A Novel Role for Sclerostin in Aortic Valve Stenosis

Abstract

In 2017 the sclerostin targeting monoclonal antibody Romosozumab was approved as a treatment for post-menopausal osteoporosis (PMO) despite cardiovascular side effects discovered in clinical trials. Previous studies indicated that sclerostin was present in the diseased aortic valve but its role was unknown. The first section of this dissertation characterizes the role of sclerostin in development of aortic valve stenosis (AVS). Mice wild-type (WT) and homozygous knockout (NULL) for the sclerostin gene (Sost) were aged on high-cholesterol diet and evaluated for development of AVS. NULL mice had no evidence of hemodynamic AVS, had thinner leaflets, and less myofibroblast activation compared to WT. This was associated with an upregulation of Hox gene expression which has recently shown to have protective effects in cardiovascular disease. This work introduces a novel role for sclerostin in AVS and a new association with Hox gene regulation.

To study the side-effects of sclerostin drug targeting, a strong pre-clinical model of PMO associated AVS must be developed. The second section of this dissertation evaluates the utility of the ovariectomy (OVX) model of PMO for the study of AVS. Mice underwent the sham and OVX procedure, were aged on high-cholesterol diet, and evaluated for development of AVS. OVX mice did not develop AVS, however there was strong evidence of left ventricle hypertrophy. While this model is insufficient for AVS study it may prove useful as a model of left ventricle hypertrophy in a PMO patient population.

The final section of this dissertation steps out of the laboratory and into the classroom to evaluate the efficacy of traditional (in-person) vs blended (combining online and in-person) learning styles in biomedical engineering education. Students in traditional and blended courses were surveyed on their experience and work samples were evaluated. Results indicated that students in the blended course had improved confidence and performance in course material compared to students in the traditional course. This research shows the potential strength of hybrid learning as virtual classroom becomes more prevalent in the wake of the COVID19 pandemic.