INTRODUCTION — Despite the use of potent immunosuppressive agents both immediately after cardiac transplantation and during long-term maintenance, acute cellular rejection (ACR) and antibody-mediated rejection (AMR) remain important problems.

This topic discusses the clinical manifestations and diagnosis of acute cardiac allograft rejection. The treatment of acute cellular and antibody-mediated cardiac allograft rejection is discussed separately. (See "Heart transplantation in adults: Treatment of acute allograft rejection".)

PREVALENCE — Acute rejection is a common problem after heart transplantation, particularly during the first three to six months after transplantation. Most early cases are due to acute cellular rejection (ACR). Antibody-mediated (noncellular, vascular, humoral) rejection (AMR) is a less well understood and less easily diagnosed process, but potentially produces much morbidity [1,2].

The incidence of treated rejection has declined: The 2018 report from the registry of the International Society for Heart and Lung Transplantation (ISHLT) noted that the incidence of any ACR between discharge and one year decreased from 30 percent for primary transplants in 2004 to 2006 to 12 percent in 2017 to 2018 [3]. This represents an underestimate for overall rejection, since the registry did not collect data on mild rejection episodes (grade 1 R) or on antibody-mediated rejection (see 'ISHLT grading system' below). Furthermore, with the recognition that mild ACR may not need acute treatment [4], the incidence of treated rejection decreased from 23 percent for primary transplants in 2004 to 2006 [5] to 12.6 percent in 2010 to 2016 [6].

There is wide variation in the reported incidence of AMR among centers, as it is not routinely screened for in most centers, unlike ACR [7]. In a review of 587 patients at a single center, 19 percent of rejection episodes were due to AMR alone, 60 percent to ACR alone, and 23 percent to mixed AMR and ACR [8].

The contribution of rejection to posttransplant mortality has decreased over time [9,10]. In the 2019 ISHLT report on causes of deaths in adult heart transplant recipients occurring from January 1995 to June 2018, acute rejection accounted for 3.9 percent of deaths during the first 30 days, 7.9 percent from 31 days to one year, 9.8 percent from one to three years, 4.7 percent from three to five years, 1.9 percent from 5 to 10 years, 0.9 percent from 10 to 15 years, and 0.5 percent after 15 years [6]. This is primarily due to improvements in maintenance immunosuppression and in the diagnosis and treatment of rejection. Nevertheless, acute heart allograft rejection remains an important clinical problem. Although acute rejection accounted for less than 10 percent of deaths in the 2019 ISHLT report, acute and chronic immune injury are likely important contributors to graft failure, which remains a leading cause of death throughout follow-up [5].

RISK FACTORS — Although acute cellular rejection (ACR) is always a potential concern in a heart transplant recipient, the likelihood of a rejection episode is influenced by several factors, particularly the time after transplantation.

Time after transplantation — ACR is much more common early after a heart transplant. In a multicenter analysis by the Cardiac Transplant Research Database of 1251 patients transplanted between 1990 and 1993, the incidence of ACR peaked at one month after transplant, then declined rapidly over the subsequent five months, reaching a low constant rate by the end of the first year [11]. The mean number of rejection episodes per patient in the first, second, third, and fourth years was 1.25, 0.18, 0.13, and 0.02, respectively. Newer immunosuppressive strategies have resulted in significant delays in the time that ACR occurs [12]. Freedom from hospitalization for rejection has improved considerably during the last 20 years [4].

AMR may occur during the first month after transplantation, in association with donor-specific antibodies (DSAs), and can occur as early as two to seven days if the recipient is presensitized to donor human leukocyte antigens (HLA), or it may occur as late as months to years after transplantation [7,8]. Graft dysfunction is present in two-thirds of early episodes, with hemodynamic compromise (shock, hypotension, decreased cardiac output, and/or a rise in pulmonary capillary wedge pressure) in approximately one-half [7,13]. By comparison, graft dysfunction is uncommon (10 to 15 percent) with late episodes but may also be associated with hemodynamic compromise [7].

Type of immunosuppression — The International Society for Heart and Lung Transplantation (ISHLT) Registry, a nonrandomized data set, has attempted to delineate important determinants for ACR in the first year following transplant. Since the data are not randomized, a cause-and-effect relationship cannot be assumed.

Patients who at transplant discharge were receiving tacrolimus-based immunosuppression, particularly when in combination with mycophenolate mofetil, had lower rates of treated rejection (but not ISHLT grade >2 R rejection) than those receiving cyclosporine in combination with mycophenolate mofetil [14]. A similar observation was noted in the 2009 ISHLT report [9]. ISHLT >2 R rejection refers to moderate or severe rejection with evidence of myocyte necrosis. These grades of rejection require therapy with additional immunosuppression.

Other — Variables that appear to increase the risk of rejection include:

●Younger recipient [11,15,16].

●Female recipient [11,16].

●Female donor [11,15,16].

●Black recipient [16].

●More HLA mismatches between the donor and recipient [16-19].

●Nonadherence to immunosuppressive therapy, which may be a factor contributing to high rates of rejection in adolescents and young adults [20,21].

●Antibodies against non-HLA antigens, such as minor histocompatibility antigens (such as MICA-A and MICA-B [or MIHA-A and MIHA-B]), as well as endothelial and epithelial surface non-HLA antigens, can cause allograft damage and AMR [22]. Whether DSAs were preexisting (ie, present pretransplant) or developed posttransplant does not affect their impact on renal allograft survival, as both can cause reduced survival [23]. DSAs appearing after the first year post-heart transplant can reduce allograft (and hence patient) survival in heart transplant recipients [24].

CLINICAL MANIFESTATIONS — Because of intensive (protocol) surveillance, most cases of acute cellular rejection (ACR) have been diagnosed by endomyocardial biopsy when the patient is asymptomatic. In a review from the Cardiac Transplant Research Database of 3367 patients experiencing 4137 episodes of ACR on either surveillance or clinically indicated endomyocardial biopsy, severe hemodynamic compromise was present in only approximately 5 percent [25]. (See 'Diagnosis' below.)

When symptoms do occur, they are most often manifestations of left ventricular dysfunction such as dyspnea on exertion or at rest, paroxysmal nocturnal dyspnea, orthopnea, palpitations, and syncope or near-syncope. Gastrointestinal symptoms, probably due to secondary hepatic congestion resulting from the increase in central venous pressure, can also be prominent and, in some cases, lead to a delay in diagnosis as other causes of gastrointestinal symptoms are pursued.

Infrequently, ACR presents with atrial arrhythmias, including premature atrial complex (also referred to a premature atrial beat, premature supraventricular complex, or premature supraventricular beat), atrial fibrillation, or atrial flutter [26,27]. Fever and a reduction in QRS voltage on electrocardiogram (ECG), which were diagnostic features of ACR in the first decade of heart transplantation, are rare in the calcineurin inhibitor era [28].

DIAGNOSIS

When to suspect acute cardiac allograft rejection — All patients undergoing cardiac transplantation receive intensive routine endomyocardial biopsy surveillance for acute cardiac allograft rejection. Additional testing is occasionally performed because of suggestive symptoms or echocardiographic evidence of new left ventricular dysfunction. The presence of left ventricular dysfunction can be confirmed by echocardiography, which may reveal an acute decrement in systolic function or a demonstrable worsening of diastolic function.

Surveillance biopsy schedule — The frequency of surveillance endomyocardial biopsies is generally greatest during the first three to six months after transplantation, the time at which ACR is most common. Late biopsies continue to detect clinically significant episodes of rejection five years after transplantation (grade 3A or greater in 8 of 77 patients in one report), and the absence of early rejection does not predict freedom from late rejection [29].

The following represents a typical biopsy schedule:

●Every week for the first four weeks

●Every two weeks for the next six weeks

●Monthly for the next three to four months

●Every three months until the end of the first year

●Some programs continue routine surveillance biopsies every three to four months in the second year

The above schedule may be modified during an attempt to wean a patient from steroids, or to make significant changes in maintenance immunosuppression. In addition, follow-up biopsies are usually obtained one to two weeks after an episode of ACR is treated to assess the adequacy of therapy [30].

Most centers no longer perform routine surveillance biopsies after the first one to two years after transplantation. The utility of continued biopsy surveillance in clinically stable patients over the long term (eg, more than one to two years posttransplant) has become controversial. A study of the Cardiac Transplant Research Database found no benefits from surveillance biopsy beyond five years posttransplant [30]. Evidence from the Invasive Monitoring Attenuation through Gene Expression (IMAGE) study of subjects six months to five years posttransplant indicates that even if rejection is not identified until graft dysfunction occurs, intermediate-term outcomes may not be worse than with earlier detection of rejection. (See 'Gene expression profiling' below.)

Many cardiac transplant centers now use blood testing with gene expression profiling (GEP) to limit the number of surveillance biopsies, primarily for patients beyond the first two months after transplantation. GEP is performed in clinically stable outpatients. (See 'Gene expression profiling' below.)

Surveillance during the COVID-19 pandemic — As recommended by the International Society for Heart and Lung Transplantation (ISHLT), during the coronavirus disease 2019 (COVID-19) pandemic, for patients with stable allograft function and low risk of rejection (such as patients >3 months from transplant with no recent history of rejection, who are not sensitized and lack a positive cross match), routine surveillance biopsies are deferred as clinically appropriate until local resources and capacity allow [31]. For patients with moderate or high risk of rejection, the benefits of surveillance biopsies are weighed against the risks of exposure to the patient and health personnel and limitations of available resources. In the COVID-19 pandemic era, many transplant programs, including ours, have arranged for home blood draws of the GEP test to screen for patients who need endomyocardial biopsies and to minimize patient trips to the hospital or blood drawing sites to reduce potential exposure to COVID-19. (See 'Gene expression profiling' below.)

How to diagnose acute rejection — The diagnosis of ACR is established by endomyocardial biopsy.

Biopsy procedure — Endomyocardial biopsies are generally performed in a specialized facility, either a cardiac catheterization laboratory or a special biopsy suite. Access is obtained through the right internal jugular vein or, less commonly, through a femoral vein. A specialized cardiac bioptome, which appears similar to bronchoscopic bioptomes, is then guided, usually under fluoroscopy, down the superior vena cava and across the right atrium and tricuspid valve into the right ventricle (using fluoroscopy or occasionally echocardiography). (See "Endomyocardial biopsy".)

A minimum of three and preferably four or more evaluable specimens of endomyocardial tissue containing at least 50 percent myocardium are obtained from the right ventricular septum and submitted for pathologic assessment [4]. Most of the biopsy specimens are fixed immediately in 10 percent buffered formalin for light microscopy; tissue can also be frozen for immunohistochemical studies.

Complications — The potential complications of endomyocardial biopsy are discussed separately. (See "Endomyocardial biopsy", section on 'Complications'.)

A complication that is relatively unique to cardiac transplant recipients, presumably because of the performance of biopsies in which the bioptome is repeatedly passed across the tricuspid valve, is tricuspid regurgitation (TR) [32]. The reported prevalence of TR ranges from 47 to 98 percent and is moderate to severe in as many as one-third of patients [32,33].

Severe TR is most often due to a flail leaflet, which probably reflects injury to the tricuspid chordae by the bioptome [32]. Other factors that may contribute include distortion of the tricuspid valve ring due to size mismatch between the donor and recipient, and pulmonary hypertension after transplantation.

The TR is usually well tolerated, but valve surgery (generally tricuspid valve replacement) is occasionally required as described by the following series:

●In a review of 17 heart transplant recipients requiring tricuspid valve surgery in the Utah program (2 percent of all cardiac transplants), the average time to valve surgery (largely valve replacement; two valve repairs) was 77 months after transplantation, and the average number of biopsies before the diagnosis of severe TR was 33 [32]. One patient died postoperatively due to cardiogenic shock, and one patient died eight months after surgery due to right heart failure. Heart failure symptoms improved in 12 cases.

●In a series of eight heart transplant recipients requiring tricuspid valve surgery at Mount Sinai Medical Center in New York (5.8 percent of all cardiac transplants), the average time to valve surgery was 21 months [34]. In four patients, the TR was attributed to annular dilation, and in four patients it was attributed to chordal rupture after biopsy injury. Tricuspid valve repair was performed in all four patients in the latter group, but two of the patients required tricuspid valve replacement within four years after valve repair.

Evaluation and management of TR are discussed separately. (See "Etiology, clinical features, and evaluation of tricuspid regurgitation" and "Management and prognosis of tricuspid regurgitation".)

Histologic findings of acute rejection — ACR is diagnosed by light microscopy of hematoxylin- and eosin-stained specimens on endomyocardial tissue. Morphologically, ACR is manifested as a mononuclear inflammatory response, predominantly lymphocytic, that is infiltrating the myocardium. In more severe cases, granulocytes are also seen [4]. Significant grades of rejection are also accompanied by evidence of cardiac myocyte injury or necrosis. (See 'ISHLT grading system' below.)

Immunohistologic assessment shows that the infiltrating mononuclear cells are predominantly T lymphocytes [35]. These cells are CD4 and CD8 positive [36] and express high-affinity interleukin 2 receptors on their surfaces. Rejection also induces increased expression of major histocompatibility complex class II molecules and intercellular adhesion molecules on the surfaces of cardiac myocytes and endothelial cells [37,38].

Occasional patients have hemodynamically significant rejection with little or no cellular infiltrate or myocyte necrosis apparent in the biopsy specimen [39]. These patients may have humoral (antibody-mediated) rejection, which is associated with antibody deposition that can be detected by immunofluorescence microscopy. A formalized description of humoral rejection has been agreed upon by the transplant community [40]. (See 'Acute antibody-mediated (humoral) rejection' below.)

ISHLT grading system — Cardiac transplant biopsies have been graded for ACR according to the standardized ISHLT nomenclature, which was introduced in 1990 [41,42] and revised in 2004 [4]. However, 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 left ventricular dysfunction, heart failure, or shock should not deter treatment for rejection. (See "Heart transplantation in adults: Graft dysfunction".)

Acute cellular rejection — The 1990 ISHLT grading system for ACR was revised by the ISHLT in 2004 and published in 2005 [4]:

●Grade 0 – No rejection

●Grade 1 R, mild – Interstitial and/or perivascular infiltrate with up to one focus of myocyte damage

●Grade 2 R, moderate – Two or more foci of infiltrate with associated myocyte damage

●Grade 3 R, severe – Diffuse infiltrate with multifocal myocyte damage, with or without edema, hemorrhage, or vasculitis

Thus, grade 1 R includes grades 1A, 1B, and 2 in the 1990 system; grade 2 R was grade 3A; and grade 3 R was grades 3B and 4 (table 1).

There is increasing recognition that there may be wide variation between pathologists and centers in the interpretation of endomyocardial biopsies. This lack of consistency, as well as the costs and potential of morbidity of the biopsy procedure, have motivated the search for alternative methods to detect rejection. (See 'Overview' below.)

Nonrejection findings — There are several processes that can produce cellular infiltration in the cardiac allograft and must be distinguished from acute rejection. The 2004 ISHLT revision included the following biopsy findings of nonrejection [4]:

●Ischemic injury – Early (up to six weeks posttransplant) and late (related to allograft coronary disease)

●Quilty effect

●Infection

●Lymphoproliferative disorder

Perioperative ischemic damage can cause myocardial necrosis as a result of donor trauma with catecholamine excess, pressor therapy during acute care, ex vivo organ ischemia, or reperfusion injury. The histologic appearance of ischemic damage early after transplant usually includes myocyte necrosis out of proportion to the cellular infiltrate, which is predominantly polymorphonuclear rather than mononuclear [43]. Later ischemic injury is related to allograft coronary disease, which is also called transplant vasculopathy. (See "Heart transplantation: Clinical manifestations, diagnosis, and prognosis of cardiac allograft vasculopathy".)

The Quilty effect describes the presence of one or more dense subendocardial monomorphic lymphocytic infiltrates, so called because they were first seen in a patient of that name [44]. Quilty lesions differ from rejection in two respects: They extend to the endocardial surface of the heart, and they include a substantial proportion of B lymphocytes. Quilty lesions are felt to have no clinical significance.

●Opportunistic infections such as cytomegalovirus (CMV) and toxoplasma myocarditis can produce lymphocytic infiltration in the allograft myocardium. These infections can be distinguished from rejection by the presence of characteristic CMV inclusion bodies in the lymphocytes or toxoplasma organisms in the myocardium [45]. (See "Infection in the solid organ transplant recipient".)

●Rarely, posttransplant lymphoproliferative disorders (PTLDs) involve the heart, with myocardial infiltration of atypical lymphocytes [46]. Most PTLDs are due to malignant transformation of B lymphocytes; immunohistologic evaluation can distinguish such infiltrates from the predominantly T cell infiltrates of rejection. In addition, Epstein-Barr virus gene expression in these cells can often be detected using in situ hybridization. (See "Treatment and prevention of post-transplant lymphoproliferative disorders".)

Acute antibody-mediated (humoral) rejection — Diagnostic criteria have been formulated to assist in the diagnosis of acute antibody-mediated rejection (AMR) [4,47]. A separate report from a national conference to assess AMR produced a formalized definition of the process [40]. In 2011, a consensus conference added to the diagnostic criteria [47].

The diagnosis is based upon the following histologic features indicative of acute myocardial capillary injury [4,7]:

●On light microscopy, myocardial capillary injury with intravascular macrophage accumulation; other findings may include intravascular thrombi and interstitial edema, hemorrhage, and neutrophilic infiltration in and around the capillaries.

●Positive immunofluorescence or immunoperoxidase staining for AMR within the capillaries including immunoglobulins (IgG, IgM, and/or IgA), complement (C4d, C3d, and/or C1q), and CD68 staining of macrophages.

These histologic findings are accompanied in almost all patients by serum antibodies directed against human leukocyte antigen (HLA) class I and II antigens in the donor; these antibodies may arise de novo after transplantation or be preformed due to transfusion, use of a left ventricular assist device, pregnancy, or previous transplantation [7,48]. Antibodies also may be formed against a variety of non-HLA antigens [7], although the role of these antibodies in AMR is not well defined.

The histologic diagnosis of AMR from endomyocardial biopsy is dependent upon both histologic and immunostaining findings. The former includes endothelial activation and intravascular macrophages. The latter includes capillary immunostaining for C4d and C3d and macrophage staining with CD68. A nomenclature for the severity of AMR was developed in 2013 by the ISHLT [49]:

●pAMR 0: Negative for pathologic AMR – Both histologic and immunopathologic studies are negative.

●pAMR 1: Histopathologic AMR alone – Histologic findings present and immunopathologic findings negative.

●pAMR 1: Immunopathologic AMR alone – Histologic findings negative and immunopathologic findings positive.

●pAMR 2: Pathologic AMR – Both histologic and immunopathologic findings are present.

●pAMR 3: Severe pathologic AMR – This category recognizes the rare cases of severe AMR with histopathologic findings of interstitial hemorrhage, capillary fragmentation, mixed inflammatory infiltrates, endothelial cell pyknosis, and/or karyorrhexis and marked edema. The reported experience of the group was that these cases are associated with profound hemodynamic dysfunction and poor clinical outcomes.

Therapies for pAMR3 are indicated, especially in the setting of hemodynamic compromise. Therapies for lower grades of AMR are controversial. Most transplant programs do not treat lower-grade AMR in the absence of hemodynamic compromise. (See "Heart transplantation in adults: Treatment of acute allograft rejection", section on 'Acute antibody-mediated (humoral) rejection'.)

Gene expression profiling — GEP of mononuclear cells in peripheral blood specimens has been studied as an alternative to endomyocardial biopsy to detect cellular rejection and is used to limit the number of surveillance biopsies [50-54].

An 11-gene polymerase chain reaction test was found to distinguish grade 0 (termed "quiescence") from moderate to severe rejection (grade ≥3A in the 1990 system; classified as ≥2 R in the 2004 system) [51]. The test correctly identified 84 percent of moderate to severe rejection. Patients with a score <30 at more than one year posttransplant were highly unlikely to have moderate to severe rejection (negative predictive value 99.6 percent). This assay has been adopted clinically by many cardiac transplant programs, primarily for patients beyond the first two months after transplantation, and is Medicare approved.

The IMAGE trial was performed as a noninferiority comparison between a commercially available GEP test and routine biopsies for a composite primary outcome of rejection with hemodynamic compromise, graft dysfunction due to other causes, death, or retransplantation [55]. The 602 patients were enrolled six months to five years following transplantation. A mandatory biopsy was performed for a GEP test score of 30 (increased to a threshold of 34 midtrial). There was no significant difference in two-year cumulative rates of the composite outcome between the GEP and routine biopsy groups (14.5 and 15.3 percent, hazard ratio 1.04, 95% CI 0.67-1.68). However, this result is consistent with as high as a 68 percent increase in risk using the GEP strategy.

Fewer treated episodes of rejection occurred in the GEP group than in the routine biopsy group (34 versus 47). Only 6 of 34 rejection episodes identified in the GEP group were detected on the basis of the profiling test, since the others were detected by heart failure symptoms or echocardiographic evidence of graft dysfunction. In the routine biopsy group, 22 of 47 rejection episodes were asymptomatic. These observations may have broader implications for posttransplant surveillance since they indicate that outcomes may not be worse if rejection is detected with graft dysfunction rather than detected early.

One criticism of the IMAGE study was that it only enrolled patients beyond six months after transplant and that 85 percent of the participants were one year or more posttransplant, while ACR occurs mainly within the first six months after transplant. E-IMAGE (Early IMAGE) is a single-center study that randomized 60 transplant patients from two to six months after transplant to either GEP or biopsy-guided therapy (30 patients in each group) [56,57]. It too was a noninferiority comparison with the same primary composite end point as the original IMAGE trial. E-IMAGE also showed no difference in the composite end point, the detection of rejection, or cardiac function between the two groups. As opposed to IMAGE, this study also included intravascular ultrasonography (IVUS) at baseline and one year after transplant and showed no difference in IVUS markers of cardiac allograft vasculopathy between the two groups. The results of E-IMAGE would suggest that GEP can be used safely in the early (two months and beyond) posttransplant period. The E-IMAGE study also showed that corticosteroids could be weaned during months 2 to 6 as effectively when guided by GEP as by biopsy.

A study of investigational GEP of endomyocardial biopsies from heart transplant patients compared 55 patients with AMR with a matched group of 55 patients without AMR and also evaluated a validation cohort of 27 cases of AMR and 71 controls [58]. AMR was found to have a distinct molecular signature characterized by endothelial activation, microcirculatory inflammation from macrophages, and natural killer (NK) cells. These gene transcripts could distinguish AMR from its absence in endomyocardial biopsies and may shed light on AMR pathogenesis. Cardiac allograft vasculopathy correlated with endomyocardial biopsy transcripts of endothelial activation, interferon-gamma, and NK cells.

Further evidence will be needed to determine the utility of this molecular diagnostic assay as a replacement for routine biopsies and its potential role in weaning immunosuppression and other aspects of long-term management of cardiac transplant recipients.

INVESTIGATIONAL METHODS

Overview — Many potential noninvasive alternatives to biopsy for detection of acute rejection have been investigated. Many markers correlate with histologic evidence of rejection, although data are generally limited. Evidence is strongest for gene expression profiling (GEP), as discussed below. The clinical efficacy of the following markers for rejection has not been definitively established:

●Donor-derived cell-free (dd-CF) DNA may provide a noninvasive approach for detecting cardiac allograft damage from acute cellular rejection (ACR) or from antibody-mediated rejection (AMR). As opposed to GEP, which can only be used beginning 55 days posttransplant, dd-CF DNA can be used beginning 15 days posttransplant, as discussed below. (See 'Donor-derived cell-free DNA' below and 'Gene expression profiling' above.)

●Measurement of cardiac troponin T [59].

●Alternations in the signal-averaged ECG. (See "Signal-averaged electrocardiogram: Overview of technical aspects and clinical applications".)

●Intramyocardial electrograms measured during ventricular pacing [60,61].

●Doppler echocardiography measures of diastolic and/or systolic function [62-65].

●Myocardial acoustic alterations detected by integrated backscatter analysis that can occur in the absence of decreased contractility [66].

●Imaging studies using radiolabeled lymphocytes, antimyosin antibodies, or annexin-V, an endogenous protein that has a high affinity for apoptotic cells [67-69].

●Cardiovascular magnetic resonance imaging [70,71]. (See "Clinical utility of cardiovascular magnetic resonance imaging".)

Donor-derived cell-free DNA — One approach to the noninvasive diagnosis of ACR is the assessment of the percentage of dd-CF DNA in the peripheral blood. dd-CF DNA is released from damaged donor heart cells and can be measured and distinguished from recipient cell-free DNA, which is a result of normal cellular turnover. Thus, an increase in the percentage of dd-CF DNA in the blood would be a reflection of injury to the transplanted (ie, donor) heart from processes like ACR or AMR. As opposed to GEP, this can be assessed beginning two weeks after transplant. Quantification of cell-free DNA has already been used clinically for the prenatal diagnosis of trisomy 21 [72] and has been applied as a research tool to develop a "liquid biopsy" for the detection of metastatic cancer [73]. In cardiac transplant recipients, a rise in peripheral blood dd-CF DNA was shown to occur after graft injury from ACR [74]. In a prospective study, dd-CF DNA rose in peripheral blood in 44 adult and 21 pediatric heart transplant recipients at the time of International Society for Heart and Lung Transplantation (ISHLT) grade 2 R ACR or ISHLT grade 2 AMR [75]. A group using a somewhat different approach to dd-CF DNA quantification in the peripheral blood noninvasively detected allograft damage from ACR and from cardiac allograft vasculopathy in 26 heart transplant recipients [76]. Further research is needed to determine the utility of quantification of dd-CF DNA in the peripheral blood as a noninvasive diagnostic technique for detecting ACR and other forms of cardiac allograft injury.

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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.)

●Basics topics (see "Patient education: Heart transplant (The Basics)")

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

SUMMARY AND RECOMMENDATIONS

●Acute cellular rejection (ACR) is a common problem after cardiac transplantation and is treated in approximately 13 percent of patients during the first year after transplantation. ACR can cause graft dysfunction and contributes to approximately 11 percent of deaths in the first three years after transplantation. Acute antibody-mediated rejection (AMR) may also occur, but its impact on morbidity and mortality is less well defined. (See 'Prevalence' above.)

●Risk factors for ACR include younger recipient, female recipient, female donor, black recipient, and greater human leukocyte antigen (HLA) mismatches between the donor and recipient. The combination of maintenance cyclosporine with mycophenolate mofetil is associated with higher rates of acute rejection than the combination of tacrolimus with mycophenolate mofetil, although a causal relationship has not been established. (See 'Risk factors' above.)

●When transplant recipients are monitored with a typical surveillance endomyocardial biopsy schedule, most cases of ACR are asymptomatic and detected initially by biopsy. Surveillance endocardial biopsies are performed most frequently during the first three to six months, with fewer biopsies typically performed after the first year. (See 'Clinical manifestations' above and 'Surveillance biopsy schedule' above.)

●Symptoms of acute rejection include symptoms of graft dysfunction including dyspnea, orthopnea, palpitations, syncope or near-syncope, and symptoms of hepatic congestion. Atrial arrhythmias are less frequent symptoms of acute rejection. Fever and decrease in electrocardiogram voltage are rare. Echocardiographic evidence of acute rejection includes worsening systolic and/or diastolic function. (See 'Clinical manifestations' above.)

●ACR is graded according to the histologic appearance of endomyocardial biopsy specimen. False-negative results can occur due to sampling error. Evidence of rejection should be distinguished from nonrejection alterations. (See 'Histologic findings of acute rejection' above and 'ISHLT grading system' above.)

●Several noninvasive markers of ACR have been investigated. Of these noninvasive tests, gene expression profiling is supported by the strongest evidence and many cardiac transplant centers now use this test to limit surveillance biopsies, primarily for clinically stable patients beyond the first two months after transplantation. Assessment of the percentage of donor-derived cell-free DNA in the peripheral blood is an investigational approach to the noninvasive diagnosis of ACR. Further study is needed to establish the efficacy of these approaches. (See 'Overview' above and 'Gene expression profiling' above and 'Donor-derived cell-free DNA' above.)

●AMR, usually due to development of donor-specific anti-HLA antibodies, can occur at any time. It is commonly accompanied by hemodynamic compromise when it occurs in the early posttransplant period. It can be diagnosed on endomyocardial biopsy and confirmed by detection of donor-specific antibodies. (See 'Acute antibody-mediated (humoral) rejection' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff would like to thank Mariell Jessup, MD, for her past contributions as an author to prior versions of this topic review.