Cardiovascular disease in fetal alcohol spectrum disorder

胎儿酒精谱系障碍中的心血管疾病

• 批准号: 10680484
• 负责人: CAROLINE E BURNS
• 金额: $ 34.34万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-10 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10680484
• 关键词: Adult; Affect; Animal Model; Biological Markers; Blood specimen; Body mass index; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cardiovascular Abnormalities; Cardiovascular Diseases; Cessation of life; Cholesterol; Clinic; Cone; Congenital Heart Defects; Data; Defect; Diagnosis; Diet; Disease Outcome; Disease model; Disease susceptibility; Double Outlet Right Ventricle; Doxorubicin; Dyslipidemias; EFRAC; Early Intervention; Early identification; Echocardiography; Embolism; Embryo; Embryonic Heart; Embryonic Induction; Ethanol; Evaluation; Fatty acid glycerol esters; Female; Fetal Alcohol Exposure; Fetal Alcohol Spectrum Disorder; Fetal alcohol effects; Future; Goals; Health; Heart; Heart Abnormalities; Heart failure; High Density Lipoproteins; Human; Hypertension; Immune; Incidence; Inflammation; Inflammatory; Larva; Longevity; Low-Density Lipoproteins; Mediating; Mediator; Metabolic; Modeling; Molecular; Molecular Profiling; Molecular Target; Morbidity - disease rate; Myocardial; Myocardial Infarction; Myocardial dysfunction; Newborn Infant; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Outcome; Overweight; Pathology; Pathway interactions; Patient-Focused Outcomes; Patients; Phenotype; Plasma; Platelet-Derived Growth Factor; Predisposition; Prevalence; Reporting; Research; Retrospective Studies; Risk; Risk Factors; Role; Severities; Stress cardiomyopathy; Stroke; Structure; Testing; Tetralogy of Fallot; Triglycerides; Ukraine; Validation; Ventricular; Work; Zebrafish; biomarker identification; cardiometabolism; cardiovascular disorder risk; cardiovascular health; clinically relevant; cohort; conotruncal heart defect; cytokine; embryonic alcohol exposure; exercise capacity; heart function; insight; male; migration; mortality; novel; patient population; predictive marker; premature; septal defect; transcriptome sequencing; vascular injury

Project Summary The incidence of congenital heart defects (CHDs) and cardiovascular disease (CVD) in patients with fetal alcohol spectrum disorder (FASD) are poorly characterized. Cardiovascular abnormalities may be common in FASD; however, comprehensive retrospective studies on lifetime CVD risk in adult patient cohorts have yet to be performed. Cellular and molecular mechanisms underlying FASD-mediated CHD and CVD are also largely unknown along with any biomarkers that would allow the patient population to be stratified based on CVD risk. Here we present preliminary data from our retrospective clinic cohort that demonstrate that females with FASD have an overall increase in CHD, myocardial infarction (MI) rate, and the likelihood of being diagnosed with any CVD in adulthood. Females with FASD also have significantly reduced ejection fraction relative to matched controls. These data suggest that FASD is a risk factor for CHD in newborns and CVD in adults. In a zebrafish model of embryonic alcohol exposure (EAE), we confirmed a primary defect in cardiomyocyte migration that causes subsequent functional and structural heart abnormalities, including contractility deficits and ventricular wall abnormalities that persist through adulthood. Our findings indicate that EAE zebrafish can serve as a model for lifelong cardiac function in the presence and absence of CHD. We propose three Specific Aims to test the central hypothesis that FASD patients have an increased incidence of CVD and that the zebrafish EAE model will uncover novel molecular mediators and biomarkers that explain and predict CVD risk. In Specific Aim 1, we will perform a retrospective study to determine CVD incidence in an adult FASD patient cohort, including CHD, hypertension, cardiomyopathy, MI, cerebrovascular accident, and embolism, as well as their association with other metabolic and inflammatory conditions. In Specific Aim 2, we will define molecular mechanisms underlying embryonic heart defects in a zebrafish EAE model by identifying and functionally evaluating the impact of molecular alterations in migratory myl7+ cardiomyocytes that form the cardiac cone through hypothesis-driven (PDGF pathway) and unbiased (bulk RNA-sequencing on FACS-isolated myl7+ cardiomyocytes) approaches. In Specific Aim 3, we will test the hypothesis that EAE adults with a CHD are susceptible to cardiac dysfunction and cardiomyopathy due to lasting alterations in cardiac structure, function, and molecular signature. Taken together, the proposed studies will provide fundamental insights into the cardiovascular health outcomes of patients with FASD, reveal novel molecular mediators of EtOH-induced CHDs, and identify biomarkers of adult cardiac dysfunction in EAE adults. Cardiovascular diseases may contribute significantly to morbidity and mortality in affected patients. By identifying which CVD outcomes impact FASD patients and what additional metabolic and inflammatory factors indicate risk, we will provide an opportunity for early intervention. Further, identification of molecular mediators of CHD and cardiomyopathy in a zebrafish model of EAE will allow us to expand our mechanistic understanding of the effects of PAE across the lifespan.

项目摘要 胎儿酒精患者的先天性心脏缺陷（CHD）和心血管疾病（CVD）的发病率 频谱障碍（FASD）的特征很差。心血管异常可能在FASD中很常见； 但是，成人患者同类群体中有关终生CVD风险的全面回顾性研究尚未 执行。 FASD介导的CHD和CVD的细胞和分子机制也很大 未知以及任何将根据CVD风险对患者群体进行分层的生物标志物。 在这里，我们介绍了回顾性诊所队列中的初步数据，该数据证明了女性具有FASD 总体上增加了CHD，心肌梗塞（MI）率，并被诊断出任何任何可能性 成年时的CVD。 FASD的女性相对于匹配的射血分数显着降低 控件。这些数据表明，FASD是新生儿和成人CVD的危险因素。在斑马鱼中 胚胎酒精暴露模型（EAE），我们证实了心肌细胞迁移的主要缺陷 导致随后的功能和结构心脏异常，包括收缩性缺陷和心室 墙上的异常在成年期间持续存在。我们的发现表明，Eae斑马鱼可以用作模型 在存在和不存在CHD的情况下终生心脏功能。我们提出了三个特定目标，以测试 中心假设是FASD患者的发生率增加了，斑马鱼EAE模型 将发现解释和预测CVD风险的新型分子介质和生物标志物。在特定目标1中，我们 将进行回顾性研究，以确定成年FASD患者队列中的CVD发病率，包括CHD， 高血压，心肌病，密歇根州，脑血管事故和栓塞及其与 其他代谢和炎症状况。在特定的目标2中，我们将定义基础的分子机制 斑马鱼EAE模型中的胚胎心脏缺陷通过识别和评估功能的影响 通过假设驱动的迁移my7+心肌细胞的分子改变 （PDGF途径）和无偏（在FACS分离的MYL7+心肌细胞上进行大量RNA）方法。 在特定的目标3中，我们将测试以下假设，即具有CHD的EAE成年人容易患心脏功能障碍 由于心脏结构，功能和分子特征的持续变化而引起的心肌病变。拍摄 拟议的研究一起将提供对心血管健康成果的基本见解 FASD患者，揭示了EtOH诱导的CHD的新型分子介质，并鉴定成人的生物标志物 EAE成年人的心脏功能障碍。心血管疾病可能对发病率和 受影响患者的死亡率。通过确定哪些CVD结果会影响FASD患者以及其他额外 代谢和炎症因素表明风险，我们将为早期干预提供机会。更远， 在EAE的斑马鱼模型中鉴定CHD和心肌病的分子介质将使我们能够 扩展我们对PAE在整个生命周期中影响的机械理解。