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- ↵⁎Reprint requests and correspondence:
Dr. Emile R. Mohler III, University of Pennsylvania Translational Research Center, 3400 Civic Center Boulevard, Building, 421, Room 11-103, Philadelphia, Pennsylvania 19104-5159
The etiology of calcific aortic stenosis (AS) is multifactorial, involving genetic and environmental factors, including congenital valve abnormalities and cardiovascular risk factors such as smoking, hypercholesterolemia, hypertriglyceridemia, diabetes mellitus, and chronic kidney disease (1). Not long ago, the cause of aortic valve calcification was thought to be a “senile” and passive process of natural aging. With the discovery of bone-related proteins in calcified cardiac valves along with inflammatory cells, the pathological process of cardiac valve calcification was evidently more complicated and resembled atherosclerosis (2). Lamellar bone produced by endochondral calcification was documented in 13% of surgically excised aortic valves and clearly showed that an active process of tissue metamorphosis was present in a subset of patients with end-stage aortic valve disease (3). Bone formation appeared only in valves that also had mineralized with hydroxyapatite crystal, so-called dystrophic calcification. So, how do osteoblasts and osteoclasts arrive in calcified aortic valves? Are they derived from cells endogenous to the valve or do they migrate in from circulating osteoprogenitor cells, or perhaps both?
A series of investigative findings now indicate that circulating osteogenic precursor (COP) cells participate in heterotopic ossification after hip arthroplasty, in a genetic syndrome of extraskeletal bone formation (fibrodysplasia ossificans progressiva [FOP]), and in end-stage aortic valvular disease, as well as in animal models of ectopic bone formation (4). Suda et al. (5) identified COP cells as a bone marrow–derived type I collagen+ osteocalcin (OCN)+ CD45+ subpopulation of mononuclear adherent cells that are present in early (pre-osseous) lesions in patients with FOP that can nucleate heterotopic ossification in a murine in vivo implantation model. Blood samples from patients with FOP and active inflammatory exacerbations that led to heterotopic ossification contain significantly higher numbers of clonally derived COP cell colonies than from those of patients with stable disease or unaffected individuals. The possibility that circulating, hematopoietically derived cells with osteogenic potential can seed inflammatory sites prompted the histological analysis of aortic valves removed from patients with end-stage aortic valve disease.
Egan et al. (6) showed that CD45+ OCN+ COP cells represent up to 1.1% of mononuclear cells and that COP cells contribute to early valve heterotopic ossification lesions. Of note, COP cells were negligible in regions of unaffected valve leaflets (no heterotopic ossification) from the same individuals. Although it is widely held that cells with an osteoblast-like phenotype are present in calcified aortic valves and that they can differentiate into bone-forming cells, the study by Egan et al. was the first to provide evidence that osteogenic progenitor cells may home to sites of vascular injury and inflammation, and once resident, contribute to heterotopic ossification.
In this issue of the Journal, Gössl et al. (7) report the role of circulating endothelial progenitor cells (EPCs) with osteoblastic phenotype (EPC-OCN) and osteogenic potential in human aortic valve calcification. The surface markers of the EPC-OCN population included CD34, KDR, and CD133, in addition to the bone protein OCN. Circulating EPC-OCN cells were studied in healthy controls and patients with varying degrees of aortic valve calcification. Patients with both severe AS and severe coronary artery disease (CAD) had significantly reduced numbers of circulating EPCs (CD34+/KDR+/OCN-) compared with controls, but a high percentage of these circulating EPCs were osteoblastic (EPC-OCN). Patients with only mild to moderate AS and normal coronary arteries had an EPC/EPC-OCN profile similar to that of patients with both severe AS and severe CAD. In contrast, patients with severe AS and normal coronaries showed normal EPC and high EPC-OCN numbers with a high percentage of EPC costaining for OCN. The authors hypothesized that patients with severe AS but normal coronary arteries may represent a subgroup of patients whose bone marrow is capable of a surge of EPC release in response to injury, leading to a more favorable EPC/EPC-OCN profile. One wonders if this process may involve an endothelial to mesenchymal transition, as noted for other forms of heterotopic ossification (8). Of note, the authors do not rule out the possibility that resident endothelial cells or pre-endothelial cells might contribute to the ossification process. In contrast, patients with both severe AS and severe CAD may not be capable of such a surge, and thus show progression of calcific atherosclerosis in multiple vascular territories due to an unfavorable imbalance between injury and repair (i.e., low EPC numbers with a high percentage of osteoblastic phenotype).
In summary, our current knowledge of calcific AS is rapidly evolving. Results of several recent investigations suggest that circulating hematopoietically derived cells with osteogenic potential are involved in the process of AS. It should not be forgotten that AS also is an inflammatory process and that progression of valve stenosis is likely directly related to pathological inflammation (9,10). Additional research is needed to determine the pathological mechanism(s) by which COP cells result in ossification. If COP cells are found predicative of aortic valve calcification and/or ossification, then an in vitro diagnostic test may make its way into the clinic. The scientific field of cytomics, the study of circulating cells, is yielding new insights into mechanisms of disease, including calcific AS.
All authors have reported that they have no relationships relevant to the contents of this paper to disclose.
↵⁎ Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
- American College of Cardiology Foundation
- Mohler E.R. 3rd.,
- Gannon F.H.,
- Reynolds C.,
- Zimmerman R.,
- Keane M.G.,
- Kaplan F.S.
- Egan K.P.,
- Kim J.H.,
- Mohler E.R. 3rd.,
- Pignolo R.J.
- Gössl M.,
- Khosla S.,
- Zhang X.,
- et al.
- Otto C.M.,
- Kuusisto J.,
- Reichenbach D.D.,
- Gown A.M.,
- O'Brien K.D.