Progression Of Aortic Stenosis Research Articles

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

Sex differences in aortic stenosis progression and myocardial response

Abstract Background Aortic stenosis (AS) produces an increased afterload and consequently left ventricular (LV) remodeling. While current guidelines recommend the same echo-doppler criteria for diagnosis and grading of AS for men and women, different sex-specific patterns of cardiac remodeling, and eventually damage, have been reported. Whether these different patterns are caused by sex-related AS progression rate or myocardial response is less well known. Aim We aim to compare longitudinal changes in aortic valve and cardiac function between women and men with AS to investigate sex-related differences in AS progression and cardiac remodeling. Methods Patients with mild-to-severe AS and LV ejection fraction (LVEF) ≥ 50 % at least in 2 transthoracic echocardiograms (TTE) were retrospectively identified. Prosthetic and bicuspid valves were excluded. Serial TTEs provided a multiparametric framework to compare AS severity, progression rate and induced cardiac changes between sexes. Results 914 patients were included (median follow-up time of 6.8 years) and 52 % (473) were female. Both sexes had similar baseline aortic peak velocities (APV) (2.9±0.9 m/s), mean pressure gradient (MPG) (27±13 mmHg) and LVEF (60±5 %). Women were older (75±9 vs 73±8 years; p&amp;lt;0.001), had smaller body surface area (BSA) (1.70±0.15 vs 1.88±0.16 m2, p&amp;lt;0.001), proportionally lower stroke volume (SV) (82±19 mL vs 91±22 mL, p&amp;lt;0.001), lower indexed LV mass (iLVM) (118±33 g/m2 vs 125±28 g/m2, p&amp;lt;0.001) and higher indexed left atrial (LA) volume (39±13 vs 49±20 mL/m2, p&amp;lt;0.001). The average annual progression rate of APV and MPG was similar for both groups (2 mmHg/year and 0.14 m s-1 year-1). After multivariate adjustment including time-dependent aortic valve replacement, women had a higher incidence of severe LV hypertrophy as measured by iLVM (HR=1.16, CI=1.08-1.91, p&amp;lt;0.01), moderate-to-severe tricuspid valve regurgitation (HR=2.03, CI=1.01-4.07, p&amp;lt;0.05) and pulmonary hypertension (PHT) (HR=1.49, CI=1.02-2.18, p=0.04) at 5 years. Similar incidence rates were seen for LV dilation, LVEF reduction and mitral valve regurgitation. All-cause mortality rates were similar between groups (p=0.30). Conclusion This study suggests that under similar static and dynamic loading conditions, women will develop severe LV hypertrophy and PHT earlier than men, possibly reflecting sex-specific response differences intrinsic to the myocardium. This suggests that the definition of AS severity may benefit from a shift from a valve-focused to a myocardial-integrative approach taking gender into account.

Predicting aortic stenosis progression using a video-based deep learning model of aortic stenosis built for single-view two-dimensional echocardiography

Abstract Background We have recently described a deep learning (DL) model that relies on 2-dimensional parasternal long axis (PLAX) videos from transthoracic echocardiography (TTE) without Doppler imaging to identify severe aortic stenosis (AS) at the point-of-care. However, the timely diagnosis of AS has traditionally required skilled examination with Doppler imaging at regular time intervals. Purpose To explore the role of a DL model previously trained to detect severe AS based on 2D-PLAX videos in predicting the rate of AS progression among patients with no, mild, or moderate AS. Methods In this retrospective cohort study, a random sample of 2354 individuals undergoing serial monitoring with at least two separate TTEs and available Doppler parameters of AS severity (peak aortic valve velocity, AV Vmax) between 2016 and 2021 in the Yale-New Haven Health system were included. Eligible participants had a left ventricular ejection fraction (LVEF) &amp;gt;=50% and no evidence of severe AS at baseline. After automated selection of PLAX videos using an automated view classifier, the baseline deep learning-based AS probability index (DL-ASi) was calculated for each patient. The absolute change in the AV Vmax was divided by the time difference between each pair of consecutive TTE studies, and then averaged to derive the mean rate of AS progression. The association between the baseline DL-ASi and the mean rate of AS progression was assessed using ordinary least squares regression with adjustment for the patient’s sex, age, and baseline LVEF and AV Vmax. To visualize the interaction between the baseline DL-ASi and AV Vmax in predicting the rate of AS progression, an interaction term was included and a contour plot was plotted for both men and women. Results We included 8473 TTE studies from 2354 unique individuals (mean age 70±14 years, n=1138 [48.3%] women) performed over a median 2.5 (IQR 1.4-3.7) years (A). Higher DL-ASi at baseline was independently associated with a more rapid rate of AS progression (βadj 0.27 [95% CI 0.20-0.33, P&amp;lt;0.001]). The rates of AV Vmax progression ranged from 0.06±0.01 m/sec/year in the &amp;lt;0.2 DL-ASi group, to 0.29±0.04 m/sec/year in the ≥0.8 DL-ASi group (B). Contour plots illustrate how, for a given AV Vmax value, DL-ASi stratified the risk of AS progression in women and men (C). Conclusion In individuals with mild to moderate AS or no AS, a DL model trained to detect features of severe AS identifies individuals with a higher rate of AS severity progression, as assessed by the mean rate of AV Vmax change. This represents a promising approach for the longitudinal, point-of-care monitoring of patients with non-severe AS outside specialized centers.

Aortic stenosis progression among patients with bicuspid aortic valve

Abstract Background Bicuspid aortic valve (BAV) is associated with an increased risk of aortic stenosis (AS). The role of AS progression rate, its determinants, and prognostic implications need to be better understood in patients with BAV-AS. Aim This study aims to compare AS progression rate between patients with BAV and tricuspid aortic valve (TAV), its determinants, and its impact on clinical outcomes. Methods We retrospectively included patients who had undergone &amp;gt; 1 transthoracic echocardiogram (TTE) documenting AS and preserved left ventricular ejection fraction (LVEF). Moderate to severe aortic valve regurgitation and aortic prosthetic valves were excluded. Patients with suspected BAV in TTE and a confirmatory CT scan were identified. A greedy matching was used to match patients with BAV and patients with TAV on age and sex in a ratio 1:1. Aortic peak velocity (APV) was modeled as a function of time using a mixed-effects nonlinear model to capture possible biphasic progression. A core model parameter reflecting AS rate of progression was calculated and compared between patients with BAV-AS and TAV-AS. Multivariate linear regression was used to explore possible predictors of AS progression. All-cause death was compared between patients with BAV and TAV. Results We matched 80 patient-pairs from within our study cohort by age and sex (age 54 ± 11 years, 40 % female). Follow-up time was higher for patients with tricuspid aortic valves (TAV) (5.9±2.6 years vs. 4.6±2.8 years, p&amp;lt;0.01). Patients with TAV-AS had a higher prevalence of cardiovascular risk factors (arterial hypertension [81 % vs. 41 %, p&amp;lt;0.001], diabetes mellitus [39% vs. 8%, p&amp;lt;0.001], and dyslipidemia [71 % vs. 26 %, p&amp;lt;0.001]). Baseline APV was similar between patients with TAV-AS and BAV-AS (2.9±0.9 m/s vs. 2.7±1.0 m/s, p=0.05), but AS progression rate was higher among patients with TAV-AS (logistic growth rate: 0.11±0.04/year vs. 0.02±0.04/year, p&amp;lt;0.001). No interaction was seen between aortic valve morphology and comorbidities with respect to AS progression rate. TAV-AS was associated with increased rate of all-cause death (p=0.02) but failed to remain a significant predictor of mortality after multivariate adjustment for baseline comorbidities and AS rate of progression. Conclusion In our matched cohort, the BAV-AS progression rate was lower than TAV-AS. BAV-AS was associated with lower mortality despite similar baseline AS severity, possibly reflecting a slower AS progression and a decreased burden of cardiovascular risk factors in this population.

The impact of postmenopausal osteoporosis on aortic valve stenosis in an animal model

Abstract Background Aortic valve stenosis (AVS) is the most prevalent heart valve disease worldwide and mainly affects the elderly. In observational clinical studies, postmenopausal osteoporosis, which affects 30 % of all women, is associated with increased aortic valve calcification and stenosis. However, there are no pathomechanistic investigations that link these diseases. In this study, we analyzed the impact of postmenopausal osteoporosis in ovariectomized C57BL6/J mice on the occurrence and progression of wire injury-induced aortic valve stenosis. Methods To induce postmenopausal osteoporosis, we performed bilateral ovariectomy (OVX) or sham operation in C57BL6/J mice. Successful OVX was confirmed by measuring the uterine weight. To distinguish the impact of estrogen deprivation from osteoporosis effects, 100 µg of the bisphosphonate zoledronic acid (ZA) or vehicle were applied i.p. weekly. Bone density was assessed through histological and µCT-analysis of the distal femur. 14 days after ovariectomy, AVS (or sham-procedure) was induced through a standardized, echocardiography-controlled injury of the aortic valve with a spring wire. Primary endpoint was the increase of peak velocity 2, 4 and 6 weeks after AVS-procedure. 8 weeks after OVX, mice were sacrificed and organs were harvested for further analysis (Fig. 1A). Results Bone mineral density and relative bone volume was significantly reduced 8 weeks after OVX. ZA led to a significant increase in bone mineral density, trabecular thickness and relative bone volume in comparison to the sham/vehicle and OVX/vehicle-groups (Fig. 1B-C). AVS was successfully induced, as shown by a significant increase in peak velocity (PV; Fig. 2A-B) 2, 4 and 6 weeks after wire injury. PV and mean pressure gradient (MPG) showed no difference between OVX- or Sham-operated mice (Fig. 2A). ZA did not significantly affect PV or MPG after AVS-procedure (Fig. 2B). Histological analysis revealed significantly greater cusp area in mice with AVS, but no difference for OVX- or ZA-groups (Fig. 2C). Picrosirius red staining showed a significantly decreased relative and absolute collagen content in aortic valves derived from mice with AVS, but no difference between OVX- or ZA-groups was detectable. Immature/degraded collagen was increased in mice with AVS. Conclusion Estrogen depletion and reduction in bone mineral density did affect AVS development in C57BL6/J mice. Application of ZA was effective in preventing bone loss, but did not change AVS-severity. Further histological analysis of the aortic valves could reveal potential differences in cardiovascular osteoclast- and immune cell-infiltration.Figure 1Figure 2

Progression of different echocardiographic parameters of aortic stenosis have different clinical associations

Abstract Background Previous reports have described the risk factors for progression of aortic stenosis (AS). However, AS is recognized as a condition of the aortic valve and ventricle, and the AS marker chosen for the assessment of progression may influence the determinants of progression. Purpose To assess whether different clinical and demographic characteristics have a different impact on the progression of echocardiographic parameters on which stroke volume has a lesser (aortic valvular area [AVA], dimensionless severity index [DSI]) or greater influence (mean pressure gradient [MPG], or peak velocity [Vmax]). Methods Patients diagnosed with at least mild AS without an aortic valvular intervention identified from an echocardiographic database from January 1, 2009, to July 26, 2022, from a tertiary level hospital were included. AS progression models were evaluated using univariable and multivariable linear regression or mixed effects. AS severity was defined based on international guidelines. Results A total of 8,720 patients with at least mild AS were included and followed for up to 13.7 years. Multivariable mixed effects models identified important clinical predictors in understanding AS progression. After adjustment for relevant covariates, AVA decreased by 0.02 cm per year (95% CI: -0.025, -0.016, p&amp;lt;0.001), DSI decreased by 0.006 per year (95% CI: -0.008, -0.005), MPG increased by 0.962 mmHg per year (95% CI: 0.818, 1.107, p&amp;lt;0.001), Vmax increased by 6.742 cm/s per year (95% CI: 5.934, 7.549, p&amp;lt;0.001). Age, calcification, revascularisation, ejection fraction below 50%, and rheumatic heart disease, were the most consistent associations of progression of all echocardiographic parameters (Figure 1). Sex was associated with progression of AVA and DSI but not gradients. Changes in gradients (but not AVA and DSI) were associated with ischemic heart disease, chronic kidney disease, and atrial fibrillation or atrial flutter. Conclusion This longitudinal data analysis demonstrates differences in impact of baseline risk factors on AS progression on different echocardiographic parameters.Figure 1.Colour map of clinical predictors

The impact of resting heart rate on adverse outcomes and haemodynamic progression of aortic stenosis

Abstract Introduction A high resting heart rate (RHR) is an established risk factor for cardiovascular disease, adverse cardiac events, accelerated calcification in coronary artery disease and carotid stenosis, and increased aortic valve calcification in patients with and without a confirmed diagnosis of aortic stenosis (AS). Aortic valve calcification is the most common precursor to AS and is associated with significantly faster disease progression. There are few studies exploring the effects of RHR on the progression of AS, the development of severe stenosis, and the risk of complications and death. Purpose We hypothesised that an elevated RHR would be associated with poorer outcomes and more rapid haemodynamic disease progression in patients with AS and tested this in a large cohort of patients without severe disease. Methods Using the National Echocardiography Database of Australia (NEDA) we undertook a retrospective observational study on patients without severe AS, a bicuspid aortic valve or prior aortic valve replacement. The association between baseline RHR and time to the composite primary endpoint of severe AS, aortic valve replacement or cardiovascular death was tested using Cox proportional hazards regression. In addition, the relationship between baseline RHR and the components of this composite was investigated. Subsequently, the relationship between annualised AS progression rate, defined as change in standard indices of AS severity (maximal jet velocity [Vmax], mean pressure gradient [MPG], and aortic valve area [AVA]), and RHR were analysed using general linear models. Results The initial study cohort comprised 55 585 individuals: 54% male, mean age 63 years and median baseline RHR 70 bpm. The composite primary endpoint, reached by 7 434 patients, was independently associated with RHR (hazard ratio [per 10bpm increase], 1.04; 95% CI, 1.02-1.05; p &amp;lt; 0.001). RHR was also independently associated with time to developing severe AS (hazard ratio [per 10bpm increase], 1.06; 95% CI, 1.01-1.12; p = 0.017) and cardiovascular death (hazard ratio [per 10bpm increase], 1.04; 95% CI, 1.02-1.06; p &amp;lt; 0.001). The event rate was significantly higher in patients with a RHR of at least 70 bpm (the median RHR) compared to those with an RHR less than 70 bpm. In addition, RHR was independently associated with rate of change of each individual measurement index of AS severity including Vmax (β = 0.65 cm/s/year [per 10 bpm increase]; p &amp;lt; 0.001), MPG (β = 0.05 mmHg/ year [per 10 bpm increase]; p&amp;lt;0.001), and AVA (β = -0.01 cm2/year [per 10 bpm increase]; p &amp;lt; 0.001). Conclusions RHR is independently associated with adverse clinical outcomes and haemodynamic progression of AS in patients without severe disease. Future randomised controlled trials should investigate the effect of lowering RHR on clinical endpoints and progression of AS.

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.

Abstract 15928: D-dimer as a New Biomarker of Aortic Stenosis Progression and Outcomes: Results From the PROGRESSA Study

Background: Aortic stenosis (AS) induces left ventricular (LV) remodeling and hypertrophy, which are key markers of the transition to heart failure. The present study aimed to evaluate the association between D-dimer plasma levels, LV hypertrophy and mortality with AS. Method: One-hundred and forty-six asymptomatic patients (mean age 65±13, men 76%) with mild or moderate AS prospectively recruited in the PROGRESSA study (NCT01679431) were included in this sub-analysis. All patients underwent Doppler-echocardiography annually to measure AS severity, LV mass indexed to body surface area (LVMi) and myocardial contraction fraction (MCF). The annualized changes in LVMi and MCF were calculated between baseline and last follow up. Results: Higher plasma levels of D-dimers at baseline were significantly associated with faster progression rate of LVMi and MCF (r 2 =0.18 and -0.22, respectively; all p&lt;0.01). On multivariable analysis adjusted for age, sex, comorbidities, creatinine level, peak aortic jet velocity at baseline, D-dimers remained significantly associated with faster change in LVMi and MCF (all, p&lt;0.01). Moreover, in multivariate analysis adjusted for age, sex, AS severity at baseline, higher levels of D-dimer were significantly associated with the progression to a higher grade of AS severity (HR [95% CI] 1.67 [1.14-2.46], p=0.009). During a median follow-up of 8.1 (5.6-9.9) years, 38 (26%) patients died. On multivariable Cox regression analysis, higher levels of D-dimer were associated with an increased risk of all-cause mortality (HR [95% CI]: 1.97 [0.98-1.97], p=0.05). Conclusion: Higher levels of D-dimer are associated with faster progression of AS severity, LV hypertrophy and dysfunction, and increased risk of mortality in patients with AS. This new blood biomarker may improve risk stratification and management of asymptomatic patients with AS. Further studies are needed to determine the mechanisms underlying this association between D-dimer and outcomes in AS.

Abstract 13260: Large Scale Plasma Proteomics Identifies MMP-12 as a Novel Biomarker of Aortic Stenosis Progression

Background: Aortic stenosis (AS) is associated with significant morbidity and mortality and is increasing in prevalence. Limited data exist regarding circulating biomarkers of AS risk. Methods: Among Atherosclerosis Risk in Communities study participants with available proteomics (Somascan v4) at study Visit 5 (2011-13; n=4,899; age 76 ± 5 years, 57% women), we used multivariable linear regression to evaluate the association of 4,877 plasma proteins with peak aortic valve (AV) velocity and AV dimensionless index. We then tested their association, when assessed at study Visit 3 (1993-95; n=11,430; age 60 ± 6, 54% women), with incident AV-related hospitalization post-Visit 3 (median follow-up 22, IQR 14 - 25 years) using multivariable Cox PH regression models. For the resulting candidate proteins, we assessed the association of Visit 5 protein levels with change in AV peak velocity over 6 years from Visit 5 to 7 (2018-19; n=2,314) and with quantitative AV calcification by cardiac CT at Visit 7 (n=1,804); associations with incident adjudicated AS in the Cardiovascular Health Study (CHS; n=3,413); and differences in AV tissue expression in normal, fibrotic, and calcific segments of explanted stenotic human AVs (n=3). Results: We identified 52 plasma proteins with consistent associations with AV peak velocity, AV dimensionless index, and incident AV hospitalization. Of these 52 proteins, MMP12 was also associated with magnitude of increase in AV peak velocity between Visits 5 and 7 (Figure), and with magnitude of AV calcification by CT at Visit 7 (adjusted OR 1.25 [95% CI 1.19-1.32], p=1.7x10 -17 ). Higher MMP12 was also associated with incident moderate or severe AS in CHS, an independent cohort. MMP12 expression was greater in calcific compared to fibrotic or normal AV tissue segments. Conclusions: Plasma MM12 is a potential novel circulating biomarker of AS risk.

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.

Impact of Variation in Commissural Angle between Fused Leaflets in the Functionally Bicuspid Aortic Valve on Hemodynamics and Tissue Biomechanics.

In subjects with functionally bicuspid aortic valves (BAVs) with fusion between the coronary leaflets, there is a natural variation of the commissural angle. What is not fully understood is how this variation influences the hemodynamics and tissue biomechanics. These variables may influence valvar durability and function, both in the native valve and following repair, and influence ongoing aortic dilation. A 3D aortic valvar model was reconstructed from a patient with a normal trileaflet aortic valve using cardiac magnetic resonance (CMR) imaging. Fluid-structure interaction (FSI) simulations were used to compare the effects of the varying commissural angles between the non-coronary with its adjacent coronary leaflet. The results showed that the BAV with very asymmetric commissures (120∘ degree commissural angle) reduces the aortic opening area during peak systole and with a jet that impacts on the right posterior wall proximally of the ascending aorta, giving rise to elevated wall shear stress. This manifests in a shear layer with a retrograde flow and strong swirling towards the fused leaflet side. In contrast, a more symmetrical commissural angle (180∘ degree commissural angle) reduces the jet impact on the posterior wall and leads to a linear decrease in stress and strain levels in the non-fused non-coronary leaflet. These findings highlight the importance of considering the commissural angle in the progression of aortic valvar stenosis, the regional distribution of stresses and strain levels experienced by the leaflets which may predispose to valvar deterioration, and progression in thoracic aortic dilation in patients with functionally bicuspid aortic valves. Understanding the hemodynamics and biomechanics of the functionally bicuspid aortic valve and its variation in structure may provide insight into predicting the risk of aortic valve dysfunction and thoracic aortic dilation, which could inform clinical decision making and potentially lead to improved aortic valvar surgical outcomes.

Influence of diabetes mellitus on the pathological profile of aortic stenosis: a sex-based approach

BackgroundDiabetes mellitus (DM) accelerates the progression of aortic stenosis (AS), but how their underlying molecular mechanisms interact is not clear. Moreover, whether DM contributes to clinically relevant sex-differences in AS is unknown. In this work we aim to characterize the sex-specific profile of major pathological mechanisms fundamental to aortic valve (AV) degeneration in AS patients with or without concomitant DM.Methods283 patients with severe AS undergoing surgical valve replacement (27.6% DM, 59.4% men) were recruited. Expression of pathological markers related to AS were thoroughly assessed in AVs and valve interstitial cells (VICs) according to sex and presence of DM. Complementary in vitro experiments in VICs in the presence of high-glucose levels (25 mM) for 24, 48 and 72 h were performed.ResultsOxidative stress and metabolic dysfunction markers were increased in AVs from diabetic AS patients compared to non-diabetic patients in both sexes. However, disbalanced oxidative stress and enhanced inflammation were more predominant in AVs from male AS diabetic patients. Osteogenic markers were exclusively increased in the AVs of diabetic women. Basal characterization of VICs confirmed that oxidative stress, inflammation, calcification, and metabolic alteration profiles were increased in diabetic VICs with sex-specific differences. VICs cultured in hyperglycemic-like conditions triggered inflammatory responses in men, whereas in women rapid and higher production of pro-osteogenic molecules.ConclusionsDM produces sex-specific pathological phenotypes in AV of AS patients. Importantly, women with diabetes are more prone to develop AV calcification. DM should be considered as a risk factor in AS especially in women.

Lp(a) in the Pathogenesis of Aortic Stenosis and Approach to Therapy with Antisense Oligonucleotides or Short Interfering RNA.

To date, no medical therapy can slow the progression of aortic stenosis. Fibrocalcific stenosis is the most frequent form in the general population and affects about 6% of the elderly population. Over the years, diagnosis has evolved thanks to echocardiography and computed tomography assessments. The application of artificial intelligence to electrocardiography could further implement early diagnosis. Patients with severe aortic stenosis, especially symptomatic patients, have valve repair as their only therapeutic option by surgical or percutaneous technique (TAVI). The discovery that the pathogenetic mechanism of aortic stenosis is similar to the atherosclerosis process has made it possible to evaluate the hypothesis of medical therapy for aortic stenosis. Several drugs have been tested to reduce low-density lipoprotein (LDL) and lipoprotein(a) (Lp(a)) levels, inflammation, and calcification. The Proprotein Convertase Subtilisin/Kexin type 9 inhibitors (PCSK9-i) could decrease the progression of aortic stenosis and the requirement for valve implantation. Great interest is related to circulating Lp(a) levels as causally linked to degenerative aortic stenosis. New therapies with ASO (antisense oligonucleotides) and siRNA (small interfering RNA) are currently being tested. Olpasiran and pelacarsen reduce circulating Lp(a) levels by 85-90%. Phase 3 studies are underway to evaluate the effect of these drugs on cardiovascular events (cardiovascular death, non-fatal myocardial injury, and non-fatal stroke) in patients with elevated Lp(a) and CVD (cardiovascular diseases). For instance, if a reduction in Lp(a) levels is associated with aortic stenosis prevention or progression, further prospective clinical trials are warranted to confirm this observation in this high-risk population.