Transplantation of Hearts Donated after Circulatory Death

Abstract

Cardiac transplantation has become limited by a critical shortage of suitable organs from brain-dead donors. Reports describing the successful clinical transplantation of hearts donated after circulatory death (DCD) have recently emerged. Hearts from DCD donors suffer significant ischemic injury prior to organ procurement; therefore, the traditional approach to the transplantation of hearts from brain-dead donors is not applicable to the DCD context. Advances in our understanding of ischemic post-conditioning have facilitated the development of DCD heart resuscitation strategies that can be used to minimize ischemia-reperfusion injury at the time of organ procurement. The availability of a clinically approved ex situ heart perfusion device now allows DCD heart preservation in a normothermic beating state and minimizes exposure to incremental cold ischemia. This technology also facilitates assessments of organ viability to be undertaken prior to transplantation, thereby minimizing the risk of primary graft dysfunction. The application of a tailored approach to DCD heart transplantation that focuses on organ resuscitation at the time of procurement, ex situ preservation, and pre-transplant assessments of organ viability has facilitated the successful clinical application of DCD heart transplantation. The transplantation of hearts from DCD donors is now a clinical reality. Investigating ways to optimize the resuscitation, preservation, evaluation, and long-term outcomes is vital to ensure a broader application of DCD heart transplantation in the future.

Keywords: Ex vivo heart perfusion; donation after circulatory death cardiac graft; donation after circulatory death heart transplantation; ex situ heart perfusion; ischemic post-conditioning.

Figure 1

Pathways for deceased organ donation. (A) Patients donating organs after brain death have intact cardiorespiratory function that allows donor heart evaluation to be undertaken before organ procurement. (B) Patients donating organs after circulatory death have suffered a hypoxemic cardiac arrest following withdrawal of life-sustaining therapy and donor heart evaluation can only be undertaken after organ resuscitation has occurred.

Figure 2

Process of heart transplantation. (A) The traditional approach to transplantation of a heart procured from a donation after brain death donor. Donor heart evaluation is carried out in the donor with intact cardiorespiratory function. Viable organs are arrested with a cardioplegic solution and stored in a profoundly hypothermic state (cold-static storage) until transplantation. Organ ischemia is limited to the time between procurement and transplantation (cold ischemic time). (B) The traditional approach to transplantation if it were utilized for a heart procured from a donation after circulatory death donor. The donor progresses to circulatory arrest following withdrawal of life-sustaining therapy (WLST). An ethically mandated standoff period must then be observed before circulatory death can be declared. Consequently, the heart has sustained a significant warm ischemic insult before organ procurement can proceed. Subsequent preservation using cold-static storage subjects the heart to an additional cold ischemic injury and does not provide an opportunity for organ resuscitation and evaluation. The traditional approach is unlikely to facilitate successful transplantation of hearts donated after circulatory death. (C) The tailored approach to transplantation of a heart procured from a donation after circulatory death donor. Following WLST and declaration of circulatory death, the heart is resuscitated using an approach tailored to minimize ischemia-reperfusion injury. The heart is then preserved using ex situ heart perfusion, which minimizes exposure to cold ischemia and facilitates organ evaluation. Organ ischemia can be limited to the time between WLST and organ resuscitation (warm ischemic time).

Figure 3

Alternative approaches to the resuscitation, preservation, and evaluation of hearts donated after circulatory arrest. (A) Direct procurement and preservation. Hearts are resuscitated with a cardioplegic solution tailored to minimize ischemia-reperfusion injury, then preserved ex situ in a normothermic beating state. Organ evaluation is carried out during ex situ preservation to identify viable organs for transplant. (B) Normothermic regional perfusion. Hearts are resuscitated in vivo on veno-arterial extracorporeal membrane oxygenation (ECMO). The donor is subsequently weaned from ECMO, in vivo assessments of heart function are carried out, and then viable organs are procured and preserved ex situ in a normothermic beating state until transplant. Supplementary organ evaluation can be carried out during ex situ preservation.

Figure 4

(A) Ionic changes during ischemia. Anaerobic metabolism results in the production of hydrogen ions that activate the sodium–hydrogen exchanger and the accumulation of sodium ions inside the myocyte. The sodium–potassium ATPase is not able to extrude the excess sodium ions and maintain the normal membrane potential due to a lack of available adenosine triphosphate (ATP). Consequently, as ischemia progresses there is an accumulation of sodium and hydrogen ions inside the myocyte and depolarization of the membrane potential. (B) Ionic changes during reperfusion. Reperfusion washes out the hydrogen ions that have accumulated in the interstitial space and creates a large gradient for sodium–hydrogen exchange. The influx of sodium ions into the myocyte during early reperfusion forces the sodium–calcium exchanger (NCX) to function in reverse mode and import calcium ions across the sarcolemma. Intracellular ionic homeostasis cannot be restored until the sodium-potassium ATPase is able to reestablish the resting membrane potential and normal intracellular sodium levels, which will allow the NCX to return to a forward mode of operation and extrude excess calcium from the cytoplasm [adapted with permission (34)].

Figure 5

Pathogenesis of ischemia–reperfusion injury. Intracellular calcium overload and the production of ROS cause opening of the MPT pore and the propagation of cell death. The normalization of intracellular pH during reperfusion is an important modulating factor in the pathogenesis of ischemia–reperfusion injury. Abbreviations: MPT, mitochondrial permeability transition; ROS, reactive oxygen species; SR, sarcoplasmic reticulum [adapted with permission (31)].