CONCLUSIONS
Stretching and mechanical stress are the initial mechanisms that trigger MV adaptation to a new hemodynamic situation. Increase in leaflets area and length and in chordal length is due to collagen uncrimping, which is able to increase leaflets and chordal dimensions by 30 to 50%. To maintain the same thickness, it is necessary to produce more collagen by activated VICs, either because of mechanical stress or TGF-β activation. The purpose is to maintain the same thickness even with a longer or larger MV, but the process can become dysregulated, such as in presence of an AMI.
TGF-β is present in the MV in a latent form. Many stimuli (stretching, mechanical stress, inflammation, turbulent flow, and others), can trigger the release of active TGF-β, which binds to a membrane receptor that in turn activate signal transducers that accumulate into the nuclei and transcripts specific genes, targeted to induce fibrotic changes. Targets can be quiescent VICs, present in the ECM, that change in activated myofibroblasts, but VECs as well. As a consequence, VECs activate and lose the adhesion to neighbor cells. The basement membrane is eroded by enzymatic secretion and the VECs migrate into the ECM, where transition to mesenchymal cells, which in turn can differentiate in other cells, such as myofibroblasts, etc. Myofibroblasts produce collagen and the excess of collagen production causes an excessive accumulation of ECM components. If this process becomes dysregulated, as often it happens after AMI, permanent scarring and increased leaflet fibrosis occurs. After a MI, VECs undergo EndMT, VICs are activated to become myofibroblasts that secrete and compact ECM, and there is evidence for valve neovascularization and leukocyte infiltration6,26,36. Infiltrating macrophages and leukocytes release growth factors and cytokines, such as TGF-β family members, which can further promote angiogenesis, collagen production, attraction of additional inflammatory cells, and transform VICs to myofibroblasts that also secrete growth factors and cytokines.
Activated TGF-β can induce phenotype changes in quiescent VICs, which change morphology and function, contributing to pathologic changes. In the ischemic setting, excessive TGF-β signaling occurs, that stimulates exuberant EndMT, resulting in profibrotic changes of the leaflets, such as markedly increased thickness, cellular proliferation, and excessive ECM turnover with collagen deposition.
It is not clear if the activation of the ECs is directly dependent by the trigger, such as mechanical stress, or induced by TGF-β since the beginning.