**6. Valve mechanobiology during LVAD support**

As explained previously, the addition of the LVAD to the heart results in a sudden increase in the pressure loading of the AV, in which tensile stress is increased, and shear is attenuated [54]. Each of these mechanical signals has been shown to play an important role in the progression of AV disease [43]. Evidence for the impact of LVAD-related increased tensile stretch and reduced shear stress on valve leaflets is found in extensive studies evaluating the role of mechanobiology in calcific AV

#### **Figure 8.**

*Images of complete (left) and partial (center and right; location at the white arrow) commissural fusion of aortic valve leaflets following LVAD support.*

*Aortic Insufficiency in LVAD Patients DOI: http://dx.doi.org/10.5772/intechopen.106173*

#### **Figure 9.**

*Microscopic evaluation of aortic valve fusion from LVAD-supported hearts shows evidence of loss of the elastin band where the leaflets fuse together (left) and fibrosis arising from the ventricular face (right).*

#### **Figure 10.**

*LVAD support produces increased stretch and reduced shear in the ventricular layer of the aortic valve leaflet, which initiates a response resulting in ECM deposition and elastin fragmentation. The subsequent contraction of collagen in the ventricularis reduces leaflet coaptation, eventually resulting in AI.*

disease and is illustrated in **Figure 10**. While this pathology manifests over a longer time and usually arises from the aortic surface of the leaflet, the same cell types are present in LVAD patients and respond to biochemical cues in the same way.

The cells responsible for valve tissue remodeling include the valvular endothelial cells (VECs), which reside in a single layer along the blood-contacting surfaces, and valvular interstitial cells (VICs), the more abundant cell type that resides throughout the tissue and is responsible for extracellular matrix maintenance [43]. VICs are usually quiescent and fibroblast-like but can be activated by abrupt changes in mechanical stress or when in a diseased state. VICs may translate between phenotypes to maintain homeostasis and can subsequently differentiate into other cell types, such as myofibroblasts, once activated [55]. Increased stretch provides a stimulus for VICs to increase collagen production and remodeling [56] by upregulating growth factors and integrins as cell-signaling mediators [57]. Stretch-activated VICs increase the production of

collagen and remodeling enzymes, which can lead to fibrosis and calcification. As the disease progresses, the differentiation of VICs to myofibroblasts can be identified by increased α smooth muscle actin (α-SMA) expression. Myofibroblasts secrete ECM such as collagen and increase tension in the matrix fibers [58, 59] and are associated with the formation of ECM disarray and fibrosis [17, 30, 60]. Tissue macrophages synthesize enzymes associated with pathological remodeling, such as MMPs, that are not released by VICs. These enzymes degrade elastin, disrupt collagen organization [61, 62] and potentiate the pathological differentiation of VICs into myofibroblasts.

The pathological differentiation of VICs into myofibroblasts is promoted by large numbers of tissue macrophages in the ventricularis layer, which contributes to the overproduction of TGF-β. Side-specific shear also plays a key role in modulating the valve tissue. VECs on the aortic side of normal valves, which experience low shear, have reduced expression of many cytokines that are known inhibitors of fibrosis and calcification compared with VECs on the ventricular side, which normally experience high shear [59]. When the high shear is virtually eliminated, as occurs with LVAD support, the expression of C-type natriuretic peptide (CNP), a paracrine factor shown to inhibit VIC differentiation, is reduced [59]. The reduction in CNP coupled with a dramatic increase in TGF-β further accelerates the population of myofibroblasts [63].
