Warfarin Induces Calcification of the Aortic Valve Through Extracellular Signal-regulated Kinase 1/2 and β-catenin Signaling

Venardos, Neil; Gergen, Anna K.; Jarrett, Michael; Weyant, Michael J.; Reece, T. Brett; Meng, Xianzhong; Fullerton, David A.

doi:10.1016/j.athoracsur.2021.03.099

Cited by 6 publications

(4 citation statements)

References 15 publications

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“…The predominance of antiplatelet use in patients with AVR was thought to be related to perioperative use in those with AVR. It has been reported that anticoagulant and antiplatelet use might influence aortic valve calcification (12,13). Thus, we could not exclude the possibility of effects of anti-coagulant and anti-platelet use on aortic valve calcification, which was a limitation of this cross-sectional study.…”

Section: Discussionmentioning

confidence: 85%

Lipoprotein (a) is a risk factor of aortic valve calcification in patients with a risk of atherosclerosis

Tserensonom,

Yagi,

Ise

et al. 2023

J. Med. Invest.

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Aortic valve calcification (AVC), which causes aortic stenosis (AS), is more common in elderly persons. Controlling for conventional risk variables did not, however, reduce the incidence of AS. Thus, residual risk factors of AS should be identified. We enrolled 513 patients who underwent coronary angiography with computed tomography because of suspicion of coronary artery disease (CAD) or ruling out of CAD before aortic valve replacement. Calcium volume was calculated with a commercially available application. Conventional and lipid-related risk factors including serum levels of Lp(a) were evaluated for all patients. Calcium volume and Lp(a) levels were significantly higher in patients who underwent aortic valve replacement than in those who did not. A single regression analysis showed that the calcium volume was positively associated with age and the Lp(a) levels and negatively associated with the estimated glomerular filtration rate. No statistical significance was observed for other risk factors, including oxidized low-density lipoprotein, omega-3 fatty acids levels. The multiple regression analysis revealed that age (P < 0.001), female sex (P < 0.05), Lp(a) (P < 0.01), and hemoglobin A1c (P < 0.01) were determinants of the calcium volume. The area under the curve in receiver operating characteristic analysis of Lp(a) for implementation of AVR was 0.65 at an Lp(a) cut-off level of 16 mg/dL. In conclusion, the serum Lp(a) level is a potent risk factor of AVC in patients with high risk of atherosclerosis.

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Section: Discussionmentioning

confidence: 85%

Lipoprotein (a) is a risk factor of aortic valve calcification in patients with a risk of atherosclerosis

Tserensonom,

Yagi,

Ise

et al. 2023

J. Med. Invest.

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“…The rat aortic valve leaflets like the mouse, are not optimal for studies on CAVD because they consist of several cell layers without the tri-layered structure of human aortic valves ( Grauss et al, 2003 ) (see above). A common model of vascular calcification and CAVD in rats is based on intravenous treatment with Warfarin, however, these rats do not develop hemo-dynamically significant aortic stenosis ( Price et al, 1998 ) and warfarin-induced aortic valve calcification differs from the naturally occurring ( Venardos et al, 2022 ). Such rats are phenotypically similar to MGP mutant mice, suggesting similar underlying mechanisms ( Tsang et al, 2016 ).…”

Section: Animal Modelsmentioning

confidence: 99%

Models and Techniques to Study Aortic Valve Calcification in Vitro, ex Vivo and in Vivo. An Overview

Bogdanova

Zabirnyk²,

Malashicheva³

et al. 2022

Front. Pharmacol.

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Aortic valve stenosis secondary to aortic valve calcification is the most common valve disease in the Western world. Calcification is a result of pathological proliferation and osteogenic differentiation of resident valve interstitial cells. To develop non-surgical treatments, the molecular and cellular mechanisms of pathological calcification must be revealed. In the current overview, we present methods for evaluation of calcification in different ex vivo, in vitro and in vivo situations including imaging in patients. The latter include echocardiography, scanning with computed tomography and magnetic resonance imaging. Particular emphasis is on translational studies of calcific aortic valve stenosis with a special focus on cell culture using human primary cell cultures. Such models are widely used and suitable for screening of drugs against calcification. Animal models are presented, but there is no animal model that faithfully mimics human calcific aortic valve disease. A model of experimentally induced calcification in whole porcine aortic valve leaflets ex vivo is also included. Finally, miscellaneous methods and aspects of aortic valve calcification, such as, for instance, biomarkers are presented.

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“…Bischoff et al [64] found that targeting β-catenin could prevent VC induced by warfarin, and identified quercetin as a potential therapeutic drug for treating the calcification. Venardos et al [65] found that warfarin induced osteogenic activity in normal and diseased isolated human aortic valve interstitial cell (AVICs). This effect is mediated by ERK1/2 in both diseased and normal AVICs, but in diseased AVICs β-catenin signaling also plays a role.…”

Section: Wnt/β-catenin Signaling In the Context Of Warfarin-induced C...mentioning

confidence: 99%

“…Venardos et al . [ 65 ] found that warfarin induced osteogenic activity in normal and diseased isolated human aortic valve interstitial cell (AVICs). This effect is mediated by ERK1/2 in both diseased and normal AVICs, but in diseased AVICs

-catenin signaling also plays a role.…”

Section: Mechanisms Underlying the Calcification Induced By Warfarinmentioning

confidence: 99%

Warfarin-Induced Calcification: Potential Prevention and Treatment Strategies

Wang¹,

Peng²,

Ma³

et al. 2022

Rev. Cardiovasc. Med.

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Warfarin is clinically used as the first choice for long-term anticoagulant therapy, and for the prevention of thromboembolic events. However, when used at low doses in the long term or high doses in the short term, warfarin treatment may result in tissue calcifications-such as calcifications in the coronary arteries, peripheral vascular system, blood vessels of patients with atrial fibrillation and chronic kidney disease, and vascular valves-and atherosclerotic plaque calcification. These warfarin-induced calcifications may affect cardiovascular function and exacerbate diseases such as diabetes and hypertension. Studies have shown that quercetin, osteoprotegerin, sclerosin, and sodium thiosulfate may alleviate these effects by interfering in the Wnt/β-catenin, TG2/β-catenin, Bone Morphogenetic Protein 2 (BMP2), and Eicosapentaenoic Acid/Matrix Metallopeptidase-9 (EPA/MMP-9) pathways, respectively. Nevertheless, the mechanism underlying warfarin-induced calcification remains unknown. Therefore, the question as to how to effectively attenuate the calcification induced by warfarin and ensure its anticoagulant effect remains an urgent clinical problem that needs to be resolved. To utilize warfarin rationally and to effectively attenuate the calcifications, we focused on the clinical phenomena, molecular mechanisms, and potential strategies to prevent calcification. Highlighting these aspects could provide new insights into the effective utilization of warfarin and the reduction of its associated calcification effects.

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Warfarin Induces Calcification of the Aortic Valve Through Extracellular Signal-regulated Kinase 1/2 and β-catenin Signaling

Cited by 6 publications

References 15 publications

Lipoprotein (a) is a risk factor of aortic valve calcification in patients with a risk of atherosclerosis

Lipoprotein (a) is a risk factor of aortic valve calcification in patients with a risk of atherosclerosis

Models and Techniques to Study Aortic Valve Calcification in Vitro, ex Vivo and in Vivo. An Overview

Warfarin-Induced Calcification: Potential Prevention and Treatment Strategies

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