Role of circulating osteogenic progenitor cells in calcific aortic stenosis.
OBJECTIVE
The purpose of this study was to determine the role of circulating endothelial progenitor cells with osteoblastic phenotype (EPC-OCN) in human aortic valve calcification (AVC).


BACKGROUND
Recent evidence suggests that rather than passive mineralization, AVC is an active atherosclerotic process with an osteoblastic component resembling coronary calcification. We have recently identified circulating EPCs with osteogenic properties carrying both endothelial progenitor (CD34, KDR) and osteoblastic (osteocalcin [OCN]) cell surface markers.


METHODS
Blood samples from controls (n = 22) and patients with mild to moderate calcific aortic stenosis (mi-moAS, n = 17), severe calcific AS (sAS, n = 26), and both sAS and severe coronary artery disease (sCAD) (n = 33) were collected during diagnostic coronary angiography. By using flow cytometry, peripheral blood mononuclear cells were analyzed for CD34, KDR, and OCN. Resected normal and calcified aortic valves were analyzed histologically.


RESULTS
Patients with mi-moAS and patients with sAS/sCAD had significantly less EPCs (CD34+/KDR+/OCN-) than controls. Patients with sAS showed significantly higher numbers of EPC-OCN (CD34+/KDR+/OCN+) than controls. In addition, the percentage of EPC costaining for OCN was higher in all disease groups compared with controls. A subgroup analysis of younger patients with bicuspid sAS showed a similar pattern of significantly lower EPCs but a high percentage of coexpression of OCN. Immunofluorescence showed colocalization of nuclear factor kappa-B and OCN in diseased and normal valves. CD34+/OCN+ cells were abundant in the endothelial and deeper cell layers of calcific aortic valve tissue but not in normal aortic valve tissue.


CONCLUSIONS
Circulating EPC-OCN may play a significant role in the pathogenesis and as markers of prognostication of calcific AS.
Cardiovascular Diseases, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.
Mario
M
Gössl
Sundeep
S
Khosla
Xin
X
Zhang
Nara
N
Higano
Kyra L
KL
Jordan
Darrell
D
Loeffler
Maurice
M
Enriquez-Sarano
Ryan J
RJ
Lennon
Ulrike
U
McGregor
Lilach O
LO
Lerman
Amir
A
Lerman
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001024:Aortic Valve Stenosis / Q000097:blood* / Q000175:diagnosis*; D015415:Biomarkers / Q000097:blood; D001775:Blood Circulation / Q000502:physiology; D002114:Calcinosis / Q000097:blood* / Q000175:diagnosis*; D005260:Female; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000502:physiology; D008297:Male; D008875:Middle Aged; D010006:Osteoblasts / Q000502:physiology*; D010012:Osteogenesis / Q000502:physiology; D013234:Stem Cells / Q000502:physiology*
D015415:Biomarkers