Heart transplantation in adults: Graft dysfunction

INTRODUCTION — The development of ventricular dysfunction after cardiac transplantation, which can be systolic, diastolic, or mixed, should be of major concern. The causes of graft dysfunction in the transplanted heart can be different, more ominous, and in some cases more responsive to treatment than those seen in the native heart. As a result, familiarity with the potential etiologies, coupled with an aggressive and systematic approach, is essential to identify the etiology and begin prompt treatment.

Graft dysfunction can occur as early as the intraoperative period or can develop many years after transplantation. The timing of graft dysfunction (days, weeks to months, or years post-transplantation) is one of the most important clues to establish a diagnosis. Graft dysfunction may present as either heart failure with preserved or reduced ejection fraction, asymptomatic ventricular dysfunction, or by elevated intracardiac filling pressures or depressed cardiac output on right heart catheterization. It can affect the right, left, or both ventricles.

The most common causes of graft dysfunction after transplantation include primary graft dysfunction, which manifests within 24 hours after surgery; cardiac allograft rejection, which is more common during the first 6 to 12 months post-transplantation; and cardiac allograft vasculopathy, which can occur at any time. Diagnostic procedures such as endomyocardial biopsy, echocardiography, and coronary angiography are important tools in elucidating the etiology, but all these studies have their limitations. (See "Heart transplantation in adults: Diagnosis of allograft rejection" and "Endomyocardial biopsy".)

EARLY GRAFT DYSFUNCTION — Early allograft dysfunction can be apparent in the intraoperative period or can develop within the hours to days after transplant surgery. It can manifest as left ventricular (LV) dysfunction, isolated right ventricular (RV) dysfunction, or biventricular dysfunction, and it is associated with significantly increased 30-day and one-year mortality. Early graft dysfunction is classified as primary or secondary graft dysfunction according to the suspected etiology.

Primary graft dysfunction — Primary graft dysfunction (PGD) is currently defined as LV, RV, or biventricular dysfunction that occurs within 24 hours after surgery and is not associated with a discernible cause such as hyperacute rejection, pulmonary hypertension, massive blood product transfusion during surgery, or prolonged graft ischemic time. PGD can affect the LV, RV, or both ventricles.

A classification system has been proposed by the International Society of Heart and Lung Transplantation based upon the ventricle affected and the degree of hemodynamic compromise [1]:

●PGD of the LV (PGD-LV):

•Mild:

-LV ejection fraction (LVEF) ≤40 percent by echocardiography, or hemodynamics with right atrial pressure (RAP) >15 mmHg, pulmonary capillary wedge pressure (PCWP) >20 mmHg, and cardiac index (CI) <2.0 L/min/m² (lasting more than one hour) requiring low-dose inotropes.

•Moderate:

-LVEF ≤40 percent, or hemodynamic compromise with RAP >15 mmHg, PCWP >20 mmHg, CI <2.0 L/min/m², and hypotension with mean arterial pressure <70 mmHg (lasting more than 1 hour).

and

-Requirement for high-dose inotropes or newly placed intraaortic balloon pump.

•Severe:

-Requirement for left or biventricular mechanical support such as extracorporeal membrane oxygenation, left ventricular assist device (LVAD), biventricular assist device, or percutaneous LVAD.

●PGD of the RV (PGD-RV):

•Hemodynamics with RAP >15 mmHg, PCWP <15 mmHg, CI <2.0 L/min/m²

or

•Transpulmonary gradient <15 mmHg and/or pulmonary artery systolic pressure <50 mmHg

or

•Need for right ventricular assist device

In practice, we also observe biventricular dysfunction, and these cases are classified under PGD-LV. Based on aggregate data from multiple centers, the incidence of mild LV, moderate LV, severe LV, and isolated RV PGD was 3.5, 6.6, 7.7, and 1.6 percent, and the one-year mortality rates were 15, 21, 41, and 35 percent. Risk factors for PGD included donor characteristics (female sex and undersized heart), recipient factors (serum creatinine, pretransplant use of amiodarone and temporary mechanical circulatory support), and prolonged graft ischemic time [2].

Although the etiology of PGD is poorly understood, it is felt that preexisting donor and recipient risk factors; injury to the donor heart during brain death; ischemia during the process of organ recovery, preservation, and re-implantation; and reperfusion injury immediately after reimplantation of the allograft and release of the aortic cross-clamp may contribute to the development of PGD.

Ischemic and reperfusion injury during surgery — Allograft injury can result from prolonged allograft ischemic time as well as from reperfusion injury immediately following reperfusion of the allograft with the recipient’s circulation. Ischemic time refers to the time from cross clamping the donor, with subsequent excision and immersion of the heart in iced saline, to removal of the cross clamp after implantation in the recipient. When using traditional static cold storage, whereby the heart is arrested (ie, placed in a crystalloid preservation solution, and stored on ice until the time of implantation), total ischemic time greater than four hours has been associated with an increased risk of PGD [3], and hearts from older donors are more susceptible to ischemic injury [4]. The injury to the allograft may be transient (myocardial stunning), lasting for 12 to 24 hours after transplantation in some cases [5], but contraction band necrosis and other evidence of ischemic injury can be seen in biopsy specimens from persistently dysfunctional hearts as well as those with functional recovery [6].

Suboptimal donor heart — Although the pool of potential heart recipients has increased, the donor pool has remained relatively stable [7]. As a result, some transplant programs have begun to consider and accept hearts from "suboptimal" donors (eg, patients over age 55 and those with mild LV hypertrophy or non-obstructive coronary artery disease) [8-10]. Additionally, some donor hearts have been subjected to higher doses of intravenous inotropes or pressor amines or have evidence of LV dysfunction attributed to the effects of brain death. Hearts from patients with significant LV hypertrophy, valvular heart disease, or obstructive coronary artery disease are still usually avoided, as are hearts damaged from trauma.

Prevention — Although PGD cannot always be prevented, the combination of using a suboptimal donor heart with prolonged static cold storage should be avoided whenever possible. Other factors that may ameliorate the effects of prolonged ischemic time include temperature-controlled cold preservation [11] and normothermic ex vivo organ perfusion, which allows preservation of the heart in a beating state by perfusing it with a warmed, donor-blood-based solution that is supplemented with nutrients and oxygen [12,13]. (See "Reperfusion injury of the heart".)

Treatment — Treatment options for PGD include the use of high-dose inotropic agents to support LV and RV function and the use of inhaled nitric oxide for RV dysfunction. If medical management does not improve the patient’s hemodynamics, then early initiation of mechanical circulatory support with an intraaortic balloon pump, extracorporeal membrane oxygenator, or temporary ventricular assist device is recommended before the development of severe end-organ dysfunction [1]. Graft function will recover in most patients after a few weeks, and retransplantation is avoided due to the high associated mortality in this context [14]. (See "Short-term mechanical circulatory assist devices" and "Treatment of advanced heart failure with a durable mechanical circulatory support device" and "Management of long-term mechanical circulatory support devices".)

Secondary graft dysfunction — Allograft dysfunction can also occur as a result of recipient and procedural factors. Causes include hyperacute rejection and excessive volume or pressure load on the right ventricle. Unrecognized pulmonary hypertension in the recipient can result in RV failure immediately after allograft implantation. Extensive intraoperative bleeding can result in massive blood product transfusion requirements and can subject the vulnerable right ventricle to volume overload and RV dysfunction.

Hyperacute rejection — Hyperacute rejection, the most ominous cause of perioperative LV dysfunction, is extremely rare and is caused by the presence of pre-formed recipient antibodies that cross-react with endothelial epitopes on the allograft [15]. It is most often due to inadvertent implantation of an ABO-mismatched allograft. It may also be seen in highly sensitized patients, such as multiparous women or those with multiple prior transfusions, who have developed pre-formed cytotoxic antibodies that are directed against major histocompatibility (MHC) antigens on the donor heart. This form of rejection occurs within the first 24 hours after transplant and may be evident after reperfusion of the allograft in the operating room. Widespread endothelial damage leads to global ischemia and catastrophic allograft failure.

Treatment — Strategies to avoid secondary graft dysfunction include double-checking ABO blood type matching of donor and recipients, preoperative screening of transplant candidates for the presence of circulating pre-formed antibodies to MHC antigens, the use of virtual or prospective crossmatching of sensitized transplant candidates with potential donors [16], evaluation of recipients for pulmonary hypertension, and careful post-transplant hemodynamic and volume management. Patients with hyperacute rejection are treated with plasmapheresis in combination with corticosteroids, antilymphocyte antibodies, and intravenous immunoglobulin (see "Heart transplantation in adults: Treatment of rejection"). Eculizumab, a monoclonal antibody that binds to the compliment protein C5 and inhibits assembly of the membrane attack complex, can be used as salvage treatment in combination with the above therapies, but experience with this drug in heart transplantation is limited [17,18]. Management of secondary graft dysfunction is otherwise similar to that for PGD.

LATE GRAFT DYSFUNCTION — Ventricular dysfunction that develops weeks to years after transplantation is most often due to allograft rejection or to ischemia caused by allograft coronary artery disease, but may also be due to infectious myocarditis or occasionally may occur without any documentable cause.

Rejection — The development of left, right, or biventricular dysfunction in the weeks to months following cardiac transplantation is most often due to acute allograft rejection [19]. Most cases of acute rejection are diagnosed by routine surveillance endomyocardial biopsy at a time when the patient is asymptomatic and ventricular function is normal [7]. The symptoms that occur typically represent signs of volume overload or low cardiac output. These include dyspnea on exertion or at rest, paroxysmal nocturnal dyspnea, orthopnea, abdominal bloating, fatigue, and syncope or near-syncope. Other clinical findings that suggest the presence of rejection include new right- or left-sided ventricular gallop sounds on auscultation, elevated jugular venous pressure, or new atrial or ventricular arrhythmias. (See "Heart transplantation in adults: Diagnosis of allograft rejection", section on 'Clinical manifestations'.)

Acute cellular rejection occurs with decreasing frequency and severity over time. Episodes may be associated with recent changes in immunosuppression, medication noncompliance, or unrecognized drug interactions that lead to decreased serum concentrations of immunosuppressive drugs. Antibody-mediated rejection is increasingly recognized as a cause of late graft dysfunction and may occur years after transplantation. Risk factors for antibody-mediated rejection include a history of pre-formed antibodies to human leukocyte antigens (HLA) prior to transplant, a positive pretransplant crossmatch, female sex, multiparity, and a history of prior transplant [20].

Diagnosis — The diagnosis of rejection is typically made by endomyocardial biopsy. Asymptomatic rejection is usually detected by routine "protocol" endomyocardial biopsy. The biopsy can also confirm the presence of rejection and identify the type and severity of rejection in patients who develop signs or symptoms of ventricular dysfunction. Noninvasive imaging techniques (eg, echocardiography) may also reveal ventricular dysfunction or evidence of severe diastolic dysfunction but cannot discriminate between graft dysfunction caused by rejection versus other causes. (See "Heart transplantation in adults: Diagnosis of allograft rejection", section on 'Acute cellular rejection' and "Heart transplantation in adults: Diagnosis of allograft rejection", section on 'Acute antibody-mediated (humoral) rejection'.)

Sampling error associated with endomyocardial biopsy may result in underestimation of the severity of rejection. As a result, the absence of pathologic evidence for severe rejection in the presence of unexplained ventricular dysfunction, heart failure, or shock should not deter treatment for rejection.

The treatment of acute allograft rejection is discussed separately. In severe cases, inotropic agents and temporary mechanical circulatory support may be needed to support the patient while antirejection and heart failure therapies are initiated. (See "Heart transplantation in adults: Treatment of rejection" and "Short-term mechanical circulatory assist devices".)

Graft ventricular function often returns to normal with successful treatment of rejection, even if severe. The long-term prognosis can be favorable; however, repeated episodes of severe acute cellular rejection are associated with a greater likelihood of persistent graft dysfunction due to myocardial fibrosis and/or the development of cardiac allograft vasculopathy [21]. (See "Heart transplantation in adults: Prognosis".)

Cardiac allograft vasculopathy — Cardiac allograft vasculopathy or transplant coronary artery disease refers to the development of a diffuse vasculopathy that is limited to the allograft, is related to both immunologic and nonimmunologic factors, and can lead to graft dysfunction months to years after transplantation. Allograft vasculopathy should always be considered as a possible cause for graft dysfunction occurring after the first year post-transplantation. (See "Heart transplantation in adults: Cardiac allograft vasculopathy pathogenesis and risk factors" and "Heart transplantation: Clinical manifestations, diagnosis, and prognosis of cardiac allograft vasculopathy".)

Based upon International Society of Heart and Lung Transplantation registry data, the prevalence of allograft vasculopathy is approximately 8 percent within the first year posttransplantation, 20 percent within five years, and 47 percent within 10 years [22]. The diagnosis is usually made by coronary angiography, but it is generally acknowledged that angiography underestimates this diffuse, concentric process. As a result, many patients who develop clinical events that are presumably due to transplant vasculopathy may not have angiographically significant disease.

Because of these limitations, adjuncts to angiography have been sought that might improve the detection of early arterial wall remodeling seen in transplant vasculopathy. Intravascular ultrasound provides a quantitative assessment of intimal wall hyperplasia and vascular lumen area, but it is still mainly used as a research tool. Optical coherence tomography, analogous to ultrasound imaging except that it uses light instead of sound, has also been used to detect vascular wall changes associated with allograft vasculopathy in both adult and pediatric heart transplant recipients [23,24]. (See "Heart transplantation: Clinical manifestations, diagnosis, and prognosis of cardiac allograft vasculopathy", section on 'Diagnosis and evaluation'.)

The clinical features and outcomes of allograft vasculopathy are discussed in detail separately. (See "Heart transplantation: Clinical manifestations, diagnosis, and prognosis of cardiac allograft vasculopathy" and "Heart transplantation in adults: Arrhythmias" and "Heart Transplantation: Prevention and treatment of cardiac allograft vasculopathy".)

Summarized briefly:

●Silent myocardial infarction, sudden death, and progressive heart failure are common presentations of transplant vasculopathy. Classic anginal chest pain is infrequent due to the presence of both afferent and efferent allograft denervation [25]. Affected patients progress at a variable rate.

●Therapy of established vasculopathy is limited [7,26]. Palliative percutaneous coronary interventions are often performed in patients with discrete lesions amenable to these approaches. Percutaneous coronary intervention is associated with an excellent procedural success rate, but a high incidence of restenosis or new lesion progression is observed [26].

●Allograft vasculopathy remains the most common barrier to long-term survival [7,27]. In one report of 54 patients with at least 40 percent stenosis in one or more coronary arteries, overall survival was 67, 44, and 17 percent at one, two, and five years [27]. Survival varied with disease severity, being worst in patients with three-vessel disease (13 percent at two years).

Retransplantation is reserved for patients with diffuse, multi-vessel coronary artery disease who develop severe graft dysfunction and/or marked symptoms of heart failure or ischemia and who have no contraindications to retransplantation. (See "Heart transplantation in adults: Prognosis", section on 'Repeat cardiac transplantation'.)

Infectious myocarditis — Toxoplasma gondii and cytomegalovirus are two opportunistic infections that can produce acute myocarditis in immunosuppressed transplant recipients. The diagnosis is established by identifying the infectious organisms or multinucleated giant cells in endomyocardial biopsy samples. Standard treatment for these infections is employed, often while attempting to attenuate the degree of chronic immunosuppression. (See "Infection in the solid organ transplant recipient".)

Recurrent myocardial disease — In rare patients, recurrence of the initial myocardial disease that resulted in failure of the native heart can lead to failure of the cardiac allograft. Examples include:

●Amyloidosis, a disorder in which transplantation is not often performed because of frequently severe extracardiac amyloid deposition. (See "Cardiac amyloidosis: Epidemiology, clinical manifestations, and diagnosis".)

●Giant cell myocarditis and sarcoidosis, which are rare diseases treated with transplantation. (See "Causes of dilated cardiomyopathy" and "Clinical manifestations and diagnosis of cardiac sarcoidosis".)

●Hereditary hemochromatosis, in which recurrent disease is avoidable by ongoing therapy to prevent iron overload. (See "Clinical manifestations and diagnosis of hereditary hemochromatosis" and "Management and prognosis of hereditary hemochromatosis".)

Nonspecific allograft dysfunction — Nonspecific allograft dysfunction is generally defined as graft dysfunction in the absence of histologic evidence of rejection on endomyocardial biopsy (ie, lack of either cellular inflammatory infiltrate or positive staining for antibody or complement deposition), significant allograft vasculopathy, or recurrent myocardial disease. A sizable number of patients with nonspecific allograft dysfunction without evidence of occlusive allograft vasculopathy on coronary angiography have evidence of significant obliterative vasculopathy affecting the arterioles and/or intra-myocardial vessels and in some cases sparing the major epicardial vessels on examination of the explanted heart at the time of death or re-transplantation [15]. Additionally, a small number of patients with acute cellular or antibody-mediated rejection will have unremarkable endomyocardial biopsy specimens due to sampling error [28]. In these patients, intensification of immunosuppression (eg, with high-dose corticosteroids, antithymocyte globulin) has been associated with clinical improvement [29].

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Beyond the Basics topic (see "Patient education: Heart transplantation (Beyond the Basics)")

SUMMARY — There is a short differential diagnosis for graft dysfunction after orthotopic cardiac transplantation that varies with time posttransplant at diagnosis. Heart failure with either reduced or preserved ejection fraction may be identified.

●Early graft dysfunction – Early allograft dysfunction occurring in the operative and immediate postoperative period is often due to ischemic and reperfusion injury during allograft procurement, transport, and reimplantation or the use of a suboptimal donor heart. Hyperacute rejection also can occur during this time period but is rare. Mild early allograft dysfunction is treated with inotropic agents, and we have a low threshold to initiate temporary mechanical circulatory support (such as the use of an intraaortic balloon pump, extracorporeal membrane oxygenator, or a percutaneous ventricular assist device) in cases of moderate or severe primary graft dysfunction. (See 'Early graft dysfunction' above.)

●Late graft dysfunction – The most important causes of late graft dysfunction are allograft rejection and vasculopathy. Prompt treatment of allograft rejection can result in improvement in graft function even in patients with cardiogenic shock. Empiric therapy may be indicated if the clinical suspicion is high, even in the absence of biopsy-proven rejection. (See "Heart transplantation in adults: Treatment of rejection".)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Allen S Anderson, MD, FACC, FAHA, who contributed to earlier versions of this topic review.