Vascular Remodeling in Overweight and Obese Adolescents

描述（由申请人提供）：大动脉血管重构，如动脉硬化和扩张，是成人高血压的生物物理前兆。在儿童中出现的新数据表明，血管重构是肥胖的一个特征，与现在和未来的高血压有关。Zachariah博士的研究项目通过评估横截面相关性和减肥后的纵向变化，检验了青少年超重与血管重塑有关的核心假设。通过联合血压计-超声心动图系统，Specific Aim 1探讨了超重将与较高的导管动脉硬度（以中心脉压（PP）、前向脉波（FPW）、特征阻抗（Zc）和颈动脉股脉波速度（CFPWV）为指标）以及动脉扩张（以较大的有效主动脉直径（Da）为指标）相关的假设。外围电阻（Zo）越低，脉冲波反射系数（RC）越高。次要假设包括：a)中心PP的大部分变异是由FPW引起的；b)超重和血管重构之间的关联将被胰岛素抵抗、瘦素抵抗、炎症和醛固酮-肾素比等循环标记物减弱。具体目标2研究了参加夏季减肥营的54名13-18岁超重青少年2个月的减肥对动脉僵硬度和脉搏负荷的影响。K23奖的教育部分将包括血管测试的实践培训和教学课程——生物标志物分析、多种生物标志物“组学”平台分析和临床试验。指导将来自博士。Jane Newburger， Vasan Ramachandran和Gary Mitchell，他们在儿科心血管疾病（CVD），成人心血管疾病，CVD循环生物标志物和CVD血管表型方面具有专门的专业知识。在美国国立卫生研究院（nih）赞助的哈佛催化剂临床转化科学部门和心脏病学系的支持下，拟议的K23奖将提供结构化的指导、受保护的研究时间，以及模块化、广泛适用的心血管研究技术的培训。该奖项将使Zachariah博士成为美国为数不多的独立资助的研究高危儿童血管医学的儿科心脏病学临床研究人员之一。

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.