Validation of Circulating Endothelial Cells and Microparticles in Youth

摘要 对儿童慢性病生物标志物的验证是至关重要的，特别是在新兴的 儿童肥胖研究领域。因为心血管疾病(CVD)是一个累积发生的过程 随着时间的推移，识别最早的迹象以便更早地干预可能会对减缓其 进步。挑战是确定哪些肥胖青年早期有血管问题。展望未来 血管内皮细胞作为损伤的征兆是一种合理的方法，因为它在起源中的突出作用 动脉粥样硬化。然而，准确量化儿童的内皮健康已被证明是一个主要的 挑战。肱动脉血流介导性扩张(FMD)是最常用的定量方法 儿童血管内皮细胞健康。然而，这种技术并不是广泛适用的，因为它需要专门的 设备、训练有素的技术人员和结果可能是高度可变的。更直接地测量内皮细胞 细胞生物学，如循环内皮细胞(CEC)和内皮微粒(EMP)可能提供更大的 准确描述内皮细胞的状态，并可能识别高危个体。尽管 CEC和EMP在成人中得到验证，尚未在青年中进行正式评估。我们在这项研究中的主要重点 将CEC和EMP作为心血管风险的生物标记物，在整个肥胖症范围内进行评估 儿童和青少年，目标是验证CEC和EMP在儿科研究中的使用。我们 提出一个稳健的研究设计，采用三层方法来验证这些生物标志物：1)评估 CEC和EMP与CVD危险因素和内皮功能指标的相关性 (FMD)和亚临床动脉粥样硬化(颈动脉内中膜厚度)，2)CEC变化的评估 和电磁脉冲对接受选择性临床治疗的极度肥胖青少年的实质性体重减轻的反应 3)CEC和EMP的可重复性的纵向评估，以告知 使用这些终点设计未来的儿科研究。

Abstract Validation of chronic disease biomarkers in children is of paramount importance especially in the burgeoning arena of pediatric obesity research. Because cardiovascular disease (CVD) is a cumulative process occurring over time, identifying the earliest signs in order to intervene sooner may have a large impact on slowing its progression. The challenge is identifying which obese youth have early vascular problems. Looking to the vascular endothelium for signs of damage is a reasonable approach because of its prominent role in the origins of atherosclerosis. However, accurately quantifying endothelial health in children has proven to be a major challenge. Brachial artery flow-mediated dilation (FMD) is the most commonly-used method to quantify endothelial health in children. However, this technique is not widely applicable because it requires specialized equipment, a highly-trained technician, and results can be highly variable. More direct measures of endothelial cell biology, such as circulating endothelial cells (CEC) and endothelial microparticles (EMP), may offer greater precision in characterizing the state of the endothelium and may identify high-risk individuals. Despite being validated in adults, CEC and EMP have not been formally evaluated in youth. Our primary focus in this study will be the evaluation of CEC and EMP as biomarkers of CVD risk, throughout a spectrum of adiposity in children and adolescents, with a goal of validating CEC and EMP for use in pediatric research studies. We propose a robust study design with a three-tiered approach toward validating these biomarkers: 1) evaluation of the association of CEC and EMP concurrently with CVD risk factors and measures of endothelial function (FMD) and sub-clinical atherosclerosis (carotid intima-media thickness), 2) evaluation of the change in CEC and EMP in response to substantial weight loss in extremely obese adolescents undergoing elective, clinically- indicated bariatric surgery, and 3) longitudinal assessment of the reproducibility of CEC and EMP to inform the design of future pediatric studies using these endpoints.