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.
(RELEVANCE): Identifying biophysical and biochemical correlates of vascular remodeling may facilitate risk stratification for CVD in children, indicate candidate biological pathways involved early in vascular remodeling, and suggest specific targets for intervention.
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