Abstract and Introduction
Abstract
Donation after circulatory death (DCD) represents a promising opportunity to overcome the relative shortage of donors for heart transplantation. However, the necessary period of warm ischemia is a concern. This study aims to determine the critical warm ischemia time based on in vivo biochemical changes. Sixteen DCD non-cardiac donors, without cardiovascular disease, underwent serial endomyocardial biopsies immediately before withdrawal of life-sustaining therapy (WLST), at circulatory arrest (CA) and every 2 min thereafter. Samples were processed into representative pools to assess calcium homeostasis, mitochondrial function and cellular viability. Compared to baseline, no significant deterioration was observed in any studied parameter at the time of CA (median: 9 min; IQR: 7–13 min; range: 4–19 min). Ten min after CA, phosphorylation of cAMP-dependent protein kinase-A on Thr197 and SERCA2 decreased markedly; and parallelly, mitochondrial complex II and IV activities decreased, and caspase 3/7 activity raised significantly. These results did not differ when donors with higher WLST to CA times (≥9 min) were analyzed separately. In human cardiomyocytes, the period from WLST to CA and the first 10 min after CA were not associated with a significant compromise in cellular function or viability. These findings may help to incorporate DCD into heart transplant programs.
Introduction
Heart transplantation remains the gold standard for treating end-stage heart failure; it results in survival at least one year after transplantation in nearly 90% of cases.[1] However, there is a relative shortage of donation after brain death (DBD) compared to the growing number of potential cardiac recipients. Indeed, the need for a fully functional organ is the major limitation to expanding the heart pool by including suboptimal donors.[2]
In this context, the possibility of expanding heart transplantation via donation after circulatory death (DCD) is promising.[3] In the last ten years, controlled DCD has increased the pool of abdominal organs and lungs, but this is not the case for hearts. Including DCD donors could increase the number of heart transplants by 15%–30%.[4–6] However, unlike conventional DBD, DCD organs undergo a period of warm ischemia during the withdrawal of life-sustaining therapy (WLST) and between circulatory arrest (CA) and heart procurement. This raises concern about graft functionality and quality.[7–9] Seeing positive results from pioneering work in Australia and United Kingdom, several groups have published case series based on different protocols, which may include direct procurement using extra-corporeal perfusion systems (DPP) or in-situ normothermic regional perfusion (NRP).[10–14] In this context, it is of paramount importance to identify the time point when myocardial function decreases and the risk of graft dysfunction increases.[15] Determining this time point could greatly assist heart transplant teams by expanding the possibility of heart procurement from DCD. However, the time point associated with irreversible myocardial cell injury is currently unknown.[3,14,15]
Therefore, the present study aims to determine the critical warm ischemia time (WIT) based on in-vivo close monitoring of biochemical changes in cardiac myocytes during the process of DCD of abdominal organs and lungs. We focused on changes closely related to contractility and functional viability, including those implicated in the regulation of calcium homeostasis, mitochondrial energetics, and apoptotic cell death.[16–18]