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Heart Transplantation Rejection

Author: Dipesh Ludhwani Author: Joseph Abraham Editor: Arun Kanmanthareddy Updated: 9/19/2022 12:00:36 PM

Introduction

Heart transplantation (HTx) is a procedure limited to patients with end-stage heart failure who remain symptomatic despite being on optimal medical and device therapy. Guidelines identifying potential HTx candidates were updated in 2016 by the International Society for Heart and Lung Transplantation (ISHLT). Stringent selection criteria and immunosuppressive therapy post-transplantation have led to improved prognosis. Despite the progress and improved overall outcomes, heart transplantation rejection (HTR) remains the Achilles heel of transplantation. The manifestation of rejection can occur as early as intraoperatively to many years after transplant. The timing of HTR plays a significant role in establishing cause and diagnosis. Based on timings, HTR can either be due to early graft dysfunction within the first 24 hours or late graft dysfunction, developing weeks to years after transplantation.

Etiology

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Etiology

Etiology for HTR varies based on the onset of rejection. Early graft dysfunction can be primary or secondary. Primary graft dysfunction (PGD): The universally accepted standard definition for PGD is lacking. Ventricular dysfunction causing cardiogenic shock and requiring circulatory support such as inotropes/mechanical support devices in the absence of recipient alloimmune response or other discernible causes is endorsed as PGD. Various factors implicated in the development of PGD are:

  1. Pre-existing donor heart disease
  2. Re-perfusion injury immediately post-transplant
  3. Allograft injury occurs during organ retrieval, conservation, and implantation.[1]

Secondary graft dysfunction: secondary graft dysfunction results from identifiable causes such as:

  1. Hyperacute graft rejection
  2. Increased pressure or volume load on the right ventricle
  3. Undiagnosed recipient pulmonary hypertension 

Acute allograft rejection can be cellular or antibody (humoral) mediated. Risk factors include younger patients, female donors or recipients, and increased HLA mismatches.[2] Cardiac allograft vasculopathy (CAV). Risk factors include elevated cholesterol levels, cytomegalovirus infection, insulin resistance, coronary heart disease in the donor and younger recipient, and a history of acute rejection. Other causes of allograft failure include recurrence of myocardial conditions such as amyloidosis, sarcoidosis, giant cell myocarditis, hereditary hemochromatosis, and malignancy such as primary cardiac lymphoma.

Epidemiology

According to ISHLT, 5,074 heart transplants were performed in 2015. Median survival for cardiac transplants performed between 1982 and June 2015 was 10.7 years for adult recipients and 16.1 years for pediatric recipients. Survival rates in adults post-transplant were 94.8%, 84.1%, and 72.3% after 1, 5, and 10 years, respectively. The rates of HTR have steadily declined with the use of immunosuppressive therapy. HTR rates after discharge to 1 year of follow-up have declined from 30.5% in 2004-2006 to 24.10% in 2010-2015.[3]

The incidence of PGD varies from 20-40%. A 6-year follow-up study published in 2018 reported a PGD incidence of 31% in post-transplant patients.[4] A similar study published in 2011 disclosed a PGD incidence rate of 23%.[5] Deaths due to acute allograft rejection reach up to 11% in the first 3 years after transplant. Nearly half of heart transplant recipients developing rejection after 7 years of transplantation have evidence of antibody-mediated rejection. The overall prevalence of CAV increases with time. CAV is the leading cause of death between 1 and 3 years after transplantation.[6] CAV accounts for 17% of death after 3 years.[7]

Pathophysiology

Primary Graft Dysfunction

The “ischemic time,” defined from cross-clamping the donor heart to implantation in the recipient patient, subjects the donor heart to various forms of insult. The effect of ischemic time on PGD depends on donor age [8]. The donor body experiences catecholamine stress during the time of brain death. This catecholamine surge increases oxygen demand, subsequently causing myocardial ischemia and desensitization of the myocardial beta-receptor transduction system, activating multiple proinflammatory mediators. Hypothermic storage before implantation slows down the metabolic activity of allograft. Prolonged storage can lead to loss of normal aerobic metabolism resulting in an anaerobic switch and causing lactic acidosis. Further, allograft reperfusion enhances calcium overload at the time of implantation, contributing to myocardial stunning. Secondary graft dysfunction resulting from hyperacute rejection is either due to ABO incompatibility or from pre-formed cytotoxic antibodies that direct their activities against significant histocompatibility (MHC) antigens on the allograft. 

Acute Allograft Rejection (Cellular versus humoral mechanism)

Acute Cellular Rejection (ACR): Major and minor histocompatibility antigens are not expressed equally among all individuals; this increases the potential of such proteins to act as alloantigens and activate alloimmunity by stimulating cytotoxic T cells. T cells respond to these donor antigens either directly or indirectly based on the method of antigen presentation. T cells can directly recognize donor MHC molecules on allograft or target when presented indirectly by recipient antigen-presenting cells (APC).[9] Interleukin-2 (IL-2), tumor necrosis factor-beta (TNF-beta), and interferon-gamma (IFN-gamma) all act as significant mediators during rejection.

Acute Humoral/Antibody Rejection (AMR)

Antibody-mediated humoral rejection is poorly understood. The antibody reacts to donor MHC antigens (HLA-I and II), leading to capillary endothelial changes. The deposition of immunoglobulin and complements within the myocardial capillary bed are detectable by immunofluorescence.[10]

CAV

Endothelial damage in CAV can be immune or non-immune-mediated. Endothelial damage leads to mild intimal thickening before progressing to diffuse fibrous thickening of the intima.[11] More recent research has established the role of effector B-cells with CAV.[12]

Histopathology

ACR is a mononuclear inflammatory response infiltrating myocardial tissue with predominant lymphocytic cells. Immunohistologic assessment can confirm the presence of CD-4 and CD-8 positive T lymphocytes with high affinity to interleukin-2 receptors. Increased intercellular adhesion molecules with high MHC-II expression on cardiac myocytes are present. These findings should be distinguished from the Quilty effect, which carries no clinical significance. Quilty lesions extend to the endocardial surface and include significant B-lymphocytes, distinguishing them from acute cellular rejection. AMR leads to intravascular macrophage accumulation with interstitial edema, hemorrhage, and neutrophilic infiltration in and around capillaries. The predominant feature of CAV is a diffuse, progressive thickening of the arterial intima that develops in the transplanted heart's epicardial and intramyocardial arteries.

Histological Grading

ISHLT ACR grading:

  • Grade 0 – No rejection
  • Grade 1 R, mild – Interstitial and/or perivascular infiltrate with up to one focus of myocyte damage. (grade 1A, 1B, and 2 in the 1990 system)
  • Grade 2 R, moderate – Two or more foci of infiltrates with associated myocyte damage. (grade 3A in 1990 system).
  • Grade 3 R, severe—Diffuse infiltrate with multifocal myocyte damage, with or without edema, hemorrhage, or vasculitis (grade 3B and 4 in the 1990 system).

Immunopathologic findings for acute AMR include positive immunofluorescent staining for C4d, C3d, and Anti HLA-DR or immunoperoxidase staining for C4d and CD68 (or C3d).

AMR grading:

  • Grade 0- Negative histologic and immunopathologic findings
  • Grade 1- Presence of positive histologic and immunopathologic findings
  • Grade 2- Presence of both histologic and immunopathologic findings
  • Grade 3- Presence of severe histologic plus immunopathologic findings

History and Physical

All patients with a history of HTx should have a thorough history and physical exam performed. Medication history and immunosuppressant therapy compliance are requisites for the patient intake process. The development of new ventricular dysfunction, systolic, diastolic, or mixed, should raise suspicion for transplant rejection. The timing of rejection can act as a clue to the diagnosis. Patients commonly present with orthopnea, shortness of breath,  paroxysmal nocturnal dyspnea, syncope, palpitations, nausea/loss of appetite, weight gain, edema, arrhythmias (atrial flutter), oliguria, and hypotension. The physical exam can reveal signs of heart failure, such as elevated jugular venous pressure, extra sounds on auscultation, and peripheral edema.

Evaluation

The presence of the above symptoms and signs should raise alarms for HTR. HTR commonly gets diagnosed during surveillance endomyocardial biopsies. Typically, biopsies are performed every week for the first 4 weeks, followed by every two weeks for the next 6 weeks, followed by monthly biopsies for 3 to 4 months, and then every 3 months until the end of the first year. Routine myocardial biopsies after the first year have not shown superior benefits.[13] Chi NH et al recommended event principle biopsies at the end of 3 years due to the low rejection rate.[14] Diagnosis should be made based on the presence of the above-mentioned histologic findings. Biopsy-negative rejection is present in up to 20% of cases warranting the use of noninvasive monitoring; this includes measurement of troponin, Doppler echocardiography, cardiac magnetic resonance imaging (MRI), imaging using radiolabeled lymphocytes, antimyocin antibodies or annexin-V.[15][16][17]. T2 weighted cardiac MRI has shown promise in detecting early myocardial edema.[18] Gene expression profiling has emerged as an alternative to endomyocardial biopsy. E-IMAGE study showed non-inferior and safe results with gene expression profiling compared to endomyocardial biopsy.[19] AMR histologic findings usually accompany serum antibodies directed against HLA class I and II allograft antigens. The presence of histologic evidence of AMR, if present, is diagnostic. In the absence of HLA antibodies, non-HLA antibodies such as anti-endothelial, anti-vimentin, and anti-MCA/MICB also merit investigation.

During the first 5 years, in patients with normal kidney functions, surveillance for CAV is performed with annual coronary angiography. Annual dobutamine stress echocardiography for patients with significant kidney disease is necessary. After 5 years, annual dobutamine stress echocardiography with or without coronary angiography should be done based on the risk status of the recipient. Intravascular ultrasound should be performed when angiographic evidence is insufficient. Compared to coronary angiography, coronary CT angiography has offered a safer and equally accurate diagnostic approach for CAV.[20]

Treatment / Management

Treatment with immunosuppressant therapy post-transplant has significantly reduced rates of rejection. Immunosuppressive therapy usually consists of steroids, antiproliferative therapy such as cyclosporine, sirolimus/tacrolimus, and antimetabolites like azathioprine, mycophenolate mofetil, and rapamycin. The thirty-fourth heart transplant consensus from the ISHLT registry reported a lower rejection rate when treated with tacrolimus-based immunosuppression compared to recipients receiving cyclosporine. Treatment strategy depends on the type of rejection.

PGD is treated with high-dose inotropes to improve ventricular function. Patients failing medical therapy benefit from mechanical circulatory support such as an intra-aortic balloon pump, extracorporeal membrane oxygenator (ECMO), or temporary ventricular assist device. Hyperacute rejection is treatable with plasmapheresis, along with corticosteroids and intravenous immunoglobulin.

ACR

The treatment strategy usually involves oral or intravenous steroids, anti-thymocyte globulin, and murine monoclonal antibody OKT3. Steroids inhibit the production of interleukin-1, 2, and 6, TNF-alpha, and IFN-gamma. Anti-thymocyte globulin prepared from immunized rabbits or horses causes cell death by complement-mediated lysis. OKT3 is a murine monoclonal antibody that inhibits T-cell function by binding to CD-3 antigen. Selection amongst these options is dictated based on the hemodynamic status of the recipient and the histologic severity of rejection.

Hemodynamic compromise is defined by the presence of 1 or more of the following:

  • Reduction in cardiac output (<4.0L/min) or cardiac index (<2.0L/min per m2)
  • A decrease in pulmonary artery saturation (<50%)
  • Elevation in the pulmonary artery to capillary wedge pressure (PCWP)

Histology-based treatment for ACR:

  1. Recipients with Grade IR rejection (grade 1A,1B, and 2 in the 1990 system) do not require treatment unless hemodynamically compromised.[21] Low-dose steroids are helpful in such cases.[22] For patients with hemodynamic compromise, pulse-dose steroids orally or intravenously have shown a significant response.
  2. Grade 2R rejection (grade 3A in the 1990 system) is treated the same way as grade IR rejection with hemodynamic compromise. An oral pulse steroid (3-5mg/kg for 3-5 days) or 500-1000mg/day of IV methylprednisolone can be used.[21] Repeat biopsies are obtained weekly for 2 weeks to verify resolution. A repeat pulse dose steroid can be attempted in the event of persistent rejection.
  3. Grade 2R rejection with hemodynamic compromise, grade 3R rejection, and steroid-resistant rejection episodes are treated with either anti-thymocyte globulin or OKT3 antibodies. The usual dose of OKT3 is 5mg/day intravenously for 10 to 14 days. Cyclosporine and mycophenolate are continued at pretreatment doses if therapeutic levels have been achieved. Other options include switching immunosuppressive therapy from cyclosporine to tacrolimus. Recipients treated with OKT3 antibodies should have levels of CD3-positive cells checked before and 3 to 5 days after the initiation of therapy.

Antibiotic, antifungal, and antiviral prophylaxis are conventional adjunct therapies for patients treated with high-dose steroids or anti-lymphocyte therapy.

AMR

AMR is hemodynamically more severe compared to ACR and has an association with a worse prognosis. Improved outcomes with Plasmapheresis in combination with corticosteroids and anti-thymocyte globulin or OKT3 antibody have undergone study. Treatment with CD20 monoclonal antibody Rituximab has shown some promise.

Recurrent or resistant rejection despite 2 to 3 courses of OKT3 or anti-thymocyte globulin requires alternative approaches. These include photopheresis, total lymphoid irradiation, and immunosuppressive regimen changes.

Differential Diagnosis

The differential diagnoses for heart transplantation rejection include the following:

  1. Primary graft dysfunction
  2. Secondary graft dysfunction
  3. Acute allograft rejection
  4. Cardiac allograft vasculopathy
  5. Amyloidosis
  6. Sarcoidosis
  7. Giant cell myocarditis
  8. Hereditary hemochromatosis
  9. Lymphoproliferative disorders such as non-Hodgkin lymphoma

Prognosis

The one-year survival rate post-HTx is close to 90%. Median survival for patients receiving HTx has improved significantly. Patients requiring extracorporeal membrane oxygenation support before HTx have a worse prognosis. Acute allograft rejection is responsible for 10% of deaths within the first 3 years. The incidence of CAV increases steadily after transplantation. Malignancy is the most common cause of mortality beginning at 5 years post-HTx. About 2-4% of heart transplant recipients end up receiving repeat retransplantation. Overall outcomes after retransplantation are inferior compared to primary HTx.

Complications

The complications that can manifest with heart transplantation rejection are as follows: 

  1. Repeated endomyocardial biopsy can cause tricuspid valve regurgitation.[22]
  2. Graft failure
  3. Atrial arrhythmia
  4. Lymphoproliferative malignancy
  5. Cardiac allograft vasculopathy
  6. Acute graft rejection
  7. Increased risk of secondary infections. 
  8. Serum sickness due to anti-thymocyte globulin
  9. Acute myocardial infarction
  10. Repeat heart transplantation
  11. Death

Deterrence and Patient Education

It is important to stress the importance of regular follow-up and medication compliance after a recent heart transplant. Patients should receive education about the risks and benefits of immunosuppressive therapy, including the potential for rejection despite using immunosuppressive therapy. Teaching patients about early symptoms and signs of rejection can help prevent dangerous consequences. Knowledge about the increased risk of atrial arrhythmia and lymphoproliferative disorder due to immunosuppressive therapy should be provided to all heart transplant patients.

Enhancing Healthcare Team Outcomes

Heart transplantation and post-transplant care are demanding and critical. It requires an interprofessional approach involving the patient, a heart transplant cardiologist, a heart transplant surgeon, a social worker, nursing staff, pharmacists, physical therapists, dietary assistants, and financial educators. The ISHLT guidelines recommend an interprofessional approach at all HTx centers. The use of an interprofessional approach has demonstrated improved chronic illness management.[23] Implementation of daily interprofessional rounds has shown improvement in recovery time post-HTx.[24] Interprofessional physician and nursing staff involvement after a heart transplant is equally important. Increasing patient education and explaining the importance of surveillance biopsy and medical compliance can improve overall outcomes in HTx patients.

References

[1]

Iyer A, Kumarasinghe G, Hicks M, Watson A, Gao L, Doyle A, Keogh A, Kotlyar E, Hayward C, Dhital K, Granger E, Jansz P, Pye R, Spratt P, Macdonald PS. Primary graft failure after heart transplantation. Journal of transplantation. 2011:2011():175768. doi: 10.1155/2011/175768. Epub 2011 Aug 1     [PubMed PMID: 21837269]

[2]

DiSesa VJ, Kuo PC, Horvath KA, Mudge GH, Collins JJ Jr, Cohn LH. HLA histocompatibility affects cardiac transplant rejection and may provide one basis for organ allocation. The Annals of thoracic surgery. 1990 Feb:49(2):220-3; discussion 223-4     [PubMed PMID: 2306143]

Level 2 (mid-level) evidence

[3]

Lund LH, Khush KK, Cherikh WS, Goldfarb S, Kucheryavaya AY, Levvey BJ, Meiser B, Rossano JW, Chambers DC, Yusen RD, Stehlik J, International Society for Heart and Lung Transplantation. The Registry of the International Society for Heart and Lung Transplantation: Thirty-fourth Adult Heart Transplantation Report-2017; Focus Theme: Allograft ischemic time. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation. 2017 Oct:36(10):1037-1046. doi: 10.1016/j.healun.2017.07.019. Epub 2017 Jul 20     [PubMed PMID: 28779893]

[4]

Nicoara A, Ruffin D, Cooter M, Patel CB, Thompson A, Schroder JN, Daneshmand MA, Hernandez AF, Rogers JG, Podgoreanu MV, Swaminathan M, Kretzer A, Stafford-Smith M, Milano CA, Bartz RR. Primary graft dysfunction after heart transplantation: Incidence, trends, and associated risk factors. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2018 Jun:18(6):1461-1470. doi: 10.1111/ajt.14588. Epub 2017 Dec 14     [PubMed PMID: 29136325]

[5]

D'Alessandro C, Golmard JL, Barreda E, Laali M, Makris R, Luyt CE, Leprince P, Pavie A. Predictive risk factors for primary graft failure requiring temporary extra-corporeal membrane oxygenation support after cardiac transplantation in adults. European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery. 2011 Oct:40(4):962-9. doi: 10.1016/j.ejcts.2011.01.064. Epub 2011 Mar 16     [PubMed PMID: 21414795]

Level 2 (mid-level) evidence

[6]

Hertz MI, Taylor DO, Trulock EP, Boucek MM, Mohacsi PJ, Edwards LB, Keck BM. The registry of the international society for heart and lung transplantation: nineteenth official report-2002. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation. 2002 Sep:21(9):950-70     [PubMed PMID: 12231366]

[7]

Ramzy D, Rao V, Brahm J, Miriuka S, Delgado D, Ross HJ. Cardiac allograft vasculopathy: a review. Canadian journal of surgery. Journal canadien de chirurgie. 2005 Aug:48(4):319-27     [PubMed PMID: 16149368]

[8]

Russo MJ, Chen JM, Sorabella RA, Martens TP, Garrido M, Davies RR, George I, Cheema FH, Mosca RS, Mital S, Ascheim DD, Argenziano M, Stewart AS, Oz MC, Naka Y. The effect of ischemic time on survival after heart transplantation varies by donor age: an analysis of the United Network for Organ Sharing database. The Journal of thoracic and cardiovascular surgery. 2007 Feb:133(2):554-9     [PubMed PMID: 17258599]

Level 2 (mid-level) evidence

[9]

Ingulli E. Mechanism of cellular rejection in transplantation. Pediatric nephrology (Berlin, Germany). 2010 Jan:25(1):61-74. doi: 10.1007/s00467-008-1020-x. Epub     [PubMed PMID: 21476231]

Level 3 (low-level) evidence

[10]

Colvin MM, Cook JL, Chang P, Francis G, Hsu DT, Kiernan MS, Kobashigawa JA, Lindenfeld J, Masri SC, Miller D, O'Connell J, Rodriguez ER, Rosengard B, Self S, White-Williams C, Zeevi A, American Heart Association Heart Failure and Transplantation Committee of the Council on Clinical Cardiology, American Heart Association Heart Failure and Transplantation Committee of the Council on Cardiopulmonary Critical Care, Perioperative and Resuscitation, American Heart Association Heart Failure and Transplantation Committee of the Council on Cardiovascular Disease in the Young, American Heart Association Heart Failure and Transplantation Committee of the Council on Clinical Cardiology, Council on Cardiovascular and Stroke Nursing, American Heart Association Heart Failure and Transplantation Committee of the Council on Cardiovascular Radiology and Intervention, American Heart Association Heart Failure and Transplantation Committee of the Council on Cardiovascular Surgery and Anesthesia. Antibody-mediated rejection in cardiac transplantation: emerging knowledge in diagnosis and management: a scientific statement from the American Heart Association. Circulation. 2015 May 5:131(18):1608-39. doi: 10.1161/CIR.0000000000000093. Epub 2015 Apr 2     [PubMed PMID: 25838326]

[11]

Costello JP, Mohanakumar T, Nath DS. Mechanisms of chronic cardiac allograft rejection. Texas Heart Institute journal. 2013:40(4):395-9     [PubMed PMID: 24082367]

Level 3 (low-level) evidence

[12]

Zorn E. Effector B cells in cardiac allograft vasculopathy. Current opinion in organ transplantation. 2019 Feb:24(1):31-36. doi: 10.1097/MOT.0000000000000591. Epub     [PubMed PMID: 30480642]

Level 3 (low-level) evidence

[13]

White JA, Guiraudon C, Pflugfelder PW, Kostuk WJ. Routine surveillance myocardial biopsies are unnecessary beyond one year after heart transplantation. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation. 1995 Nov-Dec:14(6 Pt 1):1052-6     [PubMed PMID: 8719450]

[14]

Chi NH, Chou NK, Tsao CI, Huang SC, Wu IH, Yu HY, Chen YS, Wang SS. Endomyocardial biopsy in heart transplantation: schedule or event? Transplantation proceedings. 2012 May:44(4):894-6. doi: 10.1016/j.transproceed.2012.02.010. Epub     [PubMed PMID: 22564577]

[15]

Eisen HJ, Eisenberg SB, Saffitz JE, Bolman RM 3rd, Sobel BE, Bergmann SR. Noninvasive detection of rejection of transplanted hearts with indium-111-labeled lymphocytes. Circulation. 1987 Apr:75(4):868-76     [PubMed PMID: 3030580]

Level 3 (low-level) evidence

[16]

Narula J, Acio ER, Narula N, Samuels LE, Fyfe B, Wood D, Fitzpatrick JM, Raghunath PN, Tomaszewski JE, Kelly C, Steinmetz N, Green A, Tait JF, Leppo J, Blankenberg FG, Jain D, Strauss HW. Annexin-V imaging for noninvasive detection of cardiac allograft rejection. Nature medicine. 2001 Dec:7(12):1347-52     [PubMed PMID: 11726976]

[17]

Hesse B, Mortensen SA, Folke M, Brodersen AK, Aldershvile J, Pettersson G. Ability of antimyosin scintigraphy monitoring to exclude acute rejection during the first year after heart transplantation. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation. 1995 Jan-Feb:14(1 Pt 1):23-31     [PubMed PMID: 7727472]

[18]

Giri S, Chung YC, Merchant A, Mihai G, Rajagopalan S, Raman SV, Simonetti OP. T2 quantification for improved detection of myocardial edema. Journal of cardiovascular magnetic resonance : official journal of the Society for Cardiovascular Magnetic Resonance. 2009 Dec 30:11(1):56. doi: 10.1186/1532-429X-11-56. Epub 2009 Dec 30     [PubMed PMID: 20042111]

Level 3 (low-level) evidence

[19]

Kobashigawa J, Patel J, Azarbal B, Kittleson M, Chang D, Czer L, Daun T, Luu M, Trento A, Cheng R, Esmailian F. Randomized pilot trial of gene expression profiling versus heart biopsy in the first year after heart transplant: early invasive monitoring attenuation through gene expression trial. Circulation. Heart failure. 2015 May:8(3):557-64. doi: 10.1161/CIRCHEARTFAILURE.114.001658. Epub 2015 Feb 19     [PubMed PMID: 25697852]

Level 3 (low-level) evidence

[20]

Shah NR, Blankstein R, Villines T, Imran H, Morrison AR, Cheezum MK. Coronary CTA for Surveillance of Cardiac Allograft Vasculopathy. Current cardiovascular imaging reports. 2018:11(11):26. doi: 10.1007/s12410-018-9467-z. Epub 2018 Sep 24     [PubMed PMID: 30464783]

[21]

Park MH, Starling RC, Ratliff NB, McCarthy PM, Smedira NS, Pelegrin D, Young JB. Oral steroid pulse without taper for the treatment of asymptomatic moderate cardiac allograft rejection. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation. 1999 Dec:18(12):1224-7     [PubMed PMID: 10612382]

[22]

Badiwala MV, Rao V. Tricuspid valve replacement after cardiac transplantation. Current opinion in cardiology. 2007 Mar:22(2):123-7     [PubMed PMID: 17284991]

Level 3 (low-level) evidence

[23]

Cajita MI, Baumgartner E, Berben L, Denhaerynck K, Helmy R, Schönfeld S, Berger G, Vetter C, Dobbels F, Russell CL, De Geest S, BRIGHT Study Team. Heart transplant centers with multidisciplinary team show a higher level of chronic illness management - Findings from the International BRIGHT Study. Heart & lung : the journal of critical care. 2017 Sep-Oct:46(5):351-356. doi: 10.1016/j.hrtlng.2017.05.006. Epub 2017 Jun 16     [PubMed PMID: 28624338]

[24]

Roussel MG, Gorham N, Wilson L, Mangi AA. Improving recovery time following heart transplantation: the role of the multidisciplinary health care team. Journal of multidisciplinary healthcare. 2013 Aug 22:6():293-302. doi: 10.2147/JMDH.S31457. Epub 2013 Aug 22     [PubMed PMID: 24009423]

[25]

Velleca A, Shullo MA, Dhital K, Azeka E, Colvin M, DePasquale E, Farrero M, García-Guereta L, Jamero G, Khush K, Lavee J, Pouch S, Patel J, Michaud CJ, Shullo MA, Schubert S, Angelini A, Carlos L, Mirabet S, Patel J, Pham M, Urschel S, Kim KH, Miyamoto S, Chih S, Daly K, Grossi P, Jennings DL, Kim IC, Lim HS, Miller T, Potena L, Velleca A, Eisen H, Bellumkonda L, Danziger-Isakov L, Dobbels F, Harkess M, Kim D, Lyster H, Peled Y, Reinhardt Z. The International Society for Heart and Lung Transplantation (ISHLT) guidelines for the care of heart transplant recipients. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation. 2023 May:42(5):e1-e141. doi: 10.1016/j.healun.2022.10.015. Epub 2022 Dec 20     [PubMed PMID: 37080658]

[26]

Paulo N, Prunet H, Armoiry X, Hugon-Vallet E, Mocan R, Portran P, Sebbag L, Pozzi M, Baudry G. Outcome of primary graft dysfunction rescued by venoarterial extracorporeal membrane oxygenation after heart transplantation. Archives of cardiovascular diseases. 2022 Aug-Sep:115(8-9):426-435. doi: 10.1016/j.acvd.2022.04.009. Epub 2022 Jul 5     [PubMed PMID: 35945148]

[27]

Kim PJ, Cusi V, Cardenas A, Tada Y, Vaida F, Wettersten N, Chak J, Bijlani P, Pretorius V, Urey MA, Morris GP, Lin G. Antibody Mediated Rejection is not Associated with Worse Survival in Adherent Heart Transplant Patients in the Contemporary Era. medRxiv : the preprint server for health sciences. 2023 Dec 8:():. pii: 2023.12.01.23299311. doi: 10.1101/2023.12.01.23299311. Epub 2023 Dec 8     [PubMed PMID: 38106112]

[28]

Awad MA, Shah A, Griffith BP. Current status and outcomes in heart transplantation: a narrative review. Reviews in cardiovascular medicine. 2022 Jan 11:23(1):11. doi: 10.31083/j.rcm2301011. Epub     [PubMed PMID: 35092203]

Level 3 (low-level) evidence

[29]

Ganapathi AM, Lampert BC, Mokadam NA, Emani S, Hasan AK, Tamer R, Whitson BA. Allocation changes in heart transplantation: What has really changed? The Journal of thoracic and cardiovascular surgery. 2023 Feb:165(2):724-733.e7. doi: 10.1016/j.jtcvs.2021.03.031. Epub 2021 Mar 16     [PubMed PMID: 33875259]

[30]

Hess NR, Seese LM, Mathier MA, Keebler ME, Hickey GW, McNamara DM, Kilic A. Twenty-year survival following orthotopic heart transplantation in the United States. Journal of cardiac surgery. 2021 Feb:36(2):643-650. doi: 10.1111/jocs.15234. Epub 2020 Dec 8     [PubMed PMID: 33295043]

[31]

Macdonald PS, Gorrie N, Brennan X, Aili SR, De Silva R, Jha SR, Fritis-Lamora R, Montgomery E, Wilhelm K, Pierce R, Lam F, Schnegg B, Hayward C, Jabbour A, Kotlyar E, Muthiah K, Keogh AM, Granger E, Connellan M, Watson A, Iyer A, Jansz PC. The impact of frailty on mortality after heart transplantation. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation. 2021 Feb:40(2):87-94. doi: 10.1016/j.healun.2020.11.007. Epub 2020 Nov 21     [PubMed PMID: 33279391]

[32]

Ayesta A, Urrútia G, Madrid E, Vernooij RWM, Vicent L, Martínez-Sellés M. Sex-mismatch influence on survival after heart transplantation: A systematic review and meta-analysis of observational studies. Clinical transplantation. 2019 Dec:33(12):e13737. doi: 10.1111/ctr.13737. Epub 2019 Nov 10     [PubMed PMID: 31630456]

Level 1 (high-level) evidence

[33]

Reul RM Jr, Zhang TS, Rana AA, Rosengart TK, Goss JA. Consistent improvements in short- and long-term survival following heart transplantation over the past three decades. Clinical transplantation. 2021 Apr:35(4):e14241. doi: 10.1111/ctr.14241. Epub 2021 Feb 10     [PubMed PMID: 33524177]

[34]

Taghavi S, Jayarajan SN, Wilson LM, Komaroff E, Testani JM, Mangi AA. Cardiac transplantation can be safely performed using selected diabetic donors. The Journal of thoracic and cardiovascular surgery. 2013 Aug:146(2):442-7. doi: 10.1016/j.jtcvs.2013.02.047. Epub 2013 Mar 13     [PubMed PMID: 23490247]

[35]

Tang PC, Lei I, Chen YE, Wang Z, Ailawadi G, Romano MA, Salvi S, Aaronson KD, Si MS, Pagani FD, Haft JW. Risk factors for heart transplant survival with greater than 5 h of donor heart ischemic time. Journal of cardiac surgery. 2021 Aug:36(8):2677-2684. doi: 10.1111/jocs.15621. Epub 2021 May 20     [PubMed PMID: 34018246]