Additive Prognostic Value of Left Ventricular Dispersion and Deformation in Patients With Severe Aortic Stenosis.

BACKGROUND: Speckle tracking strain echocardiography allows one to visualize the timing of maximum regional strain and quantifies left ventricular-mechanical dispersion (LV-MD). Whether LV-MD and LV-global longitudinal strain (LV-GLS) provide similar or complementary information in mortality risk stratification in patients with severe aortic stenosis (SAS) remains unknown. OBJECTIVES: The authors hypothesized that LV mechanical dyssynchrony assessed by LV-MD is associated with an increased risk of mortality and provides additional prognostic information on top of LV-GLS in patients with SAS. METHODS: A total of 364 patients with SAS (aortic valve area indexed ≤0.6 cm2/m2 and/or aortic valve area ≤1 cm2), LV ejection fraction ≥50% and no or mild symptoms were enrolled. The endpoint was overall mortality. RESULTS: During a median follow-up period of 41 months, 149 patients died. After adjustment, LV-MD ≥68 ms was significantly associated with an increased risk of mortality (adjusted HR: 1.41; 95% CI: 1.01-1.96; P = 0.044). Adding LV-MD ≥68 ms to a multivariable Cox regression model including LV-GLS ≥-15% improved predictive performance in terms of overall mortality, with improved global model fit, reclassification, and better discrimination. Patients with both criteria had an important increase in mortality compared to patients with none or one criterion (adjusted HR: 2.02; 95% CI: 1.34-3.03; P = 0.001). Interobserver reproducibility of LV-MD was good with an intraclass correlation coefficient of 0.90 (95% CI: 0.72-0.97). CONCLUSIONS: LV-MD is a reproducible parameter independently associated with an increased risk of mortality in SAS. Increased LV-MD associated with depressed LV-GLS identifies a subgroup of patients with an increased mortality risk. Whether early aortic valve replacement improves the outcome of these patients deserves further studies.

Quantifying the Survival Loss Linked to Late Therapeutic Indication in High-Gradient Severe Aortic Stenosis.

Background: International guidelines recommend aortic valve replacement (AVR) as Class I triggers in high-gradient severe aortic stenosis (HGSAS) patients with symptoms and/or left ventricular ejection fraction (LVEF) <50%. The association between waiting for these triggers and postoperative survival penalty is poorly studied. Objectives: The purpose of this study was to examine the impact of guideline-based Class I triggers on long-term postoperative survival in HGSAS patients. Methods: 2,030 patients operated for HGSAS were included and classified as follows: no Class I triggers (no symptoms and LVEF >50%, n = 853), symptoms with LVEF >50% (n = 965), or LVEF <50% regardless of symptoms (n = 212). Survival was compared after matching (inverse probability weighting) for clinical differences. Restricted mean survival time was analyzed to quantify lifetime loss. Results: Ten-year survival was better without any Class I trigger than with symptoms or LVEF <50% (67.1% ± 3% vs 56.4% ± 3% vs 53.1% ± 7%, respectively, P < 0.001). Adjusted death risks increased significantly in operated patients with symptoms (HR: 1.45 [95% CI: 1.15-1.82]) or LVEF <50% (HR: 1.47 [95% CI: 1.05-2.06]) than in those without Class I triggers. Performing AVR with LVEF >60% produced similar outcomes to that of the general population, whereas operated patients with LVEF <60% was associated with a 10-year postoperative survival penalty. Furthermore, according to restricted mean survival time analyses, operating on symptomatic patients or with LVEF <60% led to 8.3- and 11.4-month survival losses, respectively, after 10 years, compared with operated asymptomatic patients with a LVEF >60%. Conclusions: Guideline-based Class I triggers for AVR in HGSAS have profound consequences on long-term postoperative survival, suggesting that HGSAS patients should undergo AVR before trigger onset. Operating on patients with LVEF <60% is already associated with a 10-year postoperative survival penalty questioning the need for an EF threshold recommending AVR in HGSAS patients.

Impact of Sex on Severity Assessment and Cardiac Remodeling in Primary Mitral Regurgitation.

Background: Women with severe primary mitral regurgitation (MR) have lower surgery rates than men and could suffer from delayed referral for mitral valve (MV) intervention, exposing them to an increased risk of postoperative adverse outcomes. Objectives: The purpose of this study was to assess the sex-based differences in patients with primary MR. Methods: The study sample consisted of 420 patients (median age: 62 years, 26% women) with primary MR due to valve prolapse referred for preoperative assessment who underwent transthoracic echocardiography (TTE) and cardiac magnetic resonance (CMR) imaging. Multiple endpoints (abnormally increased left ventricular size, NYHA functional class III/IV, severe left atrial [LA] dilatation, pulmonary hypertension) were studied using areas under the curves and logistic regression models. Results: Women were older than men, had higher NYHA functional class and larger indexed LA volumes (all P ≤ 0.031), despite displaying lower MR effective regurgitant orifice area, regurgitant volumes (RegVol), and ventricular volumes than men (all P ≤ 0.002). The optimal cut-off values of RegVol associated with abnormally increased left ventricular size according to reference normal values were lower in women (TTE: 67 ml, CMR: 50 ml) than in men (TTE: 77 ml, CMR: 65 ml). MR regurgitant fraction, but not RegVol, was associated in women and men with NYHA functional class III/IV, severe LA dilatation, and pulmonary hypertension (all areas under the curves, P ≤ 0.024). Conclusions: Despite having hallmarks of more advanced valvular heart disease, women with significant primary MR demonstrate lower mitral RegVol and ventricular volumes than men. In contrast, the systematic calculation of MR regurgitant fraction could standardize MR quantification irrespective of sex.

Impact of left atrial and diastolic ventricular dysfunction on mortality in patients with aortic stenosis.

BACKGROUND: Diastolic dysfunction (DD) is common in severe aortic stenosis (AS) and preserved left ventricular ejection fraction (LVEF≥50%). AIM: To determine the impact of American Society of Echocardiography/European Association of Cardiovascular Imaging-recommended DD grading and left atrial strain on mortality in a cohort of patients with severe AS and preserved LVEF. METHODS: We studied patients with severe AS (aortic valve area indexed<0.6 cm2/m2 and/or aortic valve area<1cm2), LVEF≥50% and no or mild AS-related symptoms. The endpoint was all-cause mortality. RESULTS: A total of 387 patients (median age 76years; 53% women) were studied. During a median follow-up of 57 (interquartile range 37; 83) months, 158 patients died. After adjustment for prognostic factors, patients with grade II or III DD had an increased mortality risk versus patients with grade I DD (adjusted hazard ratio (aHR) 1.62, 95% confidence interval (CI) 1.11-2.38; P=0.013; aHR 4.73, 95% CI 2.49-8.99; P<0.001; respectively). Adding peak atrial longitudinal strain (PALS)≤14% to a multivariable model including DD grade improved predictive performance, with better global model fit, reclassification and discrimination. Patients with grade III DD or grade II DD+PALS≤14% displayed an increased mortality risk versus patients with grade I DD+PALS>14% (aHR 4.17, 95% CI 2.46-7.06; P<0.0001). Those with grade I DD+PALS≤14% or grade II DD+PALS>14% were at intermediate risk (aHR 1.63, 95% CI 1.07-2.49; P=0.024). CONCLUSIONS: Our results demonstrate the strong relationship between DD and mortality in patients with severe AS and preserved LVEF. Patients with grade III or grade II DD and impaired PALS are at very high risk. These data demonstrate the importance of a comprehensive assessment of diastolic function in patients with severe AS.

The evolving role of cardiovascular magnetic resonance in the assessment of mitral valve prolapse.

Mitral valve prolapse (MVP), characterized by a displacement > 2 mm above the mitral annulus of one or both bileaflets, with or without leaflet thickening, is a common valvular heart disease, with a prevalence of approximately 2% in western countries. Although this population has a generally good overall prognosis, MVP can be associated with mitral regurgitation (MR), left ventricular (LV) remodeling leading to heart failure, ventricular arrhythmia, and, the most devastating complication, sudden cardiac death, especially in myxomatous bileaflet prolapse (Barlow's disease). Among several prognostic factors reported in the literature, LV fibrosis and mitral annular disjunction may act as an arrhythmogenic substrate in this population. Cardiac magnetic resonance (CMR) has emerged as a reliable tool for assessing MVP, MR severity, LV remodeling, and fibrosis. Indeed, CMR is the gold standard imaging modality to assess ventricular volume, function, and wall motion abnormalities; it allows accurate calculation of the regurgitant volume and regurgitant fraction in MR using a combination of LV volumetric measurement and aortic flow quantification, independent of regurgitant jet morphology and valid in cases of multiple valvulopathies. Moreover, CMR is a unique imaging modality that can assess non-invasively focal and diffuse fibrosis using late gadolinium enhancement sequences and, more recently, T1 mapping. This review describes the use of CMR in patients with MVP and its role in identifying patients at high risk of ventricular arrhythmia.

Quantification of primary mitral regurgitation by echocardiography: A practical appraisal.

The accurate quantification of primary mitral regurgitation (MR) and its consequences on cardiac remodeling is of paramount importance to determine the best timing for surgery in these patients. The recommended echocardiographic grading of primary MR severity relies on an integrated multiparametric approach. It is expected that the large number of echocardiographic parameters collected would offer the possibility to check the measured values regarding their congruence in order to conclude reliably on MR severity. However, the use of multiple parameters to grade MR can result in potential discrepancies between one or more of them. Importantly, many factors beyond MR severity impact the values obtained for these parameters including technical settings, anatomic and hemodynamic considerations, patient's characteristics and echocardiographer' skills. Hence, clinicians involved in valvular diseases should be well aware of the respective strengths and pitfalls of each of MR grading methods by echocardiography. Recent literature highlighted the need for a reappraisal of the severity of primary MR from a hemodynamic perspective. The estimation of MR regurgitation fraction by indirect quantitative methods, whenever possible, should be central when grading the severity of these patients. The assessment of the MR effective regurgitant orifice area by the proximal flow convergence method should be used in a semi-quantitative manner. Furthermore, it is crucial to acknowledge specific clinical situations in MR at risk of misevaluation when grading severity such as late-systolic MR, bi-leaflet prolapse with multiple jets or extensive leak, wall-constrained eccentric jet or in older patients with complex MR mechanism. Finally, it is debatable whether the 4-grades classification of MR severity would be still relevant nowadays, since the indication for mitral valve (MV) surgery is discussed in clinical practice for patients with 3+ and 4+ primary MR based on symptoms, specific markers of adverse outcome and MV repair probability. Primary MR grading should be seen as a continuum integrating both quantification of MR and its consequences, even for patients with presumed "moderate" MR.

Is "moderate" aortic stenosis still the right name? A review of the literature.

Current guidelines recommend aortic valve replacement for symptomatic or selected asymptomatic high-risk patients with severe aortic stenosis. Conversely, a watchful waiting attitude applies to patients with moderate aortic stenosis, regardless of their risk profile and symptoms, until the echocardiographic thresholds of severe aortic stenosis are reached. This strategy is based on data reporting high mortality in untreated severe symptomatic aortic stenosis, whereas moderate aortic stenosis has always been perceived as a non-threatening condition, with a benefit-risk balance against surgery. Meanwhile, numerous studies have reported a worrying event rate in these patients, surgical techniques and outcomes have improved significantly and the use of transcatheter aortic valve replacement has become more widespread and extended to lower-risk patients, leaving this strategy open to question, especially for patients with moderate aortic stenosis and left ventricular dysfunction. In this review, we summarize the current state of knowledge about moderate aortic stenosis progression and prognosis. We also discuss the particular case of moderate aortic stenosis associated with left ventricular dysfunction, and the ongoing trials that that might change our paradigm for the management of this "moderate" valvular heart disease.

Clinical significance of myocardial contraction fraction in significant primary mitral regurgitation.

BACKGROUND: The optimal timing for mitral valve (MV) surgery in asymptomatic patients with primary mitral regurgitation (MR) remains a matter of debate. Myocardial contraction fraction (MCF) - the ratio of the left ventricular (LV) stroke volume to that of the myocardial volume - is a volumetric measure of LV myocardial shortening independent of size or geometry. AIM: To assess the relationship between MCF and outcome in patients with significant chronic primary MR due to prolapse managed in contemporary practice. METHODS: Clinical, Doppler-echocardiographic and outcome data prospectively collected in 174 patients (mean age 62 years, 27% women) with significant primary MR and no or mild symptoms were analysed. The impact of MCF< or ≥30% on cardiac events (cardiovascular death, acute heart failure or MV surgery) was studied. RESULTS: During an estimated median follow-up of 49 (22-77) months, cardiac events occurred in 115 (66%) patients. The 4-year estimates of survival free from cardiac events were 21±5% for patients with MCF <30% and 40±6% for those with ≥30% (P<0.001). MCF <30% was associated with a considerable increased risk of cardiac events after adjustment for established clinical risk factors, MR severity and current recommended class I triggers for MV surgery (adjusted hazard ratio: 2.33, 95% confidence interval: 1.51-3.58; P<0.001). Moreover, MCF<30% improved the predictive performance of models, with better global fit, reclassification and discrimination. CONCLUSIONS: MCF<30% is strongly associated with occurrence of cardiac events in patients with significant primary MR due to prolapse. Further studies are needed to assess the direct impact of MCF on patient management and outcomes.

Prognostic Implications of Discordant Low-Gradient Severe Aortic Stenosis: Comprehensive Analysis of a Large Multicenter Registry.

Background: Up to 30% of patients with severe aortic stenosis (SAS) (indexed aortic valve area [AVAi] <0.6 cm2/m2) exhibit low-transvalvular gradient despite normal ejection fraction. There is intense debate regarding the prognostic significance of this entity. Objectives: The purpose of this study was to compare the outcome of patients with discordant low-gradient SAS (DLG-SAS) vs moderate aortic stenosis (MAS) and high-gradient SAS (HG-SAS). Methods: We used the BEL-F-ASt (Belgium-France-Aortic Stenosis) registry including consecutive patients with AS. Survival was compared overall and after matching (inverse probability weighting and propensity-score matching) for clinical and imaging variables. The analysis was first performed in the overall population (n = 2,582) and then in the population of unoperated patients (n = 1,812). Results: After-inverse probability weighting-matching, the 3 groups were balanced. Five-year survival was better in MAS than in DLG-SAS and HG-SAS-patients (58.9% vs 47% vs 41.2%, P < 0.001). Similar results were obtained in unoperated patients (54.1% vs 37.9% vs 28.1%, P < 0.001). To explore the impact of MG (≤40 vs >40 mmHg) and AVAi (<0.6 vs ≥0.6 cm2/m2) on outcomes, survival of propensity score-matched cohorts of HG-vs DLG-SAS and MAS vs DLG-SAS were compared. After matching for MG, survival was better in MAS than in DLG-SAS (52% vs 40%, P < 0.001). After matching for AVAi, survival was better in DLG-SAS than in HG-SAS patients (45% vs 33%, P < 0.001). Conclusions: Survival of DLG-SAS is better than that of HG-SAS and worse than that of MAS patients. At comparable MG, the lower the AVAi, the worse the prognosis, whereas at comparable AVAi, the higher the MG, the worse the prognosis. These data argue that DLG-SAS is an intermediate form in the disease continuum.

Integrating Echocardiography Parameters With Explainable Artificial Intelligence for Data-Driven Clustering of Primary Mitral Regurgitation Phenotypes.

BACKGROUND: Primary mitral regurgitation (MR) is a heterogeneous clinical disease requiring integration of echocardiographic parameters using guideline-driven recommendations to identify severe disease. OBJECTIVES: The purpose of this preliminary study was to explore novel data-driven approaches to delineate phenotypes of MR severity that benefit from surgery. METHODS: The authors used unsupervised and supervised machine learning and explainable artificial intelligence (AI) to integrate 24 echocardiographic parameters in 400 primary MR subjects from France (n = 243; development cohort) and Canada (n = 157; validation cohort) followed up during a median time of 3.2 years (IQR: 1.3-5.3 years) and 6.8 (IQR: 4.0-8.5 years), respectively. The authors compared the phenogroups' incremental prognostic value over conventional MR profiles and for the primary endpoint of all-cause mortality incorporating time-to-mitral valve repair/replacement surgery as a covariate for survival analysis (time-dependent exposure). RESULTS: High-severity (HS) phenogroups from the French cohort (HS: n = 117; low-severity [LS]: n = 126) and the Canadian cohort (HS: n = 87; LS: n = 70) showed improved event-free survival in surgical HS subjects over nonsurgical subjects (P = 0.047 and P = 0.020, respectively). A similar benefit of surgery was not seen in the LS phenogroup in both cohorts (P = 0.70 and P = 0.50, respectively). Phenogrouping showed incremental prognostic value in conventionally severe or moderate-severe MR subjects (Harrell C statistic improvement; P = 0.480; and categorical net reclassification improvement; P = 0.002). Explainable AI specified how each echocardiographic parameter contributed to phenogroup distribution. CONCLUSIONS: Novel data-driven phenogrouping and explainable AI aided in improved integration of echocardiographic data to identify patients with primary MR and improved event-free survival after mitral valve repair/replacement surgery.

Comparison of Mitral Regurgitant Volume Assessment between Proximal Flow Convergence and Volumetric Methods in Patients with Significant Primary Mitral Regurgitation: An Echocardiographic and Cardiac Magnetic Resonance Imaging Study.

BACKGROUND: Discrepancies have been observed between transthoracic echocardiography (TTE) and cardiac magnetic resonance imaging (CMR) severity grading in primary mitral regurgitation (MR). OBJECTIVES: We sought to compare mitral regurgitant volume (RVol) determined by the TTE proximal flow convergence (proximal isovelocity surface area [PISA]) method and by volumetric methods (TTE and CMR) and to study the relationship between left ventricle (LV) size and RVol obtained by either the PISA or volumetric methods. METHODS: Two centers prospectively recruited 188 patients with at least moderate to severe primary MR due to prolapse in sinus rhythm who underwent TTE and CMR examinations. Regurgitant volume was estimated by either PISA (PISA-RVol) or volumetric methods (LV total stroke volume-systolic aortic forward outflow volume) using either CMR (CMR-RVol) or TTE (TTE-RVol). RESULTS: The PISA-RVol was weakly correlated with CMR-RVol and TTE-RVol (r = 0.29 and 0.30, respectively; P < .001 for both). On multivariable analysis, smaller CMR-left ventricular end-diastolic volume (LVEDV) and absence of mitral annular disjunction independently correlated with increased magnitude of RVol difference between PISA and volumetric methods. While PISA-RVol and LVEDV were unrelated, CMR-RVol and TTE-RVol moderately correlated with LVEDV (r = 0.66 and 0.68, respectively; P < .001 for both). In contrast, LVEDV and regurgitant fraction (RVol/LV total stroke volume), assessed with either TTE or CMR, were poorly correlated (r = 0.17, P = .02; and r = 0.12, P = .10, respectively). CONCLUSIONS: Mitral RVol values estimated by PISA and volumetric methods are not directly comparable. The expected proportional relationship between volumetric RVol and LV size, which was not observed with PISA-RVol, suggests that PISA-RVol would be inaccurate. Given that RVol assessed with volumetric methods depends on LV size, determination of a unique RVol threshold for severe MR is challenging. In contrast to RVol, calculating regurgitant fraction by volumetric methods allows the quantification of MR severity independently from LV size.

Significance of Left Ventricular Ejection Time in Primary Mitral Regurgitation.

The optimal timing for mitral valve (MV) surgery in asymptomatic patients with primary mitral regurgitation (MR) remains controversial. We aimed at evaluating the relation between left ventricular ejection time (LVET) and outcome in patients with moderate or severe chronic primary MR because of prolapse. Clinical, Doppler echocardiographic, and outcome data prospectively collected from 302 patients (median age 61 [54 to 74] years, 34% women) with moderate or severe primary MR were analyzed. Patients were retrospectively stratified by quartiles of LVET. The primary end point of the study was the composite of need for MV surgery or all-cause mortality. During a median follow-up time of 66 (25th to 75th percentile, 33 to 95) months, 178 patients reached the primary end point. Patients in the lowest quartile of LVET (<260 ms) were at high risk for adverse events compared with those in the other quartiles of LVET (global p = 0.005), whereas the rate of events was similar for the other quartiles (p = NS for all). After adjustment for clinical predictors of outcome, including age, gender, history of atrial fibrillation, MR severity, and current recommended triggers for MV surgery in asymptomatic primary MR, LVET <260 ms was associated with an increased risk of events (adjusted hazard ratio 1.49, 95% confidence interval 1.03 to 2.16, p = 0.033). In conclusion, we observed that shorter LVET is associated with increased risk of adverse events in patients with moderate or severe primary MR because of prolapse. Further studies are required to investigate whether shorter LVET has a direct effect on outcomes or is solely a risk marker in primary MR.

Unsupervised clustering of patients with severe aortic stenosis: A myocardial continuum.

BACKGROUND: Traditional statistics, based on prediction models with a limited number of prespecified variables, are probably not adequate to provide an appropriate classification of a condition that is as heterogeneous as aortic stenosis (AS). AIMS: To investigate a new classification system for severe AS using phenomapping. METHODS: Consecutive patients from a referral centre (training cohort) who met the echocardiographic definition of an aortic valve area (AVA) ≤ 1 cm2 were included. Clinical, laboratory and imaging continuous variables were entered into an agglomerative hierarchical clustering model to separate patients into phenogroups. Individuals from an external validation cohort were then assigned to these original clusters using the K nearest neighbour (KNN) function and their 5-year survival was compared after adjustment for aortic valve replacement (AVR) as a time-dependent covariable. RESULTS: In total, 613 patients were initially recruited, with a mean±standard deviation AVA of 0.72±0.17 cm2. Twenty-six variables were entered into the model to generate a specific heatmap. Penalized model-based clustering identified four phenogroups (A, B, C and D), of which phenogroups B and D tended to include smaller, older women and larger, older men, respectively. The application of supervised algorithms to the validation cohort (n=1303) yielded the same clusters, showing incremental cardiac remodelling from phenogroup A to phenogroup D. According to this myocardial continuum, there was a stepwise increase in overall mortality (adjusted hazard ratio for phenogroup D vs A 2.18, 95% confidence interval 1.46-3.26; P<0.001). CONCLUSIONS: Artificial intelligence re-emphasizes the significance of cardiac remodelling in the prognosis of patients with severe AS and highlights AS not only as an isolated valvular condition, but also a global disease.

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.

Myocardial Contraction Fraction for Risk Stratification in Low-Gradient Aortic Stenosis With Preserved Ejection Fraction.

BACKGROUND: Myocardial contraction fraction (MCF) is a volumetric measure of myocardial shortening independent of left ventricular size and geometry. This multicenter study investigates the usefulness of MCF for risk stratification in low-gradient severe aortic stenosis with preserved ejection fraction. METHODS: We included 643 consecutive patients with low-gradient severe aortic stenosis with preserved ejection fraction in whom MCF was computed at baseline and analyzed mortality during follow-up. RESULTS: Throughout follow-up with medical and surgical management (34.9 [16.1-65.3] months), lower MCF tertiles had higher mortality than the highest tertile. Eighty-month survival was 56±4% for MCF>41%, 41±4% for MCF 30% to 41%, and 40±4% for MCF<30% (P<0.001). After comprehensive adjustment, mortality risk remained high for MCF 30% to 41% (adjusted hazard ratio, 1.53 [1.08-2.18]) and for MCF<30% (adjusted hazard ratio, 1.82 [1.24-2.66]) versus MCF>41%. The optimal MCF cutoff point for mortality prediction was 41%. Age, body mass index, Charlson index, peak aortic velocity, and ejection fraction were independently associated with mortality. MCF (χ2 to improve 10.39; P=0.001), provided greater additional prognostic value over the baseline parameters than stroke volume (SV) index (χ2 to improve 5.41; P=0.042), left ventricular mass index (χ2 to improve 2.15; P=0.137), or global longitudinal strain (χ2 to improve 3.67; P=0.061). MCF outperformed ejection fraction for mortality prediction. When patients were classified by SV index and MCF, mortality risk was low when SV index was ≥30 mL/m2 and MCF>41%, higher for patients with SV index ≥30 mL/m2 and MCF≤41% (adjusted hazard ratio, 1.47 [1.05-2.07]) and extremely high for patients with SV index <30 mL/m2 (adjusted hazard ratio, 2.29 [1.45-3.62]). CONCLUSIONS: MCF is a valuable marker of risk in low-gradient severe aortic stenosis with preserved ejection fraction and could improve decision-making, especially in normal-flow low-gradient severe aortic stenosis with preserved ejection fraction.

Normative Reference Values of Cardiac Output by Pulsed-Wave Doppler Echocardiography in Adults.

Cardiac output (CO) is routinely assessed by pulsed-wave Doppler echocardiography, yet reference values in adults are lacking. We aim to establish normative values of CO and cardiac index (CI) by pulsed-wave Doppler-echocardiography and to analyze their relation with gender and age in nonobese and obese adults. We included 4,040 adults (mean age: 55 years, 53% women, 950 obese [body mass index ≥30 kg/m²]) with normal blood pressure, no history of cardiovascular disease, and normal transthoracic echocardiography. Normative reference CO and CI values for were calculated in 3,090 nonobese patients by quantile regression. CO normal limits were lower in females than in males (lower limit: 3.3 vs 3.5 L/min, upper limit: 7.3 vs 8.2 L/min). CI normal limits were identical for both genders (lower limit: 1.9 L/min/m², upper limit: 4.3 L/min/m²). Although the relation of CO to age was weak and observed only in women, CI of both genders was not influenced by age. CO of obese patients was significantly greater than that of their nonobese counterparts. CI of obese patients was not influenced by age and gender and was not significantly different than that of nonobese patients (lower limit 1.8 L/min/m², upper limit 4.1 L/min/m² for both genders). In conclusion, in a large adult population we establish normative reference values for CO and CI measured by Doppler-echocardiography. CI is a remarkably stable parameter that is not influenced by age, gender, and body size and should be used to define low- and high-output states.

Relationship Between the Ratio of Acceleration Time/Ejection Time and Mortality in Patients With High-Gradient Severe Aortic Stenosis.

Background The ratio of acceleration time/ejection time (AT/ET) is a simple and reproducible echocardiographic parameter that integrates aortic stenosis severity and its consequences on the left ventricle. No study has specifically assessed the prognostic impact of AT/ET on outcome in patients with high-gradient severe aortic stenosis (SAS) and no or mild symptoms. We sought to evaluate the relationship between AT/ET and mortality and determine the best predictive AT/ET cutoff value in these patients. Methods and Results A total of 353 patients (median age, 79 years; 46% women) with high-gradient (mean pressure gradient ≥40 mm Hg and/or aortic peak jet velocity ≥4 m/s) SAS, left ventricular ejection fraction ≥50%, and no or mild symptoms were studied. The impact of AT/ET ≤0.35 or >0.35 on all-cause mortality was retrospectively studied. During a median follow-up of 39 (25th-75th percentile, 23-62) months, 70 patients died. AT/ET >0.35 was associated with a considerable increased mortality risk after adjustment for established prognostic factors in SAS under medical and/or surgical management (adjusted hazard ratio [HR], 2.54; 95% CI, 1.47-4.37; P<0.001) or conservative management (adjusted HR, 3.29; 95% CI, 1.70-6.39; P<0.001). Moreover, AT/ET >0.35 improved the predictive performance of models including established risk factors in SAS with better global model fit, reclassification, and discrimination. After propensity matching, increased mortality risk persisted when AT/ET >0.35 (adjusted HR, 2.10; 95% CI, 1.12-3.90; P<0.001). Conclusions AT/ET >0.35 is a strong predictor of outcome in patients with SAS and no or only mild symptoms and identifies a subgroup of patients at higher risk of death who may derive benefit from earlier aortic valve replacement.

Clinical and prognostic implications of phenomapping in patients with heart failure receiving cardiac resynchronization therapy.

BACKGROUND: Despite having an indication for cardiac resynchronization therapy according to current guidelines, patients with heart failure with reduced ejection fraction who receive cardiac resynchronization therapy do not consistently derive benefit from it. AIM: To determine whether unsupervised clustering analysis (phenomapping) can identify distinct phenogroups of patients with differential outcomes among cardiac resynchronization therapy recipients from routine clinical practice. METHODS: We used unsupervised hierarchical cluster analysis of phenotypic data after data reduction (55 clinical, biological and echocardiographic variables) to define new phenogroups among 328 patients with heart failure with reduced ejection fraction from routine clinical practice enrolled before cardiac resynchronization therapy. Clinical outcomes and cardiac resynchronization therapy response rate were studied according to phenogroups. RESULTS: Although all patients met the recommended criteria for cardiac resynchronization therapy implantation, phenomapping analysis classified study participants into four phenogroups that differed distinctively in clinical, biological, electrocardiographic and echocardiographic characteristics and outcomes. Patients from phenogroups 1 and 2 had the most improved outcome in terms of mortality, associated with cardiac resynchronization therapy response rates of 81% and 78%, respectively. In contrast, patients from phenogroups 3 and 4 had cardiac resynchronization therapy response rates of 39% and 59%, respectively, and the worst outcome, with a considerably increased risk of mortality compared with patients from phenogroup 1 (hazard ratio 3.23, 95% confidence interval 1.9-5.5 and hazard ratio 2.49, 95% confidence interval 1.38-4.50, respectively). CONCLUSIONS: Among patients with heart failure with reduced ejection fraction with an indication for cardiac resynchronization therapy from routine clinical practice, phenomapping identifies subgroups of patients with differential clinical, biological and echocardiographic features strongly linked to divergent outcomes and responses to cardiac resynchronization therapy. This approach may help to identify patients who will derive most benefit from cardiac resynchronization therapy in "individualized" clinical practice.

Excess Mortality and Undertreatment of Women With Severe Aortic Stenosis.

Background Although women represent half of the population burden of aortic stenosis (AS), little is known whether sex affects the presentation, management, and outcome of patients with AS. Methods and Results In a cohort of 2429 patients with severe AS (49.5% women) we aimed to evaluate 5-year excess mortality and performance of aortic valve replacement (AVR) stratified by sex. At presentation, women were older (P<0.001), with less comorbidities (P=0.030) and more often symptomatic (P=0.007) than men. Women had smaller aortic valve area (P<0.001) than men but similar mean transaortic pressure gradient (P=0.18). The 5-year survival was lower compared with expected survival, especially for women (62±2% versus 71% for women and 69±1% versus 71% for men). Despite longer life expectancy in women than men, women had lower 5-year survival than men (66±2% [expected-75%] versus 68±2% [expected-70%], P<0.001) after matching for age. Overall, 5-year AVR incidence was 79±2% for men versus 70±2% for women (P<0.001) with male sex being independently associated with more frequent early AVR performance (odds ratio, 1.49; 1.18-1.97). After age matching, women remained more often symptomatic (P=0.004) but also displayed lower AVR use (64.4% versus 69.1%; P=0.018). Conclusions Women with severe AS are diagnosed at later ages and have more symptoms than men. Despite prevalent symptoms, AVR is less often performed in women and 5-year excess mortality is noted in women versus men, even after age matching. These imbalances should be addressed to ensure that both sexes receive equivalent care for severe AS.

Clinical Significance of Global Wasted Work in Patients with Heart Failure Receiving Cardiac Resynchronization Therapy.

BACKGROUND: The relationship between myocardial work assessment using pressure-strain loops by echocardiography before cardiac resynchronization therapy (CRT) and response to CRT has been recently revealed. Among myocardial work parameters, the impact of left ventricular myocardial global wasted work (GWW) on response to CRT and outcome following CRT has been seldom studied. Hence, the authors evaluated the relationship between preprocedural GWW and outcome in a large prospective cohort of patients with heart failure (HF) and reduced ejection fraction receiving CRT. METHODS: The study included 249 patients with HF. Myocardial work indices including GWW were calculated using speckle-tracking strain two-dimensional echocardiography using pressure-strain loops. End points of the study were (1) response to CRT, defined as left ventricular reverse remodeling and/or absence of hospitalization for HF, and (2) all-cause death during follow-up. RESULTS: Median follow-up duration was 48 months (interquartile range, 43-54 months). Median preoperative GWW was 281 mm Hg% (interquartile range, 184-388 mm Hg%). Preoperative GWW was associated with CRT response (area under the curve, 0.74; P < .0001), and a 200 mm Hg% threshold discriminated CRT nonresponders from responders with 85% specificity and 50% sensitivity, even after adjustment for known predictors of CRT response (adjusted odds ratio, 4.03; 95% CI, 1.91-8.68; P < .001). After adjustment for established predictors of outcome in patients with HF with reduced ejection fraction receiving CRT, GWW < 200 mm Hg% remained associated with a relative increased risk for all-cause death compared with GWW ≥ 200 mm Hg% (adjusted hazard ratio, 2.0; 95% CI, 1.1-3.9; P = .0245). Adding GWW to a baseline model including known predictors of outcome in CRT resulted in an improvement of this model (χ2 to improve 4.85, P = .028). The relationship between GWW and CRT response and outcome was stronger in terms of size effect and statistical significance than for other myocardial work indices. CONCLUSIONS: Low preoperative GWW (<200 mm Hg%) is associated with absence of CRT response in CRT candidates and with a relative increased risk for all-cause death. GWW appears to be a promising parameter to improve selection for CRT of patients with HF with reduced ejection fraction.