Progression Of Aortic Stenosis Research Articles

Progression of aortic stenosis in patients with diabetes mellitus type 2 compared with matched controls

Abstract Background Degenerative aortic stenosis (AS) and diabetes mellitus type 2 (DM) increase with age1,2 and their prevalence is expected to rise. Patients with DM have a higher risk to develop AS3 and the pathophysiological process leading from a normal aortic valve to AS involves factors associated with DM. AS develops over years, but it can evolve more rapidly. There is insufficient knowledge about risk factors for rapid progression in AS and monitoring strategies among patients at high risk for rapid progression. The aim of this project is to evaluate the AS progression towards combined outcome (incident heart failure, death, need for intervention) in patients with type 2 DM compared with matched controls. Methods From the Swedish National Diabetes Register (NDR) we identified all patients with type 2 DM between 01-01-2001- 31-12-2019 and for each patient 5 controls (matched for age, sex, region) from the Swedish Total Population Register. Afterwards we identified a cohort of individuals with AS from these two groups, by linking the NDR with the National Patient Register. The outcomes were: all- cause and cardiovascular mortality, and combined outcome (mortality, hospitalization for heart failure (HF) or aortic valve replacement (AVR)). We used Kaplan Meier survival curves to detect differences in all-cause mortality, cardiovascular mortality, time until AVR and combined outcome between cases and controls. Cox proportional hazards model adjusted for sex, age, obesity, renal failure, hyperparathyroidism, hypertension, hyperlipidemia was used to study the risk difference between the cases and controls for the combined outcome. Results We identified 16 144 individuals with type 2 DM and AS and 31 206 matched controls. The individuals with type 2 DM were predominately men (59% vs 53%), younger (mean age 70.6 vs 71.9), and had more comorbidities. In unadjusted analysis they were hospitalized for HF more often (8.2% vs 6.8%) and more often underwent AVR (surgically) (22.0% vs 19.0%) or transcatheter(6.6% vs 5.0%). Patients with AS and DM had higher all-cause and cardiovascular mortality and faster progression towards death, AVR or hospitalization for HF (see figure 1, A, B, C). The progression to AVR was significant, although the difference was small and not clinically relevant (plot D). In the adjusted model, the patients with AS and DM had 13% higher hazard to have the combined outcome compared with controls (see figure 2). Sex (female), hypertension and hyperlipidemia lowered the hazard for the combined event, while obesity, hyperparathyroidism and renal failure increased the hazard for the combined event. Conclusions Patients with concomitant AS and DM seem to have faster progression towards death (both all-cause and cardiovascular), and heart failure hospitalization or AVR compared with patients with AS without DM. Therefore, it might be appropriate to be more active regarding follow-up and intervention in these patients.Kaplan Meirer curvesForest plot for adjusted Cox model

Nitisinone attenuates progression of aortic stenosis in patients with alkaptonuria: an analysis of the SONIA 2 study

Abstract Background/introduction Alkaptonuria (AKU) is a rare metabolic disorder caused by a defective enzyme, resulting in deposition of unmetabolised homogentisic acid in various connective tissues throughout the body (also termed "ochronosis"). Ochronosis of the aortic valve leading to progressive aortic stenosis is a rare but serious complication. Nitisinone decreases urinary and serum homogentisic acid levels and has been shown to improve morbidity and slow disease progression in AKU but the effects of this treatment on the progression of aortic stenosis have not yet been described. This review extrapolated from the data set of the SONIA 2 study, a 4-year multi-centre, randomised controlled trial investigating the effect of nitisinone on a composite clinical measure of AKU disease activity, but looked more specifically at measures of aortic stenosis disease progression. Methods Data was obtained from echocardiograms performed on 138 patients at baseline, 12, 24, 36 and 48 months of follow-up. In measuring the degree of aortic stenosis, the peak trans-aortic velocity (Vmax) was examined. A linear mixed effects regression model was used to assess the association between treatment and Vmax and to ascertain the difference in this measure at baseline and 48 months between the treatment and control groups. The mixed effects model incorporated both fixed effects for population parameters (age, sex, baseline Vmax, follow-up time) and treatment; and random effects, to account for intra-subject correlation of longitudinal observations of Vmax, inter-subject variability of baseline measurements of Vmax, and centre. Results At baseline, 19/138 patients (13.8%) had aortic stenosis, as classified by echocardiogram findings in accordance with the European Society of Cardiology (ESC) guidance on valvular heart disease, with 9/19 having mild aortic stenosis, 6/19 having moderate aortic stenosis and 4/19 having severe aortic stenosis. 25/138 had aortic sclerosis (see figure 1). The prevalence of aortic valve disease increased with age. From the 4-year follow-up period, 613 longitudinal observations of 138 subjects across all sites were obtained. At baseline, the difference in Vmax between the control and treatment groups was 0.063 m/s [95% CI: -0.054 m/s to 0.18 m/s] and did not reach statistical significance (p=0.23). At the end of the 4-year treatment period, the difference in Vmax was 0.10 m/s [95% CI: -0.0007 m/s to 0.20 m/s] and was statistically significant (p=0.05) (see figure 2). Conclusion Nitisinone slowed progression of aortic stenosis in patients with AKU. This may be grounds for timely initiation of nitisinone in those deemed to be at high risk, as identified by echocardiography. Of note, this is the first time that any medical therapy has ever been shown to affect the natural history of aortic stenosis.

Valvular and myocardial fibroblast activation in aortic stenosis: a prospective positron emission tomography study

Abstract Introduction In patients with aortic stenosis, fibrosis is a common pathophysiological feature of leaflet thickening as well as left ventricular decompensation as it transitions from hypertrophy to heart failure. Valvular fibrosis can be quantified by contrast-enhanced computed tomography, and myocardial fibrosis by late gadolinium enhancement on magnetic resonance imaging, but neither can detect the activity of fibrosis and extracellular matrix remodelling. Gallium-68 Fibroblast Activation Protein Inhibitor (68Ga-FAPI) binds to activated fibroblasts, the key effector cell of fibrogenesis, and provides a measure of fibroblast activation and fibrosis activity. We aimed to measure fibrosis activity in the aortic valve and left ventricular myocardium of patients with aortic stenosis using 68Ga-FAPI uptake. Methods In a prospective observational cohort, patients with aortic stenosis and control subjects with normal aortic valves underwent transthoracic echocardiography, 68Ga-FAPI positron emission tomography, computed tomography, and magnetic resonance imaging. Valvular and myocardial 68Ga-FAPI uptake was quantified using the target-to-background ratio (TBRmax). Valvular non-calcific volume was quantified on computed tomography and replacement myocardial fibrosis was quantified by late gadolinium enhancement on magnetic resonance imaging. Results Fifty patients with aortic valve disease (9 with aortic sclerosis, and 7 with mild, 23 with moderate and 11 with severe aortic stenosis; 72±8 years, 70% male) and 4 control subjects (66±7 years, 50% male) participated. Increased 68Ga-FAPI uptake was observed in the aortic valves of patients with aortic sclerosis and stenosis and peaked in those with moderate disease (Figure 1). TBRmax of 68Ga-FAPI uptake correlated with the aortic valve non-calcific volume (r=0.354, p<0.05) on computed tomography. Thirty-one patients (62%) had myocardial 68Ga-FAPI uptake, of whom half (n=17; 34%) also had late gadolinium enhancement corresponding to the region of 68Ga-FAPI uptake (Figure 2). Myocardial 68Ga-FAPI uptake correlated with increased indexed left ventricular mass (r=0.333, p<0.05) and left ventricular wall thickness (r=0.385, p<0.05). Conclusions For the first time, we have identified both valvular and myocardial fibrosis activity in patients with aortic stenosis. Valvular fibroblast activation is increased in patients with aortic sclerosis and stenosis, peaking in patients with moderate disease and correlating with leaflet thickening. Myocardial fibroblast activation is seen in the majority of patients with aortic stenosis both in areas with and without established fibrosis, and is associated with indices of adverse left ventricular remodelling. Activated fibroblasts are thus an important potential treatment target in the valve and myocardium, with 68Ga-FAPI positron emission tomography holding major promise in better understanding the pathophysiology, progression and consequences of aortic stenosis.

Increased calcification by erythrophagocytosis in aortic valvular interstitial cells.

Calcific aortic valve disease (CAVD) progresses over time to severe aortic stenosis and eventually heart failure. Recent evidence indicates that intraleaflet haemorrhage (ILH) strongly promotes CAVD progression. However, it remains poorly understood how it mechanistically contributes to valvular calcification. ILH was identified as iron deposition by morphological analysis. To elucidate the underlying mechanism, human valvular interstitial cells (VIC) were cultured in the presence of fresh or senescent red blood cells (RBC), simulating ILH in vivo conditions. ILH was common in aortic valves derived from patients with severe aortic stenosis. VIC undergo erythrophagocytosis of senescent RBC, leading to intracellular iron accumulation analogous to observed following exposure to extracellular iron. The presence of senescent RBC significantly intensified VIC calcification, which was significantly mitigated by ferroptosis inhibition. Our results identify erythrophagocytosis by VIC, leading to iron accumulation and enhanced calcification through ferroptosis. This may be a crucial component of the pathophysiological mechanisms that links ILH to valvular calcification and accelerated aortic stenosis progression.

TCT-187 Effect of Sodium-Glucose Cotransporter-2 Inhibitors on the Progression of Aortic Stenosis

TCT-187 Effect of Sodium-Glucose Cotransporter-2 Inhibitors on the Progression of Aortic Stenosis

Effect of Denosumab or Alendronate on Vascular Calcification: Secondary Analysis of SALTIRE2 Randomized Controlled Trial.

Patients with osteoporosis demonstrate increased vascular calcification but the effect of osteoporosis treatments on vascular calcification remains unclear. The present study aimed to examine whether coronary or aortic calcification are influenced by denosumab and alendronic acid treatment. In a double-blind randomized controlled SALTIRE2 (Study Investigating the Effect of Drugs Used to Treat Osteoporosis on the Progression of Calcific Aortic Stenosis) trial, patients with aortic stenosis were randomized 2:1:2:1 to denosumab, placebo injection, alendronic acid, or placebo capsule. Participants underwent serial imaging with computed tomography and 18F-sodium fluoride positron emission tomography for the assessment of vascular calcium burden and calcification activity, respectively. We report the prespecified secondary analyses of 24-month change in coronary calcium score, and 12-month changes in thoracic aorta calcium score, coronary and aortic 18F-sodium fluoride activity. One hundred fifty patients with aortic stenosis (72±8 years; 21% female) were randomized to denosumab (n=49), alendronic acid (n=51), and placebo (injection n=25, capsule n=25). There were no differences in change in coronary calcium scores between placebo (16 [-64 to 148] Agatston units) and either denosumab (94 [0-212] Agatston units, P=0.24) or alendronic acid (34 [-62 to 134], P=0.99). There were no differences in change in thoracic aorta calcium scores between placebo (132 [22-512] Agatston units) and either denosumab (118 [11-340], P=0.75) or alendronic acid (116 [26-498] Agatston units, P=0.62). There were no differences in changes in coronary or aortic 18F-sodium fluoride activity between treatment groups. Neither alendronic acid nor denosumab are associated with changes in the activity or progression of coronary or aortic calcification. Osteoporosis treatments do not appear to have major impact on vascular calcification of atherosclerosis. https://www.clinicaltrials.gov; Unique identifier: NCT02132026.

Progression, Management, and Outcome of Aortic Valve Stenosis in Systemic Sclerosis: A Case Series.

In systemic sclerosis (SSc), cardiac involvement is frequent, heterogeneous, and related to a poor prognosis. Due to a longer life expectancy, the development of degenerative aortic stenosis (AS) is not uncommon. The aim of this article is to report the characteristics of AS in SSc, analyzing the rate of progression, the management, and the outcome. This is a case series conducted at the Department of Cardiology of Monaldi Hospital, Naples, Italy. From January 2007 to December 2022, we analyzed 234 patients with SSc. Ten/234 patients (4.3%) showed severe AS and were included in the analysis (age 75.5 years [IQR 58-84], nine females). Nine had limited and one diffuse SSc. Two patients were in NHYA/WHO II and eight in NYHA/WHO III. All had degenerative three-leaflet AS. Two patients showed severe AS at the first evaluation, and eight developed severe AS during the follow-up, with a time progression from moderate to severe AS of 3.2 ± 1.1 years (progression rate -0.190 ± 0.012 cm2/year for aortic valve area, 8.6 ± 6.1 mmHg/year for mean aortic gradient, 16 ± 7 mmHg/year for peak aortic gradient, and 0.5 ± 0.3 m/s/year for aortic peak velocity). Seven out of 10 patients underwent transcatheter aortic valve implantation (TAVI), one underwent surgical aortic valve replacement (SAVR), one was left untreated, and one was on a waiting list for TAVI. No major complications after TAVI or SAVR occurred. At a mean follow-up of 5.9 ± 3.9 years, eight patients are alive and two died. Severe AS is a relevant cardiac complication of SSc and must be considered in the screening and during the follow-up. Its rapid progression rate may tentatively be due to autoimmunity, degenerative burden, and chronic inflammation.

Deep Learning Model of Diastolic Dysfunction Risk Stratifies the Progression of Early-Stage Aortic Stenosis

Deep Learning Model of Diastolic Dysfunction Risk Stratifies the Progression of Early-Stage Aortic Stenosis

Association Between Serum Phosphate Levels and Progression of Aortic Stenosis

Association Between Serum Phosphate Levels and Progression of Aortic Stenosis

Th1 cells reduce the osteoblast-like phenotype in valvular interstitial cells by inhibiting NLRP3 inflammasome activation in macrophages

Background and aimsInflammation is initiates the propagation phase of aortic valve calcification. The activation of NLRP3 signaling in macrophages plays a crucial role in the progression of calcific aortic valve stenosis (CAVS). IFN-γ regulates NLRP3 activity in macrophages. This study aimed to explore the mechanism of IFN-γ regulation and its impact on CAVS progression and valve interstitial cell transdifferentiation.Methods and resultsThe number of Th1 cells and the expression of IFN-γ and STAT1 in the aortic valve, spleen and peripheral blood increased significantly as CAVS progressed. To explore the mechanisms underlying the roles of Th1 cells and IFN-γ, we treated CAVS mice with IFN-γ-AAV9 or an anti-IFN-γ neutralizing antibody. While IFN-γ promoted aortic valve calcification and dysfunction, it significantly decreased NLRP3 signaling in splenic macrophages and Ly6C+ monocytes. In vitro coculture showed that Th1 cells inhibited NLPR3 activation in ox-LDL-treated macrophages through the IFN-γR1/IFN-γR2-STAT1 pathway. Compared with untreated medium, conditioned medium from Th1-treated bone marrow–derived macrophages reduced the osteogenic calcification of valvular interstitial cells.ConclusionInhibition of the NLRP3 inflammasome by Th1 cells protects against valvular interstitial cell calcification as a negative feedback mechanism of adaptive immunity toward innate immunity. This study provides a precision medicine strategy for CAVS based on the targeting of anti-inflammatory mechanisms.Graphical

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

Survival and reverse progression outcome of fetal aortic valvuloplasty and extra-cardiac conduit or lateral tunnel Fontan procedure in evolving and evolved hypoplastic left heart syndrome: a systematic review and meta-analysis

Background: Hypoplastic left heart syndrome (HLHS) is a severe congenital heart defect characterized by the underdevelopment of the left-sided heart structures, necessitating staged univentricular palliation to repurpose the right ventricle as the systemic pumping chamber. While the Fontan procedure offers a well-established method to manage single-ventricle physiology and improve survival, the potential of fetal aortic valvuloplasty (FAV) to prevent the progression of critical aortic stenosis to HLHS and achieve biventricular circulation postnatally remains significant. However, the long-term outcomes of both interventions are still uncertain. Therefore this study aims to evaluate the survival and reverse progression outcome of fetal aortic valvuloplasty and extra-cardiac conduit or lateral tunnel Fontan procedure in evolving and evolved hypoplastic left heart syndrome Methods: The literature search was conducted using PubMed, ScienceDirect, and Google Scholar databases up to May 2024. The analyses in this study were performed using R statistical software v.3.3. Results: This analysis reviewed 25 prospective and retrospective cohort studies discussing the outcomes of the FAV procedure in evolving HLHS fetuses and the Fontan procedure in pediatric HLHS patients. Among evolving HLHS fetuses, the FAV procedure had a mortality rate of 0.18 (95% CI 0.07-0.29) and a procedural success rate of 0.81 (95% CI 0.78-0.85). In pediatric patients with evolved HLHS undergoing the Fontan procedure, the mortality rate was 0.13 (95% CI 0.00-0.25), and the procedural success rate was 0.93 (95% CI 0.85-1.00). Conclusion: The Fontan procedure has shown better results than FAV, likely due to interstage procedural interventions and more established techniques for reducing morbidity and mortality in HLHS patients.

A Multimodal Video-Based AI Biomarker for Aortic Stenosis Development and Progression

Aortic stenosis (AS) is a major public health challenge with a growing therapeutic landscape, but current biomarkers do not inform personalized screening and follow-up. A video-based artificial intelligence (AI) biomarker (Digital AS Severity index [DASSi]) can detect severe AS using single-view long-axis echocardiography without Doppler characterization. To deploy DASSi to patients with no AS or with mild or moderate AS at baseline to identify AS development and progression. This is a cohort study that examined 2 cohorts of patients without severe AS undergoing echocardiography in the Yale New Haven Health System (YNHHS; 2015-2021) and Cedars-Sinai Medical Center (CSMC; 2018-2019). A novel computational pipeline for the cross-modal translation of DASSi into cardiac magnetic resonance (CMR) imaging was further developed in the UK Biobank. Analyses were performed between August 2023 and February 2024. DASSi (range, 0-1) derived from AI applied to echocardiography and CMR videos. Annualized change in peak aortic valve velocity (AV-Vmax) and late (>6 months) aortic valve replacement (AVR). A total of 12 599 participants were included in the echocardiographic study (YNHHS: n = 8798; median [IQR] age, 71 [60-80] years; 4250 [48.3%] women; median [IQR] follow-up, 4.1 [2.4-5.4] years; and CSMC: n = 3801; median [IQR] age, 67 [54-78] years; 1685 [44.3%] women; median [IQR] follow-up, 3.4 [2.8-3.9] years). Higher baseline DASSi was associated with faster progression in AV-Vmax (per 0.1 DASSi increment: YNHHS, 0.033 m/s per year [95% CI, 0.028-0.038] among 5483 participants; CSMC, 0.082 m/s per year [95% CI, 0.053-0.111] among 1292 participants), with values of 0.2 or greater associated with a 4- to 5-fold higher AVR risk than values less than 0.2 (YNHHS: 715 events; adjusted hazard ratio [HR], 4.97 [95% CI, 2.71-5.82]; CSMC: 56 events; adjusted HR, 4.04 [95% CI, 0.92-17.70]), independent of age, sex, race, ethnicity, ejection fraction, and AV-Vmax. This was reproduced across 45 474 participants (median [IQR] age, 65 [59-71] years; 23 559 [51.8%] women; median [IQR] follow-up, 2.5 [1.6-3.9] years) undergoing CMR imaging in the UK Biobank (for participants with DASSi ≥0.2 vs those with DASSi <.02, adjusted HR, 11.38 [95% CI, 2.56-50.57]). Saliency maps and phenome-wide association studies supported associations with cardiac structure and function and traditional cardiovascular risk factors. In this cohort study of patients without severe AS undergoing echocardiography or CMR imaging, a new AI-based video biomarker was independently associated with AS development and progression, enabling opportunistic risk stratification across cardiovascular imaging modalities as well as potential application on handheld devices.

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.

Prediction of the Individual Aortic Stenosis Progression Rate and its Association With Clinical Outcomes

BackgroundThe progression rate of aortic stenosis differs between patients, complicating clinical follow-up and management. ObjectivesThis study aimed to identify predictors associated with the progression rate of aortic stenosis. MethodsIn this retrospective longitudinal single-center cohort study, all patients with moderate aortic stenosis who presented between December 2011 and December 2022 and had echocardiograms available were included. The individual aortic stenosis progression rate was calculated based on aortic valve area (AVA) from at least 2 echocardiograms performed at least 6 months apart. Baseline factors associated with the progression rate of AVA were determined using linear mixed-effects models, and the association of progression rate with clinical outcomes was evaluated using Cox regression. ResultsThe study included 540 patients (median age 69 years and 38% female) with 2,937 echocardiograms (median 5 per patient). Patients had a linear progression with a median AVA decrease of 0.09 cm2/y and a median peak jet velocity increase of 0.17 m/s/y. Rapid progression was independently associated with all-cause mortality (HR: 1.77, 95% CI: 1.26-2.48) and aortic valve replacement (HR: 3.44, 95% CI: 2.55-4.64). Older age, greater left ventricular mass index, atrial fibrillation, and chronic kidney disease were associated with a faster decline of AVA. ConclusionsAVA decreases linearly in individual patients, and faster progression is independently associated with higher mortality. Routine clinical and echocardiographic variables accurately predict the individual progression rate and may aid clinicians in determining the optimal follow-up interval for patients with aortic stenosis.

Angiotensin II Receptor Blockers Are Associated With Reduced Valvular Fibrosis in Women With Aortic Stenosis

BackgroundAngiotensin receptor blockers (ARBs) may slow down the progression of aortic stenosis (AS) through their antifibrotic effect. Women present more valvular fibrosis than men, so ARBs may have more effect in females. Our aim was to assess the impact of ARBs on the remodelling of the aortic valve in men and women. MethodsWe included patients who had an aortic valve replacement with or without coronary bypass grafting from 2006 to 2013. Patients with missing echocardiographic or histologic data were excluded. Warren-Yong and fibrosis scores of the explanted valves were performed. Patients were divided into 4 phenotypes according to their Warren-Yong and fibrosis scores: mild calcification/fibrosis, severe calcification/fibrosis group, predominant fibrosis group, predominant calcification group. ResultsAmong the 1321 included patients, the vast majority (89%) has severe AS. Patients in the predominant fibrosis group, compared with the predominant calcium group, were more often female (39% vs 31%; P = 0.008) with bicuspid valves (44% vs 34%; P = 0.002), and less often used ARBs (25% vs 30%; P = 0.046). Female sex was independently associated with being in the predominant fibrosis group (odds ratio 1.45, 95% confidence interval 1.08-1.95; P = 0.01), with a significant interaction between female sex and ARBs. Women taking ARBs compared with women not taking ARBs had significantly lower fibrosis scores (P < 0.001). This difference was not seen in men. ConclusionsIn this large series of patients with moderate-severe AS, among the women there was a negative association between intake of ARBs and valvular fibrosis. Thus, the possible effects of ARBs may be sex specific, with a larger therapeutic role in women.

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.

Numerical investigation of calcification effects on aortic valve motions and ambient flow characteristics

The pathogenesis and progression of calcific aortic stenosis pose a significant challenge in medical science due to the intricate nature of blood fluid dynamics. To better understand this crucial phenomenon, this study investigates the physiological behaviors of aortic valves with varying degrees of lesions and ambient flow conditions using an in-house CFD solver, CgLES-Y code. The code is validated by simulating two-dimensional valve opening and closure, followed by the extension to three-dimensional symmetrically simplified valve dynamics. The simulation results exhibit great agreement with other numerical, experimental and clinical data. Patient-specific models of the aortic root and inner valve geometries are developed based on CT images. Analysis of fluid dynamics traits, configuration properties and leaflet stress is performed for both normal and calcified aortic valves during the systolic and diastolic periods. The study further examines the impact of calcium deposition on abnormal flow fields and leaflet motion, which indicates that calcium deposition increases the tensional burden on healthy leaflets, therefore, the microcosmic increase in valve modulus leads to global damage extending from the root to the tip, whereas macroscopic calcification primarily induces damage in the vicinity of the calcium compound. Additionally, the generation of additional vortices on the valve surface and sinus lumen heightens the likelihood of calcium accumulation.

Valvular presence of coagulation factor XI correlates with the severity of aortic stenosis

Abstract Background The role of coagulation system as a factor involved in the progression of aortic stenosis (AS) has been proven. Considering recent studies about oral factor XIa (FXIa) inhibitor – asundexian with antithrombotic efficacy, our aim was to investigate whether FXI is present within stenotic leaflets in patients with severe AS and whether its expression correlates with valvular calcification. Methods We recruited 20 patients aged 66 ±9 years with severe AS defined as mean transvalvular pressure gradient (PGmean) ≥ 40mmHg, peak transvalvular velocity (Vmax) of ≥4.0 m/s and aortic valve area (AVA) &amp;lt;1 cm2. Stenotic aortic valves were obtained during valve replacement surgery. Aortic leaflets obtained from AS patients and from age-matched apparently healthy autopsy donors (n=3) were used to evaluate valvular expression of FXI, FIX, tissue factor (TF) and bone morphogenetic protein 2 (BMP2) by single and double-labeled immunostaining. The immunopositive valve area was computed as the ratio (%) of positively and negatively stained areas. The Ethical Committee approved the study and all participants provided written informed consent. Results AS patients with median PGmean of 54 [46-67] mmHg, Vmax of 4.5 [4.4-5.0] m/s and AVA of 0.8 [0.7-0.9] cm2 were treated with angiotensin converting enzyme inhibitors (80%), beta-blockers (90%), statins (70%) and acetylsalicylic acid (80%). In loco analysis revealed valvular expression of FXI within all studied stenotic valves, but not within control ones (Figure 1 A and B). The FXI-immunopositive valve area constituted 21.4±4.5% of the total leaflet area, while these for FIX and TF were 17.2 ±3.8% and 26.5±5.1%, respectively. The mean BMP2-positive area was 22.9±4.1%. The expression of studied proteins was observed at the aortic side of the stenotic leaflets and presented a condensed pattern of fluorescence. Moreover, the expression of FXI co-expressed with FIX in 76% and TF in 71%, suggesting local activation of FXI (Figure 1 D and E). Moreover, FXI co-expressed with BMP2 in 83% (Figure C), which may indicate that FXI activation occurs at the site of leaflet calcification. Interestingly, valvular amounts of FXI correlated with AS severity measured as PGmean (r=0.49, p=0.03), PGmax (r=0.53, p=0.02), Vmax (r=0.54, p=0.01) and AVA (r=-0.53, p=0.02). Conclusions We are the first to show the valvular presence of FXI, co-expressing with FIX and TF, which indicates FXI in loco activation. A strong co-expression of FXI with BMP2 and associations with disease severity highlight the impact of coagulation on valve calcification. It is tempting to speculate that FXIa inhibition could attenuate not only coagulation activation but also valvular calcification and thus retard AS progression. Clinical relevance of these findings requires further studies. This work was supported by the Polish National Science Centre (UMO-2021/41/N/NZ5/03323).Figure 1_ESC_2023