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Study of Heart Transplant Rejection

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00042614
Recruitment Status : Completed
First Posted : August 2, 2002
Last Update Posted : August 4, 2022
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC)

Brief 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

Condition or disease
Heart Transplantation

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.

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Study Type : Observational
Actual Enrollment : 188 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: Acute Cardiac Allograft Cellular Rejection and Cardiac Allograft Vasculopathy: Identification of Diagnostic Biomarkers and Target Pathways for Preventive Therapy
Actual Study Start Date : April 7, 2003

Resource links provided by the National Library of Medicine

Matched to patients for age, gender and race
Who have had heart transplants, awaiting, or controls screened.

Primary Outcome Measures :
  1. Rejection warranting medical intervention [ Time Frame: ongoing ]
    Medical intervention

  2. Pathologically determined tissue rejection grades irrespective of treatment. [ Time Frame: ongoing ]
    Tissue Rejection

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   18 Years to 99 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
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.@@@
  • INCLUSION CRITERIA - for Transplant Patients:

    1. Adult heart transplant center generally accepts patients within the physiologic age range of 12 to 65 years old, however, for our study heart transplant patients must be 18 years of age or above.
    2. Indication for cardiac transplantation as outlined by the 24th Bethesda Conference on Cardiac Transplantation. These are as follows:
  • Peak VO(2) less than 10 ml/kg per minute or less than 50% of maximal predicted VO(2) with achievement of anaerobic metabolism.
  • Severe cardiac ischemia consistently limiting routine activity not amenable to surgical or percutaneous revascularization.
  • Recurrent symptomatic ventricular arrhythmias refractory to all accepted therapeutic modalities.

EXCLUSION CRITERIA - for Transplant Patients:

Adult heart transplant centers exclude infants, toddlers, and children with a physiologic age less than 12, and adults with advanced physiologic age (less than 65), however, for our study we will exclude heart transplant patients less than 18 years of age.

The final decision to exclude a candidate from cardiac transplantation will be made by the hospital's heart transplant committee. The committee uses, as a guideline, the criteria outlined in the 24th Bethesda conference.

INCLUSION CRITERIA - for Control Subjects:

Any healthy normal man or women who is the appropriate age and gender for matching to a transplant patient.

EXCLUSION CRITERIA - For Control Subjects:

  1. EKG with evidence of clinically relevant heart disease.
  2. Echocardiogram with evidence of clinically relevant heart disease.
  3. Any disease process that is not well controlled by medications.
  4. Total tobacco use for greater than one month over the last 5 years.
  5. Symptoms of coronary or cardiac insufficiency.
  6. More than one major risk factor for coronary artery disease excluding gender or age.
  7. Confirmed intrauterine pregnancy in women.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT00042614

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United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, United States, 20892
Sponsors and Collaborators
National Institutes of Health Clinical Center (CC)
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Principal Investigator: Michael A Solomon, M.D. National Institutes of Health Clinical Center (CC)
Additional Information:
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Responsible Party: National Institutes of Health Clinical Center (CC) Identifier: NCT00042614    
Other Study ID Numbers: 020266
First Posted: August 2, 2002    Key Record Dates
Last Update Posted: August 4, 2022
Last Verified: April 13, 2022

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by National Institutes of Health Clinical Center (CC):
Natural History
Heart Transplant
Healthy Volunteer
Normal Control