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: 10470413
• 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/10470413
• 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; 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; Mediating; Mediator of activation protein; 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; Ukraine; Validation; Ventricular; Work; Zebrafish; base; cardiometabolism; cardiovascular disorder risk; cardiovascular health; clinically relevant; cohort; conotruncal heart defect; cytokine; embryonic alcohol exposure; exercise capacity; heart function; insight; low density lipoprotein triglyceride; 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 胎儿酒精中毒患者先天性心脏病和心血管疾病的发生率 频谱紊乱（FASD）特征很差。心血管异常可能是常见的FASD; 然而，关于成年患者队列终生心血管疾病风险的全面回顾性研究还有待于 执行。FASD介导的CHD和CVD的细胞和分子机制在很大程度上也是 未知沿着任何生物标志物，允许患者人群基于CVD风险分层。 在这里，我们提供了来自我们回顾性临床队列的初步数据，表明FASD女性患者 冠心病、心肌梗死（MI）发生率以及被诊断为任何 成年后的CVD FASD女性患者的射血分数也显著降低， 对照这些数据表明FASD是新生儿CHD和成人CVD的危险因素。在斑马鱼体内 胚胎酒精暴露（EAE）模型，我们证实了心肌细胞迁移的主要缺陷， 导致随后的功能性和结构性心脏异常，包括收缩性缺陷和心室 持续到成年期的血管壁异常我们的研究结果表明，EAE斑马鱼可以作为一个模型， 在存在和不存在CHD的情况下，终身心脏功能。我们提出了三个具体目标，以测试 FASD患者CVD发病率增加，斑马鱼EAE模型 将揭示新的分子介质和生物标志物，解释和预测心血管疾病的风险。在具体目标1中， 将进行一项回顾性研究，以确定成人FASD患者队列的CVD发病率，包括CHD， 高血压、心肌病、心肌梗死、脑血管意外和栓塞，以及它们与 其他代谢和炎症状况。在具体目标2中，我们将定义 胚胎心脏缺陷的斑马鱼EAE模型，通过识别和功能评估的影响， 通过假设驱动的形成心脏锥的迁移myl 7+心肌细胞的分子改变 (PDGF途径）和无偏（对FACS分离的myl 7+心肌细胞进行批量RNA测序）方法。 在具体目标3中，我们将检验患有CHD的EAE成人易患心功能不全的假设 以及由于心脏结构、功能和分子特征的持续改变而引起的心肌病。采取 总之，拟议的研究将提供对心血管健康结果的基本见解， FASD患者，揭示了EtOH诱导的CHD的新分子介质，并鉴定了成人FASD的生物标志物。 EAE成人的心功能障碍。心血管疾病可能会大大增加发病率， 受影响患者的死亡率。通过确定哪些CVD结局会影响FASD患者， 代谢和炎症因素提示风险，我们将提供早期干预的机会。此外，本发明的目的是， 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在整个生命周期中的影响的机械理解。