Fetal markers of neurodevelopmental outcomes in congenital heart disease

项目摘要 该提案描述了一个为期五年的培训计划，以发展临床研究的职业生涯 重点关注危重先天性心脏病（CHD）神经发育（ND）结局的胎儿预测因素。 候选人接受过儿科和胎儿心脏病学培训。 该奖项的目标是严格执行这项研究计划，利用获得的培训， 发展成为其他学员和初级教师的导师，并利用这个奖项作为一种工具，成为一个 联邦政府资助的独立调查员为了实现这些目标，申请人制定了培训计划， 将包括指导、课程工作、动手进行研究和教学教育活动。这 该项目将在帕特里克麦奎伦，医学博士，神经发育的领导者指导下进行 CHD患儿的结局。补充指导将由唐娜费列罗博士和吉姆提供 巴科维奇，专家在建立脑成像和神经系统的结果之间的相关性。这 导师团队成功地指导了学生，研究员和初级教师，包括K级奖项。一个 顾问委员会已成立，以协助指导候选人的职业发展。 这个应用程序的重点是了解脑血流和氧合的调节， 严重CHD胎儿与正常对照组的比较。此外，该议定书旨在 确定胎儿大脑调节和适应与出生后结构和功能之间的联系 大动脉转位（TGA）和左心发育不良患者的神经系统结局 综合征（HLHS），两种常见但生理上不同的心脏病变。文献表明，这些 患者在妊娠后期和出生时有大脑发育延迟的证据，并且容易受到脑损伤， 手术性白色损伤。这些发现的病因可能与脑氧含量异常有关 由于CHD而分娩，这可能继发于脑灌注减少，血液循环减少， 氧含量、新陈代谢的变化或所有这些的组合。本建议的第一部分重点是 产前时期。我们计划证明脑血流调节的差异（通过测量 经颅多普勒）和氧合（如通过T2* MRI测量）在CHD胎儿与正常胎儿相比 胎儿通过利用母体短暂的高氧来急性改变生理。因此我们 计划进行一项横断面研究，比较CHD和正常胎儿的这些指标。 这项建议的第二部分延伸到出生后的时间段，旨在了解 胎儿脑调节与出生后脑结构（出生时MRI）和功能（ND）关系 12个月时的结果）。为了实现这一目标，我们计划对胎儿进行一项前瞻性队列研究， TGA和HLHS评估这种关系，并评估心脏病变的差异。这项建议会 确定胎儿生理学对CHD胎儿ND结局的影响，为建立 未来的干预研究，最终目标是改善患有复杂CHD的儿童的ND结局。

PROJECT SUMMARY This proposal describes a five-year training program for development of a career in clinical research focused on fetal predictors of neurodevelopmental (ND) outcome in critical congenital heart disease (CHD). The candidate has training in pediatric and fetal cardiology. The goals of this award are to rigorously conduct this research proposal, to use the training obtained to develop into a mentor to other trainees and junior faculty and to use this award as a vehicle to become a federally funded independent investigator. To achieve these goals, the applicant has set up a training plan that will include mentoring, course work, hands-on conduct of research and didactic educational activities. This project will be carried out under the mentorship of Patrick McQuillen, MD, a leader in neurodevelopmental outcomes of children with CHD. Complementary mentorship will be provided by Drs. Donna Ferriero and Jim Barkovich, experts in establishing correlations between brain imaging and neurologic outcomes. This mentoring team has successfully mentored students, fellows and junior faculty, including K-level awards. An advisory committee has been assembled to help guide the candidate's career development. This application focuses on understanding the regulation of cerebral blood flow and oxygenation in fetuses with critical CHD as compared to a normal comparative group. Furthermore, the protocol aims to identify the link between fetal cerebral regulation and adaptation with postnatal structural and functional neurologic outcomes in patients with transposition of the great arteries (TGA) and hypoplastic left heart syndrome (HLHS), two common yet physiologically distinct cardiac lesions. Literature demonstrates that these patients have evidence of delayed brain development in late gestation and at birth and are vulnerable to peri- operative white matter injury. The etiology of these findings is likely related to abnormalities in cerebral oxygen delivery as a result of CHD, which may be secondary to decreased cerebral perfusion, decreased blood oxygen content, changes in metabolism or a combination of all. The first part of this proposal focuses on the prenatal time period. We plan to demonstrate differences in regulation of cerebral blood flow (as measured by trans-cranial Doppler) and oxygenation (as measured by T2* MRI) in CHD fetuses as compared to normal fetuses by utilizing brief administration of maternal hyperoxia to acutely alter physiology. To achieve this, we plan to perform a cross-sectional study comparing these measures between CHD and normal fetuses. The second component of this proposal extends to the postnatal time period and aims to understand the relationship between fetal cerebral regulation and postnatal brain structure (MRI at birth) and function (ND outcome at 12 months) in CHD. To achieve this, we plan to conduct a prospective cohort study of fetuses with TGA and HLHS to assess this relationship and to assess differences by cardiac lesion. This proposal will identify fetal physiologic effects on ND outcome in fetuses with CHD, providing critical information to set up future intervention studies with an eventual goal of improving ND outcomes in children with complex CHD.