Investigating Mitral Valve Disease Progression Using a Flow Loop Bioreactor
Connell, Patrick Sean
Doctor of Philosophy
Mitral regurgitation is a common but highly varied clinical disease that can have profound impacts on patient morbidity and mortality. While the effects of regurgitation on the rest of the cardiovascular system have been widely investigated, the direct effects on valve remodeling are understudied. From previous studies of mitral valve interstitial cells conducted using a variety of biomaterial and bioreactor platforms, it was established that valve interstitial cells respond to altered mechanical stimulation by changing their phenotype and remodeling the extracellular matrix. Here I sought to take advantage of an existing flow loop bioreactor capable of intact organ culture of porcine mitral valves, in order to investigate the remodeling response of valve tissues to the altered mechanics of the two main etiologies of mitral regurgitation. My global objective was to understand the specific changes to the biomechanical properties and extracellular matrix composition that occur in response to the altered mechanics of mitral regurgitation. The first aim successfully recreated the hemodynamic environment of non-regurgitant valves, valves experiencing mitral valve prolapse, and valves experiencing functional mitral regurgitation. Redesigning the flow loop system to enable precise control of the geometry of the valve annulus and papillary muscles enabled the creation of these models. The second aim of this study showed that previously healthy porcine mitral valves subjected to mitral valve prolapse hemodynamics undergo myxomatous remodeling, while valves placed in functional mitral regurgitation geometry and hemodynamics undergo fibrotic remodeling compared to non-regurgitant controls. The third aim showed that the pathophysiologic fibrotic remodeling of functional mitral regurgitation conditioned valves is partially reversible if valves previously cultured in functional mitral regurgitation conditions for a week are placed in non-regurgitant conditions for a subsequent week. Here the pattern of remodeling reversal was interesting, as those regions most affected both in our one-week FMR studies and in clinical samples were those that experienced reversal of fibrotic remodeling and more closely resembled controls. The impact of this thesis is to: 1) establish that the natural response of valve tissues to being placed in disease hemodynamics is to remodel in a way that resembles the disease phenotype; 2) demonstrate that this remodeling can be partially reversed if normal hemodynamics are reestablished; and 3) establish an experimental platform that can be used to explore directly the impact of physiological mechanical stimuli on valve biological functioning.