Improved DCD Heart Transplant Function Through Ferroptosis Blockade in a Model of Experimental Normothermic Ex Vivo Perfusion.

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.