Valve Calcification Research Articles

Association of aortic valve size with the degree of aortic valve calcification in severe high-gradient aortic stenosis.

Less pronounced calcification of the aortic valve (AVC) was observed in women with aortic stenosis (AS) as compared to men. Since women have smaller aortic valves (AV), this could explain a lower calcium load. We aimed to analyze the association of AV size with AVC independent from sex. Consecutive patients with high-gradient AS, who underwent cardiac computed tomography (CT), were assessed. AV annulus area and AVC with the Agatston score were measured on CT. In total, 601 patients (mean age 80±7 years, 45% female) were included. Women had smaller AV annulus areas (4.12±0.67cm2 vs 5.15 ±0.78cm2, p<0.001) and lower Agatston scores (2018 [1456-3017] vs. 3394 [2562-4530]; p<0.001) than men. We found a significant correlation (r=0.594, p<0.001) and independent association (β=926.20, p<0.001) of AV annulus area with AVC. On separate regression analyses for men and women, AVC was independently associated with AV annulus area in both sexes (βmen=887.77; βwomen=863.48, both p<0.001). When patients were stratified into AV size quartiles, patients in the lower quartiles were more likely to have AVC values below recommended sex-specific AVC thresholds. In the lowest quartile 28% of female and 27% of male patients had Agatston scores below 1200AU (women) and 2000AU (men) while this proportion decreased to 6% and 2%, respectively, in the quartiles with the largest annulus areas. In high-gradient AS, AVC strongly depends on AV annulus area. This association is not dependent on sex. Thus, AVC should be indexed to AV size in addition to sex.

Usefulness of Aortic Valve Calcification in Patients With Low-Flow Aortic Stenosis.

Aortic valve calcification (AVC) has been shown to be a powerful assessment of aortic stenosis (AS) severity and a predictor of adverse outcomes. However, its accuracy in patients with low-flow AS has not yet been proven. The objective of the study was to assess the predictive value of AVC in patients with classical low-flow (CLF, that is, low-flow reduced left ventricular ejection fraction) or paradoxical low-flow (PLF, that is, low-flow preserved left ventricular ejection fraction) AS. We prospectively included 641 patients, 319 (49.8%) with CLF-AS and 322 (50.2%) with PLF-AS, who underwent Doppler echocardiography and multidetector computed tomography. AVC ratio (AVCratio) was calculated as AVC divided by the sex-specific AVC threshold for AS severity; AVC score ≥2000 Agatston units in male patients and ≥1200 Agatston units in female patients. The primary end point of the study was all-cause mortality regardless of treatment. Sex-specific AVC thresholds identified AS severity correctly in 137 (87%) of the patients. During a median follow-up of 4.9 (4.3-5.9) years, there were 265 deaths. After comprehensive adjustment, AVCratio was associated with all-cause mortality in patients with CLF-AS (adjusted hazard ratio, 1.25 [95% CI, 1.01-1.56]; P=0.046) and PLF-AS (adjusted hazard ratio, 1.51 [95% CI, 1.14-2.00]; P=0.004). There was an interaction (P=0.001) between AVC and AS flow patterns (ie, CLF versus PLF) with regard to the prediction of mortality. The best AVCratio threshold to predict mortality was different in patients with CLF-AS (AVCratio ≥0.7) and PLF-AS (AVCratio ≥1). After a comprehensive analysis, AVCratio as a dichotomic variable was associated with all-cause mortality in all groups (P≤0.001). The addition of AVCratio to the models improved all models' predictive value (all net reclassification index >18%; all P≤0.05). In patients with CLF-AS or PLF-AS, AVC is a major predictor of mortality. Thus, AVC should be used in low-flow patients to assess AS severity and stratify risk. Importantly, in patients with reduced left ventricular ejection fraction, a nonsevere AS (ie, AVC 70% of severe) could be associated with reduced survival.

Reevaluating Normal-Flow Low-Gradient Severe Aortic Stenosis: Clinical Phenotypes and Outcomes in Severe Aortic Stenosis Among TAVR Patients.

Aortic stenosis (AS) is a complex condition with various hemodynamic subtypes, each with distinct clinical profiles and outcomes. This study aimed to assess the characteristics and outcomes of different AS phenotypes based on flow and gradient patterns. In this retrospective cohort study, we included 930 patients who underwent transcatheter aortic valve replacement (TAVR) for severe symptomatic AS at Mayo Clinic sites from 2012-2017. Patients were classified into three groups: high gradient (HG), low-flow low-gradient (LFLG), and normal-flow low-gradient (NFLG). Baseline clinical, echocardiographic, and computed tomography (CT) characteristics, including aortic valve area (AVA), aortic valve calcium score (AVCS), left ventricular ejection fraction (LVEF), and the prevalence of tricuspid regurgitation (TR) and atrial fibrillation were analyzed. One- and five-year all-cause mortality outcomes were compared using Kaplan-Meier analysis and Cox proportional hazards models. The final cohort included 273 patients in the NFLG group (29.4%), 563 in the HG group (60.5%), and 94 in the LFLG group (10.1%). After reevaluation and careful review of the echocardiograms, 41 NFLG patients were reclassified into the LFLG group. LFLG patients had the highest prevalence of atrial fibrillation/flutter (60%) and TR (17%). AVCS was significantly lower in NFLG compared to HG and LFLG groups. One-year mortality was highest in the LFLG group (17.4%), followed by HG (13.9%) and NFLG (10.9%), but the difference was not statistically significant (p=0.2). Five-year mortality rate was higher in the LFLG group (55.6%) compared to NFLG (47.2%) and HG (47.9%) but did not reach statistical significance (p=0.2). LFLG AS is associated with more comorbidities and higher mortality compared to HG and NFLG groups, though differences in mortality were not statistically significant. The NFLG group, after close review and reclassification, showed the least significant AS. Randomized trials are needed to clarify the prognosis and management of NFLG AS.

Can aortic valve calcium score predict a need for permanent pacemaker implantation after transcatheter aortic valve implantation?

IntroductionConductive disturbances requiring permanent pacemaker (PPM) implantation remain a major concern after transcatheter aortic valve implantation (TAVI).AimsTo assess the impact of aortic valve calcium score (AVCS) on conductive disturbances requiring...

Optimizing Outcomes in Transcatheter Aortic Valve Replacement Addressing Cerebrovascular Complications and Enhancing Patient Safety.

Transcatheter aortic valve replacement (TAVR) has revolutionized the treatment of severe aortic stenosis, becoming the gold standard for many patients. Despite its advantages over surgical aortic valve replacement, TAVR is associated with significant complications, including paravalvular leakage, conduction disorders, and cerebrovascular events. This review focuses on the pathophysiology, incidence, and management of cerebrovascular complications following TAVR. We explore the mechanisms leading to these events, including embolization of debris from the calcified valve and aortic arch, and the role of procedural factors. The review also discusses the timing of cerebrovascular events, diagnostic approaches, and potential preventive strategies, including embolic protection devices. Understanding these complications is crucial for improving patient outcomes and refining TAVR techniques.

Impact of Wood Smoke Exposure on Aortic Valve Mineralization: Microvesicles as Mineral Conveyors in Patients with Coronary Stenosis.

Background: Aortic valve calcification results from degenerative processes associated with several pathologies. These processes are influenced by age, chronic inflammation, and high concentrations of phosphate ions in the plasma, which contribute to induce mineralization in the aortic valve and deterioration of cardiovascular health. Environmental factors, such as wood smoke that emits harmful and carcinogenic pollutants, carbon monoxide (CO), and nitrogen oxide (NOx), as well as other reactive compounds may also be implicated. The purpose of this research was to study the impact of wood smoke on specific aortic valve characteristics, including lesion size and percentage of mineralization, in patients with aortic valve stenosis (AS). Methods: This observational study included 65 patients who underwent primary valve replacement surgery at the National Institute of Cardiology, 11 of whom were exposed to wood smoke. For each patient, approximately 0.5 cm of aortic valve tissue was collected along with a blood sample anticoagulated with sodium citrate. The valves were analyzed using scanning electron microscopy coupled with energy-dispersive X-ray spectroscopy (SEM-EDS). Since extracellular microvesicles (MVs) may induce epigenetic changes in target cells by transferring their cargo, we also analyzed their mineral content. Results: Individuals exposed to wood smoke exhibit more extensive lesion (835 µm2) characteristics compared to those with no exposure (407.5 µm2). Interestingly, FESEM images of MVs showed the presence of minerals on their surface, thus providing evidence on their possible role in the pathophysiology of mineralization. Conclusions: Our study uniquely demonstrates imaging-based evidence of structural damage and mineralization in aortic valve tissue, with chronic wood smoke exposure emerging as a significant causative factor.

Iron Deficiency Promotes Intra-leaflet Haemorrhage-induced Aortic Valve Calcification: an Experimental Study.

Interleaflet haemorrhage (IH) plays a well-recognized detrimental role in calcified aortic valve disease (CAVD). However, IH-induced fibro-osteogenic responses in valvular interstitial cells (VICs) appear to be triggered under specific pathological conditions. Iron deficiency (ID), a common co-morbidity in CAVD, may influence these responses. This study investigated the relationship between ID and pathological changes associated with CAVD, and its effects on IH-mediated fibro-osteogenic differentiation of VICs. Two independent studies were conducted, including 2,495 patients in the discovery study and 34 in the validation study. Our data demonstrated that ID was associated with CAVD severity and progression, particularly in an age-dependent manner. Based on these clinical findings, immunofluorescence and Western blot analyses revealed that TFR1, a key iron import transporter, was significantly upregulated in human calcified aortic valves. Concurrently, iron accumulation was detected by Perl's staining in both calcific and non-calcific valve sections. In vitro, VICs cultured with human serum from ID patients showed red blood cell lysis-induced iron overload and fibro-calcific differentiation. ID triggers TFR1-mediated intracellular iron overload, leading to fibrosis and calcification in human VICs, thereby contributing to IH-mediated valve remodeling and calcification. These findings supported the potential role of monitoring and correcting ID to slow or prevent the progression of valvular calcification.

Prognostic Value and Safety of Serial Exercise Echocardiography in Asymptomatic Severe Aortic Stenosis.

The prognostic value of serial exercise echocardiography (EEC) in asymptomatic severe aortic stenosis is unknown. We sought to evaluate the safety and utility of monitoring patients with asymptomatic severe aortic stenosis by annual EECs to refer them to aortic valve replacement (AVR) or to keep them under follow-up. The cohort comprised 196 patients, with a normal screening EEC and a minimal follow-up of 18 months. Follow-up was planned until there was an indication for AVR, based on a resting transthoracic echocardiography at 6 months and then every year, and an EEC at 1 year and then every year (alternating resting transthoracic echocardiography and EEC every 6 months). During follow-up, patients were referred to AVR if they reported symptoms, if rest transthoracic echocardiography was positive (left ventricular dysfunction, aortic maximal velocity ≥5 m/s, or severe valve calcification with aortic maximal velocity progression ≥0.3 m/s per year) or if EEC was positive (occurrence during exercise of any aortic stenosis-related symptoms, significant ventricular arrhythmias, a drop or an insufficient rise (<20 mm Hg) in systolic blood pressure from baseline, or a left ventricular dysfunction). Among the 196 patients (76% men, aged 76.1±11.1 years), a mean 2.85±1.22 EECs were conducted. There were no serious complications during any of the EECs. Each serial transthoracic echocardiography at rest and each EEC yielded 0%-22% and 23.5%-50% of positive results, respectively, leading to AVR. We delayed AVR by a mean of 2.93±1.95 years after the screening EEC. No cardiac-related death or sudden death was reported during the study. Our findings demonstrate the safety and prognostic utility of serial EECs in the management of patients with asymptomatic severe aortic stenosis to guide timely AVR.

Fetuin-A as a plausible biomarker for cardiac valve calcification in rheumatic heart disease patients from North India.

Rheumatic heart disease (RHD) remains a persistent public health challenge, particularly prevalent in developing and underdeveloped regions despite concerted global eradication efforts. The progressive stage of RHD, marked by valvular calcification, necessitates the imperative need to identify prognostic biomarkers. Fetuin-A, well-known for its role as a negative inhibitor of ectopic calcification, is investigated in our study as a potential biomarker for cardiac valve calcification in RHD patients. Individuals with confirmed presence of RHD via echocardiography, who exhibited moderate to severe cardiac valve involvement, were enrolled alongside age and sex-matched healthy controls. Enzyme Linked Immunosorbent Assay was performed to analyse serum concentration of fetuin-A in healthy controls and RHD patients. Cytokine profiling was carried out using Cytometric Bead Array. Sixty confirmed RHD patients along with age and sex-matched case-control were evaluated for their serum fetuin-A and serum cytokines levels. Our findings reveal significantly reduced serum fetuin-A levels in RHD patients (1.96 ± 0.608 ng/ml) compared to healthy controls (2.85 ± 0.55 ng/ml) (p < 0.0001). Cytokine profiling shows nearly two-fold elevations in interleukin (IL)-17A, tumor necrosis factor-alpha (TNF-α), interferon-gamma (IFN-γ), IL-6, IL-10, IL-4 and IL-2 levels among RHD patients versus healthy controls, with IL-6 showing the maximum elevation in serum concentration. Pearson's correlation coefficient (r) values indicate a strong negative correlation between fetuin-A levels in RHD patients and various inflammatory cytokines, including IL-17A (-0.9754), IFN-γ (-0.8142), TNF-α (-0.8281), IL-10 (-0.9183), IL-6 (-0.8479), IL-4 (-0.9182) and IL-2 (-0.9430) (p < 0.05, statistically significant). This study suggests that fetuin-A can be explored as a plausible biomarker for cardiac valve calcification and has an inverse correlation with inflammatory cytokines involved in RHD.

The influence of lipoprotein(a) on aortic valve calcification in patients undergoing transcatheter aortic valve replacement.

Elevated levels of lipoprotein(a) (Lp[a]) have been recognized as substantial risk factors for cardiovascular disease and aortic stenosis (AS). However, the specific role of Lp(a) in promoting aortic valve calcification (AVC) and influencing mortality in elderly, multimorbid patients undergoing transcatheter aortic valve replacement (TAVR) remains unclear and warrants further investigation. A retrospective analysis was conducted on all consecutive patients who underwent TAVR between August 2019 and June 2020 at our clinic. Patients with missing data or prior aortic valve replacement were excluded. The study cohort was stratified based on an Lp(a) threshold of 60 mg/dl according to guidelines for lipoprotein apheresis in UK and Germany.1,2 RESULTS: In total, 454 patients were included into the analysis. Mean age was 81 ± 6 years and patients presented with a notable cardiovascular risk profile. Lp(a) values ≥ 60mg/dl were detected in 102 (22.5%) patients, while 352 (77.5%) had Lp(a) values < 60mg/dl. The median calcium volume of the total cohort was 894.5 [570.8; 1,382.8]mm2. No significant difference was observed between the groups (p = 0.83). Furthermore, Lp(a) did not emerge as a statistically significant predictor of calcium levels before TAVR. Notably, male gender (B = 404.11, p < 0.001) and mean trans-valvular pressure gradient (B = 15.64, p < 0.001) were identified as the strongest coefficients within the robust regression analysis. Log-rank tests indicated no prognostic utility of Lp(a) for 30-day all-cause mortality (p = 0.30) or 40 months long-term all-cause mortality (p = 0.60). Lp(a) might not exert a significant effect on calcification levels or all-cause mortality in patients undergoing TAVR. Despite the study's highly selected population, these results align with current research, supporting the assumption that the influence of Lp(a) may be confined to the early stages of AS and its progression.

The m6A demethylase ALKBH5 is a novel epigenetic regulator of aortic valve calcification.

Calcific aortic valve disease (CAVD) is a common heart valve disease with significant clinical consequences. The mechanisms that drive the pathogenesis of CAVD remain to be fully elucidated. N6-methyladenosine (m6A), the most prevalent RNA epigenetic regulator, has recently been implicated in cardiovascular disease, but its role in CAVD has yet to be investigated. In this study, we investigated the potential function of m6A modification in CAVD. Using clinical samples from CAVD patients in combination with human valve interstitial cell (hVIC) calcification model, we screened the expression of m6A modulators and discovered that ALKBH5 alkB homolog 5, RNA demethylase (ALKBH5), a key m6A demethylase, was significantly down-regulated in calcified hVICs and human aortic valves. Consistently, increased m6A levels were seen in calcified hVICs, and treated with 3-deazaadenosine (DAA), an inhibitor of m6A modification, significantly reduced hVIC osteogenic differentiation and calcification. In addition, we showed that silencing of ALKBH5 expression increased global m6A levels, and accelerated hVIC osteogenic differentiation and calcification, whereas overexpression of ALKBH5 resulted in the opposite effect. We demonstrated that ALKBH5 directly modulate m6A levels of TGFBR2 and its mRNA stability, leading to altered TGFBR2 expression and SMAD2 signaling in hVICs. We further showed that inhibition of TGFBR2 or knockdown of SMAD2 attenuated ALKBH5 knockdown-induced hVIC osteogenic differentiation and calcification. The expression of the m6A reader protein YTH N6-methyladenosine RNA binding protein F1 (YTHDF1) was upregulated during the process of hVIC calcification. Intriguingly, we revealed that the ALKBH5 silencing-induced increased hVIC osteogenic differentiation and calcification were abolished after knockdown of YTHDF1. These data suggest a potential role YTHDF1 in aortic valve calcification. This study showed that ALKBH5 attenuated aortic valve calcification through the TGFBR2/SMAD2 signaling pathway via direct m6A modification of TGFBR2. .

Diagnosis of bicuspid aortic valves: CT vs. TTE.

Bicuspid aortic valfves (BAV) are a relatively common cardiac abnormality, with an associated risk of aortic stenosis, aortic regurgitation and aortopathy. First-line diagnosis is via transthoracic echocardiography (TTE), which may be impacted by valve calcification and operator variability. Electrocardiogram-gated computed tomography (CT) offers an alternative form of assessment. The aim of this systematic review and meta-analysis is to evaluate the diagnostic performance of TTE versus CT for BAV. Eligible studies were retrieved from inception through to March 2024 on OVID Medline, Embase and Cochrane Library. All primary studies regarding the diagnostic performance of TTE and/or CT with regards to BAV were included. The QUADAS-2 tool was utilized for quality assessment. Sensitivity and specificity data were statistically analyzed. Of 4698 records, 19 were eligible for inclusion, and 16 had sufficient data for inclusion in the meta-analysis. There was only data regarding TTE vs. retrospectively ECG-gated CT. There was a significant difference between the sensitivity of retrospectively ECG-gated cardiac CT (95.5% (95% CI: [91.3-97.5%]) and TTE (79.7%, 95% CI: [71.6-86.0%]) for identifying BAV. The specificity was high and not significantly different for both CT and TTE (96%, 95% CI: [92.5-98.2%] and 91.3%, 95% CI: [87.3-93.8%], respectively). Retrospectively ECG-gated CT demonstrates greater sensitivity for diagnosis of BAV compared to TTE. Both modalities are non-invasive and demonstrate good specificity for excluding BAV. Given that CT scans are easily accessible, they offer a reasonable second-line investigation for diagnosis of BAV when an initial TTE is inconclusive.

Pre-interventional renal artery calcification and survival after transcatheter aortic valve implantation

The prognostic significance of renal artery calcification (RAC) is unknown in patients with severe aortic stenosis (AS) eligible for transcatheter aortic valve implantation (TAVI). RAC can be assessed by computed tomography (CT) performed during pre-interventional planning for TAVI. This study aimed at investigating the utility of RAC for predicting survival after TAVI. In this longitudinal cohort study, RAC volume was measured by CT in 268 consecutive patients with severe AS undergoing TAVI. Association of RAC with mortality was assessed using Cox regression analysis. RAC was evaluated as a binary parameter and in a supplementary analysis as a logarithmically transformed continuous variable. Over a median follow-up time of 9.6 years, 237 (88.4%) patients died, with 174 (73.4%) deaths attributable to a cardiovascular cause. RAC was highly prevalent (N = 150 (86.2%)) among patients suffering cardiovascular death. Competing risk cumulative incidence curves revealed a higher occurrence of cardiovascular death in patients with RAC (P-value = 0.008), while this was not the case for non-cardiovascular death (P-value = 0.71). RAC was independently associated with cardiovascular death (HR 1.61 [95% CI: 1.01–2.57]; P = 0.047) after adjustment for age, sex, cardiovascular risk factors, impaired renal function, and aortic valve calcification. The presence or absence of RAC rather than its volume was important in all the analyses. RAC is a strong and independent predictor of cardiovascular death in patients with severe AS undergoing TAVI. Given its favourable properties for event prediction, RAC may be considered valuable for prognostic assessment of TAVI patients.Graphical Occurence and prognostic implications of pre-interventional renal artery calcification after transcatheter aortic valve implantation. CV, cardiovascular; CVD, cardiovascular disease; LVOT, left ventricular outflow tract; CT, computed tomography; RAC, renal artery calcification; ST, sinotubular; AA, ascending aorta; TAVI, transcatheter aortic valve implantation

Macrophages in Calcific Aortic Valve Disease: Paracrine and Juxtacrine Disease Drivers.

A significant role in the pathogenesis of CAVD is played by innate immunity cells, such as macrophages. In stenotic valves, macrophages have enhanced inflammatory activity, and the population's balance is shifted toward pro-inflammatory ones. Pro-inflammatory macrophages release cytokines, chemokines, and microRNA, which can directly affect the resident valvular cells and cause valve calcification. In CAVD patients, macrophages may have more pronounced pro-inflammatory properties, enhanced not only by paracrine signals but also by juxtacrine Notch signaling and epigenetic factors, which influence the maturation of macrophages' progenitors. In this review, we observe the accumulated data on the involvement of macrophages in CAVD development via paracrine and juxtacrine interactions.

Very severe aortic valve stenosis: Diagnostic value of computed tomography aortic valve calcium scoring

Background(A) Very severe aortic valve stenosis (VSAS; Vmax ≥ 5 ​m/s, MPG ≥60 ​mmHg) is a critical condition with unfavorable clinical outcomes. Guidelines regard VSAS as one criterion for considering valve replacement in asymptomatic patients. (B) Guidelines recommend the use of aortic valve calcium (AVC) scoring as a parameter to differentiate between moderate and severe aortic valve stenosis (SAS). The aim of our study is to propose AVC thresholds for the discrimination between SAS and VSAS. MethodsData of patients from a single center who underwent transcatheter aortic valve implantation (n ​= ​523) were retrospectively analyzed. Patients with concordant AS (n ​= ​430) were divided into SAS (n ​= ​344) and VSAS (n ​= ​86) groups and compared in terms of absolute AVC and indexed AVC (body surface area; aortic valve annulus area). ResultsMean AVC was significantly higher in men (m) than in women (w), and significantly higher in VSAS than in SAS (m: SAS 3572.0 AU; VSAS 5465.0 AU; w: SAS 2252.5 AU; VSAS 3064.5 AU; all p ​< ​0,001). ROC curve analyses showed AVC to be a predictor of VSAS in both sexes (m: AUC 0.794; p ​< ​0.001; w: AUC 0.725; p ​< ​0.001), with optimal cut-off values of 3706.5 AU (m) and 2374.5 (w). Some indexed AVC had a slightly, but not relevantly, better predictive value. ConclusionThe proposed AVC thresholds – approximately 3700 AU (m) and 2400 AU (w) - showed significant predictive power to differentiate SAS from VSAS in the study cohort.

Relationship Between Clinical Parameters and Histological Features of Epicardial Adipose Tissue and Aortic Valve Calcification Assessed on Computed Tomography.

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. Inflammation and osteogenesis in EAT, reflected by high CT density, are associated with the severity of AVC representing aortic valve degeneration.

Oxidized Phospholipids and Calcific Aortic Valvular Disease

BackgroundOxidized phospholipids (OxPLs) are carried by apolipoprotein B-100–containing lipoproteins (OxPL-apoB) including lipoprotein(a) (Lp[a]). Both OxPL-apoB and Lp(a) have been associated with calcific aortic valve disease (CAVD). ObjectivesThis study aimed to evaluate the associations between OxPL-apoB, Lp(a) and the prevalence, incidence, and progression of CAVD. MethodsOxPL-apoB and Lp(a) were evaluated in MESA (Multi-Ethnic Study of Atherosclerosis) and a participant-level meta-analysis of 4 randomized trials of participants with established aortic stenosis (AS). In MESA, the association of OxPL-apoB and Lp(a) with aortic valve calcium (AVC) at baseline and 9.5 years was evaluated using multivariable ordinal regression models. In the meta-analysis, the association between OxPL-apoB and Lp(a) with AS progression (annualized change in peak aortic valve jet velocity) was evaluated using multivariable linear regression models. ResultsIn MESA, both OxPL-apoB and Lp(a) were associated with prevalent AVC (OR per SD: 1.19 [95% CI: 1.07-1.32] and 1.13 [95% CI: 1.01-1.27], respectively) with a significant interaction between the two (P < 0.01). Both OxPL-apoB and Lp(a) were associated with incident AVC at 9.5 years when evaluated individually (interaction P < 0.01). The OxPL-apoB∗Lp(a) interaction demonstrated higher odds of prevalent and incident AVC for OxPL-apoB with increasing Lp(a) levels. In the meta-analysis, when analyzed separately, both OxPL-apoB and Lp(a) were associated with faster increase in peak aortic valve jet velocity, but when evaluated together, only OxPL-apoB remained significant (ß: 0.07; 95% CI: 0.01-0.12). ConclusionsOxPL-apoB is a predictor of the presence, incidence, and progression of AVC and established AS, particularly in the setting of elevated Lp(a) levels, and may represent a novel therapeutic target for CAVD.

Elucidating common biomarkers and pathways of osteoporosis and aortic valve calcification: insights into new therapeutic targets

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 4140121: Lipoprotein(a) Local Sybthesis And Plasma Uptake Via MDFS5 in Human Calcified Valve

Background: High circulating levels of lipoprotein(a) [Lp(a)] are associated with increased risk of calcific aortic stenosis (CAS). Targeting Lp(a) metabolism holds promise for therapeutic interventions. However, the precise mechanisms by which Lp(a) accumulates on aortic valves still not fully understood. Hypothesis: Lp(a) could be synthesized in situ in human aortic valves under specific stimuli, such as calcification, in addition to being taken up from plasma via membrane receptors, including the newly identified receptor Major Facilitator Superfamily Domain Containing 5 (MFSD5). Methods: Immunohistochemistry was used to detect the Lp(a) and its receptor MFSD5 in human aortic valves from CAS patients or controls, which were non-CAS patients. Plasma Lp(a) levels were measured in individuals undergoing aortic valve resection. Human valvular interstitial cells (VICs) were cultured in procalcifying medium, with or without Lp(a) (10uM) for 14 and 21 days. Von-kossa or Alizarin Red staining were used to assess valve calcification. Expression of Lp(a) and MFSD5 was analyzed with quantitative RT-PCR and western blot. Results: Lp(a) was nearly absent in control valve site, whereas it was abundantly present in valve site from CAS patients (p＜0.05). The higher the level of Lp(a) detected, the greater the extent of calcification noted in valve site. The mRNA and protein levels of Lp(a) extracted from calcified human valves were significantly higher compared to controls. However, the concentration of plasma Lp(a) did not affect the expression of Lp(a) in valve site (p＞0.05). In vitro studies showed that Lp(a) mRNA was minimally detectable in normal VICs, but was significantly upregulated following exposure to procalcifying medium (p &lt; 0.05). Lp(a) incubation led to severer calcification than that induced by procalcifying medium alone (p &lt; 0.05). As MFSD5 was a newly identified receptor of Lp(a), we also test its expression. MDFS5 was increased in human calcified valve (p＜0.05) and calcified VICs (p＜0.05). These results showed that the Lp(a) in valve could be increased by either uptake from serum or by synthesized locally by proper stimuli. Conclusion: Our study has shown that the degree of aortic valve calcification is correlated with the level of Lp(a) in the valve site rather than in serum. We also verified MFSD5 was the receptor of Lp(a) on human valve. Targeting Lp(a) accumulation at the valve site may offer a more effective strategy for the prevention or treatment of CAS.

Abstract 4134841: A Diagnostic Pitfall: Subclavian Stenosis Mimicking Severe Aortic Stenosis on Echocardiography"

Background: Aortic stenosis (AS) is a common and serious valve disease in the elderly, often diagnosed using echocardiography. However, certain conditions can mimic AS, leading to diagnostic challenges. This case highlights the importance of a comprehensive vascular assessment in patients with atypical symptoms and echocardiographic findings suggestive of severe AS. Case Presentation: An 80-year-old female presented with progressive dizziness and double vision over the past few months. She reported a long-standing history of lower blood pressure in her right arm compared to her left. Her medical history was significant for HER2-positive intraductal breast cancer treated with neoadjuvant chemotherapy. An echocardiogram performed two months prior to presentation, using a Pedoff probe, indicated severe AS with a peak systolic velocity of 5.1 m/sec, a mean systolic gradient of 50 mm Hg, and an aortic valve area of 0.6 cm. Investigations: Given the discrepancy in blood pressure between her arms and the wide open aortic valve on the echo which dosen't corrleate with the doppler numbers, CTA neck and chest was performed, revealing a dense calcific plaque causing severe stenosis at the origin of the left subclavian artery. An angiogram confirmed &gt;75% stenosis of the left subclavian artery, which was treated with angioplasty and stent placement, resulting in &lt;10% residual stenosis. Outcome: Following the intervention, a repeat echocardiogram showed only mild calcification of the aortic valve with a mean gradient of 4 mm Hg, significantly lower than the previous findings. Discussion: This case underscores the potential for subclavian artery stenosis to mimic severe AS on echocardiography, particularly when using the Pedhoff probe. It highlights the need for clinicians to consider vascular anomalies in the differential diagnosis when echocardiographic doppler findings do not correlate with clinical symptoms or with the structural apperance of the valves. Conclusion: Comprehensive assessment and consideration of alternative diagnoses are crucial in patients with suspected severe AS, especially when using Doppler echocardiography. Awareness of the potential for subclavian artery stenosis to cause false-positive echocardiographic findings can prevent unnecessary interventions and guide appropriate management.