Heart Transplantation

Number: 0586


  1. Human Heart Transplantation

    Aetna considers heart transplantation medically necessary for any of the following conditions (not an all-inclusive list) when the member meets the transplanting institution's protocol eligibility criteria.  In the absence of a protocol, Aetna considers heart transplantation medically necessary for heart failure with irreversible underlying etiology, including  the following indications when the selection criteria listed below are met and none of the absolute contraindications is present:

    1. Cardiac arrhythmia
    2. Cardiac re-transplantation due to graft failure
    3. Cardiomyopathy due to nutritional, metabolic, hypertrophic or restrictive etiologies
    4. Congenital heart disease
    5. End-stage ventricular failure
    6. Idiopathic dilated cardiomyopathy
    7. Inability to be weaned from temporary cardiac-assist devices after myocardial infarction or non-transplant cardiac surgery
    8. Intractable coronary artery disease
    9. Myocarditis
    10. Post-partum cardiomyopathy
    11. Right ventricular dysplasia/cardiomyopathy
    12. Valvular heart disease.

    Selection Criteria for Human Heart Transplantation (for members off protocol, all criteria listed below must be met):

    1. New York Heart Association (NYHA) classification of heart failure III or IV (see Note below) – does not apply to pediatric members; and
    2. Member has potential for conditioning and rehabilitation after transplant (i.e., member is not moribund); and
    3. Life expectancy (in the absence of cardiovascular disease) is greater than 2 years; and
    4. No malignancy (except for non-melanomatous skin cancers or low grade prostate cancer) or malignancy has been completely resected or (upon individual case review) malignancy has been adequately treated with no substantial likelihood of recurrence with acceptable future risks; and
    5. Adequate pulmonary, liver and renal function; and
    6. Absence of active infections that are not effectively treated; and
    7. Absence of uncontrolled HIV infection, defined as:

      1. CD4 count greater than 200 cells/mm3 for greater than 6 months; and
      2. HIV-1 RNA (viral load) undetectable; and
      3. On stable anti-viral therapy greater than 3 months; and
      4. No other complications from AIDS, such as opportunistic infections (e.g., aspergillus, tuberculosis, coccidiodomycosis, resistant fungal infections) or neoplasms (e.g., Kaposi's sarcoma, non-Hodgkin's lymphoma); and
    8. Absence of active or recurrent pancreatitis; and
    9. Absence of diabetes with severe end-organ damage (neuropathy, nephropathy with declining renal function and proliferative retinopathy); and
    10. No uncontrolled and/or untreated psychiatric disorders that interfere with compliance to a strict treatment regimen; and
    11. No active alcohol or chemical dependency that interferes with compliance to a strict treatment regimen.

    Note: NYHA Class III and Class IV for heart failure are defined as follows:

  2. Table 1: NYHA Class III and Class IV for heart failure
    Class Classification
    Class III: Persons with cardiac disease resulting in marked limitation of physical activity.  They are comfortable at rest.  Less than ordinary activity (i.e., mild exertion) causes fatigue, palpitation, dyspnea, or anginal pain.
    Class IV: Persons with cardiac disease resulting in inability to carry on any physical activity without discomfort.  Symptoms of cardiac insufficiency or of the anginal syndrome may be present even at rest.  If any physical activity is undertaken, discomfort is increased.

    Contraindications: Heart transplant is considered not medically necessary for persons with any of the following contraindications:

    1. Presence of irreversible end-organ diseases (e.g., renal, hepatic, pulmonary) (unless person is to undergo dual organ transplantation, e.g., heart-lung, heart-kidney, etc.); or
    2. Presence of severe pulmonary hypertension with irreversibly high pulmonary vascular resistance; or
    3. Presence of a recent intra-cranial cerebrovascular event with significant persistent deficit; or
    4. Presence of bleeding peptic ulcer; or
    5. Presence of hepatitis B antigen; or
    6. Presence of diverticulitis; or
    7. Presence of immediately life-threatening neuromuscular disorders; or
    8. Presence of HIV/AIDS with profound immunosuppression (CD4 count of less than 200 cells/mm3); or
    9. Presence of AL amyloidosis (although amyloidosis is considered a contraindication to heart transplantation, exceptions may be made in circumstances where curative therapy of amyloidosis has been performed or is planned (e.g., stem cell transplantation in primary amyloidosis, liver transplantation in familial amyloidosis)).
  3. Xenotransplantation of the Heart

    Aetna considers cardiac xenotransplantation (e.g., porcine xenografts) experimental and investigational because its safety and effectiveness has not been established.

  4. Left Ventricular Assist Device as Destination Therapy

    For Aetna's CPB policy on left ventricular assist devices as destination therapy for persons with severe heart failure, see CPB 0654 - Ventricular Assist Devices.

  5. Total Artificial Heart

    Aetna considers the use of a total artificial heart (e.g., ABIOCOR Total Artificial Heart, SynCardia temporary Total Artificial Heart (formerly known as CardioWest Total Artificial Heart)) as permanent treatment (destination therapy) (i.e., as an alternative to heart transplantation) experimental and investigational because its safety and effectiveness for this indication has not been established.

    Aetna considers an Food and Drug Administration-approved total artificial heart (e.g., CardioWest Total Artificial Heart, SynCardia Systems, Tucson, AZ) medically necessary when used as a bridge to transplant for transplant-eligible members who are at imminent risk of death (NYHA Class IV) due to biventricular failure who are awaiting heart transplantation. See CPB 0654 - Ventricular Assist Devices.

  6. Breath Test for Heart Transplant Rejection

    Aetna considers the Heartsbreath Test (Menassana Research, Inc, Fort Lee, NJ) experimental and investigational for diagnosing heart transplant rejection and for all other indications because its clinical value has not been established.  

  7. AlloMap™ Molecular-Expression Blood Test

    Aetna considers the Allomap gene expression profile medically necessary for monitoring rejection in heart transplant recipients more than six months post-heart transplant.

    Aetna considers the Allomap gene expression profile experimental and investigational for all other indications because its clinical value has not been established.

  8. Cytokine Gene Polymorphism Testing

    Aetna considers cytokine gene polymorphism testing experimental and investigational for evaluating graft rejection following heart transplantation because of insufficient evidence.

  9. Immune Repertoire Sequencing Assay

    Aetna considers the use of immune repertoire sequencing assay for measurement of the isotype and clonal composition of the circulating B cell repertoire is considered experimental and investigational to detect acute allograft rejection in heart transplant recipients because its effectiveness has not been established.

  10. myTAIHEART Testing

    Aetna considers the myTAIHEART test (TAI Diagnostics, Inc., Milwaukee, WI) experimental and investigational for evaluating graft rejection following heart transplant  and all other indications because of insufficient evidence in peer-reviewed published literature.

  11. Measurement of Cardiac Troponins

    Aetna considers measurement of cardiac troponins experimental and investigational for diagnosis of acute cellular rejection following heart transplantation because the effectiveness of this approach has not been established.

  12. Measurement of Donor-Derived Cell-Free DNA

    Aetna considers measurement of donor-derived cell-free DNA of transplant recipients experimental and investigational for monitoring of rejection because the effectiveness of this approach has not been established.

  13. Heart Molecular Microscope Diagnostic System (MMDx-Heart)

    Aetna considers the Heart Molecular Microscope Diagnostic System (MMDx-Heart) experimental and investigational for evaluation of cardiac transplant rejection because its clinical value has not been established.


Heart transplantation has become a commonly used therapeutic option for the treatment of end-stage heart disease.  It has been projected that patients who receive cardiac transplants have an in-hospital mortality rate of less than 5 %, a 1-year survival rate of about 85 %, and a 5-year survival rate of 75 % to 80 %.  Moreover, 90 % of cardiac transplant patients lead a relatively normal lifestyle having no limitations in their activity and 40 % return to work.

In adults, cardiac transplantation is most frequently performed for patients with cardiomyopathy (about 50 %), coronary artery disease (about 40 %), valvular disease (about 4 %), re-transplantation following a failed primary transplantation (about 2 %) and congenital heart disease (about 2 %).

In children, the most common indications for cardiac transplantation are congenital heart disease (about 47 %), dilated cardiomyopathy (about 45 %), and re-transplantation (about 3 %).  Moreover, survival in children with dilated cardiomyopathy relies on accurate diagnosis and aggressive treatment.  The literature indicates that patients may respond to conventional treatment for heart failure or may deteriorate, requiring mechanical support.  Extracorporeal membrane oxygenation (see CPB 0546 - Extracorporeal Membrane Oxygenation (ECMO)) has been used effectively for mechanical support in children until improvement occurs or as a bridge to transplantation.  For individuals who are listed to receive a heart transplant, the mortality rate while waiting for a donor organ averages approximately 20 %.  Survival after transplantation is good, with an intermediate survival rate of about 70 %.

The New York Heart Association (NYHA) classification of heart failure is one of the many parameters used for selecting heart recipients.  It is a 4-tier system that categorizes patients based on subjective impression of the degree of functional compromise.  The 4 NYHA functional classes are as follows:

Table 2: 4-tier system that categorizes patients based on subjective impression of the degree of functional compromise
Class Classification
Class I: Patients with cardiac disease but without resulting limitation of physical activity.  Ordinary physical activity does not cause undue fatigue, palpitation, dyspnea, or anginal pain.  Symptoms only occur on severe exertion.
Class II:  Patients with cardiac disease resulting in slight limitation of physical activity.  They are comfortable at rest.  Ordinary physical activity (e.g., moderate physical exertion such as carrying shopping bags up several flights or stairs) results in fatigue, palpitation, dyspnea, or anginal pain.
Class III:  Patients with cardiac disease resulting in marked limitation of physical activity.  They are comfortable at rest.  Less than ordinary activity (i.e., mild exertion) causes fatigue, palpitation, dyspnea, or anginal pain.
Class IV:  Patients with cardiac disease resulting in inability to carry on any physical activity without discomfort.  Symptoms of cardiac insufficiency or of the anginal syndrome may be present even at rest.  If any physical activity is undertaken, discomfort is increased.

Contraindications to cardiac transplantation include irreversible end-organ diseases (e.g., renal, hepatic, pulmonary), active malignancy or infections, systemic diseases (e.g., autoimmune, vascular), chronic gastro-intestinal disease (e.g., diverticulitis, active or recurrent pancreatitis, bleeding peptic ulcer), psychiatric disorders, and intra-cranial cerebrovascular disease.  Amyloidosis has also been considered a contraindication to cardiac transplantation due to the high likelihood of development of amyloid in the transplanted organ.  Good outcomes of cardiac transplantation have been reported after curative liver transplantation for familial amyloidosis or stem cell transplantation for primary amyloidosis.  HIV infection is not an absolute contraindication to cardiac transplantation if the HIV infection is well-controlled.  Because of the potential impact of transplant-related immunosuppression, it is especially important for HIV-infected transplant recipients to be followed by an HIV-AIDS multi-disciplinary team with expertise in this area.

Cardiac transplantation is currently the only proven curative treatment for end-stage heart disease, but the supply of donor hearts has not kept pace with the demand.  Therefore, surgical techniques such as reduction ventriculoplasty, transmyocardial laser revascularization (see CPB 0163 - Transmyocardial and Endovascular Laser Revascularization), myoreduction operations (see CPB 0182- Ventricular Remodeling Operation (Batista Operation) and Surgical Ventricular Restoration (Dor Procedure)) or dynamic cardiomyoplasty are employed to maintain heart function or provide a bridge to heart transplantation.  In addition, ventricular assist devices (see CPB 0654 - Ventricular Assist Devices) and the total artificial heart have been approved by the Food and Drug Administration (FDA) for use as a bridge to transplant in selected persons who are awaiting heart transplantation.

The FDA approval of the CardioWest Total Artificial Heart (TAH) (SynCardia Systems, Inc., Tucson, AZ) as a bridge to heart transplantation in transplant eligible patients at imminent risk of death from non-reversible biventricular failure was based on the results of a controlled multi-center clinical study that found that such patients who were implanted with the CardioWest TAH did better than similar control patients who underwent emergency cardiac transplantation (SynCardia, 2004; Copeland et al, 2004).  In this study, 95 patients were implanted with the CardioWest TAH and 35 patients were controls.  Of the 95 patients implanted, 81 met all inclusion criteria and were designated the core implant group.  All patients were in NYHA Class IV at time of enrollment.  The control group did not receive the TAH but met study inclusion criteria.  Both groups were on maximal medical therapy and were at imminent risk of death before a donor heart could be obtained.  Treatment success was defined as patients who, at 30 days post transplant, were
  1. alive,
  2. NYHA Class I or II,
  3. not bedridden;
  4. not ventilator dependent, and
  5. not requiring dialysis.
Trial success was achieved in 56 (69 %) of the 81 core patients and in 13 (37 %) of the 35 control patients, a difference that was statistically significant (p = 0.0019).  There was also statistically significant differences in favor of the core patients with respect to survival to transplant (p = 0.0008) and survival to 30 days post transplant (p = 0.0018).  Of the core patients, 64 of the 81 (79 %) reached transplant after an average of 79 days (range of 1 to 414); whereas 16 of the 35 (46 %) controls reached transplant after an average of 9 days (range of 1 to 44).  Fifty-eight (72 %) core patients and 14 (40 %) controls survived to 30 days post-transplant.

Renlund (2004) explained that a variety of devices can be used as a bridge to heart transplant.  The selection of a device depends on the type of heart failure, as well as the size of the patient, the surgeon's experience, and the institutional preference.  Implantable left ventricular assist devices, which channel blood from the left ventricle to the pump and back to the aorta, are generally inadequate for bridging to transplantation in patients with severe biventricular heart failure.  The replacement of both ventricles with a TAH may be warranted when replacement of both ventricles may be warranted in severe biventricular failure (Renlund, 2004).  Such circumstances frequently arise in patients with severe aortic insufficiency, intractable ventricular arrhythmias, an aortic prosthesis, an acquired ventricular septal defect, or irreversible biventricular failure requiring a high pump output.  Paracorporeal devices, with the pump placed outside of the body, can provide an alternative to either the ventricular assist device for supporting 1 ventricle, or to the TAH for supporting both ventricles.

Xenotransplantation of the Heart

The scarcity of donor organs has also resulted in intense research on xenotransplantation.  As a consequence of physiological compatibility as well as infectious consideration, pig is the most likely source of xenotransplantation.  The advent of transgenic pigs expressing human complement regulatory proteins and new immunosuppressive therapies have provided early promising results in the laboratory.  However, more research is needed to advance porcine xenotransplantation to clinical trials.

The Heartsbreath Test

Menssana Research, Inc. (Fort Lee, NJ) has received a humanitarian device approval (see note below) for the Heartsbreath Test for evaluation of heart transplant rejection.  According to the FDA-approved product labeling, the product is to be used as an aid in diagnosis of grade 3 heart transplant rejection in patients who have received heart transplants within the preceding year (FDA, 2004).  The labeling states that the Heartsbreath test is intended to be used as an adjunct to, and not as a substitute for endomyocardial biopsy.  The labeling states that the use of the Heartsbreath Test is limited to patients who have had endomyocardial biopsy within the previous month.

The Heartsbreath test assesses heart transplant rejection by measuring the amount of methylated alkanes, a marker of oxidative stress, in the patient's breath.  Heart transplant rejection appears to be accompanied by oxidative stress which degrades membrane polyunsaturated fatty acids, creating methylated alkanes, which are excreted in the breath as volatile organic compounds.  The value generated by the Heartsbreath Test is compared to the results of a biopsy performed the previous month to measure the probability of the implant being rejected.

According to the FDA (2004), the Heartsbreath test's greatest potential value may be in helping to separate less severe organ rejection (grades 0, 1, and 2) from more severe rejection (grade 3).  The FDA-approved labeling states that the Heartsbreath test should not be used for patients who have received a heart transplant more than 1 year ago, or who have grade 4 heart transplant rejection because the Heartsbreath test has not been evaluated in these patients.

The FDA's Humanitarian Device Approval of the Heartsbreath Test was based on the results of a multi-center clinical study entitled Heart Allograft Rejection: Detection with Breath Alkanes in Low Levels (HARDBALL), which compared the sensitivity and specificity of the Heartsbreath Test with myocardial biopsy reading by a single pathologist at the transplant site (usually a general pathologist) in distinguishing grade 3 heart transplant rejection from lesser grades of rejection, using biopsy reading by 2 cardiac pathologists as the gold standard for comparison (Phillips et al, 2004; FDA, 2004).  In this study, 1,061 breath samples were collected from 539 heart transplant recipients prior to scheduled endomyocardial biopsy.  Compared to the gold standard, the Heartsbreath Test had a sensitivity of 59.5 %, a specificity of 58.8 %, a positive- predictive value of 5.6 % and a negative-predictive value of 97.2 %.  The biopsy reading by the general pathologist had a sensitivity of 42.4 %, a specificity of 97.0 %, a positive- predictive value of 45.2 %, and a negative-predictive value of 96.7 %.  The investigators concluded that the Heartsbreath Test was more sensitive but less specific for grade 3 heart transplant rejection than a biopsy reading by a single general pathologist, but the negative-predictive values of the 2 tests are similar.  Therefore, a screening breath test may provide supportive information to help identify heart transplant recipients who are at low-risk for grade 3 rejections (Phillips et al, 2004).

In a report of the HARDBALL study results published in the New England Journal of Medicine, the investigators explained that the major potential benefit of the Heartsbreath test is in reducing the number of heart biopsies (Phillips et al, 2004).  If the breath analysis is negative, a biopsy is not needed because, with a negative-predictive value of 97 %, this test accurately predicts where there is not any organ rejection.  If the breath analysis is positive, however, the patient will need a biopsy to determine whether there is rejection, because the Heartsbreath test, with a positive-predictive value of 6 %, does not accurately predict the presence of rejection.  The investigators explained that the low positive-predictive value of this test means that it does not predict the presence of rejection.

A commentary on the HARDBALL study (Williams and Miller, 2002) noted that the study results are "difficult to evaluate" because of a "surprising inconsistency" between the biopsy interpretations of the general pathologist at the transplant site and the biopsy interpretation by the 2 cardiac pathologists used as the gold standard.  The commentary also noted that only 9 of 42 biopsies with grade 3 rejection were predicted by the Heartsbreath test.  Finally, the commentary stated that there needs to be further study of the effect of concurrent illness, such as hemodynamic compromise and infection, on the Heartsbreath test, because such illnesses could theoretically decrease the sensitivity and specificity of the Heartsbreath or any other test that is a marker of oxidative stress.

The FDA-approved product labeling of the Heartsbreath test states that the effectiveness of this device for diagnosis of grade 3 heart transplant rejection "has not been demonstrated" (FDA, 2004).  The FDA, however, approved this device based on the Center for Devices and Radiological Health conclusion that the probable benefit of this test outweighs the risk.  The FDA approval also was based on the assumption that this test would not be used as a substitute for a heart biopsy, as has been suggested by the HARDBALL study investigators (Phillips et al, 2004), but to be used as a confirmatory test in combination with myocardial biopsy to detect grade 3 heart transplant rejection (FDA, 2004).  The Humanitarian Device Exemption for the Heartsbreath was not referred to the FDA's Clinical Chemistry and Clinical Toxicology Devices Panel for review and recommendation because the Heartsbreath is used as an adjunct to myocardial biopsy rather than replacing myocardial biopsy.

According to the FDA, the major benefit of the Heartsbreath test is that it may reduce the risk of a patient getting the wrong treatment because of an erroneous biopsy report:

The benefits are of 2 kinds: 
  1. the Heartsbreath test may help identify patients with grade 3 rejections and a false-negative biopsy report, which may help protect them from under-treatment of a life-threatening condition, and
  2. the Heartsbreath test may help identify patients with a false-positive biopsy report who do not have grade 3 rejections, and may help protect them from the hazards of unnecessary treatment with steroids and other immunosuppressant medications.

The FDA states that the major risk of the Heartsbreath Test is a result that conflicts with a biopsy report.  According to the FDA, this risk, however, can be minimized by recommending secondary biopsy review of any discordant results by a 2nd pathologist prior to considering any change in treatment.

NoteA Humanitarian Use Device (HUD) is a device that has been given special approval by the FDA under the Humanitarian Device Exemption (HDE) regulations.  The standard approval process for devices requires that companies demonstrate that the devices are safe and effective (better than medicine or another procedure).  However, the FDA recognizes that sometimes a condition is so unusual that it would be difficult for a company to scientifically demonstrate effectiveness of their device in the large number of patients that usually must be tested.  In these special situations, they may grant a HDE provided that:
  1. the device does not pose an unreasonable or significant risk of illness or injury; and
  2. the probable benefit to health outweighs the risk of injury or illness from its use, taking into account the probable risks and benefits of currently available devices or alternative forms of treatment.

A HUD may only be used in facilities that have an Institutional Review Board (IRB) to supervise clinical testing of devices and after the IRB has approved the use of the device to treat or diagnose the specific disease.

On December 8, 2008, the Centers for Medicare and Medicaid Services (CMS) issued a decision memorandum in response to a formal request for Menssana Research, Inc., to consider national coverage of the Heartsbreath test as an adjunct to the heart biopsy to detect grade 3 heart transplant rejection in patients who have had a heart transplant within the last year and an endomyocardial biopsy in the prior month.  The CMS determined that the evidence does not adequately define the technical characteristics of the test nor demonstrate that Heartsbreath testing to predict heart transplant rejection improves health outcomes.

AlloMap Molecular Expression Blood Test

The AlloMap molecular expression blood test was developed by XDx Expression Diagnostics.  The test evaluates the expression of 20 genes, about half of which are directly involved in rejection while the remainder provide other information needed for rejection risk assessment.  It is hoped that the results of this test will reduce the number of endomyocardial biopsies.  Among the proposed benefits are the AlloMap test's ability to differentiate mild rejection for which histological findings may be the least accurate and the potential for monitoring physiological responses to steroid weaning.  It has been recognized that the test is not effective in monitoring rejection within the first 6 months of transplantation, and it is yet unclear what a high AlloMap score might mean in the setting of no histological rejection.

In a multi-center study called CARGO (Cardiac Allograft Rejection Gene Expression Observational study), Deng et al (2006) examined gene expression profiling of peripheral blood mononuclear cells to discriminate International Society of Heart and Lung Transplantation (ISHLT) grade 0 rejection (quiescence) from moderate/severe rejection (ISHLT greater than or equal to 3A).  Patients were followed prospectively with blood sampling at post-transplant visits.  Biopsies were graded by ISHLT criteria locally and by 3 independent pathologists blinded to clinical data.  Known alloimmune pathways and leukocyte microarrays identified 252 candidate genes for which real-time polymerase chain reaction (PCR) assays were developed.  An 11 gene real-time PCR test was derived from a training set (n = 145 samples, 107 patients) using linear discriminant analysis, converted into a score (0 to 40), and validated prospectively in an independent set (n = 63 samples, 63 patients).  The test distinguished biopsy-defined moderate/severe rejection from quiescence (p = 0.0018) in the validation set, and had agreement of 84 % (95 % confidence interval [CI]: 66 % to 94 %) with grade ISHLT greater than or equal to 3A rejection.  Patients over 1 year post-transplant with scores below 30 (approximately 68 % of the study population) are very unlikely to have grade greater than or equal to 3A rejection (negative-predictive value  = 99.6 %).  Gene expression testing can detect absence of moderate/severe rejection, thus avoiding biopsy in certain clinical settings.  The authors concluded that more research is needed to establish the role of molecular testing for prediction of clinical event prediction and management of immunosuppression.  Furthermore, an editorial (Halloran et al, 2006) that accompanied the CARGO study questioned the biological plausibilty of this technology and emphasized the need for replication of these findings.

In a subsequent study, the investigators from the CARGO study (Starling et al, 2006) provided recommendations regarding the use of the gene expression profiling (GEP) test.  However, none of the recommendations received Class I classification and/or Level A evidence.

Candidates for GEP Testing

Class IIa

  • GEP testing can be used in clinically stable cardiac transplant recipients who are 15 years of age or older and 6 months or more post-transplant to identify patients at low-risk for moderate/severe (Grade greater than or equal to 3A/2R) cellular rejection.  (Level of Evidence: B)
  • At the time of GEP testing, a thorough history and physical examination should be obtained/performed by an appropriately trained transplant physician, and a non-invasive assessment of cardiac allograft function utilizing echocardiography should be performed to evaluate allograft function.  (Level of Evidence: C)

Class III

  • GEP testing should not be used in patients at high-risk for acute rejection or graft failure, including those with (a) signs/symptoms of cardiac allograft dysfunction or hemodynamic compromise (including LVEF less than 40 % and cardiac index less than 2 L/min), (b) recurrent Grade greater than or equal to 3A/2R cellular rejection (greater than or equal to 2 episodes within the past year), or (c) a history of Grade greater than or equal to 3A/2R cellular rejection within the preceding 6 months or antibody-mediated rejection within the preceding 12 months.  (Level of Evidence: C)
  • GEP testing should not be performed in pregnant women, in patients who have had a blood transfusion in the previous 30 days, or in patients who have received hematopoietic growth factors affecting leukocytes within the previous 30 days.  (Level of Evidence: C)
  • GEP testing should not be used to rule out rejection in patients who have received high-dose steroids (intravenous bolus or oral augmentation) within the past 21 days or who are currently on greater than or equal to 20 mg/day of prednisone equivalent.  (Level of Evidence: C)
  • Molecular testing should not be used in patients less than 15 years of age.  (Level of Evidence: C)

Classification of Recommendations

Class I: Conditions for which there is evidence and/or general agreement that a given procedure/therapy is beneficial, useful, and/or effective.

Class II: Conditions for which there is conflicting evidence and/or a divergence of opinion about the usefulness/efficacy of a procedure/therapy.

Class IIa: Weight of evidence/opinion is in favor of usefulness/efficacy.

Class III: Conditions for which there is evidence and/or general agreement that a procedure/therapy is not useful/effective and in some cases may be harmful.

Level of Evidence

A: Data are derived from multiple randomized clinical trials or meta-analyses.

B: Data are derived from a single randomized trial, or nonrandomized studies.

C: Only consensus opinion of experts, case studies, or standard of care.

Starling and colleagues (2006) noted that while the performance of the GEP test has been validated in a large number of transplant recipients, the clinical outcomes associated with using a GEP-based strategy to monitor for rejection are currently unknown.  A multi-center randomized clinical study is currently underway to assess a GEP-based strategy, compared to a biopsy-based strategy, for evaluating rejection in cardiac transplant patients who are 2 to 5 years post-transplant.  This study will examine the impact of these 2 strategies with respect to clinical outcomes (e.g., graft dysfunction, death, and clinically apparent rejection), incidence of biopsy-related complications, quality of life, as well as resource utilization.

The AlloMap was assessed by the California Technology Assessment Forum (CTAF, 2006), which concluded that this technology does not meet CTAF's assessment criteria.  The CTAF assessment stated that GEP offers the potential for a non-invasive test that may replace endomyocardial biopsy as the gold standard for transplant rejection.  However, given the history of poor reproducibility of other GEP in the recent past, it is prudent to require independent confirmation of the CARGO Study results before widespread adoption of the AlloMap gene expression profile to detect early rejection in cardiac transplant recipients.  This is particularly true given the post-hoc change in the threshold used to define a positive test result in the study and the small size of the primary validation study.  Additionally, there are no studies published to date comparing the clinical outcomes of patients monitored with GEP to those of patients monitored with endomyocardial biopsies.

A subsequent randomized, controlled study of the Allomap GEP concluded that, among selected patients who had received a cardiac transplant more than 6 months previously and who were at a low-risk for rejection, a strategy of monitoring for rejection that involved Allomap GEP, as compared with routine biopsies, was not associated with an increased risk of serious adverse outcomes and resulted in the performance of significantly fewer biopsies.  In the Invasive Monitoring Attenuation Through Gene Expression (IMAGE) study (Pham et al, 2010), investigators randomly assigned 602 patients who had undergone cardiac transplantation 6 months to 5 years previously to be monitored for rejection with the use of GEP or with the use of routine endomyocardial biopsies, in addition to clinical and echocardiographic assessment of graft function.  The investigators performed a non-inferiority comparison of the 2 approaches with respect to the composite primary outcome of rejection with hemodynamic compromise, graft dysfunction due to other causes, death, or re-transplantation.  During a median follow-up period of 19 months, patients who were monitored with GEP and those who underwent routine biopsies had similar 2-year cumulative rates of the composite primary outcome (14.5 % and 15.3 %, respectively; hazard ratio with GEP, 1.04; 95 % CI: 0.67 to 1.68).  The 2-year rates of death from any cause were also similar in the 2 groups (6.3 % and 5.5 %, respectively; p = 0.82).  Patients who were monitored with the use of GEP underwent fewer biopsies per person-year of follow-up than did patients who were monitored with the use of endomyocardial biopsies (0.5 versus 3.0, p < 0.001).

An editorial accompanying the IMAGE trial (Jarcho, 2010) commented that the most notable implication of the IMAGE trial may be the evidence it offers that calls into question the importance of any form or routine screening for the early detection of rejection in the longer term after transplantation.  The editorialist explained that, of 34 rejection episodes identified in the GEP group in the trial, only 6 were detected solely on the basis of the GEP test.  All other episodes of rejection were associated with clinical manifestations of heart failure or echocardiographic evidence of allograft dysfunction.  "This observation suggests that, even if rejjection is not identified until graft dysfunction is present, the clinical outcomes may not be substantially worse than when rejection is detected early."  Other limitations of the trial include the fact that the investigators only enrolled patients who had undergone transplantation at least 6 months previously, a group that was a much lower risk of rejection than patients within 6 months of transplantation.  In addition, the non-inferiority margin was wide; the actual 95 % CI was consistent with as much as a 68 % increase in risk with the GEP strategy.

A re-assessment of the AlloMap by the California Technology Assessment Forum (Tice, 2010), considering the results of the IMAGE trial, concluded that this technology meets CTAF's assessment criteria.  The CTAF assessment stated that the AlloMap GEP has a high negative-predictive value, but a low positive-predictive value.  Thus, it may be useful to avoid biopsy in stable patients, but the high false-positive rate precludes its use to definitively diagnose acute cellular rejection.  The assessment states that endomyocardial biopsies will still need to be performed in all patients with elevated AlloMap scores and all patients with clinical signs of rejection.  CTAF found that the IMAGE trial provides data supporting the non-inferiority of a monitoring strategy for heart transplant patients incorporating the AlloMap GEP in lieu of routine endomyocardial biopsy.  However, the data only support such strategies in patients more than 1 year post-transplant.  CTAF stated that more data are needed to confirm the tests utility earlier in the post-transplant period when the majority of endomyocardial biopsies are performed.

Mehra and Uber (2007) stated that clinicians have entered a new era for managing heart transplant recipients with the use of multi-marker GEP.  Early after transplantation, when steroid modification is the main concern, gene expression testing might aid in optimizing the balance of immunosuppression, defraying the occurrence of rejection, and avoiding crisis intervention.  Late after transplantation, the reliance on endomyocardial biopsy could be reduced.  These advances, if continually validated in practice, could result in decreased immunosuppression complications, lesser need for invasive surveillance, and more clinical confidence in immunosuppressive strategies.

Total Artificial Heart

Slepian et al (2013) stated that the SynCardia™ total artificial heart (TAH; SynCardia Systems Inc., Tuscon, AZ) is the only FDA-approved TAH in the world.  The SynCardia™ TAH is a pneumatically driven, pulsatile system capable of flows of greater than 9 L/min.  The TAH is indicated for use as a bridge to transplantation (BTT) in patients at imminent risk of death from non-reversible bi-ventricular failure.  In the pivotal U.S. approval trial the TAH achieved a BTT rate of greater than 79 %.  Recently a multi-center, post-market approval study similarly demonstrated a comparable BTT rate.  A major milestone was recently achieved for the TAH, with over 1,100 TAHs having been implanted to date, with the bulk of implantation occurring at an ever increasing rate in the past few years.  The TAH is most commonly utilized to save the lives of patients dying from end-stage bi-ventricular heart failure associated with ischemic or non-ischemic dilated cardiomyopathy.  Beyond progressive chronic heart failure, the TAH has demonstrated great efficacy in supporting patients with acute irreversible heart failure associated with massive acute myocardial infarction.  In recent years several diverse clinical scenarios have also proven to be well served by the TAH including severe heart failure associated with advanced congenital heart disease, failed or burned-out transplants, infiltrative and restrictive cardiomyopathies and failed ventricular assist devices.  Looking to the future a major unmet need remains in providing total heart support for children and small adults.  As such, the present TAH design must be scaled to fit the smaller patient, while providing equivalent, if not superior flow characteristics, shear profiles and overall device thrombogenicity.  To aid in the development of a new "pediatric," TAH an engineering methodology known as "Device Thrombogenicity Emulation (DTE)", that these researchers have recently developed and described, is being employed.  Recently, to further their engineering understanding of the TAH, as steps towards next generation designs these investigators  had:
  1. assessed of the degree of platelet reactivity induced by the present clinical 70 cc TAH using a closed loop platelet activity state assay,
  2. modeled the motion of the TAH pulsatile mobile diaphragm, and
  3. performed fluid-structure interactions and assessment of the flow behavior through inflow and outflow regions of the TAH fitted with modern bi-leaflet heart valves.
Developing a range of TAH devices will afford bi-ventricular replacement therapy to a wide range of patients, for both short- and long-term therapy.

Cytokine Gene Polymorphism Testing

Yongcharoen et al (2013) performed a systematic review and meta-analysis with the aim of assessing the association between cytokine gene polymorphisms and graft rejection in heart transplantation.  These researchers identified relevant studies from Medline and Embase using PubMed and Ovid search engines, respectively.  Allele frequencies and allele and genotypic effects were pooled.  Heterogeneity and publication bias were explored.  Four to 5 studies were included in pooling of 3 gene polymorphisms.  The prevalence of the minor alleles for TNF α -308, TGF β 1-c10, and TGF β 1-c25 were 0.166 (95 % CI: 0.129 to 0.203), 0.413 (95 % CI: 0.363 to 0.462), and 0.082 (95 % CI: 0.054 to 0.111) in the control groups, respectively.  Carrying the A allele for the TNF α -308 had 18 % (95 % CI of OR: 0.46 to 3.01) increased risk, but this was not significant for developing graft rejection than the G allele.  Conversely, carrying the minor alleles for both TGF β 1-c10 and c25 had non-significantly lower odds of graft rejection than major alleles, with the pooled ORs of 0.87 (95 % CI: 0.65 to 1.18) and 0.70 (95 % CI: 0.40 to 1.23), respectively.  The authors concluded that there was no evidence of publication bias for all pooling; an updated meta-analysis is needed when more studies are published to increase the power of detection for the association between these polymorphisms and allograft rejection.

Furthermore, an UpToDate review on "Acute cardiac allograft rejection: Diagnosis" (Eisen and Jessup, 2014) does not mention cytokine gene polymorphism testing as a management tool.

Statin Use Following Heart Transplantation/for the Management of Graft Vessel Disease

Som and colleagues (2014) noted that graft vessel disease (GVD) is a significant cause of morbidity and mortality in cardiac allograft recipients.  Hyperlipidemia is a risk factor for GVD, and the majority of patients will display abnormal lipid profiles in the years following transplant.  This systematic review aimed to establish the clinical impact of statins in cardiac allograft recipients, critically appraising the literature on this subject.  These investigators performed a literature search for randomized studies assessing statin use in cardiac allograft recipients.  The Cochrane Central Registry of Controlled Trials, MEDLINE, EMBASE, clinicaltrials.gov, and the Transplant Library from the Centre for Evidence in Transplantation were searched.  The primary outcome was presence of GVD.  Secondary outcomes included graft and patient survival, acute rejection, and adverse events.  Meta-analysis was precluded by heterogeneity in outcome reporting and therefore narrative synthesis was undertaken.  A total of 7 randomized controlled trials (RCTs) were identified.  The majority of RCTs demonstrated some risk of bias, and methods of outcome measurement were variable.  Studies reporting incidence or severity of GVD suggested that statins do confer benefit.  Survival benefit from statin use is modest.  There is a low incidence of adverse events attributable to statins.  There was no difference in the overall number of episodes of rejection.  The authors concluded that while the methodological quality of evidence describing the use of statins in cardiac allograft recipients is limited, the available evidence suggested benefit from their use.  These findings need to be validated by well-designed studies.

Greenway and colleagues (2016) hypothesized that statin therapy would reduce the incidence of rejection, cardiac allograft vasculopathy (CAV) and post-transplant lymphoproliferative disease (PTLD).  This study was a retrospective review of 964 pediatric (aged 5 to 18 years) heart transplant recipients in the multi-center Pediatric Heart Transplant Study registry from 2001 to 2012.  Patients were excluded if they were undergoing re-transplantation, survived less than 1 year post-transplant, or had missing data regarding statin use.  The effects of statins beyond the 1st year were estimated by Kaplan-Meier and Cox regression multi-variable analysis for freedom from PTLD, rejection requiring treatment, any severity of CAV, and survival.  Statin use was variable among participating centers with only 30 % to 35 % of patients greater than or equal to 10 years of age started on a statin at less than 1 year post-transplant.  After the 1st year post-transplant, statin-treated children (average age at transplant of 13.24 ± 3.29 years) had significantly earlier rejection (hazard ration [HR] 1.42, 95 % CI: 1.11 to 1.82, p = 0.006) compared with untreated children (transplanted at 12 ± 3.64 years) after adjusting for conventional risk factors for rejection.  Freedom from PTLD, CAV and overall survival up to 5 years post-transplant were not affected by statin use, although the number of events was small.  The authors concluded that statin therapy did not confer a survival benefit and was not associated with delayed onset of PTLD or CAV.  Early (less than 1 year post-transplant) statin therapy was associated with increased later frequency of rejection.  The authors stated that these findings suggested that a prospective trial evaluating statin therapy in pediatric heart transplant recipients is needed.

Vallakati and associates (2016) performed a meta-analysis of published studies to evaluate the role of statins in post-cardiac transplant patients, specifically examining the effects on hemodynamically significant/fatal graft rejection, coronary vasculopathy, terminal cancer, and overall survival.  These investigators searched PubMed, Cochran Central, and Web of Science databases using the search terms "cardiac transplant" or "heart transplant", and "statin" for a literature search.  A random-effects model with Mantel-Haenszel method was used to pool the data. They identified 10 studies, 4 RCTs, and 6 non-randomized studies, which compared outcomes in heart transplant recipients undergoing statin therapy to statin-naive patients.  A pooled analysis of 9 studies reporting mortality revealed that the use of statins was associated with significant reduction in all-cause mortality (OR, 0.26; 95 % CI: 0.20 to 0.35; p < 0.0001).  Statins also decreased the odds of hemodynamically significant/fatal rejection (OR, 0.37; 95 % CI: 0.21 to 0.65; p = 0.0005), incidence of coronary vasculopathy (OR, 0.33; 95 % CI: 0.16 to 0.68; p = 0.003), and terminal cancer (OR, 0.30; 95 % CI: 0.15 to 0.63; p = 0.002).  The authors concluded that the evidence from a pooled analysis suggested that statins improve survival in heart transplant recipients.  They stated that statins may prevent fatal rejection episodes, decrease terminal cancer risk, and reduce the incidence of coronary vasculopathy; however, additional prospective studies are needed to further examine and explain this association.

Immune Repertoire Sequencing Assay

In a proof-of-concept diagnostic accuracy study, Vollmers et al (2015) hypothesized that measuring the B-cell repertoire would enable assessment of the overall level of immunosuppression after heart transplantation. These researchers implemented a molecular-barcode-based immune repertoire sequencing assay that sensitively and accurately measures the isotype and clonal composition of the circulating B cell repertoire.  They used this assay to measure the temporal response of the B cell repertoire to immunosuppression after heart transplantation.  The authors selected a subset of 12 participants from a larger prospective cohort study (ClinicalTrials.gov NCT01985412) that is ongoing at Stanford Medical Center and for which enrollment started in March 2010.  This subset of 12 participants was selected to represent post-heart-transplant events, with and without acute rejection (6 participants with moderate-to-severe rejection and 6 without).  These researchers analyzed 130 samples from these patients, with an average follow-up period of 15 months.  Immune repertoire sequencing enabled the measurement of a patient's net state of immunosuppression (correlation with tacrolimus level, r = -0.867, 95 % CI: -0.968 to -0.523, p = 0.0014), as well as the diagnosis of acute allograft rejection, which is preceded by increased immune activity with a sensitivity of 71.4 % (95 % CI: 30.3 % to 94.9 %) and a specificity of 82.0 % (95 % CI: 72.1 % to 89.1 %) (cell-free donor-derived DNA as non-invasive gold standard).  To illustrate the potential of immune repertoire sequencing to monitor atypical post-transplant trajectories, these investigators analyzed 2 more patients, 1 with chronic infections and 1 with amyloidosis.  They stated that a larger, prospective study will be needed to validate the power of immune repertoire sequencing to predict rejection events, as this proof-of-concept study is limited to a small number of patients who were selected based on several criteria including the availability of a large number of samples and the absence or presence of rejection events.  The authors concluded that if confirmed in larger, prospective studies, immune repertoire sequencing assay for measurement of the isotype and clonal composition of the circulating B cell repertoire has potential applications in the tailored management of post-transplant immunosuppression and, more broadly, as a method for assessing the overall activity of the immune system.

myTAIHEART Testing

myTAIHEART (TAI Diagnostics, Inc., Milwaukee, WI.) is a non-invasive laboratory test which measures the donor fraction of cell-free DNA (cfDNA) in blood plasma as a marker for transplanted organ injury. The myTAIHEART test is intended to aid in the identification of heart transplant recipients who have a low probability of moderate/severe acute cellular rejection (Grade 2R or higher) at the time of testing in conjunction with standard clinical assessment. This test is indicated for use in heart transplant recipients who are 2 months of age or older and at least 1 week post-transplant (≥7 days) (TAI, 2018).

The myTAIHEART test quantitates the donor fraction of cfDNA via cfDNA quantitative genotyping by quantitative PCR by multiplexed allele specific PCR of greater than 50 single nucleotide polymorphism targets. An algorithm is used to report risk of allograft rejection (AMA, 2018). This measurement distinguishes "donor specific" cfDNA originating from the engrafted heart versus "self specific" cfDNA originating from the recipient’s native cells. The myTAIHEART test reports the ratio of donor specific cfDNA to total cfDNA as the donor fraction (%) and categorizes the patient as at low or increased risk of moderate/severe acute cellular rejection: low donor fractions indicate less damage to the transplanted heart and a lower risk for rejection, while increased donor fractions indicate more damage to the transplanted heart and an increased risk for rejection. Per TAI Diagnostics, patients treated for rejection within 28 days of sample collection may have variably elevated donor fractions. Clinical judgment will be required for interpretation of results. A heart transplant recipient with a negative result should continue to be monitored according to standard clinical care. All results should be interpreted in the context of the patient’s clinical findings, history, and laboratory results (TAI, 2018).

The myTAIHEART is currently for use in single organ post-transplant patients. It is not intended for those who are pregnant, have another transplanted organ, have post-transplant lymphoproliferative disease, currently have cancer, or have had cancer within the previous 2 years, or for those who are on mechanical circulatory support (TAI, 2018).

This lab test is certified under the Clinical Laboratory Improvement Amendments of 1988 (CLIA).The myTAIHEART has not been cleared or approved by the US FDA, as the FDA "has determined that such clearance or approval is not necessary" (TAI, 2018).

Hidestrand et al (2014) stated that targeted quantitative genotyping of circulating donor specific cell free DNA (DScf-DNA) constitutes a sensitive, rapid, and cost-effective non-invasive tool potentially suitable for rejection surveillance as an alternative to endomyocardial biopsy (EMB). The authors note that the current gold standard for monitoring rejection is catheter based EMB which can be associated with risk and expense, and that DScf-DNA has been proposed as a marker for cellular injury caused by rejection. Hidestrand and colleagues evaluated this genotyping method for DScf-DNA percentage in pediatric cardiac transplant recipients in a prospective blinded pilot study. Fifty-three samples from 32 patients were analyzed and divided between 3 scenarios. Scenario 1 included cf-DNA levels from 26 patients undergoing 38 scheduled surveillance EMBs. Thirty-two (84%) samples contained <1% DScf-DNA. No patient with DScf-DNA <1% had pathological rejection. DScf-DNA levels exceeded 1% in 6 samples with the highest percentage DScf-DNA associated with asymptomatic biopsy proven rejection. The remaining 5 samples had negative biopsies. Scenario 2 included 7 samples from 6 patients prior to unscheduled diagnostic EMB to rule out rejection based on clinical criteria. Six had DScf-DNA levels >1% and one sample contained DScf-DNA <1%. Four of the six were associated with biopsy proven rejection; the other two patients had significant coronary artery vasculopathy on angiography. The single symptomatic patient with low percentage DScf-DNA had high levels of Tcf-DNA, implying that the dominant pathology was global rather than confined to the donor organ. This patient was diagnosed with culture positive sepsis, the accompanying EMB was negative for rejection and coronary angiography was normal. Scenario 3 included 4 patients with biopsy proven rejection. All pre-treatment samples collected at diagnosis contained DScf-DNA>1% (sensitivity 100%). Following IV immunosuppressive therapy, all patients demonstrated significantly decreased %DScf-DNA. The authors note that 3 to 4 days after discontinuing augmented immunosuppression, the percent DScf-DNA rebounded in 3 of the 4 patients. DScf-DNA was compared to other candidate non-invasive laboratory variables (BNP, Troponin, CRP) as well as echocardiographically determined LVEF in predicting rejection on biopsy; DS-cfDNA had the highest sensitivity and specificity (100%/84%). The authors concluded that DScf-DNA may be sufficiently sensitive to detect rejection and injury to the donor organ earlier than currently available methods; however, the results of their study are based on limited sample size. A larger validation study is needed.

Agbor-Enoh et al. (2017) state that previous studies have shown that quantitation of donor-derived cell-free DNA (%ddcfDNA) by unbiased shotgun sequencing is a sensitive, non-invasive marker of acute rejection after heart transplantation. The authors evaluated the reproducibility of %ddcfDNA measurements across technical replicates, manual vs automated platforms, and rejection phenotypes in distinct patient cohorts. The author observed concordance of technical-replicate %ddcfDNA measurements across 2 independent laboratories, as well as across manual and automated platform (p < 0.001). The %ddcfDNA measurements in distinct heart transplant cohorts had similar baselines and error rates. The %ddcfDNA temporal patterns associated with rejection phenotypes were similar in both patient cohorts; however, the quantity of ddcfDNA was significantly higher in samples with severe vs mild histologic rejection grade (p < 0.001). The authors concluded that %ddcfDNA assay is precise and reproducible across laboratories and in samples from 2 distinct types of heart transplant rejection. Agbor-Enoh and colleagues stated that their findings pave the way for larger studies to assess the clinical utility of quantitation of donor-derived cell-free DNA as a marker of acute rejection after heart transplant.

Ragalie et al. (2018) state that the novel assay to calculate donor fraction of cell-free DNA in heart transplant has excellent sensitivity for acute cellular rejection and utility in ruling out cardiac allograft vasculopathy (CAV). The authors presented their blinded pilot study which included 158 blood samples collected from heart transplant recipients at a single center prior to endomyocardial biopsy (EMB) and coronary angiography. Donor fraction (DF) of cf-DNA was quantified using a targeted approach and compared to biopsy and angiography results using two distinct methods, with donor genotype (Method 1), and without donor genotype (Method 2) (TAI Diagnostics). By Method 1, median DF was 0.11% (IQR 0.06-0.21%) in CR0 associated samples, 0.37% (IQR 0.15-0.72%) in CR1 associated samples, and 0.97% (IQR 0.88-1.06%) in CR2 associated samples (p=0.027). Empirical optimal cutpoint of DF for ruling out CR2 rejection was 0.87% (p=0.009) and area under the curve (AUC) was 0.97. Sensitivity was 100% and specificity was 93%. By Method 2, median DF was 0.25% (IQR 0.17-0.39%) in CR0 associated samples, 0.89% (IQR 0.44-5.35%) in CR1 associated samples, and 1.22% (IQR 1.04-5.18%) in CR2 associated samples (p<0.001). Empirical optimal cutpoint for ruling out CR2 rejection was 0.89% (95% CI 0.46-1.70%). AUC was 0.95. Sensitivity was 100% and specificity was 89%. 116 samples were associated with coronary angiography. By Method 1, median DF was 0.09% (IQR 0.06-0.20%) for samples not associated with CAV and 0.47% for CAV associated samples (p=0.05). By Method 2, median DF was 0.27% for samples not associated with CAV and 0.55% for CAV associated samples (p=0.057). The authors found a stepwise DF increase among CR0, CR1, and CR2 associated biopsies, suggesting progressive allograft injury with increasing rejection grades. Paired sample analysis demonstrates the ability to use this assay in the absence of donor genotyping.

A review in UpToDate on "Acute cardiac allograft rejection: Diagnosis" (Eisen, 2017) states that in cardiac transplant recipients, a rise in peripheral blood donor-derived cell-free DNA was shown to occur after graft injury from acute cellular rejection. The authors cite a prospective study in which donor-derived cell-free DNA rose in peripheral blood in 44 adult and 21 pediatric heart transplant recipients at the time of International Society for Heart and Lung Transplantation (ISHLT) Grade 2R acute cellular rejection or ISHLT Grade 2 antibody-mediated rejection. A group using a somewhat different approach to donor-derived cell-free DNA quantification in the peripheral blood noninvasively detected allograft damage from acute cellular rejection and from cardiac allograft vasculopathy in 26 heart transplant recipients. The authors concluded that "further research is needed to determine the utility of quantification of donor-derived cell-free DNA in the peripheral blood as a noninvasive diagnostic technique for detecting acute cellular rejection and other forms of cardiac allograft injury".

Measurement of Cardiac Troponin for Diagnosis of Acute Cellular Rejection Following Heart Transplantation

In an UpToDate chapter on diagnosis of acute cardiac allograft rejection, Eisen (2019) stated that the clinical efficacy of cardiac troponins as a marker for detection of acute rejection has not been established.

Fitzsimons and colleagues (2018) noted that acute cellular rejection (ACR) is a common complication in the 1st year following heart transplantation (HT).  Routine surveillance for ACR is undertaken by EMB.  Measurement of cardiac troponins (cTn) in serum is an established diagnostic test of cardiac myocyte injury.  In a systematic review, these investigators examined if cTn measurement could be used to diagnose or exclude ACR.  PubMed, Google Scholar and the JHLT archive were searched for studies reporting the result of a cTn assay and a paired surveillance EMB.  Significant ACR was defined as International Society for Heart and Lung Transplantation (ISHLT) Grade greater than or equal to 3a / greater than or equal to 2R.  Considerable heterogeneity between studies precluded quantitative meta-analysis.  Individual study sensitivity and specificity data were examined and used to construct a pooled hierarchical summary receiver-operator characteristic (ROC) curve.  A total of 12 studies including 993 patients and 3,803 EMBs, of which 3,729 were paired with cTn levels, had adequate data available for inclusion.  The overall rate of significant ACR was 12 %.  There was wide variation in diagnostic performance; cTn assays demonstrated sensitivity of 8 % to 100 % and specificity of 13 % to 88%  for detection of ACR.  The positive predictive value (PPV) was low but the negative predictive value (NPV) was relatively high (79 % to 100 %).  High-sensitivity cTn assays had greater sensitivity and NPV than conventional cTn assays for detection of ACR (sensitivity: 82 %  to 100 % versus 8 % to 77 %; NPV: 97 % to 100 % versus 81 % to 95 %, respectively).  The authors concluded that cTn assays did not have sufficient specificity to diagnose ACR in place of EMB.  However, hs-cTn assays may have sufficient sensitivity and NPV to exclude ACR and limit the need for surveillance EMB.  These investigators stated that further research is needed to evaluate this strategy.

The International Society of Heart and Lung Transplantation guidelines for the care of heart transplant recipients (Costanzo, et al., (2010) state that "The use of brain natriuretic peptide (BNP), troponin I or T, or C-reactive protein (CRP) levels for acute heart allograft rejection monitoring is not recommended."

Measurement of Donor-Specific Cell-Free DNA for Monitoring Transplant Recipients of Rejection

Knight and colleagues (2019) noted that there is increasing interest in the use of non-invasive biomarkers to reduce the risks posed by invasive biopsy for monitoring of solid organ transplants (SOTs).  One such promising marker is the presence of donor-derived cell-free DNA (dd-cfDNA) in the urine or blood of transplant recipients.  These investigators systematically reviewed the published literature investigating the use of cfDNA in monitoring of graft health following SOT.  Electronic databases were searched for studies relating cfDNA fraction or levels to clinical outcomes, and data including measures of diagnostic test accuracy were extracted.  Narrative analysis was performed.  A total of 95 articles from 47 studies met the inclusion criteria (18 kidneys, 7 livers, 11 hearts, 1 kidney-pancreas, 5 lungs, and 5 multi-organs).  The majority were retrospective and prospective cohort studies, with 19 reporting diagnostic test accuracy data.  Multiple techniques for measuring dd-cfDNA were reported, including many not requiring a donor sample; dd-cfDNA fell rapidly within 2 weeks, with baseline levels varying by organ type.  Levels were elevated in the presence of allograft injury, including acute rejection and infection, and return to baseline following successful treatment.  Elevation of cfDNA levels was observed in advance of clinically apparent organ injury.  Discriminatory power was greatest for higher grades of T cell-mediated and acute antibody-mediated rejection (AMR), with high negative predictive values (NPVs).  The authors concluded that cell-free DNA is a promising biomarker for monitoring the health of SOTs.  These researchers stated that future studies will need to define how it can be used in routine clinical practice and determine clinical benefit with routine prospective monitoring.

Khush and associates (2019) noted that standardized dd-cfDNA testing has been introduced into clinical use to monitor kidney transplant recipients for rejection.  This report described the performance of this dd-cfDNA assay to detect allograft rejection in samples from HT recipients undergoing surveillance monitoring across the United States.  Venous blood was longitudinally sampled from 740 HT recipients from 26 centers and in a single-center cohort of 33 patients at high risk for AMR.  Plasma dd-cfDNA was quantified by using targeted amplification and sequencing of a single nucleotide polymorphism (SNP) panel.  The dd-cfDNA levels were correlated to paired events of biopsy-based diagnosis of rejection.  The median dd-cfDNA was 0.07 % in reference HT recipients (2,164 samples) and 0.17 % in samples classified as acute rejection (35 samples; p = 0.005).  At a 0.2 % threshold, dd-cfDNA had a 44 % sensitivity to detect rejection and a 97 % NPV.  In the cohort at risk for AMR (11 samples), dd-cfDNA levels were elevated 3-fold in AMR compared with patients without AMR (99 samples, p = 0.004).  The authors concluded that standardized dd-cfDNA test identified acute rejection in samples from a broad population of HT recipients.  The reported test performance characteristics will guide the next stage of clinical utility studies of the dd-cfDNA assay.

Computed Tomography Angiography for Evaluation of the Coronary Arteries Following Heart Transplantation

Khan and Jang (2012) stated that cardiac/coronary allograft vasculopathy (CAV) is a significant cause of morbidity and mortality after cardiac transplantation and requires frequent surveillance with conventional catheter-based coronary angiography (CCAG).  Multi-detector row computed tomography (MDCT) has been shown to be effective in assessing atherosclerosis in native coronary arteries.  These investigators reviewed the literature to determine the accuracy of MDCT in CAV assessment.  They carried out an English-language literature search using Embase, OVID, PubMed, and Cochrane Library databases; studies that directly compared MDCT with CCAG and/or intravascular ultrasound (IVUS) for the detection of coronary artery stenosis or significant intimal thickening in cardiac transplant patients were analyzed.  Data were pooled to obtain weighted sensitivities, specificities, and diagnostic accuracies.  Negative and positive predictive values (NPV/PPV) were calculated.  A total of 7studies with a sum of 272 patients were included in this review.  There were 3 studies examining 16-slice MDCT and 4 studies looking at 64-slice MDCT in CAV.  Using per-segment analysis, MDCT assessed between 91 % and 96 % of all coronary segments when evaluating for stenosis.  Pooled estimates for sensitivity and specificity for MDCT ranged from 82 % to 89 % and 89 % to 99 %, respectively, while NPV was 99 %.  Per-patient analysis revealed a sensitivity of 87 to 100 % and NPV of 96 to 100 %; PPV was less than 50 % for 64-slice MDCT in both per-segment and per-patient analysis.  When compared with IVUS, MDCT had a sensitivity of 74 to 96 % and specificity of 88 to 92 % in assessment of intimal thickening; NPV and PPV were 80 to 81 % and 84 to 98 %, respectively.  The authors concluded that the high sensitivity and NPV of MDCT suggested that it may be a useful, non-invasive screening tool to rule out CAV.

Mittal et al (2013) examined the diagnostic accuracy of cardiac computed tomographic angiography (CTA) without the use of β-blockers compared with that of invasive angiography for the detection of CAV in HTX recipients.  Heart transplant recipients (n = 138) scheduled for routine invasive angiography were prospectively enrolled to undergo CT to evaluate coronary artery calcification and retrospectively gated cardiac CTA with a 64-section scanner.  The cardiac CTA images were systematically analyzed for image quality.  Degree of CAV was assessed by using a 15-coronary segments model.  The area under the receiver operating characteristic curve, sensitivity, specificity, NPV and PPV values of cardiac CTA for detection of CAV with any degree of stenosis and greater than or equal to 50 % stenosis were calculated.  Coronary artery calcification was absent in 82 patients, 5 (6 %) of whom had CAV with 50 % or more stenosis.  Interpretable image quality was obtained in 130 (96 %) of the 136 patients who completed the study and 1,900 (98 %) of 1,948 segments.  At the patient level, cardiac CTA had an area under the receiver operating characteristic curve, sensitivity, specificity, PPV and NPV of 0.880 (95 % confidence interval [CI]: 0.819 to 0.941), 98 %, 78 %, 77 %, and 98 %, respectively, for diagnosis of CAV with any degree of stenosis, but for CAV with 50 % or more stenosis, the corresponding values were 0.942 (95 % CI: 0.885 to 1.000), 96 %, 93 %, 72 %, and 99 %, respectively.  None of the 61 patients with normal cardiac CTA results had CAV on the basis of invasive angiographic images.  The authors concluded that the findings of this study showed that cardiac CTA compared favorably with invasive angiography in detecting CAV in HTX recipients and may be a preferable screening technique because of its non-invasive nature.  The absence of coronary artery calcification alone was not reliable enough for excluding CAV.

Wever-Pinzon et al (2014) noted that CAV limits long-term survival after heart transplantation (HTX), and screening for CAV is performed on annual basis.  Coronary computed tomography angiography (CCTA) is currently not recommended for CAV screening due to the limited accuracy reported by early studies.  Technological advances, however, might have resulted in improved test performance and might justify re-evaluation of this recommendation.  In a meta-analysis, these researchers evaluated the diagnostic accuracy of CCTA for detecting CAV in comparison with conventional coronary angiography (CCAG) alone or with IVUS.  They carried out a systematic review of Medline, Cochrane, and Embase for all prospective trials assessing CAV using CCTA using a standard approach for meta-analysis for diagnostic test and a bi-variate analysis.  A total of 13 studies evaluating 615 patients (mean age of 52 years, 83 % men) and 9,481 segments fulfilled inclusion criteria.  Patient-based analyses comparing CCTA versus CCAG for the detection of any CAV (greater than luminal irregularities) and significant CAV (stenosis greater than or equal to 50 %), showed mean weighted sensitivities of 97 % and 94 %, specificities of 81 % and 92 %, a NPV of 97 % and 99 %, a PPV of 78 % and 67 %, and diagnostic accuracies of 88 % and 94 %, respectively.  There was a strong trend toward improved sensitivity (97 % versus 91 %, p = 0.06) and NPV (99 % versus 97 %, p = 0.06) to detect significant CAV with 64-slice compared with 16-slice CCTA.  A patient-based analysis of 64-slice CCTA versus IVUS showed a mean weighted sensitivity and specificity of 81 % and 75 % to detect CAV (intimal thickening greater than 0.5 mm), whereas the PPV and NPV were 93 % and 50 %, respectively.  The authors concluded that CCTA using currently available technology is a reliable non-invasive imaging alternative to coronary angiography with an excellent sensitivity, specificity, and NPV for the detection of CAV.

Gunther et al (2018) stated that CAV is an accelerated form of atherosclerosis unique to HTX patients.  These investigators examined the detection of significant coronary artery stenosis and CAV, determinants of image quality, and the radiation dose in CCTA of HTX patients with 64-MDCT.  A total of 52 HTX recipients scheduled for invasive coronary angiography (ICA) were prospectively enrolled and underwent CCTA before ICA with IVUS.  Interpretable CCTA images were acquired in 570 (95 %) coronary artery segments greater than or equal to 2 mm in diameter.  Sensitivity, specificity, and PPV and NPV of CCTA for the detection of segments with significant stenosis (lumen reduction greater than or equal to 50 %) on ICA were 100 %, 98 %, 7.7 %, and 100 %, respectively; 12 significant stenoses were located in segments with un-interpretable image quality or vessel diameter less than 2 mm; only 1 was eligible for intervention; IVUS detected CAV (maximal intimal thickness greater than or equal to 0.5 mm) in 33/41 (81 %) patients; CCTA and ICA identified CAV (any wall or luminal irregularity) in 18 (44 %) and 14 (34 %) of these 33 patients, respectively.  The mean estimated radiation dose was 19.0 ± 3.4 mSv for CCTA and 5.7 ± 3.3 mSv for ICA (p < 0.001).  The authors concluded that CCTA with interpretable image quality had a high NPV for ruling out significant stenoses suitable for intervention.  The modest detection of CAV by CCTA implied a limited value in identifying subtle CAV.  The high estimated radiation dose for 64-MDCT was of concern considering the need for repetitive examinations in the HTX population.

An UpToDate review on "Clinical manifestations, diagnosis, and prognosis of cardiac allograft vasculopathy" (Gustafsson, 2019) states that "Early detection of CAV is challenging because symptoms of myocardial ischemia secondary to CAV are typically absent or atypical due to afferent and efferent allograft denervation.  Although there is evidence for reinnervation in some patients by 5 years after transplantation, the degree of reinnervation is generally incomplete.  As a result, patients with CAV seldom experience classic angina pectoris.  Premonitory symptoms associated with exertion such as chest pain, dyspnea, diaphoresis, gastrointestinal distress, presyncope, or syncope are often missing or atypical, so symptoms do not provide a reliable warning of disease.  This was illustrated by a study of 22 cardiac transplant recipients with 25 acute myocardial infarctions at a mean of 3.9 years after transplantation.  The most common symptoms were weakness (16), dyspnea (11), and palpitations (8); only 2 patients had chest pain, 3 patients had arm pain, and 3 patients had no symptoms … Use of multi-slice computed tomography coronary angiography to potentially replace invasive cardiac catheterization in evaluating CAV is an area of active investigation".

Furthermore, EviCore’s clinical guideline on "Cardiac Imaging Policy" (version 1.0.2019) states that "There is insufficient evidence to support routine use of coronary computed tomography angiography (CCTA) in the evaluation of the coronary arteries following heart transplantation".

Heart Molecular Microscope Diagnostic System (MMDx-Heart)

The Heart Molecular Microscope Diagnostic System (MMDx-Heart) refers to mRNA gene expression analysis of 1,283 genes utilizing microarray; it measures mRNA transcript levels in transplant heart biopsy tissue, with allograft rejection and injury algorithm reported as a probability score.

Halloran and colleagues (2017) noted that the emergence of molecular systems offers opportunities for improving the assessment of rejection in heart transplant biopsy specimens.  These researchers developed a microarray-based system for assessing heart transplant EMB specimens.  They analyzed 331 protocol or for-cause EMB specimens from 221 subjects in 3 centers (Edmonton, Bologna, and Paris).  Un-supervised principal component analysis (PCA) and archetype analysis used rejection-associated transcripts (RATs) shown in kidney transplants to be associated with antibody-mediated rejection (ABMR) or T cell-mediated rejection (TCMR), or both.  They compared EMB specimens to kidney biopsy specimens, rejection status in both was simplified to TCMR, ABMR, or no rejection.  The pattern of RAT expression was similar in EMB and kidney specimens, permitting use of RATs to assign scores and group ("cluster") membership to each EMB, independent of histology.  Three clusters emerged in EMB specimens, similar to kidney specimens: TCMR, ABMR, and no rejection.  This allowed each EMB specimen to be given 3 scores and assigned to 1 cluster by its highest score.  There was significant agreement between molecular phenotype-archetype scores or clusters-and both histologic diagnoses and donor-specific antibody; AUC estimates for predicting histologic TCMR, ABMR, and no rejection by molecular assessment were lower in EMB specimens than in kidney specimens, reflecting more uncertainty in EMB specimens, particularly in histologic diagnosis of TCMR.  The authors concluded that rejection-associated transcripts can be used to estimate the probability of TCMR and ABMR in heart transplant specimens, providing a new dimension to improve the accuracy of diagnoses and an independent system for recalibrating the histology guidelines.  These findings need to be validated by well-designed studies.

Furthermore, an UpToDate review on "Acute cardiac allograft rejection: Diagnosis" (Eisen, 2019) lists "Molecular microscopy" as one the of the investigational methods for non-invasive detection of rejection.

Table: CPT Codes / HCPCS Codes / ICD-10 Codes
Code Code Description

Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":

CPT codes covered if selection criteria are met:

33927 Implantation of a total replacement heart system (artificial heart) with recipient cardiectomy
33928 Removal and replacement of total replacement heart system (artificial heart)
33929 Removal of a total replacement heart system (artificial heart) for heart transplantation (List separately in addition to code for primary procedure)
33940 Donor cardiectomy, (including cold preservation)
33945 Heart transplant, with or without recipient cardiectomy
81595 Cardiology (heart transplant), mRNA, gene expression profiling by real-time quantitative PCR of 20 genes (11 content and 9 housekeeping), utilizing subfraction of peripheral blood, algorithm reported as a rejection risk score [Allomap]

CPT codes not covered for indications listed in the CPB:

0055U Cardiology (heart transplant), cell-free DNA, PCR assay of 96 DNA target sequences (94 single nucleotide polymorphism targets and two control targets), plasma
0085T Breath test for heart transplant rejection
0087U Cardiology (heart transplant), mRNA gene expression profiling by microarray of 1283 genes, transplant biopsy tissue, allograft rejection and injury algorithm reported as a probability score
71275 Computed tomographic angiography, chest (noncoronary), with contrast material(s), including noncontrast images, if performed, and image postprocessing
84484 Troponin, quantitative [cardiac troponins]

Other CPT codes related to the CPB:

33975 Insertion of ventricular assist device; extracorporeal, single ventricle
33976     extracorporeal, biventricular
33977 Removal of ventricular assist device; extracorporeal, single ventricle
33978     extracorporeal, biventricular
33979 Insertion of ventricular assist device, implantable intracorporeal, single ventricle
33990 Insertion of ventricular assist device, percutaneous including radiological supervision and interpretation; arterial access only
33991 both arterial and venous access, with transseptal puncture     
33992 Removal of percutaneous ventricular assist device at separate and distinct session from insertion
33993 Repositioning of percutaneous ventricular assist device with imaging guidance at separate and distinct session from insertion
93015 - 93018 Cardiovascular stress test using maximal or submaximal treadmill or bicycle exercise, continuous electrocardiographic monitoring, and/or pharmacological stress
93451- 93454 Cardiac catheterization
93798 Physician services for outpatient cardiac rehabilitation; with continuous ECG monitoring (per session)

HCPCS codes covered if selection criteria are met:

L8698 Miscellaneous component, supply or accessory for use with total artificial heart system

Other HCPCS codes related to the CPB:

G0422 Intensive cardiac rehabilitation; with or without continuous ECG monitoring with exercise, per session
S9472 Cardiac rehabilitation program, non-physician provider, per diem

ICD-10 codes covered if selection criteria are met (not all-inclusive):

I21.01 - I24.9 Acute myocardial infarction and other acute forms of ischemic heart disease
I25.10 - I25.799 Chronic ischemic heart disease
I25.810 - I25.9 Other and unspecified forms of chronic ischemic heart disease
I34.0 - I39 Nonrheumatic mitral valve, aortic valve, tricuspid valve and pulmonary valve disorders
I42.0, I42.2, I42.5,
I42.8, I42.9
Other cardiomyopathies
I42.1 Obstructive hypertrophic cardiomyopathy
I43 Cardiomyopathy in diseases classified elsewhere
I47.0 - I49.9 Cardiac dysrhythmias
I50.1 - I50.9 Heart failure
I51.4 Myocarditis, unspecified
O90.81 - O90.9 Other and unspecified complications of the puerperium, not elsewhere classified [postpartum cardiomyopathy]
Q20.0 - Q24.9 Bulbous cordis anomalies and anomalies of cardiac septal closure, endocardial cushion defects and other congenital anomalies of heart
T86.20 - T86.298 Complications of heart transplant
Z94.1 Heart transplant status

ICD-10 codes contraindicated for this CPB (not all-inclusive) :

A00.0 - B99.9 Infectious and parasitic diseases
E85.0 - E85.9 Amyloidosis
G70.0 - G73.7 Diseases of myoneural junction and muscle
I27.0 - I27.9 Other pulmonary heart diseases [severe]
I69.00 - I69.998 Sequelae of cerebrovascular disease [significant persistent deficit]
J44.9 Chronic obstructive pulmonary disease, unspecified [unless person is to undergo dual organ transplantation, e.g., heart-lung, heart-kidney, etc]
K27.0, K27.2, K27.4, K27.6 Peptic ulcer with hemorrhage
K57.00 - K57.93 Diverticular disease of intestine
K70.0 - K74.69, K76.89 Diseases of liver [unless person is to undergo dual organ transplantation, e.g., heart-lung, heart-kidney, etc]
M04.1 - M04.9 Autoinflammatory syndromes
N18.6 End stage renal disease [unless person is to undergo dual organ transplantation, e.g., heart-lung, heart-kidney, etc]

The above policy is based on the following references:

  1. Adams DH, Chen RH, Kadner A. Cardiac xenotransplantation: Clinical experience and future direction. Ann Thorac Surg. 2000;70(1):320-326.
  2. Addonizio LJ, Hsu DT, Douglas JF, et al. Decreasing incidence of coronary disease in pediatric cardiac transplant recipients using increased immunosuppression. Circulation. 1993;88(5 Pt 2):II224-II229.
  3. Agbor-Enoh S, Tunc I, De Vlaminck I, et al. Applying rigor and reproducibility standards to assay donor-derived cell-free DNA as a non-invasive method for detection of acute rejection and graft injury after heart transplantation. J Heart Lung Transplant. 2017;36(9):1004-1012.
  4. Allen MD, Fishbein DP, McBride M, et al. Who gets a heart? Rationing and rationalizing in heart transplantation. West J Med. 1997;166(5):326-336.
  5. Alpert JS. Left ventricular assist devices reduced the risk for death and increased 1-year survival in chronic end-stage heart failure. ACP J Club. 2002;136(3):88.
  6. American Medical Association (AMA). Proposed proprietary laboratory analyses panel meeting agenda: May 2018 meeting. Chicago, IL: AMA; updated April 19, 2018. 
  7. Arabia FA, Copeland JG, Pavie A, Smith RG. Implantation technique for the CardioWest total artificial heart. Ann Thorac Surg. 1999;68:698-704.
  8. Arabia FA. Update on the total artificial heart. J Card Surg. 2001;16(3):222-227.
  9. Arpesella G, Chiappini B, Marinelli G, et al. Combined heart and liver transplantation for familial amyloidotic polyneuropathy. J Thorac Cardiovasc Surg. 2003;125(5):1165-1166.
  10. Benson L, Freedom RM, Gersony W, et al. Session II: Cardiac replacement in infants and children: Indication and limitations. J Heart Lung Transplant. 1991;10(5 Pt 2):791-801.
  11. Cahoon WD, Ensor CR, Shullo MA. Alemtuzumab for cytolytic induction of immunosuppression in heart transplant recipients. Prog Transplant. 2012;22(4):344-349; quiz 350.
  12. California Technology Assessment Forum (CTAF). Gene expression profiling for the diagnosis of heart transplant rejection. A Technology Assessment. San Francisco, CA: CTAF; October 18, 2006.
  13. Carpentier A, Latrémouille C, Cholley B, et al. First clinical use of a bioprosthetic total artificial heart: Report of two cases. Lancet. 2015;386(10003):1556-1563.
  14. Centers for Medicare & Medicaid Services (CMS). Decision memo for Heartsbreath test for heart transplant rejection (CAG-00394N). Baltimore, MD: CMS; December 8, 2008. 
  15. Centers for Medicare & Medicaid Services (CMS). MLN Matters: Heartsbreath test for heart transplant rejection. MLN Matters Number: MM6366 Revised. Baltimore, MD: CMS; March 12, 2009.
  16. Centers for Medicare & Medicaid Services (CMS). NCA Tracking Sheet for Autologous Stem Cell Transplantation (AuSCT) for Amyloidosis (CAG-00050R). Baltimore, MD: CMS; July 26, 2004.
  17. Comenzo RL. Primary systemic amyloidosis. Curr Treat Options Oncol. 2000;1(1):83-89.
  18. Cooley DA. The total artificial heart. Nat Med. 2003;9(1):108-111.
  19. Copeland JG, Arabia FA, Banchy ME, et al. The CardioWest total artificial heart bridge to transplantation: 1993 to 1996 national trial. Ann Thorac Surg. 1998;66(5):1662-1669.
  20. Copeland JG, Pavie A, Duveau D, et al. Bridge to transplantation with the CardioWest total artificial heart: the international experience 1993 to 1995. J Heart Lung Transplant. 1996;15(1 Pt 1):94-99.
  21. Copeland JG, Smith RG, Arabia FA, et al. and the CardioWest Total Artificial Heart Investigators. Cardiac replacement with a total artificial heart as a bridge to transplantation. N Engl J Med. 2004;351(9):859-867.
  22. Copeland JG, Smith RG, Bose RK, et al. Risk factor analysis for bridge to transplantation with the CardioWest total artificial heart. Ann Thorac Surg. 2008;85(5):1639-1644.
  23. Corrado D, Basso C, Nava A, Thiene G. Arrhythmogenic right ventricular cardiomyopathy: Current diagnostic and management strategies. Cardiol Rev. 2001;9(5):259-265.
  24. Deng MC, Eisen HJ, Mehra MR, et al; CARGO Investigators. Noninvasive discrimination of rejection in cardiac allograft recipients using gene expression profiling. Am J Transplant. 2006;6(1):150-160.
  25. Deng MC, Smits JM, Packer M. Selecting patients for heart transplantation: Which patients are too well for transplant? Curr Opin Cardiol. 2002;17(2):137-144.
  26. DeRose JJ Jr, Oz MC. Surgical alternatives to transplantation and assist devices in the treatment of heart failure. Curr Cardiol Rep. 2000;2(6):564-571.
  27. Dubrey SW, Burke MM, Khaghani A, et al. Long term results of heart transplantation in patients with amyloid heart disease. Heart. 2001;85(2):202-207.
  28. ECRI Institute. Portable Freedom Driver for in-home support of the total artificial heart. In:  AHRQ Healthcare Horizon Scanning System Potential High-Impact Interventions: Priority Area 03: Cardiovascular. Prepared by ECRI Institute under Contract No. HHSA290201000006C. Rockville, MD: Agency for Healthcare Research and Quality; June 2013.
  29. Eisen HJ, Jessup M. Acute cardiac allograft rejection: Diagnosis. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed April, 2014.
  30. Eisen HJ. Acute cardiac allograft rejection: Diagnosis. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed August 2017, May 2019.
  31. Estep JD, Bhimaraj A, Cordero-Reyes AM, et al. Heart transplantation and end-stage cardiac amyloidosis: A review and approach to evaluation and management. Methodist Debakey Cardiovasc J. 2012;8(3):8-16.
  32. Evans RW, Williams GE, Baron HM, et al. The economic implications of noninvasive molecular testing for cardiac allograft rejection. Am J Transplant. 2005;5(6):1553-1558.
  33. eviCore Healthcare. Cardiac Imaging Policy. Clinical Guideline. Version 1.0.2019. Bluffton, SC: eviCore; effective February 15, 2019.
  34. Fitzsimons S, Evans J, Parameshwar J, Pettit SJ. Utility of troponin assays for exclusion of acute cellular rejection after heart transplantation: A systematic review. J Heart Lung Transplant. 2018;37(5):631-638.
  35. Francis GS, et al. Pathophysiology and diagnosis of heart failure. In: Hurst's The Heart. V Fuster, et al., eds. Ch. 20. 10th ed. New York, NY: McGraw Hill; 2001; 655-685.
  36. Frigerio M, Gronda EG, Mangiavacchi M, et al. Restrictive criteria for heart transplantation candidacy maximize survival of patients with advanced heart failure. J Heart Lung Transplant. 1997;16(2):160-168.
  37. Grazi GL, Cescon M, Salvi F, et al. Combined heart and liver transplantation for familial amyloidotic neuropathy: Considerations from the hepatic point of view. Liver Transpl. 2003;9(9):986-992.
  38. Greenway SC, Butts R, Naftel DC, et al. Statin therapy is not associated with improved outcomes after heart transplantation in children and adolescents. J Heart Lung Transplant. 2016;35(4):457-465.
  39. Gunther A, Aaberge L, Abildgaard A, et al. Coronary computed tomography in heart transplant patients: Detection of significant stenosis and cardiac allograft vasculopathy, image quality, and radiation dose. Acta Radiol. 2018;59(9):1066-1073. 
  40. Gustafsson F. Clinical manifestations, diagnosis, and prognosis of cardiac allograft vasculopathy. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed April 2019.
  41. Haddad H, Isaac D, Legare JF, et al. Canadian Cardiovascular Society Consensus Conference update on cardiac transplantation 2008: Executive Summary. Can J Cardiol. 2009;25(4):197-205.
  42. Halloran PF, Potena L, Van Huyen JD, et al. Building a tissue-based molecular diagnostic system in heart transplant rejection: The heart Molecular Microscope Diagnostic (MMDx) System. J Heart Lung Transplant. 2017;36(11):1192-1200. 
  43. Halloran PF, Reeve J, Kaplan B. Lies, damn lies, and statistics: The perils of the P value. Am J Transplant. 2006;6(1):10-11.
  44. Hidestrand M, Tomita-Mitchell A, Hidestrand PM, et al. Highly sensitive non-invasive cardiac transplant rejection monitoring using targeted quantification of donor specific cell free DNA. J Am Coll Cardiol. 2014;63(12):1224-1226.
  45. Hunt SA. Comment--the REMATCH trial: Long-term use of a left ventricular assist device for end-stage heart failure. J Card Fail. 2002;8(2):59-60.
  46. Jarcho JA. Fear of rejection--monitoring the heart-transplant recipient. N Engl J Med. 2010;362(20):1932-1933.
  47. Jayakar DV. Surgical treatment of chronic heart failure. What to tell patients about heart-saving options. Postgrad Med. 2001;109(3):61-70.
  48. Johnson MR, Naftel DC, Hobbs RE, et al. The incremental risk of female sex in heart transplantation: A multiinstitutional study of peripartum cardiomyopathy and pregnancy. Cardiac Transplant Research Database Group. J Heart Lung Transplant. 1997;16(8):801-812.
  49. Jouveshomme S, Baffert S, Fay A-F. Artificial heart (systematic review, expert panel). Paris, France: Comite d'Evaluation et de Diffusion des Innovations Technologiques (CEDIT), 1998:46.
  50. Khan R, Jang IK. Evaluation of coronary allograft vasculopathy using multi-detector row computed tomography: A systematic review. Eur J Cardiothorac Surg. 2012;41(2):415-422.
  51. Khush KK, Patel J, Pinney S, et al. Noninvasive detection of graft injury after heart transplant using donor-derived cell-free DNA: A prospective multicenter study. Am J Transplant. 2019;19(10):2889-2899.
  52. Knight SR, Thorne A, Lo Faro ML. Donor-specific cell-free DNA as a biomarker in solid organ transplantation. A systematic review. Transplantation. 2019;103(2):273-283.
  53. Lacroix D, Lions C, Klug D, Prat A. Arrhythmogenic right ventricular dysplasia: Catheter ablation, MRI, and heart transplantation. J Cardiovasc Electrophysiol. 2005;16(2):235-236.
  54. Li KHC, Ho JCS, Recaldin B, et al; International Health Informatics Study (IHIS) Network. Acute cellular rejection and infection rates in alemtuzumab vs traditional induction therapy agents for lung and heart transplantation: A systematic review and meta-analysis. Transplant Proc. 2018;50(10):3739-3747.
  55. Luc JGY, Choi JH, Rizvi SA, et al. Percutaneous coronary intervention versus coronary artery bypass grafting in heart transplant recipients with coronary allograft vasculopathy: A systematic review and meta-analysis of 1,520 patients. Ann Cardiothorac Surg. 2018;7(1):19-30.
  56. Magliato KE, Trento A. Heart transplantation -- surgical results. Heart Fail Rev. 2001;6(3):213-219.
  57. Mittal TK, Panicker MG, Mitchell AG, Banner NR. Cardiac allograft vasculopathy after heart transplantation: Electrocardiographically gated cardiac CT angiography for assessment. Radiology. 2013;268(2):374-381.
  58. Mohty M, Albat B, Fegueux N, Rossi JF. Autologous peripheral blood stem cell transplantation following heart transplantation for primary systemic amyloidosis. Leuk Lymphoma. 2001;41(1-2):221-223.
  59. Morrow WR. Cardiomyopathy and heart transplantation in children. Curr Opin Cardiol. 2000;15(4):216-223.
  60. Mudge GH, Goldstein S, Addonizio LJ, et al. 24th Bethesda Conference: Cardiac transplantation. Task Force 3: Recipient guidelines/prioritization. J Am Coll Cardiol. 1993;22(1):21-31.
  61. Muirhead J. Heart transplantation in children: Indications, complications, and management considerations. J Cardiovasc Nurs. 1992;6(3):44-55.
  62. Mundy L, Merlin T, Parrella A. Heartsbreath: Diagnostic test of grade III heart transplant rejection in heart transplant recipients. Horizon Scanning Prioritising Summary - Volume 5. Adelaide, SA: Adelaide Health Technology Assessment (AHTA) on behalf of National Horizon Scanning Unit (HealthPACT and MSAC); 2004
  63. Mundy L, Merlin T. Thoratec heartmate (R) left ventricular assist device for patients with heart failure who are ineligible for heart transplantation. Horizon Scanning Prioritising Summary - Volume 2. Adelaide, SA: Adelaide Health Technology Assessment (AHTA) on behalf of National Horizon Scanning Unit (HealthPACT and MSAC); 2003.
  64. National Institutes of Health, National Heart, Lung & Blood Institute. Expert Panel Review of the NHLBI Total Artificial Heart (TAH) Program. June 1998 - November 1999. Bethesda, MD: NHLBI, April 2000.
  65. Noorani HZ, McGahan L. Criteria for selection of adult recipients for heart, cadaveric kidney and liver transplantation. Technology Report. Issue 6. Ottawa, ON: Canadian Coordinating Office for Health Technology Assessment (CCOHTA); July 1999.
  66. Nose Y. Implantable total artificial heart developed by Abiomed gets FDA approval for clinical trials. Artif Organs. 2001;25(6):429.
  67. Nose Y. Totally implantable total artificial heart for clinical application. Artif Organs. 2002;26(3):214-215.
  68. Odim J, Laks H, Burch C, et al. Transplantation for congenital heart disease. Adv Card Surg. 2000;12:59-76.
  69. Olivari MT, Windle JR. Cardiac transplantation in patients with refractory ventricular arrhythmias. J Heart Lung Transplant. 2000;19(8 Suppl):S38-S42.
  70. Pennington DG, Noedel N, McBride LR, et al. Heart transplantation in children: An international survey. Ann Thorac Surg. 1991;52(3):710-715.
  71. Perrier-Melo RJ, Figueira FAMDS, Guimaraes GV, Costa MDC. High-intensity interval training in heart transplant recipients: A systematic review with meta-analysis. Arq Bras Cardiol. 2018;110(2):188-194.
  72. Pham MX, Teuteberg JJ, Kfoury AG, et al.; IMAGE Study Group. Gene-expression profiling for rejection surveillance after cardiac transplantation. N Engl J Med. 2010;362(20):1890-1900.
  73. Phillips M, Boehmer JP, Cataneo RN, et al. Heart allograft rejection: Detection with breath alkanes in low levels (the HARDBALL Study). J Heart Lung Transplant. 2004;23:701-708.
  74. Phillips M, Cataneo RN, Greenberg J, et al. Effect of age on the breath methylated alkane contour, a display of apparent new markers of oxidative stress. J Clin Lab Med. 2000;136:243-249.
  75. Razonable RR, Patel R, Wilhelm MP, et al. Fatal disseminated aspergillosis following sequential heart and stem cell transplantation for systemic amyloidosis. Am J Transplant. 2001;1(1):93-95.
  76. Regalie W, Stamm K, Hidestrand P. Novel assay to calculate donor fraction of cell-free DNA in heart transplant. J Am Coll Cardiol. 2018;71(11):supplement A764.
  77. Remme WJ, Swedberg K. Guidelines for the diagnosis and treatment of chronic heart failure. Eur Heart J. 2001;22(17):1527-1560.
  78. Renlund DG. Building a bridge to heart transplantation. N Engl J Med. 2004;351(9):849-851.
  79. Rickenbacher PR, Rizeq MN, Hunt SA, et al. Long-term outcome after heart transplantation for peripartum cardiomyopathy. Am Heart J. 1994;127(5):1318-1323.
  80. Rose EA, Gelijns AC, Moskowitz AJ, et al. Long-term mechanical left ventricular assistance for end-stage heart failure. N Engl J Med. 2001;345(20):1435-1443.
  81. Ruygrok PN, Gane EJ, McCall JL, et al. Combined heart and liver transplantation for familial amyloidosis. Intern Med J. 2001;31(1):66-67.
  82. Sarris GE, Smith JA, Bernstein D, et al. Pediatric cardiac transplantation. The Stanford experience. Circulation 1994;90(5 Pt 2):II51-II55.
  83. Schnoor M, Schäfer T, Lühmann D, Sievers HH. Bicaval versus standard technique in orthotopic heart transplantation: A systematic review and meta-analysis. J Thorac Cardiovasc Surg. 2007;134(5):1322-1331.
  84. Shaddy RE, Naftel DC, Kirklin JK, et al. Outcome of cardiac transplantation in children. Survival in a contemporary multi-institutional experience. Pediatric Heart Transplant Study. Circulation. 1996;94(9 Suppl):II69-II73.
  85. Sharma P, Perri RE, Sirven JE, et al. Outcome of liver transplantation for familial amyloidotic polyneuropathy. Liver Transpl. 2003;9(12):1273-1280.
  86. Slaughter MS, Braunlin E, Bolman RM 3rd, et al. Pediatric heart transplantation: Results of 2- and 5-year follow-up. J Heart Lung Transplant. 1994;13(4):624-630.
  87. Slepian MJ, Alemu Y, Girdhar G, et al.  The Syncardia() total artificial heart: In vivo, in vitro, and computational modeling studies. J Biomech. 2013;46(2):266-275.
  88. Som R, Morris PJ, Knight SR. Graft vessel disease following heart transplantation: A systematic review of the role of statin therapy. World J Surg. 2014;38(9):2324-2334.
  89. Starling RC, Pham M, Valantine H, et al; Working Group on Molecular Testing in Cardiac Transplantation. Molecular testing in the management of cardiac transplant recipients: Initial clinical experience. J Heart Lung Transplant. 2006;25(12):1389-1395.
  90. Steinman TI, Becker BN, Frost AE, et al. Guidelines for the referral and management of patients eligible for solid organ transplantation. Transplantation. 2001;71(9):1189-1204.
  91. Stevenson LW, Warner SL, Steimle AE, et al. The impending crisis awaiting cardiac transplantation. Modeling a solution based on selection. Circulation. 1994;89(1):450-457.
  92. Suhr OB, Svendsen IH, Andersson R, et al. Hereditary transthyretin amyloidosis from a Scandinavian perspective. J Intern Med. 2003;254(3):225-235.
  93. SynCardia Systems, Inc. CardioWest Total Artificial Heart (TAH). Directions for Use. Tucson, AZ; SynCardia; 2004.
  94. Tabarsi N, Guan M, Simmonds J, et al. Meta-analysis of the effectiveness of heart transplantation in patients with a failing Fontan. Am J Cardiol. 2017;119(8):1269-1274.
  95. TAI Diagnostics, Inc. myTAIHEART: Overview [website]. Milwaukee, WI: TAI; 2018. Available at: https://taidiagnostics.com/mytai-heart/. Accessed June 25, 2018.
  96. Theochari CA, Michalopoulos G, Oikonomou EK, et al. Heart transplantation versus left ventricular assist devices as destination therapy or bridge to transplantation for 1-year mortality: A systematic review and meta-analysis. Ann Cardiothorac Surg. 2018;7(1):3-11.
  97. Tice JA. Gene expression profiling for the diagnosis of heart transplant rejection. Technology Assessment. San Francisco, CA: CTAF; October 13, 2010.
  98. Towbin JA. Cardiomyopathy and heart transplantation in children. Curr Opin Cardiol. 2002;17(3):274-279.
  99. U.S. Food and Drug Administration (FDA), Center for Devices and Radiological Health (CDRH). Menssana Research, Inc. Heartsbreath Test for grade 3 heart transplant rejection. Humanitarian Device Exemption No. H030004. Rockville, MD: FDA; February 24, 2004.
  100. U.S. Food and Drug Administration (FDA), Center for Devices and Radiological Health (CDRH). Heartsbreath - H030004. New Humanitarian Device Approval. CDRH Consumer Information. Rockville, MD: FDA; March 10, 2004.
  101. Vallakati A, Reddy S, Dunlap ME, Taylor DO. Impact of statin use after heart transplantation: A meta-analysis. Circ Heart Fail. 2016;9(10).
  102. Vollmers C, De Vlaminck I, Valantine HA, et al. Monitoring pharmacologically induced immunosuppression by immune repertoire sequencing to detect acute allograft rejection in heart transplant patients: A proof-of-concept diagnostic accuracy study. PLoS Med. 2015;12(10):e1001890.
  103. Webber SA, McCurry K, Zeevi A. Heart and lung transplantation in children. Lancet. 2006;368(9529):53-69.
  104. Wever-Pinzon O, Romero J, Kelesidis I, et al. Coronary computed tomography angiography for the detection of cardiac allograft vasculopathy: A meta-analysis of prospective trials. J Am Coll Cardiol. 2014;63(19):1992-2004.
  105. Williams ES, Miller JM. Results from late-breaking clinical trial sessions at the American College of Cardiology 51st Annual Scientific Session. J Am Coll Cardiol. 2002;40(1):1-18.
  106. Woolley AE, Singh SK, Goldberg HJ, et al; DONATE HCV Trial Team. Heart and lung transplants from HCV-infected donors to uninfected recipients. N Engl J Med. 2019;380(17):1606-1617.
  107. Yoda M, Minami K, Fritzsche D, et al. Three cases of orthotopic heart transplantation for arrhythmogenic right ventricular cardiomyopathy. Ann Thorac Surg. 2005;80(6):2358-2360.
  108. Yongcharoen S, Rattanasiri S, McDaniel DO, et al. Meta-analysis of cytokine gene polymorphisms and outcome of heart transplantation. Biomed Res Int. 2013;2013:387184.
  109. Zijderhand CF, Veen KM, Caliskan K, et al. Biatrial vs bicaval orthotopic heart transplantation: A systematic review and meta-analysis. Ann Thorac Surg. 2020 Feb 5 [Online ahead of print].