CHAPTER 72: CARDIAC TRANSPLANTATION

Despite major advances in the treatment of end-stage heart disease, a sizable number of patients with refractory heart failure (HF), progressive angina, or uncontrolled ventricular arrhythmias cannot be stabilized with medical or interventional/surgical therapy and suffer significant morbidity and mortality.¹ In these patients, biological replacement of the heart (cardiac transplantation) has become standard therapy and is widely accepted to improve quality and quantity of life in carefully selected patients. As technologic and engineering advances occur, support or replacement of the heart by mechanical devices (mechanical circulatory support [MCS]) offers additional options for patients with end-stage heart disease as a bridge to recovery, bridge to transplantation, or destination therapy.

Early efforts to implant a functioning donor’s heart into a recipient’s circulation date back to the early part of the twentieth century. In 1905, Carrel and Guthrie² described the heterotopic transplantation of a functioning donor heart into the neck of a dog. The heart in that model functioned together with the recipient’s heart in the circulation but was not capable of supporting the circulation. Although the exact anatomic connections were not described in detail in the original publication, this model of heterotopic transplantation beat regularly for approximately 2 hours before the blood clotted in all of the chambers. Carrel and Guthrie developed innovative surgical techniques for vascular anastomosis at the University of Chicago, and those advances set the stage for future organ transplantation.³ These techniques included using ever-finer needles and sutures made slick with petroleum jelly, developing the triangulation method of small vessel anastomosis, and perfecting the everting anastomosis technique.⁴ This work was partially responsible for Carrel’s Nobel Prize for Physiology or Medicine in 1912.

It was not until 1933 that Mann and coworkers⁵ at the Mayo Clinic published their seminal report of a technique for heterotopic heart transplantation. Because this was a canine working model, the chambers did not clot immediately, and the hearts beat for a mean of 4 days. Mann and coworkers established several important surgical principles or tenets, including the importance of avoiding ventricular distention and air embolism and the prevention of thrombosis by heparin. Their most incisive observation was that failure of a transplanted heart was not always caused by faulty surgical technique “but to some biologic factor which is probably identical to that which prevents survival of other homotransplanted tissues and organs.”⁵ In what was undoubtedly the first description of acute allograft rejection, Mann and coworkers recount: “When the heart was removed just before it became quiescent … the surface of the heart was covered with mottled areas of ecchymoses … histologically, the heart was completely infiltrated by large mononuclears and polymorphonuclears.”⁵ It took another 30 years to understand and manipulate the “biologic factor” these authors had described as limiting the survival of allograft organs.

In 1960, Lower and Shumway⁶ performed orthotopic heart transplants in dogs using cardiopulmonary bypass and topical hypothermia for donor heart preservation. The dogs survived between 6 and 21 days and died of rejection. The main difference from the work of Mann and colleagues was that Lower and Shumway immersed the donor heart in cold saline, used cardiopulmonary bypass in the recipient, and combined the pulmonary venous and vena caval anastomoses into two atrial anastomoses. Lower and Shumway also recognized that “if the immunologic mechanisms of the host were prevented from destroying the graft, in all likelihood it would continue to function adequately for the normal lifespan of the animal.”⁶ Their technique remained the basis of cardiac transplantation technique through the 1990s.

In the early 1960s, the concept of pharmacologic immunosuppression was introduced; it ushered in the marriage of surgical and medical knowledge that characterizes the modern field of organ transplantation. Immunosuppression was viewed as a means to mitigate the “biologic factor” that otherwise limited organ graft survival. The first clinical transplants were of the kidney, which was a logical choice because hemodialysis was then available as a backup treatment if the graft failed, and the field has flourished since the early 1960s.⁷

The first human heart transplant was performed in South Africa in December 1967,⁸ followed shortly thereafter by the first US heart transplant by Shumway and colleagues at Stanford in January 1968. A flurry of transplant activity began at many centers, but the initial enthusiasm waned as it became evident that postoperative survival was limited by a variety of complex medical problems, including opportunistic infections and graft rejection. Most major centers discontinued their heart transplant programs in the early 1970s. It was not until the introduction of cyclosporine-based immunosuppression in 1980 and the demonstration of the attendant improvement in survival rates⁹ that the procedure re-emerged as a widely accepted therapy for end-stage heart disease. By the 1990s, many tertiary care and academic centers had established programs for heart transplantation, and most medical care payers in the United States, including the federal government, provided coverage for such care. Currently, there are almost 6 million patients in the United States with HF, with an estimated 300,000 with end-stage HF who would be potentially eligible for heart transplantation or MCS.^10,11 However, because of limited donor availability, the number of heart transplantations performed worldwide is estimated to be more than 4000 procedures annually.¹²

Indications

Given the relative scarcity of donor organs, it is essential to determine if end-stage HF patients are truly refractory to maximal medical therapy and merit transplant evaluation. The commonly acceptable indications for heart transplantation are shown in Table 72–1. Generally, the three major indications for heart transplantation are severe functional limitations, refractory angina, and ventricular arrhythmias refractory to maximal medical therapy.¹³ The most common indication for heart transplantation is intractable HF. Patients with severe angina in the absence of HF are often not considered, since the survival benefit is unclear. Intractable ventricular arrhythmias, commonly referred to as “VT storm,” may merit heart transplant evaluation and often urgent listing given the associated hemodynamic compromise and mortality.

Although these indications for cardiac transplantation are generally well accepted, identifying the subgroup of patients that is most likely to derive a benefit from transplantation can be challenging. Optimization of medical therapy is a crucial part of determining if a patient would benefit from heart transplantation. Standard of care for patients with HF with reduced systolic function includes an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker, β-receptor antagonist, and mineralocorticoid antagonists to improve symptoms and survival.¹⁴ A new class of medication, the angiotensin receptor–neprilysin inhibitor combination sacubitril/valsartan, has proven superior to an ACE inhibitor alone in reducing HF hospitalization and mortality, and will likely become standard of care instead of ACE inhibitors in HF patients.¹⁵ Digoxin reduces rehospitalization in HF patients.¹⁶ In addition to optimal medical therapy, device therapy with implantable defibrillators saves lives.¹⁷ In appropriate candidates with increased QRS duration > 120 ms, especially in those with left bundle branch block, cardiac resynchronization improves symptoms and survival.^18,19,20 For patients with ischemic cardiomyopathy, surgical revascularization may also be indicated to improve long-term survival.¹⁹ Aggressive medical therapy has led to significant improvement in stable HF patients, with a survival of close to 75% at 5 years. However, in patients refractory to medical management, survival is estimated at 20% at 5 years.¹ It is in these end-stage patients that more advanced therapy should be considered.

Thus, the goal of a heart transplant evaluation is to determine if (1) the patient’s cardiac status is limited enough, on optimal medical therapy, to benefit from heart transplantation (ie, “sick enough”); (2) the patient does not have comorbidities that would preclude heart transplantation (ie, “well enough”); and (3) the patient demonstrates compliance and possesses adequate social support (“can adapt to new transplant lifestyle”). At an advanced HF center, patients may undergo right heart and pulmonary arterial catheterization for optimization of filling pressures and cardiac output and to ensure absence of severe pulmonary hypertension, revascularization of coronary artery disease, or ablation of ventricular tachycardia, before considering heart transplantation. As a result, most heart transplant centers have evolved into centers for advanced HF management in addition to providing the opportunity for transplantation or mechanical support.

Role of Exercise Testing

In ambulatory patients, evaluation often includes cardiopulmonary exercise stress testing to determine if a patient is limited enough to merit heart transplant evaluation.^21,22 The cardiopulmonary exercise stress test measures maximal oxygen consumption (VO₂ max), which is proportional to cardiac output. Patients with a peak VO₂ of more than 14 mL/kg/min have 1- and 2-year survival rates that are comparable or better than those achieved with transplantation, and these patients should be managed medically and undergo serial exercise testing.^21,22 In the original publication, the threshold of 14 mL/kg/min was not based on a sensitivity/specificity analysis. Instead, this threshold was selected as a criterion for acceptance for cardiac transplant based on the investigators’ prior experience that patients with peak VO₂ levels below this threshold had significant functional limitations and based on exercise data in the literature. The literature at the time suggested that peak VO₂ level was an independent predictor of death²³ and that an exercise capacity under 4 metabolic equivalents (equivalent to a peak VO₂ under 14 mL/kg/min) was a stronger predictor of death in patients with HF after myocardial infarction.²⁴

Patients with a peak VO₂ between 10 and 14 mL/kg/min constitute an intermediate-risk group in which continued medical therapy may offer a survival benefit similar to heart transplantation among selected patients who are able to tolerate β-blockers and have the protection of an internal defibrillator.^25,26 In patients tolerating β-blockers, a peak VO₂ of less than 12 mL/kg/min has been suggested as an appropriate threshold to identify individuals who are likely to derive a survival benefit from transplantation.²⁷ Patients with a peak VO₂ of 10 mL/kg/min or less, regardless of β-blocker use, have significantly reduced survival rates with medical therapy compared with cardiac transplantation, and these patients should be listed for transplantation.^24,28 Adequate effort is defined as the patient’s achievement of anaerobic threshold, at which point CO₂ production exceeds O₂ consumption (indicated by the respiratory exchange ratio > 1.10).^29,30,31 Other parameters of cardiopulmonary exercise testing that are also associated with increased mortality include a predicted VO₂ max < 50%³² and minute ventilation/CO₂ production slope > 35³³ and may be considered in the evaluation for heart transplantation. A score developed by Myers and colleagues³⁴ may offer further refine the use of cardiopulmonary exercise testing in HF. Based on their score, which combines ventilator efficiency, VO₂ max, heart rate recovery, O₂ uptake efficiency slope, expired CO₂, and chronotropic response, a score > 15 portends a high 1-year mortality, in excess of 40%.

At an advanced HF center, end-stage patients may also be evaluated for MCS. MCS is considered for patients with end-stage HF as (1) a bridge to recovery, for those individuals who require temporary circulatory support and are expected to recover; (2) a bridge to transplantation, for those patients with progressive decline in organ perfusion on escalating inotropic therapy while awaiting transplantation; and (3) destination therapy, for those individuals with contraindications to heart transplantation, include advanced age.³⁵ The decision to proceed with MCS in the form of a left ventricular assist device, biventricular assist device, or total artificial heart as a bridge to transplantation will vary from center to center, depending on the patient’s projected wait time to transplantation, degree of hemodynamic compromise, and anatomic consideration (for total artificial heart). In general, heart transplantation is usually the preferred option for end-stage HF patients, and MCS is reserved for patients who are not candidates for transplantation or who cannot survive until a heart becomes available. The options considered for patients may also vary by regions as donor wait time may be significantly different.

Contraindications

Appropriate candidates for cardiac transplantation should have severe functional limitations, limited life expectancy from their heart disease, and a limited number of established contraindications (Table 72–2). Many of these factors are not absolute and need to be considered in the context of the severity of the patient’s heart disease and associated comorbidities. The degree to which they are interpreted and applied may vary considerably among transplant programs.

Advanced Age

In general, patients are considered for heart transplantation if they are 70 years of age or less, since advances in post-transplant care have shown that survival in the older age group is comparable to that of younger recipients.¹² Patients over the age of 70 years have also been reported to have acceptable outcome, but careful consideration of associated comorbidities is essential in these cases. At some centers, such patients are offered nonstandard donor hearts, including those with coronary artery disease, mildly decreased left ventricular ejection fraction, left ventricular hypertrophy, or donor age older than 55 years. This practice allows older patients to undergo heart transplantation without denying the scarce resource to younger potential recipients, with comparable outcomes.³⁶ Physiologic age may be more important than chronologic age with respect to survival and rehabilitation potential. As a result, many programs are moving away from fixed upper age limits and instead focus on a patient’s functional status, integrity of major organ systems, and the presence of comorbidities that might impact survival, rehabilitation potential, and quality of life.

Pulmonary Hypertension

Pulmonary hypertension from chronic elevation of left ventricular end-diastolic pressure is a common complication of long-standing HF and can result in irreversible changes to the pulmonary vasculature over time if left unrecognized and untreated.³⁷ In the early years of heart transplantation, it was discovered that a normal donor right ventricle is unable to increase its external workload acutely to overcome elevated pulmonary vascular resistance (PVR), resulting in acute right ventricular failure and cardiogenic shock postoperatively.³⁸ Elevated PVR remains a strong risk factor for right ventricular failure and early postoperative mortality in the modern era. Potential heart transplant candidates must therefore undergo measurements of pulmonary artery pressures and calculation of PVR in the cardiac catheterization laboratory or in the intensive care unit as part of their transplant evaluation.

A pulmonary artery systolic pressure above 50 to 60 mm Hg, a PVR value above 5 Wood units, or a transpulmonary gradient above 15 to 20 mm Hg is usually considered prohibitive of successful heart transplantation. A vasodilator challenge should be administered when the pulmonary artery systolic pressure is ≥ 50 mm Hg and either the transpulmonary gradient is ≥ 15 or the PVR is > 3 Wood units. Pharmacologic interventions for reducing PVR include administration of intravenous agents such as nitroprusside, prostaglandin E₁, nesiritide, milrinone, and dobutamine or use of inhaled nitric oxide. The use of oral phosphodiesterase-5 inhibitors (sildenafil) has been shown to improve pulmonary hypertension caused by left ventricular systolic dysfunction sufficiently to allow heart transplantation.³⁹

A vasodilator challenge is considered successful if the PVR can be reduced below 2.5 Wood units with a vasodilator while maintaining a systolic arterial blood pressure over 85 mm Hg. If the PVR cannot be reduced below 2.5 Wood units or if the systolic blood pressure falls below 85 mm Hg with reduction in the PVR, the patient remains at high risk of right HF and death after cardiac transplantation. In this situation, hospitalization with continuous hemodynamic monitoring should be performed, as often the PVR will decline after 24 to 48 hours of treatment consisting of diuretics, inotropes, and vasoactive agents. If this strategy is unsuccessful, longer-term unloading with an intra-aortic balloon pump or left ventricular assist device may be considered.²² In one study, after 6 months of left ventricular assist device support, mean PVR decreased from 3.5 to 1.5 Wood units.⁴⁰ In another study, mean PVR decreased from 5 to 2.1 Wood units after 3 months of left ventricular assist device support.^13,22,41

Infections

Patients must be free of active infection before transplantation because infections can be exacerbated by the immunosuppression that is required after transplantation to prevent rejection. The presence of an active systemic infection or severe localized infection is often considered a temporary contraindication to transplantation. Patients with a history of infection should not be activated or reactivated on the transplant waiting list until there is sufficient evidence that the infection is resolved or under control, as demonstrated by absence of fever for a minimum of 72 hours on appropriate antibiotics, a normal white blood cell count, negative blood culture results, and resolving signs or symptoms of infection.

The evaluation of patients with chronic viral infections such as hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) remains controversial, and such patients are considered poor transplant candidates by many centers.^42,43 Whether the use of the new nucleotide polymerase inhibitors that may achieve a sustained virologic response in patients with hepatitis C will change this relative contraindication is not yet clear, but is changing practice at many centers. At some centers, HIV infection is no longer considered a contraindication to heart transplantation as long as the patient has no opportunistic infections, acceptable CD4 count, and an undetectable viral load and acceptable outcomes have been achieved in selected patients.^44,45,46 Chagas disease, while uncommon in the United States, is a common indication for transplantation in South America, and reactivation of disease can occur.⁴⁷ The decision to proceed with transplantation in these situations must be made in collaboration with an infectious disease specialist well-versed in transplantation.

Malignancy

In general, patients with active malignancies, with the exception of nonmelanoma cutaneous cancers, primary cardiac tumors restricted to the heart, and low-grade neoplasms of the prostate, should be excluded from cardiac transplantation. However, pre-existing neoplasms are diverse with respect to their response to immunosuppressive therapy and risk of recurrence. Consultation with an oncologist should be obtained for any patient with a history of previous or active malignancy to assess the risk of tumor recurrence. Cardiac transplantation should be considered when the risk of tumor recurrence is low based on the tumor type, response to therapy, and negative metastatic workup. The specific amount of time to wait before transplantation after neoplasm remission should depend on the aforementioned factors, and no arbitrary time period for observation should be used.

Other Comorbidities

Potential cardiac transplant recipients are screened for the existence of other conditions or systemic diseases that may independently limit their survival or rehabilitation potential. Obese patients have a greater risk of poor wound healing, infections, and pulmonary complications after cardiac surgery, although the outcomes in heart transplant recipients are less clear.¹² Nevertheless, it is recommended that patients achieve a body mass index < 30 kg/m² before listing. This may be difficult to achieve in patients with poor functional status, and most centers will consider patients with a body mass index < 35 kg/m² or slightly higher thresholds in patients of African or Pacific Islander race.

The presence of pre-existing insulin-requiring diabetes mellitus was once considered a relative contraindication to heart transplantation because of concerns regarding diminished survival, increased infection rates, and worsening glycemic control with the initiation of corticosteroid immunosuppression. However, several reports have demonstrated similar short- and long-term survival rates in diabetic and nondiabetic groups, as well as similar rates of infection, rejection, renal function, and cardiac allograft vasculopathy.^48,49,50 Although the safety and efficacy of heart transplantation in these very carefully selected patients have been documented in the literature, most transplant programs continue to consider the presence of diabetes with end-organ damage (proliferative retinopathy, neuropathy, or nephropathy) a relative contraindication to transplantation. Corticosteroid therapy may worsen glycemic control in patients with pre-existing diabetes, and thus the presence of poorly controlled diabetes is also considered a relative contraindication for transplantation. At most centers, patients are expected to achieve control with a hemoglobin A1c under 7.5% before listing for transplantation; ongoing collaboration with an endocrinologist is helpful in achieving this goal. In patients with poorly controlled diabetes mellitus, early weaning of steroids before 6 months is sometimes considered.

Other comorbid conditions must be considered on an individual basis, but irreversible organ dysfunction, such as pulmonary fibrosis, severe emphysema, and hepatic or renal dysfunction, out of proportion to that predicted as a consequence of severe HF are strong relative contraindications. Selected patients with irreversible renal or hepatic dysfunction may be considered for multiorgan transplantation.^51,52,53,54 The presence of cardiac cirrhosis has been considered a contraindication to heart transplantation as a result of concern for progressive liver failure and increased mortality, although data are sparse.⁵⁵

Advanced noncardiac vascular disease, in the form of symptomatic cerebrovascular disease or peripheral vascular disease that is not amenable to revascularization, is considered a relative contraindication to transplantation if the condition is expected to limit survival or impair rehabilitation after transplantation.

Experience has shown that pulmonary infarcts have a high probability of becoming pulmonary abscesses after the institution of immunosuppression. For this reason, potential recipients who sustain a pulmonary infarction are usually temporarily removed from the waiting list until the infarct resolves as shown radiographically.

Psychosocial Factors

All cardiac transplant candidates should undergo a careful psychosocial assessment with emphasis on current and previous substance abuse history, compliance with medical therapy and follow-up, comprehension of, and ability to follow, a complex medical regimen, and adequacy of social support. Active cigarette smoking is a contraindication to heart transplantation, and smoking during the previous 6 months before transplant is a risk factor for poor outcomes.^13,22 At most centers, patients must display abstinence from smoking for 6 months, documented by urine nicotine screens, prior to listing. Addiction to alcohol or illicit drugs is an absolute contraindication, as it suggests that these patients will have poor compliance after transplantation, and 6 months of abstinence with participation in counseling programs are required. This assessment may be difficult to make in the critically ill patient in whom transplantation cannot be delayed for 6 months. In this scenario, consultation with social workers and psychiatrists is essential to gauge the patient’s commitment to abstinence.

In addition to freedom from dependence on cigarettes, alcohol, and illicit substances, patients must be able to demonstrate the ability to comply with medications and follow-up after transplantation, which includes social support with a dedicated caregiver. Patients have been denied transplantation as a result of lack of compliance and social support. Mental retardation and dementia are relative contraindications to heart transplantation; the former because of concerns of compliance and the latter because of overall poor prognosis.

Special Considerations

A small, but substantial, proportion of patients with advanced HF are affected by diseases expressing a phenotype not characterized by left ventricular dilation and hypokinesis, and are usually unresponsive to traditional pharmacologic and device therapy. These diseases include hypertrophic cardiomyopathy, restrictive cardiomyopathies, and infiltrative cardiomyopathies such as sarcoidosis or amyloidosis.⁵⁶ These diseases represent a challenge to the traditional management of end-stage systolic HF. Prognosis, therapeutic strategies, and indications for heart transplantation in these patients require disease-specific considerations and often assessment of extracardiac organ involvement. Furthermore, experience with MCS is limited in patients with restrictive or infiltrative cardiomyopathies⁵⁷ and not currently recommended.²²

Changing Face of Heart Transplantation

Although heart transplantation has become standard of care for the management of end-stage HF, the role of heart transplantation is changing as the characteristics of heart transplant candidates continue to evolve.⁵⁸ Heart transplant candidates are increasingly more complex: they are older, recipients of MCS, and sensitized.

The proportion of candidates aged 65 years or older has increased; in 2013, 18.2% of candidates in the United States were aged 65 years or older, compared with 10.8% in 2003.⁵⁹ The proportion of candidates with MCS (most commonly ventricular assist devices) at listing has also increased dramatically, from 7.5% in 2003 to 27.4% in 2013.⁵⁹ Furthermore, the number of heart transplant candidates with antibodies to human leukocyte antigens (HLA), so-called “sensitization,” has increased over the past decade.⁶⁰

The heart transplant candidates of the modern era—older, sensitized, with MCS—are at higher risk for poor outcomes, including primary graft dysfunction and antibody-mediated rejection.^12,59,61 Strategies to mitigate this risk are ongoing, including proposed changes in heart transplant allocation policy for more equitable organ distribution,^62,63 a better understanding of the definition and management of primary graft dysfunction,⁶⁴ and advances in the management of sensitized heart transplant candidates.^65,66 Developments in these areas could result in more equitable distribution and expansion of the donor pool and improved quality of life and survival for heart transplant recipients.

Acceptance of the concept of irreversible brain death, both legally and medically, has been integral to the emergence of organ transplantation in the modern era. Brain death is defined as irreversible cessation of all functions of the entire brain.⁶⁷ The heart does not need to stop for a valid declaration of death, and this definition has facilitated heart transplantation. Criteria for brain death have been adapted from the Harvard Ad Hoc Committee (1968)⁶⁸ and codified into law in the Uniform Determination of Death Act (1981) following the President’s Commission Report. Fundamental requirements for brain death are summarized in Table 72–3.⁶⁹

The most common causes of brain death include intracranial hemorrhage, blunt traumatic injury to the head, penetrating traumatic injury, and anoxic brain injury. Patients with irreversible brain injury accompanied by the intent to withdraw life support are also considered potential organ donors. The complete absence of brainstem function is not required; many patients who meet all the criteria for brain death do not, in fact, have irreversible cessation of all functions of the entire brain, because some of the brainstem’s homeostatic functions remain, such as temperature control and water and electrolyte balance.⁷⁰

Donor Evaluation

After a potential donor is identified, the procurement process is initiated by contacting the local, or “host,” organ procurement organization (OPO). The host OPO is responsible for obtaining consent for organ donation, verifying pronouncement of brain death, evaluating and managing the donor, and equitably allocating the donor organs. The process of donor evaluation begins with a detailed history and physical examination, focusing on cause of death, past medical history, donor height and weight, and clinical course. Basic laboratory studies, including a complete blood count, metabolic panel, ABO blood typing, and viral serologies (hepatitis B and C, HIV, human T-cell leukemia virus, Ebstein-Barr virus [EBV], and cytomegalovirus), are ordered; in addition, other serologies may be obtained in the presence of outbreaks such as West Nile virus or in donors considered high risk for infections such as Chagas disease. Additional studies include chest radiography, 12-lead electrocardiography (ECG), and echocardiography.

To be considered suitable donors for cardiac transplantation, brain-dead individuals must meet certain minimum criteria (Table 72–4). Most cardiac donors are younger than 55 years of age, although older donors may be used selectively in critically ill or older recipients. There should be no evidence of severe cardiothoracic trauma or cardiac puncture. An initial echocardiogram is performed to identify significant structural heart disease, such as left ventricular hypertrophy or dysfunction, occlusive coronary artery disease, valvular dysfunction, and congenital lesions. Donors with these conditions are typically excluded, although selected marginal organs may be allocated to higher risk recipients. Angiography is performed to exclude significant coronary artery disease in male donors older than 45 years of age and in female donors older than 50 years of age, but may also be performed in younger patients with multiple risk factors for coronary artery disease. Patients with active malignancy (excluding nonmelanocytic skin cancers and certain isolated brain tumors) or severe systemic infections are typically excluded. HIV and hepatitis B and C infections would preclude organ donation, although whether hepatitis C donors will be considered with the advent of new nucleotide polymerase inhibitors that offer a potential for cure remains to be seen.⁷¹

Donor Management

After brain death has been determined and the patient has been identified as a potential organ donor, the main goals of organ donor management are to ensure optimal organ function by providing volume resuscitation; optimizing cardiac output; normalizing systemic vascular resistance; maintaining adequate oxygenation; correcting anemia, acid-base, and electrolyte abnormalities; and correcting hormonal imbalances that occur after brain death and that can impair circulatory function. Standardized algorithms incorporating early use of invasive hemodynamic monitoring along with aggressive hemodynamic management and hormonal resuscitation with insulin, corticosteroids, triiodothyronine, and arginine vasopressin have been proposed to improve cardiac donor management and maximize organ utilization, particularly in patients with a left ventricular ejection fraction below 45% on initial echocardiography.⁷² In brain death, particularly in cases of subarachnoid hemorrhage, there is a catecholamine surge that can result in left ventricular dysfunction and regional wall motion abnormalities.⁷³ This dysfunction is often not associated with structural abnormalities and may be reversible, so such donors may ultimately be acceptable for transplantation.^74,75

Most donor hearts are currently harvested locally from the donor by an organ procurement team from the transplant center and transported back to the center for implantation. A cold ischemic period of less than 4 to 6 hours in adult hearts is generally considered optimal. This requirement for short ischemic times leads to the rationale for geographic subdivision into OPOs for cardiac allografts despite the drive for a national list for other organs.

Currently, fewer than 50% of potential organ donors in the United States become actual donors.⁷⁶ Despite ongoing efforts to increase the identification of potential donors, increase the consent rate among eligible donors, expand donor selection criteria, and maximize potential donor organ function, heart transplantation will likely remain a donor-limited field for the foreseeable future.

In an effort to expand the donor pool, recently donation after circulatory death (DCD) has been successfully employed for heart transplantation.⁷⁷ In DCD, retrieval of organs for the purpose of transplantation occurs from patients whose death is diagnosed and confirmed using cardiorespiratory criteria. Asystole must be confirmed for at least 5 minutes for declaration of death. This may occur following cardiac arrest awaited after planned withdrawal of life support in patients who are not brain dead. The challenge for heart transplantation using DCD donors is the minimization of ischemic injury of the donor organs.

One way to minimize ischemic injury would be to limit cold ischemic time through use of an ex vivo heart perfusion platform that maintains the donor heart in a warm, beating state for transplantation. In a trial to assess the safety of an ex vivo platform, 130 patients were randomized to receive donor hearts preserved with either the Organ Care System or standard cold storage. There was no difference in 30-day patient and graft survival rates or serious adverse events.⁷⁸ An ongoing phase III clinical trial, the EXPAND trial (International Trial to Evaluate the Safety and Effectiveness of the Portable Organ Care System [OCS”] Heart for Preserving and Assessing Expanded Criteria Donor Hearts for Transplantation; NCT02323321), will offer further insight into the utility of this platform.

Organ Matching and Allocation

Donor-recipient matching is performed based on ABO blood group compatibility and overall body size. Although the benefit of matching donor organs and recipients with respect to HLA has been well established in renal transplantation, HLA matching is not performed in potential heart transplant recipients because of the relative scarcity of donor organs. However, heart transplant candidates who are sensitized (those with preformed anti-HLA antibodies related to prior pregnancy, transplant, blood transfusions, or MCS) will undergo crossmatching to determine if there are potentially cytotoxic antibodies against the donor HLA. This can be performed with a prospective crossmatch whereby donor cells are mixed with recipient serum to assess for cell-dependent cytotoxicity prior to heart transplantation. Although this is the gold standard, a prospective crossmatch constrains the donor pool to OPOs where recipient serum can be banked for comparison. The “virtual crossmatch” is a relatively newer advance where the recipient’s HLA antibodies are compared to the donor’s HLA type. Donors with HLA types that correspond to the presence of HLA antibodies in the recipient are avoided. This major advance in antibody management expands the donor pool and has been found to be comparable in accuracy and safety to the prospective crossmatch in many cases.⁷⁹ However, a prospective crossmatch is still employed for heart transplant candidates with multiple high-level HLA antibodies for which potential cytotoxicity cannot be adequately predicted, and thus a virtual crossmatch is considered less reliable.⁸⁰

Allocation of thoracic organs in the United States is made according to the recipient’s priority on the United Network for Organ Sharing (UNOS) waiting list and geographic distance from the donor. Priority on the recipient waiting list is determined by a recipient’s assigned status code and time accrued within a status code. In general, patients with the highest medical urgency and lowest expected short-term survival are assigned a higher status code (Tables 72–5 and 72–6). Donor hearts are first offered to local Status 1 patients and then extended to Status 1 patients within a 500-mile radius of the donor hospital (Zone A). If no eligible recipients are identified, the organ is offered to local Status 2 patients. This process repeats in a sequence of “zones” delineated by subsequent concentric circles of 1000- and 1500-mile radii from the donor hospital.⁵⁹

As a result of the emerging MCS population and need to further reduce waitlist mortality, changes to the current US donor heart allocation scheme are being planned by the UNOS Thoracic Committee. These changes include options for improved geographic sharing and altering the status of potentially disenfranchised groups, which may result in a new multi-tiered allocation scheme. The new allocation scheme will prioritize patients with end-organ dysfunction who have increased short-term mortality.⁶²

The donor heart is explanted, or “harvested,” by a surgical team at a hospital usually remote from the transplant center, and the procedure must be coordinated with the surgical teams procuring other organs for transplantation. The donor heart is first arrested with cardioplegic solution. The original surgical technique for orthotopic heart transplantation, or biatrial technique, was described by Lower and Shumway in 1960.⁶ In this procedure, both the donor and recipient hearts are removed by transecting the atria at the midatrial level, leaving the multiple pulmonary venous connections to the left atrium intact in the posterior wall of the left atrium, and then transecting the aorta and pulmonary artery just above their respective semilunar valves. The explanted heart is cooled topically by being placed in an iced preservation solution; it is then placed in a secure container and transported expeditiously to the transplant center. Ischemic times average 3 to 4 hours.

Implantation of the heart in the orthotopic position begins with reanastomosis at the midatrial level, beginning with the atrial septum (Fig. 72–1). Efforts are made to include a generous cuff of donor right atrium so the sinoatrial node will be included. The great vessels are connected just above the semilunar valves. Commonly seen with the biatrial technique is the presence of two asynchronous P waves on ECG. One P wave emanates from the sinus node of the donor heart and the other from the sinus node in the right atrial remnant of the native heart. In recent years, the biatrial technique has been modified by leaving the donor atria intact and making anastomoses at the level of the superior and inferior vena cavae and pulmonary veins.⁸¹ This bicaval technique (Fig. 72–2) results in less distortion of atrioventricular geometry, resulting in improved atrial and ventricular function, less atrioventricular regurgitation, decreased incidence of atrial arrhythmias, and decreased incidence of donor sinus node dysfunction and heart block requiring permanent pacemaker implantation.^82,83,84

Immediate postoperative care differs little from that after more routine heart surgery, except for the institution of immunosuppression (described later) and the need for chronotropic support of the donor sinoatrial node for the first 2 to 3 postoperative days, usually with temporary pacemaker support or with β-agonist intravenous infusions. Postoperative bradycardia usually results from sinus node dysfunction because of surgical trauma, ischemia to the sinus node, or pretransplant use of amiodarone.⁸⁵ Most cases resolve within a few weeks to months. The incidence of refractory bradycardia requiring permanent pacemaker implantation is between 10% and 20% with the biatrial technique and less than 10% with the bicaval technique.⁸⁴ Patients with uncomplicated postoperative courses are discharged from the hospital as early as 7 to 10 days after heart transplantation.

Lack of Innervation

When the donor heart is placed into the recipient, both afferent (from the heart to the central nervous system) and efferent (from the central nervous system to the heart) nerve supply is lost. The loss of afferent nerve supply means that the recipient will not experience angina with the exception of a small subgroup that may have reinnervation.⁸⁶ Therefore, chest discomfort in a heart transplant recipient, especially early after transplantation, is likely not caused by coronary ischemia, and coronary ischemia will likely not present with chest discomfort. The standard practice of annual angiograms for surveillance of transplant coronary artery disease is a direct consequence of the lack of afferent nerves supplying the transplanted heart and required for early detection of allograft vasculopathy.

The consequences of the loss of efferent nerves are related to the loss of vagal tone and the postganglionic direct release of norepinephrine stores in response to exercise. With the loss of vagal tone, heart transplant recipients have a higher than normal resting heart rate, usually around 90 to 110 bpm. The lack of efferent nerves also means that the transplant recipient must rely on circulating catecholamines to respond to exercise, so there is a blunting of the heart rate’s response to exercise. Similarly, after exercise, the heart rate returns to baseline more slowly because of the gradual decline of circulating catecholamine concentrations to baseline.

Heart transplant recipients lack the baroreceptor reflex, which relies on intact baroreceptors and sympathetic and parasympathetic innervation. Thus, heart transplant recipients are more susceptible to orthostasis, and carotid sinus massage will not break a re-entrant tachycardia in these patients.

Nevertheless, heart transplant recipients often experience reinnervation of the heart, with possible angina, an improvement in exercise tolerance, and a decrease in resting heart rate. This process is variable among patients, although it tends to increase over time. Restoration of sympathetic innervation correlates with improved responses of heart rate and contractile function to exercise.⁸⁷

Response to Medications

Some cardiac drugs are not effective in the denervated heart. As a result of the lack of vagal tone, digoxin will have little effect on sinoatrial and atrioventricular conduction velocity and will not achieve rate control if the transplanted heart develops atrial fibrillation. However, the inotropic effects of digoxin persist after transplantation. Similarly, the parasympatholytic effect of atropine will not increase heart rate in transplanted hearts. As a result of the lack of baroreceptor reflexes, vasodilators such as nifedipine and hydralazine will not cause reflex tachycardia.

The lack of postganglionic sympathetic nerves in the transplanted heart results in increased receptor density and thus more sensitivity to sympathetic agonists and antagonists.⁸⁸ Clinically, this is most often seen with β-blockers; heart transplant recipients will often have exaggerated fatigue in response to administration of β-blockers, especially with exercise.

Survival

Survival after heart transplantation has steadily improved in the past three decades (Fig. 72–3). In the 1980s, 1-year survival was 70%, and the conditional half-life, the time at which 50% of patients who survived the first year are still alive, was 9.4 years. In the 2015 report from the International Society of Heart and Lung Transplantation (ISHLT) registry,¹² 1-year survival was almost 90% with a conditional half-life of 14 years. Notably, the mortality beyond 1 year after transplant has improved only marginally for patients who received allografts after 1992, and there has been no statistically significant improvement in the past two decades. This stable annual mortality of approximately 3% to 4% is higher than that of the general population and likely exists because the processes responsible for long-term mortality, including cardiac allograft vasculopathy and malignancy, remain a challenge of detection and treatment. Thus, future improvements in post-transplant survival may result from interventions aimed at the detection and treatment of cardiac allograft vasculopathy and malignancy.

An in-depth analysis of risk factors for survival at 1, 5, 10, 15, and 20 years after transplantation is provided in the ISHLT registry report.¹² The strongest risk factors for death at 1-year, associated with a 50% or more increase in the risk of death at 1-year, are mainly related to technical issues and the underlying disease responsible for transplantation, including the use of temporary circulatory support, congenital cardiomyopathy versus nonischemic cardiomyopathy, prior transplant, and pretransplant ventilatory support or dialysis. Risk factors for death at 5 and 10 years, on the other hand, are most referable to immunologic issues and toxicity related to immunosuppression, including dialysis or infection after transplant, rejection during the first post-transplant year, and lack of immunosuppression therapy with a combination of at least two of the following classes: cell cycle inhibitors, calcineurin inhibitors (CNIs), and proliferation signal inhibitors (PSIs).

Transplant era influences 20-year survival; patients transplanted in 1990 have better 20-year survival than those transplanted in 1985.¹² Other factors affecting 20-year survival include etiology for transplantation, sex, age, ischemic time, and center volume. Patients receiving retransplant and those receiving transplant for ischemic heart disease or valvular heart disease have a lower likelihood of survival past 20 years after transplant compared with patients who receive an allograft for nonischemic cardiomyopathy. The reasons for this are unclear and may be related to progression of the underlying disease or older age of recipients with ischemic or valvular disease versus nonischemic cardiomyopathy. Women also have a somewhat higher risk of death compared with their male counterparts. Younger donor age, younger recipient age, lower allograft ischemic time, and higher center volume are additional factors associated with long-term survival, and these risk factors appear consistent across countries.

Quality of Life

Patients not only gain increased quantity of life after transplantation, but quality of life is improved as well. In the first years after heart transplant, approximately 75% of recipients report having a normal healthy lifestyle or only few disease symptoms, an additional 15% participate in normal activities with some difficulty, and less than 10% report a higher degree of limitations.¹²

In-depth analysis of a smaller cohort of transplant patients indicates that the most frequently reported long-term symptoms after heart transplantation, at moderate rates of 50% to 65%, were fatigue, sexual dysfunction, memory problems, bruising, and cramps.⁸⁹ These symptoms are less common in recipients who are married and those with a higher educational level.

Based on information from the international registry, many patients return to work after transplant. Among recipients aged 25 to 55 years, approximately 50% were employed 5 years after transplantation.¹² On the basis of the functional data reviewed above, it is apparent that additional recipients could return to the workplace; however, in the United States the structure of disability benefits and health insurance considerations may represent a barrier to this process.

Immunosuppression

General Principles

Most of the immunosuppressive regimens used in clinical transplantation consist of a combination of several agents used concurrently and use several general principles. The first general principle is that immune reactivity and tendency toward graft rejection are highest early (within the first 3-6 months) after graft implantation and decrease thereafter over time. Thus, most regimens use the highest levels of immunosuppression immediately after surgery and decrease those levels over the first year, eventually settling on the lowest maintenance levels of immune suppression that are compatible with preventing graft rejection and minimizing drug toxicities. The second general principle is to use low doses of several drugs without overlapping toxicities in preference to higher (and more toxic) doses of fewer drugs whenever feasible. The third principle is that excessive immunosuppression is undesirable because it leads to a myriad of undesirable effects, such as susceptibility to infection and malignancy. Finding the right balance between over- and under-immunosuppression in an individual patient is truly an art that uses science.

Induction Therapy

Currently, about 50% of transplant programs use a strategy of augmented immunosuppression, or “induction” therapy, with antilymphocyte antibodies or interleukin-2 receptor antagonists during the early postoperative period. The goal of induction therapy is to provide intense immunosuppression during a time when the risk of allograft rejection is highest. Additionally, induction therapy allows delayed initiation of nephrotoxic immunosuppressive drugs in patients with compromised renal function after surgery. Agents used for induction therapy include polyclonal antithymocyte antibodies derived by immunization of horses (ATGAM) or rabbits (thymoglobulin) with human thymocytes. These agents may reduce the risk of early rejection, but have been associated with an increased risk of infection.^90,91 Anti–interleukin-2 (IL-2) receptor antagonists such as daclizumab result in reduced rates of moderate or severe cellular rejection among heart transplant patients treated with standard immunosuppression (cyclosporine, mycophenolate mofetil [MMF], and corticosteroids) without increasing the incidence of opportunistic infection or cancer at 1 year. However, among patients receiving daclizumab induction, there was an increased risk of fatal infection when cytolytic therapy was concomitantly used.⁹² Although induction therapy is commonly used, there have been no large randomized trials or studies based on UNOS registry data demonstrating benefit of induction therapy versus no induction therapy.

Maintenance Immunosuppression

Most maintenance immunosuppressive protocols use a three-drug regimen consisting of a CNI (cyclosporine or tacrolimus), an antimetabolite agent (MMF or azathioprine), and tapering doses of corticosteroids over the first year after transplantation. The commonly used drugs and their toxicities are outlined in Table 72–7. Recent trends in the use of these drugs are presented in Fig. 72–4.

The CNIs exert their immunosuppressive effects by inhibiting calcineurin, which is responsible for the transcription of IL-2 and several other cytokines, including tumor necrosis factor-α (TNF-α), granulocyte-macrophage colony-stimulating factor, and interferon-β. The result is blunting of T-lymphocyte activation and proliferation in response to alloantigens. The two available agents, cyclosporine and tacrolimus, inhibit calcineurin by forming complexes with different intracellular binding proteins. Since the introduction of cyclosporine in the early 1980s,⁹ the CNIs have remained the cornerstone of maintenance immunosuppressive therapy in patients undergoing solid organ transplantation. Tacrolimus is favored over cyclosporine based on evidence from clinical trials suggesting that tacrolimus-based immunosuppression is associated with decreased rates of acute rejection.^93,94 Although nephrotoxicity is seen with both agents, there is more hypertension and dyslipidemia observed with cyclosporine and a higher incidence of new-onset insulin-requiring diabetes observed with tacrolimus.^95,96

MMF has replaced azathioprine as the preferred antimetabolite agent in recent years on the basis of a clinical trial demonstrating a significant reduction in both mortality and in the incidence of treatable rejection at 1 year with MMF versus azathioprine.⁹⁷ Mycophenolate sodium is an enteric-coated, delayed-release formulation developed to improve the upper gastrointestinal tolerability of MMF. It is therapeutically similar to MMF with respect to the prevention of both biopsy-proven and treated acute rejection episodes, graft loss, or death.⁹⁸

PSIs, or mammalian target of rapamycin inhibitors, are relatively more recent advances in standard immunosuppression. The two agents in this class, sirolimus and everolimus, inhibit the proliferation of T cells, B cells, and vascular smooth muscle cells in response to growth factor and cytokine signals. Compared with azathioprine, both sirolimus and everolimus reduce the incidence of acute rejection and prevent the development of cardiac allograft vasculopathy (CAV) when used in conjunction with cyclosporine and prednisone in de novo heart transplant recipients.^99,100 Compared to MMF, everolimus is noninferior with respect to the combined end point of rejection, graft loss, and death,¹⁰¹ and demonstrates less CAV progression as measured by intravascular ultrasound (IVUS) at 1 year.¹⁰² Other benefits of sirolimus include slowing of CAV progression and reduction in the incidence of clinically significant cardiac events.¹⁰³ Also, when used in heart transplant recipients with significant renal impairment, sirolimus permits minimization or complete withdrawal of the CNIs, resulting in notable improvements in renal function without an associated increased risk of rejection.^104,105,106

Sirolimus is generally not initiated de novo after transplantation because of an increased risk of sternal wound dehiscence,¹⁰⁷ but on the basis of the benefits observed in clinical trials, it can be initiated later after transplantation for specific indications. The PSIs are often used in place of MMF in patients with rejection, allograft vasculopathy, malignancy, and viral infections such as cytomegalovirus¹⁰⁸ to prevent recurrence or progression. When used in place of the CNI, the PSIs may prevent progression of renal dysfunction.

Corticosteroids are nonspecific anti-inflammatory agents that interrupt multiple steps in immune activation, including antigen presentation, cytokine production, and proliferation of lymphocytes. Although steroids are highly effective for the prevention and treatment of acute rejection, their long-term use is associated with a number of adverse effects, including new-onset or worsening diabetes mellitus, hyperlipidemia, hypertension, fluid retention, myopathy, osteoporosis, and a predisposition toward opportunistic infections. Thus, although most programs use corticosteroids as one of the three maintenance immunosuppressive agents, they are used in relatively high doses in the early postoperative period, but are then tapered to low doses or discontinued altogether within the first 6 to 12 months.

Although dual- and triple-drug therapy are the most commonly used strategies for maintenance immunosuppression after heart transplantation, single-drug therapy using tacrolimus following early withdrawal of corticosteroids and MMF has also been shown to be safe and efficacious.¹⁰⁹ However, this strategy required higher tacrolimus trough levels, which resulted in higher serum creatinine levels at 1 year.

Drug Interactions

In managing patients on immunosuppressive drug therapy, clinicians should be aware of the potential for drug interactions when other agents are added to or deleted from the patient’s regimen.¹¹⁰ A list of the most common and clinically important drug interactions is shown in Table 72–8. The CNIs and PSIs are predominantly metabolized by the cytochrome P450 3A4 pathway in the liver. Drugs that induce the P450 3A4 pathway, such as phenytoin, rifampin, and St. John’s wort, enhance the metabolism of the CNIs and PSIs, thus lowering their blood levels and clinical effectiveness. Alternatively, drugs that inhibit the enzyme pathway, such as calcium channel blockers, antifungal agents, and HIV protease inhibitors, decrease the metabolism of cyclosporine, tacrolimus, or sirolimus, thus increasing their drug levels and potentiating their nephrotoxic effects. Finally, the lipid-lowering agents lovastatin, atorvastatin, and simvastatin have decreased clearance and increased drug concentrations when used concurrently with the CNIs. Therefore, the use of higher doses of these statins may lead to an increased risk of myopathy or rhabdomyolysis. When a drug with the potential to interact with the immunosuppressive agents is added to or deleted from a patient’s regimen, immunosuppressive drug levels and renal function should be carefully monitored.

Diagnosis

Transplant rejection remains one of the major causes of death after heart transplantation¹² and is classified as hyperacute rejection, acute cellular rejection, or antibody-mediated rejection. Hyperacute rejection is rare, but may occur in the setting of circulating preformed antibodies to the ABO blood group (in cases of ABO blood group incompatibility) or to major histocompatibility antigens in the donor. Possible risk factors include presensitization after blood transfusions, multiparity, and previous organ grafts.¹¹¹ Hyperacute rejection manifests as severe graft failure within the first few minutes to hours after transplantation. Without inotropic agents and MCS, plasmapheresis, and intense immunosuppression, the recipient usually does not survive.

Whereas the presentation of hyperacute rejection is dramatic, the signs and symptoms of acute rejection are generally nonspecific and may only manifest in the late stages. Patients may present with fatigue, low-grade fevers, HF symptoms, or hypotension. Occasionally, rejection will manifest as atrial arrhythmias or new pericardial effusions. On examination, patients may have an elevated jugular venous pressure or a new S₃ gallop. However, the majority of patients with acute cellular or antibody-mediated rejection are asymptomatic without signs of allograft dysfunction.

Because symptoms are often vague, routine testing for rejection is standard practice. Unlike renal or liver transplantation, there are no laboratory markers for rejection in heart transplantation, and the endomyocardial biopsy remains the cornerstone of rejection surveillance. Despite its limitations (sampling error and interobserver variability of interpretation among pathologists), endomyocardial biopsy has remained the gold standard for the diagnosis of acute allograft rejection. It is performed via the right internal jugular vein or femoral vein by introducing a bioptome into the right ventricle and obtaining three to five pieces of endomyocardium, typically from the right ventricular septum (Fig. 72–5).

Although the timing of biopsies will vary from center to center, in general, biopsies are performed frequently early after transplantation and less frequently over time. Most programs perform surveillance biopsies on a weekly basis for the first 4 to 6 postoperative weeks and then with diminishing frequency in a stable patient, but at a minimum of every 3 months for the first postoperative year. The need for continued surveillance biopsies after the first year in clinically stable patients has been questioned,^112,113 but many centers continue to perform them every 4 to 6 months during the first 5 years after transplantation.¹¹⁴

The purpose of the endomyocardial biopsy is to assess for myocardial damage in the form of acute cellular rejection (ACR; Fig. 72–6) or antibody-mediated rejection (AMR; Fig. 72–7). The diagnosis of ACR is made in accordance with the revised ISHLT grading scale shown in Table 72–9.^115,116 The diagnosis of AMR achieved standardization after a consensus conference in 2010 (Fig. 72–8).^66,117

Although not required for the diagnosis of AMR, many centers also perform screening for antibodies against HLAs after transplantation. Strong, and especially complement-binding, donor-specific anti-HLA antibodies (DSA) are considered potentially cytotoxic.^118,119 Their presence may merit a change in treatment, depending on the clinical situation, as discussed below.

Although performing an endomyocardial biopsy is straightforward, the morbidity associated with this invasive procedure has led to attempts to identify other means of diagnosing rejection, and the gene expression profile (GEP) test (AlloMap^®, CareDx, San Francisco, CA), an 11-gene expression signature derived from peripheral blood mononuclear cells, has emerged as a noninvasive test with a high negative predictive value for the presence of ACR.¹²⁰ In a randomized trial, GEP was shown to be noninferior to biopsy in the diagnosis of ACR¹²¹ and also useful early after transplantation.¹²² One role of the GEP is to screen low-risk patients at predetermined intervals, with biopsies performed only if the GEP score is abnormal. However, it must be emphasized that patients with a history of, or risk factors for, AMR are not candidates for GEP screening, as the test has only been validated for ACR.

Another emerging technology in the noninvasive diagnosis of rejection involves cell-free DNA technology. Cell-free donor-derived DNA is detectable in both the urine and blood of transplant recipients.^123,124 This cell-free DNA may be a candidate marker for noninvasive diagnosis of graft injury, because increased levels of donor-derived DNA correlate with ACR events as determined by endomyocardial biopsy in early studies.^125,126

Treatment

The management of rejection proceeds in a stepwise fashion based on the severity of rejection detected on biopsy and the patient’s presentation (Table 72–10). Biopsies with grade 1R or AMR 1, in the absence of clinical or hemodynamic compromise, generally merit no intervention.

More serious findings on the biopsy, including grade 2R or higher and AMR 2 or higher warrant treatment. As shown in Table 72–10, the intensity of treatment depends on the patient’s presentation. If the patient is asymptomatic (no HF symptoms and normal left ventricular ejection fraction), treatment options include oral pulse steroids, targeting higher levels of immunosuppressive medications, switching from cyclosporine to tacrolimus,^94,127 or switching from MMF to a PSI.^99,100,103 Given the equivalent success of intravenous and oral corticosteroid therapy for the treatment of asymptomatic ACR,¹²⁸ an outpatient course of oral corticosteroids is often the first-line treatment.

Asymptomatic AMR is more challenging. It may be associated with poor outcomes,^129,130,131 but it is unclear whether treatment affects outcomes. At some centers, such patients will receive an oral corticosteroid bolus, consideration of intravenous immune globulin, and monitoring of donor-specific anti-HLA antibodies.⁶⁶

For patients with HF symptoms or reduced ejection fraction, treatment is more aggressive, with intravenous corticosteroids and cytolytic therapy with antithymocyte globulin. If there is evidence of grade AMR 2 or higher, patients will also often receive intravenous immunoglobulin. If donor-specific anti-HLA antibodies are present in the setting of AMR, patients may receive more intensive therapy with rituximab or bortezomib. Plasmapheresis may also be used in this setting.

Finally, in patients presenting with cardiogenic shock, empiric aggressive treatment includes intravenous corticosteroids, cytolytic therapy, plasmapheresis, intravenous immunoglobulin, heparin (as patients often have thrombotic occlusion of the cardiac microvasculature on postmortem examination^132,133), and hemodynamic support with intra-aortic balloon counterpulsation or even extracorporeal membrane oxygenation.¹³⁴

Any rejection episode should prompt an investigation for precipitating causes such as infection, noncompliance, or drug interactions resulting in subtherapeutic immunosuppressive drug levels. A biopsy should be repeated 2 weeks after completion of treatment to document improvement or resolution of the rejection episode.

Long-Term Management

Whereas ACR is often successfully treated with corticosteroids and cytolytic therapy, resulting in a resolution of HF and normalization of the ejection fraction,¹³⁵ management of AMR is often more complicated. Patients may have a persistent reduction in ejection fraction, restrictive physiology with recurrent HF, and accelerated progression of transplant coronary artery disease.¹³⁵

The management of such patients with a persistent drop in ejection fraction after treatment of symptomatic rejection is not well established. Some centers rely on therapies to reduce the levels of donor-specific anti-HLA antibodies, including rituximab and bortezomib, as well as photopheresis to alter the function of T cells.⁶⁶ In small case series, such therapies have shown benefit,^136,137 although often such patients go on to require redo heart transplantation.

Incidence and Clinical Presentation

The incidence of CAV varies widely as a result of differences in definition of disease and patient populations, but by various estimates, it ranges from 42% at 5 years to 50% at 10 years.^138,139 CAV can occur as early as 1 year after transplantation, and this accelerated form of disease is more aggressive and associated with a worse prognosis.¹⁴⁰ Even in patients without apparent angiographic epicardial disease, microvascular abnormalities may be present and are associated with adverse outcomes.¹⁴¹ Despite improvements in immunosuppression over the past three decades, the incidence of CAV has not significantly decreased, and its development continues to limit long-term survival in patients undergoing cardiac transplantation.

Given the denervation of the transplanted heart, patients do not experience typical angina, and the presentation of CAV differs from that of nontransplant coronary artery disease (Table 72–11).¹⁴² However, over time, patients may develop cardiac reinnervation, and chest pain caused by ischemia and infarction in transplant patients has been documented.^86,143,144 In general, the atypical presentation often leads to lower utilization for revascularization therapies and worse outcomes,^145,146 including HF, arrhythmia, or sudden death. Thus, routine surveillance angiography is performed in cardiac transplant recipients, usually at 1-year intervals.

Morphologic Features

In CAV, the major epicardial vessels, their branches, and often the intramyocardial divisions display uniform, diffuse involvement extending along their entire length (Fig. 72–9). The asymmetric and calcified plaques or lesions composed of cholesterol that are characteristic of conventional atherosclerosis are not found in uncomplicated lesions of vessels affected by CAV. Histopathologic sections show a concentrically thickened intimal layer composed of modified smooth muscle cells, foamy macrophages, and variable numbers of histiocytes and lymphocytes within a connective tissue matrix that ranges from loose, edematous, and myxoid in early lesions to densely hyalinized and fibrotic in older lesions.¹⁴⁷ Intraluminal thrombosis is uncommon.

Diagnosis

CAV is usually beyond therapeutic intervention by the time symptoms develop, so surveillance is essential to monitor the development of CAV. Coronary angiography remains the mainstay of CAV detection, although it has limitations. Coronary angiography relies on the ability to compare normal segments of the vessel with diseased segments. The diffuse nature of CAV often results in underestimation of disease because there is no reference segment in which the normal diameter of the vessel can be assessed. Comparison with prior studies may help, but requires the use of the same angiographic protocol at each study to avoid confounding by technical factors.

IVUS is currently the only technique that offers cross-sectional images of the coronary vessel wall comparable to histologic sections to detect even early plaque burden (Fig. 72–10). IVUS is more sensitive than angiography in detecting CAV^{148,149,150,151} and has prognostic value: progression of intimal thickening greater than 0.5 mm in the first year after transplantation is associated with an increased risk of death and development of angiographic CAV up to 5 years later.¹⁴⁰ Nevertheless, IVUS has limitations. It is invasive and requires anticoagulation and the use of expensive single-use catheters, and evaluation is limited to the major epicardial vessels.

Treatment

Clinically apparent CAV is associated with a poor prognosis and, therefore, prevention is an important strategy. Aspirin is given because its established role in nontransplant coronary disease. Control of hypertension and hyperlipidemia is paramount. 3-Hydroxy-3-methyl-glutaryl–coenzyme A reductase inhibitors are particularly important because they also prevent allograft rejection in addition to reducing CAV development.¹⁵² The PSIs also show significant promise in reducing the progression of intimal thickening by IVUS.^{99,100,101,102}

Once clinically significant CAV is apparent, percutaneous coronary intervention is successful for focal disease, although restenosis is common and there is no evidence to date that percutaneous coronary intervention alters the prognosis of CAV.¹⁵³ Drug-eluting stents may help, but restenosis rates continue to be higher than in the nontransplant population.^154,155,156 Patients with multivessel focal disease with adequate distal target vessels may be candidates for surgical revascularization with coronary artery bypass grafting, although limited efficacy data are available.

Retransplantation may be considered for patients with advanced CAV. After retransplantation, patients have comparable survival and CAV incidence to patients undergoing a first transplant.¹⁵⁷ The scarcity of donor hearts, however, creates an ethical dilemma. Some argue that it is better to maximally distribute organs, rather than to allocate two organs to the same individual. Others contend that patients needing a second transplant should be considered on the same basis as those being evaluated for a first transplant.

Hypertension, hyperlipidemia, and the development of post-transplant diabetes mellitus are the most common metabolic complications associated with CNI and corticosteroid use (see Table 72–7). Renal dysfunction occurs in up to one-third of individuals and is related to the direct effects of the CNIs on the kidney tubules and from CNI–mediated vasoconstriction of the afferent arteriole, leading to decreased kidney perfusion. In addition to experiencing drug- and class-specific toxicities, heart transplant patients have a higher risk of developing opportunistic infections and malignancies compared with the general population.

Infection

Infections are the major cause of death during the first postoperative year and remain a threat throughout the life of a chronically immunosuppressed patient. Infections in the first postoperative month are commonly bacterial and typically related to indwelling catheters and wound infections. They involve nosocomial organisms such as Legionella, Staphylococcus, Pseudomonas, Proteus, Klebsiella, and Escherichia coli. These infections typically present in the form of pneumonias, urinary tract infections, sternal wound infections and mediastinitis, and bacteremia. Late infections (those that occur 2 months to 1 year after transplantation) are more diverse. In additional to typical pathogens, transplant patients are susceptible to viruses (particularly cytomegalovirus), fungi (Aspergillus, Candida, and Pneumocystis spp.), and Mycobacterium, Nocardia, and Toxoplasma species. Effective therapy requires an extremely aggressive approach to obtaining a specific diagnosis and a background of experience in recognizing the more common clinical presentations of cytomegalovirus, Aspergillus species, and other opportunistic infectious agents. Infection surveillance is mainly clinical, but routine chest radiography often detects infections, especially fungal and mycobacterial pulmonary infections, that may be at an early and asymptomatic stage.

Balancing the risks of infection and rejection with immunosuppression relies on an understanding of the patient’s global immune state. An immune-monitoring assay (ImmuKnow^®; Vircor-IBT, Lee’s Summit, MO) performed on peripheral blood, which measures adenosine triphosphate (ATP) release from activated lymphocytes, may offer some guidance in profoundly immunosuppressed patients.^158,159 In the largest study to date in heart transplant recipients, the average immune monitoring score was significantly lower in patients who developed an episode of infection within 1 month after the measurement compared with steady-state patients.¹⁶⁰ An immune monitoring score of less than 200 ng ATP/mL was associated with future infection. Thus, centers may target lower CNI trough levels or reduce MMF doses in patients with scores less than 200 ng ATP/mL, especially those with recurrent infections or malignancy.

Given the degree of immunosuppression, all transplant recipients receive antimicrobial prophylaxis for oral candidiasis, toxoplasmosis and pneumocystis, and cytomegalovirus over the first post-transplant year. The use of vaccines in heart transplant recipients remains controversial. Live vaccines are definitely contraindicated because of the patients’ immunosuppressed states. Even dead vaccines may pose a risk because they can promote activation of the immune system and cause rejection.¹⁶¹ At some centers, dead vaccines such as the influenza or pneumococcal vaccines are recommended only to patients more than 6 months after transplant and with no history of rejection within the previous 6 months.

Malignancy

Incidence

Malignancy is one of the most common causes of late mortality in heart transplant recipients.¹⁶² Malignancies are approximately two- to fourfold more common in heart transplant compared with renal transplant recipients.^{163,164,165,166} The enhanced risk of cancer among cardiac transplant recipients is thought to reflect the greater degree of immunosuppression that heart transplant recipients receive, possibly because of inherent immunologic requirements.¹⁶⁷

All immunosuppressive agents are believed to contribute to the cumulative risk of malignancy, with the possible exception of corticosteroids. However, the PSIs sirolimus and everolimus may have a decreased incidence and progression of malignancy compared with CNIs and antimetabolites.^168,169,170

Clinical Presentation

Cancer in solid organ transplant recipients usually presents at least 3 to 5 years after transplantation. Cutaneous malignancies are the most common type after heart transplantation, mainly squamous cell and basal cell carcinomas.¹⁷¹ Risk factors common to the general population for the development of skin cancers include fair skin, previous history of skin cancer, and geographic location (in areas of high sun exposure).¹⁷² Specifically in heart transplant recipients, increased intensity of immunosuppression and long-term voriconazole use for treatment of fungal infections such as aspergillosis are associated with a higher increased risk of developing skin cancer.¹⁷³

Post-transplant lymphoproliferative disorder (PTLD), most commonly a B-cell lymphoma related to EBV infection, may occur after transplantation.^174,175 More than 50% of patients with PTLD present with extranodal masses involving the gastrointestinal tract, lungs, skin, liver, central nervous system, and the allograft itself. Risk factors for the development of PTLD include the use of cytolytic therapy for induction¹⁷⁵ and EBV serostatus (with EBV-seronegative recipients of EBV-seropositive donors being at the highest risk).¹⁷⁶

Neoplasms common in the general population also occur in heart transplant recipients, including breast, lung, and prostate. Lung cancer is more common in heart and lung transplant recipients than in recipients of other solid organs, likely because smoking, a strong risk factor for lung cancer, may also contribute to end-stage heart and lung disease requiring transplantation.¹⁷⁷

Prevention and Treatment

The most critical point of treatment of malignancies is prevention. Heart transplant recipients should undergo routine health maintenance screenings with their primary care physicians, including mammograms, pap smears, prostate exams, and colonoscopies as indicated for nontransplant patients. In addition, patients are instructed to use sun protection and to establish care with a dermatologist for routine skin exams.

The initial approach to malignancy is reduction of immunosuppression, and this may be the only treatment required for some forms of PTLD. Patients with newly diagnosed malignancy are often switched to a PSI such as sirolimus or everolimus, because of its possible beneficial effect in malignancies,^168,169 in place of a CNI or MMF.

General Medical Management

Heart transplant recipients should receive regular care from an internist for routine health maintenance. Such patients require the same general medical surveillance as nontransplant patients, including age-appropriate cancer screening. Internists also manage the long-term complications of heart transplant recipients, including renal dysfunction, hypertension, dyslipidemia, diabetes, osteoporosis, and gout. However, it is essential that patients inform the transplant center of any new medication recommended by another physician, as there may be unforeseen interactions (see Table 72–8).

Renal insufficiency is a common adverse effect of the CNIs and often worsens over time, such that up to 8% of heart transplant recipients will develop end-stage renal disease at 5 or more years after transplantation.^162,178,179 “Renal-sparing” immunosuppressive regimens are often used in such patients, including a reduction in CNI dose or substitution of the CNI with a PSI.¹⁸⁰ CNI withdrawal should not be performed prior to 6 months as rejection risk is high. To be successful, the timing is important; if the renal dysfunction has progressed, the damage may be irreversible. When replacing CNIs with PSI, the key to preventing rejection is to withdraw CNIs gradually over a period of 2 to 4 weeks while awaiting therapeutic PSI levels.¹⁸¹

Hypertension after cardiac transplantation is primarily a result of CNI use and occurs in up to 80% of patients.¹⁶⁷ Post-transplant hypertension is often difficult to control and often requires a combination of several antihypertensive agents.^182,183 No agent has proven superior in clinical trials of renal transplant^184,185,186 or heart transplant recipients.¹⁸⁷ However, β-blockers are often avoided because the denervated heart relies on circulating catecholamines to maintain cardiac function during exercise, and thus heart transplant recipients often experience significant fatigue from β-blockers. ACE inhibitors and angiotensin receptor blockers may not be tolerated because of renal dysfunction or hyperkalemia. Dihydropyridine calcium channel blockers such as amlodipine and nifedipine are often effective, but may result in troublesome dependent edema and will increase levels of CNIs, which should be monitored after initiation.

Elevated lipid levels are common after heart transplantation, as a result of the use of steroids, CNIs, and PSIs.¹⁸⁸ Statins are effective in reducing total and low-density lipoprotein cholesterol in heart transplant recipients. Notably, statin treatment initiated within 2 weeks of transplantation is also associated with a lower frequency of hemodynamically compromising rejection episodes and improved survival over the first transplant year.¹⁵² Pravastatin is the statin of choice, because it is hydrophilic and is not metabolized by the cytochrome 3A4 system, reducing the possible interactions with CNIs.¹¹⁰

Diabetes is common before transplantation because it increases the risk of cardiovascular disease. Furthermore, the use of steroids and tacrolimus after transplantation may cause or worsen diabetes; up to 32% of patients are diabetic by 5 years after transplantation.¹⁶² Although diabetes is associated with poorer long-term survival,¹⁸⁹ optimal treatment is not clear. Because renal insufficiency is common, metformin is often avoided. Sulfonylureas may be the agents of choice for heart transplant recipients.¹¹⁰

Osteoporosis resulting in vertebral compression fractures is a common and debilitating problem after heart transplantation, exacerbated by steroid use. We recommend screening bone density examinations on an annual basis. To prevent osteoporosis, patients should receive supplemental calcium and vitamin D, engage in weight-bearing exercises, and receive bisphosphonates as recommended by the primary care physician.

Gout is common after heart transplantation. In these patients, causes of gout include CNI use, diuretic use, and renal insufficiency. Nonsteroidal anti-inflammatory agents are often avoided in heart transplant recipients because of the potential of renal insufficiency. Colchicine may be used to treat acute attacks, although there is a risk of myoneuropathy when colchicine is combined with CNIs. Thus, for acute flares, systemic or intra-articular steroids may be considered. Allopurinol is useful as suppressive therapy, as long as the patient is not receiving azathioprine, since the combination may result in severe myelosuppression.

Over the last four decades, cardiac transplantation has become the preferred therapy for select patients with end-stage heart disease. Improvements in immunosuppression, donor procurement, surgical techniques, and post-transplant care have resulted in a substantial decrease in acute allograft rejection, which had previously significantly limited survival of transplant recipients. However, major impediments to long-term allograft survival exist, including rejection, infection, CAV, and malignancy. Nevertheless, through careful balance of immunosuppressive therapy and vigilant surveillance for complications, we can expect further advances in the long-term outcomes of heart transplant recipients over the decades to come.

We would like to thank Dr. Michael X. Pham, Dr. Gerald J. Berry, and Dr. Sharon A. Hunt, who contributed to the previous version of this chapter in the 13th edition.