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Updated: Aug 22, 2025
Pre-clinical Model of Cardiac Donation after Circulatory Death
Published on: August 2, 2019
Postconditioning by Delayed Administration of Ciclosporin A: Implication for Donation after Circulatory Death (DCD)
René Ferrera1, Marie Védère1, Megane Lo-Grasso1
1University of Lyon, CARMEN Laboratory, INSERM, INRAE, Université Claude Bernard Lyon 1, 69500 Lyon, France.
Insights
Delayed application of ciclosporin-A (CsA) effectively reduces ischemia-reperfusion injury in Donation after Circulatory Death (DCD) heart models. Unlike ischemic postconditioning, CsA maintains cardioprotection even when administered with a delay, preserving heart function and mitochondrial health.
Area of Science:
- Cardiology
- Transplantation Medicine
- Cardiovascular Research
Background:
- Graft shortage is a major limitation for heart transplantation.
- Donation after Circulatory Death (DCD) offers a potential solution to increase organ availability.
- Ischemia-reperfusion injury remains a significant challenge in DCD heart preservation.
Purpose of the Study:
- To evaluate the efficacy of postconditioning strategies in mitigating ischemia-reperfusion injury in a DCD rat heart model.
- To compare the protective effects of ischemic postconditioning (POST) versus ciclosporin-A (CsA) treatment.
- To determine the impact of delayed application of these interventions on cardioprotection.
Main Methods:
- Utilized an isolated rat heart model simulating DCD conditions with 40 minutes of warm global ischemia followed by cold preservation and reperfusion.
- Assessed outcomes in control, immediate POST, and immediate CsA groups, as well as subgroups receiving delayed POST or CsA (3, 10, 20 minutes after reperfusion onset).
- Measured myocardial necrosis, cardiac function, mitochondrial respiratory index, and mitochondrial permeability transition pore (MPTP) opening.
Main Results:
- Both POST and CsA significantly reduced necrosis and improved heart function compared to controls.
- POST efficacy diminished when delayed beyond 3 minutes of reperfusion.
- Delayed CsA administration (up to 10 minutes) effectively reduced necrosis and improved functional recovery, correlating with preserved mitochondrial function.
- MPTP opening thresholds were similar across cardioprotected groups, implicating MPTP in delayed CsA protection.
Conclusions:
- Delayed CsA administration provides significant cardioprotection in DCD hearts, unlike delayed ischemic postconditioning.
- CsA's protective mechanism in delayed application appears linked to mitochondrial function and MPTP regulation.
- This finding supports the potential of delayed CsA treatment to enhance the viability of DCD donor hearts for transplantation.
Abstract:
Heart transplantation is facing a shortage of grafts. Donation after Circulatory Death (DCD) would constitute a new potential of available organs. In the present work, we aimed to evaluate whether Postconditioning (ischemic or with ciclosporin-A (CsA)) could reduce ischemia-reperfusion injury in a cardiac arrest model when applied at the start of reperfusion or after a delay. An isolated rat heart model was used as a model of DCD. Hearts were submitted to a cardiac arrest of 40 min of global warm ischemia (37 °C) followed by 3 h of 4 °C-cold preservation, then 60 min reperfusion. Hearts were randomly allocated into the following groups: control, ischemic postconditioning (POST, consisting of two episodes each of 30 s ischemia and 30 s reperfusion at the onset of reperfusion), and CsA group (CsA was perfused at 250 nM for 10 min at reperfusion). In respective subgroups, POST and CsA were applied after a delay of 3, 10, and 20 min. Necrosis was lower in CsA and POST versus controls (p < 0.01) whereas heart functions were improved (p < 0.01). However, while the POST lost its efficacy if delayed beyond 3 min of reperfusion, CsA treatment surprisingly showed a reduction of necrosis even if applied after a delay of 3 and 10 min of reperfusion (p < 0.01). This cardioprotection by delayed CsA application correlated with better functional recovery and higher mitochondrial respiratory index. Furthermore, calcium overload necessary to induce mitochondrial permeability transition pore (MPTP) opening was similar in all cardioprotection groups, suggesting a crucial role of MPTP in this delayed protection of DCD hearts.
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