Longitudinal assessment of novel biomarkers for predicting cardiovascular disease in youth

 描述（由申请人提供）：重度肥胖（BMI =第95百分位数的120%）困扰着近6%的儿童和青少年，并且患病率继续增加。患有严重肥胖症的年轻人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过程的最早表现，导致血管结构（颈动脉内膜中层厚度（cIMT））和动脉僵硬度（颈动脉增量弹性模量（cIEM））的变化。在成人中，cIMT和动脉硬度增加与CVD进展相关，并可预测未来的心血管事件。然而，儿童期早期亚临床动脉粥样硬化进展的临床相关预测因子尚未确定，传统的CVD危险因素在预测CVD进展方面并不比单独的肥胖状态更好。因此，关键是要确定新的生物标志物，将转化为临床实践，并预测CVD进展。内皮细胞生物学的生物标志物，包括循环内皮细胞（CEC）和内皮微粒（EMP），是晚期内皮细胞窘迫的标志，可能有助于识别和跟踪CVD风险最高的年轻人。虽然CEC和EMP在成人中显示出希望，但关于儿童和青少年CEC和EMP的数据很少。严重肥胖的青年是检查CEC和EMP的理想模型，因为他们表现出CVD危险因素水平升高，早期CVD死亡风险增加。此外，我们有强有力的横断面数据表明，儿童和青少年的严重肥胖与这些内皮生物标志物的不良水平有关。然而，CEC和EMP是否可以预测亚临床动脉粥样硬化随时间的变化还没有研究。为了回答这些重要的问题，拟议的纵向研究的主要目的是检查CEC和EMP的预测价值，以确定从正常体重到严重肥胖的青年亚临床动脉粥样硬化的变化。主要假设是CEC和EMP将预测从正常体重到严重肥胖的一系列青年中cIMT和动脉硬度随时间的变化。此外，我们假设，严重肥胖的年轻人将表现出更大的变化率， cIMT、动脉僵硬度、CEC和EMP。这项建议将提供新的纵向数据，在青年与严重肥胖，以帮助表征 这个新兴问题的风险。此外，该提案将为学员Justin Ryder博士提供新的技术接触和职业发展，在他的追求成为一个独立的联邦资助的临床转化科学家专注于心血管疾病的风险与肥胖的青年。

 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.