Calcific Aortic Valve Stenosis Research Articles

Type 2 Diabetes, Circulating Metabolites, and Calcific Aortic Valve Stenosis: A Mendelian Randomization Study.

Epidemiological studies have shown an association between type 2 diabetes (T2D) and calcific aortic valve stenosis (CAVS), but the potential causal relationship and underlying mechanisms remain unclear. Therefore, we conducted a two-sample and two-step Mendelian randomization (MR) analysis to evaluate the association of T2D with CAVS and the mediating effects of circulating metabolites and blood pressure using genome-wide association study (GWAS) summary statistics. The inverse variance weighted (IVW) method was used for the primary MR analysis, and comprehensive sensitivity analyses were performed to validate the robustness of the results. Our results showed that genetically predicted T2D was associated with increased CAVS risk (OR 1.153, 95% CI 1.096-1.214, p < 0.001), and this association persisted even after adjusting for adiposity traits in multivariable MR analysis. Furthermore, the two-step MR analysis identified 69 of 251 candidate mediators that partially mediated the effect of T2D on CAVS, including total branched-chain amino acids (proportion mediated: 23.29%), valine (17.78%), tyrosine (9.68%), systolic blood pressure (8.72%), the triglyceride group (6.07-11.99%), the fatty acid group (4.78-12.82%), and the cholesterol group (3.64-11.56%). This MR study elucidated the causal impact of T2D on CAVS risk independently of adiposity and identified potential mediators in this association pathways. Our findings shed light on the pathogenesis of CAVS and suggest additional targets for the prevention and intervention of CAVS attributed to T2D.

Aortic Valve Calcium Score: Applications in Clinical Practice and Scientific Research-A Narrative Review.

In this narrative review, we investigate the essential role played by the computed tomography Aortic Valve Calcium Score (AVCS) in the cardiovascular diagnostic landscape, with a special focus on its implications for clinical practice and scientific research. Calcific aortic valve stenosis is the most prevalent type of aortic stenosis (AS) in industrialized countries, and due to the aging population, its prevalence is increasing. While transthoracic echocardiography (TTE) remains the gold standard, AVCS stands out as an essential complementary tool in evaluating patients with AS. The advantage of AVCS is its independence from flow; this allows for a more precise evaluation of patients with discordant findings in TTE. Further clinical applications of AVCS include in the assessment of patients before transcatheter aortic valve replacement (TAVR), as it helps in predicting outcomes and provides prognostic information post-TAVR. Additionally, we describe different AVCS thresholds regarding gender and the anatomical variations of the aortic valve. Finally, we discuss various scientific studies where AVCS was applied. As AVCS has some limitations, due to the pathophysiologies of AS extending beyond calcification and gender differences, scientists strive to validate contrast-enhanced AVCS. Furthermore, research on developing radiation-free methods of measuring calcium content is ongoing.

Observational and genetic association of non-alcoholic fatty liver disease and calcific aortic valve disease.

Non-alcoholic fatty liver disease (NAFLD) has emerged as a predominant driver of chronic liver disease globally and is associated with increased cardiovascular disease morbidity and mortality. However, the association between NAFLD and calcific aortic valve disease remains unclear. We aimed to prospectively investigate the association between NAFLD and incident aortic valve calcification (AVC), as well as its genetic relationship with incident calcific aortic valve stenosis (CAVS). A post hoc analysis was conducted on 4226 participants from the Multi-Ethnic Study of Atherosclerosis (MESA) database. We employed the adjusted Cox models to assess the observational association between NAFLD and incident AVC. Additionally, we conducted two-sample Mendelian randomization (MR) analyses to investigate the genetic association between genetically predicted NAFLD and calcific aortic valve stenosis (CAVS), a severe form of CAVD. We repeated the MR analyses by excluding NAFLD susceptibility genes linked to impaired very low-density lipoprotein (VLDL) secretion. After adjustment for potential risk factors, participants with NAFLD had a hazard ratio of 1.58 (95% CI: 1.03-2.43) for incident AVC compared to those without NAFLD. After excluding genes associated with impaired VLDL secretion, the MR analyses consistently showed the significant associations between genetically predicted NAFLD and CAVS for 3 traits: chronic elevation of alanine aminotransferase (odds ratio = 1.13 [95% CI: 1.01-1.25]), imaging-based NAFLD (odds ratio = 2.81 [95% CI: 1.66-4.76]), and biopsy-confirmed NAFLD (odds ratio = 1.12 [95% CI: 1.01-1.24]). However, the association became non-significant when considering all NAFLD susceptibility genes. NAFLD was independently associated with an elevated risk of incident AVC. Genetically predicted NAFLD was also associated with CAVS after excluding genetic variants related to impaired VLDL secretion.

Genetic proxy of lipid-lowering drugs and calcific aortic valve stenosis: A Mendelian randomization study

BackgroundLipid metabolism plays an important role in the pathogenesis and development of calcific aortic valve stenosis. Our aim was to evaluate the causal effect of lipid-lowering drugs, such as low-density lipoprotein cholesterol (LDL-C) lowering and triglyceride lowering drugs, on the outcome of aortic valve stenosis using a two-sample Mendelian randomization (MR) study. MethodsWe used two genetic tools to represent the exposure of lipid-lowering drugs, including expression quantitative trait loci for the expression of drug target genes, and genetic variants within or near drug target genes that are associated with LDL-C and triglyceride concentrations from Genome-Wide Association Studies (GWAS). Effect estimates were calculated using summary-data-based MR (SMR) and inverse-variance-weighted MR (IVW-MR) analysis. ResultsBased on the results of SMR and IVW-MR analysis, LDL-C-lowering PCSK9 inhibitors have potential in reducing the risk of aortic valve stenosis (for SMR, OR: 1.044; 95%CI: 1.002–1.404; P = 0.047; for IVW-MR, OR: 1.647, 95%CI: 1.316–2.062, P < 0.001). However, no significant association was observed between triglyceride target gene expression, as well as triglyceride-lowering drugs, and aortic valve stenosis. ConclusionThis two-sample drug-targeted MR study suggests a potential causal relationship between PCSK9 inhibitors and the reduction of calcific aortic valve stenosis risk.

Insights into calcific aortic valve stenosis: a comprehensive overview of the disease and advancing treatment strategies

Aortic valve stenosis is a disease characterized by thickening and narrowing of the aortic valve (AV), most commonly due to calcification, which leads to left ventricular outflow obstruction called calcific aortic valve disease (CAVD). CAVD presents as a progressive clinical syndrome with cardiorespiratory symptoms, often with rapid deterioration. The modern-day pathophysiology of CAVD involves a complex interplay of genetic factors, chronic inflammation, lipid deposition, and valve calcification, with early CAVD stages resembling atherosclerosis. Various imaging modalities have been used to evaluate CAVD, with a recent trend of using advanced imaging to measure numerous AV parameters, such as peak jet velocity. Significant improvements in mortality have been achieved with transcatheter AV repair, but numerous therapeutics and modalities are being researched to delay the progression of CAVD. This article aims to provide a comprehensive review of CAVD, explore recent developments, and provide insights into future treatments with various novel modalities.

Exploring the regulation of circulating factors involved in aortic valve sclerosis onset

Abstract Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): Ministero della Salute - Ricerca Finalizzata Background Aortic valve sclerosis (AVSc), the first stage of calcific aortic valve stenosis (CAVS), has a prevalence of 25-30% in subjects older than 65 years. Being a clinically silent phase, it is characterized only by non-uniform leaflet thickening due to fibrosis and microcalcifications, without the obstruction of the blood flow with an increased local oxidative stress, inflammation, and endothelial-to-mesenchymal transition (EndMT). However, to date, AVSc is not considered a pathology but 10% of cases evolve a full-blown CAVS. Aim Our aim is to investigate which systemic process(es) are activated in AVSc, in order to better define these subjects. These evaluations will allow us to identify potential druggable targets. Methods We consecutively enrolled 157 healthy subjects and detected AVSc presence by echocardiography. Plasma and serum samples were collected to evaluate circulating microRNA (RNA-sequencing) and cytokines (Luminex), respectively. Functional analysis was performed to reveal systemic pathway regulation. Healthy human valve endothelial cells were employed to evaluate viability (MTT assay) and EndMT (morphological analysis and quantitative PCR) Results AVSc was present in 77 patients (49%) and the differential expression analysis revealed that 59 microRNAs were down-regulated, while 93 were up-regulated in these subjects compared to healthy ones (adjusted-p&amp;lt;0.05). The functional analysis revealed that the major enriched pathways in AVSc subjects were related to inflammation. Indeed, serum GROα and IL1β levels were higher in AVSc vs healthy (p&amp;lt;0.05). In vitro, chronic GROα treatment resulted in lower cell viability (100.0±17.4 vs 61.8±16.5% of vital cells; p&amp;lt;0.0001), while IL1β treatment induced a decrease in cell roundness and an increase in total area (0.40±0.18 vs 0.47±0.19AU, p&amp;lt;0.0001; and 0.75±0.73 vs 0.45±0.48AU, p&amp;lt;0.0001; respectively). Quantitative PCR revealed EndMT activation: SNAI1 (1.87±0.57 log2(foldchange), p&amp;lt;0.0001) and SNAI2 (2.19±0.46 log2(foldchange), p&amp;lt;0.0001) only after IL1β treatment. Conclusions Inflammation is the most regulated systemic pathway in AVSc subjects and its master regulator, IL1β, seems to be involved in the EndMT progression of valve endothelial cells, while GROα contributes to their death. These effects could be related to the early triggers of AVSc onset, leading to fibrosis and eventually calcification of aortic leaflets.

CCT‘S CRYSTAL BALL: PREDICTING CARDIOVASCULAR RISK IN AORTIC VALVE STENOSIS PATIENTS UNDERGOING VALVE REPLACEMENT

Abstract Background and Aims Currently, computed tomography cardiac imaging (CTCI) plays a fundamental role in the pre–procedural planning of degenerative–calcific aortic valve stenosis(AS) correction. However, its prognostic role in assessing mortality and major adverse cardiovascular events (MACE) has not been extensively explored. CTCI allows for the evaluation of coronary artery calcification(CAC), mitral annular calcifications (MAC), aortic valve calcifications (CVA), and thoracic aorta calcifications (CAT). The aim of our study was to assess whether the presence and extent of CAC, MAC, CVA, and CAT could influence non–cardiovascular mortality (NCM), cardiovascular mortality (CM), and MACE in patients undergoing valve replacement(VR). Materials and Methods We collected retrospectivelly clinical and instrumental data and reviewed CTCI using a semi–quantitative approach. CACs were classified according to the visual 2022 Coronary Artery Disease–Reporting and Data System. MACs were defined following the Guerrero et al. study, CVAs according to the Win Registry and CATs were assessed in the ascending aorta, aortic arch, and descending aorta according to the Vos classification. Results 244 patients(59% male, mean age 80.1±6.6 years), with 91% undergoing transfemoral VR, were enrolled(2016–2018). CM was significantly higher in patients with hypertension,cerebro/peripheral vascular disease, stage IV–V renal insufficiency and history of atrial fibrillation (p=0.012,p&amp;lt;0.001,p=0.005, p=0.034 and p=0.024, respectively). CM was also more pronounced in patients with STS SCORE≥6.7±5.2 and EuroSCOREII≥ 5.5±5.8(p=0.016 and p=0.037). Extensive CAC(p=0.019), a MAC score&amp;gt;7(p=0.051), moderate and severe AVC (p=0.029 and p=0.053) and TAC&amp;gt;270° in aortic arch(p=0.019) were linked to CM. In multivariate analysis, a high MAC score and the presence of moderate AVC persisted as risk factors for CM. The presence of a MAC score &amp;gt;7(p=0.006) and the extension of descending TAC &amp;gt;1.5 mm (p=0.034) were associated with an increased risk of NCM.The presence of extensive TAC (≥270°) measured in the aortic arch and descending aorta were associated with MACE (p=0.034 and p=0.0504 respectively). Conclusions CTCI emerges as a crucial tool for evaluating prognostic risk in patients undergoing VR for AS. This type of evaluation can assist clinicians in pre–procedural planning and patient management, allowing for better identification of high–risk patients and optimization of therapeutic strategies

Catheter-based and surgical treatment for aortic valve diseases

The pathophysiology of aortic valve diseases is of predominantly degenerative nature, characterized by calcific aortic valve stenosis, which is associated with areduction in prognosis. The prevalence of aortic valve insufficiency also increases with advancing age. Timely causal treatment is crucial in the management of aortic valve diseases. Following the indication for intervention, the heart team plays acentral role in evaluating the results and making therapeutic decisions that consider the patient's preferences. In the assessment of treatment options, considerations regarding the long-term perspective are particularly crucial, especially in younger patients. The most common therapeutic approach for aortic valve diseases is the introduction of anew valve prosthesis. In the majority of cases, this is now achieved through catheter-based implantation of abioprosthetic heart valve, known as transcatheter aortic valve implantation (TAVI). Open surgical aortic valve replacement (AVR) is favored in younger patients with low surgical risk or in the case that TAVI is not feasible. In AVR, both biological and the longest-lasting mechanical prosthesis types are used. Surgical repair techniques are primarily applied in cases of aortic valve regurgitation. Notably, TAVI, as well as surgical procedures for the treatment of aortic valve diseases, have undergone significant advancements in recent years, including expanded indications for TAVI and, on the surgical side, in particular the development of minimally invasive surgical techniques.

Identification of Circulating Inflammatory Proteins Associated with Calcific Aortic Valve Stenosis by Multiplex Analysis.

Calcific aortic valve stenosis (CAVS) is characterized by increasing inflammation and progressive calcification in the aortic valve leaflets and is a major cause of death in the aging population. This study aimed to identify the inflammatory proteins involved in CAVS and provide potential therapeutic targets. We investigated the observational and causal associations of 92 inflammatory proteins, which were measured using affinity-based proteomic assays. Firstly, the case-control cohort identified differential proteins associated with the occurrence and progression of CAVS. Subsequently, we delved into exploring the causal impacts of these associated proteins through Mendelian randomization. This involved utilizing genetic instruments derived from cis-protein quantitative loci identified in genome-wide association studies, encompassing a cohort of over 400,000 individuals. Finally, we investigated the gene transcription and protein expression levels of inflammatory proteins by single-cell and immunohistochemistry analysis. Multivariate logistic regression and spearman's correlation analysis showed that five proteins showed a significant positive correlation with disease severity. Mendelian randomization showed that elevated levels of two proteins, namely, matrix metallopeptidase-1 (MMP1) and sirtuin 2 (SIRT2), were associated with an increased risk of CAVS. Immunohistochemistry and single-cell transcriptomes showed that expression levels of MMP1 and SIRT2 at the tissue and cell levels were significantly higher in calcified valves than in non-calcified control valves. These findings indicate that MMP1 and SIRT2 are causally related to CAVS and open up the possibility for identifying novel therapeutic targets.

Elevated Lp(a): Guidance for Identifying and Managing Patients.

Lipoprotein(a) (Lp(a)) is a unique low-density lipoprotein-like lipoprotein that is considered an independent and causal risk factor for atherosclerotic cardiovascular disease (ASCVD) and calcific aortic valve stenosis. The Lp(a) molecule also contains apolipoprotein A and apolipoprotein B, which collectively promote atherosclerosis, thrombosis, and inflammation. Lp(a) is highly genetic and minimally responsive to nonpharmacological measures. Lp(a) serum levels ≥125 nmol/L are associated with increased ASCVD risk, but this threshold has not been accepted universally. Elevated Lp(a) is the most common genetic dyslipidemia affecting approximately 20% of the general population. Certain currently available lipid-lowering drugs, including the proprotein convertase subtilisin/kexin type 9 therapies, produce moderate reductions in Lp(a); however, none are indicated for the treatment of elevated Lp(a). There are currently four investigational RNA-based therapeutic agents that reduce Lp(a) by 70% to 100%. Two of these agents are being evaluated for ASCVD risk reduction in adequately powered outcomes trials, with results expected in 2 to 3 years. Until such therapies become available and demonstrate favorable clinical outcomes, strategies for elevated Lp(a) primarily involve early and intensive ASCVD risk factor management.

Integrative genomic analyses identify candidate causal genes for calcific aortic valve stenosis involving tissue-specific regulation.

There is currently no medical therapy to prevent calcific aortic valve stenosis (CAVS). Multi-omics approaches could lead to the identification of novel molecular targets. Here, we perform a genome-wide association study (GWAS) meta-analysis including 14,819 cases among 941,863 participants of European ancestry. We report 32 genomic loci, among which 20 are novel. RNA sequencing of 500 human aortic valves highlights an enrichment in expression regulation at these loci and prioritizes candidate causal genes. Homozygous genotype for a risk variant near TWIST1, a gene involved in endothelial-mesenchymal transition, has a profound impact on aortic valve transcriptomics. We identify five genes outside of GWAS loci by combining a transcriptome-wide association study, colocalization, and Mendelian randomization analyses. Using cross-phenotype and phenome-wide approaches, we highlight the role of circulating lipoproteins, blood pressure and inflammation in the disease process. Our findings pave the way for the development of novel therapies for CAVS.

Optimizing Anesthetic Selection in Transcatheter Aortic Valve Replacement: Striking a Delicate Balance between Efficacy and Minimal Intervention.

Patients with severe calcific native aortic valve stenosis (AS) who require valve replacement have two options, surgical aortic valve replacement (SAVR) or transcatheter aortic valve replacement (TAVR). TAVR was approved in late 2011 for extremely high-risk patients and was subsequently approved for high-risk (2012), intermediate-risk (2016), and low-risk (2019) patients. In 2019, TAVR procedures surpassed SAVR procedures for the first time in the United States. The approach to anesthesia for this procedure has also evolved. Initially, general anesthesia (GA) was preferred, but currently, conscious sedation (CS) is favored. This review aims to clarify the indications and contraindications for both approaches, as well as the advantages of one approach over the other. Recent studies show that conscious sedation has better outcomes in terms of all-cause mortality, procedure complications such as stroke, myocardial infarction, infection requiring antibiotics, acute kidney injury, and the need for inotropes or vasopressors.

A novel mouse model of calcific aortic valve stenosis.

Calcific aortic valve stenosis (CAVS) is one of the most challenging heart diseases in clinical with rapidly increasing prevalence. However, study of the mechanism and treatment of CAVS is hampered by the lack of suitable, robust and efficient models that develop hemodynamically significant stenosis and typical calcium deposition. Here, we aim to establish a mouse model to mimic the development and features of CAVS. The model was established via aortic valve wire injury (AVWI) combined with vitamin D subcutaneous injected in wild type C57/BL6 mice. Serial transthoracic echocardiography was applied to evaluate aortic jet peak velocity and mean gradient. Histopathological specimens were collected and examined in respect of valve thickening, calcium deposition, collagen accumulation, osteogenic differentiation and inflammation. Serial transthoracic echocardiography revealed that aortic jet peak velocity and mean gradient increased from 7 days post model establishment in a time dependent manner and tended to be stable at 28 days. Compared with the sham group, simple AVWI or the vitamin D group, the hybrid model group showed typical pathological features of CAVS, including hemodynamic alterations, increased aortic valve thickening, calcium deposition, collagen accumulation at 28 days. In addition, osteogenic differentiation, fibrosis and inflammation, which play critical roles in the development of CAVS, were observed in the hybrid model. We established a novel mouse model of CAVS that could be induced efficiently, robustly and economically, and without genetic intervention. It provides a fast track to explore the underlying mechanisms of CAVS and to identify more effective pharmacological targets.

Lipoprotein(a) and cardiovascular disease: sifting the evidence to guide future research.

Lipoprotein(a) (Lp(a)) is a genetically determined causal risk factor for cardiovascular disease including coronary heart disease, peripheral arterial disease, ischaemic stroke, and calcific aortic valve stenosis. Clinical trials of specific and potent Lp(a)-lowering drugs are currently underway. However, in clinical practice, widespread assessment of Lp(a) is still lacking despite several guideline recommendations to measure Lp(a) at least once in a lifetime in all adults to identify those at high or very high risk due to elevated levels. The present review provides an overview of key findings from observational and genetic Lp(a) studies, highlights the main challenges in observational Lp(a) studies, and proposes a minimum set of requirements to enhance the quality and harmonize the collection of Lp(a)-related data. Adherence to the recommendations set forth in the present manuscript is intended to enhance the quality of future observational Lp(a) studies, to better define thresholds for increased risk, and to better inform clinical trial design. The recommendations can also potentially assist in the interpretation and generalization of clinical trial findings, to improve care of patients with elevated Lp(a) and optimize treatment and prevention of cardiovascular disease.

Retracted: Identification of MMP9 as a Novel Biomarker to Mitochondrial Metabolism Disorder and Oxidative Stress in Calcific Aortic Valve Stenosis.

[This retracts the article DOI: 10.1155/2022/3858871.].

Why and when should be lipoprotein(a) level measured?

Lipoprotein(a) [Lp(a)] is composed of a low-density lipoprotein (LDL) and glycoprotein (a)—apo(a). The size and concentration of Lp(a) in serum can vary among individuals and is determined by genetic factors. The environmental factors, diet, and physical activity have a negligible effect on Lp(a) level. Observational, epidemiological, and genetic studies improved that high levels of Lp(a) &gt; 50 mg/dL (&gt; 125 nmol/L) have been associated with an increased risk of myocardial infarction (MI), stroke, and calcific aortic valve stenosis (CAVS). It is recommended to measure Lp(a) at least once in adults to identify individuals with a high cardiovascular risk. This screening is particularly important in certain populations, including: youth with a history of ischemic stroke or a family history of premature atherosclerotic cardiovascular disease (CVD; ASCVD) or high Lp(a), individuals with recurrent cardiovascular events despite optimal hypolipemic treatment and no other identifiable risk factors or patients with familial hypercholesterolemia (FH). Considering Lp(a) levels in the evaluation of cardiovascular risk can provide valuable information for risk stratification and management decisions. However, it’s important to note that the treatments of elevated level of Lp(a) are limited. In recent years, there has been ongoing research and development of new drugs targeting Lp(a): pelacarsen—antisense oligonucleotide (ASO), and olpasiran—a small interfering RNA (siRNA).

Non-invasive ultrasound therapy for calcified aortic valve stenosis.

Non-invasive ultrasound therapy for calcified aortic valve stenosis.

Causal association of calcific aortic valve stenosis and atrial fibrillation: a Mendelian randomization study

Calcific aortic valve stenosis (CAVS) is associated with an increased risk of atrial fibrillation (AF) in observational studies, but whether these associations are causal has not been determined. This study aimed to explore the potential causal relationship between CAVS and AF via Mendelian randomization (MR). Genetic variants from the genome-wide association study (GWAS) summary data of the European population for CAVS were used to investigate the association with AF. The inverse variance weighted (IVW) approach was used to obtain the primary causal inference, and several sensitivity analysis approaches, such as the MR‒Egger and weighted median (WM), were performed to assess the robustness of the results. A total of nineteen valid and independent genetic SNPs associated with CAVS were obtained from the GWAS database. Genetically predicted CAVS (OR: 1.105; 95% CI: 1.072–1.139; p = 8.60E−11) was associated with an increased risk of AF. Similar results were discovered in the sensitivity analyses by using MR Egger and weighted median approaches. An MR design was used to reduce confounding variables and the potential for reverse causality bias. The results provide genetic evidence that CAVS considerably increased the risk of AF.

Improved Reversion of Calcifications in Porcine Aortic Heart Valves Using Elastin-Targeted Nanoparticles.

Calcified aortic valve disease in its final stage leads to aortic valve stenosis, limiting cardiac function. To date, surgical intervention is the only option for treating calcific aortic valve stenosis. This study combined controlled drug delivery by nanoparticles (NPs) and active targeting by antibody conjugation. The chelating agent diethylenetriaminepentaacetic acid (DTPA) was covalently bound to human serum albumin (HSA)-based NP, and the NP surface was modified using conjugating antibodies (anti-elastin or isotype IgG control). Calcification was induced ex vivo in porcine aortic valves by preincubation in an osteogenic medium containing 2.5 mM sodium phosphate for five days. Valve calcifications mainly consisted of basic calcium phosphate crystals. Calcifications were effectively resolved by adding 1-5 mg DTPA/mL medium. Incubation with pure DTPA, however, was associated with a loss of cellular viability. Reversal of calcifications was also achieved with DTPA-coupled anti-elastin-targeted NPs containing 1 mg DTPA equivalent. The addition of these NPs to the conditioned media resulted in significant regression of the valve calcifications compared to that in the IgG-NP control without affecting cellular viability. These results represent a step further toward the development of targeted nanoparticular formulations to dissolve aortic valve calcifications.

A novel mouse model for mineral homeostasis disrupting induced calcific aortic valve stenosis

Abstract Background Calcific aortic valve disease (CAVD) is the most common valve disease that has been occurring with rapidly increasing morbidity. Chronic kidney disease (CKD) which disrupts mineral homeostasis due the impaired renal function, is one of the known factors, largely contributing to risk of CAVD, independent of atherosclerosis. To the best of our knowledge, there are few calcific aortic valve stenosis mouse models simulating conditions under CKD that develop hemodynamically significant stenosis as well as calcification, Purpose The purpose was to assess the feasibility to develop a mouse model of CAVD considering risks under CKD. Methods For this model, C57/BL6 mice were firstly underwent aortic valve wire injury by spring guidewires inserting into left ventricle via right common carotid artery. Vitamin D was subcutaneous injected on 3 consecutive days from the second day of aortic valve wire injury. Echocardiography was performed to evaluate aortic valve function at 7, 14 and 28 days. Then the mice were sacrificed and aortic valves were collected to make histological analysis. Results An obvious increase in aortic velocity was already observed at 7 days after injury by continuous echocardiographic assessment and remained stable from 14 days compared with sham mice. Alizarin red staining showed calcium nodules formation in valve leaflets 14 days after injury and became more conspicuous at 28 days. Aortic valve thickening, increased macrophage infiltration, fibrosis and remarkable osteogenic markers were found in aortic valves at 28 days after injury. Conclusions We develop a novel mouse model of CAVD, especially simulating risks under CKD and mineral homeostasis disrupting. This model may be a convenient and valuable tool to investigate the mechanism of CAVD and further explore potential therapeutic strategies.Fig1.Alizarin red staining aortic valvesFig2.Immunostaining of aortic valves