Mitral valve leaflet remodelling during pregnancy: insights into cell-mediated recovery of tissue homeostasis

Abstract

Little is known about how valvular tissues grow and remodel in response to altered loading. In this work, we used the pregnancy state to represent a non-pathological cardiac volume overload that distends the mitral valve (MV), using both extant and new experimental data and a modified form of our MV structural constitutive model. We determined that there was an initial period of permanent set-like deformation where no remodelling occurs, followed by a remodelling phase that resulted in near-complete restoration of homeostatic tissue-level behaviour. In addition, we observed that changes in the underlying MV interstitial cell (MVIC) geometry closely paralleled the tissue-level remodelling events, undergoing an initial passive perturbation followed by a gradual recovery to the pre-pregnant state. Collectively, these results suggest that valvular remodelling is actively mediated by average MVIC deformations (i.e. not cycle to cycle, but over a period of weeks). Moreover, tissue-level remodelling is likely to be accomplished by serial and parallel additions of fibrillar material to restore the mean homeostatic fibre stress and MVIC geometries. This finding has significant implications in efforts to understand and predict MV growth and remodelling following such events as myocardial infarction and surgical repair, which also place the valve under altered loading conditions.

Modeling the response of exogenously crosslinked tissue to cyclic loading: The effects of permanent set

“…In addition to the exogenously crosslinked tissue applications addressed herein, we have observed permanent set like phenomenon in mitral valve tissue during pregnancy [45]. In that study, our results suggested that much of the growth and remodeling in the MV leaflet does not begin immediately, but rather undergoes mostly passive leaflet enlargement until these parameters reach a critically low level, at which point growth and remodeling are triggered.…”

“…In addition, although the permanent set model we described only include the remodeling of the matrix due to scission-healing, the same concept can be extended by separating the rate constant into growth and resorption to simulate growth and remodeling of the matrix. Furthermore, the frame work outlined in section 5 can also be extended for the remodeling of the collagen fiber architecture, given further studies on mechanisms for how the collagen fiber architecture grows once the critical level observed in Rego et al [45] is exceeded. This is the advantage for the structural-based approach to modeling permanent set, which allows us to describe the mechanical response based on real physically measure-able quantities.…”

A noninvasive method for the determination of in vivo mitral valve leaflet strains

“…The homeostatic maintenance of MV leaflet tissue composition and microstructure, primarily mediated by interstitial cell deformation, has been shown to depend on direction‐specific loading patterns . For a physiologically relevant interpretation of strains, it is thus necessary to examine each component of the strain tensor individually.…”

“…Such alterations place the MV in a nonphysiological loading state, leading to valvular tissue growth and remodeling . In light of this, recent studies have begun to elucidate links between MV function at the organ level and the mechanobiological responses of the underlying MV interstitial cells, which ultimately drive remodeling . These investigations have uncovered and quantified detailed relationships between MV leaflet stretch and interstitial cell deformation.…”

“…These investigations have uncovered and quantified detailed relationships between MV leaflet stretch and interstitial cell deformation. Furthermore, specific cellular deformation patterns have been associated with concurrent remodeling in the extracellular matrix of the MV leaflets, mainly via biosynthetic changes to the tissue's collagen and elastin networks . These findings strongly suggest that significant MV remodeling occurs after MI and surgical repair, as both of these events result in substantial changes to the MV.…”