Cardiovascular disease in fetal alcohol spectrum disorder

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 谱系障碍(FASD)的特征很差。心血管异常可能在FASD中常见； 然而，对成年患者队列中终生心血管疾病风险的全面回顾研究尚未完成。 已执行。FASD介导的CHD和CVD的细胞和分子机制也在很大程度上 未知以及任何生物标记物，可以根据心血管疾病风险对患者群体进行分层。 在这里，我们提供了来自我们回溯性临床队列的初步数据，这些数据表明患有FASD的女性 冠心病、心肌梗死(MI)发生率和被诊断为 成年期的心脑血管疾病。患有FASD的女性与匹配的女性相比，射血分数也显著降低 控制。这些数据表明，FASD是新生儿CHD和成人CVD的危险因素。在斑马鱼身上 胚胎酒精暴露(EAE)模型，我们证实了心肌细胞迁移的一个主要缺陷，即 导致随后的心脏功能和结构异常，包括收缩功能障碍和心室 在成年期持续存在的墙体畸形。我们的发现表明，EAE斑马鱼可以作为一个模型 在存在和不存在冠心病的情况下用于终生心脏功能。我们提出了三个具体目标来测试 FASD患者心血管疾病发病率增加的中心假设以及斑马鱼EAE模型 将发现解释和预测心血管疾病风险的新的分子介质和生物标记物。在具体目标1中，我们 将进行一项回顾性研究，以确定成年FASD患者队列中心血管疾病的发病率，包括CHD， 高血压、心肌病、心肌梗死、脑血管意外和栓塞症及其与 其他代谢和炎症情况。在具体目标2中，我们将定义潜在的分子机制 斑马鱼EAE模型中胚胎心脏缺陷的识别和功能评估的影响 假说驱动下形成心锥的移行Myl7+心肌细胞的分子变化 (PDGF途径)和无偏(FACS分离的Myl7+心肌细胞的批量RNA测序)方法。 在具体目标3中，我们将检验患有冠心病的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久变化而导致的心肌病。已被占用 总之，拟议的研究将为以下人群的心血管健康结果提供基本见解 FASD患者揭示乙醇诱导的CHD的新分子介质，并确定成人的生物标志物 成人EAE患者的心功能不全。心血管疾病可能对发病率和 受影响患者的死亡率。通过确定哪些心血管结果会影响FASD患者，以及其他哪些 代谢和炎症因素预示风险，我们将提供早期干预的机会。此外， 在斑马鱼EAE模型中识别冠心病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。

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.