Biological variation between individuals occurs at the macro level, cellular level, and molecular level. Analysis of the structure of proteins and the genes that code for them indicates that some molecules can be unique to each individual. Genetically determined differences in the amino acid sequence of proteins result in alteration of their three-dimensional structure and charge. It is variation in the protein peptide components that allows the immune system to distinguish cells originating from nonself. Although individual variability may not alter a protein’s function, molecules that vary in this fashion from one individual to another are said to be polymorphic . Protein polymorphism is not the only manner by which self can be distinguished from nonself, but it is the predominant feature that drives rejection in clinical cardiac transplantation.

The effector mechanisms by which cells of the immune system eliminate nonself are operative during allograft rejection and are part of the immune response that defends humans from invasion by infectious agents or toxins. Two components of the immune system, the innate immune system, and the adaptive immune system, participate in responding to nonself molecules themselves. The innate immune system includes less specific and more immediate immune responses that are not dependent on antigen receptors on T and B lymphocytes. These nonadaptive responses to nonself depend on the process of inflammation and the humoral amplification system (complement, coagulation, fibrinolytic, and kallikrein cascades). Through secretion of soluble factors (cytokines), phagocytes are attracted to sites of infection or injury, accompanied by migration of cells involved in specific immune responses. The adaptive immune system , involving responses mediated by T lymphocytes (T cells) and B lymphocytes (B cells), requires an interval after initial exposure to nonself before destructive mechanisms are initiated.

The polymorphic cell-surface proteins, which form the primary basis for distinguishing nonself, are identified by lymphocytes that express (make available on the cell surface) protein molecules called antigen receptors that can bind to the nonself polymorphic protein peptides. These nonself peptides that are detectable by the immune system are called antigens . The “distinguishing feature” is at the end of the antigen receptor outside the cell and thus exposed to the environment. It combines with antigens, after which another portion of the molecule inside the cell initiates a series of biochemical reactions that “activate” the lymphocyte in a way that culminates in a specific immune response. T lymphocytes are the cells that can specifically detect the presence of nonself peptides through their surface antigen receptors.

Activation of B lymphocytes by nonself peptides results in the formation of antibodies , which are molecules specifically targeted by the organism against nonself peptides, cells, or portion of cells. In heart transplantation, this mechanism of eliminating foreign cells is the basis of humoral rejection. Antibodies can also facilitate the attachment of cytotoxic T cells on cells targeted for destruction and serve as points of attachment for phagocytic cells, which also participate in an immune response.

A unique feature of the immune system is that each T lymphocyte carries only one type of antigen receptor on its surface, and each antigen receptor is specific for a single antigen (peptide). A lymphocyte contains an average of about 100,000 antigen receptors on its surface, all identical and specific for a single antigen. Given the huge number of foreign antigens an individual may encounter, survival depends on an adequate variety (repertoire) of lymphocyte antigen receptors to combat invasion by foreign (nonself) peptides.

The actual process by which an antigen receptor identifies a bound peptide as “nonself” is mysterious. Specific receptors apparently do not discriminate between self and nonself in terms of antigen recognition, but rather, self/nonself discrimination is a function of lymphocyte populations that contain numerous antigen receptors. During the period of immunologic development, the process of selection takes place among T cells while they develop in the thymus, in which potential harmful lymphocytes that could react with self-antigen are usually eliminated. Certain disease states develop when this process is incomplete. A small population of lymphocytes are cross-reactive, their antigen receptors binding to more than one antigen.

The proteins primarily involved in the immune response to organ transplantation are called major histocompatibility complex (MHC) antigens. T lymphocytes recognize only antigenic peptides contained within the MHC-binding groove on the surfaces of antigen-presenting cells. In each species, MHC antigens have unique names. Human MHC antigens are termed human leukocyte antigens (HLA). The MHC consists of a group of genes on the short arm of chromosome 6 that code for a number of proteins expressed on the cell surface ( Fig. 21.1 ). These genes are polymorphic in that individuals vary in the exact nucleotide sequence of the genes and therefore the specific amino acid sequence of the protein products. Therefore, for any individual MHC gene, there are likely to be multiple variations (also called alleles ) of that gene distributed within a population of individuals.

Simplified map of human major histocompatibility complex, class I (E, H, G, and F), II, and III. The A, B, C, and DR genes are most often routinely typed at transplant centers. Genes for tumor necrosis factor (TNF) and complement components can be found in the class III region.

(From George JF. Immunology in relation to cardiac transplantation. In: Kirklin JK, Young JB, McGiffin DC, eds. Heart Transplantation . 2002:14.)

In the context of transplantation, it is important to differentiate between donor and recipient MHC molecules. Donor MHC molecules are a source of antigen in that they are ingested by the recipient antigen-presenting cells and processed into peptides that are subsequently loaded into recipient MHC molecules for presentation to recipient T cells. The more extensive the difference in amino acid sequence between donor and recipient MHC molecules, the more likely it is that the donor MHC molecule will be broken into peptides that are recognized as nonself. In the special case of direct antigen presentation (see “ T Lymphocytes ” in later text), intact donor class II MHC molecules on donor antigen-presenting cells or donor endothelial cells within the transplanted heart may play an important role in T-cell activation.

The functions of MHC molecules are closely related to their three-dimensional structure and high degree of polymorphism. Within their three-dimensional structure, there is a distinct groove formed by two α helices that lie on top of a β-pleated sheet. This groove represents the domain in which peptides are processed when they are presented to a T cell by an antigen-presenting cell. A T cell will respond only to an antigenic peptide contained in the MHC peptide-binding groove of an antigen-presenting cell. The polymorphism of the MHC molecule lies in and around the protein-binding groove, creating differences among individuals by different side grooves that may project into and out of the MHC groove for processed peptides. The MHC complex proteins are broadly subdivided into groups called class I and class II . Class I and class II proteins are most commonly considered in the context of transplantation and have similar overall three-dimensional shapes.

The human MHC class I molecules routinely typed for solid organ transplantation are called A, B , and C . Class I molecules are expressed on the surface of virtually all nucleated cells, although with varying levels of expression. The highest surface density is found on lymphocytes, with lower expression on fibroblasts, muscle cells, and endothelial cells. However, certain cytokines such as interferon (IFN)-γ can increase the level of MHC expression on these other cells. This inducibility of MHC molecules likely plays an important role in initiating and perpetuating a rejection episode. As inflammatory mediators are released during a rejection episode, it is likely the level of MHC expression on donor vascular endothelial cells and muscle cells increases further, augmenting the antigenic stimulation. MHC class I molecules consist of two polypeptide chains: a larger highly polymorphic α chain coded by a gene in the MHC complex on chromosome 6, and a smaller nonpolymorphic β chain called β ₂ -microglobulin that is coded by a gene on chromosome 15 ( Fig. 21.2 ). The α ₁ and α ₂ domains form a peptide-binding region in which they interact three-dimensionally to form a platform of eight strands forming a β-pleated sheet flanked by two long α-helical regions forming the floor and walls of the peptide-binding groove. Within this region, peptide fragments of eight or nine amino acids are present in the peptide-binding groove. The α ₃ domain is highly constant among class I MHC molecules, and the interaction between the α ₃ domain and that of β ₂ -microglobulin helps maintain the correct confirmation of the MHC molecule for cell-surface stability. The α ₃ domain interacts with the CD8 molecule on the surface of T cells, ^, which generally restricts the recognition of antigens displayed in the groove of class I HLA molecules to CD8 ⁺ T cells.

Schematic of a MHC class I molecule. It consists of two polypeptide chains. The α chain has three immunoglobulin-like domains designated α ₁ , α ₂ , and α ₃ . The α ₃ domain also serves as the binding site for the CD8 molecule. The α chain has an α-helical transmembrane portion that connects to signal transduction machinery in cell interior. Noncovalently linked to the α chain is β-microglobulin; this is required for expression of the MHC molecule on the cell surface. S–S, Disulfide bonds.

(From George JF. Immunology in relation to cardiac transplantation. In: Kirklin JK, Young JB, McGiffin DC, eds. Heart Transplantation . 2002:14.)

The primary class II molecules related to solid organ transplantation are called HLA-DR, HLA-DP , and HLA-DQ. These molecules are composed of an α chain and a β chain, each of which contains two domains designated α ₁ and α ₂ and β ₁ and β ₂ , expressed as transmembrane proteins ( Fig. 21.3 ). The α ₁ and α ₂ domains form the structure of the antigenic peptide-binding groove. The β ₂ domain interacts with CD4 molecules, which generally restricts the presentation of antigen in the groove of class II MHC molecules to CD4 ⁺ T cells. It is clinically important to include HLA typing as: HLA-A, B, C, DRB1, DQA1, DQB1, DPA1, and DPB1.

Schematic of a MHC class II molecule composed of an α and β chain, each with two immunoglobulin-like domains designated α ₁ , α ₂ , and β ₁ , β ₂ , respectively. Majority of polymorphism in MHC class II molecules is in the β chain. The α chain is nearly invariant. S–S, Disulfide bonds.

(From George JF. Immunology in relation to cardiac transplantation. In: Kirklin JK, Young JB, McGiffin DC, eds. Heart Transplantation . 2002:14.)

Two basic pathways exist for the processing of antigen that subsequently is displayed on the cell surface in the peptide-binding groove of an MHC molecule. The exogenous pathway involves proteins originating from outside the cell that present with MHC class II molecules ( Fig. 21.4 ). This pathway is the principal vehicle for processing and presenting alloantigens following organ transplantation. It is initiated when the antigen binds to the surface of the antigen-presenting cell, which then internalizes the protein via receptor-mediated endocytosis or phagocytosis. Once the peptide (which may be either MHC class I or II) is loaded into the binding groove of the class II molecule, it is transported to the cell surface for presentation to T cells. Any protein from the donor organ can serve as an antigen.

Major MHC class II molecule synthesis and processing of exogenous antigens. An exogenous antigen can be phagocytized or endocytosed (either receptor-mediated endocytosis or pinocytosis) by an antigen-presenting cell. Once internalized, the antigen is degraded into a series of acidic compartments (including lysosomes) to produce peptides that are 13 to 18 amino acids long, which can then be situated in the peptide-binding groove of a class II MHC molecule. At the same time, newly synthesized class II molecules are assembled and associated with the invariant chain in the endoplasmic reticulum. When the complex enters the endosomal compartment, the invariant chain is degraded, leaving a fragment called class II-associated invariant chain peptide (CLIP) that occupies the peptide-binding groove of the class II molecule. The class II-like molecule HLA-DM catalyzes release of CLIP and loading of the antigenic peptide into the peptide-binding groove of the class II molecule.

(From George JF. Immunology in relation to cardiac transplantation. In: Kirklin JK, Young JB, McGiffin DC, eds. Heart Transplantation . 2002:14.)

The endogenous pathway involves proteins that originate inside the cell, in which proteins complex with MHC class I molecules and are presented to T cells ( Fig. 21.5 ). This pathway appears to have a minor role in transplant rejection, and theoretically any cell (not just antigen-presenting cells) can use it in the presentation of internal peptides on MHC class I molecules. This pathway is typically used in the body’s defense against intracellular pathogens, such as viruses whose proteins can be degraded and presented on the cell surface, resulting in the cell’s destruction by cytotoxic CD8 ⁺ T cells.

Synthesis of MHC class I molecules and processing of endogenous antigens. Class I molecules are assembled in the endoplasmic reticulum with calnexin, a membrane-bound protein. β ₂ Microglobulin is then substituted for calnexin, and the class I molecule binds to the transporter associated with antigen processing (TAP). Proteins in the cytoplasm are degraded to peptides by proteasomes. Peptides are transported into the lumen of the endoplasmic reticulum by the TAP, and a peptide is loaded into the peptide-binding groove of the class I molecule. Molecule is then released from the TAP and exported to the cell surface via the Golgi complex.

(From George JF. Immunology in relation to cardiac transplantation. In: Kirklin JK, Young JB, McGiffin DC, eds. Heart Transplantation . 2002:14.)

T lymphocytes represent the most important component of the immune response to transplanted organs ( Box 21.1 ). They are defined by presence of a CD3 molecule (part of the T-cell antigen receptor) on their surface and generally with either CD4 or CD8 surface molecules. The two basic subtypes of T lymphocytes are T helper (T _H) cells and cytotoxic T cells. The T _H lymphocyte expresses CD4 molecules on its surface and functions primarily to detect nonself antigens by means of its T-cell receptors. When activated, it can also recruit other cells (CD8 ⁺ T cells, other CD4 ⁺ T cells, B cells, phagocytes, neutrophils, and other inflammatory cells) into the immune response ( Table 21.1 ).

Cytotoxic T lymphocytes differ from T _H cells in that they express CD8 molecules on their surface. The cytotoxic T lymphocyte functions primarily as an effector cell that kills target cells (cells that express nonself antigens in the groove of a class I MHC molecule), and under special circumstances may suppress other cells (prevent their activation). The T-cell receptor allows the T lymphocyte to detect the presence of a nonself antigen by providing the capability of binding to antigen and MHC molecules in a specific manner. This receptor allows detection of nonself MHC antigens in the transplanted heart. Each T-lymphocyte clone has a T-cell receptor that is unique with respect to the receptors of other T-cell clones and has a unique T-cell genetic sequence. The pool of unique T cells constitutes the T-cell repertoire , which includes more than 10 ¹² unique T-cell receptors in a given individual.

The portion of the T-cell receptor that interacts with the antigenic peptide–MHC complex is a heterodimer of two covalently linked polypeptide chains designated α and β ( Fig. 21.6 ). The α and β chains each have a variable region (V-region) that contains a highly variable amino acid sequence. The α and β chains are associated with membrane-bound proteins called the CD3 complex. It is required for expression of T-cell receptor on the cell surface and is responsible for transduction of a membrane signal when the T-cell receptor complex interacts with antigen. Ability of a lymphocyte to respond to the presence of a specific antigen is termed recognition.

Schematic of T-cell receptor (TCR). The TCR is a multichain complex consisting of a heterodimer that, in the majority of T cells, consists of an α and β chain, each of which has immunoglobulin-like domains, as indicated by the loops held together by disulfide (S-S) bonds. These chains constitute the portion of the molecule that binds the antigen–major histocompatibility complex on the surface of an antigen-presenting cell. The α and β chains are noncovalently linked to the CD3 complex, which consists of chains called γ, δ , and ε . The two additional chains can be either of two pairs composed of two ζ chains, or of a ζ chain and a η chain. The CD3 complex transmits a signal through the plasma membrane (shaded in gray) into the interior of the cell.

(From George JF. Immunology in relation to cardiac transplantation. In: Kirklin JK, Young JB, McGiffin DC, eds. Heart Transplantation . 2002:14.)

T cells recognize antigen only in the presence of self-MHC. T _H cells, which initiate the cellular response to transplant antigens, respond to antigen that is associated with an MHC complex on the cell surface through a process called antigen presentation. This process is limited to certain cell types called antigen-presenting cells . A presenting antigen must first be internalized within the antigen-presenting cell, broken down into 7 to 13 amino acid polypeptides, which are physically associated with MHC molecules, and exported to the cell surface as a complex. T _H cells respond only to those cells that express class II molecules on their surface. Cytotoxic T cells (CD8 ⁺ ) respond to cells that have class I MHC molecules on their surface.

Because cytotoxic T cells recognize antigens only on the surface of other cells that have class I MHC surface molecules, a functionally distinct class of cells has been identified that presents antigen to T lymphocytes. These antigen-presenting cells process antigens by breaking them down into individual peptides, inserting the peptides into the MHC molecule, and transporting them to the cell surface ( Box 21.2 ). Cells that function as antigen-presenting cells are dendritic cells, macrophages, and B cells. Dendritic cells are the most efficient antigen-presenting cells because they have a large surface area, increasing the probability of contact with T lymphocytes. Dendritic cells are present throughout most lymphoid and nonlymphoid tissues and possess a high density of surface MHC class II molecules. Antigen-presenting cells also provide a second signal that is necessary for T-cell activation, which is the binding of another molecule on the surface of the T cell in addition to the binding of the T-cell receptor by an antigen-MHC complex. This process is called co-stimulation which confirms alloantigen recognition and leads to cytotoxic T-cell proliferation.

B lymphocytes arise from bone marrow and do not express CD4 or CD8 molecules on their surface. They use surface immunoglobulins rather than T-cell receptors for detecting antigen, and the endproduct of B-cell activation is differentiation into antibody-secreting plasma cells and memory B cells (B cells capable of generating an immune response when there is subsequent exposure to the same antigen). Immunoglobulins (antibodies) are produced by B cells that have differentiated into plasma cells. They consist of four polypeptide chains in two pairs, each consisting of a heavy chain and a shorter light chain ( Fig. 21.7 ). The end of the molecule is called a variable region because the genes that code for the heavy and light chains are composed of segments that join together imprecisely. The other end of the heavy chain, called the constant region , contains sites for biologically important activity such as complement activation. The heavy chain constant regions form the basis for classifying immunoglobulins into isotypes IgG, IgA, IgM, IgD, and IgE.

Schematic of structure of an immunoglobulin molecule. An individual antibody molecule consists of two heavy and two light chains. Each heavy and light chain combines to form a single antigen-binding region for a total of two antigenic binding sites. Both chains contain a series of sequence motifs about 100 amino acids long that can fold into globular forms called immunoglobulin domains . The two constant region domains in each heavy chain that are farthest from the variable domains constitute the Fc receptor and complement-binding portions of the molecule. Variable domains constitute the antigen-binding site.

(From George JF. Immunology in relation to cardiac transplantation. In: Kirklin JK, Young JB, McGiffin DC, eds. Heart Transplantation . 2002:14.)

Natural killer (NK) cells are structurally similar to T and B lymphocytes but are not antigen specific and do not express either a T-cell receptor or immunoglobulin. These cells are called natural killer cells based on their ability to spontaneously lyse tumor cells in vitro. In vivo, they can lyse target cells without the requirement for prior immunization. They can lyse cell targets that lack surface expression of MHC molecules. NK cells represent about 15% of peripheral lymphoid cells.

Soluble molecules called cytokines play an important role in the immune response by stimulating secretion of proteins that alter the behavior or property of cells and facilitate recruitment of immunologic cells from distant locations. Unlike hormones, cytokines generally act locally and are not usually found in circulation in large quantities because of their short half-life. Although numerous cytokines have been identified that have diverse biological actions ( Table 21.2 ), cytokines in transplantation are particularly important in mediating inflammatory processes and regulating T-cell responses. Cytokine production is one of the hallmarks of T-cell activation. Prominent cytokines in the immunologic response to transplantation include interleukin (IL)-2, IL-6, tumor necrosis factor (TNF), and IFN-γ.

Adhesion molecules are proteins formed within cells and secreted into the environment of these cells. They function to maintain structural integrity and position of body cells and promote adhesion of leukocytes to surrounding structures. Adhesion molecules include integrins (adhesion molecules that maintain cells in position by attaching one end of the integrin to the cytoskeleton of the cell and the other end to molecules of the extracellular matrix), selectins (adhesion molecules that mediate rolling of leukocytes along the vascular endothelium), and Ig superfamily adhesion molecules. Adhesion molecules mediate the initial interaction of T cells with antigens, their migration, and their retention within a transplanted organ.

The inciting event is placing the donor heart into the recipient and perfusing it with native blood elements following aortic clamp removal. Within minutes, large quantities of donor cells, protein (some of which is soluble MHC molecules), and cellular fragments are carried to the spleen and lymph nodes, which are highly efficient in filtering antigen and trapping antigen within resident antigen-presenting cells. These cells enter the paracortex of the lymph node, which is populated by T cells, macrophages, and dendritic cells. If the T cells have a receptor capable of binding to MHC molecules containing a particular peptide, they will be activated, after which they interact with B cells, inducing the initial stages of B-cell activation. In addition, donor antigen-presenting cells migrate from the heart and encounter T cells as they circulate through the lymphoid tissues. Donor antigen-presenting cells also line the endothelial surfaces of the donor heart vasculature. Donor alloantigens containing foreign MHC complex molecules can be presented to the recipient T cells in two ways: directly and indirectly ( Table 21.3 ). Direct recognition of donor antigens by T lymphocytes involves direct engagement between the recipient T-cell receptor and the donor antigen-presenting cell (also called passenger lymphocytes ). Even though these antigen-presenting cells are nonself, the structural similarities are sufficient to allow binding with either helper or cytotoxic T lymphocytes, because both MHC class I and II molecules will be expressed. In this method of donor antigen presentation, the specific antigen presented in the groove of the complex is often unimportant because the donor antigen-presenting cell will be identified as nonself.

When shed MHC molecules from the donor organ are processed and presented by recipient antigen-presenting cells to recipient T cells, the process is termed indirect allorecognition. The exogenous pathway of processing and presenting alloantigens is generally operative in the indirect allorecognition process. The presentation of donor antigen to T lymphocytes results in T-cell activation. T-cell activation occurs in concert with changes in the expression of various cell surface molecules, secretion of soluble factors, and a change in cell morphology. Once activated, the T _H cell clone proliferates and releases cytokines that expand the immune response .

B-cell activation begins with capture of antigen by immunoglobulin molecules on the B-cell surface. The antigen is then internalized, degraded, processed into peptides, loaded into the groove of MHC class II molecules, and delivered to the cell surface. When the B-cell encounters a CD4 ⁺ T cell that has the appropriate T-cell antigen receptor for binding to the antigen-MHC complex on the B-cell surface, the T cells engage in a process termed mutual activation . B-cell differentiation into immunoglobulin-producing plasma cells requires antigen-specific signals through B-cell receptors (immunoglobulin) expressed on the cell surface and antigen-specific T-cell help in forming a co-stimulator signal and cytokine stimulation.

Cytotoxic T lymphocytes (CD8 ⁺ ) that are specific for graft antigens play an important role in the effector phase leading to acute rejection. Like T _H cells, cytotoxic T cells are not activated with a single signal, but rather require the binding of multiple surface molecules that transmit additional signals through the cell membrane. This process requires engagement by allogenic histocompatibility molecules or by an antigenic peptide MHC complex, with an additional signal via a co-stimulator molecule such as CD28. This series of signals serves to activate cytotoxic T-lymphocyte precursors that then proliferate and differentiate into cytotoxic T lymphocytes in response to IL-2. Once a cytotoxic T lymphocyte receives the appropriate signals, it can administer a lethal hit to a target cell that results in cell death either through exocytosis (release of destructive granules into the target cell) or induction of apoptosis.

Humoral rejection refers to production of antibodies or activation of complement in response to exposure to an alloantigen. B lymphocytes mediate the response, and antibodies can react with antigens in solution or on the cell surface. Antibodies associated with humoral rejection are generally IgM and IgG. Effector mechanisms associated with humoral responses include neutralization (blocking of relative sites or binding of receptors on a target cell), opsonization (antibodies acting as a “tag” that can be recognized by phagocytic cells), and complement activation. The most extreme form of humoral rejection is hyperacute rejection , mediated by preexisting antibodies that, upon entry into the donor heart vasculature following aortic clamp removal, rapidly bind to the vascular endothelium. These antibodies fix complement, which causes direct lysis of endothelial cells, and elaboration of complement components induces a massive infiltration of granulocytes. The subsequent massive cell necrosis and tissue swelling can lead to organ destruction within minutes.

Cardiac transplantation should be reserved for those patients most likely to benefit in terms of both life expectancy and quality of life. When allocating a scarce resource such as a donor heart, a balance must be achieved between appropriate use of the resource to maximize graft survival and maximizing patient survival in those with the poorest expected outcome with other available therapies.

The stated goals of organ allocation embrace two basic concepts: fairness and utility . The concept of fairness is complex, but basically states that all patients with end-stage heart disease of equivalent severity have an equal chance of obtaining a heart transplant. Unfortunately, quantifying the probability of death for various patient subsets is currently not possible, and specific criteria for listing are not uniform among institutions.

The concept of utility must also be considered in judging any allocation algorithm. This concept embodies the notion that a precious resource like transplant organs should be used to maximally extend life. Inherent is the notion that transplantation should only be offered to patients for whom transplantation would substantially and importantly improve survival over other therapeutic options. Thus, if the likely duration of survival is importantly reduced by the presence of major noncardiac organ dysfunction or comorbidities (which would either be unaffected or worsened by therapies required following transplantation), then the utility of transplantation would be unfavorable.

Based on these concepts, national organ procurement agencies establish algorithms for selecting recipients when an organ donor is identified. In the United States, this agency is the United Network for Organ Sharing (UNOS), which includes committees of transplant experts who work together to establish the rules for organ allocation.

The current allocation system in the United States gives strong priority to those patients whose heart failure is severe enough to require continuous inotropic therapy or temporary mechanical circulatory support (MCS). Priority for continuous inotropes or temporary MCS is currently given over that of transplant candidates supported with durable MCS. Because of poor survival in higher-risk subsets and paucity of available organs, current indications for cardiac retransplantation are generally limited to (1) chronic severe cardiac allograft vasculopathy with symptoms or signs of ischemia or heart failure or asymptomatic moderate or severe left ventricular dysfunction, and (2) chronic graft dysfunction with symptoms of progressive heart failure in the absence of active rejection.

Donation after Circulatory Death (DCD) has emerged as a potential solution to increase the pool of available donor organs for cardiac transplantation. The use of heart donors meeting DCD criteria involves the retrieval of organs from donors who have experienced circulatory arrest and meet the criteria for declaration of death based upon circulatory criteria (i.e., absence of blood pressure, pulse, and heartbeat). The Maastricht classification system is used to describe four different categories of DCD donors according to the circumstances of the donor’s death. Uncontrolled DCD (Maastricht Category I, II, and IV) refers to donors having suffered an unexpected cardiac arrest and unsuccessful resuscitation. Controlled DCD (Maastricht Category III) refers to donors that undergo a planned withdrawal of life-sustaining therapy and progression to circulatory arrest. DCD donors are typically patients who have suffered severe brain injury but do not meet the criteria for brain death. In these circumstances, after consent from the donor’s family, life-sustaining treatments, such as mechanical ventilation, are withdrawn, allowing the patient to progress to circulatory arrest. This is a key distinction from the traditional process of using donors meeting brain death criteria. Survival outcomes following heart transplantation with DCD heart organs is comparable to survival outcomes utilizing traditional donor heart organs from brain dead donors.

The ABO blood group antigens are carbohydrate structures carried on glycoprotein and glycolipid components of cell surfaces and tissues throughout the body, most notably on the surface of erythrocytes. In the human heart, blood group antigens are confined to the vascular endothelium and mesothelial cells on the surface of the epicardium. In individuals who lack one or more of the ABO antigens, natural antibodies against the absent antigen appear during the first 6 months of life and are present permanently thereafter.

An accepted requirement for successful cardiac transplantation beyond infancy is identical or compatible blood groups between donor and recipient. If an allograft containing A or B blood antigens on its endothelial surfaces is transplanted into a recipient who has naturally occurring anti-A or anti-B antibody, hyperacute rejection or accelerated aggressive acute rejection will likely occur. When a donor and recipient display ABO incompatibility, circulating antidonor hemagglutinins rapidly bind to endothelial cells and promote platelet deposition, granulocyte activation, and thrombosis, resulting in hyperacute rejection. Although transplantation in the presence of ABO incompatibility (donor heart A into recipient blood group B or O, B into A or O, AB into A, B, or O) would be expected to produce universal hyperacute rejection, there are notable exceptions (see also “ ABO-Incompatible Heart Transplantation ” in Section II). Considerable variability exists among individuals in the level of blood group antigen expression in tissues, such as on cardiac endothelium.

HLA antigens play a central role in the immune response, and the HLA genes are the most polymorphic known in the human genome. Haplotype refers to the set of genes on any one chromosome. Every individual has two haplotypes (one from each parent) for the genes on the short arm of chromosome 6 that code for the MHC complex. Each haplotype contains antigens determined by the HLA-A, HLA-B, HLA-C, HLA-DR, and other loci. The two haplotypes for an individual make up the HLA phenotype, which is the complete list of HLA antigens possessed by that individual. Studies of kidney graft survival have demonstrated a substantial survival benefit when the HLA antigens are matched between donor and recipient. Some benefit in freedom from rejection has also been demonstrated for heart transplantation related to the number of HLA mismatches. Some studies suggest a higher probability of rejection with HLA-DR and HLA-DQ mismatching in heart transplantation. ^, However, because of the time limitations imposed by the current state of cardiac preservation during organ procurement and the scarcity of organs, donor hearts are currently not selected on the basis of prospective histocompatibility testing.

In addition to HLA typing, the transplantation evaluation process includes routine examination of serum from a prospective transplant recipient for presence of circulating anti-HLA antibodies, also called humoral sensitization . Sensitization is established by documenting the presence of circulating anti-HLA antibodies by the panel reactive antibody (PRA) test. The most common cause of sensitization is pregnancy. Other common causes include prior blood transfusion, prior transplantation, or insertion of a ventricular assist device. Occasionally a patient will demonstrate a positive PRA with anti-HLA antibodies and no obvious sensitizing event. These antibodies may represent cross-reactivity between bacterial or viral epitopes and HLA antigens.

The crossmatch at transplantation is typically the final test of immunologic compatibility between donor and recipient prior to making the decision to transplant. The goal of the crossmatch is to prevent hyperacute rejection and accelerated severe acute rejection during the first 5 to 7 days after transplantation. The crossmatch tests the reactivity of recipient sera (with its potential anti-HLA antibodies) against donor lymphocytes obtained from peripheral blood or lymph node. With current crossmatch techniques, hyperacute rejection is extremely rare. In practice, a pretransplant prospective crossmatch is often omitted when a recent PRA is 0% because of the very low probability of hyperacute or accelerated acute rejection in that setting and because of the additional time prior to transplantation needed to obtain a crossmatch. In that instance a retrospective crossmatch is usually obtained in the hours following transplantation to make a final determination of the presence of antidonor antibodies.

A positive complement-dependent lymphocytotoxic T-cell and B-cell crossmatch is a strong predictor of hyperacute or severe accelerated acute rejection. However, presence of a negative cytotoxic crossmatch does not guarantee protection against hyperacute or severe early rejection. It has been hypothesized that minimal clonal expansion of T _H 1 and T _H 2 subsets of T cells plus B cells is sufficient to produce a brief IgM (or IgM followed by IgG) response that is promptly down-regulated, and detectable levels of IgG may not be present (thus producing a negative crossmatch). However, with sustained stimulation following transplantation, B-cell clones expand and express increased affinity for the HLA antigen. Substantial clonal expansion then occurs with T _H 1, T _H 2, and B-cell proliferation and the production of antibody. Serum anti-HLA antibodies become predominantly IgG with sustained levels, and further antibody response is readily inducible with reexposure to even small amounts of these HLA antigens.

With the current precision of flow cytometry technology in identifying circulating anti-HLA antibodies in potential recipients, many transplant centers omit formal crossmatching (with the considerable time requirement) in the presence of low PRAs and rely instead on a comparison of HLA typing of the donor with identified anti-HLA antibodies in the recipient. If there are no donor antigens against which recipient antibodies are likely to react, it is generally safe to proceed with transplantation. By comparing recipient HLA antibodies to prospective donor HLA antigens, the virtual crossmatch enables a patient to be safely matched with an appropriate donor without a prospective crossmatch.

Most donors donate multiple organs including the heart. Therefore, the donor is prepared from neck to midthigh. Preferably, a central venous line and an arterial catheter are placed because marked hypotension may occur while mobilizing the abdominal organs. A long midline incision is made from jugular notch to pubis. Volume replacement continues as needed because considerable bleeding from incisions is frequent as a result of the donor’s vasodilated state. After median sternotomy, a self-retaining retractor is inserted. While other organ procurement teams proceed, the pericardium is opened and usual stay sutures applied. The heart is examined for evidence of cardiac injury, congenital anomalies, coronary arteriosclerosis, or other acquired heart disease. The ascending aorta is dissected and mobilized as far as the brachiocephalic takeoff. The superior vena cava (SVC) is completely mobilized, including any pericardial reflection onto it. A purse-string suture is placed on the ascending aorta for cardioplegia infusion.

When cardiectomy is ready to begin, 200 units/kg of heparin are given, and the cardioplegia needle is inserted into the ascending aorta and secured. In this setting, the cardioplegic solution is infused by gravity. Several intracellular- or extracellular-type solutions provide effective preservation, and other continuous perfusion methods are now available. If a central line is in place, it is withdrawn. The SVC is clamped and later divided as far distally as possible. The right or left superior pulmonary vein (or left atrium above the entrance of the left pulmonary veins if lung procurement is planned) is partially divided to permit escape of blood from the heart ( Fig. 21.8 A). If lungs are also being harvested, the left atrium is incised for egress of pulmonary preservation solution, and later a cuff of left atrium is left around the right and left pulmonary veins for the lung allografts. The inferior vena cava (IVC) is divided, leaving part of it with the liver. After several cardiac ejections to completely empty the heart, the aorta is occluded just proximal to the brachiocephalic artery. Infusion of the cardioplegic solution is begun. Cardioplegic infusion pressure is monitored digitally while 1 to 2 L of solution is infused. Ice-cold saline or slush solution is poured into the pericardium.

Donor cardiectomy for orthotopic cardiac transplantation. (A), Inferior vena cava is divided at its junction with right atrium. Most of the intrapericardial inferior vena cava is left behind attached to the liver, because nearly all these operations are for multiorgan procurement. Right pulmonary vein is incised to vent the left heart. (When lungs are being harvested, left atrioventricular groove is generously incised to provide egress of the pulmonary preservation solution). Aorta is occluded when the heart empties. Cold cardioplegic solution is administered through the catheter to the aortic root to achieve total electromechanical arrest. (B), Heart is retracted superiorly, exposing pulmonary veins and left pulmonary artery. These are divided. (C), Aorta, superior vena cava, and right pulmonary artery are divided at or above the pericardial reflection for maximal length on recipient great arteries. All that remains to be divided is connective tissue behind the left atrium at pericardial reflection. The heart is taken from the body and aorta and pulmonary trunk separated, atrial septum checked for defect, and cardiac valves and cardiac chambers inspected. It is packed in saline solution in triple sterile bags for transport.

Coronary sinus effluent is allowed to escape into the pericardial sac through the open IVC. Cardiectomy proceeds by dividing the right pulmonary veins at the pericardial reflection. The heart is retracted superiorly and to the right to expose the left pulmonary veins, which are divided at the pericardial reflection. The left pulmonary artery is divided at the pericardial reflection ( Fig. 21.8 B). Downward traction alongside the aorta and pulmonary trunk exposes the maximal length of these vessels. The aorta is divided distal to the origin of the brachiocephalic artery ( Fig. 21.8 C). The right pulmonary artery is divided. All that remains to be divided is connective tissue behind the left atrium at the pericardial reflection and lymphatic tissue, which lies between the left atrium and the tracheal bifurcation.

The heart is removed from the body and immersed in cold preservation solution. A few minutes are spent to trim the heart and prepare it for implantation, although trimming of the heart is often left to the implanting surgeon. The right pulmonary veins are joined by incision as are left pulmonary veins. The left atrium is opened posteriorly between the pulmonary veins to provide maximum length for the left atrial suture line. The aorta is separated from the pulmonary trunk. The pulmonary trunk is opened at its bifurcation to preserve maximum circumference that may be needed to match a dilated recipient vessel. The cardiac chambers are thoroughly irrigated with cold isotonic solution and inspected to ensure absence of debris or anatomic anomalies. The organ is placed in triple sterile plastic bags filled with preservation solution and transferred to an ice chest or commercial hypothermic storage container for transport.

Donor heart preservation is a critical aspect of heart transplantation to ensure the organ remains viable and functional during the procurement and transplant process. Several methods and techniques are used to effectively preserve the donor heart. The choice of preservation method may depend on factors such as procurement and transportation time, donor condition, recipient condition, and physician and institutional experience.

The most common and long-standing method of donor heart preservation has been the method of static cold storage in ice. Following donor cardiectomy, the heart is placed in a bag containing approximately 1000 mL of a sterile preservation solution at 4 ^o C that is then sealed into a second bag containing approximately 1000 mL of a cold preservation solution. This is subsequently placed in a rigid sterile container filled with cold solution that is sealed and inserted into a cooler filled with ice to permit safe transport to the recipient location. A number of different donor organ preservation solutions have been utilized for donor heart preservation. ^, Currently, University of Wisconsin solution, Celsior solution, Custodial solution (histidine-tryptophan-ketoglutarate-HTK) and del Nido solutions are the most popular choices for preservation solution. Cold storage typically has provided approximately 4 to 6 hours of safe preservation time. ^, Preservation times exceeding about 4 to 5 hours with cold storage are associated with a somewhat higher risk of acute allograft dysfunction and failure.

Other more sophisticated methods of cold storage have recently been introduced and involve new technology that provides a more homogeneous and controlled temperature of the donor heart between 4 ^o C and 8 ^o C thus minimizing tissue injury due to ice-cold temperature exposure. The device, the Paragonix SherpaPak cardiac transport system, consists of two canisters, one internal and one external. The internal canister is filled with cold storage saline solution (4 ^o C–8 ^o C), and the donor heart is submerged into it, after being connected to the canister lid by an aortic connector. The most widely used solutions for heart preservation in this system are the Celsior and Custodial (histidine-tryptophan-ketoglutarate-HTK) solutions. The inner canister is subsequently placed into the outer one, creating an insulation air chamber and the outside of this canister is surrounded by single-use cooling ice packs. A thermometer connected to the internal canister allows continuous monitoring of temperature.

More sophisticated methods of hypothermic storage include hypothermic machine perfusion. The rationale of hypothermic machine perfusion consists of reducing metabolic requirements of the heart with an optimal and homogenous cooling (below 10 ^o C), while providing continuous metabolic support through perfusion with oxygenated, nutrient-enriched medium to limit as much as possible intracellular anerobic metabolism and consequent acidosis. The XVIVO Heart Perfusion System (currently undergoing clinical trials) consists of a roller pump, an oxygenator, a leukocyte filter, and a cooler/heater. After cardiectomy, the donor heart is connected to the XVIVO device with an aortic cannula. The organ is then submerged into a reservoir filled with 2.5 L of perfusion solution to which 500 mL of donor and recipient immunologically compatible irradiated blood is added. The oxygenated perfusion solution (hematocrit approximately 15%) is pumped into the aortic root to maintain a pressure of 20 mmHg to provide coronary blood flow between 150 and 200 mL/min in a nonbeating heart state. The temperature is constantly maintained at 8 ^o C and the pH at 7.4.

Recently, introduction of innovative technology has expanded the techniques for heart organ preservation to include warm normothermic perfusion. The TransMedics® Organ Care System is an extracorporeal perfusion system that provides normothermic perfusion of oxygenated blood to maintain the donor heart organ in a warm and beating state during transportation of the donor heart organ. Blood obtained from the organ donor is used to prime the extracorporeal perfusion system. Following standard cardioplegic arrest and donor heart cardiectomy, the donor heart organ is placed on the extracorporeal perfusion system. Although the donor organ is not maintained in a loaded state on the extracorporeal perfusion system, biochemical assessment of the donor organ is feasible with measurement of lactate levels in the arterial and venous systems. While lactate is the end point and currently best assessment of viability and functionality of the donor organ, additional parameters are measured during heart perfusion and include flow delivered to the aorta, flow through the pulmonary artery reflecting coronary artery flow, temperature, oxygen saturation, hematocrit, and pulmonary artery pressure. The pressure in the aortic root is measured and controlled with infusion of a solution containing adenosine, causing coronary dilation, reducing the outflow resistance of the pump. Increased options for employing organs from marginal donors, distant procurement sites, donation after cardiac death, and in receivers with complex anatomy are made possible by the implementation of ex vivo machine perfusion during transport. These perfusion systems may eventually become more widespread due to bioengineering innovations including the utilization of mesenchymal stem cells, viral vector delivery of gene therapy, and other devices.

In the setting of DCD heart donation, there are two methods for procurement of the donor heart organ. The first, Direct Organ Procurement, is the more traditional approach for DCD heart retrieval. With this method, the focus is on rapid retrieval of the donor heart organ from the thoracic cavity. Upon surgical exposure of the donor heart, the heart organ undergoes rapid cardioplegic cold perfusion in situ to achieve hypothermic arrest and is then excised and placed on an extracorporeal perfusion system utilizing normothermic blood perfusion with blood obtained from the donor. The heart is maintained in a beating state perfused with warm blood during transportation until just prior to transplantation into the recipient when the donor heart organ is perfused with cold cardioplegic solution to arrest the heart for the implant procedure.

In a recent randomized, noninferiority trial, adult candidates for heart transplantation were assigned in a “3:1 ratio to receive a heart after confirmation of circulatory death of the donor or a heart from a donor after declaration of brain death if that heart was available first (circulatory-death group) or to receive only a heart that had been preserved with the use of traditional cold storage after the brain death of the donor (brain-death group)”. The primary end point was the risk-adjusted survival at 6 months in the as-treated circulatory-death group as compared with the brain-death group. The primary safety end point was serious adverse events associated with the heart allograft at 30 days following transplantation. A total of 180 patients underwent transplantation; 90 (assigned to the circulatory-death group) received a heart donated after circulatory death and 90 (regardless of group assignment) received a heart donated after brain death. A total of 166 transplant recipients were included in the as-treated primary analysis (80 who received a heart from a circulatory-death donor and 86 who received a heart from a brain-death donor). The risk-adjusted 6-month survival in the as-treated population was 94% (95% confidence interval [CI], 88 to 99) among recipients of a heart from a circulatory-death donor, as compared with 90% (95% CI, 84 to 97) among recipients of a heart from a brain-death donor, indicating non-inferiority of the use of extracorporeal non-ischemic perfusion after circulatory death compared to standard cold storage after brain death. There were no substantial between-group differences in the mean per-patient number of serious adverse events associated with the heart graft at 30 days after transplantation.

The second method of DCD heart procurement, termed Normothermic Regional Perfusion (NRP), involves exposure of the donor heart organ within the thoracic cavity, ligating the major branches of the arch of the aorta (innominate, left carotid, left subclavian) and instituting CPB for in vivo reanimation of the heart and abdominal organs. The branches of the arch of the aorta are ligated to prevent reperfusion of the brain. Following reanimation of the heart, the donor can be weaned from CPB and donor heart evaluation and procurement proceeds in a similar manner to the brain-dead heart donor. While this method is utilized at a number of centers, ethical concerns regarding potential reperfusion of the brain has limited wide adoption of this technique. Recently, a study of heart transplantation using DCD heart donors found that among 558 DCD procurements, heart recovery occurred in 89.6%, and 92.5% of recovered hearts were utilized for transplant. Of 506 DCD procurements with available data, 65.0% were classified as direct donor procurement and perfusion and 35.0% were classified as NRP. Logistic regression identified that NRP, shorter agonal time, younger donor age, and highest volume of organ procurement organizations were independently associated with increased odds for heart recovery. NRP independently predicted heart utilization after recovery. Data also suggested that outcomes following procuring DCD heart organs with the NRP technique were similar to outcomes with direct donor organ procurement.

In patients with a previous sternotomy, particularly with previous bypass surgery, the likelihood of acute severe cardiac decompensation is greatly increased if there is inadvertent injury to the patient’s saphenous or internal thoracic artery graft. In this situation, routine insertion of a percutaneous femoral artery catheter for arterial pressure monitoring is advantageous. Should decompensation occur, a guidewire for inserting an IAPB can be rapidly accomplished, or CPB established with a percutaneously inserted arterial cannula. In situations in which sternotomy is considered very high risk, a guidewire can also be placed in the femoral vein for percutaneous venous cannulation if necessary.

In preparing every donor heart prior to implantation, the area of the fossa ovalis should be specifically examined. If a patent foramen ovale is identified, it must be surgically closed. Failure to do so has resulted in severe hypoxemia and right-to-left shunting early after cardiac transplantation in a situation of right ventricular dysfunction, particularly in the presence of elevated pulmonary artery pressure.

Tricuspid regurgitation detected by Doppler echocardiography is common after orthotopic cardiac transplantation. This may relate to geometry of the newly constructed right atrium; an association has been suggested between larger relative size of the donor right atrium to the recipient’s and the likelihood of tricuspid regurgitation. Thus, consideration should be given to excising excess right atrial tissue, particularly on the lower side of the anastomosis, without jeopardizing the sinoatrial node. Less commonly, mitral valve regurgitation has been observed, associated with the “snowman” configuration formed by the donor-recipient left atrial anastomosis.

During construction of the left atrial suture line, the orifice of the left pulmonary vein should be observed. Excessive protrusion of tissue from the suture line with an inverting technique can potentially obstruct pulmonary venous inflow and may also be thrombogenic. In extreme cases, surgically induced cor triatriatum secondary to anastomotic obstruction of pulmonary venous inlet has been reported.

Sinus node dysfunction occasionally occurs. Therefore, specific attention to avoiding damage to the sinoatrial node is important during harvesting and implantation. When using the biatrial technique, the ligature on the SVC should be placed 1 to 2 cm above the superior cavo–right atrial junction. The incision in the donor right atrium should be kept well above the sulcus terminalis to avoid damaging the sinoatrial node while constructing the lower right atrial suture line.

Kinking of the pulmonary trunk may occur if the length of the newly constructed pulmonary trunk is redundant. Therefore, care must be taken to trim sufficient donor and recipient pulmonary trunk to avoid redundancy after constructing the anastomosis. The newly constructed pulmonary trunk is particularly vulnerable with an oversized donor heart relative to the size of the recipient’s pericardial space. Redundancy that results in kinking of the pulmonary trunk can produce an important gradient across the pulmonary anastomosis with resultant severe right ventricular hypertension.

Adverse neurologic events can occur. Mural thrombus may be potentiated by an excessively inverting suture line, particularly in the left atrium. Effective and complete de-airing of the heart is extremely important to minimize the risk of cerebral air embolism. When systemic vascular resistance is low following heart implantation, flow rates during CPB must be adequate. Although the precise level of perfusion pressure and flow rate that contribute to neurologic events has not been clearly defined, systemic mean perfusion pressure should be maintained at 40 mmHg or greater during rewarming, with a perfusion flow rate of 4.2 to 4.8 L/min.

In the presence of important right ventricular dysfunction during rewarming, a second left atrial catheter is placed for infusion of inotropic agents, and prostaglandin E ₁ and other vasodilator agents can be infused into the central venous lines. If this is not successful and pulmonary hypertension is present, nitric oxide ^, can be used as an inhalational agent.

Usual care given to patients after cardiac surgery (see Chapter 4 ) is applied to patients who have received a cardiac transplant. Generally, subsystems function normally, and little or no special therapy is required. Cardiac function of the donor heart is usually good but is subject to influences of total denervation and the consequences of myocardial ischemia attending explant and transplant.

Atrial pacing can be used to maintain an appropriate heart rate for patient age and size. Generally, the effects of β-adrenergic agents are unchanged. Cardiac ischemia results in reduced diastolic compliance, so somewhat higher cardiac filling pressures may be required for optimal function. Impaired systolic function and contractility may also be observed, manifested by increased left atrial or pulmonary artery wedge pressure. Inotropic support is often required for 2 to 5 days, depending on the function of the donor heart.

Acute distention and failure of the right ventricle resulting from excessive right ventricular afterload are occasionally observed, most commonly in the presence of preexisting recipient pulmonary hypertension or reactive pulmonary vasoconstriction from CPB or protamine administration. Various agents may dilate pulmonary vasculature, but the most effective combination appears to be milrinone at 0.3 to 1 µg/kg/min and nitric oxide. When normal systolic and diastolic function is not achieved with discontinuation of CPB, primary graft dysfunction (PGD) is present, and special measures are indicated (see later section on “ Primary Graft Dysfunction ”).

Immunosuppressive modalities in transplantation are designed to reduce intensity of the immune response to a degree that allows acceptance of the allograft yet provides sufficiently low toxicity to permit prolonged survival. Pharmacologic agents have evolved from general suppression of the recipient’s immunologic defenses to selective blockade of intracellular immune events that maximize graft acceptance while minimizing toxicity.

Three situations require specific combinations of immunosuppressive therapies: (1) initial high-dose immunosuppression (known as induction therapy) to facilitate graft acceptance, minimize the chance of early rejection, and potentially favor induction of tolerance; (2) maintenance therapy for chronic acceptance of the allograft; and (3) augmented immunosuppression to reverse episodes of acute rejection. Specific immunotherapeutic modalities are being evaluated to prevent or reverse chronic rejection in the form of allograft vasculopathy.

The immune response to transplantation is highly dependent on T-cell activation and proliferation. The cellular events of T-cell activation are of great importance because many current immunosuppressive drugs target specific intracellular pathways of T-cell activation. A summary of modalities that interfere with specific phases of the allograft-induced immune response is given in Table 21.4 .

Antithymocyte globulin.

Antithymocyte globulin is a polyclonal anti-lymphocyte preparation containing variable amounts of specific antibodies directed against T-cell molecules. Antibodies with activity directed against HLA class I and II antigens as well as adhesion molecules (CD11a/C18) have been identified. Antithymocyte globulin is used clinically either as prophylactic induction therapy during the first 5 to 7 days after transplantation or as an immunosuppressive modality to treat recurrent or persistent rejection. In the presence of early renal dysfunction (particularly with serum creatinine in excess of 2 mg/dL), antithymocyte globulin can be substituted for the CNI until renal function stabilizes, which is usually within 5 days of transplant. The associated profound lymphopenia that results predisposes immunosuppressed patients to viral infections, particularly cytomegalovirus (CMV). Therefore, prophylactic valganciclovir should be administered following a course of antithymocyte globulin therapy. The current available commercial preparation in the United States is a rabbit antithymocyte globulin (Thymoglobulin). The reconstituted preparation contains 5 mg of Thymoglobulin, of which greater than 90% is rabbit gamma immune globulin. The standard dose of 1.5 mg/kg/day is infused through a central venous catheter over 4 to 6 hours and administered for 5 to 7 days. Clinical features and dosing of antithymocyte globulin are summarized in Table 21.4 .

Anti-CD25 (basiliximab).

Basiliximab is humanized IgG1 monoclonal antibodies that bind specifically to the α chain of the high-affinity IL-2 receptor on activated T lymphocytes. ^, These antibodies compete with the cytokine IL-2 for occupancy of the IL-2 receptor. Secretion of IL-2 by an activated T cell serves to recruit other T cells by stimulation and clonal expansion of a specific T-cell population. These anti–IL-2 receptor monoclonal antibodies are designed to be used with a calcineurin blocking agent (cyclosporine or tacrolimus) to decrease the amount of IL-2 that would be available for any unblocked IL-2 receptors. Clinical features and dosing of anti-CD25 monoclonal antibodies are presented in Table 21.4 .

Plasmapheresis.

Plasmapheresis involves removing blood from the patient, separating plasma by centrifugation or membrane filtration, and reconstituting the remaining blood to the original volume with fresh plasma or 5% albumin. In treating acute rejection, plasmapheresis has been effective in removing antibodies (antibody-mediated rejection) as well as soluble mediators potentially released during acute rejection, including IL-1, IL-6, TNF-α, and the anaphylatoxin C3a. Some of these mediators, such as TNF-α and IL-1, have a direct depressant effect on myocyte contractility, and improved ejection fraction following plasmapheresis has been observed frequently in the setting of hemodynamically compromising rejection.

The technique of plasmapheresis requires a large-bore indwelling catheter inserted into the internal jugular, subclavian, or femoral vein. Although complement-mediated reactions occasionally occur during plasmapheresis, side effects are generally mild. The potential for bleeding complications appears to be low as long as the fibrinogen level is maintained above 100 mg/dL. When used clinically to treat rejection with hemodynamic compromise, plasmapheresis is generally performed for 3 to 5 successive days as long as the fibrinogen level remains above 100 mg/dL. When anti-donor antibodies are identified in the recipient with cardiac dysfunction, plasmapheresis is also utilized.

Immunoadsorption.

Whereas plasmapheresis is a passive process in which immunoglobulins pass through the filtration membranes with the removed plasma, immunoadsorption involves removing specific antibodies using columns containing immunoadsorbents that specifically bind to immunoglobulins. Some centers use immunoadsorption techniques in the presence of recipient anti-HLA class I antibodies against the donor heart. Improved ejection fraction and decrease in PRA following acute humoral rejection have been reported with this therapy.

Photopheresis.

Photopheresis is an immunomodulatory therapy based on leukapheresis. It involves drawing blood, separating the whole blood by centrifugation, and returning the red cells and plasma to the patient. Leukocytes are treated with 8-methoxypsoralen, a photosensitizing agent, and exposed to ultraviolet light in the photoactivation chamber. These treated leukocytes are then returned to the patient ( Fig. 21.11 ).

Process of photopheresis. 8-MOP, 8-methoxypsoralen; UVA, ultraviolet light.

The mechanism of action of photopheresis has not been clearly delineated, but available evidence suggests that photopheresis induces apoptosis of leukocytes that, when reinfused into the patient, are phagocytized by dendritic cells in the circulation and in lymphoid tissue. The photoactivation process induces cross-linking of DNA, which is known to induce apoptosis ^, of lymphocytes, monocytes, macrophages, and B cells. Recent data suggest that virtually all cells become apoptotic following extracorporeal photopheresis, even terminally differentiated and slowly proliferating or nonproliferating cells such as antigen-presenting cells. Studies of extracorporeal photopheresis in a mouse heart transplant study by George and colleagues suggest that photopheresis alters the composition of recipient T lymphocytes toward a greater preponderance of T-regulatory cells, which promote down-regulation of graft-infiltrating T cells. In the mouse model, the majority of photopheresis-treated cells are phagocytized in the spleen and liver within 24 hours. Extracorporeal photopheresis reduces the infiltration of graft-specific T cells without affecting the frequency of graft-reactive T cells in the peripheral lymph nodes. Thus, based on these studies, extracorporeal photopheresis appears to alter the composition of recipient T cells toward a greater preponderance of T-regulatory cells, down-regulating a greater proportion of graft-infiltrating T cells.

A clinical study of photopheresis indicated that among patients at high risk for rejection, risk of hemodynamically compromising (potentially fatal) rejection or rejection death was substantially reduced following photopheresis therapy ( Fig. 21.12 ). These studies have generated the hypothesis that the apoptotic cells undergo phagocytosis by antigen-presenting cells. The phagocytized apoptotic cell fragments induce antigen-presenting cells to activate T-regulatory cells, which in turn induce down-regulation of T-effector cells against the allograft. The result is an increase in the proportion of natural regulatory T cells in the cardiac allograft.

Photopheresis benefit among 36 patients receiving photopheresis of 343 patients undergoing transplantation at University of Alabama at Birmingham (UAB) between 1990 and 2003. Vertical axis represents hemodynamically compromising (HC) rejections or rejection-related death per 100 patients · year ⁻¹ . The upper curve (“Pre-photo risk”) represents the hazard function for this event among high-risk patients for rejection prior to photopheresis. The next lower curve (“Post-photo risk”) represents the hazard function for this group of patients following photopheresis. The lowest curve represents risk of HC rejection or rejection death among patients at low risk for rejection. photo, photopheresis

(From Kirklin JK, Brown RN, Huang ST, et al. Rejection with hemodynamic compromise: objective evidence for efficacy of photopheresis. J Heart Lung Transplant . 2006;25:283-288.)

Antimicrobial prophylaxis after heart transplantation is an integral part of infection prevention, and the benefit has clearly outweighed the disadvantages (toxicity and antimicrobial resistance). A recommended antimicrobial prophylaxis for solid organ transplantation is outlined in Table 21.6 . Prevention of infection by active immunization is recommended for specific conditions, using killed vaccine only.

Survival at 1 year has gradually improved over the past several decades and currently approaches 91%. Risk of death is greatest during the first 3 months after operation. After 1 year, there is a constant mortality of about 4% per year. Survival at 5 years is approximately 70%, at 10 years 50%, and at 15 years 30% ( Fig. 21.13 ). ^, Median survival is 11 years. For patients alive at 1 year, median survival approaches 14 years. The most dramatic improvement in survival after heart transplantation over the past 25 years has been during the first 3 to 6 months. Despite the obvious importance of long-term survival to patients and their families, survival at 1 year has been a benchmark for comparison of institutions for survival outcomes.

Adult heart transplant survival by era. International Society for Heart and Lung Transplantation registry.

(Reproduced with permission from Khush KK, Potena L, Cherikh WS, et al. The International Thoracic Organ Transplant Registry of the International Society for Heart and Lung Transplantation: 37th adult heart transplantation report-2020; focus on deceased donor characteristics. J Heart Lung Transplant. 2020;39(10):1003-1015.)

The risk of cardiac transplantation decreased during the 1980s following introduction of cyclosporine and adoption of protocols that included triple-drug therapy. Further improvement in early and late survival after cardiac transplantation in recent eras has been attributed to more precise immunosuppression agents and regimens, less severe graft coronary disease, statin drugs, and better understanding of infection complications, with greater choice of antibiotic and antiviral agents.

Modes of death.

Mode of death during the first year and thereafter differs considerably and therefore merits separate discussion. During the first 12 months after transplant, early graft failure, infection, rejection, and multiorgan failure account for more than 70% of deaths ( Fig. 21.14 ).

Proportion of deaths from each identified cause at specified time periods after heart transplantation. International Society for Heart and Lung Transplantation registry. CAV, cardiac allograft vasculopathy; CMV, cytomegalovirus; PTLD, post-transplant lymphoproliferative disease.

(Reproduced with permission from Khush KK, Potena L, Cherikh WS, et al. The International Thoracic Organ Transplant Registry of the International Society for Heart and Lung Transplantation: 37th adult heart transplantation report-2020; focus on deceased donor characteristics. J Heart Lung Transplant. 2020;39(10):1003-1015.)

Recipient risk factors for death

General risk factors.

Among adult transplant recipients, multiple conditions or factors have been identified that are associated with increased risk of mortality during the first posttransplant year (see Figs. 21.15 and 21.16 , and Tables 21.8 and 21.9 ).

Adult heart transplants survival by recipient sex. International Society for Heart and Lung Transplantation registry.

(Reproduced with permission from Khush KK, Potena L, Cherikh WS, et al. The International Thoracic Organ Transplant Registry of the International Society for Heart and Lung Transplantation: 37th adult heart transplantation report-2020; focus on deceased donor characteristics. J Heart Lung Transplant. 2020;39(10):1003-1015.)

Adult Heart Transplants survival stratified by recipient age. International Society for Heart and Lung Transplantation registry.

(Reproduced with permission from Khush KK, Potena L, Cherikh WS, et al. The International Thoracic Organ Transplant Registry of the International Society for Heart and Lung Transplantation: 37th adult heart transplantation report-2020; focus on deceased donor characteristics. J Heart Lung Transplant . 2020;39(10):1003-1015.)

TABLE 21.8

General Risk Factors for 1-Year Mortality

Risk Factor • ECMO • Diagnosis CHD 1 • TAH 2 • Re-Tx 1 • RCM 1 • VAD 2 • VCM 1 • Prior cardiac surgery • ICM • Earlier Tx era • Older donor age • Older recipient age • Higher recipient BMI • Longer donor ischemic time • Reduced donor heart systolic function • Worse recipient liver function • Worse kidney function • Greater donor/recipient predicted heart size mismatch • Higher PRA • Higher PVR, mean PAP • Lower center transplant volume

Relative Risk 3 2.38 1.74 1.73 1.72 1.48 1.24 1.31 1.20 1.12 0.82

P -Value <.01 <.01 <.01 <.01 <.01 <.01 .02 <.01 .01 <.01 <.05 <.05 <.05 <.05 <.05 <.05 <.05 <.05 <.05 <.05 <.05

ECMO , extracorporeal membrane oxygenator; CHD , congenital heart disease; TAH, total artificial heart; Tx , transplant; RCM , restrictive cardiomyopathy; VAD , ventricular assist device; VCM , valvar cardiomyopathy; ICM , ischemic cardiomyopathy; BMI , body mass index; PRA , panel reactive antibody; PVR , pulmonary vascular resistance; PAP , pulmonary artery pressure

Histocompatibility and other patient-donor interactions.

Basic immunologic incompatibility between humans is a clear overall risk factor for premature death after cardiac transplantation. Survival after cardiac transplantation is highest among patients with a negative flow cytometry crossmatch to both HLA class I (T- and B-cell) antigens and HLA class II (B-cell) antigens. Risk of death appears to be less when the blood type of the recipient and donor is identical, but the effect is a weak one. There is evidence that donor and recipient gender do not affect outcomes, but when there is donor-recipient size mismatch (e.g., smaller female donor into larger male recipient), 1-year survival may be adversely affected. Improvement in survival that occurred when triple-drug immunosuppression began (≈1983) supports the idea that the immunologic response is a dominant determinant of outcomes.

Preoperative status of the patient.

Patients whose cardiac output is importantly depressed before operation are at increased risk of death after transplantation. When organ dysfunction is substantial and does not recover from the effects of the low cardiac output state sufficiently rapidly after transplantation, mortality is markedly increased. The kidney is particularly vulnerable to even brief periods of low cardiac output. The lung also appears to recover slowly from preoperative damage. Being on a ventilator up to the time of transplantation is a risk factor for death after transplantation. When inotropes or mechanical circulatory assistance before transplantation bring the patient to operation in a reasonably good hemodynamic state, survival is similar to that of other cardiac transplant recipients. Nevertheless, having an LVAD implanted before cardiac transplantation raises the risk of death during the first year by about 25% ( P =.02).

Elevated pulmonary vascular resistance.

High Rp has also been a risk factor for death, usually early after transplantation. The nature of the relationship between elevated Rp (or increasing transpulmonary gradient) and mortality risk is a continuous one, with progressive increase in risk as Rp rises. Preoperative response of Rp to vasodilator therapy has additional predictive value. ^, (For details of Rp, see earlier section Recipient Evaluation and Selection .)

Donor risk factors.

A number of donor characteristics are associated with increased risk following heart transplantation. Generally, these factors tend to demonstrate cumulative or additive risk so that use of a donor organ with multiple risk factors (i.e. “stacking of risk factors”) is associated with worse outcome than utilizing a donor organ with fewer or no risk factors. Utilizing a donor heart with reduced left ventricular function may have only a minor risk on posttransplant outcomes, however, when utilized in the setting of an older donor, prolonged ischemic time, and older recipient, significantly more risk is encountered. Matching unfavorable donor characteristics with favorable recipient characteristics can frequently mitigate donor risks factors. For example, selecting an older donor in a circumstance associated with a very short ischemic time and younger recipient could mitigate the risk of use of the older donor heart organ.

Age.

Donor age is an important risk factor influencing the outcomes associated with heart transplantation ( Fig. 21.17 ). Older donor hearts, typically above 50 years of age, present challenges that can impact transplant outcomes. Age-related changes in the cardiovascular system, such as increased prevalence of coronary artery disease, myocardial fibrosis, increased susceptibility to ischemic injury and reduced myocardial contractility, may compromise the function of the donated heart. These age-associated structural and functional alterations can increase posttransplant complications including PGD, early graft failure, a higher risk of acute rejection, and higher incidence of cardiac allograft vasculopathy at 5 years (RR 1.67). Careful evaluation of the older donor organ including coronary angiogram and echocardiogram is necessary to exclude contributing risk factors. Selective use of older donors is associated with satisfactory posttransplant outcomes and increasing the donor pool of heart organs.

Adult heart transplants survival by donor age. International Society for Heart and Lung Transplantation Registry.

(Reproduced with permission from Khush KK, Potena L, Cherikh WS, et al. The International Thoracic Organ Transplant Registry of the International Society for Heart and Lung Transplantation: 37th adult heart transplantation report-2020; focus on deceased donor characteristics. J Heart Lung Transplant . 2020;39(10):1003-1015.)

Left ventricular dysfunction.

Approximately 20% of donor hearts are discarded exclusively due to the presence of left ventricular dysfunction. Left ventricular dysfunction of the donor heart organ is associated with greater risk following heart transplantation, and the risk is proportional to the degree and etiology of the left ventricular dysfunction. Reversibility of left ventricular dysfunction in a donor heart, both before and following transplantation, largely depends on the underlying causes and the extent of injury to the donor heart. Brain death can contribute to left ventricular dysfunction in the donor organ that can improve prior to procurement with proper donor management or can additionally improve following procurement and transplantation. Identifying circumstances where reversibility of poor donor heart function is likely is key to mitigating the risk of left ventricular dysfunction in the donor organ. Although some data suggest that the risk of utilizing donors with left ventricular dysfunction is low, few hearts with significantly impaired left ventricular dysfunction are utilized for transplantation, and hearts with left ventricular dysfunction accepted for transplantation are likely a selected group of donors with other favorable features such as younger donor age and lack of medical comorbidities.

Left ventricular hypertrophy.

The use of donor hearts with left ventricular hypertrophy (LVH) has demonstrated varying degrees of risk in terms of recipient outcomes. Kuppahally and colleagues reported that recipients of donor heart with LVH > 1.2 cm had worse survival and higher incidence of cardiac allograft vasculopathy. Pinzon and colleagues reviewed the UNOS database between 2006 and 2010 with almost 3000 recipients and stratified donor heart into groups without LVH (<1.1 cm), with mild LVH (1.1 to 1.3 cm), and moderate-severe LVH (>1.4 cm). These authors observed similar 30-day and 1-year survival across recipients from all three groups. However, hearts from donors with additional risk factors such as older age or prolonged cold ischemic time (>4 hours) have worse survival, suggesting an interaction between LVH and other donor risk factors. The 2020 ISHLT guidelines for the care of heart transplant recipients state that using hearts from donors with LVH with wall thickness <1.4 cm and without accompanying ECG findings of LVH may be appropriate (Class IIa recommendation).

Donor biomarkers.

Donor biomarkers are not routinely used in donor selection. Some biomarkers, however, are obtained during the donor evaluation. Troponin levels correlate to the degree of myocardial necrosis. The catecholamine surge associated with brain death may cause transient myocardial ischemia and injury, resulting in elevated cardiac troponin levels. Troponin levels in donors with subarachnoid hemorrhage were found to be elevated and were associated with left ventricular dysfunction. However, the left ventricular dysfunction was largely reversible and was not associated with posttransplant outcomes. ^, A study of the UNOS database showed that receipt of a donor heart with an elevated troponin level in the context of preserved left ventricular function was not associated with PGF, CAV, or mortality.

Cocaine use.

Whether use of cocaine as part of the donor history increases the risk of posttransplant outcomes remains controversial. Guidelines from the International Society for Heart and Lung Transplantation support that hearts from donors with a history of cocaine use can be used for transplantation, provided that cardiac function is normal and ventricular hypertrophy is absent. However, many transplant centers decline cardiac allografts from overdose-death donors due to concerns over risk for coronary artery spasm, myocardial ischemic and myocarditis. Data, however, suggest that the use of donors with a history of cocaine use does not result in worse outcomes after heart transplantation including risk of cardiac allograft vasculopathy and allograft rejection. The prevalence of donors with a history of cocaine use has increased from 11% to 27% of the total donors available for transplantation from 2000 to 2018, thus carefully selected use of these donors is warranted to increase the donor pool.

Coronary artery disease.

Donor heart organs with coronary artery disease are generally not utilized for heart transplantation, limiting analyses of the impact of this characteristic on posttransplant outcomes. A recent study from Spain identified that a total of 18.3% of heart transplant recipients received donor organs with evidence of coronary artery disease, with 6.9% having significant coronary artery lesions ≥50%, and 11.4% having nonsignificant coronary artery lesions. Multivariable Cox regression did not demonstrate a statistically significant association between significant coronary artery disease and all-cause mortality; however, significant coronary artery disease was an independent predictor of cardiovascular mortality and the combined event cardiovascular death or nonfatal major adverse cardiovascular events. No statistically significant impact of nonsignificant coronary artery disease on clinical outcomes was detected.

Infection.

Hearts from donors with bacteremia can be used if (1) the donor has received 24 to 48 hours of antimicrobial therapy leading to cleared cultures, (2) the donor has normal myocardial function, and (3) there is no evidence of endocarditis in direct evaluation of the donor heart. Recipients of hearts from donors with bacteremia should receive a course of antimicrobial therapy. It is essential that a transplant infectious diseases specialist be involved in all cases of donor bacteremia, especially when there is a multidrug-resistant donor isolate. Recently, treatment for hepatitis C viremia has been curative and therefore these donor hearts have been utilized for transplantation. In heart donors with positive hepatitis C viremia, a hepatitis C virus (HCV)-specific informed consent should be obtained from the recipient. In such circumstances, the recipient should be monitored and treated according to established guidelines. Hearts from donors with encephalitis with unknown etiology should not be used for transplantation. US Public Health Service (PHS) guidelines have established criteria during the 30 days before organ procurement that indicate a donor to be at risk for HIV, HCV, or hepatitis B virus (HBV) infections.

Ischemic time (donor heart).

With current techniques of donor heart preservation, global myocardial ischemic time does not become an important risk factor until it exceeds approximately 240 minutes. Risk of death is increased considerably with ischemic times of 5 to 6 hours. Speculatively, the explanation for the much longer safe ischemic time in the setting of cardiac transplantation than in reparative cardiac surgery may be the uniformly cold temperature of the globally ischemic donor heart and possibly its complete lack of collateral circulation. Currently, a number of preservation solutions are available that have demonstrated comparable preservation effectiveness (see the section on “ Donor Heart Preservation ”). ^, Strategies for the initial phase of reperfusion may further increase safe ischemic time of donor hearts.

Alternative strategies to static cold preservation that include ex vivo machine perfusion have demonstrated safe preservation of heart organs and are potentially expanding the donor heart organ pool (see section on “ Donor Heart Preservation ”).

The TransMedics Organ Care System (OCS)™ system has undergone a number of clinical trials to validate the technology. This platform was first examined in the PROTECT I trial (Prospective Multi-Center European Trial To Evaluate the Safety and Performance of the Organ Care System for Heart Transplants), a single-arm study done in four centers in England and Germany, which demonstrated safety among 20 hearts transplanted out of 25 hearts instrumented on OCS from 2006 to 2007. The PROTECT II trial followed in 2007 to 2008, although results have not been formally published. The OCS has subsequently been CE marked for use in the European Union. The US-based PROCEED II (Randomized Study of Organ Care System Cardiac for Preservation of Donated Hearts for Eventual Transplantation) trial demonstrated noninferiority of outcomes for 67 transplants transported with the OCS platform relative to 63 cold static storage control cases. The US trial was a randomized trial limited to low-risk heart transplant cases. Both PROCEED II trials reported comparable short-term outcomes. Further analysis of a subset of the PROCEED II participants showed no significant difference in outcomes with OCS at 2 years. Further clinical testing was performed in the US-based EXPAND (International Trial to Evaluate the Safety and Effectiveness of The Portable Organ Care System Heart For Preserving and Assessing Expanded Criteria Donor Hearts for Transplantation) trial, which analyzed high-risk transplants with anticipated prolonged ischemic times (>4 hours) or marginal donor heart features (left ventricular hypertrophy, ejection fraction of 40% to 50%, donor downtime >20 minutes, donor age >55 years). The short-term results of the EXPAND trial were presented in 2019, showing excellent short-term outcomes in 75 patients transplanted from a total of 93 hearts recovered and perfused on OCS. The primary endpoint in EXPAND was freedom from death or severe PGD; the study cohort exceeded a predetermined historical performance measure to demonstrate noninferiority. A more recent clinical study of the use of the TransMedics OCS system in DCD heart donors demonstrated noninferiority of use of DCD organs compared to traditional brain-dead organ donors.

In addition to normothermic ex vivo perfusion, platforms for cardiac preservation employing hypothermic oxygenated perfusion have also been evaluated in the clinical setting. Recently a nonrandomized, single-arm, multicenter investigation of hypothermic oxygenated perfusion using the XVIVO Heart Preservation System on donor hearts with a projected preservation time of 6 to 8 hours on 30-day recipient survival and allograft function posttransplant was conducted. Each center completed one or two short preservation time followed by long preservation time cases. PGD was classified as occurring in the first 24 hours after transplantation or secondary (SGD) occurring at any time with a clearly defined cause. Trial survival was compared with a comparator group based on data from the International Society for Heart and Lung Transplantation registry. A total of 7 short and 29 long preservation time donor hearts were placed on the XVIVO system. The mean preservation time for the long preservation time cases was 414 minutes, the longest being 8 hours and 47 minutes. There was 100% survival at 30 days. One long preservation time recipient developed PGD, and one developed SGD. One short preservation time patient developed SGD. Thirty-day survival was superior to the ISHLT comparator group despite substantially longer preservation times in the trial patients.

Some degree of PGD is common after cardiac transplantation, with a reported incidence of 2% to 30%, depending on specific definitions. In current practice, the actual incidence is likely closer to 5% to 15%. Although by definition, PGD can occur anytime within the first 24 hours posttransplant, in reality it is nearly always apparent in the operating room. PGD should be considered separately from SGD, resulting from rare hyperacute rejection, pulmonary hypertension, surgical complications, or rarely sepsis. Mild PGD usually responds well to low or moderate doses of inotropic support and rapidly resolves. Whether this is a manifestation of reperfusion injury or another aspect of suboptimal myocardial preservation is unclear, but recovery of normal systolic function and cardiac output within 6 to 12 hours is usually accompanied by normal convalescence. However, moderate PGD (identified when LV ejection fraction is <0.40, CVP >16, pulmonary capillary wedge pressure (PCWP) >20, and evidence of low cardiac output despite multiple inotropes) indicates a more serious condition, and may involve one or both ventricles. The reported incidence is about 10% with current preservation techniques, with associated 30-day mortality approaching 6% (compared to <1% with normal transplant function).

Moderate or worse PGD is usually apparent in the operating room prior to discontinuation of CPB. In this situation, CPB should be continued while allowing the heart to further recover. If reperfusion injury has occurred, isolated firm areas on the posterior or lateral left ventricle (LV) may be felt. All anastomotic sites should be inspected both visually and by TEE to verify the absence of important gradients that could contribute to dysfunction. Of special importance is examining the gradient across the pulmonary artery anastomosis and both caval anastomoses with the bicaval technique. If the right ventricle (RV) is primarily involved, the possibility of air in the right coronary artery should be considered. The heart should be reinterrogated with TEE to check for residual air in the LV, and if present further de-airing is indicated. If small air bubbles are apparent in the right coronary artery, transiently increasing perfusion pressure with pharmacologic agents may help air pass through. Direct measurement of RV and pulmonary artery pressures identifies the presence of any important gradient, which if present, should be corrected. If pulmonary arterial hypertension is identified, inhaled nitric oxide is initiated. In the absence of tachycardia, isoproterenol is a potent inotropic agent that favorably affects pulmonary vascular resistance.

When moderate PGD persists after resting the heart on extended bypass, an IABP should be inserted to augment coronary blood flow and provide some increment in cardiac performance. Simultaneously, anesthesia colleagues will be correcting any acid-base derangement, optimizing calcium concentrations, and infusing combinations of vasoactive inotropes and vasodilators to target specific areas of derangement.

When right ventricular dysfunction continues to be the most prominent feature despite the interventions discussed earlier, insertion of a catheter directly into the left atrium can provide a short term site of infusion of catecholamines such as epinephrine or dopamine, which can promote pulmonary vasoconstriction if infused directly into a large systemic vein. Agents which reduce pulmonary vascular resistance can then be infused into the central venous catheter. When considerable inotropic support is required, this strategy, for the short term, can support blood pressure and cardiac output while minimizing the deleterious effects of such agents on pulmonary vasculature. An IABP further supports the peripheral perfusion pressure.

When these interventions don’t provide adequate support of systemic perfusion and atrial pressures remain elevated, severe PGD is present, which occurs in <4% of transplants, with mortality approaching 50%. In that situation, prompt consideration should be given to initiating ECMO support in the operation room, while reducing or eliminating inotropic agents which increase myocardial oxygen consumption. If the dysfunction is confined to the RV, a temporary right ventricular assist device is indicated as long as left ventricular function is preserved and oxygenation is adequate. When ECMO support is required, renal and hepatic dysfunction often follow, particularly when there is a delay of hours in the intensive care unit before initiation. However, early initiation of ECMO in the operating room is associated with reduced mortality, particularly if cannulation is uncomplicated, bleeding is well controlled, and subsystem function is maintained until cardiac recovery.

The risk factors for early mortality discussed in previous sections are generally the same factors that predict early severe PGF because major dysfunction of the transplanted heart is the major cause of early mortality.

Urgent retransplantation has been employed extensively in the past for patients with severe PGD, but the results have been generally poor. Thus, urgent retransplantation is not a suitable salvage strategy for PGF and should currently only be offered in the rare situation of PGD and ongoing MCS with preserved non-cardiac organ function, no ongoing bleeding, and stable hemodynamics on support (see later section on “ Cardiac Retransplantation ”). ^,

PGD must be clearly distinguished from isolated vasoplegia syndrome after heart transplantation, characterized by low peripheral vascular resistance in the setting of normal graft function. Although precise definitions are lacking, the incidence of mild or worse vasoplegia exceeds 30%, but only about 25% of cases are moderate to severe, as judged by the requirement for multiple vasopressors to maintain blood pressure despite normal graft function. ^, The specific etiology is unknown, but risk factors include prior continuous flow LVAD support, older age, chronic renal disease, and prolonged duration of CPB. Large infusions of vasoactive drugs such as vasopressin or Neo-Synephrine and IABP support are required to maintain a low normal blood pressure. However, in contrast with PGD, cardiac allograft function remains normal by TEE. More severe forms of vasoplegia have been associated with longer-term continuous flow LVADs. The syndrome generally resolves in 6 to 12 hours. If properly managed, it is not associated with increased early mortality, although patients typically experience longer intubation, greater blood product administration, and longer hospital stay.

The frequency of rejection episodes tends to decrease with increasing time from transplantation, related in part to the acquired state of partial unresponsiveness achieved with current maintenance immunosuppression ( Figs. 21.18 and 21.19 ). Up to 25% of patients have one or more identified rejection episodes within the first year. Although treatment modalities for acute rejection have greatly improved in recent years, rejection continues to be an important cause of early and midterm mortality, particularly if accompanied by hemodynamic compromise.

Incidence of acute rejection by 1-year posttransplant among adult heart transplant recipients by age, 2015-2016. The bars indicate the percentage of patients with rejection. International Society for Heart and Lung Transplantation registry.

(Reproduced with permission from Khush KK, Potena L, Cherikh WS, et al. The International Thoracic Organ Transplant Registry of the International Society for Heart and Lung Transplantation: 37th adult heart transplantation report-2020; focus on deceased donor characteristics. J Heart Lung Transplant . 2020;39(10): 1003-1015.)

Incidence of acute rejection by 1-year posttransplant among adult heart transplant recipients by induction status, 2015-2016. International Society for Heart and Lung Transplantation registry. RA , receptor antagonist; TCD , T-cell depletion.

(Reproduced with permission from Khush KK, Potena L, Cherikh WS, et al. The International Thoracic Organ Transplant Registry of the International Society for Heart and Lung Transplantation: 37th adult heart transplantation report-2020; focus on deceased donor characteristics. J Heart Lung Transplant . 2020; 39(10):1003-1015.)

Antibody mediated rejection (AMR).

AMR develops when recipient antibody is directed against donor-HLA antigens (and less so non-HLA antigens) on allograft endothelium, starting the complement cascade and inflicting tissue injury via inflammatory pathways. ^, Immunopathologic review can be used to diagnose AMR, which is classified into three severity levels. Intravascular macrophage accumulation within dilated capillaries and venules, as well as enlarged nuclei and expanded cytoplasmic projections within endothelial cells that may constrict or even obstruct the vessel lumen, are histopathologic characteristics of AMR. Signs of hemorrhage, interstitial edema, myocyte degeneration and necrosis, mixed inflammatory infiltrates, and endothelial cell pyknosis/karyorrhexis may be present in more severe cases. The immunopathologic component of AMR constitutes the application of a panel for different antibodies (including C4d, CD68, and anti-HLA-DR) using immunohistochemistry from paraffin sections or immunofluorescence from frozen graft sections. Based on the combination of these results, an overall pathologic AMR (pAMR) grade is assigned to the biopsy.

A consensus report on the identification and categorization of AMR in pathologic specimens was released by the ISHLT in 2013. In accordance with an ISHLT pAMR format, it includes histopathologic and immunopathologic findings that are reported as pAMR.

Histologic AMR (ISHLT grading scale) is classified into three levels of severity based on immunologic and histopathologic criteria: pAMR1(H+) or pAMR1(I+), pAMR2, and pAMR3.

The criteria for reporting the AMR grades are listed in Table 21.11 .

TABLE 21.11

ISHLT Grading Scale for Acute Antibody-Mediated Rejection

ISHLT2022

ISHLT Grading Scale for Acute Antibody-Mediated Rejection

• pAMR 0—negative for pathologic AMR: histopathologic and immunopathologic studies are both negative • pAMR 1 (H+)—histopathologic AMR alone: histopathologic findings present and immunopathologic findings negative • pAMR 1 (I+)—immunopathologic AMR alone: histopathologic findings negative and immunopathologic findings positive; that is, CD68+ and/or C4d+ for IHC and C4d+ with or without C3d+ for IF • pAMR 2—pathologic AMR: histopathologic and immunopathologic findings are both present • pAMR 3—severe pathologic AMR: interstitial hemorrhage, capillary fragmentation, mixed inflammatory infiltrates, endothelial cell pyknosis, and/or karyorrhexis and marked edema and immunopathologic findings are present

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