Perrault L P, Bidouard J P, Janiak P, Villeneuve N, Bruneval P, Vilaine J P, Vanhoutte P M
Cardiovascular Division, Institut de Recherches Servier, Suresnes, France.
J Heart Lung Transplant. 1997 Jun;16(6):643-57.
Endothelial dysfunction is one of the early events leading to atherosclerosis. It occurs early after orthotopic heart transplantation and precedes the appearance of accelerated graft coronary artery disease believed to stem from chronic rejection of the endothelium. Acute rejection may contribute to the development of graft vasculopathy.
To assess the time course and specific mechanisms of coronary endothelial dysfunction in acute untreated rejection, a swine model of retroperitoneal heterotopic heart transplantation was used. Large white swine (age 10 +/- 2 weeks, weight 25 +/- 5 kg) were serum-typed for class I antigen of the swine leukocyte antigen system and selected to ensure a similar degree of incompatibility. Donor hearts were preserved with normothermic blood cardioplegia and regional hypothermia; the mean ischemic time was 64 +/- 15 minutes. Myocardial contractility decreased from day 5 (normal) to day 14 (weak), but electrical activity was preserved. All coronary arteries were patent, and International Society for Heart and Lung Transplantation grade 4 rejection was present in all hearts beyond 5 days. The endothelial function of epicardial coronary arterial rings of native and transplanted hearts was studied in organ chambers filled with modified Krebs-Ringer bicarbonate solution and compared 1, 5, 9, and 14 days after transplantation.
Maximal endothelium-independent relaxations were unaffected at all stages. Endothelium-dependent relaxations to serotonin and alpha 2-adrenergic agonist UK 14304 (which activate receptors coupled to Gi-proteins) and to sodium fluoride (a direct G-protein activator) deteriorated progressively over time. At 14 days maximal relaxations to the calcium ionophore A23187, adenosine diphosphate, and bradykinin were also reduced, but to a lesser degree than those to serotonin and sodium fluoride. Histomorphometric studies of the allograft coronary artery rings showed progressive intimal hyperplasia from day 5 to day 14, with an increase in the incidence from 29% +/- 8.3% to 61.5% +/- 12%.
These studies show that endothelial dysfunction in untreated acute rejection after heart transplantation develops beyond 5 days and initially involves G-proteins; the dysfunction worsens over time to finally affect all endothelial mechanisms and vascular smooth muscle. The progression of the associated intimal hyperplasia parallels the alteration in endothelial function, suggesting a permissive role of the dysfunction in the development of this acute form of coronary graft vasculopathy.
内皮功能障碍是导致动脉粥样硬化的早期事件之一。它在原位心脏移植后早期发生，早于被认为源于内皮慢性排斥反应的加速性移植冠状动脉疾病的出现。急性排斥反应可能促成移植血管病变的发展。
为评估急性未经治疗的排斥反应中冠状动脉内皮功能障碍的时间进程和具体机制，使用了猪腹膜后异位心脏移植模型。大型白色猪（年龄10±2周，体重25±5千克）进行猪白细胞抗原系统I类抗原血清分型，并进行选择以确保不相容程度相似。供体心脏采用常温血液停搏液和局部低温保存；平均缺血时间为64±15分钟。心肌收缩力从第5天（正常）到第14天（减弱）下降，但电活动得以保留。所有冠状动脉均通畅，5天后所有心脏均出现国际心肺移植学会4级排斥反应。在充满改良Krebs-Ringer碳酸氢盐溶液的器官浴槽中研究原位心脏和移植心脏的心外膜冠状动脉环的内皮功能，并在移植后1天、5天、9天和14天进行比较。
在所有阶段，最大非内皮依赖性舒张均未受影响。对血清素和α2-肾上腺素能激动剂UK 14304（激活与Gi蛋白偶联的受体）以及对氟化钠（直接G蛋白激活剂）的内皮依赖性舒张随时间逐渐恶化。在第14天，对钙离子载体A23187、二磷酸腺苷和缓激肽的最大舒张也降低，但程度小于对血清素和氟化钠的降低程度。同种异体移植冠状动脉环的组织形态计量学研究显示，从第5天到第14天内膜增生逐渐加重，发生率从29%±8.3%增加到61.5%±12%。
这些研究表明，心脏移植后未经治疗的急性排斥反应中的内皮功能障碍在5天后出现，最初涉及G蛋白；功能障碍随时间恶化，最终影响所有内皮机制和血管平滑肌。相关内膜增生的进展与内皮功能的改变平行，表明这种功能障碍在这种急性形式的冠状动脉移植血管病变发展中起允许作用。
