Peritransplant Cardiometabolic and Mitochondrial Function: The Missing Piece in Donor Heart Dysfunction and Graft Failure

Abstract

Primary graft dysfunction (PGD) is an important cause of morbidity and mortality after cardiac transplantation. Donor brain stem death (BSD) is a significant contributor to donor heart dysfunction (DHD) and PGD. There remain substantial gaps in the mechanistic understanding of peritransplant cardiac dysfunction. One of these gaps is cardiac metabolism and metabolic function. The healthy heart is an 'omnivore', capable of utilising multiple sources of nutrients to fuel its enormous energetic demand. When this fails, metabolic inflexibility leads to myocardial dysfunction. Data have hinted at metabolic disturbance in the BSD donor and subsequent HTx, however, there is limited evidence demonstrating specific metabolic or mitochondrial dysfunction. This review will examine the literature surrounding cardiometabolic and mitochondrial function in the BSD donor, organ preservation, and subsequent cardiac transplantation. A more comprehensive understanding of this subject may then help to identify important cardioprotective strategies to improve the number and quality of donor hearts.

Metabolic Considerations in Direct Procurement and Perfusion Protocols with DCD Heart Transplantation

“…In turn, sympathetic activity leads to rapid catecholamine (noradrenaline, adrenaline, and dopamine) increases in the myocardial interstitial fluid [34][35][36]. The effects of catecholamines on cardiac metabolism are numerous, including increased intracellular and mitochondrial calcium; mobilization of glycogen stores; as well as stimulation of glycolysis, beta-oxidation, and lipid accumulation, as reviewed by Wells and colleagues [37]. Importantly, adrenaline treatment before ischemia has been reported to reduce post-ischemic recovery of the rat myocardium, possibly as a result of exacerbated calcium overload [38].…”

“…The catabolic pathway of BCAAs ends with the generation of acetyl-CoA and succinyl-CoA and their oxidation in the TCA cycle or anaplerosis [69]. In a healthy heart, BCAAs contribute 1-2% to the cardiac ATP production [37].…”

“…With DPP, functional warm ischemia of the cardiac graft is followed by a short p of cold static storage to prepare the heart for ESHP and prime the ESHP system. It ognized that one major protective mechanism of cold preservation is reducing met rates; however, it does not prevent ATP consumption completely [37]. To date, no sensus regarding the optimal composition of the initial cardioplegia in clinical DCD e In general, St. Thomas N°2 or Custodiol solutions supplemented with the cardioprot agents erythropoietin (EPO) and glyceryl trinitrate (GTN) are used [15,80,81].…”

Mitochondrial responses to brain death in solid organ transplant

“…The United Network of Organ Sharing (UNOS) reported that 13,861 individuals in the United States became deceased donors for organ transplants in 2021, an increase for the eleventh year in a row (1). Despite being the leading resource for organs in those needing lifesaving transplants, metabolic changes that occur due to BD and in the subsequent stages of organ procurement, storage, and implantation results in inflammatory responses in the donor organs that are then "primed" for immune recognition (2)(3)(4). The interplay between immune response and organ longevity is a of long-term graft viability and success in solid organ transplantation (2,5).…”

Whole Blood Thiamine in Organ Donors After the Neurologic Determination of Death

“…6 Impaired mitochondrial function has been implicated in peritransplant cardiac dysfunction. 7 A second characteristic of TPP relevant to organ transplantation is its role as a vital coenzyme for the transketolase reaction of the pentose phosphate pathway. The pentose phosphate pathway is a major source of reduced nicotinamide adenine dinucleotide-phosphate (NADPH) for the regeneration of reduced glutathione, an important cellular antioxidant capable of inactivating reactive oxygen species that are produced by I/R which is likely involved in delayed graft function.…”