Department of Anesthesiology and Pain Medicine, University of Alberta, Edmonton, AB, T6G 2G3, Canada.
Department of Pharmacology, University of Alberta, Edmonton, AB, Canada.
Can J Anaesth. 2019 Jun;66(6):672-685. doi: 10.1007/s12630-019-01322-x. Epub 2019 Feb 21.
Intralipid (ILE), a clinically used lipid emulsion, reduces ischemia-reperfusion (IR) injury in healthy and infarct-remodelled rat hearts. We tested whether ILE is also cardioprotective in large porcine hearts in the context of the donation after circulatory death (DCD) model, where human hearts are procured for transplantation after cardiac arrest and thus are exposed to significant IR injury.
After induction of anesthesia, surgical preparation, termination of ventilator support, and cardiac arrest, hearts of female pigs were procured following a 15 min standoff period, with an optimized normokalemic crystalloid adenosine-lidocaine cardioplegia. Hearts were then randomly allocated to ex vivo reperfusion (38°C) in the absence (control) or presence of 1% ILE. All hearts were perfused with blood and Krebs-Henseleit solution (1:1) for 30 min in Langendorff mode and for an additional 30 min in working mode to assess mechanical function. Left ventricular (LV) biopsies were obtained after five minutes of reperfusion and LV tissue was preserved at the end of reperfusion for biochemical analyses and immunohistochemistry.
Intralipid postconditioning reduced cell membrane damage as assessed by the mean (standard deviation) leakage of myocardial glutathione disulfide (39 (9) nmol·mg protein vs 19 (7) nmol·mg protein; P = 0.006), protected LV tissue from protein carbonylation (3.4 [0.6] nmol·mg protein vs 5.3 [0.9] nmol·mg protein; P = 0.006), decreased myeloperoxidase activity (35 [8] nmol·min·mg protein vs 75 [11] nmol·min·mg protein; P < 0.001), and increased inotropy (maximum rate of rise of LV pressure 2001 [345] mmHg·secvs 1584 [192] mmHg·sec; P = 0.044). Intralipid postconditioning triggered reactive oxygen species signalling at early reperfusion and activated protection signalling (Akt, signal transducer and activator of transcription 3, and glycogen synthase kinase 3β) in LV tissue, recapitulating all features of ILE-mediated protection reported in small rodent hearts.
Our data show that ILE postconditioning elicits protection signalling in large mammalian hearts while mimicking clinical conditions, and is capable of enhancing protection of DCD hearts.
Intralipid（ILE）是一种临床应用的脂肪乳剂，可减轻健康和梗死重塑大鼠的缺血再灌注（IR）损伤。我们测试了 ILE 是否也对捐赠后循环死亡（DCD）模型中的大型猪心脏具有心脏保护作用，在该模型中，人类心脏在心脏骤停后被采集用于移植，因此会受到严重的 IR 损伤。
在麻醉诱导、手术准备、呼吸机支持终止和心脏骤停后，经过 15 分钟的停搏期，使用优化的低钾晶体腺苷-利多卡因停搏液获取雌性猪的心脏。然后将心脏随机分配到不存在（对照）或存在 1%ILE 的离体再灌注（38°C）中。所有心脏均在 Langendorff 模式下用血液和 Krebs-Henseleit 溶液（1:1）灌注 30 分钟，并在工作模式下再灌注 30 分钟，以评估机械功能。再灌注 5 分钟后获取左心室（LV）活检，并在再灌注结束时保存 LV 组织进行生化分析和免疫组织化学分析。
Intralipid 后处理通过心肌谷胱甘肽二硫化物的平均（标准差）漏出（39（9）nmol·mg 蛋白与 19（7）nmol·mg 蛋白；P=0.006）评估减轻了细胞膜损伤，保护 LV 组织免受蛋白质羰基化（3.4（0.6）nmol·mg 蛋白与 5.3（0.9）nmol·mg 蛋白；P=0.006），降低髓过氧化物酶活性（35（8）nmol·min·mg 蛋白与 75（11）nmol·min·mg 蛋白；P<0.001），并增加变力（左心室压力最大上升速率 2001（345）mmHg·sec 与 1584（192）mmHg·sec；P=0.044）。Intralipid 后处理在再灌注早期触发了活性氧信号转导，并在 LV 组织中激活了保护信号（Akt、信号转导和转录激活因子 3 和糖原合酶激酶 3β），再现了在小型啮齿动物心脏中报道的所有 ILE 介导的保护特征。
我们的数据表明，ILE 后处理在模拟临床条件的情况下在大型哺乳动物心脏中引发保护信号，并能够增强 DCD 心脏的保护。
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