Warm ischemic time-dependent effects on oxidative stress, endoplasmic reticulum stress, and inflammation in cold storage human donor hearts.

Abstract

Direct procurement and cold preservation with Celsior solution are standard for donor hearts after brain death; however, whether Celsior solution can be used in donor after circulatory death hearts is unknown. Because myocardial oxidative stress, endoplasmic reticulum stress, and inflammation are pivotal in ischemic injury, we compared Celsior solution with normal saline with respect to these pathways in human donor after brain death and donor after circulatory death hearts, assessing the impact of warm ischemic time and cold ischemia. Forty-seven human donor after brain death (n = 16) and donor after circulatory death (n = 31) hearts that received Del Nido cardioplegia were procured for research and assigned to 6 groups based on donor type (donor after brain death/donor after circulatory death), preservation solution (normal saline/Celsior solution), and warm ischemic time (≤30 minutes/>30 minutes): (1) normal saline: donor after brain death (n = 10); (2) Celsior solution: donor after brain death (n = 6); (3) normal saline: donor after circulatory death 30 minutes or less (n = 6); (4) Celsior solution: donor after circulatory death 30 minutes or less (n = 7); (5) normal saline: donor after circulatory death more than 30 minutes (n = 12); and (6) Celsior solution: donor after circulatory death more than 30 minutes (n = 6) and cold stored for 6 hours. Left ventricular biopsies at 0, 2, 4, and 6 hours (T0-T6) were analyzed for oxidative stress (4-hydroxynonenal, superoxide dismutase), endoplasmic reticulum stress (activating transcription factor 6, heat shock 70 kDa protein 5), and inflammatory markers (tumor necrosis factor-α and interleukin-6). At baseline, donor after circulatory death hearts exhibited greater cellular stress and inflammation, especially with warm ischemic time of 30 minutes or more. During cold storage, Celsior solution attenuated oxidative and endoplasmic reticulum stress in both donor after brain death hearts and donor after circulatory death hearts with warm ischemic time of 30 minutes or less. Inflammatory markers were reduced by Celsior solution only in donor after brain death hearts and donor after circulatory death hearts with warm ischemic time of 30 minutes or less. Celsior solution preservation has no anti-inflammatory effect in donor after circulatory death hearts with warm ischemic time of more than 30 minutes. Warm ischemic time determines the extent of ischemic injury. Celsior solution ameliorates upstream cellular stress, but its anti-inflammatory effect is lost after prolonged warm ischemia (>30 minutes), underscoring the need for warm ischemic time-stratified preservation strategies.