Getting personal: understanding how genetic variation affects clinical outcomes in patients with tetralogy of Fallot.
Getting personal: understanding how genetic variation affects clinical outcomes in patients with tetralogy of Fallot.
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DOI：
10.1038/pr.2012.104
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发表时间：
2012-10
影响因子：
3.6
通讯作者：
Wilder, Nicole S.
中科院分区：
文献类型：
--
作者：
Russell, Mark W.;Wilder, Nicole S.
研究结果：法洛四联症(TOF)是最常见的紫蓝色心脏病(1)。在手术修复之前，通常发生在生命的前6个月，受影响的婴儿右心室压力超负荷，可能出现间歇性或持续性低氧。由此产生的低氧和压力诱导的压力可能会对心脏的结构和功能产生持久的影响。手术修复后，包括封闭室间隔缺损和加宽右室流出道至肺动脉，缺氧得到缓解，压力显著降低。不幸的是，扩大的流出道会导致喷出的血液泄漏回右心室。随着时间的推移，这种肺功能不全会导致进行性的心功能障碍，最终需要在右心室和肺动脉之间放置一个合适的瓣膜(2)。这种功能障碍的进展速度可能因患者而异，临床上决定如何选择瓣膜置换术的时机以保持心功能和运动耐量一直具有挑战性(3)。多变且往往不可预测的临床过程表明，TOF患者对心脏状况或手术修复的反应方式的个体差异可能是决定何时需要瓣膜置换以及手术改善患者临床状况的有效程度的重要因素。因此，在他们的论文《法乐四联症修复术后右室重构的遗传决定因素》中，Jeewa等人(4)对我们理解其中一些个体差异可能是什么做出了重要贡献，并为为什么右室功能障碍的进展似乎在不同患者之间存在差异提供了洞察。鉴于低氧诱导因子1α(HIF1a)的重要性，低氧诱导转录因子(HIF1a)在调节一系列下游基因的表达以应对低氧(5，6)，研究小组检查了与HIF1a表达增强相关的遗传标记与(I)手术修复时的纤维化程度以及(Ii)术后随访期间右室结构和功能之间的相关性。他们指出，低表达的HIF1a变异体与手术时较少的纤维化有关，但在手术修复后增加了不利的心室重塑。这表明，控制低氧应激反应的遗传途径的个体差异可能在决定临床病程方面发挥重要作用。虽然还需要进行更多的研究来证实这一发现，但它提出了一种重要的可能性，即临床医生可能能够使用有重点的基因测试来识别哪些患者有可能更快地发展为不可逆性心功能障碍，并根据他们的风险对他们进行治疗。个体差异的重要性Jeewa和他的同事的文章的重要性超出了研究结果对TOF患者的影响。越来越多的证据表明，患者之间的遗传变异对决定先天性心脏病患者的预后具有重要作用，这是一个重要的贡献。Gaynor等人报告了基因变异对这类患者的临床结果产生重大影响的第一个证据。
StUDy fiNDiNgS Tetralogy of Fallot (TOF) is the most common form of cyanotic heart disease (1). Prior to surgical repair, which usually occurs within the first 6 months of life, affected infants have pressure overload on the right ventricle of the heart and can have episodic or persistent hypoxia. The resulting hypoxic and pressure-induced stress may have lasting effects on the structure and function of the heart. After surgical repair, which involves closing a ventricular septal defect and widening the right ventricular outflow tract to the pulmonary artery, the hypoxia is relieved and the pressure dramatically reduced. Unfortunately, the widened outflow tract leads to leakage of ejected blood back into the right ventricle. Over time, this pulmonary insufficiency causes progressive ventricular dysfunction that will eventually require placement of a competent valve between the right ventricle and the pulmonary artery (2). The rate at which this dysfunction progresses can vary from one patient to the next, and clinical determination of how to time valve replacement to preserve ventricular function and exercise tolerance has been challenging (3). The variable and often unpredictable clinical course suggests that individual differences in how patients with TOF respond to their heart condition or the surgical repair may be important in determining when valve replacement will be necessary and how effective the surgery will be in improving a patient’s clinical condition. Therefore, in their paper “Genetic determinants of right ventricular remodeling after tetralogy of Fallot repair,” Jeewa et al.(4) have made an important contribution to our understanding of what some of those individual differences may be and provide insight into why the progress of the right ventricular dysfunction seems to vary between patients. Given the importance of Hypoxia Inducible Factor, 1 alpha (HIF1A), a hypoxia-inducible transcription factor, in regulating the expression of a broad range of downstream genes in response to hypoxia (5, 6), the study team examined the correlation between genetic markers associated with enhanced HIF1A expression and (i) the degree of fibrosis at the time of surgical repair and (ii) the right ventricular structure and function during postoperative follow-up. They noted that low-expression HIF1A variants were associated with less fibrosis at the time of surgery but enhanced adverse ventricular remodeling after surgical repair. This suggests that individual differences in genetic pathways that govern the hypoxic stress response may have an important role in determining clinical course. Although additional studies will need to be performed to confirm this finding, it raises the important possibility that clinicians may be able, using focused genetic tests, to identify patients who are at risk for more rapid development of irreversible ventricular dysfunction and treat them patients according to their risk. iMPoRtANCe of iNDiviDUAl DiffeReNCeSThe importance of Jeewa and colleagues’ article extends beyond the implications of the findings for patients with TOF. It is an important contribution to the growing body of evidence that genetic variation between patients has an important role in determining outcomes in patients with congenital heart defects. Perhaps the first demonstration of a significant impact of genetic variation on clinical outcomes in this patient population was reported by Gaynor et al.(7), who examined the
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影响因子：
4.5
作者：
Dekanty A;Romero NM;Bertolin AP;Thomas MG;Leishman CC;Perez-Perri JI;Boccaccio GL;Wappner P
通讯作者：
Wappner P
影响因子：
37.8
作者：
Mital S;Chung WK;Colan SD;Sleeper LA;Manlhiot C;Arrington CB;Cnota JF;Graham EM;Mitchell ME;Goldmuntz E;Li JS;Levine JC;Lee TM;Margossian R;Hsu DT;Pediatric Heart Network Investigators
通讯作者：
Pediatric Heart Network Investigators
影响因子：
2.8
作者：
Therrien, J;Provost, Y;Webb, G
通讯作者：
Webb, G
DOI：
10.1016/s0022-5223(03)01188-7
发表时间：
2003-12-01
影响因子：
6
作者：
Gaynor, JW;Gerdes, M;Jarvik, GP
通讯作者：
Jarvik, GP
影响因子：
3.6
作者：
Jeewa, Aamir;Manickaraj, Ashok Kumar;Mital, Seema
通讯作者：
Mital, Seema