Potential drug targets for calcific aortic valve disease

Abstract

Calcific aortic valve disease (CAVD) is a major contributor to cardiovascular morbidity and mortality and, given its association with age, the prevalence of CAVD is expected to continue to rise as global life expectancy increases. No drug strategies currently exist to prevent or treat CAVD. Given that valve replacement is the only available clinical option, patients often cope with a deteriorating quality of life until diminished valve function demands intervention. The recognition that CAVD results from active cellular mechanisms suggests that the underlying pathways might be targeted to treat the condition. However, no such therapeutic strategy has been successfully developed to date. One hope was that drugs already used to treat vascular complications might also improve CAVD outcomes, but the mechanisms of CAVD progression and the desired therapeutic outcomes are often different from those of vascular diseases. Therefore, we discuss the benchmarks that must be met by a CAVD treatment approach, and highlight advances in the understanding of CAVD mechanisms to identify potential novel therapeutic targets.

Figure 1

Cardiovascular inflammation and calcification. a | Mouse aortic valve leaflets have a similar gross morphology to human leaflets. b | Molecular imaging can be used to identify a high level of inflammation in the leaflets. c | This inflammation is closely associated with regions of calcification. d | The association between calcification and inflammation is observed throughout cardiovascular tissues. Panels a–c reprinted from Aikawa, E. et al. Arterial and aortic valve calcification abolished by elastolytic cathepsin S deficiency in chronic renal disease. Circulation 119 (13), 1785–1794 (2009). Panel d reprinted from Aikawa, E. et al. Osteogenesis associates with inflammation in early-stage atherosclerosis evaluated by molecular imaging in vivo. Circulation 116 (24), 2841–2850 (2007).

Figure 2

Structure–function relationship in aortic valve biomechanics. a | Systolic contraction of the left ventricle forces the aortic valve leaflets to open, allowing blood to enter the aorta. b | The reversed pressure gradient, created when the heart rests in diastole, causes the aortic valve leaflets to close, preventing retrograde blood flow into the heart. The circumferential alignment of collagen allows the leaflets to stretch in the radial direction so that apposing leaflets meet and seal the valve annulus, while providing the tensile strength required to prevent leaflet prolapse. c | Imaging of picrosirius red stained collagen fibres using polarized light illustrates the alignment of collagen fibres within the aortic valve leaflets. Panel c reprinted from Aikawa, E. et al. Human semilunar cardiac valve remodeling by activated cells from fetus to adult: implications for postnatal adaptation, pathology, and tissue engineering. Circulation 113 (10), 1344–1352 (2006).

Figure 3

The evolution of in vitro calcific nodules. a | Early studies reported calcific nodules formed by apoptotic VICs in culture after treatment with transforming growth factor β₁. b | Subsequent studies showed the formation of dystrophic calcific nodules in real-time owing to aggregation of myofibroblastic VICs. c | This aggregation process is exacerbated by the addition of mechanical strain, where a necrotic core (red fluorescence) is surrounded by a ring of apoptotic VICs (green fluorescence).^, d | Calcific nodules with osteogenic characteristics (osteopontin staining shown) can be generated on soft culture substrates. These nodules have a similar morphology to dystrophic nodules with VICs radiating from the nodule. e | By contrast, alizarin red staining of calcification in smooth muscle cell cultures is observed in association with intact smooth muscle cells (arrow). Abbreviation: VIC, valvular interstitial cell. Panel a reprinted from Ann. Thorac. Surg. 75 (2) Jian, B. et al. Progression of aortic valve stenosis: TGF-1 is present in calcified aortic valve cusps and promotes aortic valve interstitial cell calcification via apoptosis. 457–765 © 2003, with permission from Elsevier. Panel b reprinted from Benton, J. A. et al. Statins block calcific nodule formation of valvular interstitial cells by inhibiting α-smooth muscle actin expression. Atheroscler. Thromb. Vasc. Biol. 29 (11), 1950–1957 (2009). Panel c reprinted from Hutcheson, J. D. et al. Cadherin-11 regulates cell–cell tension necessary for calcific nodule formation by valvular myofibroblasts. Atheroscler. Thromb. Vasc. Biol. 33 (1) 114–120 (2013). Panel d reprinted from Yip, C. Y. et al. Calcification by calve interstitial cells is regulated by the stiffness of the extracellular matrix. Atheroscler. Thromb. Vasc. Biol. 29 (6), 936–942 (2009).

Figure 4

Biomechanical consequence of cardiovascular calcification. a | Aortic valve leaflets rely on appropriate biomechanical responses to open during systole and seal the valve during diastole. Similarly, vessels expand under systolic pressure. b | However, fibrocalcific remodelling is detrimental to aortic valve function. Leaflet stiffening in calcific aortic valve disease impairs the opening and closing of the leaflets. Localized calcification is not detrimental to vessel function, and fibrotic collagen accumulation is often desired to stabilize atherosclerotic plaques and prevent thrombosis.