Aortic Valve Area Research Articles

Combined Value of Dimensionless Index and Transvalvular Flow Rate in Risk Stratification of Aortic Stenosis

Aortic stenosis (AS) is difficult to phenotype. The metrics of severity are frequently discordant, making prognostication challenging. Flow state is central to accurately determining severity. We sought to evaluate the prognostic value of dimensionless index (DI) and transvalvular flow rate (Q) in AS. We evaluated 2 independent, longitudinal registries of ≥ moderate severity AS (aortic valve area ≤1.5cm2 or mean gradient ≥20mm Hg) with complete data follow-up. In the primary cohort (n=1,104, 77 ± 11years, 40% female), the DI and Q category significantly predicted mortality (p <0.001) (Figure 1), with the highest risk being low DI and low Q (DI <0.25, Q ≤210 mL/s). In the validation cohort (n=939, 70 ± 13years, 42% female), similar results were seen in Kaplan-Meier (p <0.001) and multivariable Cox model analyses (p <0.01). We advocate for wider combined use of DI and Q in AS assessment to augment current diagnostic and prognostic approaches.

Predicting pressure gradient using artificial intelligence for transcatheter aortic valve replacement

ObjectiveAfter transcatheter aortic valve replacement, the mean transvalvular pressure gradient indicates the effectiveness of the therapy. The objective is to develop artificial intelligence to predict the post–transcatheter aortic valve replacement aortic valve pressure gradient and aortic valve area from preprocedural echocardiography and computed tomography data. MethodsA retrospective study was conducted on patients who underwent transcatheter aortic valve replacement due to aortic valve stenosis. A total of 1091 patients were analyzed for pressure gradient predictions (mean age 76.8 ± 9.2 years, 57.8% male), and 1063 patients were analyzed for aortic valve area predictions (mean age 76.7 ± 9.3 years, 57.2% male). An artificial intelligence learning model was trained (training: n = 663 patients, validation: n = 206 patients) and tested (testing: n = 222 patients) to predict pressure gradient, and a separate artificial intelligence learning model was trained (training: n = 640 patients, validation: n = 218 patients) and tested (testing: n = 205 patients) for predicting aortic valve area. ResultsThe mean absolute error for pressure gradient and aortic valve area predictions was 3.0 mm Hg and 0.45 cm2, respectively. Valve sheath size, body surface area, and age were determined to be the top 3 predictors for pressure gradient, and valve sheath size, left ventricular ejection fraction, and aortic annulus mean diameter were identified to be the top 3 predictors of post–transcatheter aortic valve replacement aortic valve area. A training dataset size of more than 500 patients demonstrated good robustness of the artificial intelligence models for pressure gradient and aortic valve area. ConclusionsThe artificial intelligence–based algorithm has demonstrated potential in predicting post–transcatheter aortic valve replacement transvalvular pressure gradient predictions for patients with aortic valve stenosis. Further studies are necessary to differentiate pressure gradient between valve types.

Right ventricular function in severe aortic stenosis assessed by echocardiography and MRI.

The prevalence of aortic valve stenosis (AS) is increasing due to an ageing population. Despite that right ventricular function has prognostic value for postoperative outcome, the right ventricle (RV) is not extensively studied and often not routinely assessed in AS. Our aim was to explore the relation between severe AS and RV function in a surgical aortic valve replacement (SAVR) cohort, comparing two imaging modalities for RV evaluation. Patients with severe AS, underwent cardiovascular magnetic resonance imaging (CMR) and transthoracic echocardiography (TTE) before SAVR. RV dysfunction was defined as one or more of the following: tricuspid annular plane systolic excursion (TAPSE) < 17 mm, RV free wall strain (RVFWS) > -20% by TTE and RV ejection fraction (RVEF) <50% by CMR. Sixteen (33%) patients were found to have RV dysfunction. Patients with RV dysfunction showed significantly lower indexed aortic valve area, left ventricular (LV) ejection fraction as well as RV and LV stroke volumes compared to patients with maintained RV function. All patients with reduced RVEF also had changes in TAPSE or RVFWS and a larger number of patients had a reduced longitudinal RV function despite a normal RVEF. In a SAVR cohort one-third of the patients had RV dysfunction, defined by RVEF, TAPSE or RVFW strain. Echocardiography detected subtle changes in RV function before RVEF was reduced. It is likely that the more pronounced the AS, the more frequent the occurrence of RV dysfunction.

Treatment of severe symptomatic aortic valve stenosis using non-invasive ultrasound therapy: a cohort study

Calcific aortic stenosis is commonly treated using surgical or transcatheter aortic valve replacement; however, many patients are not considered suitable candidates for these interventions due to severe comorbidities and limited life expectancy. As such, non-invasive therapies might offer alternative therapeutic possibilities in these patients. This study aimed to assess the safety of non-invasive ultrasound therapy and its ability to improve valvular function by softening calcified valve tissue. This prospective, multicentre, single-arm series enrolled 40 adult patients with severe symptomatic aortic valve stenosis at three hospitals in France, the Netherlands, and Serbia between March 13, 2019, and May 8, 2022. Patients were treated with transthoracically delivered non-invasive ultrasound therapy. Follow-ups were scheduled at 1, 3, 6, 12, and 24 months. The primary endpoints were procedure-related deaths within 30 days and improved valve function. We report the 6-month data. This study is registered at ClinicalTrials.gov, NCT03779620 and NCT04665596. 40 high-risk patients with a mean Society of Thoracic Surgeons score of 5·6% (SD 4·4) and multiple severe comorbidities were included. The primary endpoint, procedure-related mortality, did not occur; furthermore, no life-threatening or cerebrovascular events were reported. Improved valve function was confirmed up to 6 months, reflected by a 10% increase in mean aortic valve area from 0·58 cm2 (SD 0·19) at baseline to 0·64 cm2 (0·21) at follow-up (p=0·0088), and a 7% decrease in mean pressure gradient from 41·9 mm Hg (20·1) to 38·8 mm Hg (17·8; p=0·024). At 6 months, the New York Heart Association score had improved or stabilised in 24 (96%) of 25 patients, and the mean Kansas City Cardiomyopathy Questionnaire score had improved by 33%, from 48·5 (SD 22·6) to 64·5 (21·0). One serious procedure-related adverse event occurred in a patient who presented with a transient decrease in peripheral oxygen saturation. Non-serious adverse events included pain, discomfort during treatment, and transient arrhythmias. This novel, non-invasive ultrasound therapy for calcified aortic stenosis proved to be safe and feasible. Cardiawave.

Biomechanical Evaluation of Aortic Valve Stenosis by Means of a Virtual Stress Test: A Fluid-Structure Interaction Study.

The impact of aortic valve stenosis (AS) extends beyond the vicinity of the narrowed leaflets into the left ventricle (LV) and into the systemic vasculature because of highly unpredictable valve behavior and complex blood flow in the ascending aorta that can be attributed to the strong interaction between the narrowed cusps and the ejected blood. These effects can become exacerbated during exercise and may have implications for disease progression, accurate diagnosis, and timing of intervention. In this 3-D patient-specific study, we employ strongly coupled fluid-structure interaction (FSI) modeling to perform a comprehensive biomechanical evaluation of systolic ejection dynamics in a stenosed aortic valve (AV) during increasing LV contraction. Our model predictions reveal that the heterogeneous ∆P vs. Q relationship that was observed in our previous clinical study can be attributed to a non-linear increase (by ~ 1.5-fold) in aortic valve area as LV heart rate increases from 70 to 115bpm. Furthermore, our results show that even for a moderately stenotic valve, increased LV contraction during exercise can lead to high-velocity flow turbulence (Re = 11,700) in the aorta similar to that encountered with a severely stenotic valve (Re ~ 10,000), with concomitant greater viscous loss (~3-fold increase) and elevated wall stress in the ascending aorta. Our FSI predictions also reveal that individual valve cusps undergo distinct and highly non-linear increases (>100%) in stress during exercise, potentially contributing to progressive calcification. Such quantitative biomechanical evaluations from realistic FSI workflows provide insights into disease progression and can be integrated with current stress testing for AS patients to comprehensively predict hemodynamics and valve function under both baseline and exercise conditions.

Aortic Valve Planimetry in Aortic Stenosis Quantification: Reliability of Three-Dimensional-Multiplane Reconstruction and Comparison With Established Methods

We aim to evaluate the reliability and consistency of measuring the aortic valve area (AVA) using 3-dimensional (3D) transesophageal echocardiography and compare it with invasive and noninvasive methods using a continuity equation (CE). Measurements were taken from 119 patients with different severity of aortic stenosis and with normal aortic valve who underwent elective transesophageal echocardiography encompassing the whole spectrum of aortic opening. Three methods were compared to determine AVA. First, the effective AVA was calculated with the standard CE, where the left ventricular outflow tract area was calculated from its 2-dimensional diameter (AVA-CEstd). Second, a modified CE method (AVA-CEmod) was used, in which the left ventricular outflow tract area was measured using 3D-multiplane reconstruction. Third, the geometric AVA was directly measured using 3D-multiplane reconstruction planimetry (AVA-3D). Interobserver and intraobserver variability were analyzed using intraclass correlation coefficients (ICCs). The values were measured by two blinded readers for interobserver variability and by one observer on the same dataset. AVA-3D was significantly larger than AVA-CEmod and AVA-CEstd (1.87 ± 1.00 cm2 vs 1.81 ± 0.92 cm2 p = 0.03 and 1.87 ± 1.00 cm2 vs 1.71 ± 0.85 cm2 p <0.001). However, in the subset of patients with AVA-3D <1.5 cm2, there was no significant difference between AVA-3D and AVA-CEmod (1.06 ± 0.24 vs 1.08 ± 0.26 cm2, paired t test: t=0.77, degree of freedom=58, p=0.44). The ICC between the measurements of AVA-3D and AVA-CEmod (ICC 0.979), and AVA-3D and AVA- CEstd (ICC 0.940), were excellent. AVA-3D delivers very similar results as compared with more established echocardiographic parameters. The difference between effective and geometric AVA did not appear to be clinically relevant in patients with a higher degree of stenosis.

Short- and Long-term Clinical Outcomes of Balloon-expandable Versus Self-expanding Valves in Patients Undergoing Transcatheter Aortic Valve Replacement: A Meta-analysis

Background: Distinct clinical differences exist between balloon-expandable valves (BEVs) and self-expanding valves (SEVs) used in transcatheter aortic valve replacement (TAVR) for aortic stenosis. However, randomised data on comparative outcomes are limited. The aim of this meta-analysis was to analyse the differences in short- and longer-term clinical outcomes between the two valve designs. Methods: A comprehensive literature search for all studies up to and including April 2020 on the clinical outcomes of BEVs versus SEVs was performed. Study outcomes were divided into short term (in-hospital or 30 days), intermediate term (1 year) and long term (3 years). The primary outcome was all-cause mortality. Secondary endpoints were stroke or transient ischaemic attack (TIA), life-threatening or major bleeding, at least moderate paravalvular leak (PVL), permanent pacemaker (PPM) implantation, aortic valve area (AVA) and aortic valve mean pressure gradient (AV MPG). Results: A total of 41 studies (BEV, n=23,892; SEV, n=22,055) were included. At in-hospital/30 days, all-cause mortality favoured BEV (OR 0.85; 95% CI [0.75–0.96]). BEV had lower rates of PVL (OR 0.42; 95% CI [0.35–0.51]) and PPM (OR 0.56; 95% CI [0.44–0.72]), but smaller AVA (mean −0.09 cm2; 95% CI [−0.17, 0.00]) and higher AV MPG (mean 2.54 mmHg; 95% CI [1.84–3.23]). There were no significant differences in the incidence of stroke/TIA or bleeding between the two valve designs. At 1 year a lower PPM implantation rate (OR 0.44; 95% CI [0.37–0.52]), fewer PVLs (OR 0.26; 95% CI [0.09–0.77]), smaller AVA (mean −0.23 cm2; 95% CI [−0.35, −0.10]) and higher AV MPG (mean 6.05 mmHg; 95% CI [1.74–10.36]) were observed with BEV. No significant differences were observed in mortality, stroke/TIA or bleeding. There was no significant difference in mortality at 3 years between the two valve designs. Conclusion: In the short–intermediate term, SEVs had better valve haemodynamics but had higher PVL and PPM implantation rates than BEVs. However, there were no differences in intermediate–long-term mortality, stroke or TIA, or bleeding complications. A better understanding of these differences will enable TAVR operators to tailor their valve choice based on individual patient profile.

Sex Differences in Clinical Outcomes after Aortic Valve Intervention for Isolated Severe Aortic Stenosis.

There are known pathophysiologic and clinical differences according to sex in patients with aortic stenosis (AS). To evaluate if these differences persist after valve replacement, we conducted an observational study including 451 patients with symptomatic AS who survived aortic valve intervention (AVI) in two centers. Clinical data and mortality were evaluated at a mean follow-up of 5 years. 56% of patients were women. At baseline, women were older (80.6 vs. 78 years, p = 0.013), presented higher mean gradient (48 vs. 45 mmHg, p = 0.023), lower aortic valve area (0.70 vs. 0.74 cm2, p = 0.002) and higher systolic pulmonary artery pressure (36 vs. 33 mmHg, p = 0.016). They underwent percutaneous aortic valve replacement more frequently than men (47 vs. 35.9%, p = 0.017). At 5 years follow-up, women required more admissions due to heart failure (23 vs. 9%, p = 0.046) but they did not present higher cardiovascular nor overall mortality (27.7% vs. 29.8%, p = 0.741; 11.1 vs. 10.1%, p = 0.619, respectively). Female sex was an independent predictor of heart failure hospitalization at follow-up (HR 95% 1.16-4.22, p = 0.016). Women undergo AVI at a more advanced stage than men, resulting in a higher frequency of readmissions due to heart failure during the follow-up period, but not in higher mortality.

Correlation of transesophageal echocardiography acquired 3D-multiplane reconstruction-planimetry of aortic valve area (AVA) with AVA determined by standard and modified continuity equation

Abstract Background Currently the most accepted method for measuring aortic valve area is the continuity equation. Planimetry is an alternative method that allows the direct measurement of the Aortic valve area (AVA). There are, however, pitfalls in this method, such as artifacts caused by valve calcification and difficulty with the correct alignment of the cusps. Furthermore, these measurements may not correlate linearly, as effective AVA may vary due to contraction of flow and specific 3-dimensional conformation of the aortic valve. The advent of new technology with three-dimensional multiplane reconstruction echocardiography (3D-MPR) could overcome some of those limitations. Methods Measurements were taken from 119 patients who underwent elective transesophageal echocardiography (TEE), encompassing the whole spectrum of aortic opening. AVA was first calculated with the standard continuity equation (CE) in which left ventricular outflow tract (LVOT) area was calculated from its 2D diameter (AVA-CEstd). Secondly, a modified CE (AVA-CEmod) was used, measuring the LVOT area with 3D-MPR. Thirdly, the AVA was directly measured by 3D-MPR planimetry using the maximal opening at mid-systole (AVA-3D). In a subset of 30 Patients in which right and retrograde left heart catheterization was clinically indicated and performed, cardiac output was estimated by the Fick formula and AVA was calculated by the Gorlin formula (AVAGorling). We determined the correlation and level of agreement of AVA-3D with AVA-CEstd, AVA-CEmod and AVAGorling. Lastly, inter-observer reproducibility was evaluated for AVA-3D. Results The mean AVA-3D, AVA-CEmod and CEstd were as wollows: 1.87cm2, 1.81cm2 and 1.69cm2 respectively. There was a strong correlation between AVA-3D and AVA-CEmod (r = 0.963, p &amp;lt; 0.001) with a mean difference of 0.056 cm2 ± 0.273. There was a strong correlation between AVA-3D and AVA-CEstd (r = 0.877, p &amp;lt; 0.001) with a mean difference of 0.179 cm2 ± 0.477. There was a moderate correlation between AVAGorling , AVA-3D (r = 0.40, p &amp;lt; 0.001), AVA-CEmod (r = 0.54, p &amp;lt; 0.001) and AVA-CEstd (r = 0.49, p &amp;lt; 0.001). Intra-observer (ICCs 0.991) and inter-observer (ICCs 0.983) agreement for AVA-3D measurements were excellent. Conclusion Comparison between AVA-3D, AVA-CEmod and CEstd showed a strong correlation and intra-observer and inter-observer variability for AVA-3D were excellent. The correlation of AVAGorling with the AVAs assessed by echocardiography was weaker. The mean differences and variability can be explained by the known hemodynamic and conceptual differences between the geometric AVA, effective AVA and AVA assessed by the Gorlin formula. We can therefore conclude that AVA-3D assessed by TEE is a useful tool in daily clinical practice as it overcomes some pitfalls of the planimetry method, although some of the limitations remain.

Dobutamine stress echocardiography in low-gradient aortic stenosis

Abstract Background Dobutamine stress echocardiography (DSE) is recommended to distinguish between true-severe and pseudo-severe aortic stenosis (AS) in patients with low flow low-gradients and left ventricular ejection fraction (LVEF) &amp;lt;50%. However, DSE has mostly been tested in the setting of LVEF&amp;lt;35%. Purpose The purpose of this study was to examine the diagnostic accuracy of DSE according to aortic valve calcification (AVC) score, in patents with low-flow, low-gradient AS across a wide range of LVEF. Methods Patients with aortic mean gradient &amp;lt;40 mmHg, aortic valve area (AVA) &amp;lt;1.0 cm2, and stroke volume index (SVi) ≤35 mL/m2 undergoing DSE were identified from three prospectively collected patient cohorts, and stratified according to LVEF; &amp;lt;35%, 35-50% and &amp;gt;50%. Severe AS was defined as AVC score ≥2000 AU among men, and ≥1200 AU for women. Recommendation for severe AS according to DSE, are an AVA &amp;lt;1.0 cm2 combined with an aortic mean gradient ≥40 mmHg or peak velocity ≥4 m/s. Receiver operating characteristic curves for DSE-derived AVA, mean gradient and Vmax were used to identify optimal cut-off points for each LVEF subgroup. Results Of the 221 patients included in the study, 78 (35%) presented with LVEF &amp;lt;35%, 67 (30%) with LVEF 35-50%, and 76 (34%) with LVEF &amp;gt;50%. Baseline characteristics are presented in the table. Based on AVC, severe AS was present in 102 (46%) of patients. Using recommended thresholds for severe AS for AVC and DSE, led to a sensitivity of 49%, a specificity of 84% and an accuracy of 67% for DSE for all patients with LVEF &amp;lt;50%, but with significant heterogeneity between groups figure. AVA performed rather uniformly across LVEF subgroups; (AUC =0.68 vs 0.62 vs 0.54, p=0.36) LVEF&amp;lt;35%, LVEF 35-50%, LVEF&amp;gt;50% respectively and displayed a rather uniform optimal cut-off (1.0 cm2 vs 0.9 cm2 vs 0.8 cm2). However, mean gradient and Vmax during DSE, both showed significantly diagnostic heterogeneity across LVEF groups (AUC= 0.90 vs 0.67 vs 0.65, p=&amp;lt;0.001 and AUC= 0.90 vs 0.66 vs 0.60, p=&amp;lt;0.001) with different optimal thresholds (30 mmHg &amp; 3.8 m/s, 45 mmHg &amp; 4.3 m/s and 37mmHg &amp; 4 m/s, LVEF&amp;lt;35%, LVEF 35-50%, LVEF&amp;gt;50%, respectively). Conclusion Our study shows, that the association between DSE gradients and AS severity assessed by AVC demonstrates important heterogeneity depending on LVEF. While DSE had the highest accuracy in patients with LVEF&amp;lt;35% both patients with LVEF 35-50%, and patients with LVEF&amp;gt;50% showed significantly less concordance between DSE and AVC.

Exploring the mechanisms responsible for afterload mismatch in severe aortic stenosis

Abstract Introduction Afterload mismatch (AM) is defined as a reduced ejection fraction (EF) in the setting of severe aortic stenosis (AS) (aortic valve area (AVA) of &amp;lt; 1cm2), but with transaortic pressure gradients in the severe range. The pathomechanism underlying the impaired EF remains unclear, especially with regards to the impact of ventricular hypertrophy and fibrosis, the role of afterload, and the integrity of the intrinsic contractile myocardial strength in AM. This knowledge gap unmasks a lack of understanding into the natural disease progression in AS. Purpose To characterise the morphological and functional contractile mechanics that distinguishes patients with reduced EF from patients with preserved EF in the setting of AS with high transvalvular gradients. Methods A prospective comparative analysis was performed on 21 sequential cases of patients with severe AS, 9 with AM (AVA &amp;lt; 1.0cm2; MG &amp;gt; 40mmHg; EF &amp;lt; 50%) and 12 with normal flow high gradient (NFHG) AS (AVA &amp;lt; 1.0cm2; MG &amp;gt; 40mmHg; EF &amp;gt; 50%). Patients with concomitant valve lesions or previously diagnosed myocardial infarction, were excluded. Myocardial morphology, function and tissue characteristics were evaluated using a) transthoracic echocardiography, b) cardiac magnetic resonance imaging, and c) an invasive hemodynamic study with pressure-volume loop derived data. Results Intrinsic load independent contractile muscle function parameters were similar between AM and NFHG AS (p-value non-significant for cardiac index, dP/dT(max), preload recruitable stroke work slope, end systolic pressure volume relationship slope and Starling contractile index slope). Afterload indices as assessed by peak systolic wall stress and valvuloarterial impedance were significantly higher in AM cases compared to NFHG AS (32.5 vs 19.9 N/cm2; p &amp;lt; 0.01 and 4.8 vs 3.4mmHg/ml; P = 0.05). This was driven by disproportionally higher degrees of valvular stenosis in the AM group (valve area 0.46 vs 0.78cm2; p &amp;lt; 0.01). The AM group expressed a more advanced disease phenotype with more symptoms (NYHA 3.3 vs 2.3; p=0.02), more pulmonary hypertension (50 vs 30mmHg; p=0.04), and more extensive myocardial fibrosis (24% vs 13% of left ventricular mass; p=0.03) (see Figure 1). Neither more severe LVH nor higher degrees of fibrosis in the AM group, was associated with a demonstrable impairment in the intrinsic contractile muscle function. Conclusion Our data suggest that the central problem in AM is related to an excessively increased afterload, primarily driven by more severe valvular stenosis, with preserved intrinsic left ventricular contractile function. AM is characterised by more severe myocardial fibrosis, as a marker of a more advanced disease phenotype, but this did not translate into worse intrinsic contractile muscle function. The known time dependence of progressive valvular stenosis and myocardial fibrosis would suggest that AM is an intermediate phase between NFHG AS and so-called low flow low gradient severe AS.A more advanced phenotype

Dobutamine stress echocardiography remains indispensable for the diagnosis of low-flow low-gradient severe aortic stenosis

Abstract Background In patients with low-gradient aortic stenosis (AS) and low transvalvular flow, current guidelines recommend dobutamine stress echocardiography (DSE) to determine valve stenosis severity. Additionally, aortic valve calcification (AVC) scores are also used with this intent. Previous studies have determined cut-off values of ≥2000AU for men and ≥1200AU for women to distinguish between true severe AS and pseudosevere AS. Purpose To assess the relationship between AVC and DSE in low-flow low-gradient aortic stenosis. Methods We performed a multicenter international registry study including patients that underwent DSE to determine AS severity and multi-slice computed tomography (MSCT) of sufficient quality to determine AVC scores. Severe AS was diagnosed when resting peak aortic valve velocity was ≥4.0 m/s, or stress aortic valve area (AVA) remained &amp;lt;1.0cm2 at peak dobutamine stress levels; moderate AS was diagnosed when resting AVA was ≥1.0cm2 and peak velocity was &amp;lt; 4.0m/s or stress AVA exceeded 1.0cm² at peak stress. Using the previous cut-off values, MSCT-AVC scores were compared to DSE-derived AS diagnoses to determine sensitivity and specificity of AVC, and the positive and negative predictive values of high and low scores. Subsequently, we performed a receiver-operating characteristics (ROC)-curve analysis for men and women separately. Results We included 271 patients from 8 centers, of which 231 patients had sufficiently interpretable DSE and MSCT. Median age was 79 years (Interquartile range (IQR): 71-84), median BMI was 26.4 kg/m2 (IQR: 24.1-30.0) and median BSA was 1.9 m2(IQR: 1.8-2.1). Left ventricular ejection fraction was reduced (&amp;lt;50%) in 209 (90.5%) patients. Bicuspid valve morphology was present in 20 patients (8.7%). DSE confirmed severe AS in 103 patients, 4 of whom already had resting peak aortic valve velocity ≥4.0m/s. Moderate AS was diagnosed in 128 patients, of which 76 had a resting AVA ≥ 1.0cm2. Characteristics of these patients are summarized the table. Of the patients with severe AS, 49 (47.6%) had a high AVC score (≥2000 for men or ≥1200 for women) and of patients with moderate AS, 75 (58.6%) had an AVC score below those cut-off values. This corresponds to a sensitivity of 47.6%, a specificity of 58.4% and positive and negative predictive values of 53.5% and 51.6%, respectively. The ROC-curves are shown in the figure; the area under the curve was 0.55 for men and 0.52 for women, signifying poor discriminative performance. Conclusion In this multicenter international registry we found that aortic valve calcification scores correlated poorly with AS severity and therefore DSE remains the preferred technique to assess borderline AS severity.Table.Patient characteristicsFigure.ROC curve

An artificial intelligence algorithm for detection of severe aortic stenosis: a clinical cohort study

Abstract Background/Introduction Despite guideline based indications, nearly 1/3 of patients with symptomatic severe aortic stenosis (AS) are not referred for intervention. Artificial Intelligence Decision-Support Algorithms (AI-DSAs) may be helpful to identify individuals with AS at risk for premature mortality but few have been validated for use. Purpose To evaluate an AI-DSA based on echocardiogram report data to augment the detection of severe AS within a well-resourced health care setting. Methods Blinded to clinical information, an AI-DSA trained to identify an aortic valve area (AVA) &amp;lt;1cm2 using minimal input data was applied to routine transthoracic echocardiogram reports from 31,141 US Medicare beneficiaries (≥ 65 years old) at a large US academic medical center (2003-2017) (Figure). Results Performance of the AI-DSA to detect an AVA &amp;lt;1cm2 was excellent (sensitivity 95.2%, specificity 94.8%, negative predictive value 99.8%). The AI-DSA identified 1,549 (5.0%) individuals with guideline-defined severe AS plus 463 (1.5%), 979 (3.1%), and 28,150 (90.4%) individuals with a severe AS (not meeting guidelines), moderate AS, and low-probability AS phenotypes. Five-year mortality was 73.9%, 77.1%, 71.2%, and 43.6% respectively (adjusted HR compared to low-probability AS, HR 1.40, 95% CI 1.31-1.50 [guideline severe], HR 1.31, 1.17-1.46 [non-guideline severe], HR 1.21, 1.12-1.23 [moderate], p &amp;lt; 0.001 for all). Overall, rates of aortic valve replacement (AVR) remained low, even in those with an AVA &amp;lt;1cm2 (21.9%), despite it being associated with improved survival. Findings remained consistent among outpatients, those investigated in the past decade and those with left ventricular systolic dysfunction. Conclusions Without relying on left ventricular outflow tract measurements, an AI-DSA used echocardiographic reports to reliably identify those with severe AS. These results suggest possible utility for this AI-DSA to enhance detection of individuals with the phenotype of severe AS, at risk for adverse outcomes.Figure:Graphical Abstract

Determinants of exercise-induced B-lines in asymptomatic severe aortic stenosis

Abstract Background Guidelines recognize the role of exercise stress testing in evaluating functional capacity in patients with asymptomatic severe aortic stenosis (AS). Exercise stress echocardiography (ESE) allows the detection of pulmonary congestion with B-lines by lung ultrasound (LUS). Aim To identify the prevalence, determinants, and functional correlates of B-lines during ESE in asymptomatic severe AS. Methods We enrolled 35 asymptomatic patients (age= 69±16 years, 69% male) with severe AS, aortic valve area (AVA) &amp;lt;0.6 cm2/m2, mean aortic gradient (MAG) ≥ 40 mmHg, left ventricular ejection fraction ≥55%. All patients were referred for ESE (treadmill in 1, bicycle in 34 patients) in 7 experienced centers from 4 countries between 2021-2022. ESE assessment at rest and peak stress included global longitudinal strain (GLS), left atrial volume index (LAVI) and cardiac output (CO). B-lines were assessed by simplified LUS from 4 lung zones across the third intercostal space (2 on each side). Heart rate reserve (HRR) was measured as the peak/rest heart rate. CO reserve was calculated as the difference between peak stress CO and rest CO. Results B-lines (≥2) were present in 2 patients at rest and in 15 patients during ESE (6% vs 43%, p&amp;lt;0.001). When compared to patients without B-lines during ESE (Group 1, n=20), patients with B-lines during ESE (Group 2, n=15) were older (Group 1= 64±18 vs Group 2=75±8 years, p=0.030) had larger LAVI, higher logNT-pro-BNP and a trend to higher systolic pulmonary artery pressures (SPAP), see Table. The 2 groups showed similar values of resting AVA (Group 1= 0.52±0.11 vs Group 2=0.47±0.15 cm2/m2, p=0.311), stress AVA (Group 1= 0.45±0.09 vs Group 2=0.49±0.13 cm2/m2, p=0.663), resting MAG (Group 1= 45±15 vs Group 2=46±10 mm Hg, p=0.491), and stress MAG (Group 1= 59±19 vs Group 2=58±11 mm Hg, p=0.665). Patients with B-lines during ESE showed lower HRR and CO reserve, with a trend towards lower peak GLS, see Table. Conclusions Exercise-induced pulmonary congestion as evidenced by development of sonographic B- lines on LUS were present commonly (43%) among patients with "asymptomatic" severe AS undergoing ESE. Patients with exercise-induced B-lines have larger resting LAVI, higher NT-pro-BNP levels, lower CO reserve, and blunted HRR. Exercise-induced B-lines might provide an early sign of cardiac decompensation in "asymptomatic" patients with severe AS, which is an important factor to consider in the decision to intervene.TableFigure

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

Survival and predictors of outcome in moderate mixed aortic valve disease

Abstract Background Coexisting moderate aortic stenosis and regurgitation (MAVD) is common. The haemodynamic effect of MAVD is poorly understood with sparse data to guide risk stratification. Purpose This study aims to compare all-cause mortality in moderate MAVD with matched controls and identify markers associated with prognosis. Methods Patients with both moderate aortic stenosis (aortic valve area [AVA] 1.0-1.5cm2) and regurgitation (vena contracta [VC] 0.3-0.6cm) were identified from a multicentre registry. All-cause mortality was compared to an age and sex matched UK population. The association between echocardiographic and clinical metrics with all-cause mortality was evaluated. Results 207 patients were included, age 78 [66-84] years and moderate MAVD (AVA 1.2 [1.1- 1.4]cm2 and VC 0.4 [0.4-0.5]cm). Over a median follow up of 3.2 years, 75/207 (36.2%) patients died. Patients with moderate MAVD had a significantly higher mortality compared to age and sex matched controls (36% versus 14.3%), p&amp;lt;0.001. Peak aortic jet velocity (Vmax) was the only haemodynamic metric independently associated with mortality [hazard ratio (HR): 0.61, 95% confidence interval (CI): 0.39-0.93; p=0.02] in a multivariate model along with age, creatinine and previous cerebrovascular accident. Compared to patients with Vmax &amp;gt;3m/sec, those with Vmax ≤3.0m/s had lower LVEF and stroke volume and a higher mortality (HR: 1.76, 95% CI: 1.10-2.80; p=0.017). Conclusions Moderate MAVD is associated with reduced survival compared to age and sex matched controls. Patients with discordant low Vmax ≤3 m/sec, have disproportionately worse outcome and may represent a high risk ‘low flow’ phenotype.Figure 1

Cardiac magnetic resonance correlates of staging algorithm in patients with asymptomatic severe aortic stenosis

Abstract Background The staging algorithm recently proposed to risk stratify patients with severe aortic stenosis (AS) has not been largely applied to patients who are asymptomatic. While the presence of severe tricuspid regurgitation, pulmonary hypertension and right ventricular dysfunction (stages 3-4) is expected to be low, the prevalence of left ventricular damage (LV), mitral regurgitation, left atrial (LA) dilation and atrial fibrillation (stages 1-2) can be higher in patients with asymptomatic severe AS. The cardiac magnetic resonance (CMR) correlates of the staging algorithm have not been described. Purpose To investigate the distribution of patients with asymptomatic severe AS in the staging algorithm and its differences with CMR findings. In addition, differences in CMR data between patients presenting with AS-related adverse events at 1-year follow-up and patients free of events were compared. Methods Patients with asymptomatic severe AS (aortic valve area, AVA&amp;lt;1.0 cm2) and preserved LV ejection fraction (EF) (&amp;gt;50%) that were referred to CMR were included. Biomarkers, echocardiographic and CMR data were assessed retrospectively. CMR-derived parameters included LV and right ventricular (RV) volumes and systolic function, LA volumes and tissue characterization were reported at baseline and compared with AS-related events (a composite of all-cause mortality, symptoms onset, or need for aortic valve replacement) during 1-year follow-up. Results Of 97 patients included (73±9 years old; 36% males), 3 (%) patients were classified in Stage 0, 34 (35%) in Stage 1, 59 (61%) in Stage 2, and 1 (1%) in Stage 3 or 4. Compared to stage 1, patients in stage 2 were older (P=0.006) and had a higher prevalence of overweight (P=0.037), hypertension (P=0.018), NT-proBNP (P=0.030) and hsTnT (p=0.011) levels. On CMR, they showed higher LV volumes and mass index, larger LA volumes and reduced LA ejection fraction, but no differences on myocardial tissue characteristics (Table 1). Regarding prognosis, 45 (46.5%) patients presented AS-related events at 1-year follow-up. Those with events were mainly in stage 2 (36%) and presented higher NT-proBNP levels despite showing no differences in AVA. On CMR, those with events had lower LVEF, greater LV to RV end-diastolic volume ratio, greater left atrio-ventricular coupling index, reduced LA function and a higher extension of late gadolinium enhancement (Table 2). Conclusions In our cohort, most patients with severe asymptomatic AS were in stage 2. Stage 2 patients presented a higher degree of left-chambers remodelling on CMR compared to patients in stage 1. Patients in stage 2 or with lower LVEF, LV remodelling or reduced LAEF on CMR were those with an increased risk for events at follow-up.

Impact on clinical outcome of ventricular arrhythmias in patients undergoing transcatheter aortic valve implantation (TAVI)

Abstract Background Transcatheter aortic valve implantation (TAVI) in the treatment of severe aortic stenosis has considerably grown in the latest years. There are limited data, however, about predictors of long-term prognosis in this population. Particularly, whether ventricular arrhythmic burden is associated with clinical outcome has poorly been investigated. Purpose The aim of our study was to investigate the association between ventricular arrhythmias and adverse clinical outcomes in patients undergoing TAVI. Methods We performed a 24-hour 3-channel ECG Holter monitoring (HM) in 267 consecutive patients who underwent TAVI for severe aortic stenosis at our Centre within 30 days from a successful procedure (average 10.2 days, range 2-30). For each patient we obtained the number of premature ventricular complexes (PVCs) and the presence of non-sustained ventricular tachycardia (NSVT, &amp;gt;3 PVCs with a rate &amp;gt;100 bpm). Frequent PVCs were defined as the presence of at least 30 PVCs per hour. We also collected clinical and echocardiographic findings for each patient. Assessment of clinical events at follow-up was performed by clinical visits or telephone interviews of patients or relatives (in case of fatal events). The primary endpoint of the study was the occurrence of cardiovascular events (CVE), a composite of cardiovascular death and resuscitation from cardiac arrest. All-cause-mortality was assessed as secondary endpoint. Survival Cox regression was applied to assess the univariate and multivariate association of clinical, echocardiographic and HM variables with endpoints. Results Clinical outcome could be obtained for 228 patients (85%), for an average follow-up of 3.5 years (range 1.0-8.6). Among these patients, frequent PVCs (≥30/hour) and episodes of NSVT at HM were found in 47 (20.6%) and 52 (22.4%) patients, respectively. CVE occurred in 26 patients (11.4%) and 63 patients died (27.6%). Frequent PVCs at HM were detected in 12 patients with (46.2%) and 35 patients without (17.3%) CVE (HR 2.29; 95% CI 1.03-5.09; p=0.04). One or more episodes of NSVT were detected in 9 patients with (34.6%) and 43 patients without (21.3%) CVE (HR 2.29; 95% CI 1.03-5.09; p=0.04), although it was not predictive of all-cause mortality (HR 1.18; 95% CI 0.48-2.77; p=0.52). Both the presence of PVCs&amp;gt;30/hour (HR 1.19; 95% CI 0.69-2.08; p=0.53) and NSVT (HR 0.93; 95% CI 0.52-1.65; p=0.22) were not significantly associated with all-cause mortality. Moreover, no clinical (age, gender, cardiovascular risk factors) and echocardiographic (aortic valve area, trans-aortic mean gradient, left ventricle mass and ejection fraction) variable showed significant association with both the primary and secondary outcome in our patients. Conclusions In our study the detection of frequent PVCs at HM after TAVI was a major predictor of CVE (cardiovascular death/cardiac arrest), suggesting that a 24-hour HM after TAVI can be helpful for risk stratification of these patients.

The traditional classification of aortic stenosis: impact on mortality

Abstract Background The clinical course of patients with aortic stenosis (AS) depends on the stage of the disease which is defined by the degree of the aortic valve stenosis and left ventricular (LV) function. Objectives This study sought to analyze the mortality of different stages of the AS defined by the traditional classification, based on aortic valve area (AVA; cm2), peak velocity across the aortic valve (VP; m/sec), mean pressure gradient across the aortic valve (MGP; mmHg), left ventricular ejection fraction (EF; %) and stroke volume (SV; ml). Methods Single-center, retrospective study. Patients were classified into four groups: Group 1 (moderate AS: 1≤AVA &amp;lt;1.5 cm2 and (20&amp;lt;mg&amp;lt;= 3&amp;lt;vp&amp;lt;="4)),"&amp;gt;40), Group 3 (paradoxical low flow, low gradient AS: AVA&amp;lt;1.0 and MPG≤40 and EF ≥50 and SV&amp;lt; 67) and Group 4 (classical low flow, low gradient AS: AVA&amp;lt;1. and MPG≤40 mmHg and EF&amp;lt;50 and SV&amp;lt;67). Results 2619 patients evaluated for AS between Jan 2014 and Dec 2021 in the central echocardiographic laboratory of the university medical center were initially analyzed. Of them, 1645 patients completed follow-ups and were included in this study. The basic patient characteristics were as follows: mean age 69.6±10.5 yrs, 59% were male, 33% had diabetes mellitus, 15% had atrial fibrillation. The baseline echocardiographic measurements were as follows: VP 4.06±1.4 m/s, PG 67±25 mmHg, MG 40±16 mmHg, AVA 0.83±0.28cm2, LV EDD 5.3±0.73cm, LA diameter 4.4±0.7cm, RV diameter 2.5±0.4cm, RVSP 40.5±12.9 mmHg, EF 60.0±11.8%, SV 70.7±23.7ml. The distribution of patients according to the stages of AS is Group 1: 30%, Group 2: 54%, Group 3: 11%, and Group 4: 5%. During the median 52 months of follow-up, 60% of patients had a surgical aortic valve replacement. In the whole cohort, during the first 5 years, 61.2% of patients died with a significant difference in mortality across the groups: Group 1 vs Group 2 vs Group 3 vs Group 4: 56.5% vs 63.8% vs 54.1% vs 79.4%, p=0.022. The survival analysis (Kaplan Meier) (Picture 1) confirmed significant differences in survival (for overall comparisons: Log Rank (Mantel-Cox) Chi-Square 16.263, p=0.001). The pairwise survival analysis between the groups revealed significant differences between Group 1 vs Group 2 (p=0.018), Group 1 vs Group 4 (p&amp;lt;0.001), Group 2 vs Group 3 (p=0.044), Group 2 vs Group 4 (p=0.021) and Group 3 vs Group 4 (p=0.001). Conclusion Patients with aortic stenosis have still significant mortality during long-term follow-up. It depends on the severity/stages (phenotype) of the disease defined by the traditional classification with an increasing mortality rate from moderate AS, towards classical severe AS and classical LF/LG severe AS, whereas patients with paradoxical LF/LG severe AS have similar survival compared to patients with moderate AS. The impact of early intervention in moderate and paradoxical LFF/LG severe AS patients deserves further investigation.

Impact of hypertension on mean transvalvular gradients in aortic stenosis Lessons learned from in silico modelling

Abstract Introduction The influence of hypertension on the diagnostic assessment of aortic stenosis (AS) severity is unclear, yet clinically relevant. To clarify the effect of hypertension on transvalvular gradients, requires a better understanding of the impact that blood pressure change has on mean flow rate. Also, the effect of various degrees of AS severity, the valve geometry and intrinsic left ventricular contractile function (elastance) on this interaction, needs to be clarified. Existing clinical research on this topic is limited by not incorporating the full complement of factors that influences the directionality and magnitude of mean transvalvular gradient change for any given change in blood pressure. Purpose To use validated flow dynamics modelling grounded in fundamental physics principles to create a digital platform where various parameters can be manipulated to quantify the effects of bloodpressure change on mean transvalvular gradients in various pathological states. Methods A validated, zero-dimensional electro-hydraulic analogue computer model of the human cardiovascular circulatory system was generated. It was used to assess the impact of blood pressure changes on left ventricular pressure and transvalvular gradients at various flow rates, left ventricular elastances, a range of aortic valve areas and for different aortic valve morphologies. Results Mean transvalvular gradients are flow dependent. The impact of hypertension on mean flow rate (MFR), and hence on mean gradient (MG), is influenced by the aortic valve area as well as the underlying left ventricular elastance (Figure 1). Subsequently, the relationship between MFR and MG could be modelled (Figure 2). Generally, for a given change in systemic arterial pressure, the impact on MG will be the most marked for lower flow rate states such as is expected in more severe degrees of AS and for worse intrinsic left ventricular (LV) contractility. Furthermore, for a constant hemodynamic valve area, the hydraulic valve orifice area was found to be smaller in rheumatic AS compared to degenerative AS. This results in less susceptibility to blood pressure induced changes in mean transvalvular gradient. Similarly, the size of the aortic root was found to be inversely related to the susceptibility to induce a change in mean gradient for a change in blood pressure. Conclusion The interaction between hypertension and mean gradients in AS is complex. The current work places previous recommendations in perspective by quantifying the magnitude of the effect that a change in blood pressure has on mean gradient in various pathophysiological states. By doing so it provides more granularity into this multifaceted interaction compared to previously oversimplified deductions from clinical studies. The findings of this study creates a basic science framework based on first principles that dictates the scope of parameters that should be considered in future clinical research on the topic.Modelling 1Modelling 2