Department of Cardiology and Vascular Medicine, University of Mainz, Langenbeckstrasse 1, Mainz, Germany.
J Heart Lung Transplant. 2009 Nov;28(11):1119-26. doi: 10.1016/j.healun.2009.05.038. Epub 2009 Sep 26.
Cardiac allografts are known to develop myocardial fibrosis, which may be a cause of progressive cardiac dysfunction. Apart from the renin-angiotensin and transforming growth factor-beta system, hypoxia has been proposed as an important player in the pathogenesis of fibrosis, but its significance remains unclear. This study examines the degree of myocardial fibrosis, cellular remodeling and hypoxic signaling over a time-course of 10 years after human cardiac allograft transplantation.
Serial right ventricular biopsies of 57 patients were collected in 6-month intervals after cardiac transplant surgery for a total of 10 years to allow a retrospective longitudinal analysis. Over this period, tissue remodeling, including interstitial fibrosis and cellular changes, were determined morphometrically. Immunohistochemistry (IHC) was used to analyze expression of the following hypoxia-related proteins: hypoxia-induced factor 1-alpha (HIF1alpha); the oxygen sensor prolyl hydroxylase 3 (PHD3); and vascular endothelial growth factor (VEGF).
Fibrosis increased significantly from 12.6 +/- 6.5% at the point of transplantation throughout follow-up to 28.8 +/- 7.7% at 10 years. The DNA content and number of nuclei changed over the period of follow-up, displaying signs of cellular hypertrophy and a loss of myocytes. Whereas HIF1alpha expression revealed a U-shaped pattern with both early and late elevation during fibrogenesis, PHD3 and VEGF expression patterns showed a gradual increase with PHD3 decreasing again in later fibrogenesis.
In cardiac allografts, extensive and progressive tissue remodeling is present. Hypoxia may play a role in this process by up-regulating HIF1alpha and leading to differential regulation of pro-angiogenic signals.
已知同种异体心脏移植物会发生心肌纤维化，这可能是心脏功能进行性障碍的原因之一。除了肾素-血管紧张素和转化生长因子-β系统之外，缺氧也被认为是纤维化发病机制中的一个重要因素，但它的意义仍不清楚。本研究在同种异体心脏移植后 10 年内的时间过程中，检查了心肌纤维化、细胞重构和缺氧信号的程度。
在心脏移植手术后的 6 个月间隔内，对 57 例患者的右心室活检进行了连续采集，共 10 年，以允许进行回顾性纵向分析。在此期间，通过形态计量学确定组织重构，包括间质纤维化和细胞变化。免疫组织化学（IHC）用于分析以下与缺氧相关的蛋白质的表达：缺氧诱导因子 1-α（HIF1α）；氧传感器脯氨酰羟化酶 3（PHD3）；和血管内皮生长因子（VEGF）。
纤维化从移植时的 12.6%±6.5%显著增加，整个随访期间增加到 10 年时的 28.8%±7.7%。DNA 含量和核数在此期间发生变化，显示出细胞肥大和心肌细胞丧失的迹象。虽然 HIF1α表达呈现出纤维化过程中早期和晚期升高的 U 形模式，但 PHD3 和 VEGF 表达模式显示出逐渐增加，PHD3 在晚期纤维化中再次减少。
在同种异体心脏移植物中，存在广泛而进行性的组织重构。缺氧可能通过上调 HIF1α并导致促血管生成信号的差异调节在这个过程中发挥作用。
