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.