Division of Cardiothoracic Transplantation and Circulatory Support, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas, United States.
Department of Regenerative Medicine Research, Texas Heart Institute, Houston, Texas, United States.
Am J Physiol Heart Circ Physiol. 2024 Mar 1;326(3):H548-H562. doi: 10.1152/ajpheart.00616.2023. Epub 2024 Jan 5.
This study investigated cardiac stress and mitochondrial oxidative phosphorylation (OxPhos) in human donation after circulatory death (DCD) hearts regarding warm ischemic time (WIT) and subsequent cold storage and compared them with that of human brain death donor (DBD) hearts. A total of 24 human hearts were procured for the research study-6 in the DBD group and 18 in the DCD group. DCD group was divided into three groups ( = 6) based on different WITs (20, 40, and 60 min). All hearts received del Nido cardioplegia before being placed in normal saline cold storage for 6 h. Left ventricular biopsies were performed at , , , and . Cardiac stress [nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunits: 47-kDa protein of phagocyte oxidase (p47), 91-kDa glycoprotein of phagocyte oxidase (gp91)] and mitochondrial oxidative phosphorylation [OxPhos, complex I (NADH dehydrogenase) subunit of ETC (CI)-complex V (ATP synthase) subunit of ETC (CV)] proteins were measured in cardiac tissue and mitochondria respectively. Modulation of cardiac stress and mitochondrial dysfunction were observed in both DCD and DBD hearts. However, DCD hearts suffered more cardiac stress (overexpressed NADPH oxidase subunits) and diminished mitochondrial OxPhos than DBD hearts. The severity of cardiac stress and impaired oxidative phosphorylation in DCD hearts correlated with the longer WIT and subsequent cold storage time. More drastic changes were evident in DCD hearts with a WIT of 60 min or more. Activation of NADPH oxidase via overproduction of p47 and gp91 proteins in cardiac tissue may be responsible for cardiac stress leading to diminished mitochondrial oxidative phosphorylation. These protein changes can be used as biomarkers for myocardium damage and might help assess DCD and DBD heart transplant suitability. First human DCD heart research studied cardiac stress and mitochondrial dysfunction concerning WIT and the efficacy of del Nido cardioplegia as an organ procurement solution and subsequent cold storage. Mild to moderate cardiac stress and mitochondrial dysfunction were noticed in DCD hearts with WIT 20 and 40 min and cold storage for 4 and 2 h, respectively. These changes can serve as biomarkers, allowing interventions to preserve mitochondria and extend WIT in DCD hearts.
本研究调查了循环死亡（DCD）供心在不同热缺血时间（WIT）及随后的冷藏后的心内应激和线粒体氧化磷酸化（OxPhos）情况，并与脑死亡供心（DBD）供心进行了比较。共有 24 个人心脏用于研究-6 个在 DBD 组，18 个在 DCD 组。DCD 组根据不同的 WIT（20、40 和 60 分钟）分为三组（n=6）。所有心脏均在使用 Del Nido 心脏停搏液前置于生理盐水冷藏 6 小时。左心室活检分别在 、 、 和 进行。心肌组织中测量心内应激[烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶亚基：吞噬细胞氧化酶 47kDa 蛋白（p47），吞噬细胞氧化酶 91kDa 糖蛋白（gp91）]和线粒体氧化磷酸化[OxPhos，电子传递链（ETC）中 NADH 脱氢酶复合体 I（CI）-ETC 中 ATP 合酶复合体 V（CV）]蛋白。在 DCD 和 DBD 心脏中均观察到心内应激和线粒体功能障碍的调节。然而，DCD 心脏的心内应激（NADPH 氧化酶亚基过度表达）和线粒体 OxPhos 减少比 DBD 心脏更为严重。DCD 心脏的心内应激和氧化磷酸化受损的严重程度与较长的 WIT 和随后的冷藏时间相关。WIT 为 60 分钟或更长时间的 DCD 心脏变化更为明显。心肌组织中 p47 和 gp91 蛋白过度产生导致 NADPH 氧化酶的激活可能是导致心内应激导致线粒体氧化磷酸化减少的原因。这些蛋白变化可用作心肌损伤的生物标志物，并可能有助于评估 DCD 和 DBD 心脏移植的适宜性。首次对人类 DCD 心脏进行研究，探讨了 WIT 以及 Del Nido 心脏停搏液作为器官获取解决方案及随后冷藏对心内应激和线粒体功能障碍的影响。在 WIT 为 20 和 40 分钟且冷藏 4 和 2 小时的情况下，DCD 心脏中均观察到轻度至中度心内应激和线粒体功能障碍。这些变化可用作生物标志物，以干预保存线粒体并延长 DCD 心脏的 WIT。
