Transplant Medicine
Michael Pham
BACKGROUND
The first human heart transplant was performed in South Africa in 1967, followed by the first U.S. procedure in 1968 by Dr. Norman Shumway at Stanford University. Over 4,000 heart transplants are performed worldwide each year; the number of procedures is currently limited by the availability of organ donors. Survival rates are 81%, 74%, 68%, and 50% at 1, 3, 5, and 10 years.1
INDICATIONS FOR TRANSPLANTATION
Systolic heart failure with severe functional limitation and/or refractory symptoms despite maximal medical therapy
Left ventricular ejection fraction (LVEF) usually <35%, but a low LVEF is not an adequate indication for transplantation
NYHA Functional Class III-IV
Maximum oxygen uptake (VO2 max) of > 12 to 14 cc/kg/min on exercise testing
Cardiogenic shock not expected to recover
Acute myocardial infarction
Myocarditis
Ischemic heart disease with intractable angina
Not amenable to surgical or percutaneous revascularization
Refractory to maximal medical therapy
Intractable ventricular arrhythmias, uncontrolled with antiarrhythmic medications, ICD therapy, and/or ablation
Severe symptomatic hypertrophic or restrictive cardiomyopathy
Congenital heart disease
Cardiac tumors with low likelihood of metastasis
CONTRAINDICATIONS
Irreversible severe pulmonary arterial hypertension: Considered an absolute contraindication by most programs
Pulmonary vascular resistance (PVR) >4 to 5 Wood units
Pulmonary vascular resistance index (PVRI) >6
Transpulmonary gradient (mean PA – PCWP) >16 to 20 mm Hg
PA systolic pressure >50 to 60 mm Hg or >50% of systemic pressures
Advanced age: Many programs are moving away from “absolute” age limits and considering rehabilitation potential, end-organ function, and presence of comorbid conditions when evaluating older patients. Some programs still have an age cutoff between 65 and 70 years of age.
Active systemic infection: Patients can typically be listed after the infection has been identified and adequately treated (i.e., absence of fever, leukocytosis, and bacteremia).
Active malignancy or recent malignancy with high risk of recurrence. Exceptions include nonmelanoma skin cancers, primary cardiac tumors restricted to the heart, and low-grade prostate cancers. Consultation with an oncologist is recommended.
Diabetes mellitus with either poor glycemic control (variable definitions, but usually HbA1c >7.5) or end-organ damage (neuropathy, nephropathy, and proliferative retinopathy)
Marked obesity (body mass index [BMI] >30 kg/m2 or >140% of ideal body weight). Most programs will have variable cutoffs for BMI.
Severe peripheral arterial disease not amenable to revascularization
Systemic process with high probability of recurrence in the transplanted heart
Amyloidosis
Sarcoidosis
Hemochromatosis
Irreversible severe renal, hepatic, or pulmonary disease. Occasional combined heart/kidney, heart/lung, or heart/liver transplants are done at selected centers.
Recent or unresolved pulmonary infarction due to the high probability of progression into pulmonary abscesses after initiating immunosuppression
Psychosocial factors that may impact on patient’s ability to receive posttransplant care
History of poor compliance with medications or follow-up appointments
Lack of adequate support system
Uncontrolled psychiatric illness
Active or recent substance abuse (alcohol, tobacco, or illicit drugs)
PRETRANSPLANT EVALUATION
History
Does patient meet indications for transplantation?
Has adequate medical, device, and/or surgical therapy been attempted?
Does patient have significant contra-indications to transplantation?
Psychosocial Evaluation
Assess patient’s understanding of transplant procedure and willingness to undergo lifelong immunosuppression and follow-up
Assess adequacy of social support system
Assess for uncontrolled psychiatric illness or active/recent substance abuse that may impact posttransplant care.
Lab Exams and Imaging
Blood tests: Complete blood count, electrolytes, renal and hepatic function, ABO typing; human leukocyte antigens (HLA) antibody screen against panel of common antigens (PRA); hepatitis, syphilis, and HIV serologies
Chest x-ray
Electrocardiogram
Echocardiogram
Coronary angiography (or review most recent study) if known coronary artery disease (CAD) or if patient has risk factors for CAD
Right heart catheterization to document pulmonary artery pressures. Pharmacologic intervention with vasodilators (intravenous nitride or inhaled nitric oxide) may be used to document reversibility of pulmonary hypertension.
Pulmonary function testing
Carotid ultrasound and lower extremity ABIs
Age and sex-appropriate cancer screening (PAP smear, mammogram, colonoscopy, prostate-specific antigen (PSA) with DRE)
Most candidacy determinations are made after review of patient’s history and workup by a multidisciplinary Transplant Selection Committee comprising cardiologists, surgeons, social workers, and/or psychologists.
ORGAN MATCHING AND PRIORITIZATION
Recipient waiting list maintained by United Network of Organ Sharing (UNOS)
Recipients and donors are matched by blood type, weight, priority status (Table 11-1), and time accrued on waiting list.
Prospective HLA matching between donor and recipient is typically not performed unless a recipient has high levels of preformed antibodies (PRA >20%).
Waiting times range from days to years and are dependent upon priority status (shortest for 1A, longest for 2), blood type (longest for blood group O), weight (longer for large recipients), and geographic location.
TABLE 11-1 UNOS prioritization of heart transplant recipients | ||||||||||||||||||||||||||||||||||||||||||||
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SURGICAL TECHNIQUE
Most donor hearts are implanted in the orthotopic position (i.e., in the same position as the explanted heart).
The original technique involved anastomosis of the donor heart at the level of the atria (biatrial technique), leaving a cuff of donor atria. In recent years, the biatrial technique has been modified to make the anastomoses at the level of the superior and inferior vena cavae and pulmonary veins (bicaval technique). This results in less A-V valve regurgitation, decreased incidence of atrial arrhythmias, and decreased incidence of donor sinus node dysfunction and heart block requiring permanent pacemaker implantation.
Ischemic times of 3 to 4 hours are preferred.
PHYSIOLOGY OF TRANSPLANTED HEART
The transplanted heart is initially completely denervated. Cardiac denervation has several important clinical implications:
Patients exhibit a faster resting heart rate (usually between 95 to 110 bpm)
Many patients will not experience angina. Typical presentations of ischemia include congestive heart failure, myocardial infarction, or sudden death.
Drugs that act through the autonomic nervous system (e.g., atropine) will have little to no effect on a transplanted heart.
IMMUNOSUPPRESSION
General Principles
The risk of rejection is highest immediately after transplantation and decreases over time. Most rejection episodes occur during the first year; therefore, immunosuppression is highest during this time.
The goal of immunosuppression is to use the lowest doses of drugs to prevent rejection while minimizing toxicities (particularly renal insufficiency) and immunosuppression-related complications (infection and cancer).
Induction Therapy
Currently, induction is used by 50% of transplant centers to provide a period of intense immunosuppression in the early (first 6 months) posttransplant period, when the risk of rejection is highest.
Advantages: Decreases the incidence of rejection during the first 6 months, allows delayed initiation of nephrotoxic immunosuppressive drugs in patients with compromised renal function after surgery
Disadvantages: May simply be shifting rejection to the late period (6-12 months) after transplantation; may increase the risk of infection and malignancy
Agents used for induction include
Cytolytic agents are antibodies that result in near complete depletion of T-lymphocytes (OKT3, Thymoglobulin)
Interleukin-2 receptor antagonists are antibodies that inhibit IL-2 mediated proliferation of activated T-lymphocytes (daclizumab, basiliximab).
Maintenance Immunosuppression
Most maintenance protocols employ a two- to three-drug regimen with no more than one agent from each class to avoid overlapping toxicities (see Table 11-2). The dosing, target drug levels, and side effect profile of each agent is shown in Table 11-3.
TABLE 11-2 Typical immunosuppressive regimens | |||||||||||||||||||||||||
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