This project focuses on two specific mechanisms: the accelerated calcification of the valve and the abnormal remodeling of the aorta in the biscuspid aortic valve setting. We will study the effects of mechanical forces and signals transmitted from the soundings of the biscuspid aortic valve to the valve cells, as well as to cells embedded in the extracellular matrix.

Methods to be used during this study include experimental (3D PIV) and computational fluid dynamics, bioreactor design, cell and tissue cultures, immunohistochemistry, western blotting, and zymography.

Cardiovascular Tissue Engineering and Pre-conditioning
The challenges of aortic valve replacement include multiple operations for the implantation of a mechanical or bioprosthetic heart valve.  The latter of which, because it does not remodel, progressively loses its structure and, thus, its effectiveness. Over the past decade, some studies have produced structures that look and function similar to a valve, but these structures are not yet viable.

We believe the hemodynamic environment of a valve regulates tissue remodeling and that better understanding and identifying the optimal mechanical environment of growing tissue in vitro could enable the production of a biologically and mechanically functional tissue-engineered heart valve.

This project employs tissue engineering, mechanical testing, bioreactor design, immunohistochemistry, protein inhibition, western blotting, and zymography.

Fluid-based Multi-scale Modeling of Cardiovascular Disease Progression
The interactions of the cardiovascular system with its hemodynamic environment are critical to understanding both cardiovascular disease (the ways in which the disease initiates and progresses) and the way in which cardiovascular tissue remodels. Yet, the very nature (three-dimensionality of motions, deformations, organs and structures) of the system has limited the amount of information that could be captured. Because of this, the current approach to the flow environment of the cardiovascular system has been to focus on the development of computational models.

Our thrust is similar in nature, but we are complementing our models with the mechanobiological results obtained from the other projects in the Multi-scale Cardiovascular Bioengineering Laboratory. This will allow us to develop multi-scale computational fluid dynamic tools capable of more accurately predicting disease progression and tissue regeneration in specific hemodynamic conditions. Ideally, the outcome will aid in earlier diagnoses of cardiovascular pathologies, improve drug-related treatment efficacy, and lessen the need for replacement surgeries.

Balachandran K., Sucosky P., Jo H., Yoganathan A.P. "Elevated Cyclic Stretch Alters Matrix Remodeling in Aortic Valve Cusps - A Precursor to Degenerative Aortic Valve Disease". American Journal of Physiology - Heart
and Circulatory Physiology. 2009 (in press).

Sucosky P., Elhammali A., Balachandran K., Jo H., Yoganathan A.P. (2009) "Altered Shear Stress Stimulates Upregulation of Endothelial VCAM-1 and ICAM-1 in a BMP-4- and TGF-β1-Dependent Pathway". Arteriosclerosis, Thrombosis, and Vascular Biology. 2009; 29 (2):254-260.

Sucosky P., Padala M., Elhammali A., Balachandran K., Jo H., Yoganathan A.P. "Design of an Ex Vivo Culture System to Investigate the Effects of Shear Stress on Cardiovascular Tissue". Journal of Biomechanical Engineering.
2008; 130 (3):035001-035008.