Comparing the Role of Mechanical Forces in Vascular and Valvular Calcification Progression

Abstract

Calcification is a prevalent disease in most fully developed countries and is predominantly observed in heart valves and nearby vasculature. Calcification of either tissue leads to deterioration and, ultimately, failure causing poor quality of life and decreased overall life expectancy in patients. In valves, calcification presents as Calcific Aortic Valve Disease (CAVD), in which the aortic valve becomes stenotic when calcific nodules form within the leaflets. The initiation and progression of these calcific nodules is strongly influenced by the varied mechanical forces on the valve. In turn, the addition of calcific nodules creates localized disturbances in the tissue biomechanics, which affects extracellular matrix (ECM) production and cellular activation. In vasculature, atherosclerosis is the most common occurrence of calcification. Atherosclerosis exhibits as calcific plaque formation that forms in juxtaposition to areas of low blood shear stresses. Research in these two manifestations of calcification remain separated, although many similarities persist. Both diseases show that the endothelial layer and its regulation of nitric oxide is crucial to calcification progression. Further, there are similarities between vascular smooth muscle cells and valvular interstitial cells in terms of their roles in ECM overproduction. This review summarizes valvular and vascular tissue in terms of their basic anatomy, their cellular and ECM components and mechanical forces. Calcification is then examined in both tissues in terms of disease prediction, progression, and treatment. Highlighting the similarities and differences between these areas will help target further research toward disease treatment.

Keywords: CAVD; atherosclerosis; biomechanics; oscillatory stress; shear stress; valvular calcification; vascular calcification.

Figure 1

Gross morphology of the aortic valve and branching carotid artery. (A) Bisected aortic valve opened to show the three leaflets (outlined in yellow). On the left, the two coronary leaflets can be seen with the coronary outflows circled in white superior to the leaflets. (B) An intact aortic valve shows the leaflets coapting, starting at the commissure edges (black arrows). (C) The carotid artery at its bifurcation–the separation of one large artery into multiple smaller arteries. Shown with white arrows, the common carotid splits into the internal and external carotids. Tissue obtained from young adult (6–9 month) porcine specimens (Animal Technologies, Tyler, TX).

Figure 2

ECM and cell composition of aortic leaflets and vascular walls. Both (A) aortic valve leaflets and (B) vessel walls are tri-laminar structures with specific cell and extracellular matrix in each layer. These specialized layers impart different mechanical properties to the tissues, which are important for their functions.

Figure 3

Diastolic and systolic forces on the valve leaflets. (A) Forces experienced during diastole include compression and oscillatory shear on the fibrosa VECs and tensile strain on the VICs. The oscillatory forces (shown with yellow dashed arrows) are thought to be the cause of initial calcification. (B) Under systolic forces, the ventricularis VECs experience straight shear while the VICs feel bending forces.

Figure 4

Hemodynamic forces in vasculature. Wall shear stresses in vasculature tissue is highly dependent on geometry. At straight sections, high unidirectional shear forces are predominant. At bifurcations and curved regions, oscillatory shear (shown with yellow dashed arrows) is experienced at lower pressures and leads to calcification.

Figure 5

Calcification changes cell expression in the aortic valve. The oscillatory shear stresses experienced by VECs on the fibrosa side of the valve can lead to endothelial layer disruption as well as specific changes in cellular pathway expressions. Changes in cellular expression can change the macro structure of the valve leaflets, which creates a positive feedback loop instigating calcification. Changes marked with red diamonds have been expressly linked to mechanical shear stresses in the aortic valve.

Figure 6

The Effects of calcification on blood flow in the aortic valve. Healthy valve leaflets are able to move according to blood flow which allows them to open completely under systolic forces and coapt under diastolic. In calcified valves, leaflets lose their flexibility and become rigid. This results in valves that can neither open or close fully, which reduces mean ejection fraction and increases regurgitation.