Physical and physiological effects of dobutamine stress echocardiography in low-gradient aortic stenosis.

Dobutamine stress echocardiography (DSE) is a useful tool for assessing low-gradient significant aortic stenosis (AS) and contractile reserve (CR), but its prognostic utility has become controversial in recent studies. We evaluated the impact of DSE on aortic valve physiological, structural, and left ventricular parameters in low-gradient AS. Consecutive patients undergoing DSE for low-gradient AS evaluation from September 2010 to July 2016 were retrospectively studied, and DSE findings were divided into four groups: with and without severe AS and/or CR. Relationships between left ventricular chamber quantification, CR, aortic valve Doppler during DSE, and calcium score [by computerized tomography (CT)] were analyzed. There were 258 DSE studies performed on 243 patients, mean age 77.6 ± 10.8 yr and 183 (70.1%) were males. With increasing dobutamine dose, apart from systolic blood pressure, left ventricular ejection fraction, flow, cardiac power output, and longitudinal strain magnitude, along with aortic valve area and mean aortic gradient were all significantly increased (P < 0.05). Flow and mean gradient increased in both the presence and absence of CR, whereas stroke volume and aortic valve area increased mainly in those with CR only. The aortic valve area increased in both patients with low and high calcium scores; however, the baseline area was lower in those with a higher calcium score. During DSE, aortic valve area increases with increase in aortic valve gradient. Higher calcium score is associated with lower baseline aortic valve area, but the aortic valve area still increases with dobutamine even in presence of a high calcium score.NEW & NOTEWORTHY We show that even in most severe aortic stenosis, there is some residual valve pliability. This suggests that a complete loss of pliability is not compatible with survival.

The incidence and prognostic implications of worsening right ventricular function after surgical or transcatheter aortic valve replacement: insights from PARTNER IIA.

Aims: In patients randomized to transcatheter or surgical aortic valve replacement (TAVR, SAVR), we sought to determine whether SAVR is associated with worsening right ventricular (RV) function and whether RV deterioration is associated with mortality. Methods and results: In 1376 patients from PARTNERIIA with paired baseline and 30-day core lab echocardiograms, worsening RV function was defined as decline by at least one grade from baseline to 30 days. Our primary outcome was all-cause mortality from 30 days to 2 years. Among 744 patients with TAVR, 62 (8.3%) had worsening RV function, compared with 156 of 632 patients with SAVR (24.7%) (P < 0.0001). In a multivariable model, SAVR [odds ratio (OR) 4.05, 95% confidence interval (CI) 2.55-6.44], a dilated RV (OR 2.38, 95% CI 1.37-4.14), and more than mild tricuspid regurgitation (TR) (OR 2.58, 95% CI 1.25-5.33) were associated with worsening RV function. There were 169 deaths, and patients with worsening RV function had higher all-cause mortality [hazard ratio (HR) 1.98, 95% CI 1.40-2.79]. This association remained robust after adjusting for clinical and echocardiographic variables. Among patients with worsening RV function, there was no mortality difference between TAVR and SAVR (HR 1.16, 95% CI 0.61-2.18). The development of moderate or severe RV dysfunction from baseline normal RV function conferred the worst prognosis (HR 2.87, 95% CI 1.40-5.89). Conclusion: After aortic valve replacement, worsening RV function is more common in patients with baseline RV dilation, more than mild TR, and in patients treated with SAVR. Worsening RV function and the magnitude of deterioration have important prognostic implications.

Characteristics and Outcomes of Patients With Severe Bioprosthetic Aortic Valve Stenosis Undergoing Redo Surgical Aortic Valve Replacement.

BACKGROUND: With improved event-free survival of patients undergoing primary bioprosthetic aortic valve replacement (AVR), reoperation to relieve severe prosthetic aortic stenosis (PAS) is increasing. We sought to (1) identify of the characteristics of patients with severe bioprosthetic PAS undergoing redo AVR, and (2) assess the outcomes of these patients, along with factors associated with adverse outcomes. METHODS AND RESULTS: We studied 276 patients with severe bioprosthetic PAS (64±16 years, 58% men) who underwent redo-AVR between 2000 and 2012 (excluding mechanical PAS, severe other valve disease, and transcatheter AVR). Society of Thoracic Surgeons score was calculated. Severe PAS was defined as AV area <0.8 cm(2), mean AV gradient ≥40 mm Hg, or dimensionless index <0.25. A composite outcome of death and congestive heart failure admission was recorded. Mean Society of Thoracic Surgeons score and mean AV gradients were 8±8 and 53±17 mm Hg, whereas 28% had >II+ aortic regurgitation. Only 39% had an isolated redo AVR, the rest were combination surgeries (coronary bypass and/or aortic surgeries). At 4.2±3 years, 64 (23%) patients met the composite end point (48 deaths and 19 congestive heart failure admissions, 2.5% 30-day deaths). On multivariable Cox survival analysis, higher Society of Thoracic Surgeons score (hazard ratio, 1.35), higher grades of aortic regurgitation (hazard ratio, 1.29), and higher right ventricular systolic pressure (hazard ratio, 1.3) were associated with worse longer-term outcomes (all P<0.01). CONCLUSIONS: At an experienced center, in patients with severe bioprosthetic PAS undergoing redo AVR, the majority undergo combination surgeries but have excellent outcomes.

Predictors of long-term outcomes in patients with significant myxomatous mitral regurgitation undergoing exercise echocardiography.

BACKGROUND: Significant myxomatous mitral regurgitation leads to progressive left ventricular (LV) decline, resulting in congestive heart failure and death. Such patients benefit from mitral valve surgery. Exercise echocardiography aids in risk stratification and helps decide surgical timing. We sought to assess predictors of outcomes in such patients undergoing exercise echocardiography. METHODS AND RESULTS: This is an observational study of 884 consecutive patients (age, 58 ± 14 years; 67% men) with grade III+ or greater myxomatous mitral regurgitation who underwent exercise echocardiography between January 2000 and December 2011 (excluding functional mitral regurgitation, prior valvular surgery, hypertrophic cardiomyopathy, rheumatic valvular disease, or greater than mild mitral stenosis). Clinical and echocardiographic data (mitral regurgitation, LV ejection fraction, LV dimensions, right ventricular systolic pressure) and exercise variables (metabolic equivalents, heart rate recovery at 1 minute after exercise) were recorded. Composite events of death, myocardial infarction, stroke, and progression to congestive heart failure were recorded. Mean LV ejection fraction, indexed LV end-systolic dimension, resting right ventricular systolic pressure, peak stress right ventricular systolic pressure, metabolic equivalents achieved, and heart rate recovery were 58 ± 5%, 1.6 ± 0.4 mm/m(2), 31 ± 12 mm Hg, 46 ± 17 mm Hg, 9.6 ± 3, and 33 ± 14 beats, respectively. During 6.4 ± 4 years of follow-up, there were 87 events. On stepwise multivariable Cox analysis, percent of age/sex-predicted metabolic equivalents (hazard ratio, 0.99; 95% confidence interval, 0.98-0.99; P=0.005), heart rate recovery (hazard ratio, 0.29; 95% confidence interval, 0.17-0.50; P<0.001), resting right ventricular systolic pressure (hazard ratio, 1.03; 95% confidence interval, 1.004-1.05; P=0.02), atrial fibrillation (hazard ratio, 1.91; 95% confidence interval, 1.07-3.41; P=0.03), and LV ejection fraction (hazard ratio, 0.96; 95% confidence interval, 0.92-0.99; P=0.04) predicted outcomes. CONCLUSIONS: In patients with grade III+ or greater myxomatous mitral regurgitation undergoing exercise echocardiography, lower percent of age/sex-predicted metabolic equivalents, lower heart rate recovery, atrial fibrillation, lower LV ejection fraction, and high resting right ventricular systolic pressure predicted worse outcomes.

Longitudinal Assessment of Left Atrial Remodeling in Patients With Chronic Severe Aortic Regurgitation.

BACKGROUND: There are significant sex and age differences in left ventricular (LV) remodeling that may lead to disparity in outcomes when used to inform the timing of aortic regurgitation (AR) intervention. OBJECTIVES: The aim of this study was to examine whether left atrial (LA) parameters might represent better criteria than LV parameters to inform the timing of AR intervention. METHODS: Using data on patients with moderate to severe or severe AR with serial echocardiography (2010-2016), the longitudinal trends in left atrial volume index (LAVI) and left atrial reservoir strain (LAr) were evaluated by sex and age. The incremental utility of these parameters in predicting adverse events over LV parameters was also determined. RESULTS: In 525 patients (25.7% women) with 1,687 echocardiograms over a median follow-up period of 2.0 years (Q1-Q3: 1.0-3.6 years), there was significant increase in LAVI (1.0 mL/m2 per year [95% CI: 0.76-1.2 mL/m2 per year]) and decrease in LAr (-1.3% per year [95% CI: -1.6% to -0.92%]), without a significant interaction by sex or age category (P for interaction ≥ 0.17). In addition, both LAVI and LAr were significant predictors of adverse events independent of LV parameters. The optimal discriminatory thresholds were 37 mL/m2 for LAVI and 35% for LAr. These thresholds were similar across categories of sex and age. Within the relatively short-term follow-up, surgery was associated with survival benefit among patients with LAVI ≥37 mL/m2 (HR: 0.33 [95% CI: 0.15-0.72]; P = 0.006) but was not statistically significant among patients with LAVI <37 mL/m2 (HR: 0.46 [95% CI: 0.18-1.17]; P = 0.09). Similarly, surgery was associated with survival for the subgroup with LAr ≤35% but not among those with LAr >35%. CONCLUSIONS: Unlike LV remodeling, LA remodeling demonstrates a similar rate of progression between categories of sex and age among patients with AR. In addition, LA parameters provide incremental prognostic value over LV parameters.

Impact of Age and Sex on Left Ventricular Remodeling in Patients With Aortic Regurgitation.

BACKGROUND: Current guidelines for aortic regurgitation (AR) recommend the same linear left ventricular (LV) dimension for intervention regardless of age and sex. OBJECTIVES: The purpose of this study was to evaluate the impact of age and sex on the degree of LV remodeling and outcomes. METHODS: We included consecutive patients with severe AR who were serially monitored by echocardiogram between 2010 and 2016. The 2 main endpoints were as follows: 1) LV end-systolic volume indexed to body surface area (LVESVi) and LV end-diastolic volume indexed to body surface area; and 2) adverse events (AE). We evaluated the longitudinal rate of LV remodeling and determined the association between LV volume and AE by age and sex. RESULTS: A total of 525 adult patients (26% women) with a median echocardiogram follow-up of 2.0 years (IQR: 1.0-3.6 years) were included. At baseline, older patients (age ≥60 years) had smaller LV volumes compared with younger patients (age <60 years), eg, the mean LVESVi was 27.3 mL/m2 vs 32.3 mL/m2, respectively. Similarly, women had smaller LV volumes compared with men (mean LVESVi was 23.3 mL/m2 vs 32.4 mL/m2). On serial evaluation, older patients and women maintained smaller LV volumes compared with younger patients and men, respectively. There were 210 (40%) AE during follow-up. The optimal discriminatory threshold for AE varies by age and sex, eg, the LVESVi threshold was highest for young men (50 mL/m2), intermediate for older men (35 mL/m2), and lowest for women (27 mL/m2). CONCLUSIONS: On serial evaluation, older patients and women with chronic AR maintained smaller LV volumes than younger patients and men, respectively, and develop AE at lower LV volumes.

Diagnostic and Prognostic Performance of Aortic Valve Calcium Score with Cardiac CT for Aortic Stenosis: A Meta-Analysis.

PURPOSE: To evaluate the diagnostic and prognostic performance of the aortic valve calcium score (AVCS) with the Agatston method using CT in aortic stenosis (AS) and to assess mean AVCS according to AS severity. MATERIALS AND METHODS: In this meta-analysis, PubMed, Embase, and Cochrane were searched from January 1, 1980, to December 31, 2020, for studies reporting sensitivity and specificity of AVCS using CT for severe AS, mean AVCS in severe and nonsevere AS, and/or hazard ratios for all-cause mortality in AS. Data were pooled using random effect models and meta-analysis software. RESULTS: Twelve studies (six diagnostic, three prognostic, and 10 reporting mean AVCS by AS severity) were included for analysis. A total of 4101 patients (2255 with severe AS) were described in these 12 studies. Pooled sensitivity and specificity were 82% (95% CI: 80, 84) and 78% (95% CI: 75, 81), respectively. Pooled mean AVCS were 3219 (95% CI: 2795, 3643) for severe AS, compared with 1252 (95% CI: 863, 1640) for nonsevere AS, 1808 (95% CI: 1163, 2452) for moderate AS, and 584 (95% CI: 309, 859) for mild AS. Pooled hazard ratio for AVCS as a binary threshold to predict mortality was 2.11 (95% CI: 1.11, 4.12). CONCLUSION: AVCS had moderate to high sensitivity and specificity for identifying severe AS and was also a useful prognostic imaging marker in AS. Mean AVCS categorized by AS severity may help guide clinical management.Keywords CT, Aortic Valve, Valves, Meta-Analysis© RSNA, 2021.

Defining the reference range for right ventricular systolic strain by echocardiography in healthy subjects: A meta-analysis.

BACKGROUND: Right ventricular (RV) systolic strain has recently demonstrated prognostic value in various cardiovascular diseases. Despite this, the reference range including the lower limit of normal (LLN) and factors associated with RV strain measurements are not well-established. This meta-analysis aimed to determine the mean and LLN of two- (2D) and three-dimensional (3D) right ventricular global (RVGLS), free wall (RVFWLS) and interventricular septal wall (IVSLS) longitudinal strains in healthy individuals and factors that affect strain measurements. METHODS: In this meta-analysis, Pubmed, Embase and Cochrane databases were searched until 31 July 2020 for eligible studies reporting RVGLS, RVFWLS and/or IVSLS in at least 30 healthy subjects. We pooled the means and LLNs of RV strains by two- (2D) and three- (3D) dimensional echocardiography, and performed meta-regression analyses. RESULTS: From 788 articles screened, 45 eligible studies totaling 4439 healthy subjects were eligible for analysis. Pooled means and LLNs with 95% confidence intervals for 2D- RV strains were RVGLS -23.4% (-24.2%, -22.6%) and -16.4% (-17.3%, -15.5%) in 27 studies; RVFWLS -26.9% (-28.0%, -25.9%) and -18.0% (-19.2%, -16.9%) in 32 studies; and IVSLS -20.4% (-22.0%, -18.9%) and -11.5% (-13.6%, -9.6%) in 10 studies, and similar results for 3D- RV strains. Right ventricular fractional area change and vendor software were associated with 2D-RVGLS and RVFWLS means and LLNs. CONCLUSION: We reported the pooled means and LLNs of RV systolic strains in healthy subjects, to define thresholds for abnormal, borderline and normal strains. Important factors associated with RV systolic strains include right ventricular fractional area change and vendor software.

Outcomes of contemporary imaging-guided management of sinus of Valsalva aneurysms.

BACKGROUND: Sinus of Valsalva aneurysms (SVAs) are rare. We assessed the role of multimodality imaging in guiding the contemporary management. METHODS: A single-center retrospective cohort study over a 20-year period was performed. RESULTS: Between January 1997 and June 2017, 103 patients were diagnosed with SVAs (median age: 58 years). Eighty patients presented with non-ruptured SVAs, and 23 with ruptured SVAs. Seventy-six patients underwent surgery, and 27 were conservatively managed. The median durations of follow-up were: 48 months (surgical group) vs. 37.5 months (conservative group). There was no mortality directly attributable to SVA surgery. There were no late complications in the conservative group. Transthoracic echocardiography (TTE) was the first-line imaging investigation (100.0% in surgical group vs. 92.6% in conservative group, P=0.019). Additional imaging studies included: (I) transesophageal echocardiography (TEE): 93.4% in surgical group vs. 22.2% in conservative group, P<0.001; (II) multi-detector cardiac computed tomography (MDCT): 61.8% in surgical group vs. 37.0% in conservative group, P=0.041; (III) cardiac magnetic resonance (CMR): 22.4% in surgical group vs. 14.8% in conservative group, P=0.579. At diagnosis, SVA diameters were: TTE: 4.80 cm (range, 3.30 cm); TEE: 5.40 cm (range, 4.00 cm); MDCT: 5.20 cm (range, 3.90 cm); CMR: 4.80 cm (range, 3.70 cm). CONCLUSIONS: In a 20-year cohort, proper selection for surgery and conservative management resulted in excellent outcomes for SVAs. TTE was the first-line imaging investigation for assessment of SVAs, although many patients underwent an additional imaging investigation. The contemporary outcomes of imaging-guided SVA management were excellent.

Incidence and Clinical Significance of Worsening Tricuspid Regurgitation Following Surgical or Transcatheter Aortic Valve Replacement: Analysis From the PARTNER IIA Trial.

[Figure: see text].

Sinus of Valsalva Aneurysms: A State-of-the-Art Imaging Review.

Cardiovascular imaging has an important role in the assessment and management of aortic root and thoracic aorta ectasia and aneurysms. Sinus of Valsalva aneurysms are rare entities. Unique complications associated with sinus of Valsalva aneurysms make them different from traditional aortic root aneurysms. Established guidelines on the diagnosis and management of sinus of Valsalva aneurysms are lacking. This article reviews the applications of multimodality cardiovascular imaging (echocardiography, cardiac computed tomography, and cardiac magnetic resonance imaging) for the dedicated assessment and imaging-guided management of sinus of Valsalva aneurysms.

Long-Term Outcomes in Patients With Mixed Aortic Valve Disease and Preserved Left Ventricular Ejection Fraction.

Background Concurrent presence of aortic stenosis and aortic regurgitation is termed mixed aortic valve disease (MAVD). Although multiple articles have addressed patients with "isolated" aortic stenosis or aortic regurgitation, the natural history, impact, and outcomes of MAVD are not well defined. Here, we evaluate long-term outcomes in patients with MAVD and cardiovascular adaptations to chronic MAVD. Methods and Results This observational cohort study evaluated 862 adult patients (56.8% male) with preserved left ventricular ejection fraction and at least moderate aortic regurgitation and moderate aortic stenosis. Primary outcome was all-cause mortality. Subgroup analysis was based on treatment modality (aortic valve replacement [AVR] versus medical management). A regression analysis of longitudinal echocardiographic parameters was performed to assess the natural history of MAVD. Mean age was 68±15 years, and mean left ventricular ejection fraction was 58±5%. At 4.6 years (25th-75th percentile range, 1.0-8.7), 58.6% of patients underwent an AVR and 48.8% patients died. In both unadjusted and adjusted Cox survival analysis, AVR was associated with improved survival (hazard ratio, 0.41; 95% CI, 0.34-0.51, P<0.001). Impact of AVR persisted when stratifying the cohort by symptom status and baseline aortic valve area (log rank, P<0.001 for both) and after propensity-score matching (hazard ratio, 0.40; 95% CI, 0.32-0.50; P<0.001). In the longitudinal analysis, there were statistically significant changes over time in aortic valve peak gradient (P<0.001) and aortic valve area (P<0.001) and only mild increases in left ventricular end-diastolic (P<0.007) and -systolic (P<0.001) volumes. Conclusions MAVD confers a high risk of all-cause mortality. However, AVR significantly reduces this risk independent of aortic valve area, symptom status, and after controlling for confounding variables.

Effect of cell-based intercellular delivery of transcription factor GATA4 on ischemic cardiomyopathy.

Recent loss-of-function studies highlight the importance of the transcription factor GATA4 in the myocardial response to injury in the adult heart. However, the potential effects of gain-in-function of GATA4 overexpression, and transcription factors in general, is hindered by the fact that transcription factors are neither secreted nor taken up by cells. Chimeric proteins incorporating motifs of cell-penetrating proteins are secreted from cells and internalized by surrounding cells. We engineered a chimeric protein consisting of GATA4 and the cell-penetrating protein VP22. Cardiac fibroblasts stably transfected with the GATA4:VP22, GFP:VP22, or green fluorescent protein (GFP) constructs were transplanted into Lewis rats 1 month after left anterior descending ligation. GATA4:VP22 expression in the border zone was associated with increased cardiac myosin expression and cardiac myocyte size (30 mum versus 19 mum, P<0.01). Compared with the GFP:VP22 control group, 6 weeks after cardiac fibroblast transplantation (10 weeks after myocardial infarction), animals that received GATA4:VP22-expressing cardiac fibroblasts demonstrated increased cardiac function and less negative remodeling. These data demonstrate a novel strategy for transcription factor delivery to injured myocardium and indicate that the delivery of GATA4 locally to the infarct border zone induces multiple local effects in the border zone cardiac myocytes resulting in beneficial ventricular remodeling and improved global left ventricular function.

Characteristics and longer-term outcomes of paravalvular leak after aortic and mitral valve surgery.

BACKGROUND: Paravalvular leak (PVL) is often seen after aortic (AV) and mitral valve (MV) surgery, either due to infection or valve dehiscence. We sought to describe predictors of longer-term outcomes in patients who developed PVL after AV and MV surgery and were considered eligible for reoperative cardiac surgery (RCS). METHODS: We studied 495 such patients (65 ± 14 years, 65% men, 47% with MV PVL) who presented at our center between January 2003 and December 2011. Patients with severe mitral/aortic stenosis, patients with less than mild PVL, and those with prohibitive risk precluding RCS were excluded. Society of Thoracic Surgeons (STS) score was calculated. Primary endpoint was mortality. RESULTS: At baseline, mean STS score and left ventricular ejection fraction were 5.8 ± 4% and 52 ± 12%, respectively. In total, 105 (21%) had infective PVL and 72% had moderate or greater PVL. At a median of 8 days, 351 (71%) patients underwent RCS to repair PVL (3% in-hospital postoperative mortality), and at 6.6 ± 4 years, 230 (47%) patients died. On multivariable Cox survival analysis, greater STS score (hazard ratio or HR 1.35), mitral versus aortic PVL (HR 1.66), infectious etiology (HR 2.05), and greater right ventricular systolic pressure (HR 1.09) were associated with greater longer-term mortality, whereas surgery (HR 0.58) was associated with improved longer-term survival (all P < .05). CONCLUSIONS: Patients who develop mild or greater PVL after AV/MV surgery have a high rate of longer-term mortality, despite excellent perioperative outcomes. Greater STS score, right ventricular systolic pressure, infectious etiology, and MV (vs AV) involvement were all independently associated with long-term mortality, whereas RCS for PVL closure was associated with improved longer-term survival.

Characteristics and Outcomes in a Contemporary Group of Patients With Suspected Significant Mitral Stenosis Undergoing Treadmill Stress Echocardiography.

BACKGROUND: In contemporary patients with suspected significant mitral stenosis (MS) undergoing rest and treadmill stress echocardiography, we assessed characteristics and factors associated with longer-term survival. METHODS: We studied 515 consecutive patients (asymptomatic/atypical symptoms, mean left ventricular ejection fraction 58±2%; 43% male) with suspected at least moderate MS ([1] native mitral valve [MV]: resting mean MV gradient ≥5 mm Hg or area ≤1.5 cm2 and [2] prosthetic valve: resting mean MV gradient ≥5 mm Hg or effective orifice area ≤2 cm) who underwent rest and treadmill stress echocardiography between 1/2003 and 12/2013. MS was categorized as rheumatic (n=170, 33%), postsurgical (prior mitral repair/replacement, n=245, 48%), and primary nonrheumatic (n=100, 19%). Primary outcome was all-cause mortality. RESULTS: Mean resting MV gradient and right ventricular systolic pressure were 8.5±3 and 39±13 mm Hg. Patients achieved 95±29% age-sex predicted metabolic equivalents; peak-stress MV gradient and right ventricular systolic pressure were 17±7 and 61±14 mm Hg, respectively. At 54 days (median), 224 (44%) underwent invasive mitral procedure. At 6±4 years, 76 (15%) died. On survival analysis, primary nonrheumatic MS (hazard ratio [HR], 4.92), higher Society of Thoracic Surgeons score (HR, 1.92), lower % age-sex predicted metabolic equivalents (HR, 1.22), and higher peak-stress right ventricular systolic pressure (HR, 1.35), was associated with higher mortality, while invasive mitral procedures were associated with improved survival (HR, 0.67; all P<0.01). CONCLUSIONS: In asymptomatic patients (or with atypical symptoms) with significant MS undergoing treadmill stress echocardiography, higher mortality was associated with primary nonrheumatic MS, lower % age-sex predicted metabolic equivalents, and higher peak-stress right ventricular systolic pressure, while invasive MV procedures were associated with survival.

Contemporary Outcomes in Low-Gradient Aortic Stenosis Patients Who Underwent Dobutamine Stress Echocardiography.

Background Detection of flow reserve ( FR ) by dobutamine stress echocardiography is used for risk stratification in low-gradient aortic stenosis ( AS ). Prognostic significance of dobutamine stress echocardiography in the transcatheter aortic valve replacement era is unclear. We aimed to assess the current relevance of FR . Methods and Results We studied 235 patients with low-gradient severe AS (rest aortic valve area ≤1.0 cm2 or indexed aortic valve area ≤0.60 cm2/m2; mean aortic valve gradient <40 mm Hg) and left ventricular ejection fraction <50%) with dobutamine stress echocardiography done September 2010 through July 2016. FR was defined by ≥20% stroke volume increase. We diagnosed "true-severe AS " if peak aortic valve velocity ≥4 m/s occurred with aortic valve area ≤1.0 cm2 (or indexed aortic valve area ≤0.6 cm2/m2). At a median time of 51 days, 128 patients underwent aortic valve replacement,either surgical aortic valve replacement (n=42) or transcatheter aortic valve replacement (n=86). FR was observed in 138 patients, while 86 patients had true-severe AS . During median follow-up of 2.3 years, 138 patients died. In a multivariable model, aortic valve replacement (hazard ratio 0.41, 95% CI : 0.29-0.58, P <0.001) and lower Society of Thoracic Surgeons score (hazard ratio 1.06, 95% CI : 1.04-1.09, P<0.001) were associated with better survival, while FR was not predictive. aortic valve replacement was associated with survival regardless of the presence or absence of FR or AS severity stratification. Conclusions In low-gradient AS with reduced ejection fraction, FR or AS severity stratification by dobutamine stress echocardiography was not associated with survival. Aortic valve replacement was associated with better survival in low-gradient AS independent of FR .