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Background The mortality risk attributable to moderate aortic stenosis (AS) remains incompletely characterized and has historically been underestimated. We aim to evaluate the association between moderate AS and all‐cause death, comparing it with no/mild AS (in a general referral population and in patients with heart failure with reduced ejection fraction). Methods and Results A systematic review and pooled meta‐analysis of Kaplan–Meier‐derived reconstructed time‐to‐event data of studies published by June 2023 was conducted to evaluate survival outcomes among patients with moderate AS in comparison with individuals with no/mild AS. Ten studies were included, encompassing a total of 409 680 patients (11 527 with moderate AS and 398 153 with no/mild AS). In the overall population, the 15‐year overall survival rate was 23.3% (95% CI, 19.1%–28.3%) in patients with moderate AS and 58.9% (95% CI, 58.1%–59.7%) in patients with no/mild aortic stenosis (hazard ratio [HR], 2.55 [95% CI, 2.46–2.64]; P <0.001). In patients with heart failure with reduced ejection fraction, the 10‐year overall survival rate was 15.5% (95% CI, 10.0%–24.0%) in patients with moderate AS and 37.3% (95% CI, 36.2%–38.5%) in patients with no/mild AS (HR, 1.83 [95% CI, 1.69–2.0]; P <0.001). In both populations (overall and heart failure with reduced ejection fraction), these differences correspond to significant lifetime loss associated with moderate AS during follow‐up (4.4 years, P <0.001; and 1.9 years, P <0.001, respectively). A consistent pattern of elevated mortality rate associated with moderate AS in sensitivity analyses of matched studies was observed. Conclusions Moderate AS was associated with higher risk of death and lifetime loss compared with patients with no/mild AS.

Background: Aortic Valve Calcification (AVC) is intrinsic to aortic stenosis (AS). While established concepts assume homogeneous calcification causing AS, wide variability in hemodynamic severity at any given AVC burden suggests other operative mechanisms. Multidetector computed tomography (MDCT) now accurately measures global AVC, but AVC spatial distribution remains elusive due to imaging orientation. Methods and Results: We developed ‘en-face’ imaging by re-registration of 4D-MDCT to quantify AVC spatial distribution and analyzed global AVC load and AVC distribution in 418 patients with AS (76±9 years; mean gradient 35±17 mmHg). 4D-volume-rendered MDCT datasets were re-oriented to en-face view of aortic valve for AVC spatial scoring with individual cusp calcification load, cusp-edge calcification and AVC asymmetry. Despite high total AVC load (450 [250-666] AU/cm 2 ), asymmetry was frequent (50%), with a difference between most- and least-calcified cusp of 112 [66-182] AU/cm 2 . Maximum AVC was in the non-coronary cusp in 61% (p<0.001). Cusp edge calcification was none-mild in 26%, moderate in 62% and severe in 12%. Adjusting for total AVC, severe AS (mean gradient >40 mmHg) was more likely with symmetrical AVC (odds ratio [OR] 2.36, p<0.001) and with edge calcification moderate (OR 4.16, p=0.001 vs none-mild) to severe (OR 10.7, p=0.001). Inclusion of AVC distribution improved models predicting AS severity over total AVC (p<0.001). Conclusions: Four-dimensional MDCT en-face re-registration and AVC quantitation provides new insight into AS pathophysiology. Contrary to classical concepts, AVC is frequently inhomogeneous and asymmetric. Hemodynamic AS severity is independently affected not only by global AVC but also by variations in AVC distribution and location within cusps, emphasizing the importance of 4D AVC assessment in AS. Impact of quantified AVC asymmetry and location on outcome of transcutaneous aortic valve replacement should be evaluated.

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) &lt;50%. However, DSE has mostly been tested in the setting of LVEF&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 &lt;40 mmHg, aortic valve area (AVA) &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; &lt;35%, 35-50% and &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 &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 &lt;35%, 67 (30%) with LVEF 35-50%, and 76 (34%) with LVEF &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 &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&lt;35%, LVEF 35-50%, LVEF&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=&lt;0.001 and AUC= 0.90 vs 0.66 vs 0.60, p=&lt;0.001) with different optimal thresholds (30 mmHg & 3.8 m/s, 45 mmHg & 4.3 m/s and 37mmHg & 4 m/s, LVEF&lt;35%, LVEF 35-50%, LVEF&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&lt;35% both patients with LVEF 35-50%, and patients with LVEF&gt;50% showed significantly less concordance between DSE and AVC.

Objective CT aortic valve calcium score (AVCscore) and density (AVCdensity) thresholds have been recommended for aortic stenosis (AS) severity assessment in tricuspid aortic valve (TAV). We aimed to compare AVCscore and AVCdensity in bicuspid aortic valve (BAV) versus TAV. Methods Retrospective single-centre study of patients with echocardiographic AS-severity and CT-AVC assessments within 6 months, and left ventricular ejection fraction ≥50%, all referred for clinical AS evaluation. Severe AS was defined as aortic valve area (AVA) ≤1 cm2 or indexed AVA ≤0.6cm2/m2 plus mean gradient ≥40 mm Hg or peak velocity ≥4 m/s. AVC was assessed by Agatston method. Results Of the 1957 patients, 328 had BAV and 1629 had TAV, age 65±11 vs 80±9 years (p<0.001), men 65% vs 56% (p=0.006), respectively. BAV morphology was associated with higher AVCscore and AVCdensity independent of age, comorbidities and AS severity (p<0.001) in men only (sex and BAV interaction p<0.001). In patients with severe AS, mean AVCscore and AVCdensity were higher in BAV-men than that in TAV-men (both p<0.001), but similar in BAV-women and TAV-women (both p≥0.4). Such patterns remained the same after adjustment for clinical covariates and AS severity. Best thresholds for severe AS diagnosis in BAV-men were 2916 AU by AVCscore and 600 AU/cm2 by AVCdensity which were higher than the guideline-recommended thresholds, while thresholds in BAV-women (1036 AU and 282 AU/cm2) were similar to guideline-recommended ones. Conclusion Valve calcification in AS differs according to valve morphology and sex. BAV-men with severe AS exhibit greater AVCscore and AVCdensity than TAV-men. This presents a diagnostic challenge to the current guidelines, which needs confirmation in larger studies.

Introduction: Aortic valve calcification (AVC) is the key pathophysiology underlying aortic stenosis (AS). We aimed to assess computed tomography AVC in AS by valve morphology (bicuspid [BAV] vs. tricuspid aortic valve[TAV]) and sex. Methods: Retrospective study of patients with echocardiographic AS severity and AVC assessments within six months. Patients with > moderate aortic regurgitation, prosthetic aortic valve, or indeterminate aortic valve morphology were excluded. Severe AS with high mean gradient (MG) was defined as aortic valve area (AVA)≤1cm2 or indexed AVA≤0.6 cm2/m2 + MG≥40 mmHg. Results: Of 2647 patients, 361(65% men) had BAV and 2286(59% men) had TAV, age 65±11 vs. 80±9 years(p<0.001), AVA 1.07±0.42 vs. 0.90±0.25 cm2(p<0.001), MG 41±16 vs.42±14 mmHg(p=0.4) for BAV and TAV, respectively. For both BAV and TAV groups, age, MG, and severe AS frequency were similar between women and men(all p≥0.06). BAV morphology affected AVC-AS severity and AVC-sex associations (p for interactions <0.001): as AS severity increased, mean AVC difference became larger between BAV-men and TAV-men, but smaller between BAV-women and TAV-women. Similar patterns were observed in AVC density (AVCd, AVC divided by left ventricular outflow tract diameter)-AS severity and AVCd-sex associations (p for interactions < 0.001). In patients with concordant AS severity and MG levels, the best BAV AVC-cutoff for detecting severe AS + high MG by area-under-the-curve analysis was 924 AU for BAV-women and 2851 AU for BAV-men, different from guideline-recommended AVC-thresholds (1200 for women and 2000 for men). The best BAV AVCd cutoff was 289 for BAV-women and 476 for BAV-men, similar to the cutoffs for patients predominantly with TAV (292 for women and 476 for men from Clavel MA JACC 2013). The BAV-AVC threshold identified more patients with severe AS than guideline-recommended threshold in BAV-women (84% vs 74%, p<0.001), but not in BAV-men. Conclusions: Valvular calcium accretion in AS was different by valve morphology and sex. As compared to TAV, BAV-women exhibited the least calcification while BAV-men exhibited the highest. Such patterns may impact the sensitivity of guideline-recommended AVC thresholds for detecting severe AS in BAV patients.

Introduction: Left ventricular longitudinal strain (LV-LS) 1) predicts mortality in patients with aortic stenosis (AS) and 2) is highly correlated to type-B natriuretic peptide (BNP) values. The BNP ratio (measured BNP/maximal expected BNP value specific for age and sex) is a powerful independent predictor of death in patients with AS. Hypothesis: we hypothesize that BNP activation (i.e. BNP ratio >1) affects the association between LV-LS and mortality in patients with asymptomatic AS and preserved LV ejection fraction (EF ≥50%). Methods: 315 patients (age 74±12 years, 56% men and mean aortic valve area = 1.02±0.15cm2) underwent simultaneous Doppler echocardiographic and BNP measurements. LV-LS was calculated as the average of 12 LV segments from apical 2- and 4-chamber views using Velocity Vector Imaging. Results: Mean LV-LS was -16.8±3.2%, LV EF 66±7%, median BNP level 121 (interquartile 48-320) pg/ml. 58% of patients had BNP activation. Better LV-LS was associated with lower log BNPratio (regression coefficient 0.10, p<0.001). After a median follow-up of 6.5 yrs (interquartile: 3.6-8.2), 119 deaths occurred. After adjustment for age, sex, Charlson score index, hemoglobin level, aortic valve replacement (as a time dependent variable), LV-LS and log BNPratio were separately associated with increased risk for death (all p<0.01). Further adjustment for predictors of mortality, LV-LS and log-BNP ratio remained associated with increased risk for death (hazard ratio HR [95%CI]: 1.09 [1.03-1.15]; p=0.003 and 1.82 [1.52-2.19]; p<0.0001 respectively). In patients without BNP activation (i.e. normal BNP), LV-LS was associated with mortality (HR: 1.22 [1.04-1.43]; p=0.01) while it was not in patients with BNP activation (p=0.22). Conclusions: In patients with asymptomatic AS, without clinically obvious myocardial impairment (i.e. normal LVEF), a notable proportion of patients present with myocardial alterations detected by an elevated BNPratio or reduced LV-LS. These signs of myocardial alterations were predictive of mortality after diagnosis. Thus both BNP and LV-LS should be assessed in the clinical setting to provide complementary information on prognosis in patients with asymptomatic AS and preserved LV EF.

Introduction: Levels of type-B natriuretic peptide (BNP) adjusted for age and sex are a powerful predictor of mortality after the diagnosis of aortic stenosis (AS). Objective: To assess whether BNP activation (compared to normal values) affects mortality after aortic valve replacement (AVR). Methods: In 494 patients with AS, plasma level of BNP was measured pre-operatively at the time of Doppler-Echocardiography. BNP was normalized as BNPratio (BNP measured/BNP maximum normal value for age and sex) to evaluate the impact of BNP activation on post-operative outcomes. Results: Mean age was73±11 years and 300 (61%) patients were male. Mean aortic valve area was 0.82±0.20cm2, mean gradient 51±16mmHg, and mean Left Ventricular Ejection Fraction 59±15%. Incidence of hypertension was 65%, diabetes 27% and chronic kidney disease 22%. Median of BNP was 211 (interquartile: 87-508) and BNPratio 2.2 (1.0-5.2). After adjustment age, gender, body surface area, Charlson score index, presence of symptoms, creatinine, hemoglobin, systolic blood pressure, indexed aortic valve area and left ventricular ejection fraction, the BNPratio (log transformed) was a predictor of long-term mortality (p<0.0001) with an hazard ratio 1.34 (1.14-1.60). Moreover, stratification by BNPratio showed increasing long-term post-operative mortality with BNPratios>2 (Figure). Conclusions: BNP activation defined using BNPratios (normalized for age and sex) is a powerful independent predictor of long-term mortality after aortic valve replacement for AS. Furthermore, patients with a BNPratio>2 before aortic valve replacement incur excess mortality during follow-up in relation to the increasing BNPratio. These data support the use of the BNPratio to guide the timing of AVR.

The need for multiple transducer positions, especially from right parasternal windows, is consistently mentioned in the recommendations for the accurate measurement of peak velocities across a stenotic aortic valve, but yet poorly adopted. We performed a subanalysis of the largest prospective series on the right parasternal acoustic windows in patients with aortic stenosis (330 consecutive) to calculate the degree of misalignment and estimate the potential outcome implication of this often-forgotten approach. The right parasternal view was highly feasible with an average estimated misalignment from the apical view of 14 ± 16 degree; in 10 cases, an estimated misalignment >40 degree. Right parasternal assessment (vs. apical alone) provided a significant reclassification from moderate to severe or even very-severe aortic valve stenosis. Considering a wellestablished survival benefit provided by either percutaneous or surgical valve replacement in patients with severe aortic stenosis the reclassification would result in approximately 1 life-year saved for every 30–35 patients in whom parasternal view were effectively utilized.