Molecular and cellular aspects of calcific aortic valve disease

Abstract

Calcific aortic valve disease (CAVD) increasingly afflicts our aging population. One third of our elderly have echocardiographic or radiological evidence of calcific aortic valve sclerosis, an early and subclinical form of CAVD. Age, sex, tobacco use, hypercholesterolemia, hypertension, and type II diabetes mellitus all contribute to the risk of disease that has worldwide distribution. On progression to its most severe form, calcific aortic stenosis, CAVD becomes debilitating and devastating, and 2% of individuals >60 years are affected by calcific aortic stenosis to the extent that surgical intervention is required. No effective pharmacotherapies exist for treating those at risk for clinical progression. It is becoming increasingly apparent that a diverse spectrum of cellular and molecular mechanisms converge to regulate valvular calcium load; this is evidenced not only in histopathologic heterogeneity of CAVD, but also from the multiplicity of cell types that can participate in valve biomineralization. In this review, we highlight our current understanding of CAVD disease biology, emphasizing molecular and cellular aspects of its regulation. We end by pointing to important biological and clinical questions that must be answered to enable sophisticated disease staging and the development of new strategies to treat CAVD medically.

Keywords: aortic valve, calcification of; vascular calcification; vascular senescence.

Figure 1. True ectopic bone formation occurs in a substantial portion of calcified human aortic valves

Fitzpatrick and colleagues identified bone protein expression and true ectopic bone formation by histology in calcifying native human aortic valves. Open arrows, osteocytes; close arrows, osteoblasts. Of note, Mohler et al subsequently identified that approximately 13% of calcifying valve specimens have histological ectopic bone replete with hematopoietic elements. See text for details. Reproduced with permission from the Journal of Clinical Investigation.

Figure 2. Asymmetric sclerosis of aortic valve leaflets

Male LDLR−/− mice fed high fat diabetogenic diets typical of Westernized societies develop progressively severe arteriosclerosis and vascular fibrosis. Left panel, picrosirius red staining for collagen demonstrates mural fibrosis (asterisk), fibrotic caps on atherosclerotic plaques (dashed arrows), and aortic valve fibrosis (closed arrow). Right panel, higher power magnification reveals asymmetric sclerosis of aortic valves. The aortic surface of the valve leaflet preferentially accumulates collagen deposition (closed arrows) as compared to the ventricular surface (open arrows).

Figure 3. Sources of aortic valve osteoprogenitors: a heterogenous mix

Mineralizing cell types relevant to the pathobiology of CAVD have been shown to arise from the osteogenic trans-differentiation of VICs, circulating osteoprogenitors, and the EnMT. Annular chondrocytes that produce the cardiac valve “skeletal scaffold” may contribute as well. Osteogenic nodules initially form in the interstitium oriented towards the aortic surface. However, once initiated, epitaxial deposition of amorphous calcium phosphate can occur without cell-mediated regulation. True ectopic bone formation occurs in approximately 13% of specimens, and likely requires the recruitment of a circulating osteoprogenitor that is capable of organizing a marrow microenvironment replete with hematopoietic elements. See text for details.

Figure 4. DNA damage in the osteogenic programming of VICs: An emerging osteogenic regulatory cascade

Recent studies from Ferrari and colleagues converge with that of Chau et al to suggest the indicated osteogenic signaling cascades downstream of cellular DNA damage. The ATM kinase mediates activation of (a) Smad1 signals; (b) p53 dependent cell cycle arrest vs. apoptosis; and (c) H2AX and Ku antigen-dependent DNA damage repair; and (d) KSRP-dependent microRNA processing. See text for details.

Figure 5. The role for Sox9 in limiting the osteogenic mineralization of VICs: A working model

In a regulatory network first identified by Yutzey et al, Sox9 plays a critical role in valve biology by maintaining proliferative renewal with chondroid matrix biosynthesis, and by inhibiting osteogenic differentiation and mineralization. Garg et al recently expanded this model by demonstrating that Notch1 functions to sustain Sox9 expression in VICs -- an action that diverges from that of Notch1 signaling in skeletal chondrocytes.