Driven by an ever-increasing shortage of donor organs, the use of organs donated after declaration of cardiocirculatory death (DCD) has become routine clinical practice in both solid organ and lung transplantation. Although the use of the DCD hearts could significantly increase the number of heart available for transplantation, they are typically not transplanted due to concerns about the negative impact of the global warm ischemia (WI) inherent to DCD donation, on their viability.
Fig. 1 Isolated perfused working heart perfusion circuit
Our group’s works focuses on ex-vivo machine perfusion as method for experimental recovery and viability assessment of DCD hearts. For this purpose, hearts were subjected to varying periods of in-situ WI in a rodent DCD model. Following explantation, the hearts were reconditioned ex-vivo in a machine perfusion apparatus, after which their viability was assessed in an isolated perfused Langendorff- or working heart-model (Fig. 1), to simulate transplantation. We have found that 1 h of ex-vivo reconditioning with normothermic machine perfusion using diluted autologous blood, restored left ventricular function to near normal levels and replenished myocardial adenosine triphosphate (ATP) (Fig. 2&3). We subsequently sought to establish the optimal reconditioning temperature, hypothesizing a reduction in temperature may provide an optimal balance between ATP synthesis and use, and passive and active ion transport. Here, we found that moderate hypothermia during reconditioning (≈ 25-30°C) ameliorated I/R injury and promoted myocardial recovery (Fig. 3)(2).
Fig. 2 Myocardial ATP following reconditioning
However, although the reconditioned ischemic hearts showed significant improvement, signs of considerable ischemia-reperfusion (I/R) injury were still evident. Current work is therefore focused at further improving our approach by specifically targeting problems we observed: reducing inflammation by perfusate leucodepletion and supplementation with anti-oxidants anti-inflammatory compounds, improving myocardial perfusion by the use of vasodilators, thrombolytics and anti-adhesive substances, and promoting ATP replenishment by perfusate supplementation with Krebs-cycle intermediates and branched-chain amino-acids (BCAA’s). Furthermore, we are using various numerical models to predict organ viability upon transplantation by correlating graft behavior during ex-vivo reconditioning, with viability during ex-vivo reperfusion. In addition, we plan to test our findings in-vivo, using both rodent- and large animal (porcine) heart transplant models. We believe that once further refined validated, machine perfusion could be a powerful tool to enable the safe use of hearts from DCD donors.
Fig. 3 Heart rate and contractility during Langendorff reperfusion
- 1. Moderate hypothermia during ex vivo machine perfusion promotes recovery of hearts donated after cardiocirculatory death. Tolboom H, Olejníčková V, Reser D, Rosser B, Wilhelm MJ, Gassmann M, Bogdanova A, Falk V. Eur J Cardiothorac Surg. 2015 Mar 3. Epub ahead of print
2. Recovery of donor hearts after circulatory death with normothermic extracorporeal machine perfusion. Tolboom H, Makhro A, Rosser BA, Wilhelm MJ, Bogdanova A, Falk V.
Eur J Cardiothorac Surg. 2015 Jan;47(1):173-9.