Bolling S F, Benedict M B, Tramontini N L, Kilgore K S, Harlow H H, Su T P, Oeltgen P R
Section of Thoracic Surgery, University of Michigan Medical Center, Ann Arbor, USA.
Circulation. 1998 Nov 10;98(19 Suppl):II220-3; discussion II223-4.
Hypothermic cardioplegia provides myocellular protection, yet postischemic dysfunction remains a significant problem. Interestingly, the subcellular changes in hibernation parallel the altered biology of induced cardiac ischemia but are well tolerated by hibernated mammalian myocardium. An uncharacterized factor derived from hibernating animals, hibernation induction trigger (HIT), has been shown to induce hibernation in active animals and afford myocardial protection after ischemia-reperfusion injury. Therefore, it was of interest to further characterize the cardioprotective effects of HIT in the setting of ischemia-reperfusion injury.
To determine whether HIT could improve myocardial recovery after global ischemia, isolated rabbit hearts received either standard cardioplegia or HIT in the cardioplegia or underwent preperfusion with HIT before cardioplegia. Alternatively, to determine whether HIT requires metabolic alteration, additional rabbits had in vivo pretreatment with HIT from 15 minutes to 5 days before ischemia. All hearts underwent 2 hours of global ischemia at 34 degrees C. Recovery of postischemic isovolumic developed pressure, coronary flows, and MVO2 were compared. Compared with vehicle pretreatment, HIT pretreatment (1 hour) significantly enhanced indexes of functional recovery, including developed pressure (38 +/- 3 versus 69 +/- 7 mm Hg) and coronary flow (46 +/- 2 versus 82 +/- 11 mL/min). In addition, ultrastructural morphology was preserved but only with in vivo pretreatment. Liver protein content was not increased in rabbits treated from 12 hours to 5 days with HIT versus controls, belying a protein neosynthesis mechanism. However, the temporal sequences suggested conversion of an inactive HIT profactor to an active form.
Administration of serum derived from hibernating black bears to rabbits affords protection against ischemia-reperfusion injury compared with vehicle (saline)-treated animals in a rabbit isolated heart preparation. It is apparent that HIT deserves further identification and mechanistic study in the setting of ischemia-reperfusion injury.
低温心脏停搏可提供心肌细胞保护作用，但缺血后功能障碍仍是一个重大问题。有趣的是，冬眠时的亚细胞变化与诱导性心肌缺血时改变的生物学特性相似，但冬眠的哺乳动物心肌对此具有良好的耐受性。一种源自冬眠动物的未被鉴定的因子——冬眠诱导触发因子（HIT），已被证明能诱导活跃动物进入冬眠状态，并在缺血再灌注损伤后提供心肌保护。因此，进一步明确HIT在缺血再灌注损伤情况下的心脏保护作用很有意义。
为了确定HIT是否能改善全心缺血后的心肌恢复情况，将离体兔心在心脏停搏液中给予标准心脏停搏液或HIT，或者在心脏停搏前用HIT进行预灌注。另外，为了确定HIT是否需要代谢改变，让额外的兔子在缺血前15分钟至5天进行HIT的体内预处理。所有心脏在34℃下进行2小时的全心缺血。比较缺血后等容收缩压、冠状动脉血流量和心肌耗氧量的恢复情况。与载体预处理相比，HIT预处理（1小时）显著提高了功能恢复指标，包括收缩压（38±3对69±7mmHg）和冠状动脉血流量（46±2对82±11mL/min）。此外，超微结构形态得以保留，但仅在体内预处理时出现这种情况。与对照组相比，用HIT处理12小时至5天的兔子肝脏蛋白含量并未增加，这排除了蛋白质新合成机制。然而，时间顺序表明一种无活性的HIT前体因子转化为了活性形式。
在兔离体心脏制备中，与用载体（生理盐水）处理的动物相比，给兔子注射源自冬眠黑熊的血清可提供针对缺血再灌注损伤的保护作用。显然，HIT在缺血再灌注损伤情况下值得进一步鉴定和进行机制研究。
