Review
Molecular and cellular mechanisms of aortic stenosis

https://doi.org/10.1016/j.ijcard.2009.03.108Get rights and content

Abstract

Calcific aortic stenosis is the most common cause of aortic valve replacement in developed countries, and this condition increases in prevalence with advancing age. The fibrotic thickening and calcification are common eventual endpoint in both non-rheumatic calcific and rheumatic aortic stenoses. New observations in human aortic valves support the hypothesis that degenerative valvular aortic stenosis is the result of active bone formation in the aortic valve, which may be mediated through a process of osteoblast-like differentiation in these tissues. Additionally histopathologic evidence suggests that early lesions in aortic valves are not just a disease process secondary to aging, but an active cellular process that follows the classical “response to injury hypothesis” similar to the situation in atherosclerosis. Although there are similarities with the risk factor and as well as with the process of atherogenesis, not all the patients with coronary artery disease or atherosclerosis have calcific aortic stenosis. This review mainly focuses on the potential vascular and molecular mechanisms involved in the pathogenesis of aortic valve stenosis. Namely extracellular matrix remodeling, angiogenesis, inflammation, and eventually osteoblast-like differentiation resulting in bone formation have been shown to play a role in the pathogenesis of calcific aortic stenosis. Several mediators related to underlying mechanisms, including growth factors especially transforming growth factor-β1 and vascular endothelial growth factors, angiogenesis, cathepsin enzymes, adhesion molecules, bone regulatory proteins and matrix metalloproteinases have been demonstrated, however the target to be attacked is not defined yet.

Section snippets

Calcification and aortic stenosis

Histologically, the aortic valve consists of three principal layers, the ventricularis at the inflow surface containing collagen and elastin, the spongiosa in the center composed of glycosaminoglycans and the fibrosa at the outflow surface containing densely packed collagen fibers [3]. The outer surface of the valvular leaflets is lined by endothelial cells that cover interstitial mesenchymal cells located throughout the leaflets [4]. Normally, aortic valves are avascular and their oxygen

Non-rheumatic aortic stenosis and atherosclerosis

Histopathologic evidence suggests that early lesions in aortic valves are not just a disease process secondary to aging, but an active cellular process that follows the classical “response to injury hypothesis” similar to the situation in atherosclerosis [19].

The growing body of literature suggests that hypercholesterolemia may play a role in aortic valve calcification. Dr. Rajamannan's laboratory has studied the hypothesis whether experimental hypercholesterolemia may play a key role in the

Lipid lowering and progression of aortic valve stenosis

The effects of statin treatment on aortic stenosis has gained importance recently based on the data of several trials [6], [38], [39], [40], [41]. In one of these trials, the use of a statin was inversely associated with the progression of aortic stenosis [38]. Regarding statins and their association with AS, there is evidence that statin therapy is associated with markedly lower hemodynamic progression of AS. Furthermore, Rosenhek et al. [6] have demonstrated that this effect is independent of

Angiogenesis, growth factors and non-rheumatic aortic stenosis

Angiogenesis is defined as the outgrowth of new capillaries from pre-existing capillaries and is regulated by a balance between angiogenic activators such as VEGF, FGF-2 and PDGF, and angiogenic inhibitors [46]. It has been reported that the activation of angiogenesis in aortic valves occurs in a close association with valvular stenosis, particularly with calcified aortic valve stenosis [47]. Calachour et al. [47] have demonstrated that the formation of angiogenic sprouts from stenotic valves

Extracellular matrix remodeling in aortic stenosis

A number of ECM proteins normally found in bone, including osteocalcin, osteopontin, osteonectin, bone morphogenetic protein, matrix metalloproteinase-2 (MMP-2), and MMP-9, are present in cardiovascular calcifications, including calcified valves, but in general are not found in normal cardiovascular tissue [15], [74], [75], [76], [77], [78], [79]. Matrix metalloproteinases are most commonly evaluated extracellular matrix proteins in the pathogenesis of calcific aortic stenosis. Those are a

Infection, inflammation and aortic stenosis

The first findings indicating that there might be an association of infection and non-rheumatic calcific aortic stenosis was reported in 1973 [102]. Shor et al. [103] was the first to morphologically demonstrate C. pneumoniae within human arteries affected by atherosclerosis, initially by electron microscopy and subsequently confirmed by immunofluorescence. So far the evidence for C. pneumoniae as a potential causative agent for CAD have been reported, based on the findings of numerous

Conclusions

In conclusion there are several pathophysiologic mechanisms which are supposed to be responsible for the occurrence of non-rheumatic calcific aortic stenosis. Although there are similarities with the process of atherogenesis as well as with some risk factors, not all the patients with coronary artery disease or atherosclerosis develop calcific aortic stenosis. So there must be some differentiating process. Still, the impact of cardiovascular risk factors on calcific aortic stenosis is not clear

Acknowledgement

The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology [127].

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