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Background: Previous reports have indicated an association between red blood cell distribution width (RDW) and cardiovascular disease. However, few relevant studies exist on the relationship between RDW and aortic valve calcification (AVC). Explore the correlation and predictive value of RDW concerning the occurrence and severity of aortic valve calcification. Methods: Blood examination results were analyzed from 1720 hospitalized patients at the Second Affiliated Hospital of Soochow University. Logistic regression analysis and the Cox proportional hazards model examined the relationship between RDW and the incidence and severity of AVC. Results: The RDW value in cases with AVC was significantly higher than in the control group. Red cell distribution width-standard deviation (RDW–SD) and red cell distribution width-coefficient of variation (RDW–CV) increased with calcification severity. Both RDW–SD and RDW–CV demonstrated high predictive values for the occurrence of aortic valve calcification. Conclusions: Red blood cell distribution width significantly correlated with the occurrence and severity of aortic valve calcification. [ABSTRACT FROM AUTHOR]

Background In recent years, triglyceride glucose (TyG) index, as a popular metabolic index, has been proposed as an alternative index of insulin resistance, and it has been proved to be associated with many cardiovascular diseases, but the relationship between it and aortic valve calcification is still unknown. Methods A total of 450 aortic valve disease patients were enrolled in this study, including 361 patients with aortic valve calcification (AVC) (calcification group) and 89 patients without (control group). According to the severity of AVC, patients with AVC included severe calcification, moderate calcification and low calcification. The TyG index was calculated based on fasting triglyceride and fasting blood glucose levels. Results The TyG index in the calcification group was significantly higher than that in the control group (P  < .05), and with the increase of the degree of calcification, the TyG index showed an increasing trend. The univariate and multivariate logistic regression analysis showed TyG index has a high predictive value for the presence of AVC (OR (95% CI): 1.743 (1.036–2.933)) and severe AVC (OR (95% CI): 1.608 (1.143–2.262)). In assessing the predictive value of the TyG index distribution width for AVC, with the first quartile as a reference, the last quartile of the TyG index had significant predictive value for the presence of AVC and severe AVC. Conclusions TyG index was significantly associated with the presence and severity of AVC, suggesting that TyG index may be a valid predictor of AVC. Key messages What is already known on this topic. Triglyceride glucose (TyG) index is a reliable and specific index of insulin sensitivity in vivo. TyG index is closely related to various traditional risk factors for cardiovascular disease. What this study adds. TyG index was significantly associated with the presence and severity of AVC. How this study might affect research, practice or policy. This study lays the groundwork for investigating the mechanism underlying the association between the TyG index and AVC, and proposes the potential of attenuating the progression of AVC by judiciously reducing the TyG index in patients. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: The combined effect of systemic immune-inflammation index (SII) and aortic valve calcification (AVC) on the risk of major adverse cardiovascular events (MACE) in patients with coronary heart disease (CHD) remains unclear. This study aimed to investigate their combined association with MACE in CHD. Methods: This retrospective cohort study included 846 CHD patients. SII was calculated as platelet count × neutrophil count / lymphocyte count, and AVC status was determined by echocardiography. Patients were divided into four groups based on median SII and AVC presence: Low SII + AVC (-), High SII + AVC (-), Low SII + AVC (+), and High SII + AVC (+). Cox regression, subgroup and sensitivity analyses assessed the association between SII + AVC and MACE. Results: Multivariate Cox regression revealed that, compared to the Low SII + AVC (-), MACE risk increased 6.542-fold in the High SII + AVC (+) group and 1.605-fold in the High SII + AVC (-) group (P < 0.05). Subgroup analysis indicated that, compared to the Low SII + AVC (-), MACE risk was significantly elevated in the High SII + AVC (-) group for patients over 60, both genders, with hypertension, hyperlipidemia, or without diabetes (P < 0.05). In the Low SII + AVC (+) group, MACE risk was elevated only in males (P < 0.05). The High SII + AVC (+) group had increased MACE risk in all subgroups except those with diabetes (P < 0.05). After excluding patients with estimated glomerular filtration rate < 60 mL/min/1.73m², the high SII + AVC (+) group remained significantly associated with increased MACE risk (P = 0.001), as did the High SII + AVC (-) group (P = 0.031). Conclusion: The combination of SII and AVC is significantly associated with MACE risk in patients with CHD. [ABSTRACT FROM AUTHOR]

The presented literature review allows us to understand and supplement the existing ideas about the pathogenesis of coronary calcification and aortic valve calcification at the stage of formation of these changes. To study in detail the participation of the most studied immunocompetent cells of innate immunity, such as macrophages, dendritic and mast cells, neutrophils, natural killers in calcification of arteries and aortic valve, their functional role in the progression of this process. The review also presents gaps and missing data present in the study of these cell populations, the replenishment of which will contribute to the development of targeted therapy for the calcification process.The search for literature sources was conducted in the following databases: Scopus, web of Science, MedLine, The Cochrane Library, RSCI, Springer, Science Direct — taking into account the year of publication (no more than 10 years), language of publication (English/Russian), availability of full-text publications and access to them.

KaiMing Wei,1,2,&ast; Yuan Cao,1,3,&ast; XiangJin Kong,1,2 ChuanZhen Liu,1,2 XingHua Gu1,2 1Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, People’s Republic of China; 2Department of Cardiovascular Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, People’s Republic of China; 3National Key Laboratory for Innovation and Transformation of Luobing Theory; The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences; Department of Cardiology, Qilu Hospital of Shandong University, Jinan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: XingHua Gu, Email guxinghua@email.sdu.edu.cnBackground: Cardiovascular diseases, such as aortic valve calcification (AVC) and carotid atherosclerosis (CAS), impose substantial health challenges on a global scale. Both disorders have overlapping risk factors, which might trigger similar immune-inflammatory reactions in both diseases.Methods: Shared differentially expressed genes (DEGs) were identified in the AVC and CAS datasets from the Gene Expression Omnibus (GEO). Candidate hub genes associated with immunity were identified using LASSO and immune cell infiltration analysis, and single gene set enrichment analysis (GSEA) was performed on the datasets. Subsequently, the hub genes were confirmed by qRT‒PCR validation in tissue samples.Results: A total of 140 upregulated and 65 downregulated common genes were screened. Enrichment analyses highlighted immune system processes, response to stress, and cytokine pathways among the identified CEGs. LASSO identified candidate hub genes, including ANGPTL1, CX3CR1, and CCL4. Immune cell infiltration analysis emphasized the participation of immune cells, including macrophages, γδ T cells, and resting NK cells. The three hub genes were validated by qRT‒PCR analysis.Conclusion: Our study explored immunological processes, including immune-related genes and cells, involved in the development of AVC and CAS. In particular, the identified hub genes ANGPTL1, CX3CR1, and CCL4 play crucial roles in mediating immune-inflammatory responses, which are central to the pathogenesis of these cardiovascular diseases, and the involvement of these genes in key immune pathways suggests that they could serve as potential biomarkers for early diagnosis or as targets for therapeutic strategies.Keywords: aortic valve calcification, carotid atherosclerosis, immune-related genes

Aims Aortic valve calcification (AVC) is prognostic in patients with aortic stenosis (AS). We assessed the AVC prognostic value in non-severe AS patients. Methods and results We conducted a retrospective study of 395 patients with non-severe AS, LVEF ≥ 50%. The Agatston method was used for CT AVC assessment. The log-rank test determined the best AVC cut-offs for survival under medical surveillance: 1185  arbitrary unit (AU) in men and 850 AU in women, lower than the established cut-offs for severe AS (2064 AU in men and 1274 AU in women). Patients were divided into 3 AVC groups based on these cut-offs: low (<1185 AU in men and <850 AU in women), sub-severe (1185–2064 AU in men and 850–1274 AU in women), and severe (>2064 AU in men and >1274 AU in women). Of 395 patients (mean age 73 ± 12 years, 60.5% men, aortic valve area 1.23 ± 0.30 cm2, mean pressure gradient 28 ± 8 mmHg), 218 underwent aortic valve intervention (AVI) and 158 deaths occurred during follow-up, 82 before AVI. Median survival time under medical surveillance was 2.1 (0.7–4.9) years. Compared with the low AVC group, both sub-severe and severe AVC groups had higher risk for all-cause death under medical surveillance after comprehensive adjustment including echocardiographic AS severity and coronary artery calcium score (all P ≤ 0.006); while mortality risk was similar between sub-severe and severe AVC groups (all P ≥ 0.2). This mortality risk pattern persisted in the overall survival analysis after adjustment for AVI. AVI was protective of all-cause death in the sub-severe and severe AVC (all P ≤ 0.01), but not in the low AVC groups. Conclusion Sub-severe AVC is a robust risk stratification parameter in patients with non-severe AS and may inform AVI timing. [ABSTRACT FROM AUTHOR]

Background and Aims Valve interstitial cells (VICs) undergo a transition to intermediate state cells before ultimately transforming into the osteogenic cell population, which is a pivotal cellular process in calcific aortic valve disease (CAVD). Herein, this study successfully delineated the stages of VIC osteogenic transformation and elucidated a novel key regulatory role of lumican (LUM) in this process. Methods Single-cell RNA-sequencing (scRNA-seq) from nine human aortic valves was used to characterize the pathological switch process and identify key regulatory factors. The in vitro , ex vivo , in vivo , and double knockout mice were constructed to further unravel the calcification-promoting effect of LUM. Moreover, the multi-omic approaches were employed to analyse the molecular mechanism of LUM in CAVD. Results ScRNA-seq successfully delineated the process of VIC pathological transformation and highlighted the significance of LUM as a novel molecule in this process. The pro-calcification role of LUM is confirmed on the in vitro , ex vivo , in vivo level, and ApoE−/−//LUM−/− double knockout mice. The LUM induces osteogenesis in VICs via activation of inflammatory pathways and augmentation of cellular glycolysis, resulting in the accumulation of lactate. Subsequent investigation has unveiled a novel LUM driving histone modification, lactylation, which plays a role in facilitating valve calcification. More importantly, this study has identified two specific sites of histone lactylation, namely, H3K14la and H3K9la, which have been found to facilitate the process of calcification. The confirmation of these modification sites' association with the expression of calcific genes Runx2 and BMP2 has been achieved through ChIP-PCR analysis. Conclusions The study presents novel findings, being the first to establish the involvement of lumican in mediating H3 histone lactylation, thus facilitating the development of aortic valve calcification. Consequently, lumican would be a promising therapeutic target for intervention in the treatment of CAVD. [ABSTRACT FROM AUTHOR]

Aims Aortic valve calcification (AVC) of surgical valve bioprostheses (BPs) has been poorly explored. We aimed to evaluate in vivo and ex vivo BP AVCs and its prognosis value. Methods and results Between 2011 and 2019, AVC was assessed using in vivo computed tomography (CT) in 361 patients who had undergone surgical valve replacement 6.4 ± 4.3 years earlier. Ex vivo CT scans were performed for 37 explanted BPs. The in vivo CT scans were interpretable for 342 patients (19 patients [5.2%] were excluded). These patients were 77.2 ± 9.1 years old, and 64.3% were male. Mean in vivo AVC was 307 ± 500 Agatston units (AU). The AVC was 562 ± 570 AU for the 183 (53.5%) patients with structural valve degeneration (SVD) and 13 ± 43 AU for those without SVD (P < 0.0001). In vivo and ex vivo AVCs were strongly correlated (r = 0.88, P < 0.0001). An in vivo AVC > 100 AU (n = 147, 43%) had a specificity of 96% for diagnosing Stage 2–3 SVD (area under the curve = 0.92). Patients with AVC > 100 AU had a worse outcome compared with those with AVC ≤ 100 AU (n = 195). In multivariable analysis, AVC was a predictor of overall mortality (hazard ratio [HR] and 95% confidence interval = 1.16 [1.04–1.29]; P = 0.006), cardiovascular mortality (HR = 1.22 [1.04–1.43]; P = 0.013), cardiovascular events (HR = 1.28 [1.16–1.41]; P < 0.0001), and re-intervention (HR = 1.15 [1.06–1.25]; P < 0.0001). After adjustment for Stage 2–3 SVD diagnosis, AVC remained a predictor of overall mortality (HR = 1.20 [1.04–1.39]; P = 0.015) and cardiovascular events (HR = 1.25 [1.09–1.43]; P = 0.001). Conclusion CT scan is a reliable tool to assess BP leaflet calcification. An AVC > 100 AU is tightly associated with SVD and it is a strong predictor of overall mortality and cardiovascular events. [ABSTRACT FROM AUTHOR]

The utility of assessment of cardiovascular calcifications for predicting stroke incidence remains unclear. This study assessed the relationship between cardiovascular calcifications including coronary artery calcification (CAC), aortic valve (AVC), and aortic root (ARC) assessed by coronary computed tomography (CT) and stroke incidence in patients with suspected CAD. In this multicenter prospective cohort study, 1187 patients suspected of CAD who underwent coronary CT were enrolled. Cardiovascular events including stroke were documented. Hazard ratio (HR) and confidence interval (CI) were assessed by Cox proportional hazard model adjusted for the Framingham risk score. C statistics for stroke incidence were also examined by models including cardiovascular calcifications. A total of 980 patients (mean age, 65 ± 7 years; females, 45.8%) were assessed by the CAC, AVC, and ARC Agatston scores. During a median follow-up of 4.0 years, 19 patients developed stroke. Cox proportional hazard model showed severe CAC (Agatston score ≥ 90th percentile [580.0 value]) and presence of AVC and ARC were associated with stroke incidence (HR; 10.33 [95% CI; 2.08–51.26], 3.08 [1.19–7.98], and 2.75 [1.03–7.30], respectively). C statistic in the model with CAC and AVC severity for predicting stroke incidence was 0.841 (95% CI; 0.761–0.920), which was superior to the model with CAC alone (0.762 [95% CI; 0.665–0.859], P < 0.01). CAC, AVC, and ARC were associated with stroke incidence in patients suspected of CAD. Assessment of both CAC and AVC may be useful for prediction of stroke incidence. [ABSTRACT FROM AUTHOR]

In patients with low-gradient aortic stenosis (AS) and low transvalvular flow, dobutamine stress echocardiography (DSE) is recommended to determine AS severity, whereas the degree of aortic valve calcification (AVC) supposedly correlates with AS severity according to current European and American guidelines. The purpose of this study was to assess the relationship between AVC and AS severity as determined using echocardiography and DSE in patients with aortic valve area <1 cm2 and peak aortic valve velocity <4.0 m/s. All patients underwent DSE to determine AS severity and multislice computed tomography to quantify AVC. Receiver-operating characteristics curve analysis was used to assess the diagnostic value of AVC for AS severity grading as determined using echocardiography and DSE in men and women. A total of 214 patients were included. Median age was 78 years (25th-75th percentile: 71-84 years) and 25% were women. Left ventricular ejection fraction was reduced (<50%) in 197 (92.1%) patients. Severe AS was diagnosed in 106 patients (49.5%). Moderate AS was diagnosed in 108 patients (50.5%; in 77 based on resting transthoracic echocardiography, in 31 confirmed using DSE). AVC score was high (≥2,000 for men or ≥1,200 for women) in 47 (44.3%) patients with severe AS and in 47 (43.5%) patients with moderate AS. AVC sensitivity was 44.3%, specificity was 56.5%, and positive and negative predictive values for severe AS were 50.0% and 50.8%, respectively. Area under the receiver-operating characteristics curve was 0.508 for men and 0.524 for women. Multi-slice computed tomography–derived AVC scores showed poor discrimination between grades of AS severity using DSE and cannot replace DSE in the diagnostic work-up of low-gradient severe AS. [Display omitted] [ABSTRACT FROM AUTHOR]

Background: 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). Methods: 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. Results: 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. Conclusions: 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. [ABSTRACT FROM AUTHOR]

Background and Purpose: Our previous studies have found that andrographolide (AGP) alleviates calcific aortic valve disease (CAVD), but the underlying mechanism is unclear. This study explores the molecular target and signal mechanisms of AGP in inhibiting CAVD. Experimental Approach: The anti‐calcification effects of the aortic valve with AGP treatment were evaluated by alizarin red staining in vitro and ultrasound and histopathological assessment of a high‐fat (HF)‐fed ApoE−/− mouse valve calcification model. A correlation between the H3 histone lactylation (H3Kla) and calcification was detected. Molecular docking and surface plasmon resonance (SPR) experiments were further used to confirm p300 as a target for AGP. Overexpression (oe) and silencing (si) of p300 were used to verify the inhibitory effect of AGP targeting p300 on the H3Kla in vitro and ex vivo. Key Results: AGP significantly inhibited calcium deposition in valve interstitial cells (VICs) and ameliorated aortic valve calcification. The multi‐omics analysis revealed the glycolysis pathway involved in CAVD, indicating that AGP interfered with lactate production by regulating lactate dehydrogenase A (LDHA). In addition, lactylation, a new post‐translational modification, was shown to have a role in promoting aortic valve calcification. Furthermore, H3Kla and H3K9la site were shown to correlate with Runx2 expression inhibition by AGP treatment. Importantly, we found that p300 transferase was the molecular target of AGP in inhibiting H3Kla. Conclusions and Implications: Our findings, for the first time, demonstrated that AGP alleviates calcification by interfering with H3Kla via p300, which might be a powerful drug to prevent CAVD. [ABSTRACT FROM AUTHOR]

The morbidity and death rates of calcified aortic valves|calcific aortic valve (CAV) disease (CAVD) remain high for its limited therapeutic choices. Here, we investigated the function, therapeutic potential, and putative mechanisms of Enoyl coenzyme A hydratase 1 (ECH1) in CAVD by various in vitro and in vivo experiments. Single‐cell sequencing revealed that ECH1 was predominantly expressed in valve interstitial cells and was significantly reduced in CAVs. Overexpression of ECH1 reduced aortic valve calcification in ApoE−/− mice treated with high cholesterol diet, while ECH1 silencing had the reverse effect. We also identified Wnt5a, a noncanonical Wnt ligand, was also altered when ECH1 expression was modulated. Mechanistically, we found that ECH1 exerted anti‐calcific actions through suppressing Wnt signaling, since CHIR99021, a Wnt agonist, may significantly lessen the protective impact of ECH1 overexpression on the development of valve calcification. ChIP and luciferase assays all showed that ECH1 overexpression prevented Runx2 binding to its downstream gene promoters (osteopontin and osteocalcin), while CHIR99021 neutralized this protective effect. Collectively, our findings reveal a previously unrecognized mechanism of ECH1‐Wnt5a/Ca2+ regulation in CAVD, implying that targeting ECH1 may be a potential therapeutic strategy to prevent CAVD development. [ABSTRACT FROM AUTHOR]

IntroductionRenal failure associated aortic valve calcification (AVC) is the result of hyperphosphatemia and hyperparathyroidism. Calcimimetics is an effective tool for management of secondary hyperparathyroidism. Our goal was to evaluate the effect of the medical intervention with calcimimetic R568 on the AVC process.Methods and resultsThe experimental design consisted of administering a uremia-inducing phosphate-enriched diet to rats for six weeks. Rats received a daily R568 injection at different times. Biochemical analysis demonstrated increased urea (34.72 ± 3.57 vs. 5.18 ± 0.15 mmol/L, p

Background Thresholds of aortic valve calcification (AVC) to define hemodynamically moderate aortic stenosis (AS) from mild are lacking. We aimed to establish a novel grading classification of AVC as quantified by computed tomography and determine its prognostic value. Methods and Results This study included 915 patients with at least mild AS (mean age 70±12 years, 30% women) from a multicenter prospective registry. All patients underwent Doppler‐echocardiography and noncontrast computed tomography within 3 months. Primary end point was the occurrence of all‐cause death. Receiver operating characteristic curves analyses were used to determine the sensitivity and specificity of sex‐specific thresholds of AVC to identify hemodynamically moderate AS. Optimal thresholds (ie, with best sensitivity/specificity) of AVC to distinguish moderate (aortic valve area 1.0–1.5 cm2 and mean gradient 20–39 mm Hg) from mild AS (aortic valve area >1.5 cm2 and mean gradient

Background: The goal of our study is to evaluate a method to quantify aortic valve calcification (AVC) in contrast-enhanced computed tomography for patients with suspected severe aortic stenosis pre-interventionally. Methods: A total of sixty-five patients with aortic stenosis underwent both a native and a contrast-enhanced computed tomography (CECT) scan of the aortic valve (45 in the training cohort and 20 in the validation cohort) using a standardized protocol. Aortic valve calcification was semi-automatically quantified via the Agatston score method for the native scans and was used as a reference. For contrast-enhanced computed tomography, a calcium threshold of the Hounsfield units of the aorta plus four times the standard deviation was used. Results: For the quantification of aortic valve calcification in contrast-enhanced computed tomography, a conversion formula (691 + 1.83 x AVCCECT) was derived via a linear regression model in the training cohort. The validation in the second cohort showed high agreement for this conversion formula with no significant proportional bias (Bland–Altman, p = 0.055) and with an intraclass correlation coefficient in the validation cohort of 0.915 (confidence interval 95% 0.786–0.966) p < 0.001. Conclusions: Calcium scoring in patients with aortic valve stenosis can be performed using contrast-enhanced computed tomography with high validity. Using a conversion factor led to an excellent agreement, thereby obviating an additional native computed tomography scan. This might contribute to a decrease in radiation exposure. [ABSTRACT FROM AUTHOR]

Abstract Aims There is evidence to suggest that the subtype of aortic stenosis (AS), the degree of myocardial fibrosis (MF), and level of aortic valve calcification (AVC) are associated with adverse cardiac outcome in AS. Because little is known about their respective contribution, we sought to investigate their relative importance and interplay as well as their association with adverse cardiac events following transcatheter aortic valve replacement (TAVR). Methods and results One hundred consecutive patients with severe AS and indication for TAVR were prospectively enrolled between January 2017 and October 2018. Patients underwent transthoracic echocardiography, multidetector computed tomography, and left ventricular endomyocardial biopsies at the time of TAVR. The final study cohort consisted of 92 patients with a completed study protocol, 39 (42.4%) of whom showed a normal ejection fraction (EF) high‐gradient (NEFHG) AS, 13 (14.1%) a low EF high‐gradient (LEFHG) AS, 25 (27.2%) a low EF low‐gradient (LEFLG) AS, and 15 (16.3%) a paradoxical low‐flow, low‐gradient (PLFLG) AS. The high‐gradient phenotypes (NEFHG and LEFHG) showed the largest amount of AVC (807 ± 421 and 813 ± 281 mm3, respectively) as compared with the low‐gradient phenotypes (LEFLG and PLFLG; 503 ± 326 and 555 ± 594 mm3, respectively, P LEFHG > PLFLG > NEFHG, P PLFLG 26.7% > LEFHG 15.4% > NEFHG 2.5%; P = 0.023). In patients with a high MF burden, a higher AVC was associated with a lower mortality following TAVR (P = 0.045, hazard ratio 0.261, 95% confidence interval 0.07–0.97). Conclusions MF is associated with adverse CV outcome following TAVR, which is most prevalent in low EF situations. In the presence of large MF burden, patients with large AVC have better outcome following TAVR. Conversely, worse outcome in large MF and relatively little AVC may be explained by a relative prominence of an underlying cardiomyopathy. The better survival rates in large AVC patients following TAVR indicate TAVR induced relief of severe AS‐associated pressure overload with subsequently improved outcome.

Aortic valve calcification (AVC) is a common cardiovascular disease and a risk factor for sudden death. However, the potential mechanisms and effective therapeutic drugs need to be explored. Atorvastatin is a statin that can effectively prevent cardiovascular events by lowering cholesterol levels. However, whether atorvastatin can inhibit AVC by reducing low-density lipoprotein (LDL) and its possible mechanism of action require further exploration. In the current study, we constructed an in vitro AVC model by inducing calcification of the valve interstitial cells. We found that atorvastatin significantly inhibited osteogenic differentiation, reduced the deposition of calcium nodules in valve interstitial cells, and enhanced autophagy in calcified valve interstitial cells, manifested by increased expression levels of the autophagy proteins Atg5 and LC3B-II/I and the formation of smooth autophagic flow. Atorvastatin inhibited the NF-κB signalling pathway and the expression of inflammatory factors mediated by NF-κB in calcified valve interstitial cells. The activation of the NF-κB signalling pathway led to the reversal of atorvastatin's effect on enhancing autophagy and alleviating valve interstitial cell calcification. In conclusion, atorvastatin inhibited the NF-κB signalling pathway by upregulating autophagy, thereby alleviating valve interstitial cell calcification, which was conducive to improving AVC.

Background and aimsBone and mineral metabolism has been implicated in the pathophysiology of cardiac valve calcification. Whether bone demineralization, a common aging-related disorder, promotes calcific valve disease remains uncertain. We tested the hypothesis that low bone mineral density (BMD) is associated with greater incidence/progression of cardiac valve calcification in the Multi-Ethnic Study of Atherosclerosis.MethodsUsing linear mixed-effects models, we related baseline measurement of BMD of the thoracic vertebrae by computed tomography (CT) in 6768 participants to serial CT assessments of aortic valve calcification (AVC) and mitral annular calcification (MAC) obtained over a >10-year period.ResultsAfter multivariable adjustment, lower BMD (per SD decrement) was associated with accelerated increase in AVC over time in women (0.76 [95% CI 0.42,1.09] Agatston -units [AU]/year) and men (1.41 [95% CI 0.48,2.33] AU/year), as well as for MAC in women (3.22 [95% CI 1.16,5.28] AU/year) and men (3.59 [95% CI 2.09,5.09] AU/year). Significant effect modification was observed, with more pronounced BMD-related acceleration of AVC and MAC progression in older or white participants of one or both sexes, as well as by estimated glomerular filtration rate, though the latter differed by sex for AVC and MAC.ConclusionsIn this multi-ethnic cohort, low thoracic BMD was significantly, but modestly, associated with increased AVC and MAC progression. This suggests that altered bone mineral metabolism does not have a major impact on calcific valve disease in the general population, but the possibility of a more meaningful influence in higher-risk individuals with osteoporosis will require further investigation.

Purpose of Review: This review explores current clinical value of aortic valve calcification (AVC) in classifying aortic valve stenosis (AS) severity, refining patient's follow-up, as well as novel and potential applications of this highly accurate marker in improving outcomes for AS patients. AVC limitations and important particularities regarding sex, valve phenotype, and ethnicity will also be addressed. Recent Findings: Sex-specific AVC cut-offs have been included in current guidelines to identify severe AS when echocardiography is inconclusive. AVC is also associated with AS progression and could help refine the timing for patient's follow-up. Summary: In patients with AS, Doppler echocardiography is the gold standard for the assessment of AS severity. However, in more than one-third of patients, echocardiographic parameters are discordant, casting shadow on the true severity of the disease. Considering active leaflet calcification is the driving mechanism of AS, quantification of AVC has been shown to be of great interest for distinguishing true-severe from pseudo-severe AS. Moreover, AVC is closely associated with AS progression and outcomes. [ABSTRACT FROM AUTHOR]

Aims: There is evidence to suggest that the subtype of aortic stenosis (AS), the degree of myocardial fibrosis (MF), and level of aortic valve calcification (AVC) are associated with adverse cardiac outcome in AS. Because little is known about their respective contribution, we sought to investigate their relative importance and interplay as well as their association with adverse cardiac events following transcatheter aortic valve replacement (TAVR). Methods and results: One hundred consecutive patients with severe AS and indication for TAVR were prospectively enrolled between January 2017 and October 2018. Patients underwent transthoracic echocardiography, multidetector computed tomography, and left ventricular endomyocardial biopsies at the time of TAVR. The final study cohort consisted of 92 patients with a completed study protocol, 39 (42.4%) of whom showed a normal ejection fraction (EF) high‐gradient (NEFHG) AS, 13 (14.1%) a low EF high‐gradient (LEFHG) AS, 25 (27.2%) a low EF low‐gradient (LEFLG) AS, and 15 (16.3%) a paradoxical low‐flow, low‐gradient (PLFLG) AS. The high‐gradient phenotypes (NEFHG and LEFHG) showed the largest amount of AVC (807 ± 421 and 813 ± 281 mm3, respectively) as compared with the low‐gradient phenotypes (LEFLG and PLFLG; 503 ± 326 and 555 ± 594 mm3, respectively, P < 0.05). Conversely, MF was most prevalent in low‐output phenotypes (LEFLG > LEFHG > PLFLG > NEFHG, P < 0.05). This was paralleled by a greater cardiovascular (CV) mortality within 600 days after TAVR (LEFLG 28% > PLFLG 26.7% > LEFHG 15.4% > NEFHG 2.5%; P = 0.023). In patients with a high MF burden, a higher AVC was associated with a lower mortality following TAVR (P = 0.045, hazard ratio 0.261, 95% confidence interval 0.07–0.97). Conclusions: MF is associated with adverse CV outcome following TAVR, which is most prevalent in low EF situations. In the presence of large MF burden, patients with large AVC have better outcome following TAVR. Conversely, worse outcome in large MF and relatively little AVC may be explained by a relative prominence of an underlying cardiomyopathy. The better survival rates in large AVC patients following TAVR indicate TAVR induced relief of severe AS‐associated pressure overload with subsequently improved outcome. [ABSTRACT FROM AUTHOR]

Background: Aortic valve calcification (AVC) has a strong association with cardiovascular outcomes in patients with type 2 diabetics (T2D). The objective of this study was to determine the prevalence and risk factors for AVC in Japanese T2D. Methods: We conducted a cross-sectional study of 193 consecutive T2D with estimated glomerular filtration rate (eGFR) ≥ 60 mL/min/1.73 m2 and without overt heart disease (110 men, mean age 61 years). AVC was determined as bright echoes > 1 mm on at least one cusp of the aortic valve by echocardiography. Results: Eighty-two (42%) diabetic patients had AVC, 9 patients had aortic valve stenosis, and 25 had regurgitation. Patients with AVC were older (67 vs. 55 years), with longer diabetic duration (15 vs. 11 years), lower HbA1c (9.1 vs. 10.0%), higher presence of diabetic retinopathy (66 vs. 47%), lower BMI (24 vs. 26 kg/m2), and lower eGFR (82.1 vs. 90.4 mL/min/1.73 m2) (p < 0.01) than patients without AVC. By logistic regression analysis, older age (p < 0.001) and presence of diabetic retinopathy (p < 0.05) were independent risk factors for AVC in T2D. Conclusions: The prevalence of AVC was 42% in Japanese T2D. Diabetic retinopathy associates with presence of AVC.

Aortic valve calcification (AVC) is a common valvular abnormality that predisposes to stenosis; AVC progression and factors associated with it remain unclear. We investigated the association of clinical factors and serum biomarkers with AVC progression in a population-based cohort of older adults. Participants enrolled in both the Cardiovascular Abnormalities and Brain Lesion study (CABL; years 2005–2010) and the Subclinical Atrial Fibrillation And Risk of Ischemic Stroke study (SAFARIS;2014–2019) represent the study cohort. AVC was defined as bright dense echoes >1 mm in size on ≥1 cusps; each cusp was graded on a scale of 0 (normal) to 3 (severe calcification) at baseline and follow up. Serum biomarkers were measured at the time of follow-up assessment. 373 participants (mean 68.1 ± 7.6 years of age, 146 M/ 227F) were included. 139 (37%) had AVC progression;93 (25%) had mild progression (1 grade), and 46 (12%) had moderate-severe progression (≥2 grades). The only significant clinical predictor of any progression was the use of anti-hypertensive medication which was associated with older age, higher BMI and more frequent hypertension, diabetes and hyperlipidemia. In multivariable analysis including biomarkers, transforming growth factor beta 1 (TGF-β1) was significantly associated with both all and moderate-severe AVC progression. A significant number of elderly subjects with AVC show progression of their valve disease; individual vascular risk factors are not associated with AVC progression, although a combined effect may exist. Higher levels of TGF-β1 are observed in individuals with AVC progression. [Display omitted] • Aortic valve calcification (AVC) is a common progressive valvular abnormality. • We measured AVC in elderly subjects at baseline and after a mean 8 year follow up. • Individual vascular risk factors are not associated with AVC progression. • Higher levels of transforming growth factor beta in subjects with AVC progression. [ABSTRACT FROM AUTHOR]

Aims To study sex-specific differences in the amount and distribution of aortic valve calcification (AVC) and to correlate the AVC load with paravalvular leakage (PVL) post-transcatheter aortic valve intervention (TAVI). Methods and results This registry included 1801 patients undergoing TAVI with a Sapien3 or Evolut valve in two tertiary care institutions. Exclusion criteria encompassed prior aortic valve replacement, suboptimal multidetector computed tomography (MDCT) quality, and suboptimal transthoracic echocardiography images. Calcium content and distribution were derived from MDCT. In this study, the median age was 81.7 (25th–75th percentile 77.5–85.3) and 54% male. Men, compared to women, were significantly younger [81.2 (25th–75th percentile 76.5–84.5) vs. 82.4 (78.2–85.9), P ≤ 0.01] and had a larger annulus area [512 mm2 (25th–75th percentile 463–570) vs. 405 mm2 (365–454), P < 0.01] and higher Agatston score [2567 (25th–75th percentile 1657–3913) vs. 1615 (25th–75th percentile 905–2484), P < 0.01]. In total, 1104 patients (61%) had none-trace PVL, 648 (36%) mild PVL, and 49 (3%) moderate PVL post-TAVI. There was no difference in the occurrence of moderate PVL between men and women (3% vs. 3%, P = 0.63). Cut-off values for the Agatston score as predictor for moderate PVL based on the receiver-operating characteristic curve were 4070 (sensitivity 0.73, specificity 0.79) for men and 2341 (sensitivity 0.74, specificity 0.73) for women. Conclusion AVC is a strong predictor for moderate PVL post-TAVI. Although the AVC load in men is higher compared to women, there is no difference in the incidence of moderate PVL. Sex-specific Agatston score cut-offs to predict moderate PVL were almost double as high in men vs. women. [ABSTRACT FROM AUTHOR]

Background and aimsGlycA is a novel composite biomarker of systemic inflammation reflecting posttranslational glycosylation of acute phase reactants. GlycA has been associated with coronary artery calcium, cardiovascular disease (CVD) events and mortality. Vascular calcifications outside of the coronary arteries are risk markers of CVD and mortality. Whether GlycA is linked to extra-coronary calcifications (ECC) is not well established.MethodsWe studied 6462 MESA participants free of clinical CVD who had plasma GlycA measured at baseline. ECCs [calcification in aortic valve (AVC), mitral annulus (MAC), ascending and descending thoracic aorta (ATAC, DTAC)] were ascertained at baseline and follow-up visit (median 2.3-yrs later) by cardiac CT. Poisson regression models with robust variance estimation assessed associations of GlycA with prevalent and incident ECC. Linear mixed models assessed the cross-sectional and 2-year change in ECC. Models were adjusted for demographic and lifestyle factors.ResultsIn cross-sectional analysis, GlycA (per SD increment) was positively associated with prevalent AVC, ATAC and DTAC with adjusted prevalence ratios (95% CI) of 1.08 (1.01-1.14), 1.18 (1.03-1.34) and 1.10 (1.06-1.14), respectively. There was also a significant association between GlycA and baseline extent of both ATAC and DTAC. Longitudinally, GlycA was positively associated with incident MAC and DTAC, with adjusted incidence ratios of 1.18 (1.03-1.37) and 1.17 (1.07-1.28), respectively. GlycA was also associated with 2-year change in MAC and DTAC extent.ConclusionsIn this diverse cohort free from clinical CVD, we found GlycA was positively associated with prevalent and incident ECC measures, in particular for progression of MAC and DTAC.

Abdul Ghafar Sherzad,1,2 Muhibullah Shinwari,3 M Azim Azimee,2 Arash Nemat,1,4 Qingchun Zeng1,5 1Department of Cardiology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, People’s Republic of China; 2Department of Biochemistry, Faculty of Medicine, Nangarhar University, Nangarhar, Afghanistan; 3Department of Physiology, Faculty of Medicine, Nangarhar University, Nangarhar, Afghanistan; 4Department of Microbiology, Kabul University of Medical Sciences, Kabul, Afghanistan; 5Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou, 5100050, People’s Republic of ChinaCorrespondence: Abdul Ghafar Sherzad, Department of Biochemistry, Faculty of Medicine, Nangarhar University, Nangarhar, Afghanistan, Tel +937 83545284, Email ghafarsherzad15@gmail.com Qingchun Zeng, Department of Cardiology, Nanfang Hospital, Southern Medical University, 1838 Northern, Guangzhou Ave, Guangzhou, 510515, People’s Republic of China, Tel/Fax +86 20-61360416, Email qingchunzeng@smu.edu.cnObjective: Evidence from previous studies suggests that calcific aortic valve disease (CAVD) is not an unavoidable consequence of aging, and may be linked to explicit risk factors. However, little is known regarding the Afghan population in this context. The current study aimed to identify the clinical features of CAVD and determine independent risk factors for CAVD in the Afghan population.Patients and Methods: A case-control study was conducted among 1072 Afghan participants (age > 18 years) from January 2018 to December 2020. The study participants were divided into two groups based on echocardiographic findings: 536 individuals with CAVD and 536 age- and sex-matched controls. Data were collected using questionnaires from the medical records of all cases and controls. The independent predictors of CAVD were evaluated using multivariate logistic regression analysis.Results: The mean age of study participants was 65.3 ± 13.5 years (range, 20– 100 years). Of the 536 patients with CAVD, 77 (14.4%) had aortic valve stenosis, 415 (77.4%) had aortic valve calcification, and 44 (8.2%) had bicuspid aortic valve. Multivariate logistic regression analysis revealed that sedentary lifestyle (odds ratio [OR] = 2.517, p = 003), diabetes mellitus (DM) (OR = 1.902, p = 006), high body mass index (BMI ≥ 30 kg/m2) (OR = 1.776, p = 005), good socioeconomic status (OR = 1.724, p = 021), and hypertension (OR = 1.664, p ˂0.001) were independent risk factors for CAVD in the Afghan population.Conclusion: It was observed that sedentary lifestyle, diabetes mellitus, high BMI (≥ 30 kg/m2), good socioeconomic status, and hypertension are independent risk factors for the development of CAVD compared to those with a normal aortic valve in the Afghan population.Keywords: aortic valve sclerosis, aortic valve calcification, aortic valve stenosis, risk factors for atherosclerosis, independent risk factors

To assess aortic valve calcification (AVC) and aortic root calcification (ARC) and to examine their usefulness for predicting major adverse cardiovascular events (MACE). This multicenter prospective cohort study recruited 1187 patients suspected of coronary artery disease (CAD) who underwent coronary computed tomography. MACE included cardiovascular death, myocardial infarction, stroke, revascularization and hospitalization for unstable angina, heart failure or aortic disease. Cox proportional hazard model and C-statistic were used to assess mutual associations between Framingham risk score, coronary artery calcification (CAC) and AVC or ARC with incident MACE. A total of 980 patients (mean age, 65 ± 7 years; female, 45.8%) with assessment of AVC and ARC Agatston scores were analyzed. Among them, 86 developed MACE during a median follow-up of 4.04 years. Cox proportional hazard analyses showed that the presence or severity of AVC and ARC was significantly associated with MACE development after adjusting the CAC Agatston score. Compared with the model of Framingham risk score alone, C-statistics of the model adding AVC or ARC Agatston score to Framingham risk score increased (ΔC-statistic; + 0.013 or + 0.032, respectively). However, they were not superior to the model adding CAC Agatston (ΔC-statistic; − 0.077 and − 0.058, respectively). AVC or ARC on the top of CAC was a predictive factor for increased MACE in patients with suspected CAD. However, an additional model of AVC or ARC score to Framingham risk score was not as effective as that of CAC Agatston score. [ABSTRACT FROM AUTHOR]

Calcification starts with hydroxyapatite (HA) crystallization on cell membranous components, as with aortic valve interstitial cells (AVICs), wherein a cell-membrane-derived substance containing acidic phospholipids (PPM/PPLs) acts as major crystal nucleator. Since nucleic acid removal is recommended to prevent calcification in valve biosubstitutes derived from decellularized valve scaffolds, the involvement of ribosomal RNA (rRNA) and nuclear chromatin (NC) was here explored in three distinct contexts: (i) bovine AVIC pro-calcific cultures; (ii) porcine aortic valve leaflets that had undergone accelerated calcification after xenogeneic subdermal implantation; and (iii) human aortic valve leaflets affected by calcific stenosis. Ultrastructurally, shared AVIC degenerative patterns included (i) the melting of ribosomes with PPM/PPLs, and the same for apparently well-featured NC; (ii) selective precipitation of silver particles on all three components after adapted von Kossa reactions; and (iii) labelling by anti-rRNA immunogold particles. Shared features were also provided by parallel light microscopy. In conclusion, the present results indicate that rRNA and NC contribute to AVIC mineralization in vitro and in vivo, with their anionic charges enhancing the HA nucleation capacity exerted by PPM/PPL substrates, supporting the concept that nucleic acid removal is needed for valve pre-implantation treatments, besides better elucidating the modality of pro-calcific cell death. [ABSTRACT FROM AUTHOR]

Tingting Tao, Junnan Zheng, Yu Han, Qiqi Yang, Yiming Ni, Liang Ma Department of Cardiovascular Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People’s Republic of ChinaCorrespondence: Liang Ma, Department of Cardiovascular Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, 79#, Qingchun Road, Hangzhou, Zhejiang, 310003, People’s Republic of China, Tel +86 571 87236841, Fax +86 571 87236843, Email ml1402@zju.edu.cnObjective: Calcific aortic valve disease (CAVD) is a prevalent type of valvular heart disease, its association with dyslipidemia remains controversial.Methods: Of 449 CAVD patients who underwent aortic valve replacement, 228 formed the aortic valve calcification (AVC) group, and 221 were the non-calcification group. We retrospectively reviewed the preoperative and one-year postoperative plasma lipoprotein levels of both and performed a logistic regression to evaluate the factors associated with AVC.Results: Preoperatively, AVC patients had significantly higher coronary heart disease (43.0% vs 24.9%, p< 0.001), peripheral vascular disease (41.7% vs 26.2%, p< 0.001), and heart failure rates (63.6% vs 47.1%, p< 0.001), and a higher level of total cholesterol (4.1± 0.9 vs 3.9± 0.8 mmol/L, p=0.032) and very low-density cholesterol (0.6 (0.4– 0.7) vs 0.5 (0.3– 0.7) mmol/L, p=0.054). Echocardiography revealed a significant difference of aortic stenosis in both AVC and non-AVC groups (p< 0.05), and also identified aortic regurgitation (AR) with a significant difference between these two groups (p=0.003). The peak transaortic jet velocity, peak transaortic gradient, and mean transaortic gradient were significantly higher in the calcification group (all p< 0.001), but the aortic valve area (0.7 (0.5– 1.0) vs 4 (0.9– 4.5) cm2; p< 0.001) was smaller. Age (OR=1.023), total cholesterol (OR=1.272), and mean transaortic gradient (OR=1.182) were AVC risk factors. A larger aortic valve area (OR=0.010) were protective factors. The one-year mortality and perivalvular leakage rates were significantly higher in the calcification group.Conclusion: Total cholesterol was significantly higher in AVC patients and may be an AVC risk factor along with age and mean transaortic gradient. AVC patients had a relatively poorer outcome within one year.Keywords: aortic valve calcification, total cholesterol, plasma lipoprotein levels, low-density lipoprotein, aortic valve replacement

Abstract Background Aortic valve stenosis (AS) has a high prevalence and poor prognosis in patients who receive maintenance dialysis. However, few large-scale observational studies in Japan have investigated patients with AS who underwent dialysis. In this study, we investigated the prevalence and factors associated with AS in Japanese patients who underwent dialysis. Methods In this cross-sectional analysis, we enrolled patients who underwent dialysis and transthoracic echocardiography between July 1, 2017 and June 30, 2018. Patients with a maximum aortic jet velocity (Vmax) ≥ 2.0 m/s, pressure gradient (PG) between the left ventricle and ascending aorta (mean PG) ≥ 20 mmHg, or aortic valve area (AVA) ≤ 1.0 cm2 were categorized into the AS group (G1). Patients with Vmax ≥ 3.0 m/s, mean PG ≥ 20 mmHg, or AVA ≤ 1.0 cm2 were categorized into the moderate and severe AS groups (G2). We performed multivariate logistic regression analysis and compared G1 and G2 with the non-AS group to determine the risk factors for AS. We also investigated the risk factors for aortic valve calcification, which is a pre-stage for AS. Results Of the 2,786 patients investigated, 555 (20.0%) and 193 (6.9%) were categorized into G1 and G2, respectively. Multivariate logistic regression analysis revealed that age, long-term dialysis, and elevated serum phosphorus levels were associated with AS in both the groups (p 6.0 mg/dL showed a higher risk of AS than those with serum phosphorus levels measuring

Background Description of cerebral and retinal infarction in patients with bicuspid aortic valve (BAV) is limited to case reports. We aimed to characterize cerebral and retinal infarction and examine outcomes in patients with BAV. Methods and Results Consecutive patients from 1975 to 2015 with BAV (n=5401) were retrospectively identified from the institutional database; those with confirmed cerebral or retinal infarction were analyzed. Infarction occurring after aortic valve replacement was not included. Patients were grouped according to infarction pathogenesis: embolism from a degenerative calcific BAV (BAVi); non‐BAV, large artery atherosclerotic or lacunar infarction (LAi); and non‐BAV, non‐large artery embolic infarction (nLAi). There were 83/5401 (1.5%) patients, mean age 54±12 years and 28% female, with confirmed cerebral or retinal infarction (LAi 23/83 [28%]; nLAi 30/83 [36%]; BAVi 26/83 [31%]; other 4/83 [5%]). Infarction was embolic in 72/83 (87%), and 35/72 (49%) were cardioembolic. CHA2DS2‐VASc score was 1.4±1.2 in BAVi (P=0.188 versus nLAi) and 2.3±1.2 in LAi (P=0.005). Recurrent infarction occurred in 41% overall (50% BAVi, P=0.164 and 0.803 versus LAi and nLAi). BAVi was more commonly retinal (39% BAVi versus 13% LAi, P=0.044 versus 0% nLAi, P=0.002). Patients with BAVi and LAi were more likely to have moderate‐to‐severe aortic stenosis and undergo aortic valve replacement compared with patients with nLAi. Conclusions Cardioembolism, often from degenerative calcification of the aortic valve, is a predominant cause of cerebral and retinal infarction in patients with BAV and is frequently recurrent. Cerebral and retinal infarction should be regarded as a complication of BAV.

Background: Aortic valve calcification correlates with the severity of aortic valve stenosis and a high calcium score is associated with conduction disturbances and paravalvular leakage after transcatheter aortic valve replacement. The 3mensio Structural Heart is a semiautomated software package to facilitate aortic root analysis by multislice computed tomography.The aim of the contemporary study is to validate a semiautomated calcium quantification scoring tool with a conventional manual calcium quantification tool. Methods: Fifty randomly selected patients who underwent multislice computed tomography for preprocedural planning were retrospectively selected to compare the semiautomated aortic valve Agatston calcium score by 3mensio with the manually obtained score using IntelliSpace Portal as standard reference. Results: Patients had a mean age of 76.7 ± 7.4 years and 60% were male. The median Agatston score was 3390 [interquartile range 1877-4509] with 3mensio and 3434 [interquartile range 1839-4620] with IntelliSpace.The mean difference was -0.18 [95% confidence interval (CI) −53.8 to 53.4]. The intraclass correlation coefficient between the Agatston scores using IntelliSpace and 3mensio showed an excellent correlation of 0.995 [95% CI 0.992-0.997], p ≤ 0.001. The interobserver and intraobserver variability was 0.993 ([95% CI 0.961-0.998], p ≤ 0.001) and 0.995([95%CI 0.981-0.999], p =

Data are limited on whether valvular calcification is associated with aortic wall stiffness. We tested whether aortic valve calcification (AVC) and/or mitral valve calcification (MVC) is inversely associated with aortic distensibility (AD). Cross-sectional study conducted in a subset of the Multi-Ethnic Study of Atherosclerosis (MESA) included 3676 MESA participants aged 44 to 84 years with AD measured with magnetic resonance imaging and with AVC and MVC measured with noncontrast cardiac computed tomography scans. Both AVC and MVC were divided into 3 categories: zero, < median values (low), and ≥ median values (high) for patients with nonzero values. Overall, 88% (n = 3256) and 92% (n = 3365) of participants had zero AVC and MVC, while 6% (n = 211) and 4% (n = 156) had low, and 6% (n = 209) and 4% (n = 155) had high values of AVC and MVC, respectively. The AVC was independently associated with AD after adjusting for age, gender, and ethnicity ( P = .035). No association was noted between AVC groups and AD after adjustment for all covariates or MVC groups and AD in any model.

Low-dose computed tomography (LDCT) is predominantly applied in lung cancer screening programs. Tobacco smoking is the main risk factor for developing lung cancer but is also common for cardiovascular diseases, including aortic stenosis (AS). Consequently, an increased prevalence of cardiovascular diseases is expected in lung cancer screenees. Therefore, initial aortic valve calcification evaluation should be additionally performed on LDCT. The aim of this study was to estimate a calcium score (CS) cutoff point for clinically significant AS diagnosis based on LDCT, confirmed by echocardiographic examination. The study included 6631 heavy smokers who participated in a lung cancer screening program (MOLTEST BIS). LDCTs were performed on all individuals and were additionally assessed for aortic valve calcification with the use of CS according to the Agatston method. Patients with CS ≥ 900 were referred for echocardiography to confirm the diagnosis of AS and to evaluate its severity. Of 6631 individuals, 54 met the inclusion criteria and underwent echocardiography for confirmation and assessment of AS. Based on that data, receiver operating characteristic (ROC) curves of CS were plotted, and cutoff points for clinically significant AS diagnosis were established: A CS of 1758 for at least moderate AS had 85.71% (CI 65.36–95.02%) sensitivity and 75.76% (CI 58.98–87.17%) specificity; a CS of 2665 for severe AS had 87.5% (CI 73.89–94.54%) sensitivity and 76.92% (CI 49.74–91.82%) specificity. This is the first study to assess possible CS cutoff points for diagnosing clinically significant AS detected by LDCT in lung cancer screening participants. LDCT with CS assessment could enable early detection of patients with clinically significant AS and therefore identify patients who require appropriate treatment. [ABSTRACT FROM AUTHOR]

Growing studies show that lipoprotein (a) [Lp(a)] is related to calcified aortic valve diseases in general population, while the relationship between Lp(a) and aortic valve calcification (AVC) in patients with new-onset acute myocardial infarction (AMI) remains unclear. Therefore, this study was to evaluate the correlation between Lp(a) and AVC in patients with new-onset AMI. This cross-sectional study included 410 patients with new-onset AMI who were hospitalised in Zhongda Hospital affiliated to Southeast University from January 1, 2020 to December 31, 2021. Multivariable logistic regression, subgroup analysis, generalised additive model, threshold and saturation effect and receiver operator characteristic (ROC) curve were used to explore the association between Lp(a) and AVC. Patients with AVC had higher levels of Lp(a) than those without AVC. Multivariable logistic regression analysis showed that higher Lp(a) was still associated with higher risk of AVC after adjusting for confounding factors, and this correlation was robust in most subgroups and sensitivity analyses (p < 0.05). Additionally, the generalised additive model showed that there was a nonlinear correlation between Lp(a) and AVC (P for nonlinearity = 0.037). Threshold and saturation effect analysis indicated that when Lp(a) < 840 mg/L, it was positively correlated with the prevalence of AVC (p < 0.05), but when Lp(a) ≥ 840 mg/L, this correlation no longer existed. Besides, ROC curve analysis demonstrated that Lp(a) had a good diagnostic performance for AVC. Lp(a) was independently associated with the prevalence of AVC in patients with new-onset AMI. [ABSTRACT FROM AUTHOR]

In patients with coronary artery calcification (CAC), a predictor of adverse cardiovascular events, coronary computed tomography angiography (CCTA) also shows valvular calcification. In this study, we evaluated common clinical indicators in CAC patients with aortic (AoVC) and mitral valve (MVC) calcification. CAC and valvular calcification were quantified using the Agatston score in 636 hospitalised patients with CAC who underwent CCTA. Valvular calcification was found in 30.5% of patients, with 25.2% (160 patients) showing AoVC. Age was an independent predictor of AoVC in both men (odds ratio (OR), 1.086; 95% confidence interval (CI), [1.054–1.119]; p < 0.001) and women (OR, 1.109; CI, [1.066–1.154]; p < 0.001). In men, we also found that a history of cerebral infarction was an independent predictor of AoVC (OR, 2.402; CI, [1.177–4.902]; p < 0.05). The independent predictors of AoVC in the 60- to 69-years age group were BMI (OR, 1.181; CI, [1.061–1.316]; p < 0.01) and history of cerebral infarction (OR, 3.187; CI, [1.283–7.919]; p < 0.05). Age is a key independent predictor of AoVC in CAC patients. History of cerebrovascular disease was also an independent predictor of AoVC, but only in men and patients aged 60–69 years. Our results indicate that a history of cerebral infarction may be used as a risk factor when identifying AoVC in patients with CAC. [ABSTRACT FROM AUTHOR]

To discuss the effect and mechanism of circular-CCND1 (circ-CCND1) on the regulation of calcified aortic valve disease (CAVD). Differentially expressed circRNAs were screened through the GSE155119 data set and biological prediction. Subsequently, the miR-138-5p, CCND1, and circ-CCND1 expression were detected in the non-calcified and calcified aortic valve. Then Pearson correlation analysis was performed to analyze the correlation between the above expression, and dual luciferase and RNA-pull down assays for verifying the target relationship. Porcine aortic valve interstitial cells (AVICs) were isolated and transfected with pcDNA-circ-CCND1, miR-138-5p inhibitor, and miR-138-5p mimics. The alkaline phosphatase (ALP) activity was quantitatively analyzed by ALP staining, and alizarin-red staining was to check the calcium nodules formation. Finally, Western blot was applied to detect the expression of proteins associated with osteogenic differentiation (Runx2, Osterix, OPN) and CCND1/P53/P21 pathway proteins. Circ-CCND1 was highly expressed in calcific aortic valves. After inhibiting circ-CCND1 expression, a significant reduction was shown in ALP activity, the degree of ossification and the formation of calcium nodules in AVICs, and osteogenic differentiation-related protein expression and CCND1/P53/P21 pathway protein expression. By contrast, inhibition of miR-138-5p and circ-CCND1 together promoted the calcification of AVICs and expression of CCND1/P53/P21 pathway proteins. P53 inhibitor (PFT-α) could significantly reduce activation of CCND1/P53/P21 pathway protein expression by circ-CCND1 overexpression. However, P53 activator (Nutlin-3) significantly restored the suppression of the above pathway-related protein expression by downregulation of circ-CCND1. Circ-CCND1 sponges miR-138-5p to regulate CCND1 expression, thereby promoting the calcification of AVICs. [ABSTRACT FROM AUTHOR]

Background: The relationships of the clinical and biological attributes of epicardial adipose tissue (EAT) with aortic valve calcification (AVC) have not been characterized. We evaluated the relationships of the clinical and histological features of EAT with AVC assessed using computed tomography (CT)., Methods and results: We enrolled 43 patients undergoing cardiac CT examination prior to elective cardiac surgery in whom AVC was identified on CT. EAT volume and density, coronary calcium score (CCS), AVC score (AVCS), and coronary atherosclerosis on CT angiography were evaluated in each patient. During cardiac surgery, 2 EAT samples were obtained for immunohistochemistry. The number of CD68- and CD11c-positive macrophages and osteocalcin-positive cells was counted in 6 random high-power fields of EAT sections. EAT density, but not EAT volume normalized to body surface area, was positively correlated with the number of macrophages and osteocalcin-positive cells in EAT. There was a positive correlation between ln(AVCS), but not ln(CCS+1), and the number of macrophages and osteocalcin-positive cells in EAT. Multivariate analysis revealed significant positive correlations for ln(AVCS) with EAT density (β=0.42; P=0.0072) and the number of CD68-positive macrophages (β=0.57; P=0.0022), CD11c-positive macrophages (β=0.62; P=0.0003), and osteocalcin-positive cells (β=0.52; P=0.0021) in EAT., Conclusions: Inflammation and osteogenesis in EAT, reflected by high CT density, are associated with the severity of AVC representing aortic valve degeneration.

Importance: Guidelines recommend the use of dobutamine stress echocardiography (DSE) in patients with low-gradient aortic stenosis (AS) and left ventricular ejection fraction (LVEF) <50%. However, a paucity of DSE data exists when LVEF >35%., Objective: To examine the diagnostic accuracy of DSE in patients with low-gradient AS with a wide range of LVEF and to examine the interaction between the diagnostic accuracy of DSE and LVEF., Design, Setting, and Participants: Patients with mean gradient <40 mm Hg, aortic valve area <1.0 cm 2 , and stroke volume index ≤35 mL/m 2 undergoing DSE and cardiac computer tomography (C-CT) were identified from 3 prospectively collected patient cohorts and stratified according to LVEF: LVEF<35%, LVEF 35% to 50%, and LVEF>50%., Exposure: Dobutamine stress echocardiography and C-CT were performed on patients with low-gradient AS., Main Outcomes and Measures: Severe AS was defined as aortic valve calcification score ≥2,000 arbitrary units (AU) among men and ≥1,200 AU for women on C-CT., Results: Of 221 patients included in the study, 78 (35%) presented with LVEF <35%, 67 (30%) with LVEF 35% to 50%, and 76 (34%) with LVEF >50%. Mean-gradient and aortic valve peak velocity during DSE showed significant diagnostic heterogeneity between LVEF groups, being most precise when LVEF <35% (both areas under the curve [AUC] = 0.90), albeit with optimal thresholds of 30 mm Hg and 377 cm/sec and a limited diagnostic yield in patients with LVEF ≥35% (AUC = 0.67 and 0.66 in LVEF 35% to 50% and AUC = 0.65 and 0.60 in LVEF ≥50%). Using guideline thresholds led to a sensitivity/specificity of 49%/84% for all patients with LVEF <50%., Conclusion and Relevance: While DSE is safe and leads to an increase in stroke volume in patients with low-gradient AS regardless of LVEF, the association between DSE gradients and AS severity assessed by C-CT demonstrates important heterogeneity depending on LVEF, with the highest accuracy in patients with LVEF <35%., Competing Interests: Conflicts of Interest None, (Copyright © 2024 American Society of Echocardiography. Published by Elsevier Inc. All rights reserved.)

IntroductionThis study aimed to investigate the association of aortic arch calcification (AoAC) and aortic valve calcification (AVC) with major adverse cardiovascular events (MACE) and cardiovascular and all-cause mortality in patients on maintenance hemodialysis (MHD).MethodsThis study enrolled 297 adult patients with end-stage kidney disease who were on MHD. They were divided into those with an AoAC score

BackgroundAlthough advanced surgical and interventional treatments are available for advanced aortic valve calcification (AVC) with severe clinical symptoms, early diagnosis, and intervention is critical in order to reduce calcification progression and improve patient prognosis. The aim of this study was to develop therapeutic targets for improving outcomes for patients with AVC.Materials and methodsWe used the public expression profiles of individuals with AVC (GSE12644 and GSE51472) to identify potential diagnostic markers. First, the R software was used to identify differentially expressed genes (DEGs) and perform functional enrichment analysis. Next, we combined bioinformatics techniques with machine learning methodologies such as random forest algorithms and support vector machines to screen for and identify diagnostic markers of AVC. Subsequently, artificial neural networks were employed to filter and model the diagnostic characteristics for AVC incidence. The diagnostic values were determined using the receiver operating characteristic (ROC) curves. Furthermore, CIBERSORT immune infiltration analysis was used to determine the expression of different immune cells in the AVC. Finally, the CMap database was used to predict candidate small compounds as prospective AVC therapeutics.ResultsA total of 78 strong DEGs were identified. The leukocyte migration and pid integrin 1 pathways were highly enriched for AVC-specific DEGs. CXCL16, GPM6A, BEX2, S100A9, and SCARA5 genes were all regarded diagnostic markers for AVC. The model was effectively constructed using a molecular diagnostic score system with significant diagnostic value (AUC = 0.987) and verified using the independent dataset GSE83453 (AUC = 0.986). Immune cell infiltration research revealed that B cell naive, B cell memory, plasma cells, NK cell activated, monocytes, and macrophage M0 may be involved in the development of AVC. Additionally, all diagnostic characteristics may have varying degrees of correlation with immune cells. The most promising small molecule medicines for reversing AVC gene expression are Doxazosin and Terfenadine.ConclusionIt was identified that CXCL16, GPM6A, BEX2, S100A9, and SCARA5 are potentially beneficial for diagnosing and treating AVC. A diagnostic model was constructed based on a molecular prognostic score system using machine learning. The aforementioned immune cell infiltration may have a significant influence on the development and incidence of AVC.

AimsThe number of trans-catheter aortic valve replacement (TAVR) procedure is increasing; However, the incidence of leaflet thrombosis is higher in TAVR than in surgical aortic valve replacement (SAVR). In this study, the risk factors for leaflet thrombosis after TAVR and its effects on hemodynamics and clinical course were investigated.Methods and resultsMultidetector computed tomography (MDCT) was performed at 1year after TAVR in 94 patients from January 2015 to October 2020 at Samsung Medical Center in South Korea. Among the 94 patients, subclinical leaflet thrombosis occurred in 20 patients, and risk factors were analyzed. In addition, the difference in aortic valve (AV) hemodynamics between the two groups was examined and clinical outcomes compared. Indexed mean sinus of Valsalva (SOV) diameter, AV calcium volume, and post-procedure effective orifice area (EOA) were predictive of subclinical leaflet thrombosis with the area under the curve (AUC) value of 0.670 (P-value = 0.020), 0.695 (P-value = 0.013), and 0.665 (P-value = 0.031), respectively. In echocardiography performed at the time of follow-up CT, the value of AV max velocity and AV mean pressure gradient were higher in the thrombosis group and the EOA and Doppler velocity index values were lower in the thrombosis group than in the no thrombosis group. Clinical outcome was not significantly different between the two groups (log-rank P-value = 0.26).ConclusionLarger indexed SOV diameter, higher AV calcium volume, and smaller post-procedure AV EOA were risk factors for subclinical leaflet thrombosis after TAVR. Subclinical leaflet thrombosis has a benign course when properly managed.

Since the first groundbreaking procedure in 2002, transcatheter aortic valve implantation (TAVI) has revolutionized the management of aortic stenosis (AS). Through striking developments in pertinent equipment and techniques, TAVI has now become the leading therapeutic strategy for aortic valve replacement in patients with severe symptomatic AS. The procedure streamlining from routine use of conscious sedation to a single arterial access approach, the newly adapted implantation techniques, and the introduction of novel technologies such as intravascular lithotripsy and the refinement of valve-bioprosthesis devices along with the accumulating experience have resulted in a dramatic reduction of complications and have improved associated outcomes that are now considered comparable or even superior to surgical aortic valve replacement (SAVR). These advances have opened the road to the use of TAVI in younger and lower-risk patients and up-to-date data from landmark studies have now established the outstanding efficacy and safety of TAVI in patients with low-surgical risk impelling the most recent ESC guidelines to propose TAVI, as the main therapeutic strategy for patients with AS aged 75 years or older. In this article, we aim to summarize the most recent advances and the current clinical aspects involving the use of TAVI, and we also attempt to highlight impending concerns that need to be further addressed.

Background: Aortic valve calcification (AVC) is associated with increased cardiovascular risk in the general population. We sought to investigate whether AVC identified by transthoracic echocardiography could be a predictor of long‐term adverse events after primary percutaneous coronary intervention (PCI) in patients with acute myocardial infarction. Methods: Patients undergoing primary PCI were consecutively enrolled in this cohort study between 1 January 2009 and 31 December 31 2018. The presence of AVC was identified by transthoracic echocardiography one to three days after PCI. The primary endpoint was major adverse cardiovascular and cerebral events (MACCE) during follow‐up. Propensity score matching was adopted to adjust for the baseline differences between groups. Results: Of 2117 patients enrolled in the study, 566 (26.7%) were found to have AVC. Patients with AVC were older, more likely to be women, and disposed to have comorbidities and complex lesions. During a median follow‐up period of 6.1 years, 699 cases of MACCE occurred, including 243 (42.9%) cases in patients with AVC and 456 (29.4%) cases in patients without AVC. After 1:1 propensity score matching, the presence of AVC increased the risk of MACCE (adjusted hazard ratio: 1.442, 95% confidence interval: 1.186 to 1.754, p < 0.001). This difference persisted when sensitivity and subgroup analyses were made. Conclusions: AVC identified by transthoracic echocardiography independently increased the long‐term risk of MACCE after primary PCI in patients with acute myocardial infarction. This imaging feature will contribute to better risk stratification in this population. [ABSTRACT FROM AUTHOR]

Arterial and aortic valve calcifications are the most prevalent pathophysiological conditions among all the reported cases of cardiovascular calcifications. It increases with several risk factors like age, hypertension, external stimuli, mechanical forces, lipid deposition, malfunction of genes and signaling pathways, enhancement of naturally occurring calcium inhibitors, and many others. Modern-day lifestyle is affected by numerous environmental factors and harmful toxins that impair our health rather than providing benefits. Applying the combinatorial approach or targeting the exact mechanism could be a new strategy for drug designing or attenuating the severity of calcification. Most of the non-communicable diseases are life-threatening; thus, altering the phenotype and not the genotype may reveal the gateway for fighting with upcoming hurdles. Overall, this review summarizes the reason behind the generation of arterial and aortic valve calcification and its related signaling pathways and also the detrimental effects of calcification. In addition, the individual process of epigenetics and how the implementation of this process becomes a novel approach for diminishing the harmful effect of calcification are discussed. Noteworthy, as epigenetics is linked with genetics and environmental factors necessitates further clinical trials for complete and in-depth understanding and application of this strategy in a more specific and prudent manner. [ABSTRACT FROM AUTHOR]

The prevalence of aortic valve calcification (AVC) increases with age. However, the sex-and race-specific burden of AVC and associated cardiovascular risk factors among adults ≥75 years are not well studied. We calculated the sex-and race-specific burden of AVC among 2283 older Black and White adults (mean age:80.5 [SD:4.3] years) without overt coronary heart disease from the Atherosclerosis Risk in Communities Study who underwent non-contrast cardiac-gated CT-imaging at visit 7 (2018–2019). Using Poisson regression with robust variance, we calculated the adjusted prevalence ratios (aPR) of the association of AVC with cardiovascular risk factors. The overall AVC prevalence was 44.8%, with White males having the highest prevalence at 58.2%. The prevalence was similar for Black males (40.5%), White females (38.9%), and Black females (36.8%). AVC prevalence increased significantly with age among all race-sex groups. The probability of any AVC at age 80 years was 55.4%, 40.0%, 37.3%, and 36.2% for White males, Black males, White females, and Black females, respectively. Among persons with prevalent AVC, White males had the highest median AVC score (100.9 Agatston Units [AU]), followed by Black males (68.5AU), White females (52.3AU), and Black females (46.5AU). After adjusting for cardiovascular risk factors, Black males (aPR:0.53; 95%CI:0.33–0.83), White females (aPR:0.68; 95%CI:0.61–0.77), and Black females (aPR:0.49; 95%CI:0.31–0.77) had lower AVC prevalence compared to White males. In addition, systolic blood pressure, non-HDL-cholesterol, and lipoprotein (a) were independently associated with AVC, with no significant race/sex interactions. AVC, although highly prevalent, was not universally present in this cohort of older adults. White males had ∼50–60% higher prevalence than other race-sex groups. Moreover, cardiovascular risk factors measured in older age showed significant association with AVC. [Display omitted] • The prevalence of aortic valve calcification in a cohort of older adults was 44.8%. • A significant proportion of older adults did not have any aortic valve calcification. • White males had the highest prevalence, nearly 50–60% higher than other race-sex groups. • Cardiovascular risk factors were associated with aortic valve calcification with no race/sex interactions. [ABSTRACT FROM AUTHOR]