Aortic Valve Calcification Density Measured by MDCT in the Assessment of Aortic Stenosis Severity.

BACKGROUND: Aortic valve calcification (AVC) indexation to the aortic annulus (AA) area measured by Doppler echocardiography (AVCdEcho) provides powerful prognostic information in patients with aortic stenosis (AS). However, the indexation by AA measured by multidetector computed tomography (AVCdCT) has never been evaluated. The aim of this study was to compare AVC, AVCdCT, and AVCdEcho with regard to hemodynamic correlations and clinical outcomes in patients with AS. METHODS: Data from 889 patients, mainly White, with calcific AS who underwent Doppler echocardiography and multidetector computed tomography within the same episode of care were retrospectively analyzed. AA was measured both by Doppler echocardiography and multidetector computed tomography. AVCdCT severity thresholds were established using receiver operating characteristic curve analyses in men and women separately. The primary end point was the occurrence of all-cause mortality. RESULTS: Correlations between gradient/velocity and AVCd were stronger (both P≤0.005) using AVCdCT (r=0.68, P<0.001 and r=0.66, P<0.001) than AVC (r=0.61, P<0.001 and r=0.60, P<0.001) or AVCdEcho (r=0.61, P<0.001 and r=0.59, P<0.001). AVCdCT thresholds for the identification of severe AS were 334 Agatston units (AU)/cm2 for women and 467 AU/cm2 for men. On a median follow-up of 6.62 (6.19-9.69) years, AVCdCT ratio was superior to AVC ratio and AVCdEcho ratio to predict all-cause mortality in multivariate analyses (hazard ratio [HR], 1.59 [95% CI, 1.26-2.00]; P<0.001 versus HR, 1.53 [95% CI, 1.11-1.65]; P=0.003 versus HR, 1.27 [95% CI, 1.11-1.46]; P<0.001; all likelihood test P≤0.004). AVCdCT ratio was superior to AVC ratio and AVCdEcho ratio to predict survival under medical treatment in multivariate analyses (HR, 1.80 [95% CI, 1.27-1.58]; P<0.001 compared with HR, 1.55 [95% CI, 1.13-2.10]; P=0.007; HR, 1.28 [95% CI, 1.03-1.57]; P=0.01; all likelihood test P<0.03). AVCdCT ratio predicts mortality in all subgroups of patients with AS. CONCLUSIONS: AVCdCT appears to be equivalent or superior to AVC and AVCdEcho to assess AS severity and predict all-cause mortality. Thus, it should be used to evaluate AS severity in patients with nonconclusive echocardiographic evaluations with or without low-flow status. AVCdCT thresholds of 300 AU/cm2 for women and 500 AU/cm2 for men seem to be appropriate to identify severe AS. Further studies are needed to validate these thresholds, especially in diverse populations.

Interstitial Fibrosis and Arrhythmic Mitral Valve Prolapse: Unravelling Sex-Based Differences.

Background: Interstitial fibrosis as quantified by cardiac magnetic resonance (CMR) has been demonstrated in arrhythmic mitral valve prolapse (MVP), a condition with known female predominance. However, prior studies included only MVP cases with significant mitral regurgitation (MR) or mitral annular disjunction (MAD). We sought to evaluate the association between interstitial fibrosis and complex ventricular ectopy (ComVE) in MVPs unselected for MAD or severe MR, and to investigate the contribution of sex to this association. Methods: We performed contrast CMR in consecutive individuals with MVP between 2020 and 2022. Extracellular volume fraction (ECV%), a surrogate marker for interstitial fibrosis, was quantified using T 1 mapping. Replacement fibrosis was assessed using late gadolinium enhancement (LGE). ComVE, defined as frequent premature ventricular contractions and/or non-sustained/sustained ventricular tachycardia (VT), was detected using ambulatory ECG monitoring. Results: We identified 59 MVP cases without severe MR (49% women, 80% with mild or less MR) and available ECV% measurement. Among these, 23 (39%) had ComVE, including a case of aborted ventricular fibrillation (VF) and one with sudden arrhythmic death, both females. Global ECV% was significantly greater in ComVE versus non-ComVE (31%[27-33] vs 27%[23-30], p=0.002). In MVP-ComVE, higher segmental ECV% was not limited to the inferolateral/inferior LV wall, but was also demonstrated in atypical segments including the anterior/anterolateral wall (p<0.05). The association between ComVE and ECV% was driven by female sex (32%[30-33] vs 28%[26-30], p=0.003 in females; 31%[25-33] vs 26%[23-30], p=0.22 in males). ECV% remained independently associated with an increased risk of ComVE, including VT/VF, after adjustment for cardiovascular risk factors, MAD, and LGE (p<0.01). Conclusion: In MVP without significant MR, interstitial fibrosis by CMR is associated with an increased risk of ComVE, suggesting a primary myopathic process. The stronger association between interstitial fibrosis and ComVE in females may explain why severe arrhythmic complications are more prevalent among women.

Prognostic utility of N-terminal pro B-type natriuretic peptide ratio in mixed aortic valve disease.

OBJECTIVE: We aimed to assess the incremental prognostic value of N-terminal-pro-B-type natriuretic peptide (Nt-proBNP) for risk stratification in mixed aortic valve disease (MAVD) patients. METHODS: We included 556 (73±12 years, 37% women) consecutive patients with at least a moderate aortic stenosis (AS) or aortic regurgitation (AR) lesion with a concomitant AS or AR of any severity in whom Nt-proBNP was measured and expressed as its ratio (measured Nt-proBNP divided by the upper limit of normal Nt-proBNP for age and sex). The primary endpoint was all-cause mortality. RESULTS: Baseline median Nt-proBNP ratio was 3.8 (IQR: 1.5-11.3), and the median follow-up was 5.6 years (4.8-6.1). Early aortic valve replacement (AVR) was performed within 3 months in 423 (76%) patients, while 133 (24%) remained initially under medical treatment. In comprehensive multivariable analyses, Nt-proBNP ratio was significantly associated with excess mortality (continuous variable: HR (95% CI): 1.24 (1.04 to 1.47), p=0.02; Nt-proBNP ratio ≥3: 2.41 (1.33 to 4.39), p=0.004). The independent prognostic value was also observed in patients with severe or non-severe AS/AR, and those treated by early-AVR (all p<0.04). Nt-proBNP ratio as continuous and dichotomic (≥3) variables showed incremental prognostic value (all net reclassification index >0.42, all p≤0.008). After early-AVR, Nt-proBNP ratio ≥3 was associated with higher 30-day mortality (9 (4%) vs 1 (0.5%), p=0.02). CONCLUSIONS: In this series of MAVD patients, Nt-proBNP ratio was a powerful predictor of early and long-term mortality, even in patients with both non-severe AS/AR. Moreover, early-AVR may be an option for patients with Nt-proBNP ratio ≥3. Further randomised studies are needed to validate this last point.

Mechanical Dispersion Discriminates between Arrhythmic and Non-Arrhythmic Sudden Death: From the POST SCD Study.

Background: Global longitudinal strain (GLS) and mechanical dispersion (MD) by speckle-tracking echocardiography can predict sudden cardiac death (SCD) beyond left ventricular ejection fraction (LVEF) alone. However, prior studies have presumed cardiac cause from EMS records or death certificates rather than gold-standard autopsies. Objectives: We sought to investigate whether abnormal GLS and MD, reflective of underlying myocardial fibrosis, are associated with autopsy-defined sudden arrhythmic death (SAD) in a comprehensive postmortem study. Methods: We identified and autopsied all World Health Organization-defined (presumed) SCDs ages 18-90 via active surveillance of out of hospital deaths in the ongoing San Francisco POstmortem Systematic InvesTigation of Sudden Cardiac Death (POST SCD) Study to refine presumed SCDs to true cardiac causes. We retrieved all available pre-mortem echocardiograms and assessed LVEF, LV-GLS, and MD. The extent of LV myocardial fibrosis was assessed and quantified histologically. Results: Of 652 autopsied subjects, 65 (10%) had echocardiograms available for primary review, obtained at a mean 1.5 years before SCD. Of these, 37 (56%) were SADs and 29 (44%) were non-SADs; fibrosis was quantified in 38 (58%). SADs were predominantly male, but had similar age, race, baseline comorbidities, and LVEF compared to non-SADs (all p>0.05). SADs had significantly reduced LV-GLS (median: -11.4% versus -18.5%, p=0.008) and increased MD (median: 14.8 ms versus 9.4 ms, p=0.006) compared to non-SADs. MD was associated with total LV fibrosis by linear regression in SADs (r=0.58, p=0.002). Conclusion: In this countywide postmortem study of all sudden deaths, autopsy-confirmed arrhythmic deaths had significantly lower LV-GLS and increased MD than non-arrhythmic sudden deaths. Increased MD correlated with higher histologic levels of LV fibrosis in SADs. These findings suggest that increased MD, which is a surrogate for the extent of myocardial fibrosis, may improve risk stratification and specification for SAD beyond LVEF. PERSPECTIVES: Competency in medical knowledge: Mechanical dispersion derived from speckle tracking echocardiography provides better discrimination between autopsy-defined arrhythmic vs non-arrhythmic sudden death than LVEF or LV-GLS. Histological ventricular fibrosis correlates with increased mechanical dispersion in SAD.Translational outlook: Speckle tracking echocardiography parameters, in particular mechanical dispersion, may be considered as a non-invasive surrogate marker for myocardial fibrosis and risk stratification in SCD.

Effect of race on pressure recovery adjustment for prevention of aortic stenosis grading discordance.

OBJECTIVE: We sought to evaluate the potential impact of racial difference (Asians vs Caucasians) on the clinical usefulness of pressure recovery (PR) adjustment for preventing discordant aortic stenosis (AS) grading in patients with severe AS. METHODS: Data from 1450 patients (mean age, 70.2±10.6 years; 290 (20%) Caucasians; aortic valve area (AVA), 0.77±0.26 cm2) were retrospectively analysed. PR-adjusted AVA was calculated using a validated equation. Discordant grading of severe AS was defined as AVA of <1.0 cm2 and mean gradient of <40 mm Hg. The frequency of discordant grading was assessed in the overall cohort and the propensity score-matched cohort. RESULTS: Before PR adjustment, 1186 patients showed AVA values of <1.0 cm2; after PR adjustment, 170 (14.3%) were reclassified as having moderate AS. PR adjustment decreased the frequency of discordant grading from 31.4% to 14.1% in Caucasians and from 13.8% to 7.9% in Asians. Patients with reclassification to moderate AS after PR adjustment had a significantly lower risk of a composite of aortic valve replacement or all-cause death than did those with severe AS after PR adjustment (HR 0.38; 95% CI 0.31-0.46; p<0.001). In propensity score-matched cohorts (173 pairs), the frequency of discordant grading before PR adjustment was 42.2% and 43.9% in the Caucasian and Asian patients, respectively, which decreased to 21.4% and 20.2%, respectively, after PR adjustment. CONCLUSIONS: Clinically relevant PR occurred, regardless of race in patients with moderate to severe AS. Routine PR adjustment may be useful for reconciling discordant AS grading.

Determinants of Aortic Stenosis Progression in Bicuspid and Tricuspid Aortic Valves.

Background: Bicuspid aortic valve (BAV) is associated with a faster progression of aortic stenosis (AS). Whether the determinants of AS progression are the same or different in patients with BAV vs tricuspid aortic valve (TAV) is unknown. The aim of this study was to identify the factors associated with the progression of AS in patients with BAV vs patients with TAV. Methods: Patients with AS were prospectively recruited in the Metabolic Determinants of the Progression of Aortic Stenosis (PROGRESSA) study (ClinicalTrials.gov Identifier: NCT01679431). The haemodynamic progression rate of AS was assessed by the annualized progression rate of peak aortic jet velocity (Vpeak). Univariable and multivariable linear regression analyses were used to identify the factors associated with a faster progression of AS in patients with BAV vs patients with TAV. Results: There were 79 patients with BAV and 208 patients with TAV. The baseline severity of AS was similar between the 2 groups of patients as well as the annualized progression rate of AS. In patients with BAV, obesity (ß = 0.25, P = 0.04), diabetes (ß = 0.26, P = 0.02), and BAV with right-noncoronary cusp fusion (ß = 0.29, P = 0.01) were found to be independently associated with a faster progression of AS, whereas in patients with TAV, AS baseline severity (baseline Vpeak, ß = 0.14, P = 0.04) and chronic kidney disease (ß = 0.16, P = 0.02) were significantly associated with AS progression. Conclusion: Factors associated with progression rate of AS are different in BAV and TAV. The main factors associated with a faster progression of AS appear to be obesity, diabetes, right-noncoronary cusp fusion in patients with BAV vs chronic kidney disease in patients with TAV.

Contexte: La bicuspidie valvulaire aortique (BVA) est associée à une progression plus rapide de la sténose aortique (SA). On ignore toutefois si les facteurs en cause dans la progression de la SA sont les mêmes chez les patients qui présentent une BVA et chez ceux qui présentent une valve aortique tricuspide. Le but de cette étude était de déterminer les facteurs associés à la progression de la SA chez les patients présentant une BVA par rapport à ceux ayant une valve aortique tricuspide. Méthodologie: Des patients présentant une SA ont été recrutés dans l'étude PROGRESSA (Metabolic Determinants of the Progression of Aortic Stenosis), une étude prospective sur les déterminants métaboliques de la progression de la SA (ClinicalTrials.gov : NCT01679431). Pour calculer le taux de progression hémodynamique de la SA, on a utilisé les mesures annualisées de la vélocité maximale du jet transaortique (Vmax). Des analyses de régression linéaire univariées et multivariées ont permis de mettre en évidence les facteurs associés à une progression plus rapide de la SA en présence d'une BVA par rapport à une valve aortique tricuspide. Résultats: Parmi les patients évalués, 79 présentaient une BVA et 208, une valve aortique tricuspide. La gravité de la SA au départ était comparable entre les deux groupes de patients, tout comme le taux de progression annualisé de la SA. Chez les patients avec BVA, l'obésité (ß = 0,25, P = 0,04), le diabète (ß = 0,26, P = 0,02) et la BVA avec fusion des feuillets coronaire droit et non coronaire (ß = 0,29, P = 0,01) ont été associés de manière indépendante à une progression plus rapide de la SA, tandis que chez les patients ayant une valve tricuspide, la gravité de la SA au départ (Vmax initiale, ß = 0,14, P = 0,04) et la présence d'une néphropathie chronique (ß = 0,16, P = 0,02) ont été significativement associées à une progression de la SA. Conclusion: Les facteurs associés au taux de progression de la SA sont différents selon qu'il y a ou non présence d'une BVA. Les principaux facteurs associés à une progression plus rapide de la SA semblent être l'obésité, le diabète et la fusion des feuillets coronaire droit et non coronaire pour la BVA, tandis que la néphropathie chronique serait le facteur aggravant chez les patients présentant une valve aortique tricuspide.

Validation of aortic valve calcium quantification thresholds measured by computed tomography in Asian patients with calcific aortic stenosis.

AIMS: Sex-specific thresholds of aortic valve calcification (AVC) have been proposed and validated in Caucasians. Thus, we aimed to validate their accuracy in Asians. METHODS AND RESULTS: Patients with calcific aortic stenosis (AS) from seven international centres were included. Exclusion criteria were ≥moderate aortic/mitral regurgitation and bicuspid valve. Optimal AVC and AVC-density sex-specific thresholds for severe AS were obtained in concordant grading and normal flow patients (CG/NF). We included 1263 patients [728 (57%) Asians, 573 (45%) women, 837 (66%) with CG/NF]. Mean gradient was 48 (26-64) mmHg and peak aortic velocity 4.5 (3.4-5.1) m/s. Optimal AVC thresholds were: 2145 Agatston Units (AU) in men and 1301 AU in women for Asians; and 1885 AU in men and 1129 AU in women for Caucasians. Overall, accuracy (% correctly classified) was high and comparable either using optimal or guidelines' thresholds (2000 AU in men, 1200 AU in women). However, accuracy was lower in Asian women vs. Caucasian women (76-78% vs. 94-95%; P < 0.001). Accuracy of AVC-density (476 AU/cm2 in men and 292 AU/cm2 in women) was comparable to absolute AVC in Caucasians (91% vs. 91%, respectively, P = 0.74), but higher than absolute AVC in Asians (87% vs. 81%, P < 0.001). There was no interaction between AVC/AVC-density and ethnicity (all P > 0.41) with regards to AS haemodynamic severity. CONCLUSION: AVC thresholds defining severe AS are comparable in Asian and Caucasian populations, and similar to those proposed in the guidelines. However, accuracy of AVC to identify severe AS in Asians (especially women) is sub-optimal. Therefore, the use of AVC-density is preferable in Asians.

Cardiac Damage Staging Classification in Asymptomatic Moderate or Severe Primary Mitral Regurgitation.

Background: Optimal timing for intervention remains uncertain in asymptomatic patients with primary mitral regurgitation (MR). We aimed to assess the prognostic value of a new cardiac damage staging classification in patients with asymptomatic moderate or severe primary MR. Methods: Clinical, Doppler-echocardiographic, and outcome data prospectively collected in 338 asymptomatic patients (64 ± 15 years, 68% men) with at least moderate primary MR were retrospectively analyzed. Patients were hierarchically classified as per the following staging classification: no cardiac damage (stage 0), mild left ventricular or left atrial damage (stage 1), moderate or severe left ventricular or left atrial damage (stage 2), pulmonary vasculature or tricuspid valve damage (stage 3), or right ventricular damage (stage 4). Results: There was a stepwise increase in 10-year mortality rates as per cardiac damage stage: 20.0% in stage 0, 25.6% in stage 1, 31.5% in stage 2, and 61.3% in stage 3-4 (p < 0.001). The staging classification was significantly associated with increased risk of mortality (hazard ratio = 1.41 per one-stage increase, 95% confidence interval: 1.07-1.85, p = 0.015) and the composite of cardiovascular mortality or hospitalization (hazard ratio = 1.51 per one-stage increase, 95% confidence interval: 1.07-2.15, p = 0.020) in multivariable analysis adjusted for EuroSCORE II, mitral valve intervention as a time-dependent variable, and other risk factors. The proposed scheme showed incremental value over several clinical variables (net reclassification index = 0.40, p = 0.03). Conclusions: The new staging classification provides independent and incremental prognostic value in patients with asymptomatic moderate or severe MR.

Computed Tomography Aortic Valve Calcium Scoring in Patients With Bicuspid Aortic Valve Stenosis.

Background: Sex-specific thresholds of computed tomography (CT)-derived aortic valve calcification (AVC) or AVC density (AVCd) to identify severe aortic stenosis (AS) have been established in populations that consisted mainly of Caucasians with a tricuspid aortic valve. The objective of this study was to evaluate the accuracy (i.e., sensitivity and specificity) of previously established thresholds to identify severe AS in patients with bicuspid aortic valve (BAV) and according to ethnicity: Caucasian vs. Asian. Methods: We built a multicenter registry of echocardiographic and CT data collected in BAV patients with at least mild AS and preserved left ventricular ejection fraction from 7 different centers. Anatomic severity of AS obtained by CT-derived AVC and AVCd was compared to hemodynamic severity of AS obtained by echocardiography. Results: Among 485 BAV patients (60% men, 73% Asians), the best thresholds of AVC and AVCd to identify severe AS in BAV patients were 2315 arbitrary units (AU) (sensitivity [Se]/specificity [Spe] = 82/78%) in men, 1103 AU (Se/Spe = 80/82%) in women, and 561 AU/cm2 (Se/Spe = 86/91%) in men, and 301 AU/cm2 (Se/Spe = 83/82%) in women, respectively. According to ethnicity, thresholds for severe AS in Caucasian patients were, respectively, in men and women: 2208 AU (Se/Spe = 83/83%) and 1230 AU (Se/Spe = 87/82%) for AVC and 474 AU/cm2 (Se/Spe = 88/83%) and 358 AU/cm2 (Se/Spe = 80/82%) for AVCd. In Asian patients, they were 2582 AU (Se/Spe = 76/78%) and 924 AU (Se/Spe = 84/80%) for AVC and 640 AU/cm2 (Se/Spe = 82/89%) and 255 AU/cm2 (Se/Spe = 86/80%) for AVCd. Conclusions: The optimal thresholds to identify hemodynamically severe AS in BAV patients are similar in Caucasians but appear to be higher in Asian men, compared with thresholds previously reported in tricuspid aortic valve patients. Nonetheless, the thresholds currently proposed in the guidelines have good accuracy and can be applied in BAV patients to confirm AS severity.

Hemodynamic and Clinical Outcomes in Redo-Surgical Aortic Valve Replacement vs. Transcatheter Valve-in-Valve.

Background: Transcatheter valve-in-valve replacement (ViV-TAVR) has emerged as an alternative to redo-surgical aortic valve replacement (Redo-SAVR) for the treatment of failed surgical aortic bioprostheses. However, the benefit of ViV-TAVR compared with Redo-SAVR remains debated with regard to short-term hemodynamic results and short- and long-term clinical outcomes. Objective: This study aimed to compare short-term hemodynamic performance and long-term clinical outcomes of ViV-TAVR vs. Redo-SAVR in patients treated for surgical aortic bioprosthetic valve failure. Methods: We retrospectively analyzed the data prospectively collected in 184 patients who underwent Redo-SAVR or ViV-TAVR. Transthoracic echocardiography was performed before and after the procedure and analyzed in an echocardiography core laboratory using the new Valve Academic Research Consortium-3 criteria. An inverse probability of treatment weighting was used to compare the outcomes between both procedures. Results: ViV-TAVR showed lower rate of intended hemodynamic performance (39.2% vs. 67.7%, p < 0.001) at 30 days, which was essentially driven by a higher rate (56.2% vs. 28.8%, p = 0.001) of high residual gradient (mean transvalvular gradient ≥20 mm Hg). Despite a trend for higher 30-day mortality in the Redo-SAVR vs. ViV-TAVR group (8.7% vs. 2.5%, odds ratio [95% CI]: 3.70 [0.77-17.6]; p = 0.10), the long-term mortality was significantly lower (24.2% vs. 50.1% at 8 years; hazard ratio [95% CI]: 0.48 [0.26-0.91]; p = 0.03) in the Redo-SAVR group. After inverse probability of treatment weighting analysis, Redo-SAVR remained significantly associated with reduced long-term mortality compared with ViV-TAVR (hazard ratio [95% CI]: 0.32 [0.22-0.46]; p < 0.001). Conclusions: ViV-TAVR was associated with a lower rate of intended hemodynamic performance and numerically lower mortality at 30 days but higher rates of long-term mortality compared with Redo-SAVR.

Accuracy of stroke volume measurement with phase-contrast cardiovascular magnetic resonance in patients with aortic stenosis.

BACKGROUND: Phase contrast (PC) cardiovascular magnetic resonance (CMR) in the ascending aorta (AAo) is widely used to calculate left ventricular (LV) stroke volume (SV). The accuracy of PC CMR may be altered by turbulent flow. Measurement of SV at another site is suggested in the presence of aortic stenosis, but very few data validates the accuracy or inaccuracy of PC in that setting. Our objective is to compare flow measurements obtained in the AAo and LV outflow tract (LVOT) in patients with aortic stenosis. METHODS: Retrospective analysis of patients with aortic stenosis who had CMR and echocardiography. Patients with mitral regurgitation were excluded. PC in the AAo and LVOT were acquired to derive SV. LV SV from end-systolic and end-diastolic tracings was used as the reference measure. A difference ≥ 10% between the volumetric method and PC derived SVs was considered discordant. Metrics of turbulence and jet eccentricity were assessed to explore the predictors of discordant measurements. RESULTS: We included 88 patients, 41% with bicuspid aortic valve. LVOT SV was concordant with the volumetric method in 79 (90%) patients vs 52 (59%) patients for AAo SV (p = 0.015). In multivariate analysis, aortic stenosis flow jet angle was a strong predictor of discordant measurement in the AAo (p = 0.003). Mathematical correction for the jet angle improved the concordance from 59 to 91%. Concordance was comparable in patients with bicuspid and trileaflet valves (57% and 62% concordance respectively; p = 0.11). Accuracy of SV measured in the LVOT was not influenced by jet eccentricity. For aortic regurgitation quantification, PC in the AAo had better correlation to volumetric assessments than LVOT PC. CONCLUSION: LVOT PC SV in patients with aortic stenosis and eccentric jet might be more accurate compared to the AAo SV. Mathematical correction for the jet angle in the AAo might be another alternative to improve accuracy.

Markers of Myocardial Damage Predict Mortality in Patients With Aortic Stenosis.

BACKGROUND: Cardiovascular magnetic resonance (CMR) is increasingly used for risk stratification in aortic stenosis (AS). However, the relative prognostic power of CMR markers and their respective thresholds remains undefined. OBJECTIVES: Using machine learning, the study aimed to identify prognostically important CMR markers in AS and their thresholds of mortality. METHODS: Patients with severe AS undergoing AVR (n = 440, derivation; n = 359, validation cohort) were prospectively enrolled across 13 international sites (median 3.8 years' follow-up). CMR was performed shortly before surgical or transcatheter AVR. A random survival forest model was built using 29 variables (13 CMR) with post-AVR death as the outcome. RESULTS: There were 52 deaths in the derivation cohort and 51 deaths in the validation cohort. The 4 most predictive CMR markers were extracellular volume fraction, late gadolinium enhancement, indexed left ventricular end-diastolic volume (LVEDVi), and right ventricular ejection fraction. Across the whole cohort and in asymptomatic patients, risk-adjusted predicted mortality increased strongly once extracellular volume fraction exceeded 27%, while late gadolinium enhancement >2% showed persistent high risk. Increased mortality was also observed with both large (LVEDVi >80 mL/m2) and small (LVEDVi ≤55 mL/m2) ventricles, and with high (>80%) and low (≤50%) right ventricular ejection fraction. The predictability was improved when these 4 markers were added to clinical factors (3-year C-index: 0.778 vs 0.739). The prognostic thresholds and risk stratification by CMR variables were reproduced in the validation cohort. CONCLUSIONS: Machine learning identified myocardial fibrosis and biventricular remodeling markers as the top predictors of survival in AS and highlighted their nonlinear association with mortality. These markers may have potential in optimizing the decision of AVR.

A Machine-Learning Framework to Identify Distinct Phenotypes of Aortic Stenosis Severity.

OBJECTIVES: The authors explored the development and validation of machine-learning models for augmenting the echocardiographic grading of aortic stenosis (AS) severity. BACKGROUND: In AS, symptoms and adverse events develop secondarily to valvular obstruction and left ventricular decompensation. The current echocardiographic grading of AS severity focuses on the valve and is limited by diagnostic uncertainty. METHODS: Using echocardiography (ECHO) measurements (ECHO cohort, n = 1,052), we performed patient similarity analysis to derive high-severity and low-severity phenogroups of AS. We subsequently developed a supervised machine-learning classifier and validated its performance with independent markers of disease severity obtained using computed tomography (CT) (CT cohort, n = 752) and cardiovascular magnetic resonance (CMR) imaging (CMR cohort, n = 160). The classifier's prognostic value was further validated using clinical outcomes (aortic valve replacement [AVR] and death) observed in the ECHO and CMR cohorts. RESULTS: In 1,964 patients from the 3 multi-institutional cohorts, 1,346 (68%) subjects had either nonsevere or discordant AS severity. Machine learning identified 1,117 (57%) patients as having high-severity and 847 (43%) as having low-severity AS. High-severity patients in CT and CMR cohorts had higher valve calcium scores and left ventricular mass and fibrosis, respectively than the low-severity group. In the ECHO cohort, progression to AVR and progression to death in patients who did not receive AVR was faster in the high-severity group. Compared with the conventional classification of disease severity, machine-learning-based severity classification improved discrimination (integrated discrimination improvement: 0.07; 95% confidence interval: 0.02 to 0.12) and reclassification (net reclassification improvement: 0.17; 95% confidence interval: 0.11 to 0.23) for the outcome of AVR at 5 years. For both ECHO and CMR cohorts, we observed prognostic value of the machine-learning classifications for subgroups with asymptomatic, nonsevere or discordant AS. CONCLUSIONS: Machine learning can integrate ECHO measurements to augment the classification of disease severity in most patients with AS, with major potential to optimize the timing of AVR.

Left ventricular asymmetric remodeling and subclinical left ventricular dysfunction in patients with calcific aortic valve stenosis - Results from a subanalysis of the PROGRESSA study.

BACKGROUND: LV asymmetric remodeling (LVAR) is a feature commonly found in AS patients and it is presumed to be mainly related to the severity of valve stenosis. The aim of this study was to determine the associated factors and impact on left ventricular (LV) systolic function of LVAR in patients with mild and moderate aortic valve stenosis (AS). METHODS: Clinical, Doppler-echocardiographic and computed-tomographic data of 155 AS patients with preserved LV ejection fraction (≥50%) prospectively recruited in the PROGRESSA study (NCT01679431) were analyzed. LVAR was defined as a septal wall thickness ≥ 13 mm and a ratio of septal/posterior wall thickness > 1.5. LV global longitudinal strain (LV-GLS) was available in 129 patients. Plasma levels of N-terminal natriuretic B-type peptides (Nt-proBNP) were also measured. RESULTS: Mean age was 63 ± 15 years (70% men). LVAR was present in 21% (n = 33) of patients. A series of nested multivariate analysis revealed that age was the only factor associated with LVAR (all p ≤ 0.03). Additionally, these patients had higher baseline Nt-proBNP ratio (median [25-75 percentiles]: 1.04 [0.66-2.41] vs. 0.65 [0.33-1.19], p = 0.02), and significantly reduced LV-GLS (17.9[16.6-19.5] vs. 19.3[17.4-20.7] |%|, p = 0.04). A 1:1 matched analysis showed a significant association of LVAR with reduced LV-GLS (17.9[16.6-19.5] vs. 19.8[18.1-20.7] |%|, p = 0.02) and elevated Nt-proBNP (134[86-348] vs. 83[50-179]pg/ml, p = 0.03). Multivariable analysis also revealed that LVAR remains significantly associated with reduced LV-GLS (p = 0.03) and elevated Nt-proBNP (p = 0.001). LVAR was significantly associated with increased risk of major adverse cardiac events and death (Hazard ratio [95% confidence interval]: 2.32[1.28-4.22], p = 0.006). CONCLUSIONS: LVAR was found in ~20% of patients with mild or moderate AS and was not related to the degree of AS severity or concomitant comorbidities, but rather to older age. LVAR was significantly associated with reduced LV longitudinal systolic function, increased Nt-proBNP levels, and higher risk of major adverse events and death. These findings provide support for closer clinical and echocardiographic surveillance of patients harboring this adverse LV remodeling feature.

The Role of Extravalvular Cardiac Damage Staging in Aortic Valve Disease Management.

Current management of patients with aortic valve disease, including aortic valve stenosis (AS), aortic valve regurgitation (AR), and mixed aortic valve disease (MAVD), remains challenging. American and European guideline recommendations regarding the timing of intervention are mainly based on the assessment of disease severity (ie, grading), presence of symptoms related to aortic valve disease, left ventricular systolic dysfunction, or LV enlargement. Furthermore, the decision regarding the type of intervention (ie, surgical vs transcatheter) is primarily based on risk assessment from surgical risk scores. There is, however, less emphasis on the importance of the assessment of anatomic and functional cardiac repercussions of aortic valve disease to guide the clinical management of these patients. Recently, a novel approach has been proposed to improve the management of aortic valve disease with 2 main components for risk stratification of the disease: 1) grading the severity of aortic valve disease, and 2) staging the extent of extravalvular cardiac damage associated with aortic valve disease with the use of echocardiography. To date, this novel approach of extravalvular cardiac damage staging was proposed and validated only in the context of AS but could be extended to other valvular heart diseases, including AR and MAVD. Further studies are also needed to test the incremental value of additional imaging parameters (eg, myocardial fibrosis by magnetic resonance) as well as blood biomarkers (eg, natriuretic peptide, cardiac troponin, and others) to the existing cardiac damage staging schemes.

Effect of Regional Upper Septal Hypertrophy on Echocardiographic Assessment of Left Ventricular Mass and Remodeling in Aortic Stenosis.

BACKGROUND: Transthoracic echocardiography (TTE) is the reference method for evaluation of aortic stenosis (AS), and it is extensively used to quantitate left ventricular (LV) mass and volumes. Regional upper septal hypertrophy (USH) or septal bulge is a frequent finding in patients with AS and may lead to overestimation of LV mass when using linear measurements. The objective of this study was to compare estimates of LV mass obtained by two-dimensional transthoracic echocardiographic LV dimensions measured at different levels of the LV cavity with those obtained by cardiovascular magnetic resonance (CMR). METHODS: One hundred six patients (mean age, 63 ± 15 years; 68% men) with AS were included in this subanalysis of the PROGRESSA study. Two-dimensional transthoracic echocardiographic measurements of LV dimensions were obtained at the basal level (BL; as recommended in guidelines), immediately below the septal bulge (BSB), and at a midventricular level (ML). Regional USH was defined as a basal interventricular septal thickness ≥ 13 mm and >1.3 times the thickness of the septal wall at the ML. Agreement between transthoracic echocardiographic and CMR measures was evaluated using Bland-Altman analysis. RESULTS: The distribution of AS severity was mild in 23%, moderate in 57%, and severe in 20% of patients. Regional USH was present in 28 patients (26%). In the whole cohort, two-dimensional TTE overestimated LV mass (bias: BL, +60 ± 31 g; BSB, +59 ± 32 g; ML, +54 ± 32 g; P = .02). The biplane Simpson method slightly but significantly underestimated LV end-diastolic volume (bias -10 ± 20 mL, P < .001) compared with CMR. Overestimation of LV mass was more marked in patients with USH when measuring at the BL and was significantly lower when measuring LV dimensions at the ML (P < .025 vs BL and BSB). CONCLUSIONS: Two-dimensional TTE systematically overestimated LV mass and underestimated LV volumes compared with CMR. However, the bias between TTE and CMR was less important when measuring at the ML. Measurements at the BL as suggested in guidelines should be avoided, and measurements at the ML should be preferred in patients with AS, especially in those with USH.