Association for Academic SurgeryAortic valve calcification is mediated by a differential response of aortic valve interstitial cells to inflammation
Introduction
Calcific aortic stenosis is the third most prevalent cardiovascular disease in the United States, exceeded in prevalence only by hypertension and coronary artery disease [1]. It is the leading indication for heart valve replacement surgery. Although calcification of the aortic valve is common, it is noteworthy that calcification of the other heart valves is not.
The pathogenesis of calcific aortic stenosis is not well understood. It has traditionally been considered a degenerative process, one in which calcium passively accumulates on the aortic valve leaflets. However, evidence is accumulating that aortic stenosis is an active disease process—one in which mechanisms of inflammation play an important role [2], [3].
The valve interstitial cell (VIC) is the principle cell type found in cardiac valve leaflets [4]. In the aortic valve, the aortic VIC has been implicated in the pathogenesis of calcific aortic stenosis [5]. In response to proinflammatory stimulation via activation of toll-like receptor 4 (TLR-4), the aortic VIC has been shown to undergo a phenotypic change from that of a myofibroblast to that of an osteogenic and inflammatory phenotype [6]. In aortic VICs, such osteogenic phenotypic changes are characterized by the production of the important bone-forming protein, bone morphogenetic protein 2 (BMP-2), and an inflammatory phenotype is characterized by the production of intra-cellular adhesion molecule 1 (ICAM-1) [6]. Previous studies have also demonstrated that these inflammatory responses are exaggerated in VICs isolated from stenotic aortic valves [7], [8], further emphasizing their importance to the disease process.
Little is known about the biological behavior of VICs from the mitral, tricuspid, and pulmonary valves. It is interesting to note that these three valves rarely, if ever, calcify. But as the aortic VIC has been implicated in calcification of the aortic valve, we hypothesized that intrinsic differences may exist among the four cardiac valves that help to explain why aortic valves calcify but the mitral, tricuspid, and pulmonary valves rarely, if ever, do. We specifically hypothesized that unlike aortic VICs, the VICs from mitral, tricuspid, and pulmonary valves do not undergo an osteogenic phenotypic change in response to proinflammatory stimulation.
Using isolated human VICs from aortic, mitral, tricuspid, and pulmonary valves, the purposes of this study were to determine the differences in TLR-4–induced expression of an osteogenic phenotype and an inflammatory phenotype. The results of this study demonstrate that TLR-4 stimulation induced an inflammatory response in all four types of VICs. However, TLR-4 stimulation induced an osteogenic phenotype only in aortic VICs.
Section snippets
Materials and methods
This study was approved by the Colorado Multiple Institutional Review Board at the University of Colorado School of Medicine.
Patient characteristics
Aortic, pulmonary, mitral, and tricuspid valves were obtained from four male patients who underwent cardiac transplantation for idiopathic dilated cardiomyopathy. Patient ages ranged from 20–49 y. Before transplantation, these patients all had echocardiograms showing no significant valvular disease. All patients also underwent coronary angiography before transplantation, and none had coronary artery disease. None of the patients used tobacco.
VICs from all four valves demonstrated a myofibroblast phenotype
Aortic, pulmonic, mitral, and tricuspid VICs were
Discussion
The results of the present study demonstrate an important difference in the response to TLR-4 stimulation among the VICs from the four types of heart valves. TLR-4 expression was not different among the different types of VICs. In addition, TLR-4–induced production of ICAM-1 and MCP-1 increased in all four types of VICs. However, TLR-4 stimulation induced an osteogenic phenotype as characterized by BMP-2 production in aortic VICs but not VICs from mitral, tricuspid, or pulmonary valves. These
Conclusions
The results of the present study demonstrated that although TLR-4 expression was not different among VICs from all four heart valves, the response to TLR-4 stimulation was different; TLR-4 stimulation induced an osteogenic phenotype in aortic VICs but not in VICs from mitral, tricuspid, or pulmonary valves. Such a differential response to proinflammatory stimulation in human aortic VICs offers mechanistic insight into the observation that the aortic valve commonly calcifies and the other three
Acknowledgment
Author contributions: N.V., N.A.N., M.J.W. and T.B.R. contributed to the conception of the article. N.V., N.A.N., M.J.W., T.B.R., X.M. and D.A.F. contributed to the design of the article. N.V., M.J.W., T.B.R., X.M. and D.A.F. did the analysis. N.V., M.J.W., X.M. and D.A.F. did the interpretation. N.V., N.A.N. and Q.Z. did the data collection. N.V. and D.A.F. wrote the article. X.M. and D.A.F. did the critical revision of the article and obtained funding.
The study was funded by grants from the
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