Despite treatment with new drug regimens and high-risk cardiac surgery, many patients with heart failure (HF) progress to advanced stages characterized by marked symptomatic limitation and profound hemodynamic compromise. Cardiac transplantation is the first-line therapy for select patients with end-stage HF. In the United States, 135 transplant centers perform approximately 2000 procedures annually. Unfortunately, the limited supply of donor hearts has restricted the growth of cardiac transplantation and has led to the search for alternative strategies, such as mechanical circulatory support (MCS). The recent explosion in MCS technology offers the promise of a universally available therapy to decrease morbidity and mortality rates in all patients with end-stage HF. Taken together, cardiac transplantation and MCS are often referred to as advanced HF therapies, and their availability is generally limited to advanced HF centers.
Patient Selection for Advanced Heart Failure Therapies
Although important differences exist in patient selection for cardiac transplantation and MCS, a number of considerations are shared. An algorithm for patient selection for advanced HF therapies is shown in Figure 15-1 . Selection issues specific to each modality are addressed in their respective sections of this chapter.
Human cardiac transplantation was first performed in 1967. Over more than 4 decades, cardiac transplantation has evolved into the gold standard therapy for many patients with end-stage HF. This evolution has been made possible by significant advances in every aspect of cardiac transplantation: recipient and donor selection and management, organ preservation, surgical technique, immunosuppression, and management of acute and chronic posttransplantation complications. More than 3000 cardiac transplantations are performed worldwide each year, and the 1-, 5-, and 10-year survival rates after cardiac transplantation are approximately 88%, 75%, and 56%, respectively. Long-term survival (more than 15 years) is not uncommon, with a graft half-life in the modern era of transplant of 12.9 years, largely as a result of more limited and targeted immunosuppression. The total number of cardiac transplantations performed annually has not changed substantially in the past 20 years, mostly owing to limited donor availability.
During this same period, dramatic advances have been made in the medical and nontransplant surgical therapy of patients with advanced HF. Comprehensive pharmacotherapy has significantly delayed the progression of HF to its advanced stages. Biventricular pacemakers and implantable cardioverter-defibrillator devices (ICDs) have contributed importantly to reductions in the rates of HF morbidity and mortality. In addition, surgical advances have allowed the benefits of coronary revascularization and valvular repair to be extended to patients with poor ventricular function. Nevertheless, cardiac transplantation remains the best option for many patients with advanced HF.
Although cardiac transplantation offers excellent patient outcomes, it has several important limitations. Among these are inadequate donor availability, significant perioperative risk, and substantial posttransplantation morbidity and mortality. Consequently, optimizing patient selection for the procedure is critical. The overriding principle is to select patients whose cardiac dysfunction substantially impairs their lifestyle and threatens their life span, but who do not have sufficient extracardiac comorbidities to importantly compromise posttransplant outcome. Individual transplant programs establish their own inclusion and exclusion criteria; a representative list of criteria is shown in Box 15-1 .
Advanced heart failure with refractory New York Hospital Association class III and IV symptoms and markedly shortened life expectancy
Advanced coronary artery disease with refractory angina
Malignant ventricular arrhythmias unresponsive to standard therapies
Irreversible pulmonary hypertension
Chronic noncardiac illness that compromises survival and functional recovery
Severe peripheral vascular disease
Active or recent malignancy
Active infection (excluding chronic drive line infections of mechanical circulatory support devices)
Human immunodeficiency virus seroconversion
Drug, tobacco, or alcohol abuse within the previous 6 months
Psychiatric or psychosocial instability
Cardiac transplantation is most commonly performed for chronic severe left ventricular (LV) systolic dysfunction, although it is occasionally used in patients with other advanced cardiac pathology such as coronary artery disease, hypertrophic cardiomyopathy, restrictive cardiomyopathy, and others. A standard array of cardiac tests is generally performed to thoroughly assess each patient’s cardiac status. The goals of cardiac testing are to determine that 1) the cardiac disease limits functional status or anticipated survival to a degree sufficient to warrant consideration of transplantation; 2) no acceptable alternative therapies, medical or surgical, are available for the cardiac disease; 3) irreversible pulmonary hypertension is not present; and 4) appropriate therapy is chosen to bridge the patient to transplantation.
Assessment of Cardiac Disease Severity
The assessment of the severity of cardiac disease is based on anatomic, functional, and hemodynamic data. The functional assessment includes a determination of New York Heart Association (NYHA) class, as well as more objective measures of exercise capacity, such as peak oxygen consumption (VO 2 ) or 6-minute walk distance. Peak VO 2 is measured by breath-to-breath respiratory gas analysis during either bicycle ergometry or graded treadmill exercise. In a seminal study, peak VO 2 was found to predict death in patients with advanced HF. Based on this study, a peak VO 2 of 14 mL/kg/min or less is commonly used as a threshold for listing the patient for cardiac transplantation. Studies have suggested that in patients with advanced HF who are treated with β-adrenergic antagonists, this threshold may be too high, and a lower peak VO 2 may be more appropriate for transplant listing. Other parameters obtained during these studies—including minute ventilation/carbon dioxide (VE/CO 2 ) slope, a measure of ventilatory efficiency—have been shown to predict outcome, and these measures may be useful in the evaluation of a patient’s candidacy for cardiac transplantation.
The 6-minute walk distance has been shown to correlate well with peak VO 2 , suggesting that this simpler measure of functional capacity can be used in place of the more cumbersome oxygen-consumption study. A number of readily available clinical and laboratory parameters—such as hyponatremia, azotemia, anemia, and cachexia—along with intolerance of neurohormonal antagonists or dependence on inotropic support identify patients with a poor prognosis. Calculation of a risk score based on clinical variables has been advocated by some as a more refined predictor of outcome in patients with advanced HF.
Assessment of the Pulmonary Vasculature
An important determinant of candidacy for cardiac transplantation is the status of the pulmonary circulation. Patients with long-standing left-sided HF frequently develop pulmonary hypertension, which may or may not reverse with acute or chronic vasodilator therapy. Agents commonly used to assess pulmonary vasoreactivity acutely include sodium nitroprusside, prostaglandin E1 (PGE1), milrinone, and inhaled nitric oxide. Patients with reversible pulmonary hypertension have posttransplant survival rates similar to those with normal pulmonary pressures prior to transplant. Patients with irreversible pulmonary hypertension (pulmonary vascular resistance persistently >2.5 U) have a significantly worse posttransplant survival, largely due to failure of the donor right ventricle (RV). For these patients, alternative strategies may be considered, such as MCS as a bridge to a decision on transplant candidacy, combined heart-lung transplantation, or heterotopic heart transplantation with retention of the native heart to take advantage of its “trained” RV.
Other Cardiac Transplantation Candidacy Issues
Many adult cardiac transplant programs establish an upper age cutoff of 65 years for transplant candidacy. Data from the International Society for Heart and Lung Transplantation (ISHLT) Registry have suggested that survival after cardiac transplantation declines with increasing recipient age after 50 years of age; this effect is most striking above 70 years of age. Among the possible explanations for this association is the apparent increased risk of posttransplantation malignancy in older versus younger patients. Despite this, several reports of acceptable outcomes in an older patient population have emerged.
Many cardiac transplantation programs list significant, irreversible, noncardiac organ dysfunction as an exclusion criterion. Examples include intrinsic kidney disease with a creatinine clearance of 40 mL/min or less, intrinsic lung disease with spirometric values less than 50% of predicted, and biopsy-proven liver cirrhosis. However, a number of successful multiorgan transplantations have been reported, most commonly combined heart-kidney, heart-lung, and heart-liver transplants. Moreover, some of these abnormalities may reverse with MCS. Similarly, significant noncardiac comorbidities, such as diabetes with end-organ dysfunction, may exclude patients from cardiac transplantation, although reports of acceptable outcomes in these populations do exist. Other relative contraindications to transplant include conditions that are likely to worsen with corticosteroid therapy, such as obesity and osteoporosis.
Although rarely an exclusion for cardiac transplantation by itself, immunologic sensitization of potential transplant recipients—that is, the presence of anti–human leukocyte antigen (HLA) donor-specific antibodies—can pose a significant challenge. All potential recipients undergo immunologic assessment, usually via a complement-dependent cytotoxicity assay or panel-reactive antibodies (PRA). If elevated (>10%), further evaluation of antibody specificity is warranted using a more sensitive solid-phase assay, such as flow cytometry. Highly sensitized candidates commonly have a history of multiple pregnancies, prior transfusions, or prior placement of an MCS device; they require careful donor selection and perioperative immunologic management, which will be described here.
Listing for Cardiac Transplantation
The United Network of Organ Sharing (UNOS) was created in 1986 by the United States Congress to oversee the allocation of organs on a nationwide basis to recipients who have been registered by transplant programs on regional waiting lists. Local Organ Procurement Organizations (OPOs) are nonprofit agencies responsible for evaluating the suitability of potential donor organs and for coordinating organ recovery, preservation, and transport to the transplant center. Organs are allocated according to ABO blood typing, size matching, duration on the waiting list, and severity of disease. In 1999, UNOS updated the criteria by which disease severity affects patient priority on the waiting list. Table 15-1 summarizes the current UNOS status criteria.
|1A||Patient admitted to the listing center with: |
|1B||Patient on low-dose single inotrope or on uncomplicated mechanical VAD for more than 30 days|
|2||Patient not meeting 1A or 1B criteria|
|7||Patient listed but temporarily unsuitable for cardiac transplantation|
Improved success rates with cardiac transplantation have inevitably led to efforts to expand the procedure to previously excluded patient populations. One controversial strategy that has been used by some centers is the creation of a second or alternate list for those candidates deemed to be at higher risk. Organs accepted for patients on this list are those judged to be marginal, such as organs from older donors or from donors with single-vessel coronary disease, and are therefore not acceptable for most candidates who meet standard listing criteria, although some have argued that using suboptimal donor organs for higher risk candidates will lead to worse outcomes.
Pretransplantation Patient Management
Patients deemed to be acceptable candidates for cardiac transplantation require careful management as they await the procedure. Standard pharmacologic and device therapies for HF, as well as appropriate lifestyle modifications, are recommended for all patients. Patients with intractable signs and symptoms related to low cardiac output and end-organ hypoperfusion (kidney or liver dysfunction or poor nutritional status) may require continuous inotropic therapy or MCS, both of which affect the priority status of the patient in the UNOS system. Patients managed with continuous intravenous (IV) inotropic therapy or MCS require careful surveillance for, and aggressive therapy of, infection. Similarly, patients with evidence of pulmonary hypertension require careful follow-up of their pulmonary pressures. Chronic LV unloading with MCS may prevent worsening of pulmonary hypertension, and it may even reverse previously refractory pulmonary hypertension and allow for successful transplantation.
Patients found to be highly immunologically sensitized may benefit from immunomodulatory therapy before undergoing cardiac transplantation. Numerous protocols have been described in the literature, including those that use immunoglobulin, rituximab, and plasmapheresis. The goal of these protocols is to reduce the patient’s burden of preformed antibodies to commonly encountered antigens, both to increase the possibility of finding a donor with a negative prospective crossmatch, thus shortening the waiting time, and to decrease the chance of rejection of the transplanted heart.
Cardiac Transplantation Surgical Technique
The surgical technique for cardiac transplantation has remained fairly constant for the last two decades. One significant modification of the original operation has been the adoption of a bicaval anastomotic technique in place of the standard biatrial anastomosis. With both techniques, the donor left atrium is anastomosed to a retained cuff of recipient left atrium with the pulmonary veins left intact. In the bicaval technique, the donor and recipient vena cavae are anastomosed after complete excision of the recipient right atrium. Studies indicate that the bicaval technique results in improved atrial function and decreased incidence of atrial arrhythmias. A further modification, termed total orthotopic cardiac transplantation, combines a bicaval anastomosis with pulmonary vein anastomoses. This technique has not as yet been shown to offer significant benefit over biatrial or bicaval techniques.
Advances have also been made in the area of organ preservation after harvest. This may have contributed to the observation that outcomes with longer donor ischemic times are not markedly worse compared with those with shorter ischemic times. Further technological development, including beating-heart donor transport, may improve outcomes further. In addition, immediate postoperative management has improved with the judicious use of inotropic agents, acute pulmonary vasodilators, and even temporary mechanical cardiac support for instances of transient allograft dysfunction related to ischemia, elevated pulmonary pressures, or both.
Management of the Patient After Cardiac Transplantation
The management of the patient after cardiac transplantation involves three main strategies: 1) optimization of immunosuppressive therapy, 2) prevention of allograft rejection and complications resulting from the transplant or the immunosuppressive agents, and 3) treatment of allograft rejection and associated complications when they arise. The relative impact of these various conditions on mortality rates varies over time after cardiac transplantation.
Rejection is an important cause of morbidity and mortality after cardiac transplantation. Rejection after transplantation is due to an alloimmune response involving naïve and memory lymphocytes. Specifically, after foreign antigen recognition and appropriate presentation, the immune response is activated, targeting the allograft. The response may be humoral (antibody), cell mediated (T cell), or a combination of both. Current immunosuppression focuses on multiple pharmacologic targets in this cascade.
Despite intensive investigation of potential noninvasive indicators of rejection, transvenous endomyocardial biopsy remains the diagnostic tool of choice; current ISHLT criteria for grading acute rejection are shown in Table 15-2 . Of note, however, a recently published multicenter study suggested that peripheral blood gene expression profiling of circulating leukocytes may be able to identify low-risk patients for whom it is safe to defer endomyocardial biopsy. The risk of acute cellular rejection is highest in the first year after cardiac transplantation and declines significantly thereafter. This observation underlies the strategy of more intensive immunosuppression and surveillance for rejection early after transplantation, with a gradual decrease in both over time ( Table 15-3 ). The incidence of infection correlates with the degree of immunosuppression and is higher in the months following transplantation, and it declines thereafter. Accordingly, prophylaxis against opportunistic infections is generally indicated early after transplantation, when the level of immunosuppression is highest.
|Grade 0 R||No rejection|
|Grade 1 R, mild||Interstitial and/or perivascular infiltrate with up to one focus of myocyte damage|
|Grade 2 R||Two or more foci of infiltrate with moderate associated myocyte damage|
|Grade 3 R||Diffuse infiltrate with multifocal myocyte damage ± edema ± hemorrhage ± vasculitis|
|DISCHARGE TO WEEK 4||MONTH 1 TO MONTH 3||MONTH 4 TO YEAR 1||YEAR 1 TO YEAR 5||AFTER YEAR 5|
|Office visit||1 week||2 week||1-2 months||3-6 months||6 months to 1 year|
|Bloodwork||1 week||2 week||1-2 months||3 months||3 months|
|Right heart catheterization and biopsy||1 week||2 week||1-2 months||3 months to 1 year||As needed|
|Echocardiogram||As needed||At month 3||3 months||6 months to 1 year||As needed|
|Dopamine stress echocardiogram||—||—||At year 1||1 year||1 year|
|Coronary angiogram||—||—||At year 1||2 year||As needed|
After cardiac transplantation, other conditions assume greater importance over time in determining patient outcome. Hypertension, diabetes, and dyslipidemia are quite common, occurring in 76%, 27%, and 74% of patients within the first year after cardiac transplantation, respectively. The high incidence of these conditions reflects the fact that they are frequent comorbidities in patients who require transplantation and that immunosuppressive therapy can cause or exacerbate these conditions. Aggressive therapy of each is recommended, although data indicating that this improves outcomes in patients following cardiac transplantation are limited. Among the important sequelae that may be prevented or delayed with such therapy are cardiac allograft vasculopathy (CAV) and renal insufficiency. Late mortality after cardiac transplantation is predominantly related to CAV, renal failure, and malignancy.
The risk of rejection is at its maximum during the initial period of exposure to the allograft, and consequently the level of immunosuppression is maintained at its highest level during the first 6 months posttransplant. For long-term survival, limiting the complications of immunosuppression is of primary importance and leads to a critical additional management goal: to limit rejection with the lowest level of immunosuppression possible.
Prevention and Treatment of Cardiac Rejection
The primary management goal of immunosuppressive therapy is to limit episodes of acute rejection and minimize long-term drug-related morbidity. Strategies to achieve these goals may vary from center to center, but several underlying fundamental approaches are commonly used, based on the timing of medication and its mechanism of action or its origin. Immunosuppressants can be classified in one of three ways: by use as 1) induction therapy, 2) maintenance therapy, or 3) therapy of rejection. Some medications can be used for dual purposes. Induction therapy is generally administered immediately prior to transplant, intraoperatively, or in the immediate postoperative period in an effort to minimize the immune response immediately after transplantation. Maintenance therapy is taken indefinitely from the time of transplant to minimize the long-term risk of rejection. Medications used for treatment of rejection are generally used as a short course of therapy to reverse the ongoing immunologic attack on the allograft.
Classification of immunosuppressive therapy by mechanism of action and origin reveals several distinct classes of medications: monoclonal antibodies, polyclonal antibodies, calcineurin inhibitors, antimetabolites, proliferation signal inhibitors, and corticosteroids ( Tables 15-4 and 15-5 ).
|DRUG||DESCRIPTION||MECHANISM||USE *||TOXICITY AND COMMENTS|
|Basiliximab||Chimeric monoclonal antibody |
|Binds to and blocks the IL-2 receptor on activated T cells, depleting them and inhibiting IL-2–induced T-cell |
|Induction||Hypersensitivity reactions (uncommon); |
2 doses required; no monitoring
|Alemtuzumab||Humanized monoclonal antibody |
|Binds to CD52 on all B and T cells, most monocytes, macrophages, and natural killer cells, causing cell lysis and prolonged depletion||Induction/ACR||Mild cytokine release syndrome, neutropenia, anemia, idiosyncratic pancytopenia, autoimmune thrombocytopenia, thyroid disease|
|Antithymocyte globulin||Polyclonal IgG from horses or rabbits immunized with human thymocytes||Blocks T-cell membrane proteins, causing altered function, lysis, and prolonged T-cell depletion||Induction/ACR||Cytokine release syndrome (fever, |
chills, hypotension), thrombocytopenia,
leukopenia, serum sickness
|Rituximab||Chimeric monoclonal antibody |
|Binds to CD20 on B cells and mediates B-cell lysis||AMR||Infusion reactions, hypersensitivity |
|DRUG||CLASS||MECHANISM||MONITORING †||TOXICITY AND COMMENTS|
|Cyclosporine||CI||Binds to cyclophilin; complex inhibits calcineurin phosphatase and T-cell activation||2-hour postdose blood level or trough: initially 200-375 ng/mL, decreasing to 150-250 ng/mL ≥6 months from transplant *||Nephrotoxicity, hemolytic-uremic syndrome, hypertension, neurotoxicity, gum hyperplasia, skin changes, hirsutism, posttransplantation diabetes mellitus, hyperlipidemia|
|Tacrolimus||CI||Binds to FKBP12; complex inhibits calcineurin phosphatase and T-cell activation||Trough: Initially 10-15 ng/mL, decreasing to 5-10 ng/mL ≥6 months from transplant||Effects similar to those of cyclosporine but with a lower incidence of hypertension, hyperlipidemia, skin changes, hirsutism, and gum hyperplasia and a higher incidence of posttransplantation diabetes mellitus and neurotoxicity|
|Sirolimus||PSI||Binds to FKBP12; complex inhibits target of rapamycin and interleukin-2–driven T-cell proliferation||Trough: 4-12 ng/mL when used with a CI||Hyperlipidemia, increased toxicity of calcineurin inhibitors, thrombocytopenia, delayed wound healing, delayed graft function, mouth ulcers, pneumonitis, interstitial lung disease; lipid monitoring required; recipients whose risk of rejection is low to moderate can stop cyclosporine treatment 2 to 4 mo after transplantation|
|Everolimus||PSI||Derivative of sirolimus||Trough: 3-8 ng/mL when used with a CI||Similar to sirolimus|
|Mycophenolate mofetil or mycophenolic acid||AM||Inhibits synthesis of guanosine monophosphate nucleotides; blocks purine synthesis, preventing proliferation of T and B cells||Routine monitoring of MPA levels; cannot be recommended at this time||Gastrointestinal symptoms (mainly diarrhea), colitis, neutropenia, mild anemia; absorption reduced by cyclosporine|
|Azathioprine||AM||Converts 6-mercaptopurine to tissue inhibitor of metalloproteinase, which is converted to thioguanine |
nucleotides that interfere with DNA synthesis; prevents proliferation of T and B cells
|No routine blood level monitoring available; blood count monitoring required||Leukopenia, bone marrow suppression, macrocytosis, liver toxicity (uncommon)|
|Prednisone||Steroid||Block cytokine activation, interfere with cell migration, recognition, and cytotoxic effector mechanisms||No routine blood level monitoring available||Glucose intolerance, osteopenia, skeletal myopathy, hypertension, hyperlipidemia, weight gain, and cataracts|
Postoperative immunosuppression can vary greatly from program to program; however, the combination of tacrolimus, mycophenolate mofetil (MMF) or mycophenolic acid, and prednisone continue to be the most commonly prescribed immunosuppressive choices after heart transplantation. Several centers have published data describing rapid steroid weaning after transplantation with similar rejection rates compared with more traditional extended corticosteroid use. Also, with the use of newer induction agents, it is possible to safely minimize or completely avoid maintenance corticosteroid use. The use of induction immunosuppression has gradually increased over the last 15 years with 54% of centers worldwide using induction therapy. The majority of these patients receive an interleukin-2 receptor (IL2R) antagonist, and slightly fewer receive polyclonal antilymphocytic antibodies.
Drug interactions are a common concern with immunosuppressants. Prescription and over-the-counter medications, supplements, and nutraceuticals can have both pharmacodynamic and pharmacokinetic effects on many immunosuppressive agents ( Box 15-2 ) Frequently, interactions can occur with tacrolimus, cyclosporine, sirolimus, and everolimus, which are all metabolized by the cytochrome P450 3A4 isoenzyme. Numerous drugs that inhibit or induce this system are known to increase (diltiazem, allopurinol, amiodarone) or decrease (nafcillin, phenobarbitol, phenytoin) immunosuppressant exposure. Some drug interactions with immunosuppressants are significant enough to cause major morbidity, therefore careful consideration is required before initiation of additional drug therapy in this patient population.
Decrease Immunosuppression Levels
Antacids containing magnesium, calcium, or aluminum (tacrolimus only)
St. John’s wort
Increase Immunosuppression Levels
Protease inhibitors (general)
Prevention and Treatment of Posttransplant Complications
The major complications that occur following cardiac transplantation include infection, hypertension, diabetes, dyslipidemia, osteoporosis, CAV, renal insufficiency, and malignancy. The top three causes of mortality in patients who survive more than 5 years after transplant are malignancy, CAV, and graft failure. Changes in immunosuppression, alternative drug therapy, and lifestyle modification are techniques employed to minimize posttransplant morbidity and mortality.
Infections after transplantation occur in three distinct phases, with different risks associated with each. The early phase (<1 month) includes donor/recipient derived infections and nosocomial infections. The intermediate phase (1 to 6 months) includes infections by a number of viruses and bacteria—most notably herpesviruses, cytomegalovirus (CMV), Pneumocystis carinii pneumonia, Listeria, Toxoplasma gondii, Nocardia, and oropharyngeal Candida . The late phase (>6 months) includes more traditional infections: urinary tract infections, community-acquired pneumonia, late CMV, Aspergillus, Nocardia, and polyomavirus. The major focus of infection prophylaxis is in the early and intermediate phases.
The risk of viral opportunistic infection is related to the intensity and type of immunosuppression and the viral status of both the donor and the recipient. A recipient without prior CMV exposure who receives a heart from a CMV-positive donor has a 50% to 75% risk of developing CMV disease; a recipient with prior CMV exposure has a 10% to 15% chance, regardless of donor status. Patients at high risk for CMV disease generally receive oral ganciclovir (1000 mg PO three times daily) or valganciclovir (900 mg/day PO) with adjustment for renal function for 3 to 6 months or IV ganciclovir (5 to 10 mg/kg/day) for 1 to 3 months; some centers add CMV immune globulin. Patients at lower risk may use these regimens or preemptive therapy, monitoring with nucleic acid testing or CMV antigenemia assays and treating when patients test positive.
CMV disease is notorious for nonspecific symptoms and findings: the clinical presentation can range from a mild influenza-like illness to life-threatening pneumonitis or enteritis; therefore a high index of suspicion for CMV is required when evaluating constitutional, respiratory, or gastrointestinal (GI) complaints.
Pneumocystis carinii pneumonia is infrequently seen with current prophylactic strategies. The risk of this disease is greatest during the period of highest corticosteroid dosing, prompting the use of prophylactic trimethoprim-sulfamethoxazole (single-strength 80/400 mg tablet PO every day or double strength on alternate days) for the first 6 to 12 months, with less frequent dosing or discontinuation thereafter. This agent also appears to be effective against a variety of other pathogens, including Toxoplasma gondii, Listeria, and urinary tract pathogens. Atovaquone or dapsone may be acceptable alternatives in patients with sulfa allergy or in those who develop renal insufficiency or hyperkalemia on trimethoprim-sulfamethoxazole, and nystatin liquid or mycostatin troches are usually effective in preventing oropharyngeal candidiasis. Although these pathogens represent the most common targets for antibiotic prophylaxis in patients following cardiac transplantation, many other opportunistic and nonopportunistic infections can occur, and a high index of suspicion for opportunistic infections is required. A full discussion of the therapy of established infections is beyond the scope of this chapter.
Hypertension occurs frequently in cardiac transplant recipients; the incidence in long-term follow-up has been reported to be more than 70% at 1 year and as much as 95% at 5 years. Hypertension after cardiac transplantation may have several etiologies, including preexisting essential hypertension, chronic use of calcineurin inhibitors, chronic kidney disease, and alterations in function of the renin-angiotensin-aldosterone system.
Most standard antihypertensive agents are safe and are likely to be effective in patients following cardiac transplantation. A randomized comparison of diltiazem and lisinopril in hypertensive transplant patients found both agents to be safe, but neither consistently provided adequate blood pressure control when used as monotherapy. Diltiazem may have the ancillary benefits of raising calcineurin levels and, in one study, of slowing the development of CAV. In practice, multidrug regimens for the control of hypertension are common and often include adrenergic antagonists such as α-blockers or clonidine. A thorough understanding of potential drug interactions is mandatory.
Cardiac transplantation in patients with diabetes at the time of surgery appears to offer a similar outcome to transplant in patients without diabetes. In the first year after cardiac transplantation, however, preexisting diabetes frequently becomes much more difficult to treat. In addition, many patients will develop diabetes for the first time during this period, primarily as a result of corticosteroid and calcineurin therapy. This is why many innovative immunosuppression strategies have been used to either minimize steroid exposure or use no steroids after transplantation.
Either oral agents or insulin may be effective in the treatment of transplant-related diabetes. Metformin is generally avoided because of concerns over renal dysfunction. Referral to a diabetes management specialist or program can help to optimize glycemic control and address modifiable factors such as obesity. Consensus guidelines for the management of diabetes in transplant recipients have been published.
Dyslipidemia develops in 50% of patients at 1 year and in more than 80% at 5 years and appears to be more severe in patients treated with cyclosporin A as compared with tacrolimus; fewer patients treated with tacrolimus require lipid-lowering therapy. A small, randomized trial in patients with posttransplant dyslipidemia compared simvastatin, gemfibrozil, and cholestyramine and demonstrated superior total and LDL cholesterol–lowering effects for simvastatin, whereas gemfibrozil improved triglyceride levels. A larger, longer-term randomized trial of simvastatin started early after heart transplantation versus dietary therapy alone revealed significant reduction in mortality, rates of CAV, and severe rejection without significant adverse effects in the simvastatin group. This and other studies suggest that statins may have beneficial immunomodulatory effects independent of their effects on lipids. A head-to-head nonrandomized comparison of simvastatin and pravastatin suggested greater safety and efficacy of pravastatin. Atorvastatin also appears to be safe and effective in the treatment of dyslipidemia in the transplant patient. Accordingly, pravastatin and atorvastatin are the generally preferred agents. The risk of myositis and rhabdomyolysis is increased with statin use in patients following cardiac transplantation, necessitating use of lower doses and less aggressive lipid targets along with heightened clinical surveillance for such complications when using higher doses or combinations of agents.
Cardiac Allograft Vasculopathy
CAV is now the most common cause of late allograft dysfunction in patients following cardiac transplantation. Risk factors for the development of CAV include the frequency and severity of cellular rejection, smoking, dyslipidemia, diabetes, antecedent coronary artery disease in either the recipient or donor, and older age of either the recipient or donor. Studies indicate a potential role of systemic inflammation and infectious agents in the development of CAV, which is associated with both worse functional status and worse survival, with late manifestations that include refractory HF and sudden cardiac death. During transplantation, the innervation to the heart is disrupted, and the transplanted heart becomes reinnervated only infrequently, and only partially; because of this, most patients do not develop angina, so a regular screening strategy is necessary. Intravascular ultrasound is the most sensitive diagnostic test for the detection of CAV, but it is infrequently used because of cost considerations and center inexperience. Thus coronary angiography, radionuclide perfusion imaging, and dobutamine stress echocardiography are the screening tests of choice (see Table 15-3 ). CAV may be a diffuse, concentric, and often distal process not amenable to percutaneous or surgical revascularization. On occasion, however, it may manifest as discrete, proximal stenoses treatable by standard revascularization techniques.
Medical therapy of CAV generally includes the use of a statin to aggressively lower cholesterol and changes in maintenance immunosuppression. In addition to their beneficial effects on serum lipid levels, statins preserve coronary endothelial function and modulate the elaboration of proinflammatory cytokines in the transplanted heart. Long-term follow-up data also suggest that statins improve survival in heart transplant recipients. When combined with CsA, corticosteroids, and statins, everolimus decreased the incidence of CAV within the first year after cardiac transplantation compared with azathioprine added to the same combination. In patients with established CAV, substituting sirolimus for azathioprine or MMF, in combination with corticosteroids and a calcineurin inhibitor, may attenuate disease progression. Coronary angioplasty and stenting have both been used with acceptable results in the treatment of CAV. In addition, standard, off-pump, and minimally invasive coronary artery bypass grafting (CABG) have been successfully performed in highly select patients who have undergone cardiac transplantation. Retransplantation for CAV appears to have greater success than when it is used for acute graft failure or acute cellular rejection. Although the rate of early mortality following retransplantation for CAV is comparable with that of initial transplantation, long-term survival is worse.
The risk of renal insufficiency is related to patient age, baseline renal function, and the development of hypertension. The incidence of end-stage renal disease after cardiac transplantation is 6.3% in patients who survive 10 years, and survival in those who experience renal failure is significantly worse than in those with preserved renal function. It is generally accepted that calcineurin inhibitor use increases the risk of renal insufficiency. The conversion of patients from a calcineurin inhibitor–based immunosuppressive regimen to one based on MMF and sirolimus or everolimus appears to be safe and effective and is associated with an improvement in renal function. Hemodialysis, peritoneal dialysis, and renal transplantation have all been reported to be acceptable therapies for end-stage renal disease in cardiac transplant patients.
The final major cause of morbidity and mortality in patients after cardiac transplantation is malignancy, which is the leading cause of death in patients who survive more than 5 years after transplantation. Additionally, according to the heart transplant registry data, 14% of 5-year and 30% of 10-year survivors after transplant have had some form of malignancy. Recipients of organ transplants have a greater risk of developing most cancers, and heart transplant recipients in particular seem to have a significantly higher risk of developing lymphomas (Epstein-Barr virus–associated posttransplant lymphoproliferative disease [PTLD]) and skin cancers. One large study of patients after heart transplantation found an overall incidence of PTLD of 6% and an incidence among long-term survivors of 15%. In general, the risk of malignancy appears to correlate with the intensity and duration of immunosuppression. Patients exposed to lytic induction therapy and those who receive lytic therapy for treatment of severe rejection are at particularly high risk. Although younger recipients of cardiac transplants may be at higher risk for PTLD, patients who are older at the time of transplantation appear to be at significantly increased risk for non-PTLD cancers. PTLD often responds to a decrease in the intensity of immunosuppression, with or without concomitant antineoplastic therapy. Disease progression can often be monitored with serial positron emission tomography (PET) or computed tomography (CT) scanning. An anti-CD20 monoclonal antibody, rituximab, has been reported to be of benefit in select cases.
Skin cancers that develop in transplant recipients, particularly squamous or basal cell carcinomas, generally respond well to local excision. Additional treatment may include oral retinoids or topical chemotherapy agents ; however, recurrence is common regardless of therapy. Because of this high rate of recurrence, many programs may choose to alter maintainance immunosuppression in an effort to decrease risk. Specifically, calcineurin-free therapy, utilizing either sirolimus or everolimus in addition to a low-dose MMF product has been used in stable, low-risk patients. The majority of these data are from the renal and liver transplant populations, but the results are impressive, with up to a threefold reduction in risk of solid organ and skin cancer. These benefits can occur as early as 2 years after calcineurin discontinuation. Alterations in long-standing maintenance immunosuppression carry inherent risks of rejection, therefore close immunologic and histologic surveillance is necessary.
The last several decades have seen significant improvements in the management of patients before and after cardiac transplantation. One challenge for the future will be to extend the life expectancy of patients following transplantation. This will depend on our ability to prevent and treat the long-term complications of transplantation, including many of the long-term consequences of immunosuppression. Toward this end, extensive investigation is underway into possible strategies for minimization of maintenance immunosuppression. If successful, such strategies would likely yield an optimal posttransplant outcome. Ongoing investigation in the fields of xenotransplantation and regenerative medicine may offer the possibility of an unlimited supply of donor organs and allow for expansion of transplantation to increasing numbers of patients.