Abstract 17341: Novel Lipid Markers of Calcific Aortic Valve Stenosis

Introduction: Calcific aortic valve stenosis (CAVS) is the most prevalent cardiac valvular pathology, leading to a high incidence of morbidity and mortality if left untreated. The exact pathophysiology of CAVS is largely undefined. Genetic studies have shown a strong correlation of the Lp(a) gene to developing CAVS. Lp(a) is known to be the carrier of plasma Oxidized Phosphatidylcholine and results in Lysophosphatidic acid (LPA) accumulation. The focus of the present study was to determine if OxPC and LPA in calcific human aortic valves relate with echocardiographic markers of CAVS. Methods: Aortic valves (n=98) were obtained from patients undergoing AVR. OxPC and LPA were extracted from pulverized aortic valves and analyzed using a targeted mass spectrometry approach. Lipid values are represented relative to an internal standard and normalized by homogenate and leaflet weights. The severity of calcification and aortic stenosis were measured anatomically by Echocardiographic calcification (ECC) score and hemodynamically by mean AV pressure gradient. Results: One-palmitoyl-2-(9-oxo)-nonanoyl- sn- glycero-3-phosphocholine (PONPC) was the most abundant OxPC among 58 OxPC molecules detected (49.3±3.8ng), in AV tissue. When valves were graded by ECC score, scores of 1 (no calcification) had observably attenuated amounts of mean total OxPC’s (135.3±39.3ng) compared to those with a score of 4 (severe calcification) (310.1±34.8 ng). Total valvular OxPC increased linearly with increased ECC score. Total non-fragmented OxPC’s were also significantly lower in valves with ECC scores of 1 and 2 compared to a score of 4 ( P =0.03). Six LPA species were also identified with 16:0 and 18:1 being the most prevalent. Mean AV pressure gradient had a significant, positive correlation with Total LPA amounts (r 2 =0.580, p <0.001), suggesting that elevated LPA concentrations in CAVS tissue is associated with disease severity. Conclusions: Our study is the largest lipidomics study of human aortic valve tissue demonstrating that OxPC and LPA molecules play a significant role in the etiology of CAVS and provides a novel therapeutic target for mitigating disease progression.

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Influences of aortic pressure gradient and ventricular septal thickness with systolic coronary flow in aortic valve stenosis

The American Journal of Cardiology ◽

10.1016/s0002-9149(96)00618-2 ◽

1996 ◽

Vol 78 (11) ◽

pp. 1303-1306 ◽

Cited By ~ 10

Author(s):

Gloria Tamborini ◽

Paolo Barbier ◽

Elisabetta Doria ◽

Claudia Galli ◽

Anna Maltagliat ◽

...

Keyword(s):

Aortic Valve ◽

Pressure Gradient ◽

Aortic Valve Stenosis ◽

Coronary Flow ◽

Aortic Pressure ◽

Septal Thickness ◽

Systolic Coronary Flow

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COX-2 Is Downregulated in Human Stenotic Aortic Valves and Its Inhibition Promotes Dystrophic Calcification

International Journal of Molecular Sciences ◽

10.3390/ijms21238917 ◽

2020 ◽

Vol 21 (23) ◽

pp. 8917

Author(s):

Francesco Vieceli Dalla Sega ◽

Francesca Fortini ◽

Paolo Cimaglia ◽

Luisa Marracino ◽

Elisabetta Tonet ◽

...

Keyword(s):

Aortic Valve ◽

Clinical Analysis ◽

Dystrophic Calcification ◽

Calcific Aortic Valve Disease ◽

Aortic Valves ◽

Inflammatory Drugs ◽

Cox 2 ◽

Anti Inflammatory ◽

Induced Apoptosis ◽

Human Aortic Valve

Calcific aortic valve disease (CAVD) is the result of maladaptive fibrocalcific processes leading to a progressive thickening and stiffening of aortic valve (AV) leaflets. CAVD is the most common cause of aortic stenosis (AS). At present, there is no effective pharmacotherapy in reducing CAVD progression; when CAVD becomes symptomatic it can only be treated with valve replacement. Inflammation has a key role in AV pathological remodeling; hence, anti-inflammatory therapy has been proposed as a strategy to prevent CAVD. Cyclooxygenase 2 (COX-2) is a key mediator of the inflammation and it is the target of widely used anti-inflammatory drugs. COX-2-inhibitor celecoxib was initially shown to reduce AV calcification in a murine model. However, in contrast to these findings, a recent retrospective clinical analysis found an association between AS and celecoxib use. In the present study, we investigated whether variations in COX-2 expression levels in human AVs may be linked to CAVD. We extracted total RNA from surgically explanted AVs from patients without CAVD or with CAVD. We found that COX-2 mRNA was higher in non-calcific AVs compared to calcific AVs (0.013 ± 0.002 vs. 0.006 ± 0.0004; p < 0.0001). Moreover, we isolated human aortic valve interstitial cells (AVICs) from AVs and found that COX-2 expression is decreased in AVICs from calcific valves compared to AVICs from non-calcific AVs. Furthermore, we observed that COX-2 inhibition with celecoxib induces AVICs trans-differentiation towards a myofibroblast phenotype, and increases the levels of TGF-β-induced apoptosis, both processes able to promote the formation of calcific nodules. We conclude that reduced COX-2 expression is a characteristic of human AVICs prone to calcification and that COX-2 inhibition may promote aortic valve calcification. Our findings support the notion that celecoxib may facilitate CAVD progression.

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Expression of the Frizzled receptors and their co-receptors in calcified human aortic valves

Canadian Journal of Physiology and Pharmacology ◽

10.1139/cjpp-2017-0577 ◽

2018 ◽

Vol 96 (2) ◽

pp. 208-214 ◽

Cited By ~ 7

Author(s):

Ateeque Siddique ◽

Bin Yu ◽

Kashif Khan ◽

Ryan Buyting ◽

Hamood Al-Kindi ◽

...

Keyword(s):

Aortic Valve ◽

Wnt Signaling ◽

Quantitative Polymerase Chain Reaction ◽

Disease Process ◽

Receptor Expression ◽

Cellular Mechanisms ◽

Aortic Valves ◽

Major Player ◽

Frizzled Receptors ◽

Human Aortic Valve

The cellular mechanisms that induce calcific aortic stenosis are yet to be unraveled. Wnt signaling is increasingly being considered as a major player in the disease process. However, the presence of Wnt Frizzled (Fzd) receptors and co-receptors LRP5 and 6 in normal and diseased human aortic valves remains to be elucidated. Immunohistochemistry and quantitative polymerase chain reaction were used to determine Fzd receptor expression in normal and calcified human aortic valve tissue, as well as human aortic valve interstitial cells (HAVICs) isolated from calcified and normal human aortic valves. There was significantly higher mRNA expression of 4 out of the 10 Fzd receptors in calcified aortic valve tissues and 8 out of the 10 in HAVICs, and both LRP5/6 co-receptors in calcified aortic valves (P < 0.05). These results were confirmed by immunohistochemistry, which revealed abundant increase in immunoreactivity for Fzd3, 7, and 8, mainly in areas of lipid core and calcified nodules of diseased aortic valves. The findings of abundant expression of Fzd and LRP5/6 receptors in diseased aortic valves suggests a potential role for both canonical and noncanonical Wnt signaling in the pathogenesis of human aortic valve calcification. Future investigations aimed at targeting these molecules may provide potential therapies for aortic valve stenosis.

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Augmented cannabinoid receptors expression in human aortic valve stenosis

International Journal of Cardiology ◽

10.1016/j.ijcard.2010.04.067 ◽

2010 ◽

Vol 145 (3) ◽

pp. 535-537 ◽

Cited By ~ 5

Author(s):

Yoshiro Naito ◽

Takeshi Tsujino ◽

Hirokuni Akahori ◽

Mitsumasa Ohyanagi ◽

Masataka Mitsuno ◽

...

Keyword(s):

Aortic Valve ◽

Aortic Valve Stenosis ◽

Cannabinoid Receptors ◽

Human Aortic Valve

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Zinc ameliorates human aortic valve calcification through GPR39 mediated ERK1/2 signalling pathway

Cardiovascular Research ◽

10.1093/cvr/cvaa090 ◽

2020 ◽

Cited By ~ 4

Author(s):

Ziying Chen ◽

Flora Gordillo-Martinez ◽

Lei Jiang ◽

Pengcheng He ◽

Wanzi Hong ◽

...

Keyword(s):

Aortic Valve ◽

Osteogenic Differentiation ◽

Zinc Supplementation ◽

Zinc Transporter ◽

Signalling Pathway ◽

Valve Disease ◽

Zinc Treatment ◽

Aortic Valves ◽

Human Aortic Valve

Abstract Aims Calcific aortic valve disease (CAVD) is the most common heart valve disease in the Western world. It has been reported that zinc is accumulated in calcified human aortic valves. However, whether zinc directly regulates CAVD is yet to be elucidated. The present study sought to determine the potential role of zinc in the pathogenesis of CAVD. Methods and results Using a combination of a human valve interstitial cell (hVIC) calcification model, human aortic valve tissues, and blood samples, we report that 20 μM zinc supplementation attenuates hVIC in vitro calcification, and that this is mediated through inhibition of apoptosis and osteogenic differentiation via the zinc-sensing receptor GPR39-dependent ERK1/2 signalling pathway. Furthermore, we report that GPR39 protein expression is dramatically reduced in calcified human aortic valves, and there is a significant reduction in zinc serum levels in patients with CAVD. Moreover, we reveal that 20 μM zinc treatment prevents the reduction of GPR39 observed in calcified hVICs. We also show that the zinc transporter ZIP13 and ZIP14 are significantly increased in hVICs in response to zinc treatment. Knockdown of ZIP13 or ZIP14 significantly inhibited hVIC in vitro calcification and osteogenic differentiation. Conclusions Together, these findings suggest that zinc is a novel inhibitor of CAVD, and report that zinc transporter ZIP13 and ZIP14 are important regulators of hVIC in vitro calcification and osteogenic differentiation. Zinc supplementation may offer a potential therapeutic strategy for CAVD.

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