Felkin Leanne E, Lara-Pezzi Enrique, George Robert, Yacoub Magdi H, Birks Emma J, Barton Paul J R
Harefield Heart Science Centre, National Heart and Lung Institute, Imperial College London, Harefield, Middlesex, UK.
J Heart Lung Transplant. 2009 Feb;28(2):117-22. doi: 10.1016/j.healun.2008.11.910.
Abnormalities in the extracellular matrix (ECM) can occur in heart failure. In this study we analyzed ECM gene expression in patients with advanced dilated cardiomyopathy who did and did not develop sustained myocardial recovery after left ventricular assist device (LVAD) unloading combined with pharmacologic therapy.
Myocardial gene expression of collagens (COL1A1 and COL3A1), fibronectin (FN), matrix metalloproteinases (MMPs 1 to 14), tissue inhibitors of metalloproteinases (TIMPs 1 to 4), connective tissue growth factor (CTGF), transforming growth factor-beta1 (TGF-beta1) and THY1 was measured by real-time reverse transcriptase-polymerase chain reaction (RT-PCR) at LVAD implantation and again at explantation (recovery, n = 11) or transplantation (non-recovery, n = 5).
The non-recovery group had higher levels of pro-fibrotic markers (COL1A1, TGF-beta1 and THY1) at implantation compared with the recovery group (1.82 +/- 0.74-, 1.81 +/- 0.69- and 3.01 +/- 1.70-fold, respectively; p <or= 0.05). Both recovery and non-recovery groups showed no significant difference in gene expression after treatment, but levels of pro-fibrotic genes (COL1A1, COL3A1, FN and THY1) correlated negatively with post-explant ejection fraction in the recovery group. Of all genes analyzed only TIMP4 showed a significant change, with expression reduced during recovery (0.55 +/- 0.25-fold at explant vs implant, p = 0.001). All other genes showed complex patterns between individuals with both increased and decreased expression of pro-fibrotic markers, MMPs and TIMPs in recovery patients.
Patients who did not recover had higher myocardial expression of pro-fibrotic genes at LVAD implantation, and in recovered patients higher levels at explant were negatively associated with subsequent ejection fraction. However, individual patients showed complex expression patterns and a decrease in pro-fibrotic markers was not required for recovery.
细胞外基质（ECM）异常可发生于心力衰竭。在本研究中，我们分析了晚期扩张型心肌病患者在左心室辅助装置（LVAD）卸载联合药物治疗后出现或未出现持续性心肌恢复的患者的ECM基因表达情况。
通过实时逆转录聚合酶链反应（RT-PCR）在LVAD植入时以及再次在心脏移植时（恢复组，n = 11）或移植时（未恢复组，n = 5）测量胶原蛋白（COL1A1和COL3A1）、纤连蛋白（FN）、基质金属蛋白酶（MMPs 1至14）、金属蛋白酶组织抑制剂（TIMPs 1至4）、结缔组织生长因子（CTGF）、转化生长因子-β1（TGF-β1）和THY1的心肌基因表达。
与恢复组相比，未恢复组在植入时促纤维化标志物（COL1A1、TGF-β1和THY1）水平更高（分别为1.82±0.74倍、1.81±0.69倍和3.01±1.70倍；p≤0.05）。恢复组和未恢复组在治疗后基因表达均无显著差异，但恢复组中促纤维化基因（COL1A1、COL3A1、FN和THY1）水平与心脏移植后射血分数呈负相关。在所有分析的基因中，只有TIMP4表现出显著变化，其表达在恢复过程中降低（移植时相对于植入时为0.55±0.25倍，p = 0.001）。所有其他基因在恢复患者中表现出复杂的模式，促纤维化标志物、MMPs和TIMPs的表达既有增加也有减少。
未恢复的患者在LVAD植入时心肌促纤维化基因表达较高，而恢复患者在心脏移植时较高水平与随后的射血分数呈负相关。然而，个体患者表现出复杂的表达模式，恢复并不需要促纤维化标志物降低。
