供体年龄增加对循环死亡后捐献啮齿动物模型中心肌缺血耐受性的影响。
The Effect of Increasing Donor Age on Myocardial Ischemic Tolerance in a Rodent Model of Donation After Circulatory Death.
作者信息
Villanueva Jeanette E, Chew Hong C, Gao Ling, Doyle Aoife, Scheuer Sarah E, Hicks Mark, Jabbour Andrew, Dhital Kumud K, Macdonald Peter S
机构信息
Physiology and Transplantation, Victor Chang Cardiac Research Institute, Darlinghurst, NSW, Australia.
Faculty of Medicine, St Vincent's Clinical School, University of New South Wales Sydney, Randwick, NSW, Australia.
出版信息
Transplant Direct. 2021 May 18;7(6):e699. doi: 10.1097/TXD.0000000000001148. eCollection 2021 Jun.
UNLABELLED
Hearts from older donors or procured via donation after circulatory death (DCD) can alleviate transplant waitlist; however, these hearts are particularly vulnerable to injury caused by warm ischemic times (WITs) inherent to DCD. This study investigates how the combination of increasing donor age and pharmacologic supplementation affects the ischemic tolerance and functional recovery of DCD hearts and how age impacts cardiac mitochondrial respiratory capacity and oxidative phosphorylation.
METHODS
Wistar rats (12-, 18-, and 24-mo-old) were subjected to DCD with 20-min fixed WIT. Hearts were procured, instrumented onto a Langendorff perfusion circuit, flushed with Celsior preservation solution with or without supplementation (glyceryl trinitrate [GTN]/erythropoietin [EPO]/zoniporide [Z]) and perfused (Krebs-Henseleit buffer, 37°C Langendorff 30-min, working 30-min). Cardiac functional recovery of aortic flow (AF), coronary flow (CF), cardiac output (CO), and lactate dehydrogenase release were measured. Native heart tissue (3-, 12-, and 24-mo) were assessed for mitochondrial respiratory capacity.
RESULTS
Unsupplemented 18- and 24-month DCD hearts showed a 6-fold decrease in AF recovery relative to unsupplemented 12-month DCD hearts. GTN/EPO/Z supplementation significantly increased AF and CO recovery of 18-month DCD hearts to levels comparable to supplemented 12-month hearts; however, GTN/EPO/Z did not improve 24-month DCD heart recovery. Compared to 12-month heart tissue, 24-month hearts exhibited significantly impaired mitochondrial oxygen flux at complex I, II, and uncoupled maximal respiration stage.
CONCLUSIONS
Reduced ischemic tolerance after DCD was associated with increasing age. Pharmacologic supplementation improves functional recovery of rat DCD hearts but only up to age 18 months, possibly attributed to a decline in mitochondrial respiratory capacity with increasing age.
未标注
来自老年供体的心脏或通过循环死亡后捐赠（DCD）获取的心脏可以缓解移植等待名单；然而，这些心脏特别容易受到DCD固有的热缺血时间（WIT）所导致的损伤。本研究调查了供体年龄增加与药物补充的组合如何影响DCD心脏的缺血耐受性和功能恢复，以及年龄如何影响心脏线粒体呼吸能力和氧化磷酸化。
方法
将Wistar大鼠（12、18和24月龄）进行20分钟固定WIT的DCD。获取心脏，安装到Langendorff灌注回路，用含或不含补充剂（硝酸甘油[GTN]/促红细胞生成素[EPO]/唑尼泊酯[Z]）的Celsior保存液冲洗，并进行灌注（ Krebs-Henseleit缓冲液，37°C Langendorff 30分钟，工作30分钟）。测量主动脉流量（AF）、冠状动脉流量（CF）、心输出量（CO）和乳酸脱氢酶释放的心脏功能恢复情况。评估天然心脏组织（3、12和24月龄）的线粒体呼吸能力。
结果
未补充的18个月和24个月DCD心脏的AF恢复相对于未补充的12个月DCD心脏下降了6倍。GTN/EPO/Z补充剂显著提高了18个月DCD心脏的AF和CO恢复，使其达到与补充的12个月心脏相当的水平；然而，GTN/EPO/Z并没有改善24个月DCD心脏的恢复。与12个月的心脏组织相比，24个月的心脏在复合体I、II和解偶联最大呼吸阶段的线粒体氧通量明显受损。
结论
DCD后缺血耐受性降低与年龄增加有关。药物补充可改善大鼠DCD心脏的功能恢复，但仅在18个月龄之前有效，这可能归因于随着年龄增长线粒体呼吸能力下降。
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