imaging (CMRI), right heart catheterization, and positron emission tomography
           (PET).

        5. Finally, to evaluate the impact of acute and repetitive rejection on myocardial graft
           function measured by standard 2D echocardiography and advanced echocardiography with
           analysis of longitudinal myocardial function.

      Hypothesis

        1. Timing of development and degree of CAV can be measured non-invasively combining
           myocardial longitudinal deformation measurement by advanced echocardiography and
           coronary flow velocity reserve (CFVR) by echocardiography and PET. This combination of
           methods can detect CAV before it is angiographic visual and gives supplementary
           information of the impact on myocardial graft function. This setup might be more
           appropriate in evaluation of the myocardial graft function and CAV than standard
           echocardiography and coronary angiography (CAG). Optical coherence tomography (OCT) can
           detect CAV in early phases and gives supplementary characterization of the plaque.

        2. Modern non-invasive methods (longitudinal deformation, 3D echocardiography, CMRI and
           PET) can be used in RV and LV myocardial function assessment and represents more valid
           markers of the function than standard echocardiography in HTX patients.

        3. During exercise patients with CAV will show impaired longitudinal myocardial deformation
           and restrictive filling with significant increasing LV and RV filling pressures.

        4. Myocardial longitudinal deformation is a better marker of acute rejections than
           conventional ejection fraction (EF). After an episode of severe acute rejection the
           graft function will improve, but instances of repetitive rejections will lead to
           impaired longitudinal systolic function with preserved LV EF.

      Background Mean survival after HTX at our center is 15.6 years. Complications remain frequent
      and serious. In the first postoperative year the main causes of death are graft failure,
      rejections and infection. At long term follow up main causes of death are CAV and
      malignancies.

      CAV is characterized by diffuse concentric intima thickening involving both epicardial
      vessels and the coronary microvascular system. After 10 years more than 50% of patients shows
      angiographic signs of CAV.

      In our clinical approach HTX-patients are followed with annual CAG and standard
      echocardiography with estimation of LV systolic function by EF. EF is often within normal
      range even though CAV lesions are evident by CAG, suggesting that LV EF is an inappropriate
      parameter for detecting impaired myocardial function in CAV. Symptoms of graft dysfunction
      first present themself with severe CAV. Studies have shown that CAG often misses CAV in early
      phases. OCT is a novel intravascular imaging modality with excellent spatial resolution. It
      has been used in a few small cross sectional studies with HTX patients and seems like a
      promising tool for detecting CAV and gives supplementary characterization of the plaque.

      In various cardiac diseases it is well known that ischemia and fibrosis often affect the
      endocardial longitudinal oriented layers leading to abnormal systolic function of both LV and
      RV. Longitudinal deformation by tissue Doppler and strain analysis has shown to be better
      markers for systolic function in HTX patients compared to standard measurements such as LV
      EF. Longitudinal LV systolic function is dependent of endocardial perfusion. CFVR represents
      the capacity of the coronary circulation to dilate, due to increased myocardial metabolic
      demands and is expressed by the difference between the hyperaemic and resting flow. CFVR has
      been shown to correlate with the degree of decreased longitudinal deformation in myocardial
      infarction. CFVR measurements in HTX patients with color Doppler echocardiography and PET
      scan have shown a significant correlation to CAV.

      RV failure is an early, potentially fatal, complication to HTX. Standard echocardiographic
      measurement does not seem to reflect the overall RV systolic performance and clinical status
      of the patient. Prior studies have found impaired RV function after HTX, but most studies of
      RV function were not performed with simultaneous right heart catheterization or assessment of
      RV EF by CMRI (golden standard). Overall the function and change over time of RV have not
      been fully studied using modern echocardiographic techniques or assessment by CMRI.

      Acute rejection is an inflammatory response most frequently in the first 6 months after HTX.
      Two thirds experience rejection episodes within first year.

      Rejections are often asymptomatic and associated with poor outcome, including development of
      CAV. Patients are followed with routine biopsies (gold standard), but these are expensive,
      time consuming and inconvenient for the patient. The role of conventional echocardiography
      has not yet found a significant role in the diagnostics of acute rejections and furthermore
      how repeated rejections influence on graft function is not well described.

      Study objective, design and methods Study 1 Design: A cross sectional study consisting of 50
      stabile HTX patients. These will be selected with 25 patients with no or light CAV and 25
      patients with moderate or severe CAV. 25 matched controls.

      Methods:

      Severity of CAV will be evaluated by:

        -  CAG supplied with OCT.

        -  CFVR measurement by echocardiography with adenosine induced hyperemia.

        -  CFVR measurement with H215O-PET.

      Graft function will be evaluated by:

        -  2D and 3D echocardiography (including longitudinal deformation and tissue Doppler)

        -  Diastolic (and systolic) stress test: Bicycle exercise with simultaneously
           echocardiography and right heart catheterization.

      Blood samples are taken for analysis of myocardial fibrosis markers, CRP, TNT and NT-proBNP.

      Study 2 Design: A prospective cohort study with 20 newly transplanted patients over a period
      of 12 months.

      Methods: LV and RV function shall be measured by:

        -  2D and 3D echocardiography (including longitudinal deformation, tissue Doppler, CFVR, LV
           and RV EF),

        -  CMRI for LV and RV EF, strain and mass

        -  Right heart catheterization

        -  H215O-PET at baseline and after 3 month in the assessment of RV function

        -  Coronary angiography after 3 and 12 month will be supplied with OCT for early signs of
           CAV development.

      Biopsies are performed according to routine protocol after transplantation. Blood samples for
      analysis of myocardial fibrosis markers, CRP, TNT and NT-proBNP.

      Study 3 Design: Prospective examination of correlation between graft function, CAV and
      rejection. Information of former episodes of acute rejection is collected retrospective.
      Study objectives are all living HTX patients (approx. 200) in the period of 2011-2013.

      Methods: Advanced echocardiography (including longitudinal deformation and tissue Doppler),
      biopsies (rejection evaluation) and CAG (CAV evaluation).

      Publication Plan:

      Positive as well as negative result from study 1-3 will be published. We aim at publishing
      study 1-3 in peer review international, scientific journals. Study 3 is expected to be
      published in 2014 and study 1 and 2 in 2016. MD, PhD student Tor Skibsted Clemmensen will
      draft the manuscripts and be 1st author hereof.

      Ethical considerations Adenosine, used for CFVR measurement and PET, often causes mild facial
      flushing, chest discomfort and dyspnoea. After suspended infusion symptoms last less than one
      minute since half time is below 10 seconds.

      Right heart catheterisation is part of the standard protocol after HTX. Only patients in
      study 1 might be subjected to more catheterisations than normally. Complications are rare
      with experienced operators.

      The radiation dose of H215O-PET is 2-2,5 mSv, approximately the same as one year background
      radiation. Patients in study 1 will be subjected to one examination, patients in study 2 two
      examinations.

      No additional CAG are made in the studies. OCT examination is considered very safe with a
      risk of complication <0,5%.

      The investigators are convinced that the possible risks are outweighed by the expected
      benefits from this study and no study-related examinations will be conducted until informed
      consent form has been signed.

      Regional Scientific Ethical Committee of Central Denmark has approve the studies.
    

Intervention name(s): OCT and coronary angiography; Right heart cat.; PET; Echocardiography; exercise test; blood samples
Intervention type(s): Procedure; Procedure; Radiation; Procedure; Procedure; Other
Observational model: Case-Control
Time perspective: Cross-Sectional
Sampling method: Non-Probability Sample
Study population: 
        Design: A cross sectional study consisting of 50 stabile HTX patients. These will be
        selected with 25 patients with no or light CAV and 25 patients with moderate or severe CAV.
        25 matched controls.
      
Biospecimen description: 
      At each visit blood samples are taken. These will include:

      1 x 10 ml EDTA-blood

      1 x 10 ml Lithiumheparin-blood

      1 x 10ml Koagel -blood
    
Keywords: heart transplantation,; rejection; cardiac vasculopathy; optical coherence tomography; speckle tracking; Positron Emission Tomography .; exercise capacity