Aortic Valve Disease Research Articles (Page 1)

Association of cardiac reverse remodeling with prognosis after transcatheter aortic valve replacement in patients with mixed aortic valve disease.

Calcific aortic valve disease (CAVD) is characterized by a fibrocalcific remodeling of the aortic valve. This pathology is the most prevalent valvular heart disease worldwide and is associated with a poor prognosis. Despite extensive research, no pharmacological treatments are available to slow or reverse valvular degeneration, making aortic valve replacement the only current therapeutic option. This lack of clinical success may stem from an incomplete understanding of the disease's mechanisms and the limitations of current preclinical models, which do not fully replicate the complexity of CAVD and its associated risk factors and comorbidities. Indeed, while existing models offer valuable insights, a deeper understanding of CAVD requires incorporating comorbidities, gender-specific mechanisms, and dynamic cellular and tissue-level changes. This review aims to provide the reader with an overview of preclinical models developed in recent years to study CAVD, assessing their strengths and limitations. We review how these models can be used to mimic and/or investigate the cellular and molecular mechanisms involved in CAVD development, and highlight how key risk factors and comorbidities can be incorporated to enhance the translational potential of research. We hope that this approach will help guide researchers in selecting the most appropriate model for their studies, with the goal of advancing the identification of effective therapeutic candidates.

Clinical management of moderate mixed aortic valve disease.

Background: The Ross procedure has favorable outcomes in young and middle-aged patients with aortic valve disease. However, one challenge is early-onset pulmonary homograft stenosis. Perivascular leukocytic infiltration on histology indicates an inflammatory etiology. Homograft upsizing has been shown to reduce the need for reintervention, but remains imperfect. Hypothesis: We hypothesized that a prophylactic anti-inflammatory regimen in addition to homograft upsizing would reduce the incidence of homograft stenosis following the Ross procedure. Methods: Data were collected retrospectively from patients who underwent the Ross procedure at our institution between 6/2020-10/2024. Patients who had surgery 12/2022 or later were prescribed a methylprednisolone taper and a non-steroidal anti-inflammatory drug (NSAID) for 6 months. Outcomes included at least moderate pulmonic stenosis (PS), defined as peak gradient 36 mmHg or higher, and need for re-intervention. Results: A total of 103 patients were included, with 55 in the standard group and 48 patients in the NSAID group. Baseline characteristics were similar between groups. Pulmonary homograft size was higher in the NSAID group (30 mm [IQR 28,31] vs 27 mm [IQR 26,27], p<0.001). There were no major bleeding events. Two patients discontinued NSAIDs due to side effects. The incidence of at least moderate PS was significantly higher in the standard group at 20.0% versus 6.25% in the NSAID group (p=0.042). Among those who completed 6 months of NSAIDs, only 1 patient had moderate PS (2.8%). Logistic regression demonstrated NSAID use was significantly associated with a lower likelihood of PS during follow-up (OR 0.171, CI 0.018, 0.749, p=0.016). Multivariate analysis was limited by study size. Reduction in incidence of PS persisted when patients were stratified by homograft size (Figure 1). In the standard group, 3 patients (5.4%) required pulmonic valve re-intervention. No patients in the NSAID group required re-intervention, although the difference was not significant (p=0.197, Figure 2). No patients in either group died or required aortic valve re-intervention. Conclusion: Implementation of an anti-inflammatory regimen in combination with pulmonary homograft upsizing was associated with a significantly lower incidence of homograft stenosis following the Ross procedure. No patients treated with the NSAID regimen have required pulmonic re-intervention, although longer follow-up will be needed to see if the difference persists.

Introduction: Patients with aortic valve disease, such as bicuspid aortic valve (BAV), require regular echocardiography or cardiovascular (CV) MRI to monitor for complications such as valve stenosis (AS) and aortic dilation. However, repeated imaging can be burdensome and incur substantial cost. Seismocardiogram (SCG) chest acceleration measurements recorded by inexpensive wearable devices can give indicators of valve-mediated hemodynamic changes, and as such may have supplemental value for such patients. This study investigated using SCG recordings coupled with a novel machine-learned (ML) classifier for SCG signals to identify patient valve type and presence/absence of aortic valve stenosis (AS). Hypothesis: We hypothesize that accurate classification of aortic valve type and AS can be made from SCG recordings with ML analysis compared to those from standard-of-care imaging (ground truth: cardiac MRI or echo). Methods: Healthy controls (no known CV disease) and aortic valve disease patients with tricuspid (TAV), BAV, or post-repair mechanical valve who received echo or MRI (clinical CV protocol) were enrolled for same-day 2-minute wearable SCG measurement (fig. A). Standard clinical assessment of valve/flow function was used (fig. B). Informed consent was given with IRB oversight. Clinical imaging used 4D flow MRI (1.5T,1-3mm3/30-40ms) or 2D Doppler echo (1.7-3.3MHz,12-40FPS). From clinical read of valve type/function, subjects were grouped in four classes: AS (any degree), BAV no-AS, TAV no-AS, mechanical. A hybrid network with convolutional neural network and multi-layer perceptron was trained (80/20 train/test) to classify patient valve status from SCG wavelet coefficients and demographics (age/sex/height/weight). Performance was evaluated by 20-fold cross-validation. Results: Enrolment was 129 subjects (97 MRI/32 echo): 46 controls (45.9±17.4y/20F) and 83 patients (22.4±15.8y/20F; 67 BAV/6 TAV/10 mech.). Classification area-under-curve (AUC) was high for all classes (AUC≥0.79). Across all ML validations, correct classification was achieved for ≥75% of subjects. Conclusion: This evaluation of a machine-learned classifier for SCG indicate potential utility in screening for valve-mediated hemodynamic changes, which reverberate through the chest and cause altered vibrations. The low cost and ease of acquisition for SCG would make it an appealing complement to imaging as the current standard for aortic valve abnormality screening and management.

Introduction: Air and noise pollution are recognized public health concerns. However, their long-term impact on valvular heart disease (VHD) remains unclear. Methods: This study analyzed 453,413 participants from the UK Biobank. Air pollution was quantified using the air pollution score based on PM 2.5 , PM 2.5-10 , PM 10 , NO x , and NO 2 levels. Road traffic noise (L den and L night ) exposure was estimated based on baseline residential addresses. Participants were categorized into quintiles (Q1-Q5) of exposure. VHD diagnoses were identified from hospitalization and cause-of-death records. Multivariable Cox proportional hazard models were used to assess the association between pollution exposures and VHD risk, presented as hazard ratios (HR) with 95% confidence intervals (CI). Results: During a median follow-up of 13.9 years, 18,806 cases of VHD were recorded. Participants exposed to the highest levels of pollution exposures had a significantly increased risk of developing VHD compared to those in the lowest exposure group (Q5 vs. Q1: air pollution score [HR 1.73, 95% CI 1.61-1.87], PM 2.5 [HR 1.69, 95% CI 1.57-1.82], PM 2.5-10 [HR 1.43, 95% CI 1.34-1.53], PM 10 [HR 1.29, 95% CI 1.22-1.36], NO 2 [HR 1.59, 95% CI 1.47-1.71], NO X [HR 1.64, 95% CI 1.53-1.77], L den [HR 1.66, 95% CI 1.56-1.77], and L night [HR 1.67, 95% CI 1.57-1.78]). These associations persisted significantly regardless of the genetic risk to VHD and extended across all VHD subtypes, including non-rheumatic, rheumatic, aortic, mitral, tricuspid, and pulmonary valve diseases. Conclusion: This study demonstrates a significantly positive association between long-term exposure to air and noise pollution and increased VHD risk.

Introduction: Hemodynamics and wall biomechanics jointly drive ascending-aortic remodeling in bicuspid aortic valve (BAV) disease, yet most in silico studies model only flow or strain. Manual segmentations yield noisy meshes, impeding strain and computational fluid dynamics (CFD) analyses. We present an end-to-end framework integrating patient-specific CFD and dynamic strain mapping via our Bayesian remeshing algorithm, preserving geometry and eliminating manual mesh edits. Objective: Develop and validate an end-to-end approach to automate mesh generation, quantify surface strain, and enable strain mapping and patient-specific CFD in ascending aortas of normal and bicuspid aortic valves. Methods: We retrospectively analyzed 12 ECG-gated 4D CT datasets from 11 adults in a BAV study. Two observers performed semi-automated segmentation in ITK-SNAP using manual annotation, random forest voxel classification, and contour evolution; interobserver agreement—Dice coefficient, mean surface distance (MSD)—is reported as median [IQR]. Segmentations were converted to surface meshes and remeshed via a Bayesian adaptive algorithm. A reference mesh was propagated across cardiac phases using deformable registration; registration accuracy was assessed by MSD against meshes from manual segmentations. Areal strain was computed as fractional area change from end-diastole (Figure 1). Transient-dynamic CFD was performed on three patients to simulate flow and wall shear stress (WSS); aortic growth, reported in Figure 2, was derived from follow-up CT-based maximum diameters. Results: Table 1 summarizes patient characteristics. Manual segmentations showed strong interobserver agreement (Dice 0.96 [0.95–0.99]; MSD 0.45 mm [0.17–0.70]). Propagated meshes had a median MSD of 0.42 mm [IQR 0.34–0.74] (n = 24) against manual references. Peak areal strain ranged 7–23%, and WSS 2–6 Pa. Figure 2 shows strain and WSS maps for two representative BAV cases. In these cases, lower peak WSS/velocity coincided with faster radial growth over subsequent scans, mirroring inverse WSS-growth trends seen in larger BAV cohorts. Conclusions: Our 4D CT workflow produces spatially aligned WSS and areal-strain maps, without manual mesh edits. Preliminary results suggest higher peak WSS may be negatively associated with aortic growth rate, consistent with prior studies. This proof-of-concept demonstrates technical feasibility and motivates further study of WSS-strain interaction as a predictor of BAV aortic remodeling.

Introduction: Concomitant mitral stenosis (MS) is prevalent in ~10-15% of patients undergoing transcatheter aortic valve replacement (TAVR). There has been conflicting literature on the effect of multivalvular heart disease on TAVR outcomes. TAVR can induce geometric changes in the mitral apparatus, such as annular narrowing and anterior mitral leaflet restriction, which may aggravate MS or unmask previously subclinical disease. Our study aims to investigate the impact of coexisting MS on patients who undergo TAVR. Methods: Using the National Inpatient Sample (NIS) from 2020 to 2022, we retrospectively identified patients who had undergone TAVR as a primary procedure. We excluded those with concomitant valvular procedures, prior PPM, urgent procedures, and prior surgical valve repair. Co-existing non-rheumatic MS was identified, and two cohorts were created. Baseline characteristics were compared using t-tests. A multivariable logistic regression model with a 2-sided significance level of 0.05 was used. All baseline characteristics were included in the multivariate adjustment. Results: A total of 253,409 weighted hospitalizations for TAVR were identified. 1.05% (2,668) had non-rheumatic MS. The baseline characteristics are given in image-1. Patients with TAVR and concomitant MS were more likely to be female (64.8% vs 42.1%), have underlying HF (80.7% vs 70.6%), and have ESRD (7.3% vs 3.6%). On multivariate analysis, the concomitant MS were more likely to have acute respiratory failure (aOR 1.76, p < 0.001), heart block (aOR 1.81, p < 0.001), and PPM implantation (aOR 1.4, p = 0.005). This cohort was less likely to have a post-procedure systolic/diastolic heart failure exacerbation (aOR 0.58, 95% CI 0.42 to 0.82, p = 0.001). There were no differences in in-hospital mortality. Device embolization was not reported due to the low event rate. The results of the multivariate regression are shown in image-2. Conclusion: TAVR is associated with adverse clinical outcomes in patients with MS. However, there is no difference in in-hospital mortality. While the MS + TAVR cohort may have some hemodynamic improvement, as evident by a lower incidence of acute HF, there is an increased risk of PPM placement due to the TAVR valve frame and severe annular calcification affecting the conduction bundles. These findings underscore the importance of preprocedural assessment and risk stratification for patients with combined aortic and mitral valve disease.

Introduction: Calcific aortic valve disease (CAVD) is one of the most common valvular diseases, predominantly characterized by progressive calcification of the aortic valve. Although minimally invasive treatments such as transcatheter aortic valve replacement (TAVR) have advanced rapidly, there remains a lack of effective strategies to delay or reverse the progression of CAVD. This study investigates underlying molecular mechanisms of CAVD to explore new therapeutic avenues. Methods: Three publicly available human bulk RNA-seq datasets related to CAVD were analyzed. Genes upregulated across all three datasets were identified and intersected to find shared targets. Aortic valve tissues from healthy individuals and CAVD patients were collected, and Western blotting was used to validate expression levels of candidate genes. In vitro, small interfering RNA (siRNA) was used to knock down the target gene in valvular interstitial cells (VICs), evaluating its effect on calcification markers. In vivo, we generated ANPEP knockout mice (ANPEP-/-/ApoE-/-) via breeding and subjected them to a high-fat diet to induce valve calcification. Alizarin Red S staining was performed to assess the extent of calcification. Results: Only two genes—ANPEP and CTHRC1—were commonly upregulated across all datasets. CTHRC1 has been previously studied in CAVD, while ANPEP, a zinc-dependent type II metalloprotease primarily expressed on the cell membrane, has not. Western blot analysis confirmed significantly increased ANPEP expression in calcified human valve tissue. siRNA-mediated knockdown of ANPEP in VICs led to marked reductions in calcification markers such as BMP2 and RUNX2, suggesting its role in calcification. In vivo, ANPEP-deficient mice showed significantly less aortic valve calcification, aligning with in vitro findings. Conclusion: These results indicate that ANPEP plays a critical role in the progression of CAVD and may serve as a promising target for the diagnosis and treatment of aortic stenosis due to valve calcification.

Calcific aortic valve disease (CAVD) is a progressive disorder where molecular alterations occur long before visible calcification, making early biomarkers essential. Extracellular vesicles (EVs) have gained attention as stable biomarkers due to their lipid bilayer, which protects proteins, lipids, and RNAs, ensuring reliable detection even in archived samples. This review highlights the role of EVs as biomarkers and delivery tools in CAVD. EVs derived from valvular endothelial, interstitial, and immune cells carry disease-specific signatures, including osteogenic proteins (BMP-2, Annexins), inflammatory miRNAs (miR-30b, miR-122-5p), and lipid mediators. These reflect early pathogenic processes before macroscopic calcification develops. Their presence in minimally invasive samples such as blood, urine, or saliva facilitates diagnosis, while their stability supports long-term monitoring of disease progression and therapeutic response. Advances in purification and single-EV analysis increase specificity, though challenges remain in standardizing methods and distinguishing CAVD-derived EVs from those in atherosclerosis. Beyond diagnostics, engineered EVs show promise as therapeutic carriers. Delivery of anti-calcific miRNAs or combined RNA cargos has reduced calcification and inflammation in preclinical models. Overall, EVs act as molecular mirrors of CAVD, enabling early diagnosis, risk stratification, and novel therapeutic strategies. Yet, clinical translation requires technical refinement and validation of the disease-specific signatures.

Background: Calcific aortic valve disease (CAVD) is a leading cause of heart failure and cardiovascular mortality worldwide. While disruption of circadian rhythm by means of shift work has been associated with cardiovascular disease in humans, its role in CAVD remains unclear. Objective: To explore the correlation between shift work and CAVD, elucidate the mechanism of circadian rhythm disruption caused by shift work in promoting aortic valve calcification, and discover new strategies for the treatment of CAVD. Methods and results: The cohort study including 263 910 participants without valvular heart disease at baseline in the UK Biobank demonstrated that shift work exposure was associated with a higher risk of aortic stenosis (AS) [hazard ratio (HR) 1.21, 95% confidence interval (Cl) 1.06-1.38]. ApoE -/- mice were exposed to either regular light-dark cycles or weekly alternating light-dark cycles (12 hours shifts), as a well-established model for shift work. After 24-week high fat diet feeding, more severe aortic valve calcification was observed in mice exposed to alternating light-dark cycles, with increased transvalvular flow velocity, thickened valve leaflets, and elevated collagen fiber and calcium deposition within the valves. Alternate of the light-dark cycle disrupted the expression of circadian clock genes, particularly leading to downregulation of Bmal1 (brain and muscle Arnt-like protein 1). Genetic knockout of Bmal1 in mice markedly exacerbated aortic valve calcification, which was not influenced by light conditions. In parallel, silencing of BMAL1 promoted osteogenic differentiation of human aortic valve interstitial cells. Mechanistically, BMAL1 functioned as a transcription factor driving SEMA6D expression. Under the influence of downregulation of BMAL1 expression, the BMAL1-SEMA6D-PPARγ axis was inhibited, which promoted the progression of aortic valve calcification. Besides, SR8278 restored BMAL1 expression, attenuating calcification in vivo and inhibiting TNF-α-induced osteogenesis in vitro. Conclusion: Shift work exposure is associated with increased AS risk. Activation of TNF signaling pathway and downregulation of BMAL1 expression promotes aortic valve calcification by inhibiting the BMAL1-SEMA6D- PPARγ axis under weekly alternating light-dark cycles. The BMAL1 agonist SR8278 may serve as a potential adjuvant therapy for CAVD. Keywords: Calcific aortic valve disease, Circadian rhythm, shift work, TNF signaling, BMAL1

Introduction: Calcific aortic valve disease (CAVD) is a progressive condition that leads to aortic stenosis, heart failure, and premature death. Emerging evidence indicates that oxidative stress plays a significant role in the pathophysiology of CAVD by promoting damage to the endothelium lining the aortic valve. Our previous data provided evidence that sortilin orchestrates a complex intracellular signaling pathway culminating in endothelial dysfunction in mice through increased ROS production. Research Questions: To unveil the potential involvement of sortilin in the molecular mechanisms linking endothelial injury and oxidative stress in the progression of CAVD. Methods: Isolated human valve endothelial cells were used to identify the molecular mechanisms in vitro. Göttingen minipigs were randomly assigned to either a standard diet (SD) or a diet high in fat and cholesterol (HF) for 20 weeks. During this period, they received oral administration of either a placebo or the sortilin inhibitor AF38469. Blood samples were collected at baseline, during, and at the end of treatment for biochemical and oxidative stress marker analyses. Aortic cusps were analyzed histologically for cellularity, collagen, fibrosis, and calcification. Immunohistochemistry and Western blot assessed oxidative stress and osteoblast markers. Vascular reactivity studies evaluated endothelial function in isolated resistance vessels. Results: Immunohistochemistry revealed that the HF diet compromised endothelial integrity on the aortic valve surface, while sortilin inhibition preserved it. Furthermore, the HF diet group exhibited increased oxidative stress, activation of myofibroblast/osteoblast phenotypes, and mineralization in the valve, all of which were reduced by the sortilin inhibitor. Moreover, AF38469 significantly prevented the increased plasma cholesterol ( p< 0.0001) and triglyceride ( p< 0.0001) levels as well as the endothelial dysfunction observed in the placebo-treated HF diet group. Conclusions: Our data suggest that sortilin negatively regulates valvular degeneration by influencing the destruction of endothelial integrity, the increase in inflammation and oxidative stress, thereby highlighting its therapeutic potential in CAVD.

Coronary computed tomography-derived valve calcification is becoming increasingly important in the multi-modality assessment of valvular disease, especially in aortic and mitral valve disease. Separately, natural antibodies targeted against malondialdehyde-modified low-density lipoprotein (MDA-LDL), an important subset of all oxidized LDLs, are related to fewer atherosclerosis and cardiovascular events. This study sought to investigate the association between the prevalence of aortic and mitral valve calcification with IgG and IgM anti-MDA-LDL antibodies. In a substudy of the multicenter randomized controlled SCOT-HEART trial (Scottish computed tomography of the heart), blood biomarkers were measured using laboratory-developed enzyme-linked immunosorbent assays and assessed in tertiles, with adjustment for the ASSIGN cardiovascular risk score. In 830 patients (53% male, 57.6±9.8 years) with a heavy burden of cardiovascular risk factors, the highest tertile of IgM anti-MDA-LDL was associated with a lower prevalence of aortic valve calcification (odds ratio, 0.59 [95% CI, 0.36-0.96], P=0.04) and mitral valve calcification (odds ratio, 0.26 [95% CI, 0.07-0.72], P=0.02). The highest tertile of IgG anti-MDA-LDL was associated with a lower prevalence of mitral valve calcification (odds ratio, 0.36 [95% CI, 0.10-0.99], P=0.05), but not aortic calcification. Anti-MDA-LDL antibody levels were associated with a lower prevalence of aortic and mitral valve calcification. Assessment of these novel biomarkers may be useful in screening patients for valve calcification, as well as providing novel insights into potential pathological relationships.

BackgroundAortic valve interstitial cells (VICs) are considered a highly plastic heterogeneous mesenchymal cell population. Although previous studies have demonstrated their potential to differentiate into myofibroblasts, osteoblasts, chondrocytes, and adipocytes, their ability to differentiate into endothelial cells has not been confirmed. Notably, normal aortic valve tissue is avascular, but in the diseased valves of patients with calcific aortic valve disease (CAVD), we often find cells with an endothelial phenotype, but the origin of these cells is unclear.MethodsWe performed paraffin section immunofluorescence analysis on calcified aortic valves from 16 patients with CAVD. Primary VICs and valve endothelial cells (VECs) were isolated from normal porcine aortic valves. Endothelial cell-related functional assays, including in vivo Matrigel plug assay and in vitro tube formation assay, demonstrated the acquisition of endothelial functions by VICs. Transcriptome sequencing, western blot, qPCR, and immunofluorescence were used to identify the molecular mechanisms underlying mesenchymal-endothelial transition (MEndT). We constructed a CAVD mouse model by wire injury using Col1a2-CreERT: R26R-tdTomato mice. Finally, our results were further validated using publicly available single-cell sequencing data related to CAVD.ResultsWe identified a rarely discussed population of CD31-positive and α-SMA-negative non-vascular structural cells in the calcified aortic valves. Following osteogenic stimulation, we demonstrated through in vitro and in vivo experiments that VICs showed increased expression of endothelial-associated markers and acquired endothelial cell-related functions. We demonstrated that the IGF1-PI3K-AKT-HIF pathway mediates MEndT. Furthermore, in the CAVD mouse model, we confirmed that intraperitoneal injection of recombinant mouse IGF1 protein significantly increased the proportion of endothelial cells of mesenchymal origin in the aortic valve and alleviate disease progression; conversely, intraperitoneal administration of the IGF1R inhibitor BMS-536924 reversed this effect. Analysis of single-cell sequencing data from two different CAVD datasets revealed that as valve interstitial cells differentiate toward an osteogenic lineage, they also enrich biological processes related to endothelial cell function.ConclusionsWe provide the first evidence that VICs have the capability to undergo endothelial transition under calcific conditions and that MEndT occurs in aortic valve of the CAVD mouse model. These findings reveal the presence of MEndT in CAVD, offering a potential therapeutic target.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12916-025-04433-z.

Mid-Term Experience With 1,196 Ozaki Procedures.

To evaluate the percentage of adults with congenital heart disease (CHD) who are restratified according to classification of complexity classification with CT and/or CMR after an initial echocardiographic assessment. Accurate stratification of CHD complexity is relevant to determining the treatment. Echocardiography is the first-line imaging modality; nevertheless, the added value of computed tomography (CT) and cardiac magnetic resonance (CMR) as complementary modalities to restratify CHD complexity has not been fully explored. We conducted a cross-sectional study of adult patients from the record CHD Unit in a third-level cardiology hospital from 2021 to 2024. CHD patients were classified according to the European Society of Cardiology (ESC) guidelines. We compared initial echocardiographic findings with CT and/or CMR using the kappa-statistic. Among 889 patients that fulfilled the inclusion criteria (women: 57%; mean age: 38.3 ± 14.4 years; genetic syndrome: 4%), the most common CHD were isolated congenital aortic valve disease and bicuspid aorta (n = 127), secundum atrial septal defect (n = 105), and tetralogy of Fallot (n = 90). The number and percentage of patients in each complexity category were mild: 180 (20.2%), moderate: 532 (59.9%), and severe: 177 (19.9%). Ten patients (1%) were restratified: 9 from the mild to moderate category and 1 from the moderate to mild category. Both imaging modalities showed strong agreement (Kappa: 0.979, 95% CI: 0.967-0.990). Restratification of adult CHD occurred in a low percentage of cases. Our results suggest that in specialized centers, echocardiographic findings are comparable to CT and/or CMR findings.

Background: Surgical aortic valve replacement (SAVR) is the main treatment for severe aortic valve disease, the most common valvular heart disease worldwide. Methods: We evaluated the in-hospital mortality risk factors and predictors following on-pump SAVR. We retrospectively reviewed data from consecutive patients treated at a tertiary center from 2022 to 2024, focusing on routine hematological data and inflammatory indexes, alongside established factors. Results: Postoperative vasoactive-inotropic score (VIS) (OR 1.058, CI 95%: 1.007–1.112), platelet count (OR 1.033, CI 95%: 1.002–1.064), lymphocyte counts (OR 3.532, CI 95%: 1.507–8.278), and perioperative fresh frozen plasma transfusion (OR 1.335, CI 95%: 1.068–1.669) were independent risk factors for SAVR in-hospital mortality. VIS best predicted the endpoint (AUC 0.929, p = 0.001). Postoperative platelet count and platelet-to-lymphocytes ratio (PLR) outperformed the additive EuroSCORE in predicting the outcome, but not EuroSCORE II. Conclusions: Although EuroSCORE II remained superior to inflammatory indexes in predicting in-hospital death, the dynamic postoperative monitoring provided added value beyond static preoperative risk scores. This dynamic approach supported personalized monitoring and targeted therapeutic interventions. Postoperative VIS, platelet, lymphocyte counts, and PLR represent dynamic, low-cost predictors of in-hospital mortality after on-pump SAVR, offering a complementary value to EuroSCORE II–based models.

Calcific aortic valve disease is an active process characterized by compromised endothelial integrity and obstructive calcific lesions, whose emergence is poorly understood. Valves experience an equiaxial stretch in regions susceptible to calcific lesion formation, but mechanobiological mechanisms are not tested. Here, we analyze how cyclic strain regulates interstitial (PAVIC) and endothelial (PAVEC) interactions in 3D environments. Equiaxial cyclic strain was applied to 3D cultures of PAVEC, PAVIC, or PAVEC-PAVIC cocultures over 7 days in control or osteogenic media (OGM) conditions. Cell phenotype and tissue remodeling were quantitatively compared to mechanically strained (anchored) but nonstretched controls. Cyclic stretch shifted PAVIC from myofibroblastic to osteogenic phenotype with OGM, while in PAVEC, the cyclic stretch increased apoptosis. Intriguingly, we determined that PAVEC-PAVIC in coculture with OGM develop raised 3D calcified lesions (∼25-50% of gel thickness) similar to lesions seen in vivo. Lesions contained radially reoriented collagen fibers with similarly aligned PAVIC, increased local PAVEC density, and decreased PAVEC cell area. The cyclic stretch synergistically increased the lesion number and height but not the projected area. The cyclic stretch enhanced osteogenic differentiation (Runx2 and OPN) but not myofibroblastic differentiation (aSMA) in cocultures. It significantly increased VE-cadherin and eNOS and reduced VCAM1, but with OGM, the eNOS expression reduced. Finally, we determined that ROCK inhibition abolished 3D lesion formation and myofibroblastic and osteoblastic differentiation, supporting the idea that these integrated behaviors were mechanobiologically mediated by cell migration and/or contractility. Our results identify that the 3D cyclic stretch induces emergent PAVEC-PAVIC interactions not capturable in less complex environments that together control 3D calcific lesion morphology.

Male sex and aging are risk factors for fibro-calcific aortic valve disease (FCAVD), indicating an understudied influence of sex hormones. Valvular interstitial cells (VICs) from female and male donors were isolated and exposed to pro-calcifying medium (PM), and the expression of matrix gla protein (MGP), fibronectin (FN1) and bone morphogenic protein 2 (BMP2) was analyzed. The effect of sex hormones on hydroxyapatite (HA) deposition by VICs was also analyzed. Exposure to PM increased MGP gene expression in male (n = 5, +5.8-fold, p = 0.031), and female VICs (n = 6, +4.9-fold, p = 0.004). In female VICs a +3.5-fold MGP increase accompanied the transition from the fibrotic to the calcific phase (p = 0.022 vs. males) while in male VICs the increase was delayed to the calcific phase. Female VICs upregulated FN1 (+1.8-fold, p = 0.003), while male VICs upregulated BMP2 (+3.7-fold, p = 0.05). 5α-dihydrotestosterone increased HA deposition +6.3-fold in male and +5.2-fold in female VICs (p ≤ 0.001 and p < 0.04, respectively). It further decreased BMP2 (p < 0.001) in male VICs and increased MGP in female VICs (p = 0.087). Female VICs decreased HA deposition when exposed to progesterone (−2.4-fold, p = 0.037 vs. PM) and estrogen (−2.0-fold, p = 0.072). In summary, VICs show donor-sex-specific gene expression which is modifiable by 5α-dihydrotestosterone. This needs to be considered when designing in vitro regulatory studies.

Background Non-rheumatic calcific aortic valve disease (NRCAVD) has emerged as a significant health challenge globally, with China’s rapidly aging population bearing a disproportionate burden, necessitating comprehensive epidemiological analysis to guide public health strategies. Methods Utilizing data from the Global Burden of Disease (GBD) database 2021, we examined the incidence, prevalence, mortality, and disability-adjusted life years (DALYs), along with their corresponding age-standardized rates (ASRs), of NRCAVD in China from 1990 to 2021 and compared these data with global trends. The analysis employed joinpoint regression to calculate the estimated annual percentage change (EAPC) and average annual percentage change (AAPC) for evaluating NRCAVD trends over the past 32 years. Additionally, we employed the Bayesian age–period–cohort model to project these trends through 2050. Results The age-standardized incidence and prevalence rates of NRCAVD in China increased from 1.42 to 2.52 per 100,000 and 17.24 to 32.68 per 100,000, respectively, between 1990 and 2021. Favorably, the age-standardized mortality and disability-adjusted life year rates of NRCAVD decreased from 0.10 to 0.07 per 100,000 and 2.42 to 1.92 per 100,000, respectively. The rates were higher in male individuals than in female individuals across all four metrics over the study period. In China, the estimated annual percentage changes for incidence, prevalence, mortality, and disability-adjusted life years were 2.04, 2.33, −1.34%, and −1.06%, respectively, while the average annual percentage changes for incidence, prevalence, mortality, and disability-adjusted life years were 0.04, 0.50, 0.00%, and −0.02%, respectively. The projections from Bayesian age–period–cohort model showed that the burden of NRCAVD is expected to continue through 2050. Conclusion The burden of NRCAVD in China has dramatically increased from 1990 to 2021, with a notable rise associated with aging. Male individuals appear to be more susceptible than female individuals and face higher mortality risks associated with NRCAVD in China. The forecast suggests that this trend will persist until 2050, highlighting NRCAVD as a significant public health challenge in China over the next three decades.