Longitudinal assessment of novel biomarkers for predicting cardiovascular disease in youth

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 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.