CHAPTER 21: CARDIAC TRANSPLANTATION AND PROLONGED ASSISTED CIRCULATION

Advanced or end-stage heart failure is an increasingly frequent sequela of many types of heart disease, as progressively more effective palliation for the earlier stages of heart disease and prevention of sudden death associated with heart disease become more widely recognized and employed (Chap. 19). When patients with end-stage or refractory heart failure are identified, the physician is faced with the decision of advising compassionate end-of-life care or choosing to recommend extraordinary life-extending measures. For the occasional patient who is relatively young and without serious comorbidities, the latter may represent a reasonable option. Current therapeutic options are limited to cardiac transplantation (with the option of mechanical cardiac assistance as a “bridge” to transplantation) or permanent mechanical assistance of the circulation. In the future, it is possible that genetic modulation of ventricular function or cell-based cardiac repair will be options for such patients. Currently, both of the latter approaches are considered to be experimental.

Surgical techniques for orthotopic transplantation of the heart were devised in the 1960s and taken into the clinical arena in 1967. The procedures did not gain widespread clinical acceptance until the introduction of “modern” and more effective immunosuppression in the early 1980s. By the 1990s, the demand for transplantable hearts met, and then exceeded, the available donor supply and leveled off at about 4000 heart transplantations annually worldwide, according to data from the Registry of the International Society for Heart and Lung Transplantation (ISHLT). Subsequently, heart transplantation activity in the United States has remained stable at ~2200 per year, but worldwide activity reported to this registry has decreased somewhat. This apparent decline in numbers may be a result of the fact that reporting is legally mandated in the United States but not elsewhere, and several countries have started their own databases.

SURGICAL TECHNIQUE

Donor and recipient hearts are excised in virtually identical operations with incisions made across the atria and atrial septum at the mid-atrial level (with the posterior walls of the atria left in place) and across the great vessels just above the semilunar valves. The donor heart is generally “harvested” by a separate surgical team, transported from the donor hospital in a bag of iced saline solution, and reanastomosed into the waiting recipient in the orthotopic or normal anatomic position. The only change in surgical technique since this method was first described has been a movement in recent years to move the right atrial anastomosis back to the level of the superior and inferior venae cavae to better preserve right atrial geometry and prevent atrial arrhythmias. Both methods of implantation leave the recipient with a surgically denervated heart that does not respond to any direct sympathetic or parasympathetic stimuli but does respond to circulating catecholamines. The physiologic responses of the denervated heart to the demands of exercise are atypical but quite adequate for continuation of normal physical activity.

DONOR ALLOCATION SYSTEM

In the United States, the allocation of donor organs is accomplished under the supervision of the United Network for Organ Sharing, a private organization under contract to the federal government. The United States is divided geographically into eleven regions for donor heart allocation. Allocation of donor hearts within a region is decided according to a system of priority that takes into account (1) the severity of illness, (2) the geographic distance from the donor, and (3) the patient’s time on the waiting list. A physiologic limit of ~3 h of “ischemic” (out-of-body) time for hearts precludes a national sharing of hearts. This allocation system design is reissued annually and is responsive to input from a variety of constituencies, including both donor families and transplantation professionals.

At the current time, the highest priority according to severity of illness is assigned to patients requiring hospitalization at the transplantation center for IV inotropic support, with a pulmonary artery catheter in place for hemodynamic monitoring, or to patients requiring mechanical circulatory support—i.e., use of an intra-aortic balloon pump or a right or left ventricular assist device (RVAD, LVAD), extracorporeal membrane oxygenation, or mechanical ventilation. The second highest priority is given to patients requiring ongoing inotropic support, but without a pulmonary artery catheter in place. All other patients are assigned a priority according to time accrued on the waiting list, and matching generally is based only on compatibility in terms of ABO blood group and gross body size.

While HLA matching of donor and recipient would be ideal, the relatively small numbers of patients as well as the time constraints involved make such matching impractical. However, some patients who are “presensitized” and have preexisting antibodies to human leukocyte antigens (HLAs) undergo prospective cross-matching with the donor; these patients are commonly multiparous women or patients who have received multiple transfusions.

INDICATIONS/CONTRAINDICATIONS

Heart failure is an increasingly common cause of death, particularly in the elderly. Most patients who reach what has recently been categorized as stage D, or refractory end-stage heart failure, are appropriately treated with compassionate end-of-life care. A subset of such patients who are younger and without significant comorbidities can be considered as candidates for heart transplantation. Exact criteria vary in different centers but generally take into consideration the patient’s physiologic age and the existence of comorbidities such as peripheral or cerebrovascular disease, obesity, diabetes, cancer, or chronic infection.

RESULTS

A registry organized by the ISHLT has tracked worldwide and U.S. survival rates after heart transplantation since 1982. The most recent update reveals survival rates of 83% and 76% 1 and 3 years after transplantation, respectively, or a posttransplantation “half-life” of 10.00 years (Fig. 21-1). The quality of life of survivors is generally excellent, with well over 90% of patients in the registry returning to normal and unrestricted function after transplantation.

IMMUNOSUPPRESSION

Medical regimens employed to suppress the normal immune response to a solid organ allograft vary from center to center and are in a constant state of evolution, as more effective agents with improved side-effect profiles and less toxicity are introduced. All currently used regimens are nonspecific, providing general hyporeactivity to foreign antigens rather than donor-specific hyporeactivity and also causing the attendant, and unwanted, susceptibility to infections and malignancy. Most cardiac transplantation programs currently use a three-drug regimen that includes a calcineurin inhibitor (cyclosporine or tacrolimus), an inhibitor of T cell proliferation or differentiation (azathioprine, mycophenolate mofetil, or sirolimus), and at least a short initial course of glucocorticoids. Many programs also include an initial “induction” course of polyclonal or monoclonal antibodies to T cells in the perioperative period to decrease the frequency or severity of early posttransplantation rejection. Most recently introduced have been monoclonal antibodies (daclizumab and basiliximab) that block the interleukin 2 receptor and may prevent allograft rejection without additional global immunosuppression.

Cardiac allograft rejection is usually diagnosed by endomyocardial biopsy conducted either on a surveillance basis or in response to clinical deterioration. Biopsy surveillance is performed on a regular basis in most programs for the first year postoperatively (or the first 5 years in many programs). Therapy consists of augmentation of immunosuppression, the intensity and duration of which are dictated by the severity of rejection.

LATE POSTTRANSPLANTATION MANAGEMENT ISSUES

Increasing numbers of heart transplant recipients are surviving for years following transplantation and constitute a population of patients with a number of long-term management issues.

Allograft Coronary Artery Disease

Despite usually having young donor hearts, cardiac allograft recipients are prone to develop coronary artery disease (CAD). This CAD is generally a diffuse, concentric, and longitudinal process that is quite different from “ordinary” atherosclerotic CAD, which is more focal and often eccentric. The underlying etiology most likely is primarily immunologic injury of the vascular endothelium, but a variety of risk factors influence the existence and progression of CAD, including nonimmunologic factors such as dyslipidemia, diabetes mellitus, and cytomegalovirus (CMV) infection. It is hoped that newer and improved immunosuppressive modalities will reduce the incidence and impact of these devastating complications, which currently account for the majority of late posttransplantation deaths. Thus far, the immunosuppressive agents mycophenolate mofetil and the mammalian target of the rapamycin (mTOR) inhibitors sirolimus and everolimus have been shown to be associated with short-term lower incidence and extent of coronary intimal thickening; in anecdotal reports, institution of sirolimus was associated with some reversal of CAD. The use of statins also is associated with a reduced incidence of this vasculopathy, and these drugs are now used almost universally in transplant recipients unless contraindicated. Palliation of CAD with percutaneous interventions is probably safe and effective in the short term, although the disease often advances relentlessly. Because of the denervated status of the organ, patients rarely experience angina pectoris, even in advanced stages of disease.

Retransplantation is the only definitive form of therapy for advanced allograft CAD. However, the scarcity of donor hearts makes the decision to pursue retransplantation in an individual patient difficult and ethically complex.

Malignancy

An increased incidence of malignancy is a well-recognized sequela of any program of chronic immunosuppression, and organ transplantation is no exception. Lymphoproliferative disorders are among the most frequent posttransplantation complications and, in most cases, seem to be driven by Epstein-Barr virus. Effective therapy includes reduction of immunosuppression (a clear “double-edged sword” in the setting of a life-sustaining organ), administration of antiviral agents, and traditional chemo- and radiotherapy. Most recently, specific antilymphocyte (CD20) therapy has shown great promise. Cutaneous malignancies (both basal cell and squamous cell carcinomas) also occur with increased frequency among transplant recipients and can follow aggressive courses. The role of decreasing immunosuppression in the treatment of these cancers is far less clear.

Infections

The use of currently available nonspecific immunosuppressive modalities to prevent allograft rejection naturally results in increased susceptibility to infectious complications in transplant recipients. Although the incidence has decreased since the introduction of cyclosporine, infections with unusual and opportunistic organisms are still the major cause of death during the first postoperative year and remain a threat to the chronically immunosuppressed patient throughout life. Effective therapy depends on careful surveillance for early signs and symptoms of opportunistic infection, an extremely aggressive approach to obtaining a specific diagnosis, and expertise in recognizing the more common clinical presentations of infections caused by CMV, Aspergillus, and other opportunistic agents.

The modern era of mechanical circulatory support can be traced back to 1953, when cardiopulmonary bypass was first used in a clinical setting and ushered in the possibility of brief periods of circulatory support to permit open-heart surgery. Subsequently, a variety of extracorporeal pumps to provide circulatory support for brief periods have been developed. The use of a mechanical device to support the circulation for more than a few hours initially progressed slowly, with the implantation of a total artificial heart in 1969 in Texas by Cooley. This patient survived for 60 h until a donor organ became available, at which point he underwent transplantation. Unfortunately, the patient died of pulmonary complications after transplantation. The entire field of mechanical replacement of the heart then took a decade-long hiatus until the 1980s, when total artificial hearts were reintroduced with much publicity; however, they failed to produce the hoped-for treatment of end-stage heart disease. Starting in the 1970s, in parallel with the development of the total artificial heart, intense research had addressed the development of ventricular assist devices, which provide mechanical assistance for (rather than replacing) the failing ventricle.

Although conceived of initially as alternatives to biologic replacement of the heart, LVADs were introduced—and are still employed primarily—as temporary “bridges” to heart transplantation in candidates in whom medical therapy begins to fail before a donor heart becomes available. Several devices are approved by the U.S. Food and Drug Administration (FDA) and are in widespread use (see later). Those that are implantable within the body are compatible with hospital discharge and offer the patient a chance for life at home during a wait for a donor heart. However successful such “bridging” is for the individual patient, it does nothing to alleviate the scarcity of donor hearts; the ultimate goal in the field remains that of providing a reasonable alternative to biologic replacement of the heart—one that is widely and easily available and cost-effective.

CURRENT INDICATIONS AND APPLICATIONS OF VENTRICULAR ASSIST DEVICES

Currently, there are two major indications for ventricular assistance. First, patients at risk of imminent death from cardiogenic shock are eligible for mechanical support. These patients are generally managed with temporary cardiac assist devices. Second, if patients have a left ventricular ejection fraction <25% or a peak VO₂ <14 mL/kg per min or are dependent on inotropic therapy or support with intra-aortic balloon counterpulsation, they may be eligible for mechanical support. If they are eligible for heart transplantation, the mechanical circulatory assistance is termed the “bridge to transplantation.” By contrast, if the patient has a contraindication to heart transplantation, the use of the device is deemed to constitute “destination” left ventricular assistance therapy.

BASIC CONCEPTS

Pulsatile vs. nonpulsatile devices

Pulsatile devices are ventricular assist devices whose mechanism of action mandates the alternating filling and emptying of a volume chamber within the device that mimics the mechanism of action of the natural heart. Nonpulsatile devices have a mechanism of action that results in continuous blood flow through the device, eliminating the need for pulsatility. The pulsatile devices are larger, bulkier, and associated with greater energy requirements and higher rates of complications than the nonpulsatile devices. However, pulsatile devices provide greater degrees of support and may even be capable of replacing the function of the heart entirely in the form of a total artificial heart. Because of the bulkiness of these devices, many patients are too small to be supported with intracorporeal pulsatile pumps. However, paracorporeal versions are available. These devices are versatile and can be used for right, left, or biventricular assistance/replacement.

Continuous-flow (nonpulsatile) devices are further categorized on the basis of impeller design and mechanism. The older designs have tended to be axial-flow pumps, which operate on the Archimedes screw principle. These devices have an impeller that is in line with the direction of blood flow, and the inlet direction of blood is the same as the outlet direction. Continuous-flow devices have been dependent on the presence of blood-washed bearings within the pump housing and may be associated with an increased risk of blood and platelet activation. The newer devices are centrifugal in design; the blood flow takes a 90° turn between the inlet section of the pump and the outlet section. Another major difference in the newer devices is the absence of blood-washed bearings (with most devices having magnetically levitated impellers). This design allows the construction of smaller pumps with less blood-element activation than the axial-flow designs.

Available Devices

In the United States, there are currently four FDA-approved devices that are used as bridges to transplantation in adults. Of these four devices, one is also approved for use as destination therapy or as long-term mechanical support of the heart. A number of other devices are approved only for short-term support in post–cardiac surgery shock or in cardiogenic shock secondary to acute myocardial infarction or fulminant myocarditis; these will not be considered here. So far, no long-term device is totally implantable, and, because of the need for transcutaneous connections, all share a common problem with infectious complications. Likewise, all share some tendency to thromboembolic complications and are subject to the possibility of mechanical failure common to any machine.

The total artificial heart (TAH) (Syncardia, Tucson, AZ) is a pneumatic, biventricular, orthotopically implanted ventricular assist device with an externalized driveline connecting it to its console. The TAH is currently the only FDA-approved device for use in patients who have severe biventricular failure.

The Thoratec LVAD (Thoratec Corp., Pleasanton, CA) is an extracorporeal pump that takes blood from a large cannula placed in the left ventricular apex and propels it forward through an outflow cannula inserted into the ascending aorta. The extracorporeal nature of this pump allows its use in small adults for whom intracorporeal pumps would be too large. This device provides not only left but also right ventricular assistance and can be utilized for biventricular support within the same patient (BiVentricular Assist Device).

The HeartMate II LVAD (Thoratec) similarly uses a drainage cannula in the left ventricular apex to drain blood into a small chamber, where the blood is driven by an electrically powered motor that spins a rotor, accelerating blood outflow into the ascending aorta (Fig. 21-2). This device is currently the only FDA-approved axial-flow pump that can be used both as a bridge to transplantation and as destination therapy.

The HeartWare Ventricular Assist System with the HVAD pump (HeartWare Inc., Framingham, MA) is the first third-generation device to be granted FDA approval for use in patients as a bridge to transplantation. The device is a centrifugal pump that is housed completely within the patient’s pericardial cavity and provides adequate support for many patients.

RESULTS

The use of these devices in the United States is limited mainly to patients with post–cardiac surgery shock and to those who are bridged to transplantation. The results of bridging to transplantation with the available devices are quite good, with nearly 75% of younger patients receiving a transplant by 1 year and having excellent posttransplantation survival rates.

Publication of the REMATCH (Randomized Evaluation of Mechanical Assistance in the Treatment of Heart Failure) trial in 2001 documented a somewhat improved survival rate in patients who had end-stage heart disease, were not candidates for transplantation, and were randomized to a pulsatile LVAD (albeit with a high rate of complications, especially neurologic issues) as opposed to continued medical therapy. This result led to renewed interest in use of the devices for nonbiologic permanent replacement of heart function as well. Subsequently, this device was supplanted by the HeartMate II axial-flow device, which has dramatically improved the survival of patients with severe end-stage heart disease in whom medical therapy has failed. The patients who had this device implanted had a 2-year survival rate of 58%, whereas the survival rate for patients in the medically treated arm of the original REMATCH trial was only 8%. More recent experience has shown that the mean survival period of patients with a continuous-flow LVAD for destination therapy is approaching 5 years.

Several studies have evaluated the benefit of LVAD therapy as a bridge to transplantation. The most recent data come from a series of 140 patients who underwent implantation of a HeartWare HVAD. Of these patients, 94% achieved the principal outcome (defined as survival to transplantation, recovery of heart function, or ongoing device support) at 180 days. With increased experience and improved outcomes using LVADs as a bridge to transplantation, the ability to maintain end-organ function and limit the progression of pulmonary hypertension—or even to decrease pulmonary vascular resistance—makes mechanical unloading a more attractive option than continued inotropic support. The early bridge-to-transplantation experience demonstrated reduced posttransplantation survival compared with medical management; however, more recent experience has shown equivalent outcomes following transplantation. This result is likely secondary to a trend toward earlier device implantation—i.e., prior to the onset of irreversible end-organ damage.