Migliazza L, Otten C, Xia H, Rodriguez J I, Diez-Pardo J A, Tovar J A
Department of Surgery, Hospital Infantil La Paz, Madrid, Spain.
J Pediatr Surg. 1999 Sep;34(9):1352-8. doi: 10.1016/s0022-3468(99)90010-6.
BACKGROUND/PURPOSE: Cardiovascular malformations (CVM) associated with congenital diaphragmatic hernia (CDH) account in part for the high mortality caused by this defect. The aim of this study is to examine the nature of these malformations in a large series of autopsies and to assess if similar defects are also present in rat fetuses with experimental CDH.
The incidence of CVM and their nature were examined in the autopsy records of 136 stillborns and neonates with CDH admitted to our institution in the last 30 years. Experimental CDH was induced in rat fetuses by giving 100 mg of nitrofen to their mothers on gestational day 9.5, and the fetuses were harvested on day 21 (near full term). The presence of CDH and the anatomy of the heart and great vessels were studied under dissecting microscope after formalin fixation. Unexposed fetuses were used as controls.
Thirty-three newborns with CDH (24%) had CVM, either isolated or associated with other defects, and 7 had heart hypoplasia. Most CVM (ventricular septal defect, tetralogy of Fallot, transposition of the great vessels, double-outlet right ventricle) involved the outflow tract. In our animal experiments, no malformations were found in 21 control pups. Conversely, 80 of 130 nitrofen-exposed fetuses (61%) had CDH, and 59 of them (74%) had CVM. A significant association (Fisher's Exact test, P<.01) was found between CDH and CVM because only 25 of the 50 exposed animals without CDH (50%) had CVM. Again, most defects involved the outflow tract and were similar to those seen in human CDH (tetralogy of Fallot, persistent truncus, ventricular septal defect, double-outlet right ventricle, aberrant right subclavian artery, agenetic ductus, and interrupted aortic arch). Animals with CDH had significantly decreased heart weight to fetal weight ratio in comparison with controls and with those without CDH.
The similar nature of the cardiovascular defects found in babies succumbing to CDH and in nitrofen-exposed rats suggests that a similar disturbance of the regional organogenesis related to the neural crest might be involved in both settings, and further validates the use of this animal model for clarifying the cellular and molecular pathogenetic mechanisms.
背景/目的：与先天性膈疝（CDH）相关的心血管畸形（CVM）是导致该缺陷高死亡率的部分原因。本研究的目的是在大量尸检中检查这些畸形的性质，并评估实验性CDH大鼠胎儿中是否也存在类似缺陷。
在过去30年中，对我院收治的136例患有CDH的死产儿和新生儿的尸检记录进行检查，以确定CVM的发生率及其性质。在妊娠第9.5天给大鼠母亲服用100mg硝基芬，诱导大鼠胎儿发生实验性CDH，并在第21天（接近足月）取出胎儿。经福尔马林固定后，在解剖显微镜下研究CDH的存在以及心脏和大血管的解剖结构。未暴露的胎儿用作对照。
33例患有CDH的新生儿（24%）有CVM，可为孤立性或与其他缺陷相关，7例有心脏发育不全。大多数CVM（室间隔缺损、法洛四联症、大动脉转位、右心室双出口）累及流出道。在我们的动物实验中，21只对照幼崽未发现畸形。相反，130只暴露于硝基芬的胎儿中有80只（61%）患有CDH，其中59只（74%）有CVM。发现CDH与CVM之间存在显著关联（Fisher精确检验，P<0.01），因为在50只未患CDH的暴露动物中，只有25只（50%）有CVM。同样，大多数缺陷累及流出道，与人类CDH所见相似（法洛四联症、永存动脉干、室间隔缺损、右心室双出口、右锁骨下动脉异常、动脉导管未闭和主动脉弓中断）。与对照组和未患CDH的动物相比，患有CDH的动物心脏重量与胎儿体重之比显著降低。
死于CDH的婴儿和暴露于硝基芬的大鼠中发现的心血管缺陷性质相似，这表明在这两种情况下可能都涉及与神经嵴相关的区域器官发生类似紊乱，并进一步验证了使用该动物模型来阐明细胞和分子发病机制的合理性。
