Chapter 255: Cardiac Transplantation and Prolonged Assisted Circulation

Advanced heart failure, a distinct syndrome, is characterized by refractoriness to conventional therapy and represents a vexing clinical dilemma that is associated with an increased symptom burden, frequent hospitalization, a poor quality of life and high risk of death. Such individuals do not tolerate neurohormonal antagonists at recommended doses, exhibit cardiorenal syndrome, maintain markedly poor cardiac reserve on cardiopulmonary stress testing, and typically display a low cardiac output state with elevated pulmonary pressures. In general, therapeutic targets shift away from disease modifying neurohormonal therapy to surgical options that attend directly to the myocardial stress and strain relationship. Most often, prolonged circulatory assistance using mechanical pumps or cardiac transplantation is required to reliably improve quality of life and long-term survival.

A decade after Norman Shumway had accomplished the technique of a successful heart transplant in canines, Christiaan Barnard successfully performed the first human to human transplant on December 3, 1967. Now, 5 decades later, this surgery has become entrenched in the standard armamentarium for treating patients with advanced heart failure who are otherwise healthy enough to receive such a life altering treatment. Globally, >150,000 patients have undergone cardiac transplantation with a 1 year survival >80% and median survival of nearly 11 years. These gains have been ushered in due to advances in immunosuppression and identification and management of allograft rejection, as well as a comprehensive appreciation for late complications including accelerated coronary artery disease, malignancy, and renal failure.

CANDIDATES FOR CARDIAC TRANSPLANTATION

The demand for cardiac transplantation outstrips the availability of organ donors. Hence, attention to the optimal utility, equitable allocation, and patient autonomy must dominate the decisions to identify and list candidates for transplantation. Simultaneously, attempts at expanding the donor pool have surfaced. However, vigilance to evaluating candidates most likely to have a successful outcome from transplantation takes pre-eminence. In 2006, the International Society for Heart and Lung Transplantation identified a set of criteria to guide listing of patients. These criteria were updated in 2016 and include additional attention to the growing epidemiology of candidates suffering from congenital heart disease, restrictive and infiltrative cardiomyopathy (such as amyloidosis), and chronic infections in recipients (such as Chagas’ disease, tuberculosis and hepatitides). Selected general principles for listing candidates for cardiac transplantation are enumerated in Table 255-1.

PRINCIPLES OF DONOR RECOVERY AND ALLOCATION

Although listing criteria for candidates are typically adjudicated at a center level, organ allocation is handled by national regulatory processes in most countries. The allocation of donor hearts is based on (a) the urgency of the clinical situation, (b) the time spent on the waiting list, and (c) the distance from the recipient center. Thus, candidates who are hospitalized and require temporary mechanical cardiac support devices or daily invasive hemodynamic evaluation and intravenous inotropic therapy to maintain stability are given the highest urgency status, while those able to ambulate and live at home receive a lower urgency status. The geographical regional reach for allocation is based not only on territorial considerations but also on the time that a donor heart would be in transit and therefore in out of body “cold ischemia time,” which is typically limited to 4 h. The final key feature that is included in the allocation offer relates to the ABO blood group. Donor organs are offered based on these initial characteristics and then a more detailed donor assessment ensues, resulting in acceptance or decline for any given donor heart. It is important to note that the time constraints imposed on the retrieval process make it difficult to invoke HLA matching of the donor and recipient. In cases where there is a high likelihood of sensitization in the recipient (preformed circulating antibodies against donor antigens), a prospective or virtual cross match is entertained prior to acceptance. Other clinical criteria that are employed in the decision on accepting an offered donor include the donor-recipient size match, the age of the donor (typically restricted to under 55 years) and presence or absence of concomitant pathology such as coronary artery disease, left ventricular hypertrophy or severe injury to the allograft manifest by excess leak of injury markers (troponins) or poor contractile performance. In many cases, the prospective cardiac allograft can be reconditioned by use of hormonal therapy (including thyroid hormone supplementation) and used for transplantation even if the initial evaluation suggests poor function. In efforts to enhance the donor pool, systems that allow ex-vivo normothermic perfusion to evaluate and reanimate organs with a prolonged out of body time are being developed. The classic heart donor is derived from a donor with brain death; however, donors with circulatory death are being increasingly evaluated as candidates for cardiac reanimation using a variety of techniques including ex-vivo reanimation and subsequent transplantation.

SURGERY FOR CARDIAC TRANSPLANTATION

The most common contemporary operation is referred to as a “bicaval” orthotopic cardiac transplant that mimics the natural anatomic position. In this operation, the donor and recipient superior and inferior vena cava are connected as are the aortic and pulmonary great vessels. The left atrium of the recipient retains its roof including the draining pulmonary veins and the donor left atrium is then sutured to the retained atrial tissue. This technique maintains function of the donor right atrium, important for governing early postoperative right heart output, and may prevent atrial arrhythmias. The recipient is left with a surgical denervation and the allograft is not responsive to any direct sympathetic or parasympathetic stimuli. Therefore, early in the adaptive postoperative phase, high-dose catecholamines are required to maintain adequate function. Due to denervation, bradycardia in a cardiac allograft cannot be treated with atropine and the drug of choice is isoproterenol. Once the cardiac allograft adapts to its host circulation, the function is usually adequate at rest and with exercise to provide normal physical activity.

CARDIAC ALLOGRAFT REJECTION AND IMMUNOSUPPRESSION

The ability to perform endomyocardial biopsies, evaluate rejection pathologically and the introduction of the immunosuppression agent cyclosporine heralded cardiac transplantation as a viable clinical therapy. Triple drug immunosuppression, which includes a calcineurin inhibitor (cyclosporine or tacrolimus), corticosteroids and anti-proliferative immunosuppression (azathioprine, mycophenolate mofetil, sirolimus or everolimus) is now the standard cocktail used. The combination that is most commonly used and achieves the best standard outcomes includes the combination of tacrolimus, mycophenolate mofetil, and prednisone. In those at high risk for rejection (multiparous women, sensitized individuals) or in situations where use of calcineurin inhibitors is delayed (renal dysfunction), induction therapy using monoclonal (basiliximab) or polyclonal antibodies (anti-thymocyte globulin) to provide augmented immunosuppression is used. The typical management strategy includes gradual weaning of steroids over time as surveillance endomyocardial biopsies are performed and clinical as well as sub-clinical pathological quiescence is established. Table 255-2 describes the immunosuppression drugs in common use.

Acute cellular rejection (ACR) and antibody-mediated rejection (AMR) are two separate forms of cardiac allograft rejection that are recognized and can sometimes coexist. ACR occurs early after transplantation and then declines in incidence after 6 months. This occurs due to a T cell–mediated assault on the donor allograft tissue and histologically is characterized by lymphocytic infiltrates. In mild cases these infiltrates are localized to the peri-venular regions, and in severe cases progresses diffusely into the cardiac interstitium. In late stages of severe ACR, most often associated with hemodynamic compromise, multi-clonal cells such as macrophages, neutrophils, and eosinophils are observed with intramyocardial hemorrhage, myocyte injury and myocyte necrosis. Subclinical ACR is typically treated with high doses of corticosteroid pulses although some centers choose to simply observe mild forms of infiltration since it is known that these recover longitudinally. If hemodynamic compromise occurs, rescue polyclonal antibodies are used in tandem with corticosteroids. Conversely, AMR is immunologically described as a non-cellular antibody-driven phenomenon associated with a pattern of immunopathologic findings of immunoglobulin deposition and complement fixation on immunofluorescence, along with histopathologic findings of endothelial swelling and interstitial edema and cardiac allograft arteriolar vasculitis. AMR is characterized by the emergence of circulating donor-specific antibodies that are thought to fix, complement, and bind to the allograft. Commonly, AMR leads to acute allograft dysfunction and increases the risk for cardiac allograft vasculopathy, and results in worsened cardiac allograft survival compared with ACR. In this form of rejection, therapy is directed towards suppression and removal of circulating antibodies using plasmapheresis and drugs such as rituximab (chimeric monoclonal antibody directed against the CD20 antigen) or in refractory cases, bortezomib (a proteasome inhibitor) or eculizumab (a terminal complement inhibitor). The treatment with immunosuppression requires prophylaxis for opportunistic infections and ongoing surveillance and expertise in recognizing the more common clinical presentations of infections caused by cytomegalovirus (CMV), aspergillus, and other opportunistic agents such as nocardia and toxoplasmosis.

LATE COMPLICATIONS AFTER CARDIAC TRANSPLANTATION

The long-term consequences of exposure to chronic immunosuppression result in a variety of non-immunological cardio-metabolic effects such as hypertension and hyperlipidemia as well as systemic disorders of bone loss and renal dysfunction. One aggressive complication that limits late survival of cardiac allografts includes the development of an accelerated form of coronary artery disease, referred to as cardiac allograft vasculopathy (CAV). This is characterized by a proliferative thickening of the vascular intima of the vasculature that is initiated as a diffuse endothelialitis in the setting of the confluence of the consequences of brain death, ischemia reperfusion injury during the transplant process and early immunological insults. Chronically, the metabolic consequences of hypertension, hyperlipidemia, and disordered glucose regulation result in a further worsening of vascular lesions that are diffuse and noted throughout the coronary tree. Early diagnosis and preventative therapy are critical since it is commonly silent in genesis. Statins, antihypertensive agents, and anti-CMV agents all have demonstrated benefits in reducing CAV. Anti-proliferative immunosuppressive therapy such as mycophenolate mofetil and sirolimus or everolimus prevent vascular intimal thickening compared with azathioprine-based regimens. However, retransplantation is the only definitive form of therapy for advanced allograft CAV (Fig. 255-1).

Another consternation in cardiac transplantation is the development of malignancy with a greater frequency than in the normal population, suggesting that immunosuppression plays a sentinel role in its generation. Posttransplant lymphoproliferative disorders, typically driven by Epstein-Barr virus, occur most frequently and require a reduction in immunosuppression, administration of antiviral agents, and traditional chemo- and radiotherapy. Specific antilymphocyte (targeted against CD20) therapy has also shown promise. Solid cancers most often manifest as skin malignancies (both basal cell and squamous cell carcinomas), and use of sun-screens is advised. Future research is required to define strategies for immune modulation, immune suppression, and malignancy prevention, however the impact of decreasing immunosuppression in the treatment of these cancers is unclear.

The quest for a prolonged implantable mechanical circulatory support device has led to the development of continuous flow left ventricular assist systems (LVAS). Initially designed for short-term support as a bridge to recovery or to cardiac transplantation, the most frequent use today entails permanent support for lifetime therapy (“destination therapy”). The decision to implant LVAS dichotomously as either a bridge to transplantation or for destination therapy is not always clear and in several instances, these devices are used as a “bridge to decision” (in those with potentially reversible underlying relative contraindications such as renal insufficiency or pulmonary hypertension, who may become future candidates for transplantation).

LEFT VENTRICULAR ASSIST SYSTEMS AND CLINICAL TRIALS

A pivotal trial, REMATCH, published in 2001, was the first study to reliably demonstrate that survival of transplant ineligible refractory, predominantly inotropic therapy supported heart failure is improved by implantation of a LVAS. This study used an early generation pulsatile flow device and demonstrated a 48% reduction in risk of death. However, the LVAS used was of limited durability and median meaningful “out of hospital” survival was prolonged by only 5 months. Furthermore, complications of strokes, multisystem organ failure, and infections reduced enthusiasm for widespread adoption. Over time, continuous flow systems that were small turbo-pumps with minimal moving parts and no valves were introduced, leading to a more generalized world-wide adoption. A landmark trial compared the older bulky pulsatile LVAS to the newer generation axial continuous flow LVAS, the HeartMate II, and demonstrated a marked improvement in short- and long-term survival, along with an improvement in functional capacity and meaningful quality of life enhancement. A centrifugal continuous flow LVAS, the HeartWare HVAD, is also in common use. A newer centrifugal device, with a fully magnetically levitated system, the HeartMate 3 LVAS is now available. Unlike the HeartMate II LVAS, which requires an abdominal pump pocket, this smaller device is fully implanted in the pericardial space in the thoracic cavity (Fig. 255-2). Real world experience from registry analyses has pointed to a >70% 2-year survival with currently available LVAS, nearly approaching the outcomes achieved with transplantation, however long-term durability beyond 5–10 years remains a question. The patients for whom LVAS should ideally be employed include those with severe persistent systolic heart failure symptoms who have failed to respond to optimal medical management. Commonly, these patients have marked functional limitation indicated by a peak oxygen consumption of <12 mL/kg/min; or the patient is bound to continuous intravenous inotropic therapy owing to symptomatic hypotension, decreasing renal function, or worsening congestion. Currently, the role of LVAS in “less sick” patients (those with moderate symptoms) is not advocated since sufficient equipoise does not exist due to the adverse risk benefit ratio from device-related complications.

MANAGEMENT OF LVAS AND THEIR COMPLICATIONS

Continuous flow LVAS rely on pressure gradients between the left ventricular cavity and the aorta. As such, forward flow is critically dependent on management of systemic blood pressure. Due to the non-pulsatile nature of the blood flow, blood pressure is measured by using a Doppler ultrasound (mean or opening blood pressure, which is less than the systolic blood pressure) since a peripheral pulse is usually not detectable. The ideal mean arterial blood pressure should be kept to <90 mmHg and antihypertensive drug therapy prescribed using RAAS drugs or other vasodilators. A common complication encountered in patients is that of an anemia, often due to iron deficiency. The blood flow path through current devices results in increased shear stress which is manifested in the form of low grade hemolysis and the development of an acquired von Willebrand disease due to loss of high molecular weight multimers. This hematological aberration has been associated with a risk of gastrointestinal bleeding, particularly resulting from arteriovenous malformations in the intestines.

The unsupported right ventricle often demonstrates failure and results in congestion requiring diuretic therapy. While unloading of the left ventricle decreases right-sided afterload, increased device flow results in a greater right heart preload and effects of the LVAS on the septum reduce right ventricular contractile efficiency, leading to development of right ventricular dilatation and maladaptation between the right ventricle and pulmonary circuit. Cardiac arrhythmias are common in patients supported with LVAS and often require antiarrhythmic therapy for quiescence since such events can trigger low flow through the device.

Hemocompatibility-related adverse outcomes include neurological events (ischemic and hemorrhagic strokes), device-related thrombosis leading to pump malfunction, and non-surgical bleeding complications (Fig. 255-3). Antiplatelet therapy using aspirin in doses of 81–325 mg daily along with warfarin targeted to an INR of 2–3 are required for current LVAS to avoid the morbidity of hemocompatibility-related adverse events. On one hand, this therapy is protective for thrombotic complications while on another it predisposes the patient to bleeding complications. Strokes occur with a frequency ranging from 8% with the HeartMate II LVAS to as much as 29% with the HeartWare HVAD device, by 2 years of treatment. Optimal control of blood pressure is associated with improved rates of strokes; however, this complication is a critical reason for lack of adoption of device therapy to the less sick population. Another cause of morbidity is pump thrombosis requiring reoperation for device malfunction. This complication is noted in 6–12% of LVAS implants, occurs early (in the first 6 months), and is more common with the HeartMate II device than with other LVAS. The subclinical phase of LVAS thrombosis is characterized by increasing hemolysis and elevation in the device power. Progressively, inability to “unload” the left ventricle is manifest leading to decompensated heart failure and possibly hemodynamic compromise. Lactate dehydrogenase (LDH) is an excellent (although non-specific) biomarker of hemolysis and hence impending or established pump thrombosis. Patients who have suspected left ventricular assist device (LVAD) thrombosis and do not undergo LVAD exchange or cardiac transplantation have a 6-month mortality rate of 48%, inferring that medical therapy for VAD thrombosis may be inadequate (or cause harm in the case of thrombolytic use). Reoperation (pump exchange) carries a modest 6.5% perioperative mortality risk and a 65% 2-year survival following exchange.

Infection is common, most often involving the driveline (the conduit connecting the device to the external controller and batteries) and occurs in 1 in 5 patients following LVAS implant. Such an infection is treated with local internal exploration and requires long-term suppressive antibiotics unless the patient undergoes cardiac transplantation or the device is exchanged. Infection and its inflammatory sequelae predispose to thrombosis and heighten the risk of neurological complications, leading to a worsening milieu in hemocompatibility.

NOVEL DEVICES

The HeartMate 3 is a centrifugal, continuous flow pump that is placed in the thorax and is engineered to be a more hemocompatible LVAS. This device is constructed with a fully magnetically levitated motor, offers wider blood flow paths, and even exhibits a fixed intrinsic pulse (by the motor ramping its speed up and down at 2 s intervals). This pump has been tested in the large MOMENTUM 3 trial, the early 6 month results for which suggest that this LVAS incrementally improves outcome compared with the HeartMate II device. Importantly, this pump does not exhibit hemolysis or shear high molecular weight multimers of von Willebrand antigen as with other devices and is not associated with pump thrombosis. Long-term experience with this LVAS will be important in discerning whether these early short-term findings result in a reduction in hemocompatibility-related adverse events, improved quality of life, and survival.

TOTAL ARTIFICIAL HEART

Not all patients are candidates for a LVAS, particularly those with severe right-sided heart failure or conditions that do not allow placement of an LVAS (restrictive cardiomyopathy, massive anterior myocardial infarction, complex congenital heart disease). In such patients, either a biventricular assist device approach or a total artificial heart pump can be considered. The SynCardia total artificial heart is a pulsatile, implantable pump that consists of two polyurethane ventricles with pneumatically driven diaphragms, and four tilting disc valves. This requires excision of the native ventricles and thus cannot be employed as a myocardial recovery strategy. There are specific clinical issues that are unique to the total artificial heart management. This device operates on a steep physiological curve and has little adaptability to tolerate either systemic blood pressure changes or large shifts in blood volume. As the ventricles are excised, most patients exhibit a sharp decline in renal function due to the loss of natriuretic peptide expression by the myocardium. Severe hemolysis is common due to the presence of four mechanical valves and aberrant erythropoiesis is noted leading to a severe refractory anemia. Newer artificial hearts using biocompatible surfaces are under development, as well as those that use continuous flow technology.

GLOBAL CONSIDERATIONS

While LVAS are available worldwide, their use and indications vary from country to country. In the United States, payers require discrete discrimination of indication into either a bridge to transplant or destination therapy, whereas in most European countries this artificial segregation is not used. Cost effectiveness studies suggest improvement with newer devices, yet some countries only allow use of this technology as a bridge to transplantation (UK), awaiting more definitive long-term studies for lifetime use. Now, the use in moderately symptomatic ambulatory patients with chronic systolic heart failure is equally discouraged throughout the world, awaiting the availability of a more hemocompatible LVAS.