Alex M. Wisniewski and Leora T. Yarboro
This chapter is a revision and update of that included in the previous editions of the TSRA Review written by Muath Bishawi (2nd edition) and George M. Comas (1st edition).
History of Cardiac Transplantation
The first ever human-to-human heart transplant was performed by Christiaan Barnard on December 3, 1967 in Cape Town, South Africa. Just weeks later, Norman Shumway went on to perform the first heart transplant to take place in the United States. At the time of these pioneers, the only immunosuppressive therapies that existed consisted of azathioprine, corticosteroids, and anti-lymphocyte serum, which most likely contributed to the poor, short-term patient outcomes from graft rejection. However, with the advent of cyclosporine in the early 1980s, solid-organ transplantation was catapulted into the modern era, enabling this therapeutic remedy to serve as the current gold standard for end-stage cardiac disease.
Indications and Organ Allocation
Heart transplant is indicated for those patients with end stage heart disease who would otherwise be expected to have a life span of >10 years. There are numerous indications involving acute and chronic heart failure where transplant should be considered. Patients may present requiring mechanical circulatory support devices including ECMO or can present as a more progressive decline as seen with advanced ischemic cardiomyopathy. Patients with NYHA Class III-IV with symptoms refractory to optimal medical management and or surgery would also be considered for heart transplant. Other indications for heart transplant include those with intractable or severe angina with coronary artery disease unamenable to percutaneous or surgical revascularization and patients presenting with refractory life-threatening arrhythmias.
Objective measurements of cardiac performance including, ECHO, right heart catheterization and VO2 max are useful in the evaluation of patients with advanced heart disease. A peak VO2 ≤14 mL/kg/min (without beta blockade) is associated with poor long-term survival in adults and is someone in whom heart transplant could be considered. Other risk scoring systems exist including Heart Failure Survival Score which uses several patient specific factors to predict 1-year survival.
While there are few absolute contraindications to heart transplant, there are some relative ones. Some general principles include exclusion of patients with active infection/septic shock, systemic disease with secondary organ involvement (e.g., advanced diabetes, PVD), active malignancy other than skin cancer with less than 2-5 years disease-free survival, irreversible liver or renal disease, chronic irreversible pulmonary hypertension unresponsive to pharmacologic intervention (PASP >50 mmHg, TPG >15 mmHg or PVR> 5-6 Woods units), and finally social/psychiatric factors including poor compliance, cognitive impairment, and severe depression. Previous contraindications such as advanced age >70 years, amyloidosis, and HIV have seen change as centers have begun performing more and more transplants in these patient populations with somewhat comparable outcomes.
The UNOS organ allocation system provides the most critically ill patients awaiting transplant access to available donor matches. It attempts to maximize the number of quality life years gained with the limited availability of organs. As ventricular assist devices have become more durable and are now seen as a viable, long-term alternative to cardiac transplant, the allocation system has subsequently been revised, most recently in 2018. Patients awaiting transplant are now classified by the following:
- Status 1. Patients on VA ECMO; those with non-dischargeable, surgically implanted, non-endovascular biventricular support devices; patients on mechanical circulatory assist device (MCSD) with life-threating ventricular arrhythmia
- Status 2. Patients with non-dischargeable, surgically implanted, non-endovascular LVAD; those with IABP; those with V-tach/V-fib, mechanical support not required; MCSD with device malfunction/mechanical failure; Total Artificial Heart (TAH), BiVAD, RVAD, or VAD for single ventricle patients; percutaneous endovascular MCSD
- Status 3. Dischargeable LVAD for discretionary 30 days; multiple inotropes or single high-dose inotrope with continuous hemodynamic monitoring; VA ECMO after 7 days; percutaneous endovascular circulatory support device or IABP after 14 days; non-dischargeable, surgically implanted, non-endovascular LVAD after 14 days; MCSD with one of the following: device infection, hemolysis, pump thrombosis, right heart failure, mucosal bleeding, or aortic insufficiency
- Status 4. Dischargeable LVAD without discretionary 30 days; inotropes without hemodynamic monitoring; retransplant; one of the following diagnoses: congenital heart disease, ischemic heart disease with intractable angina, hypertrophic cardiomyopathy, restrictive cardiomyopathy, or amyloidosis
- Status 5. On the waitlist for at least one other organ at the same hospital
- Status 6. All remaining active candidates
The aforementioned allocation system pertains to adults, while pediatric patients adhere to the previous allocation system:
- Status 1A. Patients requiring continuous hemodynamic monitoring in the setting of either single high-dose or multiple intravenous inotropes; those with MCSD such as TAH, IABP, ECMO; those with VAD for a discretionary 30-day period; or those with device related complications
- Status 1B. Patients with a VAD or continuous infusion of inotropes
- Status C. Patients stable on home oral medications
Candidates eligible for heart transplantation should undergo a variety of tests including 12-lead electrocardiogram, Holter monitoring, echocardiography, and right-sided heart catheterization. If heart failure is due to an unknown etiology, patients should also undergo endomyocardial biopsy, which can assist in therapeutic decisions. Additionally, patients need neuropsychiatric assessment and experienced social work assessment for presence of adequate social and financial support.
Donor selection
Donor hearts undergo an important evaluation process. This includes echocardiography to assess overall function and any baseline valve pathology, right heart catheterization, and coronary angiography (for males >45 years or females >50, if history of cocaine use, or if three risk factors for CAD including hypertension, diabetes, smoking history, dyslipidemia, or family history of premature CAD). Determining distance to the transplant center is also important as the goal ischemic time for heart transplant should be <4 hours using traditional preservation techniques.
It is also important to screen intraoperatively at the time of organ procurement by looking for evidence of previous infarction, myocardial contusions in the case of blunt trauma mechanism, gross coronary artery calcifications, and right ventricular function.
Immunologic aspects
Matching of donor to recipient is largely based on ABO compatibility and predicted heart mass, which involves a calculation based on age, gender, height, and weight. Screening for anti-HLA antibodies is now also routine for transplant candidates. HLA compatibility has demonstrated an important role as patients with higher levels of preformed panel reactive antibodies (PRA) to HLAs may experience higher rates of rejection and decreased survival. A high PRA (>50%) is indicative of a highly sensitized recipient translating to an increased risk of early graft loss. This can be most often positive in pregnancy, patients with prior blood transfusions and those with recent LVAD support. The previous utility of this test was minimal as the logistics of transplant did not allow for direct cross-match between donor cells and recipient serum prior to transplantation. However, as tests have improved in identifying HLA subtypes, we have been able to identify the specificities of the recipients’ alloantibodies and therefore “virtually” cross-match by looking at the donor HLA type in comparison to the recipient alloantibody specificities. Those found to be highly sensitized require treatment pre-operatively to lower the antibody burden and prevent humoral rejection.
Implantation
A high percentage of heart transplant patients will have had previous cardiac surgery. Recent imaging will help to identify the location of structures relative to the sternum as well as quality of vessels for peripheral bypass should that be necessary.
Sternotomy is performed per normal fashion with cannulation of the distal ascending aorta. Bicaval cannulation is achieved and a left ventricular vent is placed via the right superior pulmonary vein. If a VAD is present, the outflow graft should be clamped prior to initiation of CPB to prevent regurgitation through the device. The aorta is freed from its adventitial attachments to the pulmonary arteries, umbilical tapes are used to snare the IVC and SVC proximal to the cannula insertion sites, and a cross clamp is applied. The aorta and pulmonary trunk are then transected just above the semilunar commissures and the atria are incised along the atrioventricular grooves, leaving cuffs for subsequent anastomosis of the donor heart. Further dissection of the aorta and pulmonary artery is undertaken to achieve 1-2 cm separation in preparation of anastomosis.
There are two main techniques currently being used for heart implantation. The bicaval technique is the most commonly performed method. The anastomoses (in typical order) include: (1) LA, (2) IVC, (3) Aorta, (4) PA, and (5) SVC with removal of the cross-clamp following aortic anastomosis. If there is extended donor ischemic time or longer cross-clamp times, it is sometimes preferred to perform aortic anastomosis following LA anastomosis, to facilitate early cross-clamp removal and reperfusion. Proponents of performing a bicaval technique (compared to using a right atrial cuff) argue for the advantages of preserving atrial anatomy, which is thought to play a role in improving atrial contractility, tricuspid valve function, and possibly decreasing arrhythmias. The disadvantage of this technique is longer preparation time (especially in the reoperative setting) and implantation time, and an increased risk of caval stenosis. Therefore, a patient-by-patient selection of technique choice is important.
Postoperative care
Given the denervation that occurs to the heart during explantation and re-implantation, the SA node will fire at its intrinsic rate of 90 to 110 BPM. The transplanted heart will also rely on extra-cardiac sources of catecholamine release and may have a delayed response to hypoxia and anemia. Furthermore, in cases where the overall ischemic time is long, elements of early graft dysfunction such as reduced diastolic compliance and impaired systolic function and contractility are treated with the use of higher filling pressures and short-term inotropic support. If right heart failure is suspected, early treatment is very important. The donor heart may be “untrained” to the recipient’s degree of pulmonary hypertension and often requires assistance through use of agents that help decrease PVR such as milrinone and nitric oxide. In cases of severe RV dysfunction, mechanical support might be necessary.
Complications and Rejection
A feared intraoperative complication occurring following implantation of the donor heart is primary graft dysfunction, which remains the leading cause of early mortality. It is defined as severe ventricular dysfunction of the donor graft resulting in failure to meet circulatory demands of the recipient after transplant. It may manifest as either single or biventricular dysfunction with low cardiac output and hypotension despite adequate filling pressures. Management consists primarily of supportive care with inotropic support. If inadequate, subsequent therapy is typically insertion of an IABP or ECMO cannulation if full support required.
Rejection is another common cause of mortality in the postoperative period. Within the first month, despite optimal medical management, 40% of patients will experience some evidence of rejection although only 5% of rejection episodes (other than hyperacute) will be associated with significant hemodynamic compromise.
Different types of rejection are classified based on timing of occurrence and whether they are driven by immune cells (cellular) vs. antibodies (humoral):
- Hyperacute rejection is rare today due to ABO and cross-matching and consists of preformed host antibodies against the donor’s HLA epitopes.
- In acute rejection, a lymphocytic attack against the transplanted heart is seen, affecting both ventricles equally. Humoral rejection involves host antibodies against the antigens in the donor heart’s endothelial surface. This is first seen clinically as increased vascular permeability, and micro-vascular thrombosis usually occurring within the first 6 months. Right ventricular endomyocardial biopsy is the gold standard for diagnosing acute rejection and is usually performed every 7-10 days in the early postoperative period.
Standardized Cardiac Biopsy Grading for Acute Cellular Rejection is as follows:
- Grade 0 = No rejection
- Grade 1 (Mild) = interstitial and/or perivascular infiltrate with up to 1 focus of myocyte damage; does not require treatment but should be monitored by repeat biopsy
- Grade 2 (Moderate) = two or more foci of infiltrate with associated myocyte damage
- Grade 3 (Severe) = diffuse infiltrate with multifocal myocyte damage +/- edema, hemorrhage or vasculitis
If a rejection episode is associated with hemodynamic compromise, a number of important steps must be taken. The event should be treated as a life-threatening with prompt methylprednisolone 1g IV given for 3 days. Inotropic support may be required with Swan-Ganz catheter placement for close monitoring of filling pressures. Thymoglobulin/OKT3 are usually reserved for severe rejection episodes. Following resolution of the episode, endomyocardial biopsy should be performed 7-10 days after cessation of treatment.
- Chronic rejection manifests as allograft vasculopathy. The incidence is ~10% per year after transplant or ~50% at 5 years. Chronic rejection is the most common cause of long-term death after the first year following transplant. The vasculopathy develops de novo and is not a progression of donor disease. Angina is rare as the transplanted heart is denervated; thus, diagnosis and routine surveillance is critical. Cardiac allograft vasculopathy resembles atherosclerosis in some ways. However, it differs mainly by its concentric nature of vessel wall thickening and diffuse disease as opposed to the eccentric intimal proliferation and focal plaques present in atherosclerosis. Surveillance consists of serial angiography although intravascular ultrasound may be more sensitive due to the diffuse nature of CAV that angiography may underestimate.
- Statins started within 2 weeks after transplantation can lower cholesterol and lead to decreased graft CAD and better graft survival. Steroids and blood pressure control do not alter the course of allograft vasculopathy.
- Treatment options include all forms of revascularization; however, there is rarely a discrete proximal lesion with a well-preserved distal vessel. Reoperative bypass surgery for allograft vasculopathy carries a 50% mortality. Ventricular hypertrophy increases mortality from post-transplant vasculopathy.
Immunosuppression
The management of immunosuppression for transplanted patients is complex. Immunosuppressive regimens fall into three categories: induction, maintenance, and rejection treatment. Table 74-1 shows the different phases of immunomodulation, the target, drugs used, and commonly cited side effects.
Table 74-1. Immunosuppression for heart transplantation.
| Phase | Target | Agents | Side Effects |
| Initial (induction) | Anti CD25 block IL-2 receptors Targeting T-cell receptors and removal from cell surface | Daclizumab Basiliximab Antithymocyte globulin OKT3 | Hepatitis, hypersensitivity reactions, nausea, diarrhea Cytokine release syndrome, fever/chills/headaches, post-transplant lymphoproliferative disorder, increase susceptibility to CMV infection |
| Maintenance | Blocking production and release of IL-2, and stopping cytotoxic Th cell proliferation Inhibition of cytokine transcription, macrophage function and overall levels of circulating lymphocytes | Cyclosporine Tacrolimus Mycophenolate mofetil Azathioprine Methotrexate Cyclophosphamide Corticosteroids | Gingival hyperplasia, nephrotoxic, neurotoxic, hepatotoxic, hyperkalemia GI symptoms, leukopenia, cutaneous malignancies Leukopenia, hepatic toxicity Bone marrow suppression, hemorrhagic cystitis Diabetes, bone disorders, decreased healing, psychiatric disorders, infections |
Following induction therapy and transplantation, patients are usually maintained on a 3-drug maintenance immunosuppressive regimen including a calcineurin inhibitor, antimetabolite, and tapering dose of corticosteroids. Tacrolimus tends to be preferred as the calcineurin inhibitor as its side effect profile is more favorable. Mycophenolate has almost exclusively replaced azathioprine as the antimetabolite of choice as clinical trials have demonstrated improved survival and lower rejection rates with its use.
In addition to initiation of an appropriate immunosuppressive regimen, transplanted patients are also started on aspirin to decrease the risk of coronary arteriosclerosis that occurs at a much faster rate once a heart is transplanted, as well as prophylactic histamine H2-receptor antagonist given the effects of steroids on the gastric mucosa.
Post-transplant infections
Post-transplant infections are very common, occurring in 40-50% of patients. The most common sites are the lungs (Pneumocystis carinii and CMV) and the urinary tract. Bacterial infections usually present within the first month and viral infections are normally seen after. Postoperatively, patients are usually given piperacillin/tazobactam and vancomycin for 2-4 days. Of the viral infections, CMV is the most common especially in the first 3 months after transplant. It affects multiple organs, with the lungs being the most common, followed by the GI system. It can also cause hepatitis in post-transplant patients, as well as chorioretinitis. CMV infections in the post-heart transplant patient should be considered life threatening and treated promptly with valganciclovir. Typically, patients postoperatively are given valganciclovir for 3 months to prevent infection; they may be indicated for longer if CMV positive.
Post-transplant malignancy
Heart transplant patients are 100 times more likely to have a new malignancy after transplantation than the general population. This is believed to be mainly due to chronic immunosuppression. The most likely cancers to recur in heart transplant patients are lung cancer, lymphoma, skin cancer, and carcinoma of the bladder. Post-transplant lymphoproliferative disorder (PTLD) is related to EBV infection of the recipient’s B lymphocytes. The risk factors for this condition include a heart transplant (compared to liver and kidney transplantation), EBV sero-negative status prior to transplantation, co-infection with CMV, and higher doses of immunosuppression. These patients may present with a vague mononucleosis-like illness or a specific organ system presentation (GI bleeding, pulmonary nodules, neurologic symptoms). While the optimal strategy for treatment is not yet clear, oftentimes it includes reduction of immunosuppression, surgical removal of focal lesions, anti-B cell antibodies/chemotherapy and antivirals. Patients with multi-visceral disease and central nervous system involvement have the worst post-PTLD survival.
Cardiac transplantation outcomes
Operative, 30-day mortality for heart transplantation ranges from 5-10%. Overall, one-year survival after heart transplantation is 90%, with a median post-transplant survival of >12 years, and >15 years in those who survive the first post-transplant year. In the pediatric population, survival is even better with >70% of recipients alive at 10 years after transplant. Death during the first year is mainly due to primary graft dysfunction, infection, and rejection. After the first year, the rates of allograft CAD and malignancy become more frequent mechanisms of mortality. In fact, allograft CAD is the number one cause for re-transplantation. Cardiac transplant patients are unique in this situation given that many of them fail to experience angina as a warning sign of significant disease (secondary to denervation). For many, heart failure from silent MIs, ventricular arrhythmias, and sudden death are the presenting symptoms.
Novelties in transplantation
Since the first heart transplant more than 50 years ago, there have been many new advances in the field of transplantation leading to improved recipient outcomes and also increased donor pools. Expansion of the donor pool has been led by efforts to include positive hepatitis C donors due to improvements in treatment. Studies have demonstrated comparable 1-year survival for patients receiving HCV+ donor hearts compared to HCV- donors. Ex vivo organ perfusion through preservation of warm, beating hearts, has been shown to be comparative to cold storage techniques with regards to 30-day outcomes. Finally, donation after circulatory death has become a potentially new opportunity for increasing the donor pool, although ethical considerations exist. The specific use of ex vivo perfusion in these cases has allowed for reports of success in this cohort of donors.
Suggested Readings
- Cardiac Surgery in the Adult, 5th Edition – Cohn, Adams p. 1279–1330.
- Stehlik J, Kobashigawa J, Hunt SA, Reichenspurner H, Kirklin JK, et al. Honoring 50 Years of Clinical Heart Transplantation in Circulation: In-Depth State-of-the-Art Review. Circulation. 2018;137(1):71-87.
