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      Hemodynamics and Mechanobiology of Aortic Valve Inflammation and Calcification

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          Abstract

          Cardiac valves function in a mechanically complex environment, opening and closing close to a billion times during the average human lifetime, experiencing transvalvular pressures and pulsatile and oscillatory shear stresses, as well as bending and axial stress. Although valves were originally thought to be passive pieces of tissue, recent evidence points to an intimate interplay between the hemodynamic environment and biological response of the valve. Several decades of study have been devoted to understanding these varied mechanical stimuli and how they might induce valve pathology. Here, we review efforts taken in understanding the valvular response to its mechanical milieu and key insights gained from in vitro and ex vivo whole-tissue studies in the mechanobiology of aortic valve remodeling, inflammation, and calcification.

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          Clinical factors associated with calcific aortic valve disease. Cardiovascular Health Study.

          B Stewart, D Siscovick, B K Lind … (1997)
          The aim of this study was to determine the prevalence of aortic sclerosis and stenosis in the elderly and to identify clinical factors associated with degenerative aortic valve disease. Several lines of evidence suggest that degenerative aortic valve disease is not an inevitable consequence of aging and may be associated with specific clinical factors. In 5,201 subjects > or = 65 years of age enrolled in the Cardiovascular Health Study, the relation between aortic sclerosis or stenosis identified on echocardiography and clinical risk factors for atherosclerosis was evaluated by using stepwise logistic regression analysis. Aortic valve sclerosis was present in 26% and aortic valve stenosis in 2% of the entire study cohort; in subjects > or = 75 years of age, sclerosis was present in 37% and stenosis in 2.6%. Independent clinical factors associated with degenerative aortic valve disease included age (twofold increased risk for each 10-year increase in age), male gender (twofold excess risk), present smoking (35% increase in risk) and a history of hypertension (20% increase in risk). Other significant factors included height and high lipoprotein(a) and low density lipoprotein cholesterol levels. Clinical factors associated with aortic sclerosis and stenosis can be identified and are similar to risk factors for atherosclerosis.
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            Characterization of the early lesion of 'degenerative' valvular aortic stenosis. Histological and immunohistochemical studies.

            C Otto, J. Kuusisto, D Reichenbach … (1994)
            Nonrheumatic stenosis of trileaflet aortic valves, often termed senile or calcific valvular aortic stenosis, is considered a "degenerative" process, but little is known about the cellular or molecular factors that mediate its development. To characterize the developing aortic valvular lesion, we performed histological and immunohistochemical studies on Formalin-fixed and methanol-Carnoy's-fixed paraffin-embedded aortic valve leaflets or on frozen sections obtained at autopsy from 27 adults (age, 46 to 82 years) with normal leaflets (n = 6), mild macroscopic leaflet thickening (n = 15), or clinical aortic stenosis (n = 6). Focal areas of thickening ("early lesions") were characterized by (1) subendothelial thickening on the aortic side of the leaflet, between the basement membrane (PAS-positive) and elastic lamina (Verhoeff-van Gieson), (2) the presence of large amounts of intracellular and extracellular neutral lipids (oil red O) and fine, stippled mineralization (von Kossa), and (3) disruption of the basement membrane overlying the lesion. Regions of the fibrosa adjacent to these lesions were characterized by thickening and by protein, lipid, and calcium accumulation. Control valves showed none of these abnormalities. Immunohistochemical studies were performed using monoclonal antibodies directed against macrophages (anti-CD68 or HAM-56), and contractile proteins of smooth muscle cells or myofibroblasts (anti-alpha-actin and HHF-35) or rabbit polyclonal antiserum against T lymphocytes (anti-CD3). In normal valves, scattered macrophages were present in the fibrosa and ventricularis, and occasional muscle actin-positive cells were detected in the proximal portion of the ventricularis near the leaflet base, but no T lymphocytes were found. In contrast, early lesions were characterized by the presence of an inflammatory infiltrate composed of non-foam cell and foam cell macrophages, occasional T cells, and rare alpha-actin-positive cells. In stenotic aortic valves, a similar but more advanced lesion was seen. The early lesion of "degenerative" aortic stenosis is an active inflammatory process with some similarities (lipid deposition, macrophage and T-cell infiltration, and basement membrane disruption) and some dissimilarities (presence of prominent mineralization and small numbers of smooth muscle cells) to atherosclerosis.
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              The emerging role of valve interstitial cell phenotypes in regulating heart valve pathobiology.

              Jeffrey C. Liu, Avrum Gotlieb, Vineet R Joag (2007)
              The study of the cellular and molecular pathogenesis of heart valve disease is an emerging area of research made possible by the availability of cultures of valve interstitial cells (VICs) and valve endothelial cells (VECs) and by the design and use of in vitro and in vivo experimental systems that model elements of valve biological and pathobiological activity. VICs are the most common cells in the valve and are distinct from other mesenchymal cell types in other organs. We present a conceptual approach to the investigation of VICs by focusing on VIC phenotype-function relationships. Our review suggests that there are five identifiable phenotypes of VICs that define the current understanding of their cellular and molecular functions. These include embryonic progenitor endothelial/mesenchymal cells, quiescent VICs (qVICs), activated VICs (aVICs), progenitor VICs (pVICs), and osteoblastic VICs (obVICs). Although these may exhibit plasticity and may convert from one form to another, compartmentalizing VIC function into distinct phenotypes is useful in bringing clarity to our understanding of VIC pathobiology. We present a conceptual model that is useful in the design and interpretation of studies on the function of an important phenotype in disease, the activated VIC. We hope this review will inspire members of the investigative pathology community to consider valve pathobiology as an exciting new frontier exploring pathogenesis and discovering new therapeutic targets in cardiovascular diseases.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Int J Inflam
                Journal ID (publisher-id): IJI
                Title: International Journal of Inflammation
                Publisher: SAGE-Hindawi Access to Research
                ISSN (Electronic): 2042-0099
                Publication date Collection: 2011
                Publication date (Electronic): 6 July 2011
                Volume: 2011
                Electronic Location Identifier: 263870
                Affiliations
                1Wyss Institute for Biologically Inspired Engineering, School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138, USA
                2Department of Aerospace and Mechanical Engineering, University of Notre Dame, 143 Multidisciplinary Research Building, Notre Dame, IN 46556-5637, USA
                3The Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, 313 Ferst Drive, Suite 1121, Atlanta, GA 30332-0535, USA
                Author notes

                Academic Editor: Elena Aikawa

                Article
                DOI: 10.4061/2011/263870
                PMC ID: 3133012
                PubMed ID: 21760982
                SO-VID: 5d225a3e-5476-47d0-8447-9ac7f45e295e
                Copyright © Copyright © 2011 Kartik Balachandran et al.
                License:

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 18 March 2011
                Date accepted : 29 April 2011
                Categories
                Subject: Review Article

                ScienceOpen disciplines: Immunology
                Data availability:
                ScienceOpen disciplines: Immunology

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