T lymphocyte infiltration in non-rheumatic aortic stenosis: a comparative descriptive study between tricuspid and bicuspid aortic valves

Wallby, Lars; Janerot-Sjöberg, Birgitta; Steffensen, Thora S.; Broqvist, Mats

doi:10.1136/heart.88.4.348

Cited by 157 publications

(100 citation statements)

References 24 publications

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“…79 However, although tricuspid and bicuspid aortic valve lesions share many common epidemiologic risk factors and histopathologic lesion characteristics, 21 it may be that genetic factors, as typified by NOTCH1 mutations, 25 are more potent and more prevalent in the subset of patients who progress from aortic sclerosis to AS. 4 Thus, it might be that currently-proposed pharmacological therapies directed against atherogenic risk factors [31][32][33][34][35][36]62 are relatively less effective in the subset of AS patients with a genetic defect affecting valve morphology and/or may need to be started at an earlier time point to achieve a therapeutic benefit.…”

Section: O'brien Pathogenesis Of Calcific Aortic Valve Diseasementioning

confidence: 99%

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Pathogenesis of Calcific Aortic Valve Disease

O’Brien

2006

ATVB

254

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Background-Over the past 10 to 15 years, calcific aortic valve disease, which includes aortic sclerosis and aortic stenosis, has come to be recognized as an active process, based on: (1) epidemiologic studies demonstrating associations of specific risk factors with increased prevalence or rate of progression of aortic valve disease; (2) identification, in valve lesions, of histopathologic features of chronic inflammation, lipoprotein deposition, renin-angiotensin system components, and molecular mediators of calcification; and (3) identification of cell-signaling pathways and genetic factors that may participate in valve disease pathogenesis. These studies will be reviewed and organized into a proposed global hypothesis for the pathogenesis of calcific aortic valve disease. Key Words: aortic valve disease Ⅲ calcification Ⅲ lipoproteins Ⅲ matrix Ⅲ angiotensin II C alcific aortic valve disease is identified by thickening and calcification of the aortic valve leaflets in the absence of rheumatic heart disease. It is divided, on a functional basis, into aortic sclerosis, in which the leaflets do not obstruct left ventricular outflow, and aortic stenosis, in which obstruction to left ventricular outflow is present. Aortic sclerosis is present in more than 25% of patients over age 65 1 and is associated with a 50% increase risk of cardiovascular events. 2 Aortic stenosis is present in 2% to 5% of very elderly patients, 1,3 is the second most common indication for cardiac surgery, 4 and carries an 80% 5-year risk of progression to heart failure, valve replacement, or death. 5 Though the disease is associated with substantial clinical consequences, there currently is no effective therapy for the disease other than surgical aortic valve replacement.The lack of medical therapies for calcific aortic valve disease can be traced to at least two important issues, one intellectual, the other practical. The first was the long-held notion that calcific aortic valve disease was a "degenerative," and therefore unmodifiable, condition. 6 However, more recent studies have demonstrated convincingly that calcific aortic valve lesions have many features characteristic of an active pathobiological process, including chronic inflammation, 7-9 lipoprotein deposition, 10 -12 active calcification, [13][14][15][16][17][18] and renin-angiotensin system activation. 19,20 These features are present in both trileaflet and bileaflet aortic valve lesions. 21 Also, an emerging body of literature is investigating how genetic factors might influence disease development. [22][23][24][25] The second issue is that, for many years, there were no animal models that faithfully replicated the key histological features of the disease. Recently, rabbit models been developed, 16,26,27 with that of Rajamannan and colleagues already providing a number of novel insights. 16 -18,28,29 In particular, these models have implicated the Wnt 18 and Runx2/ Cbfa1 16,17,27 signaling pathways in disease pathogenesis. Only very recently has a purported mouse model of calcif...

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Section: O'brien Pathogenesis Of Calcific Aortic Valve Diseasementioning

confidence: 99%

“…19,20 These features are present in both trileaflet and bileaflet aortic valve lesions. 21 Also, an emerging body of literature is investigating how genetic factors might influence disease development. [22][23][24][25] The second issue is that, for many years, there were no animal models that faithfully replicated the key histological features of the disease.…”

mentioning

confidence: 99%

Pathogenesis of Calcific Aortic Valve Disease

O’Brien

2006

ATVB

254

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“…The modified valve mesenchymal cells also express genes characteristic of osteoblasts suggesting that calcification results from an active, regulated osteogenic process (Mazzone et al 2004, Rajamannan et al 2003. Since CAS is more prevalent in anatomically variant bileaflet aortic valves and occurs at younger ages in this population, the finding of similar T lymphocyte infiltration in biscupid valves further emphasized the importance of this inflammation in the pathogenesis of CAS (Wallby et al 2002). However questions regarding the immunologic nature of the T cell infiltrate in the valve, its significance and whether it is part of a broader systemic immune response remain unanswered.…”

Section: Introductionmentioning

confidence: 70%

“…The concept of inflammation in CAS was etched by Olssen and Otto and their colleagues who were among the first to clearly demonstrate a variable, but often quite appreciable T lymphocyte infiltration in this disease (Olsson, Dalsgaard, et al 1994, Otto et al 1994. Further work showed that most T cells infiltrating the valve are concentrated in regions of calcification or arrayed around newly appearing blood vessels that express VEGF, VEGF receptors, ICAM-1 and VCAM-1 (Mazzone et al 2004, Soini et al 2003, Wallby et al 2002. The T cells within the valve tissue exhibit evidence of activation, including expression of CD25 and HLA-DR, while cells in the surrounding valvular mesenchymal tissues also strongly express HLA-DR, consistent with the release of inflammatory mediators such as interferon- from activated lymphocytes (Olsson, Dalsgaard, et al 1994.…”

Section: Introductionmentioning

confidence: 99%

The Inflammatory Infiltrate in Calcific Aortic Stenosis is Characterized by Clonal Expansions of T Cells and is Associated with Elevated Proportions of Circulating Activated and Effector Memory CD8 T Cells

Winchester¹,

Kodali²

2011

Aortic Stenosis - Etiology, Pathophysiology and Treatment

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“…Histopathologic studies of aortic sclerosis show focal subendothelial plaquelike lesions on the aortic side of the leaflet that extend to the adjacent fibrosa layer. Similarities to atherosclerosis are present in these lesions, with prominent accumulation of "atherogenic" lipoproteins, including LDL and lipoprotein(a), evidence of LDL oxidation, an inflammatory cell infiltrate and microscopic calcification (Olsson et al, 1999;Otto et al, 1999;Wallby et al, 2002). The initiation of these lesions is possibly due to increased mechanical or decreased shear stress, similar to that seen in early atherosclerotic lesions (Freeman & Otto, 2005).…”

Section: The Diseased Stenotic Aortic Valvementioning

confidence: 83%