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Cardiovascular Research Advance Access [Accepted Manuscript] published online on April 5, 2008
Cardiovascular Research, doi:10.1093/cvr/cvn088
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org
The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that the original authorship is properly and fully attributed; the Journal, Learned Society and Oxford University Press are attributed as the original place of publication with correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions@oxfordjournals.org

Uremic Hyperparathyroidism Causes a Reversible Inflammatory Process of Aortic Valve Calcification in Rats

Mony Shuvy, MD1, Suzan Abedat, MSc1, Ronen Beeri, MD1, Haim D. Danenberg, MD1, David Planer, MD1, Iddo Z. Ben-Dov, MD2, Karen Meir, MD3, Jacob Sosna, MD4 and Chaim Lotan, MD1

1 Cardiovascular Research Center, Heart Institute, Jerusalem, Israel
2 Minerva Center for Calcium and Bone Metabolism, Jerusalem, Israel
3 Department of Pathology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
4 Department of Radiology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

Address for correspondence: Mony Shuvy MD Heart institute, Hadassah University Hospital, Ein Karem, P.O. Box 12000, Jerusalem 91120, Israel. Telephone: +972-26776451, Fax: +972-26778190E-mail: monysh{at}gmail.com

Aims: Renal failure is associated with aortic valve calcification. Our aim was to develop an animal model for exploring the pathophysiology and reversibility of aortic valve calcification, utilizing rats with diet-induced kidney disease.

Methods: Sprague Dawley rats (n=23) were fed a phosphate-enriched, uremia-inducing diet for 7 weeks followed by a normal diet for 2 weeks ("diet group"). These rats were compared to normal controls (n=10) and to uremic controls fed a phosphate-depleted diet ("low phosphate group", n=10). Clinical investigations included serum creatinine, phosphate and parathyroid hormone levels, echocardiography and multi-slice computed tomography. Pathological examinations of the valves included histological characterization, Von Kossa staining, and antigen and gene expression analyses. Eight diet group rats were further assessed for reversibility of valve calcification following normalization of their kidney function.

Results: At 4 weeks, all diet group rats developed renal failure and hyperparathyroidism. At week 9, renal failure resolved with improvement in the hyperparathyroid state. Echocardiography demonstrated valve calcifications only in diet group rats. Tomographic calcium scores were significantly higher in the diet group compared with controls. Von Kossa stain in diet group valves revealed calcium deposits, positive staining for osteopontin and CD68. Gene expression analyses revealed overexpression of osteoblast genes and nuclear factor {kappa}B activation. Valve calcification resolved after diet cessation in parallel with normalization of parathyroid hormone levels. Resolution was associated with down-regulation of inflammation and osteoblastic features. Low phosphate group rats developed kidney dysfunction similar to that of the diet group but with normal levels of parathyroid hormone. Calcium scores and histology showed only minimal valve calcification.

Conclusions: We developed an animal model for aortic valve calcification. The process is related to disturbed mineral metabolism. It is associated with inflammation and osteoblastic features. Furthermore, the process is reversible upon normalization of the mineral homeostasis. Thus, our model constitutes a convenient platform for studying aortic valve calcification and potential remedies.

Time for primary review: 35 days


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