Vascular Remodeling in Overweight and Obese Adolescents

描述(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先兆。在儿童中出现的数据表明，血管重塑是肥胖的一个特征，肥胖与现在和未来的高血压有关。撒迦利亚博士的研究项目通过评估减肥后的横向相关性和纵向变化，检验了青少年超重与血管重塑有关的中心假设。通过结合眼压测量-超声心动图系统，特定目标1探索了这样的假设：超重与中心脉压(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)指标的导管动脉僵硬有关，以及与较大的有效主动脉内径(Da)指标的动脉扩张有关。外围电阻(Zo)将更低，从而导致以全局反射系数(RC)为指标的更高的脉搏波反射。第二个假设包括：a)中心脉压的大部分变化将是由于FPW，以及b)超重和血管重构之间的联系将被胰岛素抵抗、瘦素抵抗、炎症和醛固酮/肾素比率的循环标记物所减弱。具体目的2检验参加夏季减肥夏令营的54名13-18岁超重青少年的2个月减肥对动脉僵硬和脉动负荷的影响。这项K23奖项的教育部分将包括血管测试和生物标记物分析的教学课程的实践培训，多个生物标记物“组学”平台的分析，以及临床试验。导师将来自简·纽伯格博士、瓦桑·拉马钱德兰博士和加里·米切尔博士，他们在儿童心血管疾病(CVD)、成人心血管疾病、心血管循环生物标记物以及心血管疾病的血管表型方面拥有特定的专业知识。在NIH赞助的哈佛催化剂临床转化科学部和心脏病学部的支持下，拟议的K23奖项将在模块化、广泛适用的心血管研究技术方面提供结构化的指导、受保护的研究时间和培训。该奖项将使撒迦利亚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药物。

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.