Heart Transplantation







  • Outline



  • Evaluation and Management of Heart Transplant Candidates 631




    • Indications for Transplant 631



    • Evaluation of the Heart Transplant Candidate 631




  • The Heart Transplant Procedure 633




    • Donor Heart Evaluation and Management 633



    • Donor Heart Allocation 634



    • Surgical Procedure 635



    • Postoperative Care 635




  • Immune Management of the Heart Transplant Recipient 636




    • Overview 636



    • Clinical and Pathologic Subtypes of Cardiac Allograft Rejection 637



    • Noninvasive Monitoring for Allograft Rejection 638



    • Treatment of Allograft Rejection 639



    • Immunosuppression in Heart Transplantation 640




      • Historical Perspective 640



      • The Pharmacology of Immunosuppression 640



      • Clinical Trials of Immunosuppressive Agents 642





  • Complications in the Heart Transplant Recipient 643




    • Overview of Outcomes After Heart Transplant 643



    • Cardiac Allograft Vasculopathy 643




  • Infection 646





  • Future Innovations 647




    • Novel Strategies to Enlarge the Donor Heart Pool 647



    • Improving Access and Outcomes for Allosensitized Patients 647



    • Novel Approaches to the Detection of Rejection 647



The first human heart transplant (HT) was performed more than 50 years ago, in 1967, by Christiaan Barnard at Groote Schuur Hospital in Cape Town, South Africa. Since that time over 100,000 lives have been saved by this procedure. Despite steady progress in the field of mechanical circulatory support (MCS), HT remains the therapy that provides the best quality of life and long-term survival for patients with end-stage heart failure. The availability of better immunosuppressive agents and other improvements in the care of HT recipients have led to dramatic increases in median survival time after HT, from several days in the beginning to 11 years in the current era. Furthermore, the percentage of HT recipients surviving to 1 year posttransplant has progressively increased over the last 25 years, from 84% for HT performed in 1990 to 90% for HT performed in 2015 ( Fig . 44.1 ). Long-term survival has also improved, with the percentage of HT recipients surviving to 10 years posttransplant increasing from 45% for HT performed in 1990 to 56% for HT performed in 2005.




Fig. 44.1


Survival after heart transplantation has improved over successive years between 1988 and 2016. For each year of transplant on the x -axis, the percentage of recipients who survived to 1 year (dark blue) , 3 years (light blue) , 5 years (yellow) , and 10 years (red) posttransplant is plotted on the y -axis.

Unpublished data from United Network for Organ Sharing.




Evaluation and Management of Heart Transplant Candidates


Indications for Transplant


Given the scarcity of donor hearts available as well as the risks inherent to the procedure, patients with cardiomyopathy should be referred for consideration of HT only once they have developed advanced heart failure symptoms (NYHA class III or greater) refractory to all medical and device therapies. Within this patient population substantial heterogeneity exists with regard to prognosis. Cardiopulmonary exercise testing can serve as an important test to improve risk stratification for adverse outcomes. A peak oxygen consumption (VO 2 ) of 14 mL/kg per minute or less has traditionally served as one of several thresholds for listing for HT.


Once end-stage cardiomyopathy is present, early referral for consideration of HT is important, given that a prolonged waiting time may be necessary before an organ becomes available. Clinical criteria for referral for HT have been developed and may assist the general cardiologist in the identification of patients who would benefit from HT. Specific indicators include hypotension (systolic blood pressure ≤90 mm Hg, creatinine ≥1.8 mg/dL, hemoglobin ≤12 g/dL, and inability to tolerate a beta-blocker or renin-angiotensin receptor antagonist.)


The demographics of heart failure have changed within the US population over the last 30 years, and indications for HT have paralleled these changes. Most significantly, better treatments for coronary artery disease (CAD) have led to an increased incidence of heart failure due to ischemic heart disease, but fewer of these patients required HT. Comparing 1990 with 2017, the percentage of HT performed for ischemic cardiomyopathy in the United States decreased substantially from 56% to 35% ( Fig . 44.2 ). With this, there was an increase in the percentage of HT performed for all other indications, including dilated cardiomyopathy (increased from 40% to 54%), restrictive/hypertrophic cardiomyopathy (increased from 1% to 6%), redo HT (increased from 2% to 3%), and congenital heart disease (increased from 1% to 3%).




Fig. 44.2


Indications for heart transplantation in the United States between 1988 and 2016. During this 28-year period, 55,844 heart transplants were performed for adult recipients. For cases where the cause of the recipient’s cardiomyopathy was known, 45% were performed for ischemic disease, 46% for dilated cardiomyopathy, 4% for restrictive/hypertrophic or right ventricular cardiomyopathy, 3% were retransplants, and 2% were for congenital heart disease. Over this time the percentage of transplants performed for ischemic disease has decreased, while the percentage performed for all other indications has increased. ARVD, Arrhythmogenic right ventricular dysplasia; HCM, hypertrophic cardiomyopathy.

Unpublished data from United Network for Organ Sharing.


Evaluation of the Heart Transplant Candidate


Owing to the scarcity of donor hearts, candidates for HT must undergo a rigorous evaluation process to ensure that they will have good outcomes after HT. Evaluation should be performed with three main goals in mind. The first goal of evaluation is to confirm that the candidate has end-stage heart failure and that there are no alternative therapies other than HT that may be suitable. The next goal is to ensure that the function of noncardiac organs (despite optimal medical therapy) will not affect posttransplant outcomes. This includes a rigorous evaluation of endocrine, kidney, liver, and lung function to identify potential collateral organ dysfunction that could limit outcomes after HT. The exact testing required varies by transplant program but generally includes specialist consultations as well as laboratory and imaging studies ( Table 44.1 ). Lastly, a history of compliance with medications and medical recommendations must be present as well as adequate social support to help the patient through the HT process.



TABLE 44.1

Evaluation for Heart Transplantation














































Area of Assessment Specific Testing
Cardiology Goal: Confirm that end-stage heart failure is present and there are no further treatment options beyond transplant
Echocardiogram
Right heart catheterization
Coronary angiogram
Cardiac magnetic resonance imaging
Cardiopulmonary exercise test
Cardiac surgery Goal: Determine anatomic suitability for transplant and surgical risk assessment
ABO type
Computed tomography of the chest
Dental Goal: Confirm the absence of any dental contraindications to transplant
Endocrine Goal: Confirm that there is no active endocrine disease; if present, confirm that diabetes is well controlled
Glycated hemoglobin, thyroid-stimulating hormone
Infectious disease Goal: Confirm that there are no active infectious diseases present; infectious disease risk assessment
Infectious disease serologies including hepatitis viruses
Nutrition Goal: Confirm that the patient is not malnourished
Oncology Goal: Confirm there is no active neoplastic disease present
Mammogram (women over 40)
Papanicolaou test/human papillomavirus screening
Prostate-specific antigen (men)
Psychiatric Goal: Confirm that there is no active psychiatric diseases present
Pulmonary Goal: Confirm that there is no active pulmonary disease present
Pulmonary function test
Renal Goal: Confirm that there is no active renal disease present
Glomerular filtration rate
Assessment of urinary protein
Social work Goal: Confirm that the patient has demonstrated compliance with medications and that there is adequate social support for transplantation
Vascular Goal: Confirm that there is no active vascular disease present
Carotid ultrasound
Lower extremity ankle-brachial index and ultrasound
Gastroenterology Goal: Confirm that there is no active gastrointestinal/liver disease present
Colonoscopy
Liver ultrasound (if liver function tests abnormal)


The unique physiology of the donor heart coupled with the technical aspects of the surgical procedure lead to several issues that require special consideration for HT candidates. First, the presence of pulmonary hypertension in the HT candidate requires careful assessment and management ( see also Chapter 34, Chapter 43 ). The donor heart is very sensitive to right ventricular afterload owing to the lack of conditioning to elevated pulmonary pressures as well as the effects of brain death on the right ventricle. Thus pulmonary hypertension is an important risk factor for right ventricular dysfunction of the cardiac allograft early posttransplant.


The criteria for pulmonary hypertension as a contraindication for HT as recommended by the International Society for Heart and Lung Transplantation (ISHLT) include a pulmonary artery systolic pressure ≥50 mm Hg and either a pulmonary vascular resistance of ≥3 Woods units or a transpulmonary gradient ≥15 mm Hg. If elevated pulmonary pressures are identified, a vasodilator challenge should be undertaken using intravenous vasodilator agents such as nitroglycerin, nitroprusside, or milrinone. If the pulmonary hypertension is reversible, then the patient is an acceptable candidate for HT, as the presence of “reversible” pulmonary hypertension does not affect posttransplant outcomes.


Obese HT recipients experience an increased risk of mortality. The ISHLT Listing Criteria for HT recommend that candidates with a body mass index greater than 35 kg/m 2 undergo weight loss before being listed for HT. As obesity has become increasingly prevalent in the United States, the acceptable limits of body size for HT candidates have become a salient issue. As discussed in more detail further on, size matching is an important factor affecting donor heart selection, and donor weight is typically limited to no less than 30% of recipient weight. As a result, obese HT candidates have longer waiting times and consequently higher mortality on the wait list.


HT candidates who possess circulating anti–human leukocyte antigen (HLA) antibodies, a problem known as allosensitization, have diminished access to transplantation. This is because of the need to exclude from the potential donor pool donors with HLA antigens to which the HT candidate has antibodies in order to prevent the possibility of hyperacute rejection. The degree of a candidate’s allosensitization was originally assessed using the panel-reactive antibody (PRA) assay. The development of solid-phase methods of antibody identification has led to the use of the calculated panel-reactive antibody (CPRA), which uses the gene frequencies of the excluded HLA antigens in historic donors. CPRA summarizes the percentage of the potential donor population with the candidate’s unacceptable HLA antigens for both the class I and II specificities as a single numeric value. As the CPRA value increases, HT candidates experience longer waiting times and an increased risk for adverse outcomes such as death and removal from the wait list for worsening condition ( Fig. 44.3 ).




Fig. 44.3


Plot of frequency of waiting list outcomes for sensitized heart transplant candidates grouped by calculated panel reactive antibody (CPRA) value. Candidates were sorted into five groups by their initial CPRA value. As the CPRA increased, the percentage of candidates who received a transplant decreased and the percentage of candidates who were still waiting for a transplant, were removed from the waiting list, or died increased.

From Kransdorf EP, Kittleson MM, Patel JK, Pando MJ, Steidley DE, Kobashigawa JA. Calculated panel-reactive antibody predicts outcomes on the heart transplant waiting list. J Heart Lung Transplant . 2017;36[7]:787–796.


There are several strategies to improve access to transplantation for allosensitized candidates. First, careful consideration should be given to the process of identifying which HLA antigens to exclude. Multiple techniques including the traditional cell-based cross-match and solid-phase methods should be used for this purpose. Next, immune-modulating therapies can be utilized to reduce the level of circulating HLA antibodies, a process known as desensitization. The optimal approach for managing allosensitized patients, both prior to and after HT, has not been established.


After optimizing cardiac function, renal dysfunction is common in patients with advanced heart failure and is another important consideration in HT candidates. On the basis of the estimated glomerular filtration rate (eGFR) cutoffs used to define chronic kidney disease, Habib et al. showed that 46% of HT recipients had a baseline eGFR of less than 60 mL/min per 1.73 m 2 . After adjustment for covariates, eGFR consistent with moderate (30–44 mL/min per 1.73 m 2 ) or severe (<30 mL/min per 1.73 m 2 ) renal dysfunction was strongly associated with posttransplant mortality. Thus HT candidates with an eGFR of less than 30 to 40 mL/min per 1.73 m 2 should be considered for a combined heart-kidney transplant.




The Heart Transplant Procedure


Donor Heart Evaluation and Management


The number of donor hearts that become available is limited; therefore there is a continual excess of candidates waiting for a HT as compared with the number of donor hearts that become available. Thus the careful evaluation and medical optimization of each potential heart donor is of upmost importance. There are several steps in the donor evaluation and management process ( Fig . 44.4 ).




Fig. 44.4


Steps in the donor evaluation process. The process starts with identification of potential organ donors and concludes with transplant of the donor heart into the recipient.

From Kransdorf EP, Stehlik J. Donor evaluation in heart transplantation: the end of the beginning. J Heart Lung Transplant . 2014;33[11]:1105–1113.


Deceased donors are persons that have suffered brain death, most commonly due to traumatic injury or stroke. After brain death has been declared by two separate neurologists, the family is approached regarding the possibility of organ donation by representatives of the clinical team or by representatives of the local organ procurement organization (OPO). OPOs are a group of nonprofit organizations that evaluate and manage donors throughout the United States. If consent for organ donation is granted by the deceased patient’s family, representatives of the OPO will begin the donor evaluation and management process.


The general evaluation of deceased donors includes screening for infectious diseases (e.g., human immunodeficiency virus, hepatitis A/B/C, syphilis) and occult malignancy. If the donor is acceptable from this standpoint, cardiac tests such as echocardiography and pulmonary artery catheterization are performed. Coronary angiography is frequently performed for older donors or those with risk factors for CAD. Abnormalities of cardiac function by echocardiography and angiography are strong predictors for rejection of the donor heart. Overall only about 30% of deceased donors become heart donors. The physiologic effects of brain death can lead to cardiac dysfunction, so throughout the donor evaluation process the donor is managed by the OPO to maintain optimal cardiac function.


Donor Heart Allocation


Through the allocation process, donor hearts that become available are assigned to a HT candidate on the wait list. The process begins with the OPO, which generates a list of potential recipients for a donor heart. This list is termed a “match list” and enumerates all potential recipients that are compatible with the donor and who could receive the organ. The order of potential recipients on the match list is specified by an allocation algorithm developed by the Organ Procurement and Transplantation Network/United Network for Organ Sharing (OPTN/UNOS), which places potential recipients into priority bins first by geographic location, then medical urgency, and then blood type compatibility.


Medical urgency is assessed using a tiered system composed of six statuses of increasing urgency. Patients in the most urgent tier, status 1, are primarily patients requiring extracorporeal membrane oxygenation (ECMO) ( Fig . 44.5 ). Patients in status 2 are mostly those requiring an intra-aortic balloon pump or temporary left ventricular assist device (for 14 days or less). Patients requiring high-dose inotropic agents, who in the previous medical urgency system composed the bulk of the status 1A group, now make up the status 3 group. Status 4, akin to status 1B in the previous medical urgency system, is composed of patients on inotropes without hemodynamic monitoring, those with a dischargeable left ventricular assist device (after using their discretionary 30 days of status 3 time), and those with certain cardiomyopathy diagnoses such as congenital heart disease and restrictive cardiomyopathy. Status 6 is composed of all other candidates, frequently those with ambulatory heart failure.




Fig. 44.5


Medical urgency tiers in the heart allocation system. Extracorporeal membrane oxygenation largely constitutes status 1. Patients with temporary intra-aortic balloon pumps or temporary mechanical circulatory support compose the bulk of status 2. There is regional sharing of these upper tiers. Candidates requiring multiple inotropes or a durable left ventricular assist device for 30 days constitute status 3. Candidates with single/low-dose inotropic support without hemodynamic monitoring or a durable left ventricular assist device after 30 days constitute status 4. Candidates for dual-organ transplant constitute status 5. All other candidates constitute status 6. BiVAD, Biventricular assist device; IABP, intra-aortic balloon pump; LVAD, left ventricular assist device; MCSD, mechanical circulatory support device; TAH, total artificial heart; VAD, ventricular assist device; VA ECMO, venoarterial extracorporeal membrane oxygenation.

From Organ Procurement and Transplantation Network Adult heart allocation. UNOS Transplant Pro. Available at: optn.transplant.hrsa.gov/learn/professional-education/adult-heart-allocation .


Within each priority bin, donor hearts are allocated by the accumulated active waiting time (i.e., candidates with longer waiting time will have a lower sequence number on the match list and are more likely to receive the organ) ( Fig . 44.6 ). The transplant program for each potential recipient is notified of the potential for allocation to one of the candidates on the wait list and performs an assessment of the quality of the donor heart for that recipient. Numerous parameters are considered during this assessment, but critical elements include the donor-recipient match for size, sex, and age as well as donor factors such as left ventricular function, left ventricular hypertrophy, and ischemic time. To be an acceptable donor, donor weight is recommended to be no more than 30% below that of the recipient except when a female donor is being used for a male recipient, in which case donor weight is recommended to be no more than 20% below that of the recipient. Donor age is frequently kept to age 55 or less. As discussed earlier, abnormal left ventricular function that fails to improve during donor management as well as significant left ventricular hypertrophy are common reasons that organs are declined.




Fig. 44.6


Algorithm for donor heart allocation in the United States. Adult donor hearts are first allocated by geographic zone according to the location of the donor: local (within the same donor service area/organ procurement organization), zone A (0–500 miles), zone B (>500 to 1000 miles), zone C (>1000 to 1500 miles), zone D (>1500 to 2500 miles) and zone E (>2500 miles). Hearts are then allocated by medical urgency (status 1A, then 1B, then 2). Then hearts are allocated by ABO compatibility (primary = donor and recipient with identical ABO as well as O→B, A→AB and B→AB; secondary = O→A and O→AB). Last, within each priority bin, donor hearts are allocated by the accumulated active waiting time.

From Colvin-Adams M, Valapour M, Hertz M, et al. Lung and heart allocation in the United States. Am J Transplant . 2012;12[12]:3213–3234.


If the transplant program finds the organ is appropriate for the recipient, the offer is accepted. Ultimately the donor heart will be placed with the potential recipient with the lowest sequence number whose transplant program accepted the organ offer. The transplant program for the recipient to whom the donor heart was placed will work with the OPO to coordinate the heart procurement.


Surgical Procedure


The HT procedure requires two surgeons. One surgeon travels to the hospital where the deceased donor is located and procures the donor heart. This surgeon performs an assessment of quality of the donor heart on arrival by first reviewing the echocardiogram, hemodynamics, and coronary angiogram (if performed). If the organ is acceptable, the procurement surgery proceeds. Once the heart has been surgically exposed, the surgeon makes a final check of the coronary arteries via palpation. If there are no abnormalities, the heart is arrested using cardioplegia solution, explanted, and placed in cold storage on ice. This marks the beginning of the cold ischemic time. The procurement team then travels back to the hospital, where the recipient has already been prepared for surgery.


Upon hearing that the donor heart is acceptable, the second surgeon proceeds with the recipient cardiectomy. A sternotomy is performed. The recipient is placed on cardiopulmonary bypass via placement of cannulas in the aorta and superior and inferior vena cavae. The aorta is cross-clamped and the recipient’s heart is removed. Then the donor heart is brought onto the surgical field and the left atrial anastomosis is made, followed by the inferior vena cava, pulmonary artery, and aortic anastomoses ( Fig . 44.7 ). The aortic cross-clamp is released and the heart begins to be perfused with blood. It will typically start to beat spontaneously. Inotropic and vasopressor support is initiated. Then then the patient is weaned from cardiopulmonary bypass. Hemostasis is achieved and the chest is closed. The recipient is then transported to the intensive care unit (ICU) for ongoing care.




Fig. 44.7


Schematic of the orthotopic heart transplant procedure. After the sternotomy has been completed, the recipient is placed on cardiopulmonary bypass and the aorta is cross-clamped. The recipient’s heart is removed. Then the donor heart is brought onto the surgical field and the left atrial anastomosis is made, followed by the inferior vena cava, pulmonary artery, and aortic anastomoses.

From Reichart B, Rose AG, Reichenspurner H. Herz- und Herz-Lungen. Transplantation. Percha, Germany: RS Schulz Verlag; 1987.


Postoperative Care


During the initial phase the recipient is cared for in the ICU, where the focuses of care are hemodynamic support of the recently transplanted heart and the usual requirements after cardiothoracic surgery such as mechanical ventilation and chest tube drainage. Once the recipient’s hemodynamic status has stabilized, he or she is transferred to the cardiac floor, where the main focus of care is on physical strengthening and learning the complex medical regimen that will be required at discharge.


While in the ICU, the recipient may be maintained on multiple inotropic and vasopressor medications. In general, inotropic support is needed to combat the effects of ischemia-reperfusion injury which affects the donor heart early posttransplant. Vasopressor support is also frequently needed, and up to 35% of HT recipients will experience vasoplegia after HT. Vasoplegia is more common in patients who have previously undergone thoracic surgery or were supported with MCS.


Primary graft dysfunction (PGD) is an important cause of morbidity and mortality that presents immediately or within the first few hours after HT. PGD occurs when the recently implanted donor heart displays dysfunction of the left ventricle, right ventricle, or both in the absence of discernible secondary causes such as pulmonary hypertension or hyperacute rejection. Dysfunction frequently manifests as hypotension, low cardiac output/index, and high filling pressures. The incidence of PGD varies by institution from around 5% to 25% of all HT. Risk factors for PGD include amiodarone use, African American ethnicity, diabetes mellitus, donor age, high right atrial pressure, increasing ischemic time, inotrope dependence, and recipient age. When severe PGD is present, the use of MCS with an IABP or ECMO is frequently needed. Even with aggressive management of PGD, mortality remains high.


Immunosuppression is another important consideration of early posttransplant care, as “induction” immunosuppression is administered shortly after HT. Induction immunosuppression agents include antithymocyte globulin (ATG) as well as the interleukin-2 antagonist basiliximab. Although induction immunosuppression has not been proven to be of benefit via a randomized clinical trial, it is used routinely by half of HT programs in the United States with the intent of enhancing tolerance to the donor graft. The use of induction immunosuppression has been used in two other circumstances as well: for recipients with renal dysfunction in whom induction immunosuppression is used to delay introduction of a calcineurin inhibitor and for recipients at an elevated immunologic risk in whom induction immunosuppression is used for its long-term effects on memory T lymphocytes. Recent studies have suggested improved survival with ATG as compared with basiliximab.


Many HT recipients experience markedly decreased physical functioning after HT as a result of several factors, including a prolonged period of pretransplant illness, the surgical procedure itself, and high-dose corticosteroids. Another contributing factor to decreased exercise tolerance after HT is cardiac denervation. The vagus nerve is severed at the time of the HT surgery and, as a result, there is initially no parasympathetic or sympathetic innervation of the transplanted heart. HT recipients have high baseline heart rates and experience a delayed increase in heart rate with exercise; therefore they frequently report fatigue with exercise, especially in the early period posttransplant. Thus cardiac rehabilitation is an essential component of care for HT recipients, which will result in an improvement in their exercise tolerance. Furthermore, studies have shown that participation in a cardiac rehab program improves cardiac function and reduces the risk of hospital readmission.




Immune Management of the Heart Transplant Recipient


Overview


HT recipients must be maintained on immunosuppressive medications for life in order to keep their immune systems in a quiescent state. Without this immune quiescence, the recipient’s immune system will mount a cellular and humoral response against the donor heart, leading to allograft dysfunction and failure. The clinical syndrome caused by this immune response is termed allograft rejection (AR). The primary goal of care of the HT recipient is to prevent AR. On the other hand, immunosuppression predisposes HT recipients to infections with typical as well as atypical pathogens. Thus the modus operandi in caring for HT recipients is to monitor and adjust the level of immunosuppressive medications to maintain a balance between “enough” and “too much” ( Fig . 44.8 ).




Fig. 44.8


The primary goal of care of the heart transplant recipient is to use immunosuppressive therapy to prevent allograft rejection by inducing a state of immune quiescence. This requires achieving a delicate balance between immunosuppression in excess of what is required, referred to as “overimmunosuppression,” and immunosuppression below what is required. Inadequate immunosuppression can lead to rejection/graft dysfunction, and overimmunosuppression can cause infection, drug toxicities, and cancer (over long periods of time).

Modified from Patel J, Kobashigawa JA. Minimization of immunosuppression: transplant immunology. Transpl Immunol . 2008;20[1–2]:48–54.


From the early days of HT it was recognized that the risk of rejection was highest early after transplant, usually in the first year posttransplant, and that it decreases over time. It is worth noting that diminution of immunosuppression below a certain threshold or augmentation of the recipient’s immune system—for example due to subtherapeutic immunosuppressive drug levels or infection, can lead to rejection even long after HT. As a consequence of this, the clinical approach to immunosuppression is to apply a high level of immunosuppression early after transplant and gradually decrease this level over time while monitoring for the development of AR.


The initially universal incidence of rejection led to the practice of performing surveillance for rejection in asymptomatic patients via percutaneous endomyocardial biopsy (EMB) in an effort to identify rejection earlier and thus treat it before hemodynamic sequelae developed. Although in the current era the incidence of rejection within the first year of HT is substantially lower, at 15%, the importance of identifying rejection before severe clinical sequelae develop has led to persistence of the practice of performing routine surveillance EMB.


Clinical and Pathologic Subtypes of Cardiac Allograft Rejection


For HT recipients presenting with a clinical syndrome consistent with rejection, the three immediate goals should be to assess cardiac function, achieve hemodynamic stability, and initiate treatment of rejection via immunomodulation. As part of the assessment process, an echocardiogram and EMB should be performed for all patients with symptoms possibly consistent with rejection.


Patients with rejection present along a clinical spectrum, varying from an asymptomatic patient to a patient with fulminant cardiogenic shock ( Table 44.2 ). Asymptomatic patients usually come to clinical attention at the time of a surveillance EMB showing rejection. Factors affecting the severity of hemodynamic perturbations in rejection have not been fully elucidated, but predictors of severity include right ventricular involvement, as well as the physiologic inability to respond to the decreased allograft function with an increased systemic vascular resistance. Arrhythmias can also occur, including atrial fibrillation in symptomatic rejection and polymorphic ventricular tachycardia/ventricular fibrillation in hemodynamic compromise rejection.



TABLE 44.2

Clinical Presentation of Transplant Rejection

































Asymptomatic Symptomatic Hemodynamic Compromise
Symptoms None Dyspnea, orthopnea, abdominal pain, weight gain
Physical examination ↑JVP ↑JVP, +S3, cool extremities
Echo findings Normal function ↓ RV and LV function (EF ∼40%) ↓↓ RV and LV function (EF ∼20%)
Hemodynamics Normal ↑JVP, ↑PCWP, ↓CI ↑↑JVP, ↑↑PCWP, ↓↓CI
Hemodynamic management None Inotropes Inotropes, MCS

CI , Cardiac index; JVP , jugular venous pulsation; MCS , mechanical circulatory support; PCWP , pulmonary capillary wedge pressure.


The major pathologic types of rejection are acute cellular rejection (ACR) and antibody-mediated rejection (AMR), the features of which are discussed here. Mixed rejection, where both ACR and AMR coexist on the biopsy, is not uncommon but is not felt to be a distinct type of rejection. Similarly, a patient can present with clinical rejection and the EMB may show no evidence of rejection. This situation is termed biopsy-negative rejection and may be due to sampling error of the EMB or possibly to an atypical form of AMR (e.g., non-HLA antibody-mediated AMR).


ACR is the most common form of rejection; in a large analysis by Kfoury et al. of patients undergoing HT between 1985 and 2014, it was found in 24% of biopsies. Mechanistically, ACR is due to direct and indirect allorecognition, which leads to T-cell activation and infiltration of the allograft. Histopathology shows infiltration of lymphocytes and macrophages, with the grade of rejection corresponding to the extent of cellular infiltration and myocyte injury. EMB samples are graded according to a common set of criteria developed by the ISHLT ( Table 44.3 ; Fig . 44.9 A and B ).



TABLE 44.3

Grading and Pathologic Findings for Cellular Rejection and Antibody-Mediated Rejection








































Type Grade Pathologic Findings
Cellular rejection 0R None
1R Interstitial and/or perivascular infiltrate with up to one focus of myocyte damage
2R Two or more foci of infiltrate with associated myocyte damage
3R Diffuse cellular infiltrate with multifocal myocyte damage with or without edema, hemorrhage, and vasculitis
Antibody-mediated rejection 0 None
Rejection 1I or 1H Immunopathology (I) or histology (H) positive
2 Immunopathology and histology positive
3 Interstitial hemorrhage, capillary fragmentation and marked edema



Fig. 44.9


Photomicrographs of endomyocardial biopsy samples showing cellular and antibody-mediated rejection. (A) Myocardium with lymphocytic infiltrate consistent with International Society for Heart and Lung Transplantation grade 2R cellular rejection (100× magnification). (B) Sample as in (A) at a higher magnification (200× magnification). (C) Sample showing capillaries with activated endothelial cells and intravascular macrophages consistent with antibody-mediated rejection (400× magnification). (D) Immunoperoxidase staining positive for CD68, highlighting intravascular macrophages (brown) in antibody-mediated rejection (400× magnification).

From Kransdorf EP, Kobashigawa JA. Genetic and genomic approaches to the detection of heart transplant rejection. Per Med. 2012;9[7]:693–705.


AMR is the next most common form of rejection, occurring in 9% of biopsies. AMR is due predominantly to the binding of antibodies against HLA antigens to cardiac tissue, leading to complement activation and tissue injury. The ISHLT formulation for the diagnosis of AMR involves both an immunological and a histological component (see Table 44.3 ). Immunologically, complement components C3d or C4d are seen in a capillary pattern. Histological findings suggestive of AMR include endothelial cell activation, intravascular macrophage accumulation and interstitial edema ( see Fig. 44.9C and D ).


Mixed rejection is the situation where an EMB displays both ACR and AMR, which has been found to occur in 8% of biopsies. About 50% of mixed rejection biopsies show mild ACR and AMR (ACR grade 1R and AMR grade 1I/1H), and another 30% show mild CR but more severe AMR (ACR grade 1R and AMR grade 2). The pathological findings of each rejection type in mixed rejection are similar to the findings of each type when present individually, so mixed rejection is most likely a coexistence of the two rejection types.


The risk of rejection varies significantly between individuals. The basis for this variability has not yet been fully elucidated, but several clinical and genetic factors have been identified as contributory. Clinical risk factors for rejection include medication non-compliance, younger age of the recipient, African American ethnicity, and circulating anti-HLA antibodies. Genetic risk factors include increasing donor to recipient HLA mismatch and genetic polymorphisms within the cytokine genes.


Noninvasive Monitoring for Allograft Rejection


The EMB has several important limitations that have encouraged the development of alternative methods of diagnosis for rejection. First and foremost, the EMB is an invasive procedure that has potential to cause complications, albeit rarely, including tricuspid valve injury and tamponade. Second, because the site for an EMB is chosen at random, sampling error is frequently known to occur. Biopsy-negative rejection, where rejection is suspected clinically but the biopsy shows no histological evidence of rejection, is not uncommon. Finally, evaluation of the EMB for rejection by expert pathologists has significant inter-observer variability due to the presence of artifacts, which can include previous biopsy site, infection, and the Quilty effect (subendocardial lymphocyte infiltration that is felt to be benign).


Gene expression profiling was established as a potentially clinically useful, noninvasive method for the diagnosis of ACR via the Cardiac Allograft Rejection Gene Expression Observational (CARGO) study. The CARGO study tested the hypothesis that gene expression profiling, performed using a sample of mononuclear cells isolated from the peripheral blood, could discriminate significant ACR (ISHLT grade 2R and above) from immune quiescence. In this study, gene discovery was first performed using 247 samples from patients with ACR and 38 control samples. This led to the identification of 252 candidate genes, which were then individually analyzed in 109 samples from patients with rejection and 36 control samples. Ultimately, 11 genes were selected that provided the best discrimination between ACR and quiescence. In practice, the levels of these 11 genes are measured and combined to yield an expression score with a value between 0 and 40. Lower scores suggest immune quiescence and higher scores suggest immune activity potentially compatible with ACR.


This assay became available for clinical use as the AlloMap test (CareDx, Brisbane, CA) in 2005. The clinical experience with AlloMap showed that using a threshold score of 34, the negative predictive value for significant ACR approached 99%, while the positive predictive value is only 7%. As such, AlloMap can serve as a test to indicate a quiescent state with the presence of significant ACR (ISHLT grade 2R or higher) being very unlikely, and thus avoiding the need for an EMB. However, the test is not sufficiently specific to serve as a stand-alone test for rejection. Patients with elevated scores require an EMB to confirm the presence of rejection. It is important to remember that AlloMap was developed to assess only for ACR. There are several important contraindications to the use of AlloMap, which are detailed in Table 44.4 .



TABLE 44.4

Clinical Contraindications to the Use of AlloMap for Cellular Rejection Monitoring























Active cardiac allograft dysfunction
Hemodynamic rejection in the last 6 months
Antibody-mediated rejection in last 12 months
Pregnancy
Blood transfusion in last 30 days
Hematopoietic growth factors in last 30 days
Patient less than 15 years of age
High-dose steroids in the last 21 days
Daily prednisone administration >20 mg
Dual organ transplant recipient (e.g., heart and kidney)


The clinical utility of the AlloMap was demonstrated through two clinical trials, the Invasive Monitoring Attenuation through Gene Expression (IMAGE) and Early Invasive Monitoring Attenuation through Gene Expression (EIMAGE) trials. In the IMAGE trial, a total of 602 adult patients between 6-months and 5-years posttransplant were randomized to a rejection surveillance protocol using primarily AlloMap or EMB. In the AlloMap arm of the trial, a threshold score of 34 or above triggered an EMB, as did symptoms or signs of AR or a decrease in ejection fraction of ≥25% from baseline. Over a median duration of 19 months, the primary composite outcome of rejection with hemodynamic compromise, graft dysfunction due to non-rejection causes, death or retransplantation, was similar between the AlloMap and EMB arms (14.5% and 15.3%, respectively). Patients in the AlloMap group had 67% fewer EMBs. Interestingly, there was a higher number of treated rejection episodes in the EMB arm, but given that there was a similar number of adverse events in both groups, a small number of rejection events are not detected by AlloMap but are clinically insignificant.


Since HT recipients are more likely to develop rejection early after HT and because most patients in the IMAGE trial were between 1 and 3 years posttransplant, the EIMAGE trial was performed to confirm the utility of AlloMap in monitoring for rejection early after HT. In this trial, HT recipients ≥55 days but less than 185 days posttransplant were randomized to rejection surveillance via AlloMap or EMB. A similar primary composite outcome was used in EIMAGE and IMAGE. The trial showed a slightly higher percentage of endpoints in the EMB arm compared to the AlloMap arm (17% vs. 10%) that was not statistically significant. Thus, AlloMap is safe and effective for ACR monitoring in HT recipients starting as early as 55 days posttransplant and can reduce the number of invasive EMB required for rejection surveillance.


Treatment of Allograft Rejection


Once rejection has been confirmed by clinical and pathological evaluation, hemodynamic stabilization and immunomodulation should be initiated immediately. If the patient displays evidence of cardiogenic shock as evidenced by laboratory and/or hemodynamic parameters, inotropic support should be initiated and consideration should be given to placement of MCS. The use of both temporary (as a bridge to recovery) and permanent (as a bridge to retransplant) MCS have been reported in AR. ECMO may be especially useful for hemodynamic compromise rejection as it can be implemented quickly and provides biventricular support while treatment for rejection is provided. If ECMO is to be initiated, better outcomes occur when it is initiated at the time of worsening hemodynamic status, as compared to salvage therapy (at the time of cardiac arrest).


The treatment regimen for rejection depends on both the clinical status of the patient and the pathological evaluation of the EMB. For patients hospitalized with symptomatic or hemodynamic compromise rejection, a bolus dose of corticosteroids and ATG are frequently administered. In addition to immunosuppression, we administer intravenous heparin, as coronary microvascular thrombosis occurs in severe rejection and heparin has been shown to improve coronary microvascular endothelial function in this setting. For patients with AMR, plasma exchange and intravenous immunoglobulin are frequently administered. The Cedars-Sinai protocol for management of rejection is presented in Table 44.5 . If the initial EMB shows AR, we repeat an EMB 2 weeks later to confirm that the augmented immunosuppression regimen has been effective at eradicating the AR. For patients that do not respond fully to medical treatment and display continued allograft dysfunction, extracorporeal photopheresis is frequently initiated with the hopes of improving allograft function. For patients with no response to treatment who display fulminant graft failure, retransplantation is not advisable, as it is associated with poor outcomes in the setting of AR.


Jan 2, 2020 | Posted by in CARDIOLOGY | Comments Off on Heart Transplantation
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