Study of Heart Transplant Rejection
Condition: Heart Transplantation
Study type: Observational

Summary: 
      This study will investigate the causes of acute and chronic rejection of transplanted hearts.
      To find better ways to detect, treat and possibly prevent heart transplant rejection, more
      information about the cause is needed. Acute and chronic heart transplant rejection may be
      caused by certain substances the body produces in response to the new heart. This study will
      try to find a blood or urine test that detects genes and proteins that can serve as markers
      of rejection. Such a test may lead to earlier detection and improved treatment.

      Patients 18 years and above who are on a wait list for heart transplant at a UNOS-approved
      heart transplant center, whose institutional review board has approved this protocol, may be
      eligible for this study. Healthy volunteers will also be included in the study to establish a
      database of normal values for comparison with patients undergoing heart transplant. In
      addition, patients who have had a heart transplant within the past 1 to 5 years will be
      enrolled in a pilot study. Normal volunteers will be screened for participation with an
      electrocardiogram (EKG) and echocardiogram, non-invasive tests to evaluate heart function.

      Participants will undergo the following procedures:

        -  Review of medical records Patients who have had a heart transplant and those on a wait
           list to receive a heart will have their medical records reviewed to collect information
           on their condition.

        -  Blood samples 60 cc (about 3 tablespoons) of blood will be collected from all
           participants by needle stick in a vein. The sample will be analyzed for genes and
           proteins that might predict heart rejection. In addition, many genes in blood cells and
           cells lining blood vessels that are unrelated to heart transplant rejection and whose
           functions or significance are unknown will also be examined for ideas for future
           research. Patients enrolled while on a wait list will, after transplantation, have an
           additional 44 cc (about 2 tablespoons) of blood collected at each heart biopsy and
           rejection episode during the first year of transplant, and 60 cc collected with each
           yearly biopsy for the next 9 years.

        -  Urine samples Between 100 and 300 cc (3 to 10 ounces) of urine may be collected from all
           participants to confirm blood test results
    

Detailed description: 
      Cardiac transplantation has been successful in improving survival in end stage heart failure.
      But graft rejection has limited survival after transplantation. In the first year, acute
      cellular rejection and infection remain the most common causes of morbidity and mortality.
      Afterwards, cardiac allograft vasculopathy (CAV), as a result of chronic vascular rejection,
      is the major cause of morbidity and mortality. Within the first year post-transplantation,
      almost two-thirds of recipients will experience at least one rejection episode. At five years
      post-transplantation, nearly 50% of survivors will have CAV. Clinically, the symptoms of
      acute rejection are relatively nonspecific (fatigue, dyspnea, fever). Most CAV patients
      remain asymptomatic until they develop serious problems such as myocardial infarction, heart
      failure, ventricular dysrhythmias or sudden cardiac death. Presently, the gold standard for
      diagnosing acute cardiac allograft rejection is right ventricular endomyocardial biopsy. This
      is an invasive method of diagnosis subject to morbidity and random sampling and
      interpretation error. Likewise, the gold standard for diagnosing CAV is cardiac
      catheterization with intravascular ultrasound, an invasive procedure also subject to
      morbidity. Noninvasive methods such as electrocardiography, echocardiography, and nuclear
      studies all have been studied, but have been unsuccessful, thus far, for either condition.
      Peripheral blood evaluations of cytokines and cytoimmunologic markers have also been
      unsuccessful in either condition. This clinical trial studies the feasibility of using
      functional genomics and proteomics to identify genes and proteins respectively that can serve
      as reliable biomarkers of acute cardiac cellular rejection and CAV. We plan to recruit
      subjects who are on the transplant waiting list. We will analyze the blood of these patients
      pre-transplant and serially post-transplant over one year and then regularly on a yearly
      basis. By correlating putative biomarkers with clinical, histological, and imaging based
      evidence of allograft disease we hope to build a database comprised of functional genomics,
      cytokine, cytoimmunologic and proteomics data relevant to the immunologic relationship
      between the donor organ and recipient. With this database we hope to obtain a minimal subset
      of differentially expressed genes, cytokines, cytoimmunologic and protein change profiles
      that is most predictive of both acute allograft rejection and CAV. This will eventually serve
      as the basis for a diagnostic blood test. Thus, with the application of functional genomics,
      cytokine, and cytoimmunologic analysis and proteomics we hope to derive a noninvasive method
      to detect both acute cellular cardiac allograft rejection and CAV, thereby minimizing the
      need for invasive methods of diagnosis. Further better understanding the genetic programs
      triggered and protein changes induced during rejection may lead to the identification of
      target pathways for developing new therapeutic approaches aimed at prevention.

      Recently, several published reports have established that detection of donor DNA in recipient
      s blood can serve as a diagnostic tool of graft injury. The level of donor DNA measured as
      percentage of circulating cell-free donor DNA (%ccfdDNA) accurately diagnoses acute rejection
      with a high sensitivity and specificity, at times several months before the diagnosis by
      examining endomyocardial biopsies. The ability of cell free DNA to diagnose graft injury
      early opens a new window to re-examine markers of rejection. These markers are traditionally
      evaluated using biopsy results, often positive late during rejection. %ccfdDNA offers an
      opportunity to better characterize our analyses.
    

Observational model: Cohort
Time perspective: Prospective
Sampling method: Probability Sample
Study population: 
        Patients who have had heart transplants, Patients Awaiting Heart Transplant, and Controls
        screened to obtain. Controls matched to patients for age, gender and race.@@@
      
Keywords: Genes; Heart; Lymphocytes; Proteomics; Transplant; Natural History; Heart Transplant; Healthy Volunteer; HV; Normal Control