Kessler Elise L, Nikkels Peter Gj, van Veen Toon Ab
Department of Medical Physiology, University Medical Center Utrecht, 3584CM Utrecht, The Netherlands.
Department of Pathology, University Medical Center Utrecht, 3584CX Utrecht, The Netherlands.
Hum Pathol. 2017 Sep;67:101-108. doi: 10.1016/j.humpath.2017.07.012. Epub 2017 Jul 29.
Dilated cardiomyopathy (DCM) leads to disturbed contraction and force transduction, and is associated with substantial mortality in all age groups. Involvement of a disrupted composition of the intercalated disc (ID) has been reported. However, in children, little is established about such subcellular changes during disease, because of the pathological mix-up with the ongoing cardiac maturation. This leaves maladaptive remodeling often undetected. We aimed at illustrating subcellular alterations in children diagnosed with DCM compared to age-matched controls, focusing on ID proteins known to be crucially stable under healthy conditions and destabilized during cardiac injury in adults. Left ventricular or septal pediatric specimens were collected from 7 individuals diagnosed with DCM (age: 23 weeks in utero to 8 weeks postnatal) and age-matched controls that died of non-cardiovascular cause. We determined the amount of fibrosis and localization of ID proteins by immunohistochemistry. In pediatric DCM, most ID proteins follow similar spatiotemporal changes in localization as in controls. However, although no mutations were found, the signal of the desmosomal protein Desmoglein-2 was reduced in all pediatric DCM specimens, but not in controls or adult DCM patients. Endocardial and transmural fibrosis was increased in all pediatric DCM patients compared to age-matched controls. Composition of the ID in pediatric DCM patients is similar to controls, except for the localization of Desmoglein-2 and presence of severe fibrosis. This suggests that the architecture of desmosomes is already disturbed in the early stages of DCM. These findings contribute to the understanding of pediatric DCM.
扩张型心肌病（DCM）会导致收缩和力传导紊乱，并与所有年龄组的高死亡率相关。据报道，其涉及闰盘（ID）成分的破坏。然而，在儿童中，由于与持续的心脏成熟过程存在病理混淆，关于疾病期间这种亚细胞变化的了解甚少。这使得适应性不良的重塑常常未被发现。我们旨在阐明与年龄匹配的对照组相比，被诊断为DCM的儿童的亚细胞改变，重点关注已知在健康条件下至关重要且在成人心脏损伤期间不稳定的ID蛋白。从7名被诊断为DCM的个体（年龄：子宫内23周至出生后8周）和因非心血管原因死亡的年龄匹配对照组中收集左心室或室间隔儿科标本。我们通过免疫组织化学确定纤维化的程度和ID蛋白的定位。在儿科DCM中，大多数ID蛋白的定位时空变化与对照组相似。然而，尽管未发现突变，但桥粒蛋白桥粒芯糖蛋白-2在所有儿科DCM标本中的信号均降低，而在对照组或成人DCM患者中则未降低。与年龄匹配的对照组相比，所有儿科DCM患者的心内膜和透壁纤维化均增加。儿科DCM患者的ID组成与对照组相似，除了桥粒芯糖蛋白-2的定位和严重纤维化的存在。这表明在DCM的早期阶段桥粒结构已经受到干扰。这些发现有助于对儿科DCM的理解。
