Determination of Optimal Coronary Flow for the Preservation of “Donation after Circulatory Death” in Murine Heart Model

Abstract

Donation after circulatory death donors (DCD) have the potential to increase the number of heart transplants. The DCD hearts undergo an extended period of warm ischemia, which mandates the use of machine perfusion preservation if they are to be successfully recovered for transplantation. Because the minimum coronary artery flow needed to meet the basal oxygen demand (DCRIT) of a DCD heart during machine perfusion preservation is critical and yet unknown, we studied this in a DCD rat heart model. Adult male rats were anesthetized, intubated, heparinized, and paralyzed with vecuronium. The DCD hearts (n = 9) were recovered 30 minutes after circulatory death whereas non-DCD control hearts (n = 12) were recovered without circulatory death. Hearts were perfused through the aorta with an oxygenated Belzer Modified Machine Perfusion Solution (A3-Bridge to Life Ltd. Columbia, SC) at 15°C or 22°C starting at a flow index of 300 ml/100 g/min and decreasing by 40 ml/100 g/min every 10 minutes. Inflow (aortic) and outflow (inferior vena cava) perfusate samples were collected serially to assess the myocardial oxygen consumption index (MVO2) and O2 extraction ratio. The DCRIT is the minimum coronary flow below which the MVO2 becomes flow dependent. The MVO2, DCRIT, and oxygen extraction ratios were higher in DCD hearts compared with control hearts. The DCRIT for DCD hearts was achieved only at 15°C and was significantly higher (131.6 ± 7 ml/100 g/min) compared with control hearts (107.7 ± 8.4 ml/100 gm/min). The DCD hearts sustain warm ischemic damage and manifest higher metabolic needs during machine perfusion. Establishing adequate coronary perfusion is critical to preserving organ function for potential heart transplantation.

Heart transplantation from donation after circulatory death donors: Present and future

“…An ex situ perfusion apparatus and a suitable perfusate need to be defined. Our studies on DCD murine hearts demonstrated that “oxygen debt” was higher in DCD hearts compared to DBD hearts and that with nonblood‐based perfusate one cannot keep a DCD heart in aerobic state above temperature of 15°C, 18 (b) there are no definitive tests to assure that the DCD hearts supported on a perfusion rig will function well after transplantation. These two challenges are being worked out at present.…”

“…Successful small and large animal model DCD heart transplantations were reported using normothermic blood‐based perfusates 12,13 . However, nonblood‐based perfusates required hypothermia where functional parameters of DCD hearts could not be obtained conclusively 18 . More importantly, several agents know to be protective in myocardial ischemia/reperfusion‐related injury were investigated for their effectiveness in DCD hearts.…”

“…TransMedics OCS has facilitated DCD heart transplantations but it has significant limitations. Since the heart has the highest metabolic demands of transplantable organs, only blood‐based perfusates would allow it to stay in an aerobic condition at normothermia 18 . It is plausible that the DCD donor blood may carry with it very high levels of catecholamines and other drugs that may adversely affect the heart.…”

“…Its large size also requires modifications during transportation. As the heart's metabolism decreases by 5% with each °C drop in temperature (50% reduction in the metabolic rate at 27°C compared to 37°C) it is desirable to store/transport DCD heart at lower temperatures 18 . Novel nonblood‐based perfusates such as modified UW‐MPS that incorporated polyethylene glycol (PEG‐20K) as impermeant has shown promising results in preserving DCD kidney and livers 41,42 .…”

“…12,13 However, nonblood-based perfusates required hypothermia where functional parameters of DCD hearts could not be obtained conclusively. 18 More importantly, several agents know to be protective in myocardial ischemia/reperfusion-related injury were investigated for their effectiveness in DCD hearts. Iyer et al 12 systematically studied the individual or combined effects of perfusing erythropoietin, a promotor of Janus kinase 2-signal transducer and activator of transcription 3 signaling pathway, zoniporide, a Na + /H + exchanger inhibitor, and glyceryl trinitrate, a potent nitric oxide donor, to DCD hearts before reanimation and transplantation.…”