Validation of Circulating Endothelial Cells and Microparticles in Youth

摘要 儿童慢性疾病生物标志物的验证至关重要，特别是在新兴的 儿童肥胖研究的竞技场。因为心血管疾病（CVD）是一个累积的过程， 随着时间的推移，识别最早的迹象，以便更快地进行干预，可能会对减缓其 进展目前的挑战是确定哪些肥胖青年有早期血管问题。展望 血管内皮损伤的迹象是一个合理的办法，因为它的突出作用的起源 动脉粥样硬化然而，准确地量化儿童内皮健康已被证明是一个主要的 挑战.肱动脉血流介导的舒张（FMD）是最常用的方法来量化 儿童的内皮健康。然而，这种技术并不广泛适用，因为它需要专门的 设备，训练有素的技术人员，结果可能是高度可变的。更直接的测量内皮细胞 细胞生物学，如循环内皮细胞（CEC）和内皮微粒（EMP），可以提供更大的 精确地表征内皮的状态，并且可以识别高风险个体。尽管是 CEC和EMP在成人中得到验证，但尚未在青年中进行正式评估。我们在这项研究中的主要焦点 将是CEC和EMP作为CVD风险的生物标志物的评估，在整个肥胖范围内， 儿童和青少年，目的是验证CEC和EMP用于儿科研究。我们 我提出了一个稳健的研究设计，采用三层方法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（颈动脉内膜中层厚度），2）CEC变化的评价 和电磁脉冲在极端肥胖青少年接受选择性，临床- 3）纵向评估CEC和EMP的再现性，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.