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| *Severe symptomatic [[Congenital heart disease cyanotic|cyanotic congenital heart disease.]] | | *Severe symptomatic [[Congenital heart disease cyanotic|cyanotic congenital heart disease.]] |
| *Presence of some degree of [[pulmonary hypertension]] with the potential risk of developing fixed and irreversible elevation of [[pulmonary vascular resistance]] (PVR) <ref name="pmid25132975">{{cite journal| author=Thrush PT, Hoffman TM| title=Pediatric heart transplantation-indications and outcomes in the current era. | journal=J Thorac Dis | year= 2014 | volume= 6 | issue= 8 | pages= 1080-96 | pmid=25132975 | doi=10.3978/j.issn.2072-1439.2014.06.16 | pmc=4133537 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25132975 }} </ref> | | *Presence of some degree of [[pulmonary hypertension]] with the potential risk of developing fixed and irreversible elevation of [[pulmonary vascular resistance]] (PVR) <ref name="pmid25132975">{{cite journal| author=Thrush PT, Hoffman TM| title=Pediatric heart transplantation-indications and outcomes in the current era. | journal=J Thorac Dis | year= 2014 | volume= 6 | issue= 8 | pages= 1080-96 | pmid=25132975 | doi=10.3978/j.issn.2072-1439.2014.06.16 | pmc=4133537 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25132975 }} </ref> |
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| '''Section 3: Evaluation of patients for heart transplantation:'''
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| An exhaustive evaluation of patients intended for heart transplant listing is indicated in all cases.
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| 1. Initial demographic assessment: This includes consideration for the patient’s age, gender and the body-mass index. Patients up to 70 years of age are eligible for heart transplant. However, on some occasions and at some centers, appropriate patients >70 years of age may be considered. Body mass index (BMI) ≤ 35 kg/m<sup>2</sup> is recommended prior to listing(11). Extremes of BMI (BMI >35 kg/m<sup>2</sup> or < 18 kg/m<sup>2</sup>) are both associated with adverse post-transplant outcomes.
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| 2. Blood group: Knowledge of the patient’s blood type is paramount to reduce incompatible transplants. Though ABO-incompatible heart transplant has been described in infants due to relative immaturity of their immune system (12), if done in adults it can result in hyperacute rejection. Notably, blood group O patients have the longest wait time for transplant as they can only accept group O donors (13). Blood groups A and B can accept their own group as well as group O donors. Group AB have the least waiting time as they can theoretically accept any blood group donor (13). Discussion of this with the patients before-hand can help manage expectations and risk stratify them accordingly. A case can also be made to consider mechanical circulatory support early in blood group O patients anticipating longer wait times (13).
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| 3. Echocardiography: Echocardiography is the ultrasound assessment of the heart function, valve function, restrictive diastolic changes and structural measurements. It can also help estimate right ventricular pressure, delineate the anatomy of congenital heart disease and even evaluate myocardial viability through stress modalities. Echocardiography is an important requirement for all patients (adult and pediatric) undergoing heart transplant evaluation.
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| 4. Cardiopulmonary exercise stress test (CPX): CPX is a stress test performed in patients able to exercise on a treadmill or a stationary bicycle. During the test, the patient wears a non-rebreathing mask while exercising and the exchange of oxygen and carbon dioxide is measured. The speed or the work-effort on the treadmill or bicycle is increased gradually. The patient continues to exercise until fatigue sets in and the patient has to stop. The peak oxygen consumption (peak Vo<sub>2</sub>) is measured at this time point. The test is considered maximal if the anerobic threshold is reached. This is the point when the body switches from predominantly aerobic to anerobic metabolism and is marked by a sudden surge in the carbon dioxide being exhaled compared to oxygen consumption. Respiratory exchange ratio (RER) is the ratio of carbon dioxide output to oxygen uptake (Vco<sub>2</sub>/Vo<sub>2</sub>) and an RER ratio >1.05 is considered maximal test. A patient with poor heart function will reach anerobic threshold early and have low peak Vo<sub>2</sub>. On the other hand, patients who are physically deconditioned or put in a poor effort during exercise will not reach anerobic threshold during the CPX test. The test will then be considered non-diagnostic.
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| If the anerobic threshold is reached and the peak Vo<sub>2</sub> value is < 14 ml/kg/min in the absence of beta-blocker or a value of < 12 ml/kg/min in the presence of a beta-blocker, then such a patient is estimated to have a survival of < 80% at 1 year. This could be considered a criteria for heart transplantation(11). In patients unable to reach anerobic threshold, the slope of minute ventilation (VE) and Vco<sub>2</sub> can be used for prognostication. This ratio estimates the amount of ventilation needed to exhale 1 unit of carbon dioxide. A high value (>35) is indicative of slow delivery of carbon dioxide to the lungs and hence poor right ventricular hemodynamics. This again could be considered a criterion for listing(11). There are other CPX parameters which have also been proposed for prognostication, however peak Vo<sub>2</sub> and the VE/V<sub>CO2</sub> slope are the ones used predominantly. It is important to keep in mind that the results of the test cannot be the sole reason for listing.
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| 5. Right heart catheterization (RHC): RHC is an invasive test involving guiding a pressure measurement catheter through a venous access site (jugular, femoral etc.) into the right ventricle and then the pulmonary artery. The test aims to measure the pressures in the right ventricle, pulmonary artery and capillary wedge pressure which is the surrogate for the left ventricular end-diastolic pressure. The test can also measure cardiac output in liters/minute, vascular resistance in the pulmonary and systemic circuits and other parameters. The procedure is ideally done while the patient is euvolemic or maximally fluid optimized. RHC is vital in assessment of the patient’s baseline cardiac output, fluid status and pressure in all chambers of the heart. This data can help optimize the hemodynamics and also estimate the severity of heart failure and hence the urgency of listing.
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| 6. Left heart catheterization or non-invasive myocardial assessment: In certain patients with newly diagnosed heart failure or with previously known coronary artery disease, a coronary artery angiography or non-invasive viability testing may be indicated to exclude underlying coronary artery disease which could be amenable to further invasive treatments. Heart transplant listing should ideally only be pursued after all potential invasive or surgical options have been exhausted.
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| 7. Non-cardiac organ assessment: A comprehensive evaluation of all non-cardiac organ function is important to exclude life-threatening disease elsewhere independent of the incident heart failure. This is most often the most time-consuming step, but an exhaustive evaluation is paramount to a successful post-transplant outcome. A multidisciplinary team approach is essential to interpret the data and to provide expert consultation on the prognosis.
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| Serum creatinine is often used to calculate the estimated glomerular filtration rate (eGFR). An eGFR < 30 ml/min/1.73 m2 is an absolute contraindication to heart transplant alone (11). Similarly, an elevation of serum transaminases, bilirubin or prothrombin time should prompt further evaluation for cirrhosis. Patients >50 years of age or patients at risk should undergo appropriate screening for peripheral vascular disease. Females >50 years age or with risk factors (steroid use or post-menopausal), are recommended to undergo a bone density assessment for osteoporosis as this may interfere with post-transplant rehabilitation and mobility (14).
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| 8. Diabetes: Diabetes is common among heart failure patients (15) and is sometimes uncovered for the first time during a patient’s initial evaluation for their heart failure. Therefore, hemoglobin A1c should be obtained in all patients. Poorly controlled diabetes with hemoglobin A1c >7.5%, especially with an evidence of end-organ involvement (excluding non-proliferative retinopathy) is indicative of poor prognosis independent of heart failure. Such patients are also at risk of poor outcomes post-transplant due to recurrent infections, coronary artery disease in the graft or recurrent heart failure (16). Poorly controlled diabetes is, thus, considered a relative contraindication to listing(11).
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| 9. Antibodies to human leukocyte antigens (HLA): HLA are antigens present on the surface of majority of the cells in the body. These antigens are used by the body’s immune cells to identify them as ‘belonging to the body’. They function like ‘identity cards’ carried by all the nucleated cells in the body to prevent the immune cells from attacking them. The immune cells identify foreign cells when they encounter non-self HLA antigens on the foreign cells. The immune system then mounts an attack through direct cellular injury or antibody-mediated injury, eventually killing these foreign cells. This is one of the ways the body ‘rejects’ a donor organ- by identifying the organ as non-self by the recipient’s immune system.
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| Most of the antibodies against non-self HLA antigens are formed after exposure to the donor organ. This process of identifying non-self HLA and mounting an attack can take some time, usually days. However, some patients have pre-formed antibodies due to prior exposure to blood transfusions, other organ transplant, pregnancy, previous mechanical devices etc. These preformed antibodies can mount an attack almost immediately after the donor organ is transplanted resulting in a hyper-acute rejection, which can be fatal. Identification of such pre-formed antibodies is thus important prior to the transplant, in order to avoid a donor who has that particular HLA which the patient is sensitized to. In some cases, it is possible to reduce the pre-formed antibodies through certain desensitization protocols involving anti-cancer and other medications/procedures directed against immune cells and antibodies (17).
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| 10. Cancer screening: As discussed above, performing an age and gender-appropriate cancer screening is important to exclude non-cardiac life-threatening disease prior to heart transplant. This is especially important as the immunosuppressant medications used after the transplant increase the risk of developing cancer or worsening a pre-existing cancer (18). So much so that, cancer is one of the predominant causes of death post-transplant (18). Prior history of cancer usually necessitates consultation with an oncological expert to ascertain prognosis in terms of survival, relapse risk and response to chemotherapy.
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| 11. Substance abuse screening: Tobacco smoking is associated with early graft failure, premature coronary allograft vasculopathy (CAV) and overall poor outcomes post-transplant(19,20). All patients should be screened for alcohol, tobacco or illicit drug use history. An abstinence for 6 months may be necessary to consider for listing based on the individual institution policy.
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| 12. Social, financial and psychiatric screening: All patients should be informed about the financial impact of heart transplantation. Apart from the medication and surgical costs, this also includes the inability to go back to work immediately, the need for translocation closer to the transplanting hospital, transportation costs, etc. A stable financial condition is desirable for optimal outcome post-transplant (21). Psychosocial assessment should include an evaluation of a patient’s ability to comprehend and comply with medical instructions and exhibit a strong caregiver support to help with the post-transplant care. Presence of active psychiatric illness which could impact medication compliance should be taken into consideration.
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| '''Section 4: Special considerations:'''
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| 1. Congenital heart disease (CHD): The overall survival of previously fatal congenital heart disease keeps improving with the advent of new surgical techniques. Consequently, patients are now surviving to adulthood more often. CHD patients frequently have manifestations not commonly seen in other patients due to their altered physiology. This includes higher incidence of liver disease (22) and other forms of right ventricular failure, higher incidence of pulmonary hypertension (23), protein losing enteropathy (24), multiple prior open-heart surgeries, higher incidence of HLA antibodies and cachexia or failure to thrive (25). Evaluation and management of CHD patients for heart transplant are therefore ideal in high volume centers with experience (11).
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| A thorough anatomical evaluation is important prior to heart transplant to define the underlying physiology and plan the surgical technique beforehand. In CHD patients with severe irreversible multi-organ failure, heart transplant alone may not alter the eventual prognosis (11).
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| 2. Pulmonary hypertension: Presence of severe pulmonary hypertension can result in immediate post-transplant right ventricular failure of the graft (26). The most common cause of pulmonary hypertension in heart failure patients is the chronic elevation of the left ventricular filling pressures (27). However, there are other causes which can be ascertained by performing a RHC at the time of initial evaluation. Knowledge of the etiology can help plan treatment and optimization of the pulmonary hemodynamics prior to listing for heart transplant. During the RHC procedure, a vasodilator test can be performed if the pulmonary capillary wedge pressure is not elevated. This test is performed using medicines such as inhaled nitric oxide, intravenous adenosine or epoprostenol. A drop in the mean pulmonary artery pressure by ≥ 10mmHg to reach a value of ≤ 40 mmHg, without worsening of the cardiac output is considered a positive test (28). A positive response indicates responsiveness to calcium channel blocker therapy in primary pulmonary hypertension.
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| The presence of severe pulmonary hypertension requires repeat RHC in 3-6 months after instituting the chosen therapy in order to document reversibility. Irreversible, severe pulmonary hypertension is considered a contraindication to heart transplant (11).
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| 3. Human immunodeficiency virus (HIV): Presence of HIV is not considered a contraindication to heart transplantation(29,30). Appropriate patients with undetectable HIV RNA and CD4 counts >200 cells/μl on stable combination antiretroviral therapy for >3 months may be considered (11,31). Patients with active HIV viremia or a history of opportunistic infections or malignancy (Kaposi sarcoma, lymphoma etc.) need further input from an infectious disease expert and generally considered a contraindication for heart transplant (29).
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| 4. Hepatitis B and C: Patients with chronic HBV and HCV infections usually need a thorough liver anatomical and functional evaluation due to increased risk of cirrhosis and hepatocellular carcinoma. The presence of acute fulminant HBV or HCV infection is a contraindication for heart transplantation (11).
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| 5. Retransplantation: Retransplantation of heart in a patient with prior heart transplant may be reasonable in some patients who have severe coronary artery vasculopathy or recurrence of heart failure (reduced ejection fraction or restrictive cardiomyopathy) resulting in severe functional limitations (32). Retransplantation should not be considered in patients with active rejection due to the risk of rejection of the new heart (33). Notably, it is frequent for patients being considered for retransplant to also need a renal transplant due to progressive renal damage sustained from immunosuppressant medications.
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| In summary, the incidence of heart failure continues to rise while the discrepancy with the available donor organs continue to widen. Now more than ever, it is imperative to perform an exhaustive evaluation to choose the appropriate patients for heart transplantation to provide the most benefit from the gift of donation. This can only be achieved through a close collaboration with a multidisciplinary team and a non-biased assessment of all patient factors to ensure a fair and equitable heart transplantation.
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| '''References:'''
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| 1. Hobbs FD, Roalfe AK, Davis RC, Davies MK, Hare R. Prognosis of all-cause heart failure and borderline left ventricular systolic dysfunction: 5 year mortality follow-up of the Echocardiographic Heart of England Screening Study (ECHOES). European heart journal 2007;28:1128-34.
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| 2. Taylor CJ, Ryan R, Nichols L, Gale N, Hobbs FR, Marshall T. Survival following a diagnosis of heart failure in primary care. Family practice 2017;34:161-168.
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| 3. Hershberger RE, Nauman D, Walker TL, Dutton D, Burgess D. Care processes and clinical outcomes of continuous outpatient support with inotropes (COSI) in patients with refractory endstage heart failure. Journal of cardiac failure 2003;9:180-7.
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| 4. Khush KK, Cherikh WS, Chambers DC et al. The International Thoracic Organ Transplant Registry of the International Society for Heart and Lung Transplantation: Thirty-sixth adult heart transplantation report - 2019; focus theme: Donor and recipient size match. J Heart Lung Transplant 2019;38:1056-1066.
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| 5. Rossano JW, Singh TP, Cherikh WS et al. The International Thoracic Organ Transplant Registry of the International Society for Heart and Lung Transplantation: Twenty-second pediatric heart transplantation report - 2019; Focus theme: Donor and recipient size match. J Heart Lung Transplant 2019;38:1028-1041.
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| 6. Procurement O, Network T. Adult heart allocation changes 2016. 2016.
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| 7. Maron BJ, Towbin JA, Thiene G et al. Contemporary definitions and classification of the cardiomyopathies: an American Heart Association Scientific Statement from the Council on Clinical Cardiology, Heart Failure and Transplantation Committee; Quality of Care and Outcomes Research and Functional Genomics and Translational Biology Interdisciplinary Working Groups; and Council on Epidemiology and Prevention. Circulation 2006;113:1807-16.
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| 8. Alraies MC, Eckman P. Adult heart transplant: indications and outcomes. J Thorac Dis 2014;6:1120-8.
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| 9. Hunt SA, Abraham WT, Chin MH et al. ACC/AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure): developed in collaboration with the American College of Chest Physicians and the International Society for Heart and Lung Transplantation: endorsed by the Heart Rhythm Society. Circulation 2005;112:e154-235.
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| 10. Hunt SA, Abraham WT, Chin MH et al. 2009 focused update incorporated into the ACC/AHA 2005 Guidelines for the Diagnosis and Management of Heart Failure in Adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines: developed in collaboration with the International Society for Heart and Lung Transplantation. Circulation 2009;119:e391-479.
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| 11. Mehra MR, Canter CE, Hannan MM et al. The 2016 International Society for Heart Lung Transplantation listing criteria for heart transplantation: A 10-year update. J Heart Lung Transplant 2016;35:1-23.
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| 12. Irving C, Gennery A, Kirk R. Pushing the boundaries: the current status of ABO-incompatible cardiac transplantation. J Heart Lung Transplant 2012;31:791-6.
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| 13. Vaidya GN, Trivedi J, Vijayakrishnan R et al. Effect of Blood Group on Heart Transplant Waitlist Mortality in the Ventricular Assist Device Era. Asaio j 2019.
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| 14. Mehra MR, Kobashigawa J, Starling R et al. Listing Criteria for Heart Transplantation: International Society for Heart and Lung Transplantation Guidelines for the Care of Cardiac Transplant Candidates-- 2006. The Journal of Heart and Lung Transplantation 2006;25:1024-1042.
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| 15. Tousoulis D, Oikonomou E, Siasos G, Stefanadis C. Diabetes Mellitus and Heart Failure. Eur Cardiol 2014;9:37-42.
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| 16. Higgins J, Pflugfelder PW, Kostuk WJ. Increased morbidity in diabetic cardiac transplant recipients. Can J Cardiol 2009;25:e125-9.
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| 17. Patel J, Everly M, Chang D, Kittleson M, Reed E, Kobashigawa J. Reduction of alloantibodies via proteasome inhibition in cardiac transplantation. J Heart Lung Transplant 2011;30:1320-6.
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| 18. Van Keer J, Droogné W, Van Cleemput J et al. Cancer After Heart Transplantation: A 25-year Single-center Perspective. Transplant Proc 2016;48:2172-7.
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| 19. Sanchez-Lazaro IJ, Almenar L, Martinez-Dolz L et al. Impact of smoking on survival after heart transplantation. Transplant Proc 2007;39:2377-8.
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| 20. Nagele H, Kalmar P, Rodiger W, Stubbe HM. Smoking after heart transplantation: an underestimated hazard? European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery 1997;12:70-4.
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| 21. Axelrod DA. Economic and financial outcomes in transplantation: whose dime is it anyway? Curr Opin Organ Transplant 2013;18:222-8.
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| 22. Hilscher MB, Kamath PS. Congenital Heart Disease and the Liver. Clin Liver Dis (Hoboken) 2019;14:138-141.
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| 23. Pascall E, Tulloh RM. Pulmonary hypertension in congenital heart disease. Future Cardiol 2018;14:343-353.
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| 24. Itkin M, Piccoli DA, Nadolski G et al. Protein-Losing Enteropathy in Patients With Congenital Heart Disease. J Am Coll Cardiol 2017;69:2929-2937.
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| 25. Poskitt EM. Failure to thrive in congenital heart disease. Arch Dis Child 1993;68:158-60.
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| 26. Kanwar M, Raina A, Aponte MP, Benza R. Pulmonary hypertension in potential heart transplant recipients: current treatment strategies. Curr Opin Organ Transplant 2015;20:570-6.
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| 27. Vachiery JL, Adir Y, Barbera JA et al. Pulmonary hypertension due to left heart diseases. J Am Coll Cardiol 2013;62:D100-8.
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| 28. Galie N, Humbert M, Vachiery JL et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). European heart journal 2016;37:67-119.
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| 29. Blumberg EA, Rogers CC. Human immunodeficiency virus in solid organ transplantation. Am J Transplant 2013;13 Suppl 4:169-78.
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| 30. Castel MA, Pérez-Villa F, Miró JM. Heart transplantation in HIV-infected patients: More cases in Europe. The Journal of Heart and Lung Transplantation 2011;30:1418.
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| 31. Rodger AJ, Lodwick R, Schechter M et al. Mortality in well controlled HIV in the continuous antiretroviral therapy arms of the SMART and ESPRIT trials compared with the general population. AIDS (London, England) 2013;27:973-9.
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| 32. Johnson MR, Aaronson KD, Canter CE et al. Heart Retransplantation. American Journal of Transplantation 2007;7:2075-2081.
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| 33. Miller RJH, Clarke BA, Howlett JG, Khush KK, Teuteberg JJ, Haddad F. Outcomes in patients undergoing cardiac retransplantation: A propensity matched cohort analysis of the UNOS Registry. J Heart Lung Transplant 2019;38:1067-1074.
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| ==References== | | ==References== |