Valvular osteoclasts in calcification and aortic valve stenosis severity

Nagy, Edit; Eriksson, Per; Yousry, Mohamed; Caidahl, Kenneth; Ingelsson, Erik; Hansson, Göran K.; Franco‐Cereceda, Anders; Bäck, Magnus

doi:10.1016/j.ijcard.2013.01.207

Cited by 41 publications

(31 citation statements)

References 44 publications

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“…14 Circulating and valve tissue levels of RUNX2 significantly correlated with valve stenosis severity. 41 In this study, we demonstrated that 2 SNPs in perfect linkage disequilibrium, rs114193529 and rs144071310, located in intron 1 of RUNX2 were moderately associated with AS. Whether one of these variants is functional or in linkage disequilibrium with another rare variant in RUNX2 is unclear from this study.…”

Section: Discussionmentioning

confidence: 58%

Calcium Signaling Pathway Genes RUNX2 and CACNA1C Are Associated With Calcific Aortic Valve Disease

Guauque-Olarte

Messika–Zeitoun

Droit

et al. 2015

Circ Cardiovasc Genet

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Background Calcific aortic valve stenosis (AS) is a life-threatening disease with no medical therapy. The genetic architecture of AS remains elusive. This study combines genome-wide association studies, gene expression, and expression quantitative trait loci mapping in human valve tissues to identify susceptibility genes of AS. Methods and Results A meta-analysis was performed combining the results of 2 genome-wide association studies in 474 and 486 cases from Quebec City (Canada) and Paris (France), respectively. Corresponding controls consisted of 2988 and 1864 individuals with European ancestry from the database of genotypes and phenotypes. mRNA expression levels were evaluated in 9 calcified and 8 normal aortic valves by RNA sequencing. The results were integrated with valve expression quantitative trait loci data obtained from 22 AS patients. Twenty-five single-nucleotide polymorphisms had P<5×10−6 in the genome-wide association studies meta-analysis. The calcium signaling pathway was the top gene set enriched for genes mapped to moderately AS-associated single-nucleotide polymorphisms. Genes in this pathway were found differentially expressed in valves with and without AS. Two single-nucleotide polymorphisms located in RUNX2 (runt-related transcription factor 2), encoding an osteogenic transcription factor, demonstrated some association with AS (genome-wide association studies P=5.33×10−5). The mRNA expression levels of RUNX2 were upregulated in calcified valves and associated with eQTL-SNPs. CACNA1C encoding a subunit of a voltage-dependent calcium channel was upregulated in calcified valves. The eQTL-SNP with the most significant association with AS located in CACNA1C was associated with higher expression of the gene. Conclusions This integrative genomic study confirmed the role of RUNX2 as a potential driver of AS and identified a new AS susceptibility gene, CACNA1C, belonging to the calcium signaling pathway.

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Section: Discussionmentioning

confidence: 58%

Calcium Signaling Pathway Genes RUNX2 and CACNA1C Are Associated With Calcific Aortic Valve Disease

Guauque-Olarte

Messika–Zeitoun

Droit

et al. 2015

Circ Cardiovasc Genet

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“…In the COFRASA study, Hekimian et al (2013) reported that progression of AVS was associated with calciumphosphorus metabolism and a bone resorptive remodeling. Recently, Nagy et al (2013) found a close relation between circulating mediators of bone homeostasis and severity of AVS.…”

Section: Relation Between Mineral Metabolism Disturbance and Cavdmentioning

confidence: 97%

Mineral metabolism disturbances are associated with the presence and severity of calcific aortic valve disease

Yang

Zhao

Fang

et al. 2015

J. Zhejiang Univ. Sci. B

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Abstract:Objective: We investigated whether disturbance of calcium and phosphate metabolism is associated with the presence and severity of calcific aortic valve disease (CAVD) in patients with normal or mildly impaired renal function. Methods: We measured serum levels of calcium, phosphate, alkaline phosphatase (AKP), intact parathyroid hormone (iPTH), 25-hydroxyvitamin D (25-OHD), and biomarkers of bone turnover in 260 consecutive patients with normal or mildly impaired renal function and aortic valve sclerosis (AVSc) (n=164) or stenosis (AVS) (n=96) and in 164 age-and gender-matched controls. Logistic regression models were used to determine the association of mineral metabolism parameters with the presence and severity of CAVD. Results: Stepwise increases were observed in serum levels of calcium, phosphate, AKP, and iPTH from the control group to patients with AVS, and with reverse changes for 25-OHD levels (all P<0.001). Similarly, osteocalcin, procollagen I N-terminal peptide, and β-isomerized type I collagen C-telopeptide breakdown products were significantly increased stepwise from the control group to patients with AVS (all P<0.001). In patients with AVS, serum levels of iPTH were positively, in contrast 25-OHD levels were negatively, related to trans-aortic peak flow velocity and mean pressure gradient. After adjusting for relevant confounding variables, increased serum levels of calcium, phosphate, AKP, and iPTH and reduced serum levels of 25-OHD were independently associated with the presence and severity of CAVD. Conclusions: This study suggests an association between mineral metabolism disturbance and the presence and severity of CAVD in patients with normal or mildly impaired renal function. Abnormal bone turnover may be a potential mechanism.

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“…49 In the latter study, treatment with a hypomethylator in addition decreased promoter methylation and increased 5-lipoxygenase transcription and leukotriene production, 49 which may participate in the pathological processes of aortic stenosis. 17 In addition, several genes encoding osteogenic proteins associated with heterotopic bone formation in aortic valves 5,50 are regulated by GC-rich promoters sensitive to methylation/hypomethylation. Interestingly, osteopontin gene methylation is decreased in response to shear stress in murine bone marrow-derived progenitor cells, associated with increased osteopontin expression.…”

Section: Cellular Responses To Biomechanical Factorsmentioning

confidence: 99%

Biomechanical factors in the biology of aortic wall and aortic valve diseases

Bäck

Gasser

Michel

et al. 2013

Cardiovascular Research

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208

143

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The biomechanical factors that result from the haemodynamic load on the cardiovascular system are a common denominator of several vascular pathologies. Thickening and calcification of the aortic valve will lead to reduced opening and the development of left ventricular outflow obstruction, referred to as aortic valve stenosis. The most common pathology of the aorta is the formation of an aneurysm, morphologically defined as a progressive dilatation of a vessel segment by more than 50% of its normal diameter. The aortic valve is exposed to both haemodynamic forces and structural leaflet deformation as it opens and closes with each heartbeat to assure unidirectional flow from the left ventricle to the aorta. The arterial pressure is translated into tension-dominated mechanical wall stress in the aorta. In addition, stress and strain are related through the aortic stiffness. Furthermore, blood flow over the valvular and vascular endothelial layer induces wall shear stress. Several pathophysiological processes of aortic valve stenosis and aortic aneurysms, such as macromolecule transport, gene expression alterations, cell death pathways, calcification, inflammation, and neoangiogenesis directly depend on biomechanical factors.

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Valvular osteoclasts in calcification and aortic valve stenosis severity

Abstract: These findings suggest a critical role of bone turnover as a determinant of aortic stenosis severity.

Cited by 41 publications

References 44 publications

Calcium Signaling Pathway Genes RUNX2 and CACNA1C Are Associated With Calcific Aortic Valve Disease

Calcium Signaling Pathway Genes RUNX2 and CACNA1C Are Associated With Calcific Aortic Valve Disease

Mineral metabolism disturbances are associated with the presence and severity of calcific aortic valve disease

Biomechanical factors in the biology of aortic wall and aortic valve diseases

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