Date of Graduation
School of Medicine
Physiology, Pharmacology & Neuroscience
Heart failure is a lifelong disability that for over half of those affected leads to mortality within five years after initial diagnosis. Left ventricular hypertrophy (LVH) is one of the most reliable independent predictors of heart failure. Pathological LVH is irreversible, but early diagnosis is often missed due to its asymptomatic nature. Obese Zucker rats (OZR), which develop obesity due to dysfunctional leptin signaling, naturally exhibit a LVH that mimics the obese human condition. Animal models are necessary because human donor tissue is scarce. The central hypothesis is that genes and proteins that are differentially expressed during development of LVH, relative to sex and obesity status, will serve as clinical biomarkers or therapeutic targets for detection and prevention of heart failure. No previous studies have addressed LVH on an exome-wide basis. In the present research, I address these knowledge gaps with transcriptome analysis of rat and human left ventricles in a sex- and obesity-specific manner. Specific genes (NPPA, NPPB, HBB, MYL7, PDK4) known to be involved in cardiac development and function were then validated proteomically to form a LVH gene signature that may be useful for future diagnosis or represent targets for intervention. This work defines novel LVH transcriptomes in humans and OZR and these datasets allow for confirmation of whether an individual gene or geneset is translationally-relevant for further investigation in LVH. Future work should address transcriptomic and proteomic changes throughout LVH development and whether intervention targeting specific gene products can ameliorate onset of LVH.
Newman, Mackenzie Shelby, "Obese Zucker Rats as a Reverse Translational Model of Human Left Ventricular Hypertrophy" (2020). Graduate Theses, Dissertations, and Problem Reports. 7982.
Available for download on Monday, August 16, 2021