Non-severe Aortic Stenosis Research Articles

Aortic valve tissue quantification in bicuspid aortic valve stenosis

Abstract Background The relative contribution of calcific versus noncalcific aortic valve tissue volume to aortic stenosis (AS) in bicuspid aortic valve (BAV) is unclear. Purpose We aimed to assess the association of aortic valve tissue volume quantified by contrast-enhanced CT with echocardiographic AS severity, and diagnostic implication of noncalcific tissue volume for severe AS. Methods We retrospectively identified 234 patients with BAV who had echocardiographic AS severity and contrast-enhanced CT evaluation within six months and left ventricular ejection ≥50%, including 150 severe AS (aortic valve area≤1 cm2 or indexed valve area≤0.6cm2/m2 plus mean grdient≥40mmHg or peak velocity≥4 m/s), 84 nonsevere AS (61 with at least mild AS: peak veloicty≥2.0 m/s plus mean gradient ≥10mmHg, and 23 with normal aortic valve function). Contrast-enhanced CT aortic valve calcific volume and noncalcific (fibrosis) volume were quantified using patient-specific Hounsfield unit thresholds (Figure). Noncontrast CT aortic valve calcium score (AVCscore) was quantified by the Agaston method. CT measurements were indexed to echocardiographic aortic valve annulus area and square-root transformed for the analysis. Results Of 234 patients, the mean age was 64±11 years, and 64% were men. There were positive correlations of indexed calcific volume, noncalcific volume, and inverse correlations of percentages of noncalcific volume (noncalcific volume divided by the sum of calcific and noncalcific volume) with peak velocity and mean gradient (|r|=0.30 to 0.68). Among 150 patients with severe AS, 28 had an AVCscore below the severe AVC threshold (1200 AU in women and 2000 AU in men) while exhibited a higher percentage of noncalcific volume compared to 122 patients with severe AVCscore (67±15% vs. 39±15%, p<0.001). After excluding 122 patients with severe AS and severe AVCscore, the indexed noncalcific volume was associated with severe AS (β±S.E: 0.18±0.07, p=0.005) with an area under the curve of 0.71; in contrast, AVCscore was not (p=0.55). Conclusion Both calcific and noncalcific aortic valve tissue volume contribute to AS severity in patients with BAV. Notably, noncalcific tissue volume is a key factor in determining severe AS in patients without severe AVCscore, suggesting its potential diagnostic value.Figure

Prognostic Value of Aortic Valve Calcification in Nonsevere Aortic Stenosis with Preserved Ejection Fraction.

Aortic valve calcification(AVC) is prognostic in patients with aortic stenosis(AS). We assessed the AVC prognostic value in nonsevere AS patients. We conducted a retrospective study of 395 patients with nonsevere AS, LV ejection fraction ≥50%. The Agatston method was used for computed tomography AVC assessment. The log-rank test determined the best AVC cutoffs for survival under medical surveillance: 1185 AU in men and 850 in women, lower than the established-cutoffs for severe AS(2064AU in men and 1274 in women). Patients were divided into three AVC groups based on these cutoffs: low(<1185 AU men and <850 women), sub-severe(1185-2064AU men and 850-1274 women) and severe(>2064AU men and >1274 women). Of 395 patients(mean age 73 ± 12 years, 60.5% men, aortic valve area 1.23 ± 0.30cm2, mean pressure gradient 28 ± 8 mmHg), 218 underwent aortic valve intervention(AVI) and 158 deaths occurred during follow-up, 82 before AVI. Median survival time under medical surveillance was 2.1[0.7-4.9]years. Compared to the low AVC group, both sub-severe and severe AVC groups had higher risk for all-cause death under medical surveillance after comprehensive adjustment including echocardiographic AS severity and coronary artery calcium score(all p ≤ 0.006); while mortality risk was similar between sub-severe and severe AVC groups(all p ≥ 0.2). This mortality risk pattern persisted in the overall survival analysis after adjustment for AVI. AVI was protective of all-cause death in the sub-severe and severe AVC(all p ≤ 0.01), but not in the low AVC groups. Sub-severe AVC is a robust risk-stratification parameter in patients with nonsevere AS and may inform AVI timing.

Energy Loss Index and Dimensionless Index Outperform Direct Valve Planimetry in Low-Gradient Aortic Stenosis.

Background/Objectives: Among patients with suspected severe aortic stenosis (AS), discordance between effective orifice area (EOA) and transvalvular gradients is frequent and requires a multiparametric workup including flow assessment and calcium-scoring to confirm true severe AS. The aim of this study was to assess direct planimetry, energy loss index (Eli) and dimensionless index (DI) as stand-alone parameters to identify non-severe AS in discordant cases. Methods: In this prospective cohort study, we included consecutive AS patients > 70 years with EOA < 1.0 cm2 referred for valve replacement between 2014 and 2017. AS severity was retrospectively reassessed using the multiparametric work-up recommended in the 2021 ESC/EACTS guidelines. DI and ELi were calculated, and valve area was measured by direct planimetry on transesophageal echocardiography. Results: A total of 101 patients (mean age 82 y; 57% male) were included. Discordance between EOA and gradients was observed in 46% and non-severe AS found in 24% despite an EOA < 1 cm2. Valve planimetry performed poorly, with an area under the ROC curve (AUC) of 0.64. At a cut-off value of >0.82 cm2, sensitivity and specificity to identify non-severe AS were 67 and 66%, respectively. DI and ELi showed a higher diagnostic accuracy, with an AUC of 0.77 and 0.76, respectively. Cut-off values of >0.24 and >0.6 cm2/m2 identified non-severe AS, with a high specificity of 79% and 91%, respectively. Conclusions: Almost one in four patients with EOA < 1 cm2 had non-severe AS according to guideline-recommended multiparametric assessment. Direct valve planimetry revealed poor diagnostic accuracy and should be interpreted with caution. Usual prognostic cut-off values for DI > 0.24 and ELI > 0.6 cm2/m2 identified non-severe AS with high specificity and should therefore be included in the assessment of low-gradient AS.

Evaluation of Instantaneous Wave-Free Ratio and Fractional Flow Reserve in Severe Aortic Valve Stenosis.

The optimal functional evaluation of coronary artery stenosis in patients with severe aortic stenosis (AS) has not been established. The objective of the study was to evaluate the instantaneous wave-free ratio (iFR) and fractional flow reserve (FFR) in patients with and without severe AS. We retrospectively investigated 395 lesions in 293 patients with severe AS and 2257 lesions in 1882 patients without severe AS between 2010 and 2022 from a subgroup of the Interventional Cardiology Research In-Cooperation Society FFR Registry. All patients had FFR values, and iFR was analyzed post hoc using dedicated software only in lesions with adequate resting pressure curves (311 lesions in patients with severe AS and 2257 lesions in patients with nonsevere AS). The incidence of iFR ≤0.89 was 66.6% and 31.8% (P<0.001), while the incidence of FFR ≤0.80 was 45.3% and 43.9% (P=0.60) in the severe AS group and the nonsevere AS group, respectively. In the severe AS group, most lesions (95.2%) with iFR >0.89 had FFR >0.80, while 36.2% of lesions with iFR ≤0.89 had FFR >0.80. During a median follow-up of 2 years, FFR ≤0.80 was significantly associated with deferred lesion failure (adjusted hazard ratio, 2.71 [95% CI, 1.08-6.80]; P=0.034), while iFR ≤0.89 showed no prognostic value (adjusted hazard ratio, 1.31 [95% CI, 0.47-3.60]; P=0.60) in the severe AS group. Lesions with iFR ≤0.89 and FFR >0.80, in particular, were not associated with a higher rate of deferred lesion failure at 3 years compared with lesions with iFR >0.89 (15.4% versus 17.0%; P=0.58). This study suggested that FFR appears to be less affected by the presence of severe AS and is more associated with prognosis. iFR may overestimate the functional severity of coronary artery disease without prognostic significance, yet it can be useful for excluding significant stenosis in patients with severe AS.

Imaging Follow-up of Non-Severe Aortic Stenosis: "When the winds of change blow, some people build walls and others build windmills".

Imaging Follow-up of Non-Severe Aortic Stenosis: "When the winds of change blow, some people build walls and others build windmills".

Prognostic impact of combined non-severe aortic stenosis and mitral regurgitation on clinical outcomes: a single-centre retrospective study

ObjectivesThough the concomitant occurrence of non-severe aortic stenosis (AS) and mitral regurgitation (MR) is highly prevalent, there are limited data to guide clinical decision-making in this condition. Here, we attempt...

Development and validation of the ASGARD risk score for safe monitoring in asymptomatic nonsevere aortic stenosis.

Current guidelines recommend serial echocardiography at minimum 1-2 year intervals for monitoring patients with nonsevere aortic valve stenosis (AS), which is costly and often clinically inconsequential.We aimed to develop and test whether the biomarker-based ASGARD risk score (Aortic Valve Stenosis Guarded by Amplified Risk Determination) can guide the timing of echocardiograms in asymptomatic patients with nonsevere AS. The development cohort comprised 1,093 of 1,589 (69%) asymptomatic patients with mild-to-moderate AS who remained event-free one year after inclusion into the SEAS trial. Cox regression landmark analyses with a 2-year follow-up identified the model (ASGARD) with the lowest Akaike information criterion for association to AS-related composite outcome (heart failure hospitalization, aortic valve replacement, or cardiovascular death). Fine-Gray analyses provided cumulative event rates by ASGARD score quartiles. The ASGARD score was internally validated in the remaining 496 patients (31%) from the SEAS-cohort and externally in 71 asymptomatic outpatients with nonsevere AS from six Copenhagen hospitals. The ASGARD score comprises updated measurements of heart rate and age- and sex-adjusted N-terminal pro-brain natriuretic peptide upon transaortic maximal velocity (Vmax) from the previous year. The ASGARD score had high predictive accuracy across all cohorts (external validation: area under the curve: 0.74 [95% CI, 0.62-0.86]), and similar to an updated Vmax measurement. An ASGARD score ≤50% was associated with AS-related event rates ≤5% for a minimum of 15 months. The ASGARD score could provide a personalized and safe surveillance alternative to routinely planned echocardiograms, so physicians can prioritize echocardiograms for high-risk patients.

Aortic valve sclerosis, stenosis, and prognosis in the general population

Abstract Background The presence of aortic valve (AV) sclerosis and non-severe aortic stenosis has been a suggested marker of cardiovascular risk, but whether AV sclerosis and non-severe AV stenosis is independently associated with increased cardiovascular risk or a marker of coexistent risk factors remains to be clarified. Objective We examined clinical characteristics and prognosis associated with the presence of AV sclerosis and stenosis in the general population. Methods A total of 4,466 participants from a prospective cohort study of the general population were included. Patients with insufficient image quality (n=119) and known heart failure (n=130) were excluded, resulting in a population of 4,217 participants. Evaluation of AV sclerosis/stenosis was based on AV Doppler measurements, i.e., peak and mean AV velocity, and peak and mean AV gradient. The primary composite outcome was defined as major adverse cardiovascular events (MACE), including incident heart failure, myocardial infarction, or cardiovascular death. Multivariable Cox regression models were used to assess the association between AV sclerosis/stenosis by AV Doppler measurements and risk of the outcome. Results Mean age was 56.8 ± 17.5 years, and 56% were women. In total, 18.7% were smokers, 51% had hypertension (HTN), 5% had diabetes (DM), and 7% had ischemic heart disease (IHD). Mean left ventricular ejection fraction (LVEF) was 56.4 ± 6.4% with a median left ventricular mass index (LVMi) of 82.6 g/m2 (IQR 71.1; 96.8) and a mean AVA of 2.72 ± 0.72 cm2. Median AV peak velocity was 1.3 m/s (IQR 1.1; 1.4) and median AV peak gradient was 6.0 mmHg (IQR 5.0; 8.0). Median AV mean velocity was 0.9 m/s (IQR 0.8; 1.0) and median AV mean gradient was 3.0 mmHg (IQR 3.0; 4.0). During a median follow-up of 3.5 years (IQR 2.6; 4.3), 190 patients (4.5%) reached the composite outcome. The incidence rate per 1,000 person years in the fourth quartile of AV peak velocity (AV peak velocity &amp;gt;1.4 m/s) was more than double that of the first quartile (AV peak velocity ≤1.1 m/s) (26.6 [95% CI 21.1 – 33.6] versus 12.9 [95% CI 9.9 – 16.9], p&amp;lt;0.001). In univariable analysis, all AV measurements of sclerosis/stenosis were associated with the composite outcome (p&amp;lt;0.001 for all) (Figure 1). All AV measurements remained independent predictors of the outcome after adjustment for demographic, clinical and echocardiographic risk factors (age, gender, smoking, HTN, DM, IHD, eGFR, LVMi, LAVi, LVEF and E/e’); AV peak PG (HR 1.19 per 5 mmHg increase, 95% CI 1.06 – 1.33, p=0.002), AV peak velocity (HR 1.05 per 0.1 m/s increase [95% CI 1.01 – 1.20], p = 0.013), AV mean PG (HR 1.30 per 5 mmHg increase [95% CI 1.09 – 1.56], p=0.002), AV mean velocity (HR 1.08 per 0.1 m/s increase [95% CI 1.02 – 1.23], p=0.005). Conclusion A greater degree of AV sclerosis/stenosis was independently associated with a higher risk of MACE.Figure 1:Restricted cubic spline model

Abstract 13645: Prognostic Value of Aortic Valve Calcification in Asymptomatic Patients With Non-Severe Aortic Valve Stenosis and Preserved Ejection Fraction

Introduction: Criteria for aortic valve intervention (AVI) in severe aortic stenosis (AS) rely on symptoms, left ventricular ejection fraction (LVEF) and AS severity. Computed tomography-based aortic valve calcification (CT-AVC) scores associated with severe AS also have prognostic value, but this remains unexplored in patients with non-severe AS. We aimed to assess the prognostic value of AVC in asymptomatic patients with nonsevere AS and preserved LVEF. Methods: We retrospectively identified 395 patients with ≥mild AS but less-than-severe AS by echocardiography, who had CT-AVC assessed within six months. AVCscore was quantified offline by Agatston method (TeraRecon software), and also indexed by LV outflow track area, i.e., AVCdensity. Patients were followed until AVI or death. The primary outcome was all-cause death under medical surveillance. Results: In 395 patients, mean age was 73±12 years, 61% were men, mean aortic valve area 1.2±0.3cm2, mean gradient 28±9 mmHg, peak velocity 3.4±0.5 m/s, LVEF 64±6%. During a follow-up of 2.2[0.74-4.94] years, 220 patients had AVI and 82 patients died. Both AVCscore and AVCdensity were associated with AVI-free survival and the best AVCscore thresholds associated with mortality were 853 in women and 1183 in men by log-rank test (both p&lt;0.001). High AVCscore and high AVCdensity were associated with increased hazard for all-cause death in unadjusted and adjusted analyses (Figure), and after further adjustment for echocardiographic severity (all p ≤0.01). Conclusions: In asymptomatic patients with less-than-severe AS, sex-specific CT-AVC scores differentiate those at higher risk for death versus lower risk. Whether AVI could modify this risk remains to be proven.

Performance of Computed Tomographic Angiography-Based Aortic Valve Area for Assessment of Aortic Stenosis.

Background A total of 40% of patients with severe aortic stenosis (AS) have low-gradient AS, raising uncertainty about AS severity. Aortic valve calcification, measured by computed tomography (CT), is guideline-endorsed to aid in such cases. The performance of different CT-derived aortic valve areas (AVAs) is less well studied. Methods and Results Consecutive adult patients with presumed moderate and severe AS based on echocardiography (AVA measured by continuity equation on echocardiography <1.5 cm2) who underwent cardiac CT were identified retrospectively. AVAs, measured by direct planimetry on CT (AVACT) and by a hybrid approach (AVA measured in a hybrid manner with echocardiography and CT [AVAHybrid]), were measured. Sex-specific aortic valve calcification thresholds (≥1200 Agatston units in women and ≥2000 Agatston units in men) were applied to adjudicate severe or nonsevere AS. A total of 215 patients (38.0% women; mean±SD age, 78±8 years) were included: normal flow, 59.5%; and low flow, 40.5%. Among the different thresholds for AVACT and AVAHybrid, diagnostic performance was the best for AVACT <1.2 cm2 (sensitivity, 85%; specificity, 26%; and accuracy, 72%), with no significant difference by flow status. The percentage of patients with correctly classified AS severity (correctly classified severe AS+correctly classified moderate AS) was as follows; AVA measured by continuity equation on echocardiography <1.0 cm2, 77%; AVACT <1.2 cm2, 73%; AVACT <1.0 cm2, 58%; AVAHybrid <1.2 cm2, 59%; and AVAHybrid <1.0 cm2, 45%. AVACT cut points of 1.52 cm2 for normal flow and 1.56 cm2 for low flow, provided 95% specificity for excluding severe AS. Conclusions CT-derived AVAs have poor discrimination for AS severity. Using an AVACT <1.2-cm2 threshold to define severe AS can produce significant error. Larger AVACT thresholds improve specificity.

Transcatheter Aortic Valve Replacement in Patients With Reduced Ejection Fraction and Nonsevere Aortic Stenosis.

The potential benefit of transcatheter aortic valve replacement (TAVR) in patients with nonsevere aortic stenosis (AS) and heart failure is controversial. This study aimed to assess outcomes of patients with nonsevere low-gradient AS (LGAS) and reduced left ventricular ejection fraction undergoing TAVR or medical management. Patients undergoing TAVR for LGAS and reduced left ventricular ejection fraction (<50%) were included in a multinational registry. True-severe low-gradient AS (TS-LGAS) and pseudo-severe low-gradient AS (PS-LGAS) were classified according to computed tomography-derived aortic valve calcification thresholds. A medical control group with reduced left ventricular ejection fraction and moderate AS or PS-LGAS was used (Medical-Mod). Adjusted outcomes between all groups were compared. Among patients with nonsevere AS (moderate or PS-LGAS), outcomes after TAVR and medical therapy were compared using propensity score-matching. A total of 706 LGAS patients undergoing TAVR (TS-LGAS, N=527; PS-LGAS, N=179) and 470 Medical-Mod patients were included. After adjustment, both TAVR groups showed superior survival compared with Medical-Mod patients (all P<0.001), while no difference was found between TS-LGAS and PS-LGAS TAVR patients (P=0.96). After propensity score-matching among patients with nonsevere AS, PS-LGAS TAVR patients showed superior 2-year overall (65.4%) and cardiovascular survival (80.4%) compared with Medical-Mod patients (48.8% and 58.5%, both P≤0.004). In a multivariable analysis including all patients with nonsevere AS, TAVR was an independent predictor of survival (hazard ratio, 0.39 [95% CI, 0.27-0.55]; P<0.0001). Among patients with nonsevere AS and reduced left ventricular ejection fraction, TAVR represents a major predictor of superior survival. These results reinforce the need for randomized-controlled trials comparing TAVR versus medical management in heart failure patients with nonsevere AS. URL: https://www. gov; Unique identifier: NCT04914481.

Association of high-sensitivity troponin T with outcomes in asymptomatic non-severe aortic stenosis: a post-hoc substudy of the SEAS trial

High-sensitivity Troponin T (hsTnT), a biomarker of cardiomyocyte overload and injury, relates to aortic valve replacement (AVR) and mortality in severe aortic stenosis (AS). However, its prognostic value remains unknown in asymptomatic patients with AS. We aimed to investigate if an hsTnT level >14pg/mL (above upper limit of normal 99th percentile) is associated with echocardiographic AS-severity, subsequent AVR, ischaemic coronary events (ICE), and mortality in asymptomatic patients with non-severe AS. In this post-hoc sub-analysis of the multicentre, randomised, double-blind, placebo-controlled SEAS trial (ClinicalTrials.gov, NCT00092677), we included asymptomatic patients with mild to moderate-severe AS. We ascertained baseline and 1-year hsTnT concentrations and examined the association between baseline levels and the risk of the primary composite endpoint, defined as the first event of all-cause mortality, isolated AVR (without coronary artery bypass grafting (CABG)), or ICE. Multivariable regressions and competing risk analyses examined associations of hsTnT level >14pg/mL with clinical correlates and 5-year risk of the primary endpoint. Between January 6, 2003, and March 4, 2004, a total of 1873 patients were enrolled in the SEAS trial, and 1739 patients were included in this post-hoc sub-analysis. Patients had a mean (SD) age of 67.5 (9.7) years, 61.0% (1061) were men, 17.4% (302) had moderate-severe AS, and 26.0% (453) had hsTnT level >14pg/mL. The median hsTnT difference from baseline to 1-year was 0.8pg/mL (IQR,-0.4 to 2.3). In adjusted linear regression, log(hsTnT) did not correlate with echocardiographic AS severity (p=0.36). In multivariable Cox regression, a hsTnT level >14pg/mL vs. hsTnT ≤14pg/mL was associated with an increased risk of the primary composite endpoint (HR, 1.41; 95% CI, 1.18-1.70; p=0.0002). In a competing risk model of first of the individual components of the primary endpoint, a hsTnT level >14pg/mL was associated with ICE risk (HR 1.71; 95% CI, 1.23-2.38; p=0.0013), but not with isolated AVR (p=0.064) or all-cause mortality (p=0.49) as the first event. hsTnT level is within the reference range (≤14pg/mL) in 3 out of 4 non-ischaemic patients with asymptomatic mild-to-moderate AS and remains stable during a 1-year follow-up regardless of AS-severity. An hsTnT level >14pg/mL was mainly associated with subsequent ICE, which suggest that hsTnT concentration is primarily a risk marker of subclinical coronary atherosclerotic disease. Merck & Co., Inc., the Schering-Plough Corporation, the Interreg IVA program, Roche Diagnostics Ltd., and Gangstedfonden. Open access publication fee funding provided by prof. Olav W. Nielsen and Department of Cardiology, Bispebjerg University Hospital, Denmark.

Machine Learning to Optimize the Echocardiographic Follow-Up of Aortic Stenosis

BackgroundDisease progression in patients with mild-to-moderate aortic stenosis is heterogenous and requires periodic echocardiographic examinations to evaluate severity. ObjectivesThis study sought to explore the use of machine learning to optimize aortic stenosis echocardiographic surveillance automatically. MethodsThe study investigators trained, validated, and externally applied a machine learning model to predict whether a patient with mild-to-moderate aortic stenosis will develop severe valvular disease at 1, 2, or 3 years. Demographic and echocardiographic patient data to develop the model were obtained from a tertiary hospital consisting of 4,633 echocardiograms from 1,638 consecutive patients. The external cohort was obtained from an independent tertiary hospital, consisting of 4,531 echocardiograms from 1,533 patients. Echocardiographic surveillance timing results were compared with the European and American guidelines echocardiographic follow-up recommendations. ResultsIn internal validation, the model discriminated severe from nonsevere aortic stenosis development with an area under the receiver-operating characteristic curve (AUC-ROC) of 0.90, 0.92, and 0.92 for the 1-, 2-, or 3-year interval, respectively. In external application, the model showed an AUC-ROC of 0.85, 0.85, and 0.85, for the 1-, 2-, or 3-year interval. A simulated application of the model in the external validation cohort resulted in savings of 49% and 13% of unnecessary echocardiographic examinations per year compared with European and American guideline recommendations, respectively. ConclusionsMachine learning provides real-time, automated, personalized timing of next echocardiographic follow-up examination for patients with mild-to-moderate aortic stenosis. Compared with European and American guidelines, the model reduces the number of patient examinations.

Transcatheter Aortic Valve Implantation in Heart Failure Patients with Non-Severe Aortic Valve Stenosis

Introduction: aortic stenosis (AS) increases the afterload on the left ventricle, leading to structural changes in the heart muscle and gradual progression to heart failure (HF). The clinical guidelines recommend aortic valve replacement (surgical or transcatheter) in patients with HF and severe AS. The evidence on the benefits of Transcatheter aortic valve implantation (TAVI) for patients with less-than-severe AS and HF is still controversial and inconclusive. Methods: the literature was systematically searched on three different scientific databases (PUBMED, Google Scholar, EMBASE) using different combinations of search words (heart failure, non-severe aortic stenosis, less-than-severe aortic stenosis, mild to moderate aortic stenosis, TAVI, TAVR). Results: in heart failure patients, observational studies showed a significant reduction in mortality using TAVI to manage non-severe aortic stenosis compared to medical treatment. However, evidence from randomized controlled trials is still lacking. Conclusion:HF increases the surgical risk of AS patients; therefore, TAVI represents a safer option. The preliminary results indicated the benefit of TAVI in managing AS in HF patients, even if the AS did not reach the severe stage. Doi: 10.28991/SciMedJ-2022-04-04-05 Full Text: PDF

Risk for Mortality with Increasingly Severe Aortic Stenosis: An International Cohort Study

Aortic stenosis (AS) is the most common valvular heart disease in high-income countries. Adjusted for clinical confounders, the risk associated with increasing AS severity across the spectrum of AS severity remains uncertain. The authors conducted an international, multicenter, parallel-cohort study of 217,599 Australian (mean age, 76.0±7.3years; 49.3% women) and 30,865 US (mean age, 77.4±7.3years; 52.2% women) patients aged ≥65years who underwent echocardiography. Patients with previous aortic valve replacement were excluded. The risk of increasing AS severity, quantified by peak aortic velocity (Vmax), was assessed through linkage to 97,576 and 14,481 all-cause deaths in Australia and the United States, respectively. The distribution of AS severity (mean Vmax, 1.7±0.7m/sec) was similar in both cohorts. Compared with those with Vmax of 1.0 to 1.49m/sec, those with Vmax of 2.50 to 2.99m/sec (US cohort) or Vmax of 3.0 to 3.49m/sec (Australian cohort) had a 1.5-fold increase in mortality risk within 10years, adjusting for age, sex, presence of left heart disease, and left ventricular ejection fraction. Overall, the adjusted risk for mortality plateaued (1.75- to 2.25-fold increased risk) above a Vmax of 3.5m/sec. This pattern of mortality persisted despite adjustment for a comprehensive list of comorbidities and treatments within the US cohort. Within large, parallel patient cohorts managed in different health systems, similar patterns of mortality linked to increasingly severe AS were observed. These findings support ongoing clinical trials of aortic valve replacement in patients with nonsevere AS and suggest the need to develop and apply more proactive surveillance strategies in this high-risk population.

Measurement error in echocardiographic assessment of aortic stenosis: an epidemiological consideration of research methodology and clinical practice

Abstract Background/Introduction Current international guidelines on treatment of valvular heart disease contain recommendations for aortic valve replacement based exclusively on abnormal echocardiographic parameters in asymptomatic patients with aortic stenosis (AS). To prevent misclassification and subsequent mistreatment of patients, these recommendations require accurate and unbiased measurements of hemodynamic parameters. Purpose To illustrate consideration and impact of measurement error in echocardiographic assessment of aortic stenosis in both the research and clinical setting. Methods First, a systematic review was performed to investigate the recognition of and correction for measurement error in clinical studies on the prognostic value of peak aortic jet velocity (Vmax), mean pressure gradient (MPG), and effective orifice area (EOA). Second, all potential erroneous sources in the calculation of those primary parameters were listed stratified to random or systematic measurement error, and subsequently their magnitude was quantified. Third, the impact of various types of measurement error on current thresholds for intervention was graphically illustrated in different clinical scenarios. Results The presence of measurement error was acknowledged in 44% of the 36 included studies, while none utilized methods to correct for it. Interobserver variability ranged between 0.9–8.3% for Vmax and MPG but was substantially higher for EOA (range 7.7–12.7%) implying lower reliability (Figure 1). Furthermore, the invalid assumption of a circular left ventricular outflow tract area resulted in a median underestimation in EOA of 22.5% compared to 3D-transesophageal echocardiography (3D-TEE), computed tomography (CT), and cardiovascular magnetic resonance (CMR) planimetry. Figure 2 illustrates the impact of this discrepancy on the classification of AS using one-sided t-tests to determine the areas under the curve; the proportion of patients with non-severe AS in a hypothetical cohort (based on values from the PARTNER 3 trial [1[) increased by 42%. Conclusion(s) Measurement error is underrecognized in studies of echocardiographic assessment of aortic stenosis. This review demonstrates that random and systematic measurement errors affect echocardiographic assessment, leading to potential misdiagnosis and subsequent mistreatment. Clinicians and scientists should be aware of the implications of measurement errors to enhance rightful clinical decision-making and assure research validity. Funding Acknowledgement Type of funding sources: None.

Severe low-gradient aortic stenosis: impact of inadequate left ventricular responses to high afterload on diagnosis and therapeutic decision-making.

The fact that nearly 50% of patients with an aortic valve (AV) area < 1.0 cm2, consistent with severe aortic stenosis (AS), can have mean trans-AV pressure gradients < 40mmHg, consistent with non-severe AS, indicates that "low-gradient" (LG) severe AS, which is often associated with poor prognosis, deserves particular consideration. Inadequate left ventricular (LV) adaptation to severe AV stenosis resulting from preexistent intrinsic myocardial damages and/or maladaptive LV responses to increased afterload are typical features of severe LG-AS. The diagnosis and management of patients with severe LG-AS are particularly challenging because the discrepancy between the AV area and the trans-AV pressure gradient raises doubts concerning the actual severity of AS and therefore also about the necessity of AV replacement (AVR). LG-AS diagnosis requires integrative multimodality evaluation of both the AV and the LV and therapeutic decision-making necessitates careful individual benefit-risk estimation. Although patients with severe LG-AS associated with low trans-AV flow (i.e., stroke volume ≤ 35ml/m2) have worse outcomes after AVR than those with high-gradient severe AS, even those with reduced LV ejection fraction (LVEF) can have a significant survival benefit particularly by transcatheter AVR. Dobutamine stress echocardiography facilitates distinction between true-severe and pseudo-severe low-flow LG-AS with reduced LVEF. The review aimed to provide an updated theoretical and practical basis for those engaged in this demanding and still current topic due to the new aspects which have emerged in conjunction with both the evolving scientific knowledge about the various LV responses to the increased afterload and the increasing use of the less invasive transcatheter AVR.

Association of Annual N-Terminal Pro-Brain Natriuretic Peptide Measurements With Clinical Events in Patients With Asymptomatic Nonsevere Aortic Stenosis

Recent studies have questioned the presumed low-risk status of patients with asymptomatic nonsevere aortic stenosis (AS). Whether annual N-terminal pro-brain natriuretic peptide (NT-proBNP) measurements are useful for risk assessment is unknown. To assess the association of annual NT-proBNP measurements with clinical outcomes in patients with nonsevere AS. Analysis of annual NT-proBNP concentrations in the multicenter, double-blind Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) randomized clinical trial was performed. SEAS was conducted from January 6, 2003, to April 1, 2008. Blood samples were analyzed in 2016, and data analysis was performed from February 10 to October 10, 2021. SEAS included 1873 patients with asymptomatic AS not requiring statin therapy with transaortic maximal flow velocity from 2.5 to 4.0 m/s and preserved ejection fraction. This substudy included 1644 patients (87.8%) with available blood samples at baseline and year 1. Increased age- and sex-adjusted NT-proBNP concentrations at year 1 and a 1.5-fold or greater relative NT-proBNP concentration change from baseline to year 1. Moderate AS was defined as baseline maximal flow velocity greater than or equal to 3.0 m/s. Aortic valve events (AVEs), which are a composite of aortic valve replacement, cardiovascular death, or incident heart failure due to AS progression, were noted. Landmark analyses from year 1 examined the association of NT-proBNP concentrations with outcomes. Among 1644 patients, 996 were men (60.6%); mean (SD) age was 67.5 (9.7) years. Adjusted NT-proBNP concentrations were within the reference range (normal) in 1228 of 1594 patients (77.0%) with NT-proBNP values available at baseline and in 1164 of 1644 patients (70.8%) at year 1. During the next 2 years of follow-up, the AVE rates per 100 patient-years for normal vs increased adjusted NT-proBNP levels at year 1 were 1.39 (95% CI, 0.86-2.23) vs 7.05 (95% CI, 4.60-10.81) for patients with mild AS (P < .01), and 10.38 (95% CI, 8.56-12.59) vs 26.20 (95% CI, 22.03-31.15) for those with moderate AS (P < .01). Corresponding all-cause mortality rates were 1.05 (95% CI, 0.61-1.81) vs 4.17 (95% CI, 2.42-7.19) for patients with mild AS (P < .01), and 1.60 (95% CI, 0.99-2.57) vs 4.78 (95% CI, 3.32-6.87) for those with moderate AS (P < .01). In multivariable Cox proportional hazards regression models, the combination of a 1-year increased adjusted NT-proBNP level and 1.5-fold or greater NT-proBNP level change from baseline was associated with the highest AVE rates in both patients with mild AS (hazard ratio, 8.12; 95% CI, 3.53-18.66; P < .001) and those with moderate AS (hazard ratio, 4.05; 95% CI, 2.84-5.77; P < .001). The findings of this study suggest that normal NT-proBNP concentrations at 1-year follow-up are associated with low AVE and all-cause mortality rates in patients with asymptomatic nonsevere AS. Conversely, an increased 1-year NT-proBNP level combined with a 50% or greater increase from baseline may be associated with high AVE rates. ClinicalTrials.gov Identifier: NCT00092677.

Diagnostic and prognostic implications of myocardial work in cardiac amyloidosis and in genetic and non-genetic cardiomyopathies with hypertrophic phenotype

Abstract Funding Acknowledgements Type of funding sources: None. BACKGROUND &amp; PURPOSE. Cardiac amyloidosis (CA) is an infiltrative disorder characterized by left ventricular (LV) thickening with early systolic and diastolic dysfunction. Due to it poor prognosis, and the beneficial impact of novel treatments when started in early stages of disease, its forward detection is crucial. Aim of this study is comparing the diagnostic accuracy of classical and novel echocardiographic parameters in detecting CA among other forms of genetic and non-genetic cardiomyopathies with hypertrophic phenotype. METHODS. We enrolled 50 pts with CA (26 AL and 24 wtATTR) and 75 phenocopies (LVH group) [25 hypertrophic cardiomyopathy (HCM) pts, 25 hypertensive (HypCM) pts, and 25 pts with non-severe aortic stenosis (AS)]. Standard and novel LV morpho-functional echo parameters [LV ejection fraction (LVEF), myocardial contraction fraction (MCF), global longitudinal strain (GLS), relative regional strain ratio (RRSR), ejection fraction on strain ratio (EFSR)], and novel Myocardial Work (MW) parameters [Global Work Index (GWI), Global Constructive Work (GCW), Global Wasted Work (GWW), Global Work Efficiency (GWE)] were analyzed. RESULTS. LV standard, novel and MW-derived systolic parameters were more impaired in CA compared to LVH group. At ROC curve analysis, GCW showed the best performance in discriminating CA from other forms of LVH (AUC 0.886; 95% CI: 0.819-0.954; P &amp;lt; 0.0001), with a cut-off value &amp;lt; 1473 mmHg% showing 90% of sensitivity and 82% of specificity). At linear regression analysis, GCW correlated with many echocardiographic parameters (IVSD, PWD, RWT ratio, LVMi, MCF, LVESV, LVEF, EFSR and RRSR). At multivariate analysis, PWD (P &amp;lt; 0,029) and RWT ratio (p &amp;lt; 0,014) were the only parameters associated with GCW. At 24 months follow-up, there were 15 deaths in CA and 4 in LVH group. At Kaplan-Meier analysis the overall survival free of cardiovascular death was reduced in the lowest GCW interquartile ranges (log-rank χ2 21.5; p &amp;lt; 0.0001). At Cox hazard ratio analysis, GCW was the only prognostic parameter associated with cardiovascular mortality (β 1.006; 95% CI: 1.003-1.009; P &amp;lt; 0.0001). CONCLUSIONS. Despite CA and LVH patients shows a similar phenotype, the systolic function differs greatly. In the present study, the GCW showed the best ability in detecting CA among other forms of LVH. Its reduction in CA seems reflect the infiltrative burden and its consequences on myocardial deformation properties, while its reduction in LVH group has been attributed elsewhere to fibrotic derangement. GCW showed to be a promising novel diagnostic and prognostic factor in this setting. Abstract Figure 1 Abstract Table 1

Sex Differences in Factors Associated With Progression of Aortic Valve Calcification in the General Population.

Guidelines recommend measurement of the aortic valve calcification (AVC) score to help differentiate between severe and nonsevere aortic stenosis, but a paucity exists in data about AVC in the general population. The aim of this study was to describe the natural history of AVC progression in the general population and to identify potential sex differences in factors associated with this progression rate. Noncontrast cardiac computed tomography was performed in 1298 randomly selected women and men aged 65 to 74 years who participated in the DANCAVAS trial (Danish Cardiovascular Screening). Participants were invited to attend a reexamination after 4 years. The AVC score was measured at the computed tomography, and AVC progression (ΔAVC) was defined as the difference between AVC scores at baseline and follow-up. Multivariable regression analyses were performed to identify factors associated with ΔAVC. Among the 1298 invited citizens, 823 accepted to participate in the follow-up examination. The mean age at follow-up was 73 years. Men had significantly higher AVC scores at baseline (median AVC score 13 Agatston Units [AU; interquartile range, 0-94 AU] versus 1 AU [interquartile range, 0-22 AU], P<0.001) and a higher ΔAVC (median 26 AU [interquartile range, 0-101 AU] versus 4 AU [interquartile range, 0-37 AU], P<0.001) than women. In the fully adjusted model, the most important factor associated with ΔAVC was the baseline AVC score. However, hypertension was associated with ΔAVC in women (incidence rate ratios, 1.58 [95% CI, 1.06-2.34], P=0.024) but not in men, whereas dyslipidemia was associated with ΔAVC in men (incidence rate ratio: 1.66 [95% CI, 1.18-2.34], P=0.004) but not in women. The magnitude of the AVC score was the most important marker of AVC progression. However, sex differences were significant; hence, dyslipidemia was associated with AVC progression only among men; hypertension with AVC progression only among women. Registration: URL: https://www.isrctn.com; Unique identifier: ISRCTN12157806.