Progression Of Aortic Valve Stenosis Research Articles

Y chromosome linked UTY modulates sex differences in valvular fibroblast methylation in response to nanoscale extracellular matrix cues.

Aortic valve stenosis (AVS) is a progressive disease wherein males more often develop valve calcification relative to females that develop valve fibrosis. Valvular interstitial cells (VICs) aberrantly activate to myofibroblasts during AVS, driving the fibrotic valve phenotype in females. Myofibroblasts further differentiate into osteoblast-like cells and produce calcium nanoparticles, driving valve calcification in males. We hypothesized the lysine demethylase UTY (ubiquitously transcribed tetratricopeptide repeat containing, Y-linked) decreases methylation uniquely in male VICs responding to nanoscale extracellular matrix cues to promote an osteoblast-like cell phenotype. Here, we describe a hydrogel biomaterial cell culture platform to interrogate how nanoscale cues modulate sex-specific methylation states in VICs activating to myofibroblasts and osteoblast-like cells. We found UTY modulates the osteoblast-like cell phenotype in response to nanoscale cues uniquely in male VICs. Overall, we reveal a novel role of UTY in the regulation of calcification processes in males during AVS progression.

Lipoprotein(a) and Calcific Aortic Valve Stenosis Progression

There are currently no pharmacological treatments available to slow hemodynamic progression of aortic stenosis. Plasma lipoprotein(a) concentrations predict incident aortic stenosis but its association with hemodynamic progression is controversial. To determine the association between plasma lipoprotein(a) concentrations and hemodynamic progression in patients with aortic stenosis. The study included patients with aortic stenosis from 5 longitudinal clinical studies conducted from March 2001 to March 2023 in Canada and the UK. Of 757 total patients, data on plasma lipoprotein(a) concentrations and rates of hemodynamic progression assessed by echocardiography were available for 710, who were included in this analysis. Data were analyzed from March 2023 to April 2024. Cohort-specific plasma lipoprotein(a) concentration tertiles. Hemodynamic aortic stenosis progression on echocardiography as assessed by annualized change in peak aortic jet velocity, mean transvalvular gradient, and aortic valve area. Among the included patients, 497 (70%) were male and 213 (30%) were female. The mean (SD) age was 65.2 (13.1) years. Patients in the top lipoprotein(a) tertile demonstrated 41% (estimate, 1.41; 95% CI, 1.13-1.75) faster progression of peak aortic jet velocity and 57% (estimate, 1.57; 95% CI, 1.18-2.10) faster progression of mean transvalvular gradient than patients in the bottom tertile. There was no evidence of heterogeneity across the individual cohorts. Progression of aortic valve area was comparable between groups (estimate, 1.23; 95% CI, 0.71-2.12). Similar results were observed when plasma lipoprotein(a) concentrations were treated as a continuous variable. In this study, higher plasma lipoprotein(a) concentrations were associated with faster rates of hemodynamic progression in patients with aortic stenosis. Lowering plasma lipoprotein(a) concentrations warrants further investigation in the prevention and treatment of aortic stenosis.

Angiopoietin-2 as a potential biomarker predictive of aortic valve stenosis progression

Angiopoietin-2 as a potential biomarker predictive of aortic valve stenosis progression

Association between evolocumab use and slow progression of aortic valve stenosis.

No medications have been reported to inhibit the progression of aortic valve stenosis (AS). The present study aimed to investigate whether evolocumab use is related to the slow progression of AS evaluated by serial echocardiography. This was a retrospective observational study from 2017 to 2022 at Yokohama City University Medical Center. Patients aged ≥ 18 with moderate AS were included. Exclusion criteria were (1) mild AS; (2) severe AS defined by maximum aortic valve (AV) velocity ≥ 4.0m/s; and/or (3) no data of annual follow-up echocardiography. The primary endpoint was the association between evolocumab use and annual changes in the maximum AV-velocity or peak AV-pressure gradient (PG). A total of 57 patients were enrolled: 9 patients treated with evolocumab (evolocumab group), and the other 48 patients assigned to a control group. During a median follow-up of 33months, the cumulative incidence of AS events (a composite of all-cause death, AV intervention, or unplanned hospitalization for heart failure) was 11% in the evolocumab group and 58% in the control group (P = 0.012). Annual change of maximum AV-velocity or peak AV-PG from the baseline to the next year was 0.02 (-0.18 to 0.22) m/s per year or 0.60 (-4.20 to 6.44) mmHg per year in the evolocumab group, whereas it was 0.29 (0.04-0.59) m/s per year or 7.61 (1.46-16.48) mmHg per year in the control group (both P < 0.05). Evolocumab use was associated with slow progression of AS and a low incidence of AS events in patients with moderate AS.

Dietary Vitamin K1 Intake and Incident Aortic Valve Stenosis.

Leaflet calcification contributes to the development and progression of aortic valve stenosis. Vitamin K activates inhibitors of vascular calcification and may modulate inflammation and skeletal bone loss. Therefore, we aimed to determine whether higher dietary intakes of vitamin K1 are associated with a lower incidence of aortic stenosis. In the Danish Diet, Cancer and Health study, participants aged 50 to 64 years completed a 192-item food frequency questionnaire at baseline, from which habitual intakes of vitamin K1 were estimated. Participants were prospectively followed using linkage to nationwide registers to determine incident aortic valve stenosis (primary outcome) and aortic stenosis with subsequent complications (aortic valve replacement, heart failure, or cardiovascular disease-related mortality; secondary outcome). In 55 545 participants who were followed for a maximum of 21.5 years, 1085 were diagnosed with aortic stenosis and 615 were identified as having subsequent complications. Participants in the highest quintile of vitamin K1 intake had a 23% lower risk of aortic stenosis (hazard ratio, 0.77 [95% CI, 0.63-0.94]) and a 27% lower risk of aortic stenosis with subsequent complications (hazard ratio, 0.73 [95% CI, 0.56-0.95]), compared with participants in the lowest quintile after adjusting for demographics and cardiovascular risk factors. In this study, a high intake of vitamin K1-rich foods was associated with a lower incidence of aortic stenosis and a lower risk of aortic stenosis with subsequent complications.

Abstract 16885: Progression of Aortic Valve Stenosis in Atrial Fibrillation versus Sinus Rhythm: Implications for Clinical Practice and Severe Aortic Stenosis Diagnosis

Introduction: Rate of aortic stenosis (AS) progression in patients with concurrent atrial fibrillation (AF) has not been previously described. Objectives: To describe changes over time in aortic valve area (AVA) and associated hemodynamics during AS progression in patients in AF versus sinus rhythm (SR). Methods: Patients with AVA ≤ 1 cm 2 and preserved left ventricular ejection fraction ≥50% were identified from the Mayo Clinic Echocardiographic Laboratory Database. Serial echocardiograms prior to the development of AVA ≤ 1 cm 2 (Time 0) were examined. Inverse probability weighting was used for statistical analysis. Results: A total of 166 patients were included (SR=79 and AF=87), mean age 78.1 ± 7.8 years, females 31%. The rates of AVA reduction (-0.14±0.01 vs -0.12±0.01 cm2/year, p=0.31) and increase in trans-aortic peak velocity (+0.23 ± 0.02 vs +0.22 ± 0.02 m/sec, p=0.55) and mean gradient (MG) (3.9 ± 0.3 vs 3.8 ± 0.4 mmHg, p=0.83) did not differ between AF and SR (Figure 1). However, AF was associated with systematically lower forward stroke volume index (SVi), peak velocity and MG for the same AVA compared to SR (p&lt;0.04 for all) throughout AS progression. When AVA reached 1 cm 2 , SVi (38.8±6.6 vs 45.7 ±8.9, p=0.02), peak velocity (3.9 ± 0.6 vs 4.1 ± 0.6 m/sec, p=0.04) and MG (36.6±10.9 vs 41±12.8 mmHg, p=0.03) were lower in AF compared to SR. Conclusions: The rate of AS progression was not different in AF versus SR. However, forward flow was systematically lower in AF resulting in discordant AS during AS progression and when AVA reached 1 cm 2 . Doppler velocity and MG criteria for severe AS appear to be lower in AF versus SR which has implications for timely diagnosis of severe AS and patient management.

Increasing baseline aortic valve peak flow velocity is associated with progression of aortic valve stenosis in osteoporosis patients—a possible link to low vitamin D status

PurposeThe purpose of this study was to investigate the morphological characteristics of the aortic valve and identify factors associated with the progression of aortic valve stenosis (AS) in osteoporosis patients.MethodsIn this single-center prospective cohort study, we recruited 10 patients (mean age: 75 ± 7 years, 90% female) who were taking anti-resorptive medicines at the outpatient clinic of University of Miyazaki Hospital, Japan. Baseline assessments, including transthoracic echocardiogram, blood sampling, and dual energy X-ray absorptiometry, were performed. Follow-up assessments were conducted at 6, 12, 18, and 24 months.ResultsDuring the 2-year follow-up, three patients with aortic valve peak flow velocity (AV PFV) ≥2 m/s at baseline developed moderate AS, which is defined as AV PFV ≥3 m/s. However, seven patients with AV PFV <2 m/s did not exhibit any progression of AS. There were significant variations in terms of bone mineral density, T-score values, and biomarkers associated with bone turnover (i.e., bone alkaline phosphatase, tartrate-resistance acid phosphatase-5b) among the enrolled patients, but none of these factors were found to be associated with the progression of AS. All patients exhibited low vitamin D status, with a median level of 16.1 ng/mL (25th percentile, 9.7 ng/mL; 75th percentile, 23 ng/mL). The baseline levels of AV PFV values were negatively correlated with 25-hydroxyvitamin D levels, determined by univariate linear regression analysis (beta coefficient = -0.756, 95% confidence interval, -0.136 ̶ -0.023, p = 0.011).ConclusionOur data suggest that low vitamin D status might be a potential risk factor for the progression of AS in osteoporosis patients undergoing treatment with anti-resorptive medicines.SummaryElderly patients with osteoporosis patients exhibited a subset of aortic valve stenosis. Our data suggest that the baseline aortic valve peak flow velocity predicts the progression of aortic valve stenosis, and there might be an association between the progression and the co-existing low vitamin D status in these patients.

A Rabbit Aortic Valve Stenosis Model Induced by Direct Balloon Injury

Animal models are emerging as an important tool to understand the pathologic mechanisms underlying aortic valve stenosis (AVS) because of the lack of access to reliable sources of diseased human aortic valves. Among the various animal models, AVS rabbit models are one of the most commonly used in large animal studies. However, traditional AVS rabbit models require a long-term period of dietary supplementation and genetic manipulation to induce significant stenosis in the aortic valve, limiting their use in experimental studies. To address these limitations, a new AVS rabbit model is proposed, in which stenosis is induced by a direct balloon injury to the aortic valve. The present protocol describes a successful technique for inducing AVS in New Zealand white (NZW) rabbits, with step-by-step procedures for the preparation, the surgical procedure, and the post-operative care. This simple and reproducible model offers a promising approach for studying the initiation and progression of AVS and provides a valuable tool for investigating the underlying pathological mechanisms of the disease.

Molecular Linkage under the Bicuspid Aortic Valve with Dyslipidemia.

Dyslipidemia is correlated with diverse cardiovascular problems, such as obesity, hypertension, and atherosclerosis, which are summarized as metabolic syndrome. Bicuspid aortic valve (BAV), as one of the congenital heart defects, is shown to influence approximately 2.2% of the general population worldwide, inducing the severe pathological development of aortic valve stenosis (AVS) or aortic valve regurgitation (AVR), and also to aortic dilatation. Notably, emerging evidence showed that BAV was correlated with not only the aortic valve and wall diseases but also the dyslipidemic related cardiovascular disorders. Recent results also proposed that multiple potential molecular mechanisms inducing the progression of dyslipidemia played important roles in BAV and the progression of AVS. Several altered serum biomarkers under dyslipidemic condition, including higher low-density lipoprotein cholesterol (LDL-C), higher lipoprotein (a) [Lp(a)], lower high-density lipoprotein cholesterol (HDL-C), and different pro-inflammatory signaling pathways, have proposed to embrace a vital function in the development of BAV correlated cardiovascular diseases. In this review, different molecular mechanisms which embrace an important role in personalized prognosis in the subjects with BAV was summarized. The illustration of those mechanisms might facilitate an accurate follow-up for patients with BAV and give new pharmacological strategies to improve development of dyslipidemia and BAV.

Aortic valve stenosis progression rate according to baseline severity: A systematic review and meta-analysis

Aortic valve stenosis progression rate according to baseline severity: A systematic review and meta-analysis

Aortic Stenosis Progression: A Systematic Review and Meta-Analysis

BackgroundAortic valve stenosis is a progressive disorder with variable progression rates. The factors affecting aortic stenosis (AS) progression remain largely unknown. ObjectivesThis systematic review and meta-analysis sought to determine AS progression rates and to assess the impact of baseline AS severity and sex on disease progression. MethodsThe authors searched Medline, Embase, and the Cochrane Central Register of Controlled Trials from inception to July 1, 2020, for prospective studies evaluating the progression of AS with the use of echocardiography (mean gradient [MG], peak velocity [PV], peak gradient [PG], or aortic valve area [AVA]) or computed tomography (calcium score [AVC]). Random-effects meta-analysis was performed to evaluate the rate of AS progression for each parameter stratified by baseline severity, and meta-regression was performed to determine the impact of baseline severity and of sex on AS progression rate. ResultsA total of 24 studies including 5,450 patients (40% female) met inclusion criteria. The pooled annualized progression of MG was +4.10 mm Hg (95% CI: 2.80-5.41 mm Hg), AVA −0.08 cm2 (95% CI: 0.06-0.10 cm2), PV +0.19 m/s (95% CI: 0.13-0.24 m/s), PG +7.86 mm Hg (95% CI: 4.98-10.75 mm Hg), and AVC +158.5 AU (95% CI: 55.0-261.9 AU). Increasing baseline severity of AS was predictive of higher rates of progression for MG (P < 0.001), PV (P = 0.001), and AVC (P < 0.001), but not AVA (P = 0.34) or PG (P = 0.21). Only 4 studies reported AS progression stratified by sex, with only PV and AVC having 3 studies to perform a meta-analysis. No difference between sex was observed for PV (P = 0.397) or AVC (P = 0.572), but the level of confidence was low. ConclusionsThis study provides progression rates for both hemodynamic and anatomic parameters of AS and shows that increasing hemodynamic and anatomic baseline severity is associated with faster AS progression. More studies are needed to determine if sex differences affect AS progression. (Aortic Valve Stenosis Progression Rate: A Systematic Review and Meta-Analysis; CRD42021207726)

Abstract 12076: Longitudinal Echocardiographic Analysis of Aortic Valve Stenosis Progression

Introduction: Despite its high prevalence, the rate of progression of aortic valve stenosis (AS) remains incompletely characterized and assumed to be constant across the spectrum of AS severity. Previous studies involve limited number of patients, short follow-up, and focused on more severe stages of AS. Hypothesis: The annual rate of AS progression as defined by aortic valve mean gradient (AVMG) increases in magnitude as AS class severity increases. Methods: The study cohort included adult patients with native AS from the MGH echocardiography database from 1990 to 2020. Patients were included if AVMG was reported in at least two echocardiograms in mild, moderate, or severe AS stages. Generalized linear mixed models were employed to simultaneously model fixed effects and random effects stratified by AS severity grade. Multivariable models included age, sex, race, dyslipidemia, DM2, kidney disease, LVEF, moderate/severe AI, and AV morphology. A linear model identified risk factors for rapid progression in severe AS. Results: In 8,848 patients with 29,513 echocardiograms, baseline mean gradient for mild, moderate, and severe AS was 7.0, 20.9, and 43.0 mmHg, respectively. The annual rate of progression in mild, moderate, and severe AS was found to be 0.3, 1.0, and 4.0 mmHg/year. Female gender and white race increased the rate of AVMG by 0.57mmHg/year and 1.05mmHg/year. Conclusions: The progression of AS accelerates with worsening severity of AS. The rate of AVMG progression in severe AS is similar to historically accepted values, but rates are slower for mild and moderate AS. Female gender and white race may be associated with faster progression in severe AS.

An endogenous inhibitor of angiogenesis downregulated by hypoxia in human aortic valve stenosis promotes disease pathogenesis

Aortic valve stenosis is the most common valve disease in the western world. Central to the pathogenesis of this disease is the growth of new blood vessels (angiogenesis) within the aortic valve allowing infiltration of immune cells and development of intra-valve inflammation. Identifying the cellular mediators involved in this angiogenesis is important as this may reveal new therapeutic targets which could ultimately prevent the progression of aortic valve stenosis. Aortic valves from patients undergoing surgery for aortic valve replacement or dilation of the aortic arch were examined both ex vivo and in vitro. We now demonstrate that the anti-angiogenic protein, soluble fms-like tyrosine kinase 1 (sFlt1), a non-signalling soluble receptor for vascular endothelial growth factor, is constitutively expressed in non-diseased valves. sFlt-1 expression was, however, significantly reduced in aortic valve tissue from patients with aortic valve stenosis while protein markers of hypoxia were simultaneously increased. Exposure of primary-cultured valve interstitial cells to hypoxia resulted in a decrease in the expression of sFlt-1. We further reveal using a bioassay that siRNA knock-down of sFlt1 in valve interstitial cells directly results in a pro-angiogenic environment. Finally, incubation of aortic valves with sphingosine 1-phosphate, a bioactive lipid-mediator, increased sFlt-1 expression and inhibited angiogenesis within valve tissue. In conclusion, this study demonstrates that sFlt1 expression is directly correlated with angiogenesis in aortic valves and the observed decrease in sFlt-1 expression in aortic valve stenosis could increase valve inflammation, promoting disease progression. This could be a viable therapeutic target in treating this disease.

Osteopontin activity modulates sex-specific calcification in engineered valve tissue mimics.

Patients with aortic valve stenosis (AVS) have sexually dimorphic phenotypes in their valve tissue, where male valvular tissue adopts a calcified phenotype and female tissue becomes more fibrotic. The molecular mechanisms that regulate sex-specific calcification in valvular tissue remain poorly understood. Here, we explored the role of osteopontin (OPN), a pro-fibrotic but anti-calcific bone sialoprotein, in regulating the calcification of female aortic valve tissue. Recognizing that OPN mediates calcification processes, we hypothesized that aortic valvular interstitial cells (VICs) in female tissue have reduced expression of osteogenic markers in the presence of elevated OPN relative to male VICs. Human female valve leaflets displayed reduced and smaller microcalcifications, but increased OPN expression relative to male leaflets. To understand how OPN expression contributes to observed sex dimorphisms in valve tissue, we employed enzymatically degradable hydrogels as a 3D cell culture platform to recapitulate male or female VIC interactions with the extracellular matrix. Using this system, we recapitulated sex differences observed in human tissue, specifically demonstrating that female VICs exposed to calcifying medium have smaller mineral deposits within the hydrogel relative to male VICs. We identified a change in OPN dynamics in female VICs in the presence of calcification stimuli, where OPN deposition localized from the extracellular matrix to perinuclear regions. Additionally, exogenously delivered endothelin-1 to encapsulated VICs increased OPN gene expression in male cells, which resulted in reduced calcification. Collectively, our results suggest that increased OPN in female valve tissue may play a sex-specific role in mitigating mineralization during AVS progression.

Hydrogel cultures reveal Transient Receptor Potential Vanilloid 4 regulation of myofibroblast activation and proliferation in valvular interstitial cells.

As aortic valve stenosis develops, valve tissue becomes stiffer. In response to this change in environmental mechanical stiffness, valvular interstitial cells (VICs) activate into myofibroblasts. We aimed to investigate the role of mechanosensitive calcium channel Transient Receptor Potential Vanilloid type 4 (TRPV4) in stiffness induced myofibroblast activation. We verified TRPV4 functionality in VICs using live calcium imaging during application of small molecule modulators of TRPV4 activity. We designed hydrogel biomaterials that mimic mechanical features of healthy or diseased valve tissue microenvironments, respectively, to investigate the role of TRPV4 in myofibroblast activation and proliferation. Our results show that TRPV4 regulates VIC proliferation in a microenvironment stiffness-independent manner. While there was a trend toward inhibiting myofibroblast activation on soft microenvironments during TRPV4 inhibition, we observed near complete deactivation of myofibroblasts on stiff microenvironments. We further identified Yes-activated protein (YAP) as a downstream target for TRPV4 activity on stiff microenvironments. Mechanosensitive TRPV4 channels regulate VIC myofibroblast activation, whereas proliferation regulation is independent of the microenvironmental stiffness. Collectively, the data suggests differential regulation of stiffness-induced proliferation and myofibroblast activation. Our data further suggest a regulatory role for TRPV4 regarding YAP nuclear localization. TRPV4 is an important regulator for VIC myofibroblast activation, which is linked to the initiation of valve fibrosis. Although more validation studies are necessary, we suggest TRPV4 as a promising pharmaceutical target to slow aortic valve stenosis progression.

Genes That Escape X Chromosome Inactivation Modulate Sex Differences in Valve Myofibroblasts.

Aortic valve stenosis is a sexually dimorphic disease, with women often presenting with sustained fibrosis and men with more extensive calcification. However, the intracellular molecular mechanisms that drive these clinically important sex differences remain underexplored. Hydrogel biomaterials were designed to recapitulate key aspects of the valve tissue microenvironment and to serve as a culture platform for sex-specific valvular interstitial cells (VICs; precursors to profibrotic myofibroblasts). The hydrogel culture system was used to interrogate intracellular pathways involved in sex-dependent VIC-to-myofibroblast activation and deactivation. RNA sequencing was used to define pathways involved in driving sex-dependent activation. Interventions with small molecule inhibitors and siRNA transfections were performed to provide mechanistic insight into sex-specific cellular responses to microenvironmental cues, including matrix stiffness and exogenously delivered biochemical factors. In both healthy porcine and human aortic valves, female leaflets had higher baseline activation of the myofibroblast marker α-smooth muscle actin compared with male leaflets. When isolated and cultured, female porcine and human VICs had higher levels of basal α-smooth muscle actin stress fibers that further increased in response to the hydrogel matrix stiffness, both of which were higher than in male VICs. A transcriptomic analysis of male and female porcine VICs revealed Rho-associated protein kinase signaling as a potential driver of this sex-dependent myofibroblast activation. Furthermore, we found that genes that escape X-chromosome inactivation such as BMX and STS (encoding for Bmx nonreceptor tyrosine kinase and steroid sulfatase, respectively) partially regulate the elevated female myofibroblast activation through Rho-associated protein kinase signaling. This finding was confirmed by treating male and female VICs with endothelin-1 and plasminogen activator inhibitor-1, factors that are secreted by endothelial cells and known to drive myofibroblast activation through Rho-associated protein kinase signaling. Together, in vivo and in vitro results confirm sex dependencies in myofibroblast activation pathways and implicate genes that escape X-chromosome inactivation in regulating sex differences in myofibroblast activation and subsequent aortic valve stenosis progression. Our results underscore the importance of considering sex as a biological variable to understand the molecular mechanisms of aortic valve stenosis and to help guide sex-based precision therapies.

A bioinformatic analysis of the aortic valve stenosis transcriptome reveals chances of Rosuvastatin treatment

Background and Aims: There is epidemiological evidence that associates cardiovascular risk factors with aortic valve stenosis (AVS). The drug treatment of choice are beta-blockers and ACE inhibitors, although there is a constant demand to optimize it. On the basis of the recently published transcriptomes on the progression of AVS, we proposed a bioinformatic analysis to identify vacant molecular targets and treatment timing for rosuvastatin.

Engineered Hydrogels as Valve Tissue Mimetics That Recapitulate Sexual Dimorphisms Observed in Calcification and Osteopontin Activity

Objective: Recent clinical reports indicate that patients with calcific aortic valve stenosis (AVS) have sexually dimorphic disease phenotypes, where female patients have reduced valve calcification compared to males. Yet, the cellular mechanisms contributing to this dimorphism remain unknown. Our results reveal that diseased valve leaflets from a female tend to have reduced and smaller-scale microcalcifications compared to males. Additionally, osteopontin (OPN) expression, a pro-fibrotic but anti-calcific bone sialoprotein, is elevated in human female valve tissue sections. We hypothesize that OPN may play a role in reducing calcification in female aortic valves. Methods: To this end, we use a hydrogel system with cellularly-degradable crosslinkers and adhesive peptides to culture VICs isolated from male and female pigs in 3D. We further introduced a secondary interpenetrating network of collagen type I and studied differences in the cellular response to osteogenic stimuli. Results: The hydrogel matrix supported VIC survival, matrix remodeling, and recapitulated the mineralization differences that are observed in human diseased valve tissue. Specifically, female valve tissue and female VICs cultured in pro-calcifying hydrogels have more punctate calcification (< 3000 μm2) relative to male samples (> 3000 μm2) (Figure 1). Further, OPN localization shifted from the hydrogel extracellular matrix to the nucleus in female cells in response to exogenously delivered calcification stimuli. Conclusions: OPN localization corresponded to sites of VIC-mediated matrix calcification, suggesting OPN may have a role in suppressing mineralization growth in AVS progression. This 3D hydrogel culture system should prove useful to test additional hypotheses related to sex-specific AVS calcification and potentially guide the development of sex-specific treatments. Figure 1. Von Kossa stained histological sections display reduced calcification of female samples (left) relative to male (right), in both tissue sections of human diseased aortic valve (top) and within in vitro 3D hydrogel valve mimetics (bottom). Scale bar = 100 μm

Body mass index is associated with low postoperative cardiac output in patients undergoing aortic valve replacement

Background Overweight and obesity (O/O) generate lipotoxicity of the cardiac fiber and increase the incidence and progression of aortic valve stenosis. The low cardiac output syndrome (LCOS) is a timing complication after to aortic valve replacement (AVR) surgery. Objective The objective of the study was to investigate if body mass index (BMI) kg/m2 is a risk factor associated with LCOS and mortality in the post-operative period of AVR. Methods A historic cohort study was designed, including patients with severe aortic stenosis (SAS), who were subjected to AVR. Results 152 patients were included, 45 (29.6%), with normal weight (NW), 60 were overweight (39.5%), and 47 obese (30.9%). The prevalence of systemic hypertension (HT) was higher in O/O (p < 0.0001). Incidence of LCOS was 44.7%, being more frequent in the O/O groups compared to the NW group, 43.3%, 68.1%, and 22.2%, respectively, (p < 0.05 in overweight and p < 0.0001 in the obese). Assessing the presence or absence of LCOS associated with BMI as a numerical variable, we found that women, HT, BMI, left ventricular mass, and valve size, were associated with LCOS (p < 0.02, p < 0.02, p < 0.001, p < 0.032, and p < 0.045, respectively). Mortality was higher in patients who had LCOS (p < 0.02). Multivariate model showed that BMI was an independent risk factor for LCOS (odds ratio [OR] 1.21 [95% CI 1.08-1.35], p < 0.001). Conclusion BMI is a risk factor associated to LCOS in the post-operative period of AVR in patients with SAS.

Metabolomic Signature of Human Aortic Valve Stenosis

This study outlines the first step toward creating the metabolite atlas of human calcified aortic valves by identifying the expression of metabolites and metabolic pathways involved at various stages of calcific aortic valve stenosis progression. Untargeted analysis identified 72 metabolites and lipids that were significantly altered (p<0.01) across different stages of disease progression. Of these metabolites and lipids, the levels of lysophosphatidic acid were shown to correlate with faster hemodynamic progression and could select patients at risk for faster progression rate.