Longitudinal Assessment of Cerebrovascular Autoregulation (CA) and Associations to Neurodevelopmental Delays in Infants and Toddlers with and without Congenital Heart Disease (CHD)

先天性心脏病（CHD）是美国主要的出生缺陷之一， 1，2尽管为预防和早期发现贫困人口作出了努力， 神经发育结果（NDO），许多患有CHD的儿童将有神经功能缺损持续到 4，5手术因素只能解释20%的不良NDO，6，7导致检查因素 CHD的内在原因是不良结局的原因。一个没有被广泛研究的假设是， 脑血管自动调节（CA）是CHD婴儿NDO较差的原因。8职业发展 我的总体目标是成为一名独立的学术研究者，制定策略和干预措施， 减少或预防易受伤害的儿科人群（如CHD患者）的发育迟缓， 提高他们的生活质量。这一目标与国家护理研究所的“症状 科学”的战略计划，因为它试图了解发展的机制途径 儿童CHD的延迟。我的职业发展计划是：提高我对心血管的了解， CHD和健康婴儿的脑生理学;学习如何使用平均动脉血的相关性分析CA 近红外光谱测量压力;熟悉复杂， 多层次，时间依赖模型;并提高赠款和手稿写作技能。的环境 洛杉矶儿童医院和南加州大学有支持和基础设施 完成我的训练和项目。K23的指导和培训计划将帮助我发现 损伤的机制，并可能导致改善CA的治疗，从而预防或减轻CA 高危儿童的发育迟缓。研究的目的是评估患有和不患有CA的婴儿和幼儿 CHD，并评估CA与出生时、6、9和18个月龄时间点的NDO的相关性。目标一： 比较CHD患儿与健康对照组在4个发育时间点的CA。目标2：评估 CHD婴儿中CA与NDO的相关性以及CA与NDO的相关性是否随年龄而变化。 诊断组（CHD vs对照组）。方法本研究采用前瞻性、纵向、两组队列设计。 我们将招募64名出生[± 2周]的婴儿（32名CHD和32名年龄和性别匹配的健康对照）， 在18个月随访期间约20%脱落后，50例患者有完整数据）。CA将使用姿势进行测量- 引起脑氧合的变化。NDO将使用标准的适龄工具进行测量，例如，的 贝利婴幼儿发展量表。影响如果本研究的假设得到支持， 受损的CA将被证明是CHD中NDO较差的重要决定因素，它们将作为新的 未来的预防干预目标，以改善这些高危儿童的发展成果。两 对冠心病高危儿CA受损的认识和早期干预的时间点，将提高 在这个弱势群体中的终身NDO。

Significance Congenital heart disease (CHD) is one of the leading birth defects in the United States, affecting approximately 40,000 newborns annually.1,2 Despite efforts aimed at prevention and early detection of poor neurodevelopmental outcomes (NDO), many children with CHD will have neurologic deficits lasting into adulthood.4,5 Surgical factors explain only 20% of these poor NDOs,6,7 leading to the examination of factors intrinsic to CHD as the cause for poor outcomes. A hypothesis not extensively examined is whether impaired cerebrovascular autoregulation (CA) is responsible for poorer NDOs in infants with CHD.8 Career Development Goals My overall goal is to be an independent academic investigator creating strategies and interventions to reduce or prevent developmental delays in vulnerable pediatric populations, such as those with CHD, thereby improving their quality of life. This goal aligns with the National Institute of Nursing Research’s “Symptoms Science” strategic plan because it seeks to understand the mechanistic pathways underlying developmental delay in children with CHD. My career development plan is to: improve my knowledge of cardiovascular and brain physiology in CHD and healthy infants; learn how to analyze CA using correlations of mean arterial blood pressures with Near-Infrared Spectroscopy measures; acquire familiarity of statistical analyses of complex, multilevel, time-dependent models; and enhance grant and manuscript writing skills. The environment at Children’s Hospital Los Angeles and the University of Southern California have the support and infrastructure necessary to complete my training and project. The mentoring and training plan of the K23 will help me discover the mechanism of injury and may lead to treatments that improve CA, which will prevent or attenuate developmental delays in high-risk children. Study Aims To assess CA in infants and toddlers with and without CHD, and to evaluate the association of CA with NDOs at birth, 6, 9, and 18-months of age time points. Aim #1: Compare CA between CHD infants and healthy controls through 4 developmental time points. Aim #2: Assess the association of CA with NDOs in CHD infants and whether the association of CA with NDOs varies across diagnostic groups (CHD vs controls). Methods This study is a prospective, longitudinal, 2-group cohort design. We will enroll 64 infants at birth [± 2 weeks] (32 with CHD and 32 age- and sex-matched healthy controls to yield 50 with complete data after ~20% attrition over the 18-month follow-up). CA will be measured using posture- induced changes in brain oxygenation. NDOs will be measured using standard age-appropriate tools, e.g., the Bayley Scales of Infant and Toddler Development IV. Impact If the hypotheses of this study are supported, impaired CA will be shown to be important determinants of poorer NDOs in CHD, and they will serve as new targets for future preventive interventions to improve developmental outcomes in these high-risk children. Both the knowledge of CHD infants at higher-risk for impaired CA and the early time points to intervene, will improve lifelong NDOs in this vulnerable population.