This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 118/17/1737    most recent CIRCULATIONAHA.108.780031v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kimura, N. Articles by Fukuda, K. Search for Related Content PubMed PubMed Citation Articles by Kimura, N. Articles by Fukuda, K. Related Collections Angiogenesis Valvular heart disease CV surgery: valvular disease Other Vascular biology

(Circulation. 2008;118:1737-1747.)
© 2008 American Heart Association, Inc.

Molecular Cardiology

Local Tenomodulin Absence, Angiogenesis, and Matrix Metalloproteinase Activation Are Associated With the Rupture of the Chordae Tendineae Cordis

Naritaka Kimura, MD; Chisa Shukunami, DDS, PhD; Daihiko Hakuno, MD, PhD; Masatoyo Yoshioka, MD, PhD; Shigenori Miura, PhD; Denitsa Docheva, PhD; Tokuhiro Kimura, MD; Yasunori Okada, MD, PhD; Goki Matsumura, MD, PhD; Toshiharu Shin'oka, MD, PhD; Ryohei Yozu, MD, PhD; Junjiro Kobayashi, MD, PhD; Hatsue Ishibashi-Ueda, MD, PhD; Yuji Hiraki, PhD; Keiichi Fukuda, MD, PhD

From the Departments of Regenerative Medicine and Advanced Cardiac Therapeutics (N.K., D.H., M.Y., K.F.), Cardiovascular Surgery (N.K., R.Y.), and Pathology (T.K., Y.O.), Keio University School of Medicine, Tokyo, Japan; Department of Cellular Differentiation, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan (C.S., S.M., Y.H.); Department of Molecular Medicine, Max Planck Institute of Biochemistry, Martinstried, Germany (D.D.); Department of Cardiovascular Surgery, Heart Institute of Japan, Tokyo Women’s Medical University, Tokyo, Japan (G.M., T.S.); and Departments of Cardiovascular Surgery (J.K.) and Pathology (H.I.-U.), National Cardiovascular Center Hospital, Osaka, Japan.

Correspondence to Keiichi Fukuda, MD, PhD, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan. E-mail kfukuda{at}sc.itc.keio.ac.jp

Received March 15, 2008; accepted July 23, 2008.

Background— Rupture of the chordae tendineae cordis (CTC) is a well-known cause of mitral regurgitation. Despite its importance, the mechanisms by which the CTC is protected and the cause of its rupture remain unknown. CTC is an avascular tissue. We investigated the molecular mechanisms underlying the avascularity of CTC and the correlation between avascularity and CTC rupture.

Methods and Results— We found that tenomodulin, which is a recently isolated antiangiogenic factor, was expressed abundantly in the elastin-rich subendothelial outer layer of normal rodent, porcine, canine, and human CTC. Conditioned medium from cultured CTC interstitial cells strongly inhibited tube formation and mobilization of endothelial cells; these effects were partially inhibited by small-interfering RNA against tenomodulin. The immunohistochemical analysis was performed on 12 normal and 16 ruptured CTC obtained from the autopsy or surgical specimen. Interestingly, tenomodulin was locally absent in the ruptured areas of CTC, where abnormal vessel formation, strong expression of vascular endothelial growth factor-A and matrix metalloproteinases, and infiltration of inflammatory cells were observed, but not in the normal or nonruptured area. In anesthetized open-chest dogs, the tenomodulin layer of tricuspid CTC was surgically filed, and immunohistological analysis was performed after several months. This intervention gradually caused angiogenesis and expression of vascular endothelial growth factor-A and matrix metalloproteinases in the core collagen layer in a time-dependent manner.

Conclusions— These findings provide evidence that tenomodulin is expressed universally in normal CTC in a concentric pattern and that local absence of tenomodulin, angiogenesis, and matrix metalloproteinase activation are associated with CTC rupture.

---

 

CLINICAL PERSPECTIVE

This article has been cited by other articles:

				J. Yoshioka and R. T. Lee Vascularization as a Potential Enemy in Valvular Heart Disease Circulation, October 21, 2008; 118(17): 1694 - 1694. [Full Text] [PDF]