Vascular Remodeling in Overweight and Obese Adolescents

描述（由申请人提供）：大动脉血管重塑，如动脉硬化和扩张，是成人高血压的生物物理前提。儿童的新数据确定血管重塑是肥胖的一个特征，与现在和未来的高血压有关。Zachariah博士的研究项目通过评估减肥后的横截面相关性和纵向变化来研究青少年超重与血管重塑相关的中心假设。具体目标1使用联合的张力测定-超声心动图系统探索了以下假设：超重将与较高的管道动脉硬度（以中心脉压（PP）、前向脉搏波（FPW）、特征阻抗（Zc）和颈动脉股动脉脉搏波速度（CFPWV）为指标）以及与动脉扩张（以较大的有效主动脉直径（Da）为指标）相关。外围电阻（Zo）将较低，从而导致较高的脉搏波反射，如由全局反射系数（RC）所指示的。次要假设包括：a）中心PP的大部分变化是由FPW引起的，和B）超重和血管重塑之间的关联将被胰岛素抵抗、瘦素抵抗、炎症和醛固酮-肾素比率的循环标志物减弱。具体目标2检查了2个月的体重减轻对54名超重青少年（13-18岁）参加夏季减肥夏令营的动脉硬度和脉动负荷的影响。该K23奖项的教育部分将包括血管测试和生物标志物分析教学课程的实践培训，多个生物标志物“组学”平台的分析和临床试验。导师将来自Jane Newburger、Vasan Ramachandran和加里米切尔博士，他们在儿童心血管疾病（CVD）、成人CVD、CVD循环生物标志物和CVD血管表型方面具有特定的专业知识。在NIH赞助的哈佛催化剂临床转化科学单位和心脏病系的支持下，拟议的K23奖将提供结构化的指导，保护研究时间，并在模块化，广泛适用的心血管研究技术培训。该奖项将使Zachariah博士成为该国为数不多的独立资助的儿科心脏病学临床研究人员之一，研究高危儿童的血管医学。

DESCRIPTION (provided by applicant): Large-artery vascular remodeling, such as arterial stiffening and dilation, is a biophysical antecedent to hypertension in adults. Emerging data in children identifies vascular remodeling as a feature of obesity, which is associated with present and future hypertension. Dr. Zachariah's research project examines the central hypothesis that excess weight in adolescents is related to vascular remodeling by assessing cross-sectional correlation as well as longitudinal change after weight loss. Using a combined tonometry-echocardiography system, Specific Aim 1 explores the hypothesis that excess weight will be associated with higher conduit arterial stiffness as indexed by central pulse pressure (PP), forward pulse wave (FPW), characteristic impedance (Zc) and carotid femoral pulse wave velocity (CFPWV), as well as with arterial dilation as indexed by larger effective aortic diameter (Da). Peripheral resistance (Zo) will be lower leading to higher pulse wave reflection as indexed by global reflection coefficient (RC). Secondary hypotheses include that a) the majority of the variation in central PP will be due to FPW, and b) the association between excess weight and vascular remodeling will be attenuated by circulating markers of insulin resistance, leptin resistance, inflammation, and aldosterone-to-renin ratio. Specific Aim 2 examines the effect of 2 months of weight loss on arterial stiffness and pulsatile load in 54 excess weight adolescents 13-18 attending a summer weight loss camp The educational component of this K23 award will include hands-on training in vascular testing and didactic course- work in analysis of biomarkers, analysis of multiple biomarker "-omic" platforms, and clinical trials. Mentorship will come from Drs. Jane Newburger, Vasan Ramachandran, and Gary Mitchell who have specific expertise in pediatric cardiovascular disease (CVD), adult CVD, circulating biomarkers in CVD, and vascular phenotypes in CVD. Enhanced by support from the NIH-sponsored Harvard Catalyst Clinical Translational Science Unit and the Department of Cardiology, the proposed K23 award will provide structured mentorship, protected research time, and training in modular, broadly applicable cardiovascular research techniques. The award will position Dr. Zachariah to be one of the few independently-funded pediatric cardiology clinical researchers in the country studying vascular medicine in high-risk children.