Brain death is a hostile environment for the heart and consequent donor heart dysfunction may preclude use of the donor heart or contribute to the 20 % incidence of primary graft failure following cardiac transplantation. The causes of donor heart dysfunction can be conceptualized into two phases: those occurring with the Cushing response and those following dissipation of the Cushing response (Fig. 4.6).

The Cushing response is a “catecholamine storm” inducing hypertension, tachycardia, intense vasoconstriction, and an increase in myocardial oxygen demand, resulting in myocardial ischemia. The injury to the myocardium results in a phenomenon known as myofibrillar degeneration (which is also known as contraction band necrosis or coagulative myocytolysis) which is distinct from the coagulation necrosis seen in acute myocardial infarction. Myofibrillar degeneration is characterized histologically by the death of myofibers in a hypercontracted state with obvious contraction bands. The other important histological feature that may be seen is a mononuclear cellular infiltrate, which is evidence of the intense inflammatory response known to be activated with brain death. There are experimental studies [18, 19] that have detected upregulation of cytokines, chemokines, adhesion molecules and immunoregulatory molecules after brain death, which occur along with leukocyte activation. All of these likely have a role in endothelial cell injury and activation. When this period of intense sympathetic activity is dissipated, there is loss of sympathetic tone with a massive reduction in systemic vascular resistance contributing to the second phase of potential myocardial injury. This phase of injury can be conceptualized as abnormal loading conditions and coronary perfusion [20]. Intervention and donor management in this phase, offers some hope of retrieving donor hearts that would ordinarily have been lost. There is experimental evidence that if coronary perfusion pressure is decoupled from aortic pressure and returned to pre-brain death levels, coronary blood flow and myocardial contractility can also be restored [20]. The exact mechanisms of how the loading conditions and coronary perfusion down-regulate myocardial contractility are not completely clarified, but may occur through the Frank-Starling mechanism or other less well-characterized mechanisms such as the Anrep effect [21, 22] (maintenance of optimal stroke work over a range of afterload conditions controlled through cellular mechanism) and the garden hose effect [23, 24], which has been described in isolated heart preparations. This effect refers to the relationship between increased coronary perfusion pressure and increased contractility by direct intramyocardial vessel stretch and this mechanism may possibly come into play at a level of coronary perfusion pressure below which autoregulation is no longer operational.

Following declaration of brain death and obtaining consent, the process of determining suitability for cardiac donation is allowed to proceed. The screening process [25] (Table 4.5) has a number of goals. The general organ donation screening is to prevent the transmission of malignancies or the transmission of viral disease such as hepatitis B and C and HIV infection. Although it is generally considered that transplantation of hearts from donors who have died of primary brain tumors is safe (based on the very low incidence of extra neural spread of these tumors), transmission of primary brain tumors to a recipient has indeed been reported and for that reason organs from donors with CNS tumors of high grade malignancy should probably not be used [26]. The current recommendation [27] for the use of hearts from donors with severe infection is that they can be used provided [1] the donor infection is community acquired and death occurs within 96 h of the onset of the infection [2], repeat blood culture before organ procurement are negative [3], pathogen-specific antimicrobial therapy is administered to the donor [4], donor myocardial function is normal [5], there is no evidence of endocarditis by direct inspection of the donor heart. Exclusion of coronary artery disease (CAD) is necessary in cardiac donor males older than 40 years and females older that 45 years, although these age criteria may vary depending on the presence or absence of risk factors for CAD.

The determination of the adequacy of cardiac function should be delayed until hemodynamic stability has been obtained. Many donors have deranged loading conditions due to the very low systemic vascular resistance together with a low preload associated with the aggressive diuresis often used to control cerebral edema prior to progression to brain death and/or diabetes insipidus following brain death. As a consequence, these donor are often on high-dose adrenergic support, which, with optimization of loading conditions, can be rapidly weaned. At that stage, the echocardiogram has become the most useful test to evaluate left and right ventricular systolic function.

A number of biomarkers have been investigated as a means of discriminating donor hearts that should or should not be used for transplantation because of the possibility of post-transplant graft failure. Biomarkers that have been investigated include cardiac-specific troponins (cTnI and cTnT), TNF-α, IL-6, procalcitonin and B-Type naturetic peptide. These molecules reflect different aspects of the impact of brain death such as myocardial injury, myocardial wall stress and the pro-inflammatory environment of brain death but none have been found to be sensitive or specific enough to be useful [28].

Early graft failure represents an important cause of morbidity and mortality after cardiac transplantation and is impacted by a number of donor heart factors. However, when making a decision about the suitability of a particular donor these factors cannot be considered in isolation since they are all inextricably interrelated. Furthermore, the use of a donor heart with factors that may impair post-transplant function must always be considered in the context of the condition of the recipient and the urgency of transplantation.

A relationship exists between older donor age and the probability of graft failure and this risk is further exacerbated by increasing ischemic time (Fig. 4.7) [29]. This effect is no doubt related to the overall decline in myocardial reserves associated with increase in age. Even though this information is from an earlier era in transplantation, the same relationship between ischemic time and donor age and it’s impact on survival after cardiac transplantation has been consistently demonstrated [30]. In general, the ischemic time should be less than 5.5 h. Excessive inotropic support (dopamine at a dose of 20 mcg/kg/min or similar doses of other adrenergic agents) contraindicates the use of the heart if these inotropic drugs are required despite optimization of filling pressures. A discrete wall motion abnormality on echocardiography increases the risk of early graft failure and such a donor heart should not be used [31]. The effect of discrete wall motion abnormalities becomes increasingly pronounced with older donor age (Fig. 4.8) [31]. The development of severe concentric left ventricular hypertrophy following cardiac transplantation is a clear independent risk factor for cardiovascular and all cause mortality [32, 33], and this hypertrophy may develop for a number of reasons including post-transplant hypertension and immunosuppression. There is compelling evidence that commencing the post-transplant course with a hypertrophied donor heart also negatively impacts survival. A donor heart left ventricular wall thickness of greater than 1.4 cm is associated with reduced survival and this has been demonstrated both in a univariate analysis (Fig. 4.9) and in a multivariable model [34]. Furthermore, the impact of donor left ventricular hypertrophy on survival worsens with increasing donor age and increasing ischemic time [35].

Donor hearts with potential toxicity have been considered for transplantation. Cocaine abuse has direct effects on the heart, which include vasoconstriction, endothelial dysfunction, and myocardial toxicity. These effects have been principally related to the intravenous use of cocaine and hearts from such donors are currently regarded as unsuitable for transplantation. However, donors with a history of non-intravenous cocaine abuse who have normal left ventricular systolic function with no evidence of left ventricular hypertrophy are currently considered suitable [36].

There are direct toxic effects of alcohol on the myocardium and recipients who have received hearts from donors with a history of significant alcohol abuse have inferior survival. Hence, if a strong history of chronic alcohol abuse can be elicited, currently hearts from these donors are not used for cardiac transplantation [37]. However, it should be mentioned that there is not unanimity in the information on this issue and there is evidence [38] that suggests the exact opposite, that donor chronic alcoholism may, in fact, have a protective effect on donor hearts. Because of the finding that this protective effect may translate into superior recipient survival to that over recipients receiving hearts from non-alcoholic donors, it has been suggested that it is safe to use donor hearts regardless of a history of alcoholism.

Use of hearts from donors dying from carbon monoxide poisoning is still contentious [39]. However, use of hearts from such donors is probably safe, provided the electrocardiogram and echocardiogram are normal with minimal elevation of cardiac markers, and minimal inotropic requirements.

Transplantation of hearts from hepatitis C positive donors to hepatitis C negative recipients is associated with substantially inferior survival and this strategy cannot be recommended. However, transplantation of hearts from hepatitis C positive donors to hepatitis C recipients may be considered.

In order to increase the number of available donor hearts, a number of donor conditions may still be considered compatible with successful transplantation.

Donor CAD is not necessarily a contraindication to transplantation and coronary bypass surgery has been utilized on donor hearts. This concept of matching “recipients who would not ordinarily meet criteria for cardiac transplantation or retransplantation” to “marginal” donor hearts has given rise to the concept of the “alternate list” [40]. Survival of recipients with donors hearts that have undergone coronary bypass surgery appears to be very acceptable [41].

Although supplying only a very small number of donor hearts, the “domino procedure” (the use of a heart from a heart/lung transplant recipient) appears to provide just as good survival as the use of cadaveric donors [42].

Donor–recipient size matching should not be considered in isolation from other factors such as donor age and acuity of the transplant procedure. The use of hearts from donors whose body weight is no greater that 30 % below that of the recipient is generally considered safe. The heart from a male donor of average weight (70 kg) may be considered for any recipient of equivalent or greater weight, provided donor age is taken into account. Undersizing with older donors age is clearly associated with an increased risk [43], and certainly this information would argue against the use of small hearts from an older donor to “rescue” a critically ill recipient.

Sensitization due to the development of antibodies directed against human leukocyte antigens (HLA) is a major problem for heart transplantation and is associated with an increased risk for hyperacute rejection, acute rejection (cellular and antibody mediated), graft dysfunction, graft loss and development of coronary allograft vasculopathy. Sensitization may occur because of previous pregnancy, transfusion, previous transplantation and the use of homograft tissue that may be employed in correction of, for example, congenital heart disease. Desensitization strategies have been used with mixed results and the removal of donor specific antibodies at the time of transplantation does not necessarily prevent a memory immune response. There are a number of factors that dictate the impact of donor specific HLA antibodies on the transplanted heart (Fig. 4.10). However, there seems to be little doubt that if HLA donor specific antibodies activate complement that it is potentially very damaging to the transplanted heart. There are a number of ways of avoiding a cardiac transplant in the presence of donor specific antibodies. The complement-dependent cytotoxicity (CDC) crossmatch is the classic test which involves mixing potential recipient serum with donor T and B lymphocytes together in the presence of complement. The T-cell crossmatch generally reflects antibodies to HLA class I (expressed on all nucleated cells) and the B-cell crossmatch reflects HLA class I and II (class II expression is restricted to dendritic cells, macrophages and B-cells). There has been a move away from the CDC crossmatch to flow cytometry crossmatching which is more sensitive for detecting donor specific antibodies compared with the CDC crossmatch. A positive flow crossmatch in the presence of a negative CDC crossmatch suggests a non-complement fixing antibody, a non-HLA antibody or a low level antibody [45]. The development of solid phase matrices (beads) coated with HLA antigens has allowed the detection and identification of HLA-specific antibodies in a potential recipient. These HLA-specific antibodies can then be compared with the HLA typing of the prospective donor, a strategy known as the virtual crossmatch. Virtual crossmatching is of particular importance to cardiac transplantation where donor lymphocytes may not be available for a CDC or flow crossmatch because of time constraints and the donor being at a remote location. The accuracy of virtual crossmatching and its ability to increase the access of sensitized patients awaiting heart transplantation to potential donors has been demonstrated [46–48].

Myocardial preservation during cardiac transplantation is vitally important. Biochemical derangements induced during the ischemic process may contribute to primary graft failure, and preservation strategies that improve post-transplant graft function may allow longer ischemic times and the use of marginal donor hearts, with greater confidence that post-transplant function will be satisfactory. Biochemical processes involved in myocardial preservation are complex, but the primary methods of achieving cellular and functional integrity of the myocardium are through hypothermia and mechanical arrest of the heart. The role of hypothermia is based on the observation that in mammalian enzyme systems there is an approximately 50 % reduction in enzymatic reactions for every 10 °C decline in cardiac temperature, which decreases but does not eliminate cellular activity completely [49]. Even though the heart is mechanically arrested, ATP is still being consumed at a low level to allow breaking of actin-myosin cross-brides. If ATP depletion continues below a threshold level, irreversible contracture will occur. Although the myocardium can use stored glycogen to produce ATP by anaerobic glycolysis to maintain an ATP level above the critical threshold, once contracture commences ATP consumption markedly increases. The maintenance of ion homeostasis is also an important requirement of preservation. Even though with hypothermia Na⁺/K⁺ ATPase activity is markedly reduced, passive ion movement will still occur down a concentration gradient. As a result, intracellular H⁺ ions are exchanged for extracellular Na⁺ ions, and Ca²⁺ ions are also exchanged for Na⁺. This produces an increased intracellular solute accumulation with water entering the cell down an osmotic gradient, and this intracellular edema may result in disruption of structural integrity. It is the accumulation of Ca²⁺ in the cytoplasm that may, on reperfusion, result in hypercontracture [50].