Hemodynamics and mechanobiology of aortic valve inflammation and calcification

Abstract

Cardiac valves function in a mechanically complex environment, opening and closing close to a billion times during the average human lifetime, experiencing transvalvular pressures and pulsatile and oscillatory shear stresses, as well as bending and axial stress. Although valves were originally thought to be passive pieces of tissue, recent evidence points to an intimate interplay between the hemodynamic environment and biological response of the valve. Several decades of study have been devoted to understanding these varied mechanical stimuli and how they might induce valve pathology. Here, we review efforts taken in understanding the valvular response to its mechanical milieu and key insights gained from in vitro and ex vivo whole-tissue studies in the mechanobiology of aortic valve remodeling, inflammation, and calcification.

Figure 1

Schematic of mechanical forces experienced by the aortic valve during peak systole (a), and peak diastole (b). Insets depict qualitatively the effect of these forces on valve cells.

Figure 2

Flow patterns created at peak systole by different stenotic bioprosthetic aortic valves: (a) normal; (b) mildly stenotic; (c) moderately stenotic; (d) severely stenotic valves [6]. Schematic velocity profile at peak systole distal to (e) the normal aortic valve and (f) severely stenotic aortic valve [6].

Figure 3

Effects of steady shear stress on aortic valve biology. Collagen synthesis and sulfated glycosaminoglycan content in intact (a and b, resp.) and denuded (c and d, resp.) aortic valve leaflets under steady shear stress.

Figure 4

Inflammatory response of AV leaflets after exposure of the fibrosa to normal (native) and altered (ventricular) shear stress: immunostaining (blue: cell nuclei; green: ICAM-1/VCAM-1/TGF-β1; red: BMP-4); quantitative results (*P < .05 versus fresh).

Figure 5

Cytokine and cell-adhesion molecule expressions after exposure of the fibrosa to altered shear stress in culture medium supplemented with (a) noggin and (b) SB-431542 (*P < .05 versus fresh; ^#P < .05).

Figure 6

Cytokine and cell-adhesion molecule expressions after exposure of the fibrosa to (a) various shear stress magnitudes (*P < .05 versus fresh; ^#P < .05 versus physiologic/subphysiologic) and (b) severe supraphysiologic shear stress in medium supplemented with SB-431542 and noggin (*P < .05 versus fresh; ^#P < .05 versus standard medium (DMEM)).

Figure 7

Multiscale, hierarchical approach that is recommended for approaching the study of valve mechanobiology and mechanopathology.