Aortic valve stenosis: an active atheroinflammatory process

Helske, Satu; Kupari, Markku; Lindstedt, Ken A.; Kovanen, Petri T.

doi:10.1097/mol.0b013e3282a66099

Cited by 114 publications

(89 citation statements)

References 79 publications

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“…11,16,17 Yet, the exact role of inflammation in the pathophysiology of aortic stenosis remains unknown. The aim of this study was to associate the local inflammatory response, exerted in aortic valves through the leukotriene (LT) pathway, with the clinical features of valvular function as determined echocardiographically.…”

Section: Clinical Perspective On P 1325mentioning

confidence: 99%

Upregulation of the 5-Lipoxygenase Pathway in Human Aortic Valves Correlates With Severity of Stenosis and Leads to Leukotriene-Induced Effects on Valvular Myofibroblasts

et al. 2011

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Background-The development of aortic valve stenosis is not only associated with calcification and extracellular matrix remodeling, but also with inflammation. The aim of this study was to determine the role of proinflammatory signaling through the leukotriene (LT) pathway in aortic stenosis. Methods and Results-After macroscopic dissection of surgically removed human aortic valves, RNA was extracted from 311 preparations derived from 68 patients to differentiate normal, thickened, and calcified areas from each cusp. Subsequently, quantitative polymerase chain reaction analysis was used to correlate gene expression patterns with preoperative echocardiographic parameters. The messenger RNA levels of the LT-forming enzyme 5-lipoxygenase increased 1.6-and 2.2-fold in thickened and calcified tissue, respectively, compared with normal areas of the same valves. In thickened tissues, messenger RNA levels for Pϭ0.03), its activating protein (5-lipoxygenase activating protein; rϭϪ0.39; Pϭ0.02), and LTA 4 hydrolase (rϭϪ0.48; Pϭ0.01) correlated inversely with the velocity-time integral ratio. In addition, leukotriene A 4 hydrolase transcripts correlated inversely with aortic valve area, indexed for body surface area (rϭϪ0.52; Pϭ0.007). Immunohistochemical stainings revealed LT receptor expression on valvular myofibroblasts. In primary cultures of human myofibroblasts derived from stenotic aortic valves, Leukotriene C 4 (LTC 4 ) increased intracellular calcium, enhanced reactive oxygen species production, reduced the mitochondrial membrane potential, and led to morphological cell cytoplasm changes and calcification. Conclusions-The upregulation of the LT pathway in human aortic valve stenosis and its correlation with clinical stenosis severity, taken together with the potentially detrimental LT-induced effects on valvular myofibroblasts, suggests one possible role of inflammation in the development of aortic stenosis. (Circulation. 2011;123:1316-1325.)Key Words: aortic valve stenosis Ⅲ echocardiography Ⅲ inflammation Ⅲ leukotrienes Ⅲ myofibroblasts A lthough the primary risk factor for developing aortic stenosis is increasing age, 1 stenotic aortic valves share morphological characteristics with atherosclerotic lesions. For example, in the active disease process, lipid accumulation, 2 inflammatory infiltration, 3-5 neovascularization, 6,7 extracellular matrix degradation, 8 -10 and extensive calcification 3,5,11 take place, which eventually cause the aortic valve to narrow. However, attempts to inhibit the hemodynamic progression of aortic stenosis using lipid-lowering drugs have not been successful. [12][13][14] The poor prognosis and increased mortality from aortic stenosis after the onset of symptoms in the absence of surgical valve replacement 15 provide a rationale for the pursuit of a medical treatment that impedes the hemodynamic progression of aortic valve disease. Clinical Perspective on p 1325Inflammatory infiltration of activated macrophages and T-cells, as well as cytokine release, has been described in human s...

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Section: Clinical Perspective On P 1325mentioning

confidence: 99%

Upregulation of the 5-Lipoxygenase Pathway in Human Aortic Valves Correlates With Severity of Stenosis and Leads to Leukotriene-Induced Effects on Valvular Myofibroblasts

et al. 2011

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“…With regard to pathophysiology, it has been proven that early lesions of AVC implicate active processes similar to atherosclerosis, such as lipid deposition, macrophage infiltration, and production of osteopontin as well as other proteins (Rajamannan, 2010). Further changes associated with extracellular matrix remodeling and neovascularization ultimately lead to active calcification (Prasad and Bhalodkar, 2004;Helske et al, 2007). Experimental animal models of AVC (Rajamannan et al, 2005;Drolet et al, 2006) demonstrated that early lesions contained inflammatory cells.…”

Section: Discussionmentioning

confidence: 99%

Decreased levels of soluble receptor for advanced glycation end-products in aortic valve calcification patients

Zheng¹,

Li²,

Xie³

et al. 2015

Genet. Mol. Res.

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ABSTRACT. The soluble receptor for advanced glycation endproducts (sRAGE) shows a close relationship with atherosclerosis. The goal of this study was to compare the levels of sRAGE in patients with and without aortic valve calcification and to investigate the relationship between them. After transthoracic echocardiographic examination, 120 male patients with aortic valve calcification and 120 age-matched male controls without aortic valve calcification were included in our study. sRAGE levels were compared between groups. The prevalence of diabetes mellitus and coronary artery disease were significantly higher in the aortic valve calcification group than in the control group (63.3 versus 45%, P = 0.01, and 65 versus 51.7%, P < 0.01, respectively). The levels of sRAGE were lower in the aortic valve calcification group than in the control group (203.8 ± 34.6 versus 324.7 ± 41.6 pg/mL, H. Zheng et al. 3776©FUNPEC-RP www.funpecrp.com.br Genetics and Molecular Research 14 (2): 3775-3783 (2015) P < 0.01). In multivariate analysis, age, coronary artery disease, and sRAGE levels were independent predictors of aortic valve calcification. Our study demonstrates that sRAGE, which was proven to be a potential marker of atherosclerosis, might have a role in the development of aortic valve calcification.

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“…However, recent studies have provided evidences that inflammation plays a key role in the physiopathology of AS as well as classical cardiovascular risk factors such as hypertension, hypercholesterolemia, diabetes, smoking, age or sex [2]. Degeneration of the valve begins with an endothelial dysfunction in the aortic side as a result of the abovementioned risk factors.…”

Section: Aortic Stenosismentioning

confidence: 99%

“…Additionally, metabolomic fingerprinting involves less up-front method development when compared with targeted approaches but requires an exhaustive analysis due to the large number of identified metabolites. As well as in proteomics analyses, there are three main steps when performing a metabolomic study: [1] sample preparation; [2] metabolite detection and [3] data analysis.…”

Section: Metabolomicsmentioning

confidence: 99%

“…An ideal sample-preparation method for metabolomic fingerprinting should have the following characteristics [1] non-selective to ensure adequate metabolite coverage; [2] simple and fast, with the minimum number of steps possible to minimize metabolite loss and/or degradation of the sample and enable high-throughput; [3] reproducible and [4] incorporate a metabolism-quenching step (low temperatures, addition of acid, or fast heating) to represent true metabolome composition at the time of sampling ( Figure 5) [63]. For tissue metabolomics, the protocol includes a previous step of manual homogenization at low temperatures follow by a quenching step in liquid nitrogen [64].…”

Section: Sample Preparationmentioning

confidence: 99%

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Proteomics and Metabolomics in Aortic Stenosis: Studying Healthy Valves for a Better Understanding of the Disease

Mouriño-Álvarez¹,

Laborde²,

Barderas³

2013

Calcific Aortic Valve Disease

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Aortic valve stenosis: an active atheroinflammatory process

Cited by 114 publications

References 79 publications

Upregulation of the 5-Lipoxygenase Pathway in Human Aortic Valves Correlates With Severity of Stenosis and Leads to Leukotriene-Induced Effects on Valvular Myofibroblasts

Upregulation of the 5-Lipoxygenase Pathway in Human Aortic Valves Correlates With Severity of Stenosis and Leads to Leukotriene-Induced Effects on Valvular Myofibroblasts

Decreased levels of soluble receptor for advanced glycation end-products in aortic valve calcification patients

Proteomics and Metabolomics in Aortic Stenosis: Studying Healthy Valves for a Better Understanding of the Disease

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