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(Circulation. 2006;114:I-547 – I-552.)
© 2006 American Heart Association, Inc.

Surgery for Valvular Heart Disease

Role of Human Valve Interstitial Cells in Valve Calcification and Their Response to Atorvastatin

Lana Osman, BSc; Magdi H. Yacoub, FRS; Najma Latif, PhD; Mohamed Amrani, FRCS, PhD; Adrian H. Chester, PhD

From the Heart Science Centre (L.O., M.H.Y., N.L., A.H.C.), National Heart and Lung Institute, Imperial College, and Department of Cardiothoracic Surgery (M.A.), Royal Brompton and Harefield National Health Service Trust, Harefield, Middlesex, United Kingdom.

Correspondence to Magdi H. Yacoub, FRS, Imperial College London, Heart Science Centre, Harefield Hospital, Harefield, Middlesex, UB9 6JH United Kingdom. E-mail m.yacoub{at}imperial.ac.uk

Background— Calcific aortic valve stenosis is a common disease in the elderly and is characterized by progressive calcification and fibrous thickening of the valve, but the cellular and molecular mechanisms are not fully understood. We hypothesized that human valve interstitial cells (ICs) are able to differentiate into osteoblast-like cells through the influence of defined mediators and that this process can be modulated pharmacologically.

Methods and Results— To test this hypothesis, we treated primary cultures of human aortic valve ICs with osteogenic media, bone morphogenic proteins ([BMPs] BMP-2, BMP-4, and BMP-7), and tissue growth factor-ß ([TGF-ß] TGF-ß1 and TGF-ß3) for 21 days. These mediators induced osteoblast differentiation of valve ICs by significantly increasing the activity and expression of alkaline phosphatase ([ALP] P<0.001). A cytokine protein array revealed that atorvastatin treatment (100 µmol/L) of human valve ICs caused a downregulation in levels of expression of BMP-2, BMP-6, TGF-ß1, and TGF-ß3 after 24 hours. In addition, human valve ICs treated with atorvastatin in the presence of osteogenic media showed a significant reduction in ALP activity in comparison to cells treated with osteogenic media only (P=<0.001). This was further confirmed with immunocytochemical staining of valve ICs, whereby atorvastatin markedly reduced the expression of ALP and osteocalcin induced by osteogenic media in comparison to untreated cells.

Conclusions— These findings suggest that human valve ICs are capable of osteoblastic differentiation, by potential mediators which can be pharmacologically targeted by atorvastatin.

Key Words: inflammation • pharmacology • statins • valves