Moving Beyond the Ice Age in Heart Transplant Procurement

There is nothing like looking, if you want to find something. You certainly usually find something, if you look, but it is not always quite the something you were after. —J.R.R. Tolkien With the advent of effective immunosuppression, heart transplantation has become the preferred modality for the treatment of eligible patients with end-stage heart failure. The supply of appropriate donor organs has been insufficient to meet the burgeoning demand. One of the aspects of this procedure, which was largely unchanged during the past 50 y, was the use of ice-cold preservation solutions, including the use of various additives to slow the metabolism of the donor heart. This "ice age" has served patients and the field well and allowed advancements in surgical technique and medical management to optimize outcomes for heart transplant recipients. Such ice storage is limited to at most 4–6 h without severe injury to the allograft, and therefore, this limits heart transplants to a narrow geographic range and engenders significant expense for air transportation. Growing heart transplant volumes in a significant way will require new innovative approaches to match donor organs with the recipients who need them regardless of location. Recently, donation after circulatory determination of death (DCD) donors have been used for heart transplantation, and various ways have been developed to preserve these hearts after the death of the donor, including direct procurement and preservation (DPP) with a system such as the Transmedics Organ Care System (OCS), and more recently XVIVO's Hypothermic Oxygenated PErfusion (HOPE) system.1-3 These techniques take a donor heart that is not functioning (asystolic) and transfer it to a perfusion system) where it is perfused with warm (Transmedics OCS) or cold (XVIVO HOPE) solutions. Another approach is to restore circulation in the donor's body after death has occurred (excluding the cerebral circulation) with an extracorporeal membrane oxygenation circuit (known as normothermic regional perfusion [NRP]). This technique allows heart function to recover and metabolic abnormalities to resolve for a time, followed by a transition to transport storage. Choices for transport include OCS, HOPE, or simple melting ice and preservation solutions—static cold storage). There are issues with the new modalities of organ preservation, including the ethical potential issues with restoring cardiac function in the body of a dead donor and the costs associated with the OCS and HOPE devices.4-6 In addition, there is a finite incidence of primary cardiac graft dysfunction regardless of mode of preservation and ischemia/reperfusion injury (IRI) is central to this phenomenon. Despite our efforts to minimize ischemic damage, donor organs will still experience IRI during transplantation. Hence, in addition to interventions aimed at minimizing ischemic injury, accurately predicting the function and quality of organs remains crucial. The process of IRI involves immune activation, mitochondrial dysfunction, and oxidative stress in a complex cascade.7,8 Irreversible IRI causes irreparable mitochondrial damage, resulting in mitophagy and loss of mitochondria. This directly impacts cell energetics and may lead to apoptosis/necrosis, significantly affecting graft function.7 Indirectly, mitochondrial damage leads to the production of free radicals and oxidative stress, causing harm to DNA, proteins, other organelles, and the plasma membrane, thereby contributing to graft dysfunction.8 Assessing mitochondrial function may offer a way to evaluate the quality of donor organs because of its crucial role in IRI. To date, there have been few studies examining the role of mitochondria in cardiac transplantation. In this issue of Transplantation, Berg et al9 examined the myocardial mitochondrial function during experimental DCD transplantation with HOPE preservation. Fifteen animals were subject to asphyxiation, leading to death. In 7 animals, a 15-min period of circulatory arrest was observed, and then NRP was provided for 1 h (simulating the time it takes in a human donor to accomplish this intervention). After 1 h, the heart was procured and placed on the HOPE circuit (NRP-HOPE group). In 8 animals, the protocol was to wait for 5 min of asystole and then procure the heart and place it on the HOPE circuit directly (DPP-HOPE). However, in 2 of 8 animals, the functional warm ischemic time was prolonged (>25 min), and these hearts appeared to be very rigid ("stone heart") and were not placed on HOPE, leaving 6 hearts in the DPP-HOPE group. Mitochondrial respiratory function parameters were assessed in left ventricular biopsies at baseline, after 3 h of HOPE, and 1 h after transplantation. The authors noticed a gradual decrease in mitochondrial respiratory function during DCD involving HOPE, which was associated with myocardial damage, although to a small extent (r = 0.5). The extent of mitochondrial damage was not statistically significant between NRP-HOPE and DPP-HOPE. On the basis of these observations, the authors concluded that DPP is noninferior to NRP in the porcine model of DCD transplant when combined with HOPE. In addition to this main conclusion, there are several noteworthy points: overall, mitochondrial respiratory function and cardiac hemodynamic parameters declined significantly during DCD irrespective of NRP or DPP procurement; despite lack of statistical significance, NRP seemed to preserve mitochondrial function; and in contrast, lactate and troponin levels were higher in the NRP group. The differing observations may be because of a small number of data points. The current study contributes to the growing evidence that recognizes mitochondrial dysfunction in both the assessment of donor heart viability and the identification of therapeutic targets for reducing IRI. However, clinical translation requires randomized studies with sufficient power and long-term follow-up in both preclinical and clinical settings. The study is notable for the similarity between methods of preservation. Despite small differences, it is likely that both DPP-HOPE and NRP-HOPE are feasible approaches to preserving a DCD donor heart. Having different ways to procure these hearts will allow further adoption of DCD donors, which ultimately will lead to further expansion of heart transplant volumes worldwide. The "ice age," which ushered in the possibility of performing human heart transplantation, is ending. The practice of simply relying on a bag of ice and cold preservation solutions will yield to future innovative ways to preserve and enhance donor organs for the betterment of patients in need worldwide.