Longitudinal assessment of novel biomarkers for predicting cardiovascular disease in youth

 描述(申请人提供)：严重肥胖(BMI=第95个百分位数的120%)困扰着近6%的儿童和青少年，并且患病率继续上升。患有严重肥胖症的青少年面临长期健康并发症的严重风险，特别是心血管疾病(CVD)。内皮功能障碍是CVD过程中最早的表现，导致血管结构(颈动脉内中膜厚度(CIMT))和动脉僵硬(颈动脉增量弹性模数(CIEM))的改变。在成人中，CIMT增加和动脉僵硬与心血管疾病进展和未来心血管事件的预测有关。然而，儿童早期亚临床动脉粥样硬化进展的临床相关预测因素尚未确定，传统的心血管危险因素在预测心血管疾病进展方面并不比单纯的肥胖状态更好。因此，识别新的生物标记物是至关重要的，这些标记物将转化为临床实践，并预测CVD的进展。内皮细胞生物学的生物标志物，包括循环内皮细胞(CECs)和内皮微粒(EMP)，是晚期内皮细胞窘迫的标志，可能有助于识别和追踪患CVD风险最高的年轻人。虽然CECs和EMPs在成人中显示出了希望，但关于CECs和EMPs的数据在儿童和青少年中很少。患有严重肥胖的年轻人是检查CECs和EMP的理想模型，因为他们表现出高水平的CVD危险因素，并增加了早期CVD死亡的风险。此外，我们有强有力的横断面数据表明，儿童和青少年中的严重肥胖与这些内皮细胞生物标志物的不利水平有关。然而，CECs和EMPs是否能随着时间的推移预测亚临床动脉粥样硬化的变化还没有被研究。为了回答这些重要的问题，这项拟议的纵向研究的主要目的是检查CECs和EMPs在识别从正常体重到严重肥胖者的青少年亚临床动脉粥样硬化变化方面的预测价值。主要的假设是，CECs和EMPs将预测从正常体重到严重肥胖的一系列年轻人随着时间的推移CIMT和动脉僵硬的变化。此外，我们假设患有严重肥胖症的年轻人在 CIMT、动脉僵硬、CECs和EMPs高于正常体重和肥胖同龄人。这项提议将为严重肥胖的青少年提供新的纵向数据，以帮助描述 这个迅速发展的问题的风险。此外，这项提议将为受训人员贾斯汀·莱德博士提供新的技术接触和职业发展，他将致力于成为一名由联邦政府独立资助的临床翻译科学家，专注于肥胖青年的心血管疾病风险。

 DESCRIPTION (provided by applicant): Severe obesity (BMI =120% of the 95th percentile) afflicts nearly 6% of children and adolescents and continues to increase in prevalence. Youth with severe obesity are at serious risk for long-term health complications, particularly cardiovascular disease (CVD). Endothelial dysfunction is the earliest manifestation of the CVD process resulting in changes in vascular structure (carotid intima-medial thickness (cIMT)) and arterial stiffness (carotid incremental elastic modulus (cIEM)). In adults, increased cIMT and arterial stiffness are associated with CVD progression and predictive of future cardiovascular events. However, clinically relevant predictors of early subclinical atherosclerosis progression during childhood have yet to be identified, and traditional CVD risk factors are no better at predicting CVD progression than obesity status alone. Therefore, it is critical to identify novel biomarkers that will translate into clinical practice and are predictive of CVD progression. Biomarkers of endothelial cell biology, which include circulating endothelial cells (CECs) and endothelial micro-particles (EMPs), are hallmarks of advanced endothelial cell distress and may assist in identifying and tracking of youth at highest-risk for CVD. While CECs and EMPs have shown promise in adults, little data on CECs and EMPs exists in children and adolescents. Youth with severe obesity represent an ideal model for examining CECs and EMPs, as they exhibit elevated levels of CVD risk factors and are at increased risk for early CVD mortality. Moreover, we have strong cross-sectional data suggesting that severe obesity in children and adolescents is associated with adverse levels of these endothelial biomarkers. However, whether CECs and EMPs can predict changes in subclinical atherosclerosis over time has not been investigated. To answer these significant questions, the main aim of the proposed longitudinal study is to examine the predictive value of CECs and EMPs for identifying changes in subclinical atherosclerosis in youth ranging from normal weight to those with severe obesity. The primary hypothesis is that CECs and EMPs will be predictive of changes over time in cIMT and arterial stiffness across a spectrum of youth ranging from normal weight to severe obesity. Additionally, we hypothesize that youth with severe obesity will exhibit greater rates of change in cIMT, arterial stiffness, CECs, and EMPs than their normal weight and obese peers. This proposal will provide novel longitudinal data in youth with severe obesity to aid in characterizing the risk of the burgeoning problem. Furthermore, this proposal will provide new technical exposure and career development for the trainee, Justin Ryder, Ph.D., in his pursuit of becoming an independently federally-funded clinical translational scientist focused on CVD risk among youth with obesity.