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Updated: Jan 13, 2026
A High-Fidelity Porcine Model of Orthotopic Heart Transplantation Following Donation after Circulatory Death
Published on: June 6, 2025
Improved DCD Heart Transplant Function Through Ferroptosis Blockade in a Model of Experimental Normothermic Ex Vivo
Xuan Pan1, Jianqiang Ji1, Zekai Huang1
1Department of Cardiovascular Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China.
Insights
Liproxstatin-1 (Lip-1) protects donation after circulatory death (DCD) hearts from ischemia-reperfusion injury by inhibiting ferroptosis. This preservation strategy improves post-transplant cardiac function and reduces organ damage.
Area of Science:
- Cardiology
- Transplantation immunology
- Cellular pathology
Background:
- Donation after circulatory death (DCD) hearts increase donor availability but suffer significant ischemia-reperfusion injury (IRI).
- Ferroptosis, a form of regulated cell death, is a major contributor to IRI in DCD organs.
- Liproxstatin-1 (Lip-1) is a selective ferroptosis inhibitor with demonstrated organ protection capabilities.
Purpose of the Study:
- To evaluate the cardioprotective efficacy of Lip-1 in DCD rat hearts preserved with normothermic ex vivo heart perfusion (EVHP).
- To assess the impact of Lip-1 on IRI, ferroptosis, inflammation, oxidative stress, and apoptosis in transplanted DCD hearts.
Main Methods:
- Lewis rat hearts underwent DCD with 15-minute warm ischemia, followed by 3-hour EVHP preservation with either dimethyl sulfoxide (control) or Lip-1.
- Heterotopic heart transplantation was performed, and cardiac function was assessed during EVHP and 4 hours post-transplantation.
- Histological analysis, oxidative stress markers, inflammatory cytokines, apoptosis markers, CD31 expression, and ferroptosis markers were quantified.
Main Results:
- Lip-1 treatment significantly improved cardiac function during EVHP and post-transplantation compared to controls.
- Lip-1 attenuated myocardial ferroptosis, inflammation, oxidative stress, and apoptosis markers.
- Histological injury was reduced, and endothelial dysfunction (CD31 expression) was ameliorated in Lip-1 treated DCD hearts.
Conclusions:
- Normothermic EVHP combined with Lip-1 is a promising strategy for preserving DCD hearts.
- Lip-1 effectively alleviates myocardial IRI and endothelial dysfunction in DCD hearts by inhibiting ferroptosis.
- This approach enhances post-transplant cardiac function in DCD heart recipients.
Background:
Adopting donation after circulatory death (DCD) hearts can increase the donor pool. However, DCD hearts experience severe ischemia-reperfusion injury (IRI). Ferroptosis is a key contributor to organ IRI. Liproxstatin-1 (Lip-1), a selective ferroptosis inhibitor, markedly suppresses this form of cell death. This study evaluated the cardioprotective effect of Lip-1 on DCD hearts preserved with normothermic ex vivo heart perfusion (EVHP) in a rat heart transplantation model.
Methods:
The donor hearts of Lewis rats were subjected to the DCD procedure by suffering a 15-min warm ischemia injury, subsequently preserved with EVHP for 3 h, and then heterotopically transplanted into recipient rats. Dimethyl sulfoxide or Lip-1 was added to the perfusate of normothermic EVHP in the control or Lip-1 group. Cardiac function was assessed during EVHP and 4 h after heart transplantation. We investigated the histological changes and the levels of oxidative stress, inflammation, apoptosis, CD31 expression, and ferroptosis in the posttransplant DCD hearts.
Results:
compared with the control group, Lip-1 treatment significantly improved the cardiac function of DCD hearts in the first hour of EVHP and 4 h after heart transplantation, attenuated the levels of myocardial ferroptosis (glutathione peroxidase 4, SLC7A11, ACSL4, COX2), inflammation (interleukin-1β, interleukin-6, tumor necrosis factor-α), oxidative stress (4-hydroxynonenal), apoptosis (Bax, Bcl-2, caspase-3), reduced histological injury, and ameliorates endothelial dysfunction (CD31) in the posttransplant DCD hearts.
Conclusions:
Normothermic EVHP combined with Lip-1 treatment can be a promising DCD heart preservation strategy, which can alleviate myocardial IRI, ameliorate endothelial dysfunction, and improve posttransplant cardiac function for DCD hearts via inhibiting myocardial ferroptosis.
