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Aims: Calcific aortic valve disease (CAVD) is a chronic cardiovascular disease with high morbidity that lacks effective pharmacotherapeutics. As a natural flavonoid extracted from Ampelopsis grossedentata, dihydromyricetin (DHM) has been shown to be effective in protecting against atherosclerosis; yet, the therapeutic role of DHM in CAVD remains poorly understood. Herein, we aimed to clarify the therapeutic implications of DHM in CAVD and the underlying molecular mechanisms in human valvular interstitial cells (hVICs). Methods and Results: The protein levels of two known osteogenesis-specific genes (alkaline phosphatase, ALP; runt-related transcription factor 2, Runx2) and calcified nodule formation in hVICs were detected by Western blot and Alizarin Red staining, respectively. The results showed that DHM markedly ameliorated osteogenic induction medium (OM)–induced osteogenic differentiation of hVICs, as evidenced by downregulation of ALP and Runx2 expression and decreased calcium deposition. The SwissTargetPrediction database was used to identify the potential AVC-associated direct protein target of DHM. Protein–protein interaction (PPI) analysis revealed that c-KIT, a tyrosine-protein kinase, can act as a credible protein target of DHM, as evidenced by molecular docking. Mechanistically, DHM-mediated inhibition of c-KIT phosphorylation drove interleukin-6 (IL-6) downregulation in CAVD, thereby ameliorating OM-induced osteogenic differentiation of hVICs and aortic valve calcification progression. Conclusion: DHM ameliorates osteogenic differentiation of hVICs by blocking the phosphorylation of c-KIT, thus reducing IL-6 expression in CAVD. DHM could be a viable therapeutic supplement to impede CAVD.

Objective: To assess a new multislice computed tomography (CT) technique for three dimensional quantification of aortic valve calcification volume (3D AVCV) and to study the relation between stenosis and calcification of the aortic valve. Methods: 50 patients with echocardiographic calcification of the aortic valve underwent two separate ECG triggered multislice CT for quantification of 3D AVCV. The agreement between the two 3D AVCV scores was assessed and 3D AVCV was compared with echocardiographic markers of severity of aortic stenosis. Results: Overall the level of agreement between the two 3D AVCV scores was excellent (median interscan variability 7.9% (interquartile range 10.1); correlation coefficient, r = 0.99; repeatability coefficient 237.8 mm3 (limits of agreement −393 to 559 mm3)). However, the magnitude of the 3D AVCV did influence the interscan variability. The 3D AVCV correlated closely with the maximal predicted transvalvar gradient (r2 = 0.77) and aortic valve area (r2 = 0.73). Conclusions: Multislice CT provides a technique for quantifying 3D AVCV that has good reproducibility. There is a close non-linear relation between echocardiographic parameters of severity of valve stenosis and 3D AVCV scores.

Calcific aortic valve disease (CAVD) is the most common valvular heart disease in developed countries predominantly affecting the elderly population therefore posing a large economic burden. It is a gradually progressive condition ranging from mild valve calcification and thickening, without the hemodynamic obstruction, to severe calcification impairing leaflet motion, known as aortic stenosis (AS). The progression of CAVD occurs over many years, and it is extremely variable among individuals. It is also associated with an increased risk of coronary events and mortality. The recent insights into the CAVD pathophysiology included an important role of sex. Accumulating evidence suggests that, in patients with CAVD, sex can determine important differences in the relationship between valvular calcification process, fibrosis, and aortic stenosis hemodynamic severity between men and women. Consequently, it has implications on the development of different valvular phenotypes, left ventricular hypertrophy, and cardiovascular outcomes in men and women. Along these lines, taking into account the sex-related differences in diagnosis, prognosis, and treatment outcomes is of profound importance. In this review, the sex-related differences in patients with CAVD, in terms of pathobiology, clinical phenotypes, and outcomes were discussed.

Background: Osteoporosis and aortic valve calcification, prevalent in the elderly, have unclear common mechanisms. This study aims to uncover them through bioinformatics analysis. Methods: Microarray data from GEO was analyzed for osteoporosis and aortic valve calcification. Differential expression analysis identified co-expressed genes. SVM-RFE and random forest selected key genes. GO and KEGG enrichment analyses were performed. Immunoinfiltration and GSEA analyses were subsequently performed. NetworkAnalyst analyzed microRNAs/TFs. HERB predicted drugs, and molecular docking assessed targeting potential. Results: Thirteen genes linked to osteoporosis and aortic valve calcification were identified. TNFSF11, KYNU, and HLA-DMB emerged as key genes. miRNAs, TFs, and drug predictions offered therapeutic insights. Molecular docking suggested 17-beta-estradiol and vitamin D3 as potential treatments. Conclusion: The study clarifies shared mechanisms of osteoporosis and aortic valve calcification, identifies biomarkers, and highlights TNFSF11, KYNU, and HLA-DMB. It also suggests 17-beta-estradiol and vitamin D3 as potential effective treatments.

Aortic valve calcification (AVC) has been explored as a powerful predictor of procedural complications in patients undergoing transcatheter aortic valve implantation (TAVI). However, little evidence exists on its impact on intra-annular devices’ performance. We aimed to investigate the impact of AVC burden and distribution pattern on the occurrence of paravalvular leak (PVL), conduction disturbances requiring permanent pacemaker implantation (PPI) and 30-day clinical outcomes in patients undergoing TAVI with a self-expanding, intra-annular device. According to AVC, 103 patients enrolled in a single medical centre from November 2019 to December 2022 were divided into tertiles. Valve Academic Research Consortium (VARC)-3 definitions were used to classify procedural complications and outcomes. Patients in the highest AVC tertile showed an increased occurrence of mild or more PVL and conduction disorders (p < 0.001 and p = 0.006). AVC tertiles (highest tertile) emerged as an independent predictor of PVL (OR 7.32, 95%CI 3.10-17.28, p < 0.001) and post-TAVI conduction disturbances (OR 3.73, 95%CI 1.31–10.60, p = 0.013) but not of PPI (OR 1.44, 95%CI 0.39–5.35, p = 0.579). Considering calcium distribution, ROC analyses revealed that annular AVC but not left ventricle outflow tract (LVOT) calcium burden significantly indicated the development of PVL (AUC 0.863, 0.77–0.93, p < 0.001) and conduction disorders/PPI (AUC 0.797, 0.70–0.89, p < 0.001 and 0.723, 0.58–0.86, p = 0.018, respectively). After adjustment for age and sex, the highest tertile remained an independent predictor of the 30-day composite outcome (death, myocardial infarction, stroke, major vascular complications, type 3/4 bleedings, acute kidney injury, PPI and ≥ moderate PVL) (OR 3.26; 95%CI 1.26–8.40, p = 0.014). A higher AVC is associated with an increased risk of PVL and conduction disturbances after TAVI with a self-expanding, intra-annular device. However, our findings suggest a minor role for LVOT calcification compared with annular AVC in the performance of this specific prosthesis.

BackgroundImmune system dysregulation plays a critical role in aortic valve calcification (AVC) and metabolic syndrome (MS) pathogenesis. The study aimed to identify pivotal diagnostic candidate genes for AVC patients with MS.MethodsWe obtained three AVC and one MS dataset from the gene expression omnibus (GEO) database. Identification of differentially expressed genes (DEGs) and module gene via Limma and weighted gene co-expression network analysis (WGCNA), functional enrichment analysis, protein–protein interaction (PPI) network construction, and machine learning algorithms (least absolute shrinkage and selection operator (LASSO) regression and random forest) were used to identify candidate immune-associated hub genes for diagnosing AVC with MS. To assess the diagnostic value, the nomogram and receiver operating characteristic (ROC) curve were developed. Finally, immune cell infiltration was created to investigate immune cell dysregulation in AVC.ResultsThe merged AVC dataset included 587 DEGs, and 1,438 module genes were screened out in MS. MS DEGs were primarily enriched in immune regulation. The intersection of DEGs for AVC and module genes for MS was 50, which were mainly enriched in the immune system as well. Following the development of the PPI network, 26 node genes were filtered, and five candidate hub genes were chosen for nomogram building and diagnostic value evaluation after machine learning. The nomogram and all five candidate hub genes had high diagnostic values (area under the curve from 0.732 to 0.982). Various dysregulated immune cells were observed as well.ConclusionFive immune-associated candidate hub genes ( BEX2 , SPRY2 , CXCL16 , ITGAL , and MORF4L2 ) were identified, and the nomogram was constructed for AVC with MS diagnosis. Our study could provide potential peripheral blood diagnostic candidate genes for AVC in MS patients.

ObjectiveSex differences in risk factors of aortic valve calcification (AVC) by echocardiography have not been reported from a large prospective study in aortic stenosis (AS).MethodsAVC was assessed using a prognostically validated visual score and grouped into none/mild or moderate/severe AVC in 1725 men and women with asymptomatic AS in the Simvastatin Ezetimibe in Aortic Stenosis study. The severity of AS was assessed by the energy loss index (ELI) taking pressure recovery in the aortic root into account.ResultsMore men than women had moderate/severe AVC at baseline despite less severe AS by ELI (p<0.01). Moderate/severe AVC at baseline was independently associated with lower aortic compliance and more severe AS in both sexes, and with increased high-sensitive C reactive protein (hs-CRP) only in men (all p<0.01). In Cox regression analyses, moderate/severe AVC at baseline was associated with a 2.5-fold (95% CI 1.64 to 3.80) higher hazard rate of major cardiovascular events in women, and a 2.2-fold higher hazard rate in men (95% CI 1.54 to 3.17) (both p<0.001), after adjustment for age, hypertension, study treatment, aortic compliance, left ventricular (LV) mass and systolic function, AS severity and hs-CRP. Moderate/severe AVC at baseline also predicted a 1.8-fold higher hazard rate of all-cause mortality in men (95% CI 1.04 to 3.06, p<0.05) independent of age, AS severity, LV mass and aortic compliance, but not in women.ConclusionIn conclusion, AVC scored by echocardiography has sex-specific characteristics in AS. Moderate/severe AVC is associated with higher cardiovascular morbidity in both sexes, and with higher all-cause mortality in men.Trial registration numberClinicalTrials.gov identifier: NCT00092677

The association between aortic valve calcification (AVC) and cardiovascular (CV) events across diverse populations including patients with chronic kidney disease (CKD) remains controversial. This study aimed to determine whether AVC is associated with CV events in patients with CKD. In this prospective study, 1,279 participants with CKD were enrolled. A Cox proportional hazard model was applied to determine the association between AVC and CV events. The participants were divided into the following groups according to the number of calcified aortic cusps (CACs): no CACs ( n  = 922), one CAC ( n  = 209), and two to three CACs ( n  = 148). During a median follow-up of 2.9 years, CV events occurred in 185 participants. In multivariable Cox analyses, the hazard ratios (95% confidence intervals) of one CAC and two to three CACs for CV events compared with no CACs were 1.94 (1.32, 2.83) and 2.21 (1.46, 3.33), respectively. In a propensity score-matched cohort, participants with AVC ( n  = 284) had a significantly higher risk of CV events than those without AVC ( n  = 284). In CKD, the presence of AVC appears to be an independent risk factor for CV events, and the assessment of AVC is useful in predicting the prognosis.

The involvement of gut microbiota in calcific aortic valve disease (CAVD) pathogenesis remains underexplored. Here, we provide evidence for a strong association between the gut microbiota and CAVD development. ApoE−/− mice were stratified into easy‐ and difficult‐ to calcify groups using neural network and cluster analyses, and subsequent faecal transplantation and dirty cage sharing experiments demonstrated that the microbiota from difficult‐to‐calcify mice significantly ameliorated CAVD. 16S rRNA sequencing revealed that reduced abundance of Faecalibacterium prausnitzii (F. prausnitzii) was significantly associated with increased calcification severity. Association analysis identified F. prausnitzii‐derived butyric acid as a key anti‐calcific metabolite. These findings were validated in a clinical cohort (25 CAVD patients vs. 25 controls), where serum butyric acid levels inversely correlated with disease severity. Functional experiments showed that butyric acid effectively hindered osteogenic differentiation in human aortic valve interstitial cells (hVICs) and attenuated CAVD progression in mice. Isotope labeling and 13C flux analyses confirmed that butyric acid produced in the intestine can reach heart tissue, where it reshapes glycolysis by specifically modifying GAPDH. Mechanistically, butyric acid‐induced butyrylation (Kbu) at lysine 263 of GAPDH competitively inhibited lactylation (Kla) at the same site, thereby counteracting glycolysis‐driven calcification. These findings uncover a novel mechanism through which F. prausnitzii and its metabolite butyric acid contribute to the preservation of valve function in CAVD, highlighting the gut microbiota‐metabolite‐glycolysis axis as a promising therapeutic target. Multi‐omics sequencing and correlation analysis identified the beneficial role of Faecalibacterium prausnitzii (F. prausnitzii)‐derived butyric acid (BA) as a key metabolite in the restoration of valve function in calcific aortic valve disease (CAVD). The therapeutic efficacy of BA in attenuating CAVD progression was confirmed in vitro, ex vivo, and in vivo. Subsequent mechanistic investigations revealed that BA reshape glycolysis through site‐specific inhibition of lactylation at the Lys‐263 residue of GAPDH, which is mediated by competitive inhibition of butyrylation at the same site. Highlights The inseparable relationship between the gut microbiota and calcific aortic valve disease development. Faecalibacterium prausnitzii (F. prausnitzii)‐derived butyric acid (BA) played an important role in anti‐calcification functions. BA‐derived butyrylation (Kbu) blocked lactylation (Kla) at the same site by occupying the GAPDH 263 lysine. The gut microbial‐metabolite‐epigenetic modification pathway represents a promising therapeutic target for calcific aortic valve disease (CAVD).

Background Patients suffering coronary artery disease (CAD) with calcific aortic valve disease (CAVD) are facing worse prognosis with more complex operation strategies. As the primary stage of CAVD, it is helpful to confirm the risk factors of aortic valve calcification (AVC) in advance for exploring the secondary prevention as well as early intervention strategies of CAVD for CAD patients. Lipoprotein(a) [Lp(a)] has been confirmed as the risk factor of both CAD and CAVD. But whether Lp(a) level still affects the occurrence and development of CAVD in CAD patients has not been demonstrated yet. Objective We firstly investigate the predictive value of Lp(a) for new-onset AVC in patients with CAD. Methods Patients who were admitted to the Department of Cardiology, Zhujiang Hospital, Southern Medical University from March 2021 to December 2022 and diagnosed with CAD by elective coronary angiography(CAG)were included when met the criteria. Baseline data were collected through the electronic medical record system. Patients were followed up to repeat echocardiography with an interval at least 6 months, which was up to September 2023. The primary endpoint was new-onset AVC, according to which patients were divided into new-onset AVC group ( n  = 43) and the opposite( n  = 165). Analyses were conducted using SPSS 26.0 and GraphPad Prism 10.1.2. Results A total of 208 patients with CAD were included, with a median follow-up time of 16 (12, 20) months. Compared with AVC-free group, patients with new-onset AVC had higher body mass index (BMI) ( p  = 0.003), higher proportion of tree-vessel disease( p  < 0.001), higher rates of diabetes ( p  = 0.001) and atrial fibrillation ( p  = 0.017), higher Lp(a) levels( p  < 0.001), lower left ventricular systolic function (LVEF) ( p  < 0.001) and thicker left ventricular posterior wall (LVPW) ( p  < 0.001). Increased BMI, three-vessel disease, Lp(a) > 26.65 nmol/L, increased LVPW were found independent risk factors for new-onset AVC. Using a cutoff level of 26.65 nmol/L, Lp(a) predicted new-onset AVC with a sensitivity of 79.1% and a specificity of 59.4% (AUC: 0.740, 95% CI: 0.657–0.823, p  < 0.001). When combined with BMI, there present a higher AUC value of 0.752(95%CI: 0.668–0.836, p  < 0.001); however, the statistical significance remains limited ( p  = 0.732). Conclusion High-level serum Lp(a) was independently associated with new-onset AVC in patients with CAD. Lp(a) demonstrates a significant predictive value for the onset of new AVC in CAD patients, with an established cut-off threshold of 26.65 nmol/L.