Findings of inflammation and possible autoimmunity in calcific aortic stenosis of unknown etiology in the geriatric population (original) (raw)
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Calcific aortic valve stenosis: Immunohistochemical analysis of inflammatory infiltrate
Pathology - Research and Practice, 2012
Calcific aortic valve disease is considered a form of atherosclerosis and, like the latter, possibly of inflammatory origin. The aim of our work was to study the pattern of cellular infiltrate in calcific aortic valve stenosis (CAS). Fifteen operatively excised calcified aortic valves were examined by histology and immunohistochemistry (CD20, CD79␣, CD3, CD4, CD8, CD68, CD138, CD117, BJK, BJL, IgA, IgD, IgG, IgG4 and IgM). The findings revealed that in CAS, there were chronic inflammatory features with infiltrates comprising lymphocytes, polyclonal plasma cells, histiocytes and mast cells. In T-lymphocytes, CD4 prevailed over CD8. In B-lymphocytes, there was a slight preponderance of CD20 over CD79␣. The BJL (lambda)-positive plasma cells prevailed over the BJK (kappa) ones. The CD138-positive plasma cells comprised 24% IgA-, 20% IgD-, 41% IgG-(including 11% of IgG4-) and 15% IgM-positive cells. CAS did not fulfill the criteria of the recently described clinicopathological entity IgG4-related sclerosing systemic disease. The inflammatory process was the same in both subsets of CAS -those with trileaflet (normally formed) valves and those with congenitally bicuspid valves.
2010
We investigated the main biomolecular features in the evolution of aortic stenosis, focusing on advanced lesions. BACKGROUND "Degenerative" aortic valve stenosis shares risk factors and inflammatory similarities with atherosclerosis. METHODS We compared nonrheumatic stenotic aortic valves from 26 patients undergoing surgical valve replacement (group A) and 14 surgical control patients (group B). We performed semiquantitative histological and immunohistochemical analyses on valve leaflets to measure inflammation, sclerosis, calcium, neoangiogenesis, and intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) expression. We assessed heat shock protein 60 (hsp60) gene expression as an index of cellular stress and C-reactive protein, erythrocyte sedimentation rate, and fibrinogen as systemic inflammatory markers. RESULTS In group A valves, we found a prevalence of calcium nodules surrounded by activated inflammatory infiltrates, neovessels, and abundant ICAM-1, VCAM-1, and hsp60 gene expression. Specimens from group B were negative for all of these markers, except 2 of 14 positivity for hsp60. The presence of active inflammatory infiltrates correlated with an abundance of thin neovessels (p Ͻ 0.01) and hsp60 gene expression (p ϭ 0.01), whereas neoangiogenesis correlated with inflammation (p ϭ 0.04), calcium (p ϭ 0.01), and hsp60 gene expression (p ϭ 0.04). CONCLUSIONS "Degenerative" aortic valve stenosis appears to be a chronic inflammatory process associated with atherosclerotic risk factors. The coexistence of neoangiogenesis, T-lymphocyte infiltration, adhesion molecules, and hsp60 gene expression indicates an active immunomediated process in the final phases of the disease. (J Am Coll Cardiol 2004;43:1670-6) © 2004 by the American College of Cardiology Foundation Nonrheumatic aortic valve stenosis is the most common valve disease in Europe and North America (1). Here, aortic sclerosis is present in about 26% of the population 65 years of age and older, whereas stenosis is evident in 2% to 7% of this age group (1). Calcified aortic valve stenosis increases in prevalence with age; it has a progressive course and is the most common reason for valve replacement (2). Several studies have demonstrated cardiovascular risk factors in common with atherosclerosis, including hyperlipidemia, hypertension, and diabetes (1,3,4), and similar pathological features, including endothelial damage, lipid deposition, and inflammatory infiltrates, making early aortic valve lesions appear similar to atheromas (5-7). Further evidence exists that progressive calcified aortic stenosis is an "active" From the
Journal of Cardiology, 2016
Background: Aortic stenosis (AS) shares several similarities with atherosclerosis. Recent reports showed that B cells are implicated in atherosclerosis progression through macrophage-B cells bidirectional interaction. We aimed to study the in loco presence of B cells within aortic valves and to determine its modulators. Methods: Thirty-seven patients with severe AS were studied. Immunohistochemistry was performed on valve leaflets using antibodies against CD20, B cell-activating factor of the tumor necrosis factor family receptor (BAFF-R) and CD68. Plasma inflammatory markers were also determined. Results: The B cells were detected within aortic leaflets from 5 to 31/mm 2 (17.9 AE 11.6/mm 2). Doublestaining showed that 27 AE 13.5% of B cells express BAFF-R. There were positive correlations between the number of B cells and macrophages (r = 0.45, p = 0.018), and between macrophages and B cell-associated BAFF-R expression (r = 0.66, p = 0.002). The number of B cells was associated with the valve calcification (r = 0.41, p = 0.039), and with the maximum transvalvular gradient (r = 0.63, p = 0.02). The BAFF-R expression was positively correlated with maximum transvalvular gradient (r = 0.39, p = 0.031) and negatively with aortic valve area (r = À0.41, p = 0.048). There were no correlations between the number of B cells and plasma markers. Conclusions: It might be hypothesized that, like in atherosclerosis, increasing number of B cells within aortic valves may accelerate inflammation and thus potentiate the progression of AS.
International Journal of Molecular Sciences
Aortic stenosis (AS) is a frequent cardiac disease in old individuals, characterized by valvular calcification, fibrosis, and inflammation. Recent studies suggest that AS is an active inflammatory atherosclerotic-like process. Particularly, it has been suggested that several immune cell types, present in the valve infiltrate, contribute to its degeneration and to the progression toward stenosis. Furthermore, the infiltrating T cell subpopulations mainly consist of oligoclonal expansions, probably specific for persistent antigens. Thus, the characterization of the cells implicated in the aortic valve calcification and the analysis of the antigens to which those cells respond to is of utmost importance to develop new therapies alternative to the replacement of the valve itself. However, calcified aortic valves have been only studied so far by histological and immunohistochemical methods, unable to render an in-depth phenotypical and functional cell profiling. Here we present, for the ...
Ceskoslovenska patologie
In developed countries, calcific aortic stenosis (CAS) has become the most common acquired valvular disease. It is considered a for of atherosclerosis and, like the latter, of inflammatory origin. Majority of cases of CAS are classified etiologically as either senile ("degenerative")--developing on previously normal aortic valve with three cusps, or based on congenitally malformed--bicuspid aortic valve. Twenty-eight cases of CAS (18 of the senile type, 7 of the bicuspid valve type, and 3 of indeterminable type) were examined by means of histology and immunohistochemistry (CD31 for blood vessels; D2-40 for lymphatics). In the calcified cusps, blood vessels were present in all 28 cases, and lymphatics in 14 of them. Vascularization was associated with lymphocytic infiltrates in 24 cases. There was no difference in the pattern between the two types of CAS. The origin of the cusp vessels is discussed. Our finding in the calcified cusps of both blood and lymphatic vessels toge...
American Journal of Medicine, 1983
Fresh cardiac valvular tissues and atrial appendages removed from 106 Indian patients with rheumatic heart disease at the tlme of corrective cardiac surgery were examined to determine the characteristics of valvular Interstitial lymphocytlc infiltrates uslng conventional histologic staining along with indirect immunofluorescent techniques. Precise identification of the phenotypic profiles of inflammatory mononuclear cells was attempted using anti-LgG, anti-la, and monoclonal mouse hybridoma reagents Identifying 1 cells (OKf3) as well as 1 cell subsets (OKT4 helper/Inducer and 0KT6 suppressor/cytotoxic cells). A similar group of 21 patients undergoing cardiac valvular resection in Albuquerque was studied. The mean age of Indian patients providing valve tissues was 27.7, whereas in those in Albuquerque, it was 52 years. Twenty-five percent of rheumatic heart valves in Indian patients showed significant lnterstltial lymphold Infiltrates, and one third of the rheumatic valves from patients in Albuquerque showed similar mononuclear cell collections.
Involvement of proinflammatory S100A9/A8 in the atherocalcinosis of aortic valves
Pathologia, 2017
According to the results of the Euro-Heart Survey on Vascular Heart Disease the most common pathology is nonrheumatic aortic stenosis, it is also called as calcific aortic valve stenosis (CAVS), as in its pathogenesis the process of biomineralization of valve cusps and ring plays the main role. The aim of the work is the immunohistochemical study of mineralized tissue of aortic heart valves, which are affected by atherocalcinosis. Materials and methods. 30 samples of mineralized aortic valves (I group) and 10 samples of aortic valve without evidence of biomineralization (II group-control) were studied. Immunohistochemical study of expression of collagen (Collagen I), CD68, myeloperoxidase (MPO), calgranulin A (S100A8), calgranulin B (S100A9), caspase 3 (Casp 3) and osteopontin (OPN) was conducted in AV tissue of both groups. Results. In CAV tissues the fibrillar component (collagen I) growths was found, but the quantitative and qualitative compositions of CD68+ circulating inflammatory cells are not significantly different from the control group. CAVs contain much more MPO+-cells (p <0.001) in comparison to the group of AVs without biomineralization. Our data show a significant increase of the S100A9 and OPN expression in the mineralized tissue of AVs (p < 0.01). Also, a higher expression level of Casp3 and MPO was found in CAVs (p < 0.05). Comparing the first and the second groups of AVs connection between the expression of S100A8 was not determined. Conclusion. High Casp 3 expression confirms the increased level of cell elimination in the CAVs tissue, which is obviously connected with the impact of high local concentrations of S100A9. These facts can contribute to the development of pathological biomineralization of AV. Since osteopontin inhibits the hydroxyapatite formation by binding to the surface of the crystals, its hyperproduction is a counteracting factor against biomineralization in AV tissue.
The Journal of Immunology, 2007
Valve lesions in degenerative calcific aortic stenosis (CAS), a disorder affecting 3% of those older than 75 years, are infiltrated by T lymphocytes. We sought to determine whether the ␣ TCR repertoire of these valve-infiltrating lymphocytes exhibited features either of a polyclonal nonselective response to inflammation or contained expanded clones suggesting a more specific immune process. TCR -chain CDR3-length distribution analysis using PCR primers specific for 23 V families performed in eight individuals with CAS affecting tri-or bileaflet aortic valves revealed considerable oligoclonal T cell expansion. In five cases, -chain nucleotide sequencing in five selected V families showed that an average of 92% of the valve-infiltrating T cell repertoire consisted of expanded T cell clones, differing markedly in composition from the relatively more polyclonal peripheral CD8 or CD4 T cell subsets found even in this elderly population. Twenty-four of the valveinfiltrating T cell clones also had the same clone identified in blood, some of which were highly expanded. Interestingly, 22 of these 24 shared clones were CD8 in lineage (p ؍ 1.5 ؋ 10 ؊12 ), suggesting a possible relationship to the expanded CD8 ؉ CD28 ؊ T cell clones frequently present in the elderly. Additionally, the sequences of several TCR -chain CDR3 regions were homologous to TCR -chains identified previously in allograft arteriosclerosis. We infer that these findings are inconsistent with a nonselective secondary response of T cells to inflammation and instead suggest that clonally expanded ␣ T cells are implicated in mediating a component of the valvular injury responsible for CAS.