Fetal markers of neurodevelopmental outcomes in congenital heart disease

项目总结 这份提案描述了一项为期五年的临床研究职业发展培训计划。 重点关注危重先天性心脏病(CHD)胎儿神经发育(ND)结局的预测因素。 应聘者接受过儿科和胎儿心脏病学方面的培训。 该奖项的目标是严格执行这项研究计划，利用所获得的培训 发展成为其他受训人员和初级教员的导师，并将此奖项作为成为 联邦政府资助的独立调查员。为了实现这些目标，申请人制定了一项培训计划， 将包括指导、课程工作、实践研究和教学教育活动。这 该项目将在帕特里克·麦克奎伦医学博士的指导下进行，他是神经发育领域的领导者 儿童先心病的结局。Donna Ferriero博士和Jim博士将提供补充指导 Barkovich博士说，他是一位研究脑成像和神经学结果之间相关性的专家。这 指导团队成功地指导了学生、研究员和初级教职员工，包括K-Level奖。一个 咨询委员会已经成立，以帮助指导候选人的职业发展。 这项应用的重点是了解脑血流和氧合的调节 与正常对照组相比，患有严重冠心病的胎儿。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 大动脉转位合并左心发育不良患者的神经学转归 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 患者有证据表明妊娠晚期和出生时大脑发育迟缓，容易受到围产期疾病的影响。 手术性脑白质损伤。这些发现的病因可能与脑氧含量异常有关。 由于CHD导致的分娩，这可能是继发性的脑血流灌注减少，血液减少 含氧量、新陈代谢变化或所有这些因素的组合。这项提案的第一部分侧重于 出生前时间段。我们计划展示脑血流调节的不同(通过 CHD胎儿与正常胎儿的经颅多普勒)和氧合(T2*MRI测量) 通过短暂给药母体高氧来剧烈改变生理的胎儿。为了实现这一目标，我们 计划在CHD和正常胎儿之间进行一项横断面研究，比较这些测量方法。 这项提案的第二部分延伸到出生后时间段，目的是了解 胎儿脑调节与出生后脑结构(出生时MRI)和功能(ND)的关系 12个月时的预后)。为了实现这一目标，我们计划对具有以下特征的胎儿进行前瞻性队列研究 TGA和HLHS来评估这种关系，并根据心脏病变来评估差异。这项提议将 确定胎儿生理对先心病胎儿ND结局的影响，为建立 未来的干预研究，最终目标是改善复杂CHD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.