Cardiac Transplantation and Mechanical Circulatory Support
Dale G. Renlund
David O. Taylor
Nicholas G. Smedira
Overview
Cardiac transplantation has become the most effective treatment for selected patients with end-stage heart failure. Sound, evidence-based immunosuppressive strategies have decreased morbidity and mortality, making survival routine. Most infections and rejections are either preventable or treatable, and the temporary, pretransplant use of mechanical circulatory support (MCS) no longer portends a poor prognosis following transplantation. Although cardiac allograft vasculopathy (CAV) and malignancy limit long-term survival, approximately 50% of recipients are alive 10 years after transplantation. Because the availability of this effective treatment depends on a limited supply of donor hearts, care must be taken to ensure that individuals listed as candidates for cardiac transplantation are those who will likely benefit the most. Potentially suitable candidates should be referred early in the course of their end-stage disease to heart failure and transplant specialists so that transplantation or alternative treatment strategies can be appropriately timed and implemented. After transplantation, the care of recipients should be directed, at least in part, by transplant physicians.
Historical Perspective
Patients with severe heart failure have a 1- to 2-year mortality approaching 50% despite appropriate and advanced medical treatment (see Chapter 83). Heart transplantation alters the course of end-stage heart disease, with 1-, 3-, and 10-year survival rates exceeding 83%, 75%, and 45%, respectively. In selected patients with end-stage heart failure, heart transplantation is the most effective treatment. More than 60,000 procedures have been performed in over 330 centers worldwide, and nearly 3,000 additional procedures are performed each year (1).
Because the propensity to reject the transplanted heart decreases over time, the first year after transplantation presents the highest risk of rejection. Because higher doses of immunosuppressive agents are used during this time, the first year also presents the highest rate of infection. After the first few years, CAV and malignancy become the leading causes of death, the former accounting for one quarter of the deaths among transplant recipients (1,2,3).
Although management of end-stage heart failure and cardiac transplant patients is challenging, requiring vigilance and attention to detail, the care of potential transplant patients and posttransplant patients is important to both internists and cardiologists (4). Primary care physicians provide at least some of the care for patients awaiting cardiac transplantation (>4,000 in the United States alone) and for many cardiac transplant recipients. Moreover, knowing when to refer a patient to a heart failure and transplant specialist for evaluation is of paramount importance. Early referral of any patient who has persistent significant left ventricular dysfunction (ejection fraction <25%) despite appropriate medical therapy is warranted, not only to evaluate the patient’s potential need for cardiac transplantation but also to assess whether alternative therapies might delay or obviate the need for transplantation.
TABLE 90.1 Indications for Cardiac Transplantation Candidacy | ||
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Clinical Profile
Recipient Selection
Indications
Cardiac transplantation is indicated for any one of the many reasons listed in Table 90.1 (1,5). Before transplantation is considered, however, a thorough search for reversible or surgically repairable cardiac disease is completed and optimal medical management implemented. At the least, patients either have failed to improve with a trial of β-blocker therapy or have clear contraindications to β-blocker use. Confidence that the medical therapy is optimal is increased when the therapy is directed or administered by heart failure specialists.
Patients who require continuous intravenous inotropic support (e.g., dobutamine hydrochloride or milrinone lactate) or MCS (intraaortic balloon pump or left ventricular assist device [LVAD]) despite maximal medical therapy for heart failure are likely to benefit from transplantation and should be evaluated. Individuals whose predicted chance of survival for 1 year is less than 80% without heart transplantation warrant consideration for transplantation. Identifying all patients at high risk for death during continued medical therapy remains challenging, as does determining whether less ill, ambulatory patients with heart failure will benefit from transplantation. Most patients being considered for cardiac transplantation usually have New York Heart Association class III to IV symptoms despite receiving best medical therapy. Ambulatory candidates usually have peak oxygen consumption (VO2) values of 14 mL/kg/min or less when assessed by maximal exercise tolerance testing. Unless the test is terminated because of myocardial ischemia or ventricular arrhythmias, anaerobic threshold occurs at 50% to 70% of peak oxygen uptake. The effects of age, gender, and conditioning effects on maximal oxygen uptake must be considered in interpreting VO2 data.
Assessment of Risk of Mortality and Morbidity after Transplantation
Anecdotal experience of successfully overcoming isolated risk factors cannot justify ignoring known risks in the majority of situations (Table 90.2).
Management of the Patient Awaiting Transplantation
While the patient awaits transplantation, there should be a low threshold for hospitalization and more intensive heart failure treatment for any hemodynamic deterioration. Such deterioration may manifest as significant azotemia, refractory salt and water overload, persistent hypotension, altered mental status, or even gastrointestinal distress. Signs and symptoms of low cardiac output prompt escalation in therapy from intravenous diuretics to intravenous inotropic agents, and from intravenous inotropic agents to intraaortic balloon pump or MCS. Heart transplant candidates who nonetheless develop irreversible end-organ failure in other organ systems or who are likely to die despite transplantation are not transplanted. Therapeutic approaches to prevent sudden death, especially the use of implantable cardioverter defibrillators, are used (6).
Mechanical Circulatory Support
For patients who are unable to be stabilized on a heart failure regimen including inotropic agents, mechanical support devices have become standard. Approximately 25% to 30% of patients undergoing transplantation are bridged to transplant with a mechanical support device. The most recent LVAD registry data suggest that bridge-to-transplant survival has remained unchanged over the past 5 years (7). Approximately 65% to 70% of patients supported with an LVAD alone survive to undergo transplantation. If a right ventricular assist device is used along with an LVAD, the survival to transplant declines to 50%.
The timing of MCS deployment in a transplant candidate is challenging. Premature use of MCS is unnecessary, increases overall costs, and can potentially negate a candidate’s opportunity for transplant. If MCS is used too late, overall costs again increase, lengths of hospital stays are increased, and a candidate may not sufficiently recover to become an acceptable candidate again.
As hemodynamic compromise progresses from moderate to severe in a patient awaiting heart transplantation, not only is there an increase in the risk of dying before transplantation can be performed, but the results after transplantation also worsen. The timely use of MCS halts further deterioration, decreases the likelihood of death before transplantation can occur, and reverses metabolic, cellular, and nutritional compromise. The
temporary use of such support thus permits heart transplant with a greater expectation of long-term survival and a better quality of life (8).
temporary use of such support thus permits heart transplant with a greater expectation of long-term survival and a better quality of life (8).
TABLE 90.2 Morbidity and Mortality Risk After Cardiac Transplantation | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Because a variety of bridging devices are commercially available, the selection of a device depends on the type of heart failure, the size of the patient, the surgeon’s experience, and the institutional preference. Implantable LVADs channel blood from the left ventricle to the pump, which then circulates blood to the aorta. The currently available implantable devices are too large for patients with a body surface area of less than 1.5 m2, but investigations with smaller devices are ongoing. Meanwhile, paracorporeal devices, with the pump placed outside the body, provide an alternative for the support of one or both ventricles. LVADs are generally inadequate for bridging to transplantation in patients with severe biventricular heart failure, which requires the use of two paracorporeal devices (8).
When LVADs or paracorporeal devices are either difficult to use or contraindicated, the replacement of both ventricles with an implantable device such as a total artificial heart may be warranted. Such circumstances may arise in patients with severe aortic insufficiency, intractable ventricular arrhythmias, aortic prosthesis, acquired ventricular septal defect, or irreversible ventricular failure requiring a high pump output (8,9). The CardioWest artificial heart (SynCardia Systems, Tucson, AZ) provides a successful bridge to transplantation in most severely compromised patients (9). Of note, survival to transplantation of patients supported with the CardioWest artificial heart is reported to be 79% (9). Although high-flow biventricular support with the total artificial heart is theorized to improve outcomes, more experience with this Food and Drug Administration–approved device is needed for validation.
Many new devices are in clinical trials. These include inline or axial pumps such as the DeBakey (MicroMed Technology, Inc, Houston, TX), Jarvik 2000 FlowMaker (Jarvik Heart, Inc, New York, NY), HeartMate II (Thoratec Corp., Pleasanton, CA), and INCOR (Berlin Heart AG, Berlin, Germany).
Radial or centrifugal pumps include the DuraHeart (Terumo Corp., Ann Arbor, MI), VentrAssist (Ventracor Ltd, Sydney, Australia), CorAide (Arrow International, Reading, PA), HeartQuest (MedQuest Products, Inc., Salt Lake City, UT), and HeartMate III (Thoratec Corp., Pleasanton, CA). Only the CorAide and VentrAssist pumps are in clinical trials. These pumps are significantly smaller, are potentially more durable, and their thinner drivelines are associated with fewer infectious complications. However, initial survival to transplant is similar to older pulsatile pumps and pump thrombosis and thromboembolic rates appear higher than expected for devices without inflow or outflow valves.
Radial or centrifugal pumps include the DuraHeart (Terumo Corp., Ann Arbor, MI), VentrAssist (Ventracor Ltd, Sydney, Australia), CorAide (Arrow International, Reading, PA), HeartQuest (MedQuest Products, Inc., Salt Lake City, UT), and HeartMate III (Thoratec Corp., Pleasanton, CA). Only the CorAide and VentrAssist pumps are in clinical trials. These pumps are significantly smaller, are potentially more durable, and their thinner drivelines are associated with fewer infectious complications. However, initial survival to transplant is similar to older pulsatile pumps and pump thrombosis and thromboembolic rates appear higher than expected for devices without inflow or outflow valves.
Donor Selection
Donor selection is influenced by many factors, including ABO blood type compatibility, donor–recipient size disparity, presence of intrinsic cardiac disease, and presence of transmissible infectious or malignant diseases (10,11). The risk of using a specific donor heart is balanced against the risk with regard to a particular recipient. A decision to use a marginal donor heart may sometimes be warranted, provided that the condition of the potential recipient is sufficiently precarious and the potential recipient consents.
To identify intrinsic cardiac disease in donor hearts, electrocardiography, echocardiography, and (at times) coronary angiography are used. Electrocardiographic abnormalities that generally preclude the use of a donor heart include evidence of myocardial infarction and significant ventricular arrhythmias. Echocardiographic abnormalities that generally preclude the use of a donor heart include significant global hypokinesis, significant valvular abnormalities, and moderate to severe left ventricular hypertrophy. In addition, evidence of a significant cardiac contusion generally precludes use of the donor heart. However, far too many hearts are turned down on the basis of “poor quality.” Recovery of hearts from a consented donor is around 50%. Poor cardiac function is the reason the organ is declined in 60% of the cases. To improve recovery, management recommendations include the liberal use of pulmonary artery catheters to optimize fluid resuscitation, T3 administration, corticosteroids to reduce the inflammatory state, and vasopressin to return vascular tone rather than relying on the vasoconstricting effects of high doses of dopamine (12,13,14). This paradigm has not been proven in a randomized clinical trial, but small series support its use. Reliance on echocardiograms to determine cardiac function has significant limitations. After brain death, the catecholamine storm often induces transient ventricular dysfunction (15). Because the echocardiogram is often not repeated, a poorly functioning heart is often turned down despite the return of normal function after resuscitation. In this setting repeating the echocardiogram or inserting a pulmonary artery catheter helps to determine if the heart has recovered. If the recovery is incomplete, careful assessment of other factors such as ischemic time, likelihood of early rejection, and high pulmonary artery pressures may impact the decision to utilize the organ for a particular recipient.
The concept of using expanded donor criteria, or marginal donors, is well established. Jeevanandum et al. (16) advanced this concept in 1996 and this group demonstrated outstanding results albeit with patients initially having a more complicated early recovery. In other reports, older donors, longer ischemic times, and undersizing by more than 50% remain risk factors for early mortality (17,18). Intracerebral bleed as the cause of donor brain death may be a risk factor or just a covariate associated with older women with hypertrophied ventricles (19). Although older donor hearts are associated with higher risks, many have been successfully used (1,20). Coronary angiography is recommended in all male donors older than 45 years and in female donors older than 50 years. If risk factors for coronary artery disease are present in younger donors, coronary angiography is also recommended.
To avoid transmitting infectious disease with the donated heart, a series of tests are performed to determine the suitability for transplantation. A history of behaviors, especially recent, that predispose to human immunodeficiency virus (HIV) infection or viral hepatitis (e.g., intravenous drug use); positivity for HIV, hepatitis B surface antigen, or hepatitis C; and uncontrolled gram-negative sepsis generally preclude donor use. Typically, if the donor has a malignancy not confined to the cranium, the donor heart is not used.
Anatomic Considerations: Implantation Techniques
Minimization of donor heart ischemic time—the time of aortic cross-clamping in the donor to release of aortic cross-clamp in the recipient—is key to successful transplantation (21). Ischemic time less than 4 hours is generally acceptable. Two orthotopic techniques are used to replace the recipient heart with the donor heart: (a) the traditional Lower and Shumway technique, in which the donor right atrium is attached directly to the recipient right atrium, and (b) the increasingly employed bicaval technique, in which superior and inferior vena cavae are attached separately. The bicaval technique results in a slightly longer donor heart ischemic time, but is associated with a more “anatomic” transplant with lower right atrial pressure, lower incidence of atrial tachyarrhythmias, and less tricuspid valve incompetence (22). Despite the increasing use of the bicaval technique, tricuspid regurgitation remains a common problem both early and late after cardiac transplantation. Often thought of as just a nuisance, a recent study suggests it may have significant hemodynamic consequences. Performing prophylactic suture annuloplasty at implant not only reduced the incidence of tricuspid regurgitation, but surprisingly and inexplicably reduced perioperative mortality from graft dysfunction (23). This study was small, but an annuloplasty of the tricuspid valve could be considered at the time of transplantation.
In heterotopic cardiac transplantation, which is rarely performed, the donor heart is placed in the right lower thorax parallel to the recipient heart, which is left in place. Anastomoses are made between donor left atrium and recipient left atrium, donor and recipient aortae, donor superior vena cava and recipient right atrium or superior vena cava, and donor pulmonary artery and recipient pulmonary artery or right atrium. The indications for heterotopic cardiac transplantation include severely elevated pulmonary hypertension, a small donor heart, or a donor heart with anticipated poor initial function.
Posttransplant Complications
Most recipients experience cardiac, infectious, or other complications following cardiac transplantation. Common complications are noted in Table 90.3. Although the complications encountered after cardiac transplantation are legion, most problems can be prevented, ameliorated, or treated.
Ventricular Dysfunction
The initial function of the newly transplanted cardiac allograft is influenced by pre-explant variables (e.g., degree of inotropic support, cardiopulmonary resuscitation, and trauma), the ischemic time, effectiveness of cardioplegia, and total
denervation. Inotropic support is usually required for 2 to 5 days. If cardiac allografts function poorly because of global ischemia, they can regain normal function after as little as 1 week. Measures of left ventricular function and resting hemodynamics normalize over time.
denervation. Inotropic support is usually required for 2 to 5 days. If cardiac allografts function poorly because of global ischemia, they can regain normal function after as little as 1 week. Measures of left ventricular function and resting hemodynamics normalize over time.
TABLE 90.3 Complications After Cardiac Transplantation | |||||||||||||||||||||
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The cardiac allograft is totally denervated at the time of transplantation, and therefore responds differently to many common cardiovascular medicines. The response to direct β-adrenergic agonists (isoproterenol, dobutamine, epinephrine, norepinephrine) is qualitatively unchanged. The response to the sympathomimetic amines that act indirectly by releasing catecholamines from nerve terminals (e.g., dopamine) is likely diminished, and supersensitivity to adenosine is typically seen. Because of denervation, atropine sulfate, digoxin, and quinidine would not be expected to affect atrioventricular conduction. Over a period of months to years, the cardiac allograft reinnervates partially in the majority of recipients (24,25).
Cardiac Arrhythmias
Sinus node dysfunction is common early after transplantation, but only rarely requires a permanent pacemaker. Postoperative atrial tachyarrhythmias may occur and are generally treated as usual, except that cardiac allograft rejection is considered in the differential diagnosis (26). Early on, postoperative ventricular ectopy can be seen, but usually resolves. Late after transplantation, although rare, recipient remnant atrial to donor atrial conduction (across the suture line) has been reported (27). After the postoperative period, electrophysiologic disease may become manifest or develop. Generally, traditional measures are appropriate, including the use of antiarrhythmic agents, devices, or interventions.
Cardiac Allograft Rejection
Pathophysiology (The Immune System)
Transplantation of an organ between members of the same species is known as allotransplantation; hence, the use of the term cardiac allograft. Alloantigens are molecules recognized as foreign (or non-self) by the recipient immune system. In the absence of immunosuppression, destruction of the alloantigens—and the organ bearing them—occurs (2,28).
HLA antigens are serologically identified alloantigens that have been shown to correspond to the human major histocompatibility complex (MHC). These cell-surface antigens are subclassified as MHC class I (HLA-A, HLA-B, and HLA-C) or MHC class II (HLA-DP, HLA-DQ, and HLA-DR). Whereas HLA antigens have distinctly different roles in the rejection process, prospective HLA matching is generally not possible in heart transplantation. The sequence of events leading to cardiac allograft rejection encompasses antigen recognition, primary and secondary signals for T-cell activation, and T-cell proliferation and differentiation (Fig. 90.1).
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