Genetic determinants of right-ventricular remodeling after tetralogy of Fallot repair
Genetic determinants of right-ventricular remodeling after tetralogy of Fallot repair
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DOI：
10.1038/pr.2012.95
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发表时间：
2012-10-01
影响因子：
3.6
通讯作者：
Mital, Seema
中科院分区：
文献类型：
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作者：
Jeewa, Aamir;Manickaraj, Ashok Kumar;Mital, Seema
背景：缺氧诱导因子（HIF 1A）调节心肌对缺氧的反应和血流动力学负荷。我们研究了HIF 1A变异体与法洛四联症（TOF）修复后右心室（RV）重构的相关性。方法：对TOF儿童进行HIF 1A三个单核苷酸多态性的基因分型。分析基因型与完全修复时RV心肌蛋白表达和纤维化（n = 42）以及随访时RV扩张、面积变化分数和无肺动脉瓣/管道置换的相关性。结果：在180例TOF患者中，修复时平均年龄为1.0 ± 0.8岁，随访时间为9.0 ± 3.5岁; 82%有中度至重度肺功能不全。5年、10年和15年时无RV再介入的比例分别为92、84和67%。与对照组相比，具有更多功能性HIF 1A等位基因的患者在初始修复时具有更高的转化生长因子31表达和更多的纤维化（P < 0.05）。在随访期间，具有更多功能性HIF 1A等位基因的患者显示RV扩张较少，RV功能保留更好，RV再次介入的自由度更高（P < 0.05）。这证实了在一个复制队列的69 patients.CONCLUSION：在儿童谁了TOF修复，一个较低的数量的功能HIF 1A等位基因与RV扩张和功能障碍，表明缺氧适应未修复TOF可能会影响RV表型修复后。
BACKGROUND: Hypoxia-inducible factor (HIF1A) regulates the myocardial response to hypoxia and hemodynamic load. We investigated the association of HIF1A variants with right-ventricular (RV) remodeling after tetralogy of Fallot (TOF) repair.METHODS: Children with TOF were genotyped for three single-nucleotide polymorphisms in HIF1A. Genotypes were analyzed for association with RV myocardial protein expression and fibrosis at complete repair (n = 42) and RV dilation, fractional area change, and freedom from pulmonary valve/conduit replacement on follow-up.RESULTS: In 180 TOF patients, mean age at repair was 1.0 +/- 0.8 y with follow-up at 9.0 +/- 3.5 y; 82% had moderate to severe pulmonary insufficiency. Freedom from RV reinterventions at 5, 10, and 15 y was 92, 84, and 67%, respectively. Patients with more functioning HIF1A alleles had higher transforming growth factor 31 expression and more fibrosis at initial repair as compared with controls (P < 0.05). During follow-up, patients with more functioning HIF1A alleles showed less RV dilation, better preservation of RV function, and greater freedom from RV reinterventions (P < 0.05). This was confirmed in a replication cohort of 69 patients.CONCLUSION: In children who have had TOF repair, a lower number of functioning HIF1A alleles was associated with RV dilation and dysfunction, suggesting that hypoxia adaptation in unrepaired TOF may influence RV phenotype after repair.