Triggers that stimulate mitral valve plasticity.
When there is a change in the dynamics of the mitral valve, induced by
any cause external to the valve itself, a mechanism of adaptation starts
in order to maintain the valve function.
Trigger not related to the mitral valve geometry . This is
typical of aortic
regurgitation, where the trigger is the stretching of the AL from the
regurgitatant jet25. This is able to slowly elongate
the leaflet and the chords and to increase the mitral area in order to
close the enlarged annular area avoiding or minimizing regurgitation
(fig. 10). This mechanism of adaptation happens even if there is no MR.
Trigger related to change in mitral valve geometry . This
mechanism was
demonstrated by Dal-Bianco et al26 in sheep where the
PMs were retracted apically, short of producing MR, changing only the
mechanical stress exercised on the leaflets. Changing curvature is a
known cause of increase of mechanical stress27 and,
even without MR, it is enough to trigger a MV adaptive response. After
61 days, AL lengthened of 18% and PL of 9%, with increase in
thickness. Chords lengthened (anterior 20% and posterior 12%) with
increased diameter. Mechanical stresses imposed by PMs tethering
increase MV leaflet area and matrix thickness, with cellular changes
suggestive of reactivated embryonic valve development pathways. These
findings support the concept of an actively adapting MV even in absence
of regurgitation but only in presence of mechanical stress. This can
happen in the initial process of non-ischemic dilated cardiomyopathy,
where, in the early phase of dilation, the mitral valve is solicited to
adapt to changes in stress (fig. 1).
Trigger related to mitral regurgitation. In sheep after
tachycardia-induced
cardiomyopathy the presence of MR increases the mechanical stress on the
valve. The mitral leaflets lengthened
significantly28,29, in particular on the free
edge29. Myofibroblasts were present in the
extracellular matrix of as expression of change of phenotype in
activated cells. In another experiment Stephens et
al.30 caused MR in sheep by punching the PL and
causing a hole of 2.8 to 4.8 mm if diameter. After 12 weeks, the AL
remodeled. Elevation of matrix metalloproteinases (enzymes that are able
to degrade the basal lamina allowing the cells to go through toward the
matrix) mirrors an increased cellular turnover (VECs moving to the ECM).
These mechanisms can follow the onset of regurgitation any cause, both
anatomic and due to change of MV geometry.
Trigger related to myocardial infarction . AMI is a powerful
trigger of MV
plasticity, which often includes excessive TGF-β upregulation. This can
be due to post-MI angiotensin II activation, which in turn can activate
TGF-β expression enhancing its profibrotic activity6.
Since 1997, it was noted in an experimental setting by Quick et
al.31 that induction of AMI with/out mitral
regurgitation caused upregulation of collagen in the MV, mainly in the
AL. In a consecutive series of 91 patients with inferior
AMI32, 53.7% developed MR moderate or more, 28.4% in
patients who showed mitral plasticity (60/91, 66%) and 67.8% in
patients who did not (31/91, 34%) (p<0.003). Interestingly,
the most striking differences in length in patients with no or mild MR
vs. moderate or more MR were seen for the AL (25.5± 3.3 vs 22.4±3.1 mm;
p<0.001) and the chordal length (28.4±7.2 vs. 24.1±8.2 mm;
p< 0.01). The PL length difference was not significant
(16.1±2.6 vs. 15±3.1 mm; p=0.08). It is as well evident in many studies
that the AL increases its length more than the
PL32,33.
In patients who had AMI, and early revascularization in almost all
cases, Beaudoin et al34 demonstrated increased
thickness of the mitral leaflets 2 years post AMI and a further increase
thereafter. There was a progressive reduction of the AL excursion and
patients who developed more than mild MR had thicker mitral leaflets
than patients who did not.
It is worth noting the importance of the role of chordae
tendinae in the process of mitral plasticity. The length of the chords
is essential to reduce the regurgitation grade. In patients with
ischemic and non-ischemic cardiomyopathy chords longer 10 mm than normal
contributed, in large hearts, to reduce MR grade to absent or
mild33. In patients with the same annular diameter and
MV leaflet area, a difference of 2.5 mm in chordal length made the
difference from MR grade moderate or more and mild or absent, having
this latter group larger LV volumes35.