How the mitral valve increases its dimensions
Increase of MV (leaflets and chordae tendinae) dimensions include ECM
adaptation. A natural model of these changes is represented by
pregnancy, where MV adapts to new hemodynamics. During pregnancy, an
increased demand in oxygen to support fetal development drives an
increase in maternal blood volume by up to 40%. This volume overload
results in cardiovascular adaptation. As the heart adapts to increased
oxygen demands by ventricular hypertrophy, dilation of the periannular
tissue increases the MV orifice area (around 12%). These geometric
changes alter the radius of curvature and the tension of the leaflets
and are at the basis of tissue growth and
remodeling20.
In pregnant bovines the AL enlarges uniformly to 40% of the basal size,
in both radial and circumferential directions, with a rapid 33%
increase in leaflet area within the first 2 months of
pregnancy20, similar to the 35% increase in systolic
leaflet area reported in an echocardiographic assessment of patients
with LV dysfunction21. Collagen fibers are crimped
both in leaflet (fig. 8 A) and in chordae tendinae (fig. 5). The
increase of the area of the leaflets and of the length of
leaflets/chordae is accompanied by a remarkable loss in collagen fiber
crimp (fig. 8 B), with the percentage area occupied by crimp nearly
halved, and the crimp length nearly doubling. The overall thickness of
the leaflets remains unchanged. The simultaneous increase in area and
maintenance of thickness implies that this change is not (entirely) due
to elastic deformation but also due to the addition of mass, that is,
growth22. Loss of collagen crimps lengthen the
leaflets, but adds mechanical compression to
VICs23,24. VICs deformation (fig. 9) induces VICs
phenotypic activation and subsequent transition into a biosynthetically
active myofibroblast-like phenotype. Adding new fibrillar material into
existing fibers, collagen crimp is gradually restored (fig. 8 C). VICs
can be activated by compression caused by stretched collagen fibers
(fig. 8 B and G), but it can be due as well to TGF-β activation or to
EndMT mediated by mechanical stress or stretching.
Based on these findings, we can speculate that MV leaflet area and
leaflets/chords length increase because of loss of collagen crimp, due
mainly to stretching or mechanical stress. The thickness of the
leaflet/chords is maintained by addition of new collagen due to
activated VICs as a consequence of mechanical forces or through the
activation of TGF-β. New collagen is added, mainly to increase leaflets
thickness. It is possible that, in a pathologic situation, variability
in the intensity of the stimulus or of the cellular and humoral reaction
can up or downregulate the response to the stimulus itself, and
different levels of adaptation can occur. Leaflet area, leaflet/chords
length can or cannot increase in proportion to the stimulus and can only
thicken without increasing the size.
Then, it is possible that collagen uncrimping through mechanical stress
causes mitral leaflets/chords increase of dimensions and length, and a
secondary mechanism, mediated by VICs directly or stimulated by TGF-β,
increases the thickness of the leaflet/chords. It is likely that
individual response to mechanical stress, collagen distensibility and
excess of new collagen are at the basis of the different grade of mitral
plasticity.