Manual of Cardiovascular Medicine

I.Introduction. The year 1967 marks the historic, first heart transplant performed by Christiaan Barnard in Cape Town, South Africa. Since then, cardiac transplantation has evolved into a well-established therapeutic intervention for a select group of patients living with end-stage heart disease. It offers these patients a chance for improved survival and quality of life. However, cardiac transplantation should not be perceived as a curative procedure. Following transplant a new set of potential, long-term complications may arise primarily owing to the secondary effects of chronic immunosuppression.

Approximately 100,000 adult heart transplants have been reported according to the International Society for Heart and Lung Transplantation (ISHLT) registry from 1982 through June 2012. The majority of the transplants come from reporting centers within North America followed by Europe. Despite a growing population and heart failure cohort, the number of reported cardiac transplants over the last decade remains static, hovering around 4,000 annually.

Within the United States, the Scientific Registry of Transplant Recipients (SRTR) notes a 17.1% increase in annual cardiac transplants since 2004 with 2,407 US transplants in 2012 compared with 2,188 in 2002. This subtle increase may be reflective of changes within donor allocation criteria as outlined by the Organ Procurement and Transplantation Network. According to the United Network of Organ Sharing (UNOS), which is the national organization that maintains organ transplantation waiting lists, initiates the evaluation of potential organ donors, allocates organs when a donor is identified, and compiles annual statistics on all aspects of the transplant process, the median wait time to transplant remains problematic and is dependent on both candidate status and transplant center in addition to blood type and body size. Status 2 candidates, the least urgent, had a median wait time of approximately 20 months versus 2.4 months for status 1A (most urgent) in 2012. Despite long wait times and an increasing number of transplants occurring within patients of highest medical urgency (58.5% of transplants were performed in 1A candidates compared with 34.8% in 2002), pretransplant mortality rates continue to decline with a reported 15.8 deaths per 100 wait-list year in 2002 compared with 12.4 in 2012. This may be attributed to the growing use of both permanent and temporary mechanical circulatory support devices and increased use of an implantable cardioverter defibrillator.

Global and national characteristics of transplant patients have evolved over the last decade demonstrating similar trends with a growing, nonischemic cardiomyopathy cohort (54%) followed by ischemic cardiomyopathy (37%); other primary diagnosis conditions include retransplant, congenital, and valvular heart disease. According to the annual SRTR report from 2012, US recipient demographics demonstrate the median age range is 50 to 64 years of age, 72% are male, and 37.1% are blood type O compared with 42.2% type A versus 6.3% type AB, and 14.5% type B. As alluded to above, ISHLT data demonstrate the percent of patients requiring additional mechanical support as a bridge to transplantation has risen from approximately 20% in 2000 to almost 40% in 2011. The mainstay of this support remains left ventricular (LV) assist devices (LVAD) but includes right ventricular assist device (RVAD) and biventricular support (total artificial heart or LVAD + RVAD). Again, these numbers remain consistent with US data, with SRTR reporting that 41.3% of transplant recipients had a VAD at time of transplant in 2012 compared with 23% in 2002. Whereas mechanical circulatory support remains on the rise, the role of inotropes as a bridge to transplant has decreased from 43.4% in 2007 to 36% in 2012. The global shift in management is also reflected by the decline in patients hospitalized at time of transplant (44.3% in 2006 to 2012 compared with 60.8% in 1992 to 2000).

Survival rates post cardiac transplantation have improved over the years with the advancements of medical care and immunosuppression. The 1-year survival is 84% with a median survival of 13 years assuming the recipient survives the first year. Outcomes are influenced by multiple factors including etiology, age, and multiple comorbidities. The risk of death remains highest in the first 6 months posttransplantation predominately secondary to infection and graft failure. Examples of pretransplant multivariable factors associated with higher risk of mortality in the first posttransplant year include requiring temporary mechanical circulatory support and congenital heart disease. Historically, VAD use has been associated with increased mortality; however, SRTR survival curves from 2005 to 2007 demonstrate increased 1-year survival. Additional variables that may impact 1-year mortality include history of renal replacement therapy, mechanical ventilation, prior blood transfusion, and infection as well as recipient age, weight, and height, donor gender mismatch, pretransplant bilirubin and creatinine, ischemic time, and center volume.

The issue of supply and demand remains problematic and demonstrates why it is imperative for transplant programs to adequately screen and responsibly select potential transplant recipients.

II.Indications for Cardiac Transplantation

A.Patients failing optimal medical and device therapy for congestive heart failure, as recommended by the American College of Cardiology/American Heart Association guidelines, including but not limited to an angiotensin-converting enzyme inhibitor (ACEI) or alternative, aldosterone antagonist, β-blocker, and digoxin. When indicated, select patients should have received cardiac resynchronization therapy.

B.Medically reversible causes of decompensated congestive heart failure should be excluded, including thyroid disease, tachycardia-mediated cardiomyopathy, alcohol abuse, obstructive sleep apnea, hypertension, and medical noncompliance.

C.Surgically reversible causes of decompensated congestive heart failure should be excluded, including valvular heart disease, un-revascularized coronary artery disease, hypertrophic obstructive cardiomyopathy, and LV aneurysm for which resection would improve overall cardiac hemodynamics.

D.If the previous criteria are met, indications for a cardiac transplant evaluation are as follows:

1.Progressively worsening or refractory congestive heart failure symptoms, New York Heart Association class IIIb or IV

2.Cardiogenic shock requiring continuous intravenous (IV) inotropic therapy for hemodynamic stabilization

3.Cardiogenic shock requiring mechanical circulatory support (i.e., LVAD or intra-aortic balloon pump counterpulsation)

4.Recurrent life-threatening ventricular arrhythmias despite an implantable cardiac defibrillator, antiarrhythmic medications, and/or when appropriate an attempt at catheter-based ablation

5.Refractory angina without therapeutic options

6.End-stage complex congenital heart disease without pulmonary hypertension

III.Components of a Cardiac Transplant Evaluation and Contraindications. The purpose of a cardiac transplant evaluation is to exclude patients with medical and psychosocial comorbidities and to quantify the severity of a patient’s cardiac impairment. Recommended investigations prior to a transplantation are summarized in Table 13.1 and exclusion criteria for cardiac transplantation are summarized in Table 13.2.

TABLE 13.1 Recommended Evaluation prior to Transplantation

Complete history and physical examination

Laboratory investigations

•Complete blood count with differential and complete metabolic panel

•Thyroid function studies (thyroid-stimulating hormone)

•Liver function panel, creatinine clearance

•Lipid profile, hemoglobin A1c, and urinalysis

Immunologic data

•Blood type and antibody screen

•Human leukocyte antigen typing

•Panel reactive antibodies’ screen

Serology for infectious diseases

•Hepatitis (HBsAg, HBsAb, HBcAb, and HepCAb)

•Herpes group virus

•Human immunodeficiency virus

•Cytomegalovirus IgG antibody

•Toxoplasmosis

•Varicella and rubella titers

•Epstein-Barr virus IgG and IgM antibodies

•Venereal Disease Research Laboratory or rapid plasma reagin

Cardiovascular investigations

•Electrocardiogram, chest x-ray, and echocardiogram

•Exercise test with oxygen consumption

•Right and left heart catheterization

•Myocardial biopsy (if indicated, e.g., to rule out infiltrative process such as amyloidosis)

Vascular assessment

•Carotid Doppler

•Peripheral vascular assessment (ankle–brachial index and/or duplex ultrasound)

•Abdominal ultrasound

•Ophthalmology examination (if indicated, e.g., to rule out diabetic retinopathy)

Cancer screening

•Prostate-specific antigen (in men if indicated)

•Papanicolaou smear and mammography (in women if indicated)

•Colonoscopy (if indicated)

Psychosocial evaluation

•Support system

•Substance abuse history (alcohol, tobacco, and drug use)

•Psychiatric history

Baseline investigations

•Dental examination

•Bone density scan

•Pulmonary function tests

IgG, immunoglobulin G; IgM, immunoglobulin M.

TABLE 13.2 Exclusion Criteria for Cardiac Transplantation

Irreversible pulmonary parenchymal disease

Renal dysfunction with Cr >2.0–2.5 or CrCl <30–50 mL/min (unless for combined heart–kidney transplant)

Irreversible hepatic dysfunction

Severe peripheral and cerebrovascular disease

Insulin-dependent diabetes with end-organ damage

Acute pulmonary embolism

Irreversible pulmonary hypertension (PVR >4.0 Wood units after vasodilators)

Psychosocial instability or substance abuse

History of active malignancy or recent with probability of recurrence

Active infection

Severe osteoporosis

PVR, pulmonary vascular resistance.

A.Blood work. A standard blood workup includes a complete blood cell count with differential, complete metabolic panel, thyroid function tests, and blood type. Human leukocyte antigen (HLA) typing, panel reactive antibody (PRA), and antibody screening are also collected. A serologic assessment should also be performed to determine the recipient’s exposure to cytomegalovirus (CMV), Epstein–Barr virus (EBV), herpes simplex virus, toxoplasmosis, syphilis (rapid plasma reagin), hepatitis B and C viruses, tuberculosis, and human immunodeficiency virus (HIV). In addition, vaccine-preventable infections should be screened to allow time for intervention pretransplant: hepatitis A and B; pneumococcus; tetanus; mumps, measles, rubella, and varicella.

1.Patients who are anemic should have a thorough evaluation, including iron studies and colonoscopy. When indicated, an esophagogastroduodenoscopy and/or a hematologic evaluation, including a bone marrow biopsy, should be considered. Some patients may benefit from erythropoietin treatment to increase red blood cell counts without the need for transfusions that may expose the patient to further antigens.

2.Patients found to have an elevated serum creatinine level should undergo further evaluation to determine its relationship with low renal perfusion. A normal urinalysis result suggests the absence of renal parenchymal disease. This should include an assessment of cardiac hemodynamics and a renal ultrasound to assess renal parenchymal size and the presence of two kidneys without evidence of obstruction.

3.Patients found to have elevated hepatic enzymes should undergo further evaluation with hepatic ultrasound scan and right heart catheterization to further delineate potential etiologies of hepatic insult.

4.The patient’s serum should be screened for antibodies against HLA, both classes I (all nucleated cells) and II (antigen-presenting cells: B-cells, dendritic cells, and macrophages). These antibodies are collectively referred to as PRAs and are often elevated in multiparous women and patients with multiple transfusions (often perioperatively in the past).

Elevated PRA levels may increase the likelihood of a positive crossmatch, making it more difficult to find an ideal match. In addition, sensitized patients have associated increased posttransplant morbidity: rejection and cardiac allograft vasculopathy (CAV). Although controversial, some centers have highly sensitized patients (PRA > 80%) undergo desensitization protocols as an attempt to facilitate a negative crossmatch. The following agents have been tried: IV immunoglobulin, plasmapheresis, rituximab, and combination therapies.

Traditionally, each potential recipient undergoes a thorough HLA tissue typing analysis, via a complement-dependent cytotoxicity assay or molecular typing for assistance in finding an ideal donor. Once a possible donor is identified, random donor lymphocytes are incubated with recipient sera and evaluated by flow cytometry to determine the presence of potential donor-specific antibodies, also known as the crossmatch (see later). Currently, most programs use solid-phase assay, such as flow cytometry, to assess for preformed antibodies. This allows for the detection of weaker interactions and provides a more efficient and sensitive screening process.

B.Imaging

1.All patients should undergo coronary angiography or a functional assessment for ischemia and viability. If ischemia or viability can be demonstrated, consideration should be given to percutaneous or surgical revascularization.

2.Peripheral vascular studies may be obtained to exclude patients with significant disease including carotid and lower extremities.

3.Occasionally, an abdominal aortic ultrasound is obtained to rule out an aneurysm, particularly in patients being considered for mechanical support.

C.Functional assessment

1.Metabolic stress testing is performed to assess the severity of cardiac functional impairment. Patients with compensated congestive heart failure and a peak oxygen consumption (Vo2) of <14 mL/kg/min in patients intolerant to β-blocker or <12 mL/kg/min in the presence of a β-blocker, or <50% predicted are considered sufficiently impaired for transplantation. Adequate patient effort during the stress test can be assessed by the respiratory exchange ratio (RER). RER >1.05 denotes adequate aerobic achievement; RER <1.05 denotes a suboptimal test. The minute ventilation–carbon dioxide production relationship (VE/Vco2 slope) serves as an additional marker, >35 portends a worse prognosis.

2.Generally, a right heart catheterization is performed to assess cardiac hemodynamics and to optimize a patient’s medical therapy prior to listing for transplant and again at 3- to 6-month intervals once listed for continued assessment. An attempt should be made to medically decrease the pulmonary hypertension with inotropic agents, nitrates, or nitroprusside. Sometimes an LVAD is required to sufficiently decompress the left ventricle to reverse the pulmonary hypertension. Endomyocardial biopsy (EMB) is rarely performed, except when an infiltrative cardiomyopathy is suspected. Fixed, severe pulmonary hypertension, defined as a pulmonary vascular resistance (PVR) >4 Wood units, is a contraindication to cardiac transplantation. In this setting, the donor right ventricle will likely immediately fail after implantation because it is not accustomed to high pulmonary pressures.

3.Pulmonary function tests are performed to exclude patients with significant chronic obstructive or restrictive pulmonary disease.

D.Comorbidities and implications of heart transplant listing. Advanced age, cancer, and obesity are the three common comorbidities that remain somewhat controversial regarding their impact on whether an individual program will list a patient for heart transplantation.

1.Age criteria for eligibility were initially quite rigorous; however, it has become apparent that chronologic and physiologic age are often discrepant. Most centers do not have a fixed upper age limit, but generally patients >70 years of age are very carefully screened to rule out comorbidities. ISHLT recommends considering patients for cardiac transplantation if they are ≤70 years of age. Patients >70 years of age may be considered for cardiac transplantation at the discretion of the transplant program and should theoretically be in excellent health except for heart disease. An alternate type of program has been proposed for these patients, whereby older donor hearts would be utilized in this population.

2.Active malignancy other than skin cancer is an absolute contraindication to cardiac transplantation because of limited survival rates. Chronic immunosuppression is associated with a higher-than-average incidence of malignancy and with increased recurrence of prior malignancy. Patients with cancers that have been in remission for ≥5 years and patients with low-grade cancers such as prostate cancer are generally accepted for transplant evaluation. Preexisting malignancies are heterogeneous in nature and some are readily treatable with chemotherapy. Thus an individualized approach to these patients is required, and consultation with an oncologist regarding prognosis is often very helpful.

3.Traditionally, centers have been cautious when considering obese patients for transplantation. Most currently available data indicate that patients with a pretransplant body mass index (BMI) >35 kg/m² have poor outcomes following cardiac transplantation. Current ISHLT recommendations are that patients achieve a BMI <35 kg/m² prior to being listed for cardiac transplantation. This cutoff will vary from center to center, but generally a BMI >35 kg/m² will preclude listing for cardiac transplantation.

4.Assessment of frailty should be considered during the evaluation process including >10 lb of unintentional weight loss over a 1-year period, muscle loss, fatigue, slow gait speed, and change in activity level.

E.Consultations

1.A psychosocial assessment is a crucial component of every cardiac transplant evaluation. Accepted psychosocial contraindications for cardiac transplantations include active smoking; active substance abuse, including alcohol; medical noncompliance; and significant untreated psychological or psychiatric diagnoses. Relative psychosocial contraindications to cardiac transplantation include posttraumatic stress disorder and lack of an adequate support structure.

2.For diabetic patients, an ophthalmology consultation is obtained for an assessment of retinal end-organ damage related to the diabetes.

IV.UNOS and the Recipient List. After a patient is accepted as a potential cardiac transplant recipient by a UNOS-certified transplant program, the patient’s name is entered on a national list compiled by UNOS. The patient is given a status level based on predefined clinical criteria (Table 13.3), which can be adjusted as the patient’s clinical situation evolves. A patient’s priority on the UNOS list depends on his or her status level and the duration of time on the list. Highest priority is given to patients with status 1A and those who have been waiting the longest. A critical patient initially listed as status 1A immediately has a higher priority than a patient with a status 1B, regardless of the duration of time spent as status 1B. Whether a patient is hospitalized or not does not affect priority on the list, other than the fact that hospitalized patients are more likely to be receiving hemodynamic support (mechanical or inotropic) and are at a higher status level. A hospitalized patient on continuous inotropic therapy without invasive hemodynamic monitoring has the same status as a similar patient on home continuous inotropic therapy.

TABLE 13.3 Description of Status Levels in the United Network of Organ Sharing List
Status	Description
1A	Inpatient receiving high-dose inotropic support (i.e., dobutamine > 7.5 μg/kg/min or milrinone 0.5 μg/kg/min or two or more inotropes, regardless of dose) with invasive hemodynamic monitoring
	Inpatient receiving mechanical support: VAD, TAH, IABP, or ECMO
	LVAD and/or RVAD for 30 d following implantation
	VAD-related complication: thromboembolism, infection, mechanical failure, life-threatening ventricular arrhythmias
	Life-threatening refractory arrhythmias with or without a VAD
	Mechanical ventilation
1B	Inotrope dependent
	VAD not meeting criteria for 1A status
2	All patients who do not meet status 1A or 1B criteria
7	Inactive on list because of improved clinical status or short-term contraindications to cardiac transplantation (e.g., active infection)

ECMO, extracorporeal membrane oxygenator; IABP, intra-aortic balloon pump; LVAD, left ventricular assist device; RVAD, right ventricular assist device; TAH, total artificial heart; VAD, ventricular assist device.

V.Workup of a Potential Cardiac Donor. Potential cardiac donors are patients who are declared brain dead but otherwise have viable internal organs. Generally, these are patients with lethal head injuries or catastrophic central nervous system events (i.e., intracranial hemorrhage, stroke, or cerebral anoxia).

A.Declaration of brain death. A neurologist or a neurosurgeon usually declares the brain death of a potential organ donor. Usually, this declaration is made after a period of observation (about 12 hours) during which no neurologic improvement is seen. Physicians involved in the care of potential transplant recipients are not involved in this decision to avoid conflicts of interest. Criteria for the determination of brain death are very specific. Absence of any one of the following criteria makes the patient ineligible for organ donation:

1.A known cause of death

2.Absence of hypotension, hypothermia, hypoxemia, and metabolic perturbations

3.Absence of medical or recreational drugs known to depress the central nervous system

4.Absence of cerebral cortical function

5.No response to painful stimuli

6.Absence of brainstem reflexes

a.Pupillary constriction to light

b.Corneal reflex

c.Vestibular ocular reflexes (i.e., doll’s eyes or cold caloric testing)

d.Gag reflex

e.Cough reflex

7.Positive apnea test: no spontaneous respiration despite arterial Pco₂ >60 mm Hg for at least 10 minutes after disconnection from the ventilator

8.An electroencephalogram (EEG) is not required but may be performed at the discretion of the examining physician. The EEG should demonstrate electrical silence.

B.Potential donor screening. After a patient is declared brain dead, a local organ procurement organization (OPO), under the auspices of UNOS, performs the initial evaluation of a potential donor. This evaluation includes a thorough patient and family history, focusing specifically on cardiac risk factors and potentially transmittable diseases (i.e., malignancy and infection). Preliminary blood tests are done, including comprehensive metabolic panel, complete blood count, cardiac enzymes, hepatitis B and C serologies, HIV, toxoplasmosis, CMV, and EBV. In addition, ABO blood group typing and HLA typing are performed. An echocardiogram is routinely obtained to assess cardiac function and rule out congenital anomalies, valvular disease, and other anomalies. At the request of the potential recipient’s physician, a coronary angiogram may be acquired if the donor has significant cardiac risk factors, has positive cardiac enzymes, or is relatively advanced in age. Cardiac donor selection criteria are summarized in Table 13.4.

TABLE 13.4 Cardiac Donor Selection Criteria

Must meet legal requirements for brain death

No history of chest trauma or cardiac disease

No prolonged hypotension or hypoxemia

Normal ECG

Absence of significant coronary artery disease, if catheterization is performed

Negative HBsAg+, human immunodeficiency virus serologies, fungal infections, and active tuberculosis

Infections with special consideration: HCV, donor bacterial infections, HBsAg–, HBcAb+ (“core-positive donor”—utilized particularly for nonliver; or liver with intensive prophylaxis; preferably to vaccinated recipient)

Systolic blood pressure > 100 mm Hg or mean arterial pressure > 60 mm Hg

Central venous pressure 8–12 mm Hg

Minimal inotropic support, that is, <10 µg/kg/min dopamine to maintain blood pressure

Age < 55 y preferred

No history of active malignancy with exception of confined brain tumor

ECG, electrocardiogram; HB, hepatitis B; HCV, hepatitis C virus.

Potential recipients undergo both a virtual and a prospective crossmatch, in which the recipient’s serum is incubated with donor lymphocytes to identify potential donor–recipient HLA incompatibility. If the HLA tissue typing of the potential donor does not include the antigens against which the recipient is sensitized, it is assumed that the actual crossmatch will be negative (i.e., a “virtual” negative crossmatch). If a prospective crossmatch is not performed, a retrospective crossmatch (typically by flow cytometry) is performed using donor lymphocytes obtained from donor aortic lymph nodes retrieved at the time of harvest.

C.Donor–recipient matching. UNOS maintains a computerized list of all patients listed and waiting for cardiac transplantation. A list of potential recipients with compatible blood types is generated for each potential donor organ and is made available to the OPO. In this list, priority is given to local patients (defined as within the OPO’s territory) with the highest status level that has been waiting the longest. Allocation guidelines can be found within the organ procurement and transplantation network policy manual; see UNOS website for current guidelines.

Transplant physicians of the potential recipient may also reject a potential organ because of a positive prospective crossmatch, donor–recipient size mismatch, or a prolonged projected ischemic time (usually related to long-distance travel). Matching donor and recipient size is important, because an oversized donor organ may not allow closure of the chest without compression of the organ and an undersized donor organ may not be able to pump a sufficient quantity of blood. Current recommendations suggest a donor weight should ideally be within approximately 30% of a potential recipient’ (20% if female donor to male recipient) to avoid size mismatch.

VI.Surgical Issues Related To Cardiac Transplantation. Most surgical issues related to cardiac transplantation are beyond the scope of this chapter and are mainly of interest to the cardiac surgeon. The main surgical issue of interest to the transplant cardiologist is related to the anastomosis of the right atrium. The surgeon may suture the donor atrium to the recipient atrium (i.e., biatrial anastomosis) or suture the donor superior vena cava to the recipient superior vena cava and the donor inferior vena cava to the recipient inferior vena cava (i.e., bicaval anastomosis). The bicaval anastomosis approach is more time consuming but reduces the incidence of atrial arrhythmias (including sinus node dysfunction), reduces the incidence of posttransplant tricuspid regurgitation, and improves right atrial hemodynamics. The bicaval anastomosis approach does, however, provide some potential difficulties to the cardiologist trying to perform surveillance EMBs, because these anastomoses have a tendency to scar and narrow the central lumen over time. Currently, most centers employ the bicaval anastomosis approach, although no survival advantage has been conclusively demonstrated with this approach.

VII.Postoperative Complications After Cardiac Transplantation

A.Surgical complications. The most common surgical complication is the development of a pericardial effusion with or without tamponade. Pericardial effusions are very common because of the large potential space left behind as the dilated and dysfunctional recipient left ventricle is replaced with a more appropriately sized donor left ventricle. Rarely, pericardial tamponade develops, necessitating percutaneous or surgical evacuation of the pericardium. Other surgical complications are much less common but can be catastrophic and usually result from a problem either at a site of anastomosis or at a site of cannulation.

B.Early graft dysfunction

1.LV systolic dysfunction. It is common for transplant recipients to require inotropic support as they come off cardiopulmonary bypass. The most commonly used inotropic agents in this setting are dobutamine, milrinone, and isoproterenol, used alone or in combination. It is also common for transplant recipients to require peripheral vasoconstrictors such as epinephrine, norepinephrine, and dopamine in the early postoperative period. Most patients can be weaned off inotropic therapy and peripheral vasoconstrictors within the first few days.

2.LV diastolic dysfunction is very common soon after cardiac transplantation. It usually results from reversible ischemia or reperfusion injury to the donor organ and normally resolves over a period of days to weeks. If the ischemia or reperfusion injury is sufficiently severe to induce significant contraction band necrosis or myocardial fibrosis, as seen on EMB, chronic diastolic dysfunction can ensue. Another potential cause of diastolic dysfunction is donor–recipient mismatch, particularly with a small donor organ or acute rejection.

3.Right ventricular dysfunction is much more common than LV dysfunction after cardiac transplantation, especially in patients with preexisting pulmonary hypertension. The right ventricle is subjected to similar ischemic or reperfusion injury risks as the left ventricle. Right ventricular dysfunction is usually accompanied by right ventricular dilation and the failure of coaptation of the tricuspid valve leaflets, leading to severe tricuspid regurgitation. The treatment for perioperative right ventricular dysfunction is usually IV milrinone, dobutamine, dopamine, or pressors for those who are persistently hypotensive. In patients with persistent RV dysfunction confounded by pulmonary hypertension, prostanoids or inhaled nitric oxide should be considered.

C.Cardiac arrhythmias. Most transplant recipients require perioperative temporary atrioventricular pacing. Sinus node dysfunction is very common, probably because of a combination of surgical trauma, ischemia, or reperfusion injury, and denervation. The incidence of sinus node dysfunction is believed to be reduced with bicaval anastomosis. With time, the sinus node typically recovers and a permanent pacemaker is not necessary. Preoperative use of amiodarone increases the likelihood of bradycardia posttransplantation. Other cardiac arrhythmias are rare and may signify rejection.

D.Renal dysfunction. Preoperatively, many transplant recipients have some degree of impaired renal function. There is a risk of worsening renal function perioperatively. This risk is compounded by the fact that the major immunosuppressive agents (i.e., calcineurin inhibitors) are nephrotoxic. Induction therapy should be considered for patients who are at increased risk for perioperative renal dysfunction as a means to delay calcineurin therapy. Interleukin-2 (IL-2) receptor blocker (i.e., basiliximab or Simulect) or Thymoglobulin (rabbit—antithymocyte globulin) remains the mainstay for induction therapy, as OKT 3 and Campath have fallen out of vogue secondary to risk profile.

VIII.Systemic Immunosuppression. Much of the success in cardiac transplantation today is attributed to advances in immunosuppression. However, balancing the risk of allograft rejection against the inherent risk of immunosuppression (i.e., infection, malignancy) remains a challenge. Immunosuppressant protocols during and after cardiac transplantation vary greatly from program to program and even from patient to patient within a specific center. Triple therapy, which constitutes the cornerstone of modern immunosuppressive regimens in cardiac transplantation, includes a calcineurin inhibitor (such as cyclosporine or tacrolimus), a cell cycle–modulating or antiproliferative agent (such as mycophenolate mofetil [MMF] or azathioprine), and a corticosteroid. The ideal regimen and dosage remains in question. For example, the tacrolimus in combination, tacrolimus alone compared trial prospectively randomized 150 cardiac transplant patients in an open fashion to receive either tacrolimus monotherapy or tacrolimus and MMF. Corticosteroids were used in all patients but were successfully discontinued over 8 to 9 weeks. The addition of MMF to tacrolimus did not provide an advantage over tacrolimus alone in terms of primary end point of rejection over the first 6 months, the secondary end points of allograft vasculopathy, and 3-year survival. The trial has, however, been criticized for being underpowered to demonstrate true differences in the primary and secondary end points, its use of an unvalidated biopsy grading scale, inconsistent timing of intravascular ultrasound (IVUS), use of higher and potentially nephrotoxic levels of tacrolimus, and the lack of a control arm of routine triple-drug immunosuppression for comparison with the two study arms. Controversy remains about the advisability of using induction therapy in the nonsensitized recipient without renal failure (Table 13.5).

A.Steroids. The mechanism by which steroids serve as immunosuppressants is complex and not completely understood. Steroids bind to nuclear receptors, thereby preventing gene expression of various cytokines important for B-cell and T-cell activation and proliferation, the most important of which is IL-2. Steroids also have important anti-inflammatory properties and suppress macrophage activity. Important side effects of steroids include diabetes, hypertension, weight gain, osteoporosis, and avascular necrosis of the femoral head.

Steroid-dosing protocols also vary from one institution to another. A dose of 500 to 1,000 mg of IV Solu-Medrol is usually given to the patient intraop and then 125 to 150 mg is usually repeated every 8 hours for a total of three additional doses. Some centers then start a dose of 1 mg/kg/d and wean by 5 mg daily, whereas others start 20 mg oral daily or the equivalent of 16 mg IV methylprednisone until patient is able to tolerate an oral regimen. The dose of steroid is typically slowly tapered, provided the patient remains free of rejection. The trend in clinical practice is to wean most patients completely off steroids by the end of the first year if not sooner. Some centers continue to advocate the indefinite use of low-dose prednisone (2.5 to 5 mg daily). If a decision is made to withdraw steroids completely, it should be done approximately 1 month before the next scheduled biopsy to ensure continued lack of rejection.

Steroids are also given in “pulses” to treat episodes of acute rejection. If a patient has acute rejection associated with hemodynamic compromise, he or she is admitted for 1 g of IV Solu-Medrol daily for 3 days and may be given cytolytic therapy or plasmapheresis, or both. If no hemodynamic compromise is associated with the episode of rejection, a daily dose of 100 mg oral prednisone for 3 days is usually sufficient, followed by repeat biopsy at most 2 weeks later to ensure resolution—again this is center specific.

B.Calcineurin inhibitors. Calcineurin is a phosphatase enzyme that triggers transcription of new messenger RNA after activation of the T-cell receptor by an appropriate antigen, leading to increased gene expression of IL-2 and other important cytokines. Calcineurin antagonists inhibit this phosphatase activity, thereby preventing the synthesis of these cytokines, which prevent B-cell and T-cell proliferation.

1.Cyclosporine (Neoral, Gengraf, and Sandimmune) is a calcineurin antagonist with a highly variable pattern of bioavailability, depending on the oral formulation taken. Bioavailability of the original soft gelatin capsule (Sandimmune) was low and depended on emulsification by bile salts. The newer microemulsion formulation (Neoral) does not depend on bile salts for emulsification and has a more consistent bioavailability. Nevertheless, there remain tremendous interpatient differences in bioavailability, and dosing of Neoral is primarily based on serum drug trough levels. Because of the narrow therapeutic range of cyclosporine, drug trough levels are also important to prevent toxicity. Nephrotoxicity is the most important side effect of cyclosporine therapy and is related to renal afferent arteriolar vasoconstriction and the resultant reduced renal perfusion. Other side effects include systemic hypertension, gingival hyperplasia, and tremors. Calcium channel blockers (CCBs), particularly diltiazem, reduce hepatic metabolism of cyclosporine, thereby increasing serum drug levels. This drug interaction is frequently used clinically to reduce the oral dose of cyclosporine required to achieve a given serum drug concentration, thereby minimizing the cost of immunosuppression.

Postoperatively, once the patient is hemodynamically stable with good urine output, cyclosporine is initiated via continuous infusion at 1 mg/h. When the patient is able to take oral medicines, Neoral is begun at a dose of 100 mg twice daily, with adjustments in the dose based on serum trough levels (Table 13.6). The dose of Neoral is gradually reduced over a period of 1 year if the patient has a clean biopsy record.

TABLE 13.6 Target Serum Cyclosporine A Levels
Time (mo)	Target Level (12-h Trough) (ng/mL)
0–3	250–350
3–12	200–250
>12	150–175

2.Tacrolimus (Prograf), previously known as FK506, is another calcineurin inhibitor that has low oral bioavailability. Tacrolimus-based regimens have demonstrated lower rates of rejection compared with cyclosporine but there is no evidence to suggest a survival benefit. It has become standard of practice to change a patient’s immunosuppressive regimen from cyclosporine to tacrolimus when recurrent or persistent acute cellular rejection occurs in the setting of adequate cyclosporine levels. The major side effects of tacrolimus are nephrotoxicity and neurotoxicity (most commonly tremor).

Like cyclosporine, tacrolimus is initiated postoperatively once the patient is hemodynamically and renally stable. A dose of 0.01 mg/kg/d of tacrolimus is administered by continuous infusion. Unfortunately, IV tacrolimus is seemingly more nephrotoxic than cyclosporine. Tacrolimus can be given sublingually using an oral to sublingual dose ratio of 1:1 with dose adjustment based on serum drug levels (Table 13.7).

TABLE 13.7 Target Serum Tacrolimus (FK506 or Prograf) Levels
Time	Target Level (12-h Trough) (ng/mL)
0–30 d	12–20
1–6 mo	8–15
6–18 mo	5–15
>18 mo	5–10

C.Mycophenolate mofetil (CellCept). MMF inhibits DNA synthesis by inhibiting de novo purine synthesis. Because human lymphocytes depend on the de novo synthesis of purines for DNA replication, MMF has the unique ability to inhibit B-lymphocyte and T-lymphocyte proliferation without affecting DNA synthesis in other cell lines, which can obtain purines through the parallel and unaffected purine salvage pathway. MMF has become the preferred immunosuppressant over azathioprine at most transplant centers because of a reduced mortality rate at 1 year (6.2% vs. 11.4%; p = 0.03). The main disadvantage of MMF over azathioprine is the increased cost (approximately 20-fold) and the potential increased risk of opportunistic viral infections. Toxicities of MMF include gastrointestinal symptoms (nausea, vomiting, and diarrhea) and myelosuppression. Some patients on MMF develop clinically significant leukopenia, necessitating dose reduction or discontinuation of the drug. Most symptoms will resolve with the reduction of dose.

MMF is given intravenously or orally. Because of the high bioavailability (>90%), the initial dose of MMF is 1 g taken twice daily, regardless of the route of administration. The initial dose is given within the first 12 hours after transplantation. Routine monitoring of mycophenolic acid (MPA), the active metabolite of MMF, is not recommended; however, an MPA level <1.5 mg/L is considered subtherapeutic. Serum levels of MPA are higher when MMF is administered with tacrolimus compared with cyclosporine; therefore, it may be advisable to empirically reduce the dosage of MMF when switching from cyclosporine to tacrolimus.

D.Azathioprine (Imuran) is a purine analog that impairs DNA synthesis, thereby preventing B-lymphocyte and T-lymphocyte proliferation in response to antigen stimulation. Azathioprine has largely been replaced by MMF as the antiproliferative agent of choice in the triple immunosuppressant cocktail of today. Because there is no drug level assay available, azathioprine dosing is usually fixed between 1 and 2 mg/kg/d. The major side effect of azathioprine is myelosuppression, and the dose of azathioprine is usually adjusted to maintain a white blood cell count of >3,000/mL. Azathioprine is metabolized by xanthine oxidase, and xanthine oxidase inhibitors, such as allopurinol, can lead to toxic levels of azathioprine and profound, prolonged myelosuppression.

E.Inhibitors of the target of rapamycin (TOR) enzyme. Sirolimus (Rapamune) and everolimus (Certican, also known as RAD). TOR is activated after IL-2 stimulation of the T-cell IL-2 receptor and is critical for lymphocyte growth and proliferation. In contrast to calcineurin inhibitors, TOR inhibitors do not block cytokine production (e.g., IL-2) but rather block the cellular response to these cytokines. TOR inhibitors also inhibit vascular smooth muscle cell growth and proliferation in response to various growth factors. It is hoped that this property of TOR inhibitors will help reduce the rate of progression of CAV. Unlike calcineurin inhibitors, TOR inhibitors are not nephrotoxic. When used in combination with cyclosporine, TOR inhibitors appear to act synergistically with regard to immunosuppression. However, worsening of renal function is common but can be prevented by lowering the cyclosporine dose without worsening of immunosuppression. The main side effects of this class of compounds are significant hypertriglyceridemia, thrombocytopenia, and poor wound healing.

Sirolimus and everolimus are both TOR inhibitors. They are structurally similar, but everolimus has a much higher bioavailability than sirolimus. The appropriate dosing of these agents remains unclear, but for sirolimus, it is probably 1 to 5 mg/d, and for everolimus, it is probably 1.5 to 3 mg/d. Sirolimus appears to lower the incidence of acute cellular rejection in humans and slow the progression of transplant vasculopathy. Preliminary human studies using intravascular coronary ultrasonography (IVUS) have also shown a reduction in neointimal proliferation with both sirolimus and everolimus. It remains unclear where TOR inhibitors will fit in with current immunosuppressive protocols. The most likely scenario is their use in combination with a calcineurin inhibitor and prednisone, in place of MMF or azathioprine. One-year posttransplant IVUS data demonstrated significantly lower increase in maximal intimal thickness in patients receiving everolimus compared with MMF. Alternatively, they could be used in place of calcineurin inhibitors and in combination with MMF or azathioprine and prednisone, particularly in patients with either preexisting or worsening renal dysfunction.

F.Induction therapy and therapy for steroid-resistant acute rejection. The purpose of induction therapy is to deplete T-lymphocytes or to prevent lymphocyte proliferation during the most immunoreactive phase, which occurs immediately after transplantation. Induction therapy remains controversial, and practice patterns across centers continue to vary. According to recent SRTR data approximately 50% of centers utilize induction therapy at the time of transplant. A recent retrospective review of over 17,000 patients from UNOS registry demonstrated that the use of induction therapy did not impact overall survival. Three indications to use induction therapy are as follows: in patients with renal dysfunction, which would preclude the early introduction of calcineurin inhibitors; in the highly sensitized patient at time of transplant; and in patients with compromised graft function secondary to rejection.

1.Polyclonal antilymphocyte antibodies are produced by injecting animals with human lymphocytes or thymocytes and then collecting the animal’s serum. Two commercially available formulations are antithymocyte globulin (Atgam), which is horse based, and Thymoglobulin, which is rabbit based. The antibodies produced in this manner are directed against a variety of targets on the surface of B- and T-cells and induce complement-mediated lymphocytolysis. The recommended doses of Atgam and Thymoglobulin are 15 and 1.5 mg/kg/d, respectively; the total dose depends on the course of action: induction versus rejection. Adequate lymphocyte depletion can be ensured and dose adjustments made by quantifying the CD3 or CD2 counts. Immunity may develop to the animal component of these antibodies, rendering them ineffective if further courses of therapy are necessary. An increased incidence of posttransplant lymphoproliferative disorder (PTLD), lymphoma, and opportunistic viral infections has also been observed. Patients receiving either formulation are often prophylactically treated with ganciclovir or valganciclovir to prevent CMV infection.

2.IL-2 receptor blockers: basiliximab (Simulect) and daclizumab (Zenapax). IL-2 receptor antagonists target the IL-2R-α chain (CD25) on activated T-lymphocytes and inhibit IL-2–mediated activation of subsequent lymphocytes. Prior daclizumab studies demonstrated a reduced risk of rejection; however, one large, multicenter randomized control trial demonstrated excess risk of death. Subsequently, daclizumab was removed from the market in 2009. Basiliximab is predominately used at the time of induction; cytolitic agents like Thymoglobulin are reserved for episodes of rejection and induction.

IX.Rejection. According to the ISHLT registry, rates of rejection within the first year of transplant continue to decline and were 25% in 2010 compared with 32% in 2004. Females and young patients were at higher risk than males and older patients, respectively. Allograft rejection involves both the cellular and humoral arms of the adaptive response. An ideal immune monitoring strategy has been described as the one that would be noninvasive, would reliably distinguish between the presence and absence of rejection, and would detect over-immunosuppression. Such an ideal strategy does not exist; however, surrogate markers are available through gene expression profiling (GEP) tests and immune function assays. The immunologic status of a transplant recipient is currently monitored by immunosuppressant drug levels, echocardiographic assessment of allograft function, and EMB. Noninvasive monitoring therapies have been tested in the hope of overcoming these limitations. The GEP test, also known as AlloMap, is an example of a promising alternative when used in the appropriate substrate (see below for additional description).

A.Endomyocardial biopsy. The current gold standard of rejection surveillance after cardiac transplantation is EMB. Rejection of the cardiac allograft is usually clinically silent unless it is accompanied by significant hemodynamic compromise (i.e., congestive heart failure). As a result, EMBs are routinely performed for rejection surveillance. However, EMB is invasive, inconvenient, expensive, and subject to sampling and interpretation error. To mitigate interobserver variability, the ISHLT revised and simplified the grading criteria for acute cellular and antibody-mediated rejection (AMR) (Table 13.8). Because the likelihood of acute rejection is highest early posttransplant, the frequency of biopsies remains high during this period and then gradually tapers off, depending on the results (Table 13.9).

TABLE 13.8 Rejection Grading Scale for Endomyocardial Biopsies
Grade	Severity of Cellular Rejection	Histologic Findings
1R^a	Mild	Interstitial and/or perivascular infiltrate with up to 1 focus of necrosis
2R	Moderate	≥2 foci of infiltrate with associated necrosis
3R	Severe	Diffuse infiltrate with multifocal necrosis ± edema ± hemorrhage ± vasculitis
Grade		Histologic findings
pAMR 0		Negative for pathologic AMR. Both histologic and immunopathologic studies are negative
pAMR 1 (H+)		Histopathologic AMR alone. Histologic findings are present and immunopathologic findings are negative
pAMR 1 (I+)		Immunopathologic AMR alone. Histologic findings are negative and immunopathologic findings are positive
pAMR 2		Pathologic AMR. Both histologic and immunopathologic findings are present
pAMR 3		Severe pathologic AMR

^aR = revised.

AMR, antibody-mediated rejection.

TABLE 13.9 Example of Endomyocardial Biopsy Schedule—Center Dependent
Weeks After Transplantation	Biopsy Frequency
1–4	Weekly
5–12	Every 2 wk
13–24	Monthly
25–52	Every 2 mo
Year 2	Every 3–4 mo
Years 3–4	Every 6 mo
>4 y	Only if clinically indicated
After biopsy with acute rejection	2 wk after initial biopsy

B.Surrogate markers of rejection

1.Peripheral biomarkers. Although high levels of circulating pretransplant, donor-specific antibodies to HLAs have been demonstrated to predict greater risk of severe rejection, no peripheral markers have been shown to reliably correlate with allograft rejection posttransplantation among those evaluated, including cytokine levels, markers of myocardial necrosis (creatine kinase-muscle/brain and troponin), complement fragments, prothrombin, P-selectin fragments, CD69 membrane protein, soluble CD30, endothelin, serum nitrate, thromboxane A₂, matrix metalloproteinase-1 in brain, vascular endothelial growth factor, natriuretic peptide, and C-reactive protein.

2.Echocardiography. Echocardiography is ubiquitous in cardiac transplant centers, drawing investigative attention to it as a noninvasive surveillance alternative to EMB for cardiac allograft rejection. For it to be a useful screening tool, however, echocardiography must identify graft rejection before global LV systolic dysfunction ensues. The challenge has been to identify such sentinel markers. Myocardial performance index, pressure halftime, intraventricular relaxation time, and acoustic quantification of cardiac filling volumes have not shown consistency. Changes >10% in serial measurements of pulsed wave tissue Doppler measurements of early diastolic basal posterior wall motion velocity were able to exclude clinically relevant rejection with positive predictive value and negative predictive value of 92% and 95%, respectively. Technical limitations with this technique in the cardiac transplant population together with inconsistent observer interpretation have meant that echocardiography is neither sufficiently sensitive nor specific to supplant routine EMB.

3.Gene expression profiling. GEP is a new modality for surveillance of cardiac allograft rejection. This test uses microarray and quantitative polymerase chain reaction (PCR) of peripheral blood mononuclear cells to measure the expression of 20 genes (11 informative and 9 control and normalization). A score ranging from 0 to 40 is generated by a multigene algorithm. It has been shown to correlate strongly with histologically diagnosed cellular allograft rejection. In the Cardiac Allograft Rejection Gene Expression Observational study, a score of <34 was associated with a negative predictive value of >99% for grade ≥3A/2R rejection. Several factors influence AlloMap score, including time posttransplantation, peripheral alloimmune activity, corticosteroid dose, and CMV. Transplant vasculopathy has been shown to be associated with increased AlloMap GEP score. GEP testing can be used in clinically stable cardiac transplant recipients who are >15 years of age and 6 months or more posttransplantation. It is used to identify patients at low risk for moderate/severe (≥3A original ISHLT grade or ≥2R revised ISHLT grade) cellular rejection. In the Invasive Monitoring Attenuation through Gene Expression (IMAGE) trial, 602 patients who had undergone cardiac transplantation at least 6 months previously were randomly assigned to the AlloMap test or EMB. The composite primary outcome of the study was allograft dysfunction, death, or retransplantation. At 2 years, the cumulative rate of this composite end point was 14.5% with GEP and 15.3% with EMB. The AlloMap test was thus not inferior to EMB in detecting allograft cellular rejection. However, wholesale embrace of the IMAGE trial is tempered by the limitations of the trial, including the enrolment of only 20% of potentially eligible patients and of patients at lower risk for rejection. The noninferiority margin chosen was wide and included events that would not be associated with rejection because not all cases of graft dysfunction, death, or retransplantation are due to rejection.

The frequency of rejection surveillance using the GEP or AlloMap testing should be individualized to the patient’s rejection history, immunosuppression regimen, time posttransplantation, and transplant center protocol. GEP is a cost-effective and less expensive alternative to EMB for monitoring allograft cellular rejection in cardiac transplant patients.

C.Types of rejection

1.Hyperacute rejection is usually fatal and is the result of allograft rejection by preformed antibodies. It can occur immediately on surgical reperfusion. The incidence of hyperacute rejection is rare in the era of PRAs and virtual and prospective crossmatch.

2.Cell-mediated rejection is characterized by infiltration of mononuclear inflammatory cells that are predominantly T-cells directed against the allograft. Variability in the interpretation of histologic grading of cellular rejection of EMB by pathologists led to the revision of the grading system in 2004. Biopsy grades of ≥2R warrant accentuation of immunosuppression. If there is no hemodynamic compromise, then patients are routinely treated as outpatients with 100 mg of prednisone taken orally for 3 days; again this varies from center to center. If there is a hemodynamic compromise or persistent or recurrent severe rejection (at least grade 2R), then many therapeutic options are available: methylprednisolone, cytolytic therapy with Atgam or Thymoglobulin, plasmapheresis, photopheresis, and in severe cases total lymphoid irradiation combined with optimization of maintenance immunosuppression.

3.Antibody-mediated rejection occurs because of preformed or de novo alloantibody (immunoglobulin G or M) against donor antigens. Such antibodies and complements are deposited in the donor coronary microvasculature and are demonstrable by immunofluorescence or by immunohistochemistry staining against CD68, C4d, or C3d complement fragments that mediate vascular injury and, ultimately, allograft failure. The ISHLT proposed a framework for reporting pathologic AMR which includes any combination of histopathologic and immunopathologic findings. Treatment regimens for patients with AMR include IV or oral steroids, plasmapheresis, or immunoadsorption and are determined by degree of rejection defined by presence of graft dysfunction, pathologic, and serologic assessment.

X.Infectious Disease after Transplantation. The risk of infection is highest in the first year post cardiac transplantation, accounting for 29% of deaths. Thereafter, the risk falls but remains >10%. In the first month posttransplantation, nosocomial infections predominate. The therapeutic immunosuppression consequent upon transplantation leaves cardiac allograft recipients vulnerable to opportunistic infections or reactivation of latent infection, particularly between 1 and 6 months. Infections after 6 months are usually community acquired. An infectious disease specialist with an interest in transplantation is an invaluable resource to any transplant program. The two pathogens of particular interest in the transplant patient are CMV and Pneumocystis jiroveci pneumonia (PJP), formerly called pneumocystis carinii pneumonia, but there are several potential pathogens including Mycobacterium, Nocardia, Listeria, Candida, Aspergillus, and Strongyloides.

A.Cytomegalovirus. Primary CMV infection occurs when a CMV-negative recipient receives a CMV-positive donor organ or is infected de novo from another source. Secondary CMV infection occurs when a CMV-positive recipient has reactivation of quiescent CMV infection with viremia after immunosuppression, particularly with induction therapy or bolus immunosuppression prescribed for a rejection episode. Active CMV disease may manifest as fevers, myalgias, gastritis, colitis, pneumonitis, retinitis, or leukopenia and thrombocytopenia. The most sensitive and specific test for diagnosing CMV is quantitative PCR. PCR detects CMV deoxyribonucleic acid (DNA) in plasma and quantifies the CMV viral load. Although CMV DNA replication may be detected by PCR, most patients do not have the clinical syndrome of CMV disease. The issues of whether a detectable CMV viral load will progress to the clinical syndrome and whether to treat patients with CMV detection in the absence of symptoms remain controversial.

Prophylaxis against CMV disease is considered to be the standard of care for CMV-positive recipients (regardless of the CMV status of the donor) and CMV-negative patients with a CMV-positive donor. There is no consensus on the duration of ganciclovir therapy in these patients. Most patients are initially treated with IV ganciclovir, followed by a variable course of oral valganciclovir or acyclovir. Periodic monitoring of the CMV viral load may assist in guiding the duration of therapy in these patients.

Passive immunization with CMV immunoglobulin (CytoGam) may be considered in patients deemed at risk for CMV disease, particularly if they have low levels of serum immunoglobulins (<500 mg/dL). Patients undergoing induction therapy, polyclonal or monoclonal antibody therapy for steroid-resistant rejection, or increased immunosuppressive therapy for acute rejection should be deemed at risk for reactivation of CMV disease.

The duration of therapy with valganciclovir for active CMV disease is usually 3 to 6 weeks. An undetectable CMV viral load should be demonstrated in such patients before consideration is given for antiviral therapy discontinuation.

B.P. jiroveci pneumonia. Transplant recipients are at increased risk for the development of PJP because of their immunocompromised state. PJP is rare if appropriate prophylaxis with trimethoprim–sulfamethoxazole (TMP–SMX) is provided. Patients intolerant to TMP–SMX may be treated with inhaled pentamidine or dapsone. PJP is rarely seen at maintenance immunosuppressant doses in transplant patients. TMP–SMX may be discontinued 6 to 12 months after transplantation in most patients.

XI.Cardiac Allograft Vasculopathy. CAV is a progressive, neointimal proliferative process in the epicardial coronary arteries and microcirculation. It is common, with an incidence of 30% and >50% at 5 and 10 years, respectively, and greater posttransplant. CAV is a significant cause of mortality beyond the first year after transplantation, accounting approximately 15% after 5 years posttransplant. The pathophysiology of CAV is not completely understood. Initially CAV was thought to be an accelerated form of atherosclerosis; however, it is now clear that both immunologic and nonimmunologic factors are involved in the process. Chronic, subclinical, and immune-mediated injury at the level of the donor coronary endothelium creates a chronic inflammatory milieu. The exact mediator of the endothelial injury remains controversial, but it is probably multifactorial, including chronic humoral and cellular rejection, ischemic and reperfusion injury at the time of transplantation, and chronic CMV infection of endothelial cells. Table 13.10 lists risk factors for the development of CAV, of which older donor age and hyperlipidemia are well-established risk factors, whereas the others are potential risk factors.

TABLE 13.10 Risk Factors for the Development of Cardiac Allograft Vasculopathy

Advanced donor age

Hyperlipidemia

Donor brain death secondary to spontaneous intracranial hemorrhage

Cytomegalovirus infection

Increased C-reactive protein levels

Recurrent cellular rejection

Humoral (vascular) rejection

HLA mismatch

Donor hepatitis B and C

Female donor

Prolonged ischemic time

Pretransplant coronary atherosclerotic disease

Conventional atherosclerosis risk factors (diabetes, hypertension, and smoking)

HLA, human leukocyte antigen.

Because donor hearts are denervated at explantation, the transplant recipient typically will not experience cardiac angina from advanced CAV. The clinical presentation of CAV previously unrecognized in a patient may include symptomatic or asymptomatic LV dysfunction, myocardial infarction, or cardiac arrhythmia, including ventricular arrhythmias, heart block, syncope, or sudden cardiac death. Owing to the usually asymptomatic nature of CAV, transplant recipients require frequent surveillance studies to detect significant vasculopathy, including coronary angiography with or without IVUS, cardiac perfusion magnetic resonance imaging, and dobutamine echocardiography. The frequency and method of surveillance remain center specific. Although coronary angiography is useful for the diagnosis of nontransplant coronary artery disease, its sensitivity is considerably less in CAV because of the diffuse nature of this disease. Coronary IVUS imaging provides useful tomographic perspective to study the development and progression of CAV and is now considered by many to be the gold standard modality for diagnosing CAV. However, not all centers have access to routine IVUS imaging and thus its use will vary greatly from center to center. The recommended nomenclature for CAV is as follows:

A.CAV0 (not significant). No detectable angiographic lesion

B.ISHLT CAV1 (mild). Angiographic left main (LM) <50%, primary vessel with maximum lesion of <70%, or any branch stenosis <70% (including diffuse narrowing) without allograft dysfunction

C.ISHLT CAV2 (moderate). Angiographic LM <50%, a single primary vessel ≥70%, or isolated branch stenosis ≥70% in branches of two systems, without allograft dysfunction

D.ISHLT CAV3 (severe). Angiographic LM ≥50%, two or more primary vessels ≥70% stenosis, or isolated branch stenosis ≥70% in all three systems; or ISHLT CAV1 or CAV2 with allograft dysfunction (defined as LVEF ≤45% usually in the presence of regional wall motion abnormalities) or evidence of significant restrictive physiology (which is common but not specific).

The detection of significant CAV should prompt aggressive percutaneous or more rarely surgical revascularization. Because of its relationship with chronic rejection, advancement of the immunosuppressant regimen has also been advocated. Statins have been shown prospectively to decrease the incidence of transplant vasculopathy and improve survival, regardless of the patient’s lipid profile. Preliminary studies investigating the antiproliferative effects of TOR inhibitors suggest a significant reduction in coronary neointimal proliferation and, therefore, transplant coronary vasculopathy but larger, prospective clinical trials are needed. In severe, advanced CAV, frequently the only viable option is retransplant. Despite diagnosis of CAV the management dilemma remains.

XII.Malignancy. Malignancy is a common and devastating complication of cardiac transplantation. In immunocompetent people, the cellular arm of the immune system actively defends against a variety of neoplastic processes. With the initiation of immunosuppression after transplantation, this defense mechanism is rendered feeble and previously undeclared neoplastic foci may proliferate. Because up to 37% of patients undergo cardiac transplantation for ischemic cardiomyopathy, a significant proportion of which is smoking related, lung cancers can occur. Other common tumors include skin cancers, lymphomas, colon cancers, and breast cancers. Posttransplant malignancies are particularly common in patients who have received cytolytic or induction therapy with OKT3 (no longer used), Atgam, or Thymoglobulin, and the risk correlates with cumulative dosing of immunosuppression. The risk of developing a malignancy as a result of immunosuppression is enhanced by the inability to adequately assess for over-immunosuppression. Under-immunosuppression is readily detected because of the development of acute rejection, whereas there is no clinical finding to suggest over-immunosuppression.

PTLD is an EBV-related clonal expansion of B-lymphocytes. PTLD may develop in any location but most commonly affects the gastrointestinal tract, lungs, and central nervous system. The primary treatment for PTLD is a reduction in immunosuppression (by about 50%), which can frequently be curative. Surgical debulking, systemic chemotherapy, and antiviral therapy may also be indicated in selected patients.

XIII.Hypertension. Arterial hypertension commonly develops after cardiac transplantation secondary to the untoward effects of immunosuppression. Hypertension developing after cardiac transplantation occurs in most cyclosporine-treated and tacrolimus-treated patients. Three mechanisms proposed are as follows: direct sympathetic activation, increased responsiveness to direct circulating neurohormones, and direct vascular effects. A common end point of these proposed mechanisms is vasoconstriction of the renal vasculature, leading to sodium retention, and an elevated plasma volume. Corticosteroids play a minor role in the pathogenesis of cardiac transplant hypertension, which is described as a salt-sensitive type. Abnormal cardiorenal reflexes secondary to cardiac denervation may also contribute to salt-sensitive hypertension and fluid retention.

Patients with blood pressure consistently >140/90 mm Hg should be treated like the general population. Titrated monotherapy with either CCBs or ACEI/angiotensin receptor blocker (ARB) should be considered in diabetic patients; combination therapy with CCB and ACEI/ARB is most commonly employed. The use of diltiazem, verapamil, or amlodipine necessitates the use of lower doses of cyclosporine and initially more frequent cyclosporine level monitoring because these drugs are competitive antagonists of cyclosporine at the cytochrome P450 level. Problematic hypertensives requiring multiple agents often require diuretics as part of their regimen. Hypertension in some patients is inadequately controlled despite maximally tolerated doses of both CCBs and ACEIs. The final tier of management would be to add an α-blocker such as clonidine, doxazosin, or methyldopa, or a vasodilator such as hydralazine in refractory cases. β-blockers have traditionally been avoided because of their known tendency to reduce exercise performance and because of concerns about excessive bradycardia. Some transplant cardiologists, however, routinely use β-blockers to manage hypertension in their transplant patients. Thus, β-blockers are not contraindicated but rather may be used with caution.

XIV.Outcomes after Cardiac Transplantation. Survival outcomes after cardiac transplantation continue to improve on a yearly basis despite what is generally accepted as a population of transplant recipients at greater risk, primarily because of advancing recipient age and increasing severity of heart failure. The 1-year survival rate after cardiac transplantation is 84% nationwide, but it is frequently >90% at large transplant centers. The mortality in the first year after transplantation primarily results from postoperative complications, including multiorgan failure, primary graft failure, and systemic infection. Those surviving the first year posttransplantation have a median survival of 13 years. It is unlikely that any major improvements in early posttransplant survival will occur in light of these excellent results. However, a 10-year survival rate after cardiac transplantation is only 50%. Mortality in the long term primarily results from transplant coronary vasculopathy, malignancy, and renal failure. It is hoped that a major impact can be made on long-term survival with newer immunosuppressive drug regimens that may be less nephrotoxic and more effective at preventing transplant coronary vasculopathy.

ACKNOWLEDGMENTS: The author thanks Dr Peter Zimbwa for his contributions to an earlier edition of this chapter.