Clinical significance of energy loss index in patients with low-gradient severe aortic stenosis and preserved ejection fraction.

AIMS: We hypothesized that among patients with low-gradient severe aortic stenosis (AS) and preserved left ventricular ejection fraction (LVEF), reclassification of AS severity as moderate by pressure recovery adjusted indexed aortic valve area (AVAi) = energy loss index (ELI), may identify a subgroup of patients with a better outcome. METHODS AND RESULTS: Three hundred and seventy-nine patients with low-gradient AS (defined by AVAi ≤ 0.6 cm2/m2 and mean aortic pressure gradient < 40 mmHg) and preserved LVEF ≥50% were studied. Reclassification as moderate AS by ELI was defined as AVAi ≤0.6 cm2/m2 but with an ELI >0.6 cm2/m2. Cardiac events [cardiac mortality and/or need for aortic valve replacement (AVR)] during follow-up were studied. One hundred and forty-eight patients (39%) were reclassified as moderate AS by ELI. Reclassification as moderate AS was independently associated with decreased body surface area, normal flow status, decreased left ventricular mass index, and left atrial volume index (all P < 0.05). After adjustment for variables of prognostic interest, reclassification as moderate AS by ELI was associated with a considerable reduction of risk of cardiac events {adjusted hazard ratio (HR) 0.49 [95% confidence interval (CI) 0.33-0.72]; P < 0.001}, need for AVR [adjusted HR 0.52 (95% CI 0.34-0.81); P = 0.004], and cardiac mortality [adjusted HR 0.46 (95% CI 0.22-0.98); P = 0.044]. CONCLUSION: In patients with low-gradient severe AS and preserved LVEF, calculation of ELI permits to reclassify almost 40% of patients as having moderate AS. These reclassified patients have a considerable reduction of the risk of cardiac events during follow-up. Calculation of ELI is useful for decision-making in patients with low-gradient severe AS and preserved ejection fraction.

Prognostic Impact of the Ratio of Acceleration Time to Ejection Time in Patients With Low Gradient Severe Aortic Stenosis and Preserved Ejection Fraction.

The clinical management of patients with low gradient severe aortic stenosis (LG-SAS) and preserved left ventricular ejection fraction (LVEF) remains challenging owing to their heterogeneity. The aim to this study was to evaluate the relation between an ejection dynamic parameter linked to AS severity and outcome, the ratio of acceleration time (AT) to ejection time (ET), in a cohort of patients with LG-SAS and preserved LVEF. Three hundred and fifty-six patients with LG-AS (defined by AVA ≤1 cm² and/or AVAi ≤0.6 cm²/m² and mean aortic pressure gradient <40 mm Hg) and preserved LVEF ≥50% were studied. The relation between AT/ET and all-cause and cardiac mortality during follow-up was studied. Median follow-up was 41 months (interquartile range, 35 to 47 months). Median AT/ET was 0.32 (interquartile range, 0.29 to 0.36). The 5-year estimates of all-cause and cardiac mortality were respectively 57 ± 7%, 36 ± 7% for patients with AT/ET >0.36 versus 43 ± 4%, 16 ± 3% for patients with AT/ET ≤0.36 (p = 0.024 and p <0.001, respectively). After adjustment on known predictors of outcome including aortic valve replacement used as a time-dependent covariate, there was a significant increase in all-cause mortality risk for patients with AT/ET >0.36 (adjusted hazard ratio 2.04 [95% confidence interval, 1.32 to 3.13]; p = 0.001) and cardiac mortality risk (adjusted hazard ratio 2.89 [95% confidence interval, 1.54 to 5.43]; p<0.001) compared with patients with AT/ET ≤0.36. The association of AT/ET >0.36 and all-cause or cardiac mortality risk was consistent in subgroups of patients with LG-SAS and preserved EF. In conclusion, an AT/ET ratio of more than 0.36 is an independent predictor of mortality in patients with LG-SAS and preserved EF.

Impact of low stroke volume on mortality in patients with severe aortic stenosis and preserved left ventricular ejection fraction.

Aims: In patients with severe aortic stenosis (AS) and preserved left ventricular ejection fraction (LVEF), low flow (LF) is currently defined using Doppler-echocardiography by a stroke volume index (SVi)<35 mL/m2. However, the relationship between LF and outcome remains unclear as data on normal reference values defining LF are scarce, and previous studies did not explore the risk associated with other SVi cut-points. We analysed the relationship between LF and mortality in severe AS to establish prognostic LF values associated with mortality risk. Methods and results: This study included 1450 consecutive patients with severe AS (aortic valve area <1 cm2 and/or <0.6 cm2/m2) and preserved LVEF and 1645 controls with normal echocardiograms. Patients were stratified in three groups: (i) SVi > 35 mL/m2 or SV > 70 mL; (ii) SVi 30-35 mL/m2 or SV 55-70 mL; and (iii) SVi < 30 mL/m2 or SV < 55 mL. Mortality with medical and surgical management was analysed. Five-year survival was low for SVi < 30 mL/m2 and SV < 55 mL compared to the other groups (all P-values <0.001). After adjustment for outcome predictors, including aortic valve replacement, mortality risk was considerable with SVi < 30 mL/m2 vs. >35 mL/m2 [adjusted hazard ratio (HR) 1.60 (1.17-2.18)] and SV < 55 mL vs. >70 mL [adjusted HR 1.84 (1.32-2.58)]. Similar mortality risk was observed for SVi 30-35 mL/m2 vs. >35 mL/m2 [adjusted HR 1.05 (0.78-1.41)], and for SV 55-70 mL vs. >70 mL [adjusted HR 1.22 (0.94-1.58)]. The prognostic impact of SVi < 30 mL/m2 and SV < 55 mL was consistent in subgroups, including asymptomatic patients and patients with low-gradient severe AS. Conclusion: Low flow defined as SVi < 30 mL/m2 or SV < 55 mL is an important outcome predictor in severe AS with preserved LVEF under medical and surgical management. Further studies are needed to prospectively test these values for risk stratification and decision making.

Prospective assessment of the frequency of low gradient severe aortic stenosis with preserved left ventricular ejection fraction: Critical impact of aortic flow misalignment and pressure recovery phenomenon.

BACKGROUND: The frequency of paradoxical low-gradient severe aortic stenosis (AS) varies widely across studies. The impact of misalignment of aortic flow and pressure recovery phenomenon on the frequency of low-gradient severe AS with preserved left ventricular ejection fraction (LVEF) has not been evaluated in prospective studies. AIMS: To investigate prospectively the impact of aortic flow misalignment by Doppler and lack of pressure recovery phenomenon correction on the frequency of low-gradient (LG) severe aortic stenosis (AS) with preserved LVEF. METHODS: Aortic jet velocities and mean pressure gradient (MPG) were obtained by interrogating all windows in 68 consecutive patients with normal LVEF and severe AS (aortic valve area [AVA] ≤1cm2) on the basis of the apical imaging window alone (two-dimensional [2D] apical approach). Patients were classified as having LG or high-gradient (HG) AS according to MPG <40mmHg or ≥40mmHg, and normal flow (NF) or low flow (LF) according to stroke volume index >35mL/m2 or ≤35mL/m2, on the basis of the 2D apical approach, the multiview approach (multiple windows evaluation) and AVA corrected for pressure recovery. RESULTS: The proportion of LG severe AS was 57% using the 2D apical approach alone. After the multiview approach and correction for pressure recovery, the proportion of LG severe AS decreased from 57% to 13% (LF-LG severe AS decreased from 23% to 3%; NF-LG severe AS decreased from 34% to 10%). As a result, 25% of patients were reclassified as having HG severe AS (AVA ≤1cm2 and MPG ≥40mmHg) and 19% as having moderate AS. Hence, 77% of patients initially diagnosed with LG severe AS did not have "true" LG severe AS when the multiview approach and the pressure recovery phenomenon correction were used. CONCLUSIONS: Aortic flow misevaluation, resulting from lack of use of multiple windows evaluation and pressure recovery phenomenon correction, accounts for a large proportion of incorrectly graded AS and considerable overestimation of the frequency of LG severe AS with preserved LVEF.

Impact of pulmonary hypertension on long-term outcome in patients with severe aortic stenosis.

Aims: Pulmonary hypertension (PH) is common in severe symptomatic left-sided valvular disease, particularly in aging populations. Inconsistent results have been reported concerning the association between PH and adverse outcomes after aortic valve replacement for aortic stenosis (AS). We therefore retrospectively investigated the prognostic significance of PH using peak tricuspid regurgitation velocity (TRV), as defined by the current European Society of Cardiology (ESC)/European Respiratory Society (ERS) guidelines, in a large cohort of patients with severe AS. Methods and results: One thousand and nineteen patients (541 men; mean age 74 ± 11 years) with severe AS (aortic valve area (AVA) <1 cm2 and/or indexed AVA <0.6 cm2/m2 of body surface area) and LV ejection fraction ≥50% were included. Patients were divided into three groups according to the level of their peak TRV at the time of enrolment: Group 1 (n = 695, 68%) when TRV was ≤2.8 m/s; Group 2 (n = 212, 21%) when TRV was between 2.9 m/s and 3.4 m/s and Group 3 (n = 112, 11%) when TRV was > 3.4 m/s. Median overall follow-up was 31 [6-182] months. On univariate analysis, overall mortality during follow-up was globally different between groups (P < 0.001). On multivariate analysis, Group 3 (TRV >3.4 m/s) exhibited significant excess mortality after adjustment for covariates of prognostic importance (P = 0.032) and after further adjustment for surgery (P = 0.012), using Group 1 as the reference group. Dividing the whole population into two groups with a 3.4 m/s TRV threshold, overall mortality during follow-up was higher in the PH group [hazard ratio (HR) 1.87; 95% confidence interval [1.37-2.56]; P < 0.001)]. On multivariate analysis, after covariate adjustment, including surgery, Group 3 exhibited major excess mortality (adjusted HR 1.46 [1.10-1.95], P = 0.009). Conclusion: This study demonstrates the negative impact of pulmonary pressure, as assessed by current ESC/ERS guidelines, on long-term outcome of patients with severe AS, irrespective of functional status, chronic obstructive pulmonary disease, AS severity and surgery. Baseline TRV should therefore be taken into account in the management of severe AS.

Time course of secondary mitral regurgitation in patients with heart failure receiving cardiac resynchronization therapy: Impact on long-term outcome beyond left ventricular reverse remodelling.

BACKGROUND: The prognostic value of secondary mitral regurgitation (MR) at baseline versus immediately after and several months after cardiac resynchronization therapy (CRT), beyond left ventricular (LV) reverse remodelling, has yet to be investigated. AIM: To evaluate the clinical significance of secondary MR before and at two timepoints after CRT in a large cohort of consecutive patients with heart failure (HF) and reduced LV ejection fraction. METHODS: A total of 198 patients were recruited prospectively into a registry, and underwent echocardiography at baseline and immediately after CRT (on the day of hospital discharge). Echocardiography was also performed 9 months after CRT in 172 patients. The impact of significant secondary MR (≥moderate) on all-cause death, cardiovascular death and hospitalization for HF was studied at each stage. RESULTS: The frequency of significant secondary MR decreased from 23% (n=45) to 8% (n=16) immediately after CRT. Among the 172 patients who underwent echocardiography 9 months after CRT, 17 (10%) had significant secondary MR. During a median follow-up of 48 months, 49 patients died and 36 were hospitalized for HF. Patients with significant secondary MR immediately after or 9 months after CRT had an increased risk of all-cause death, cardiovascular death and hospitalization for HF during follow-up (P<0.05 for all endpoints). After adjustment for LV reverse remodelling, significant secondary MR 9 months after CRT remained associated with an increased risk of all-cause death (adjusted hazard ratio [HR] 3.77; P=0.014), cardiovascular death (adjusted HR 5.36; P=0.037), and hospitalization for HF (adjusted HR 7.33; P=0.001). CONCLUSIONS: Significant secondary MR despite CRT provides important prognostic information beyond LV reverse remodelling. Further studies are needed to evaluate the potential role of new percutaneous procedures for mitral valve repair in improving outcome in these very high-risk patients.

Evolution of subclinical myocardial dysfunction detected by two-dimensional and three-dimensional speckle tracking in asymptomatic type 1 diabetic patients: a long­term follow-up study.

BACKGROUND: We sought to assess the long-term evolution of left ventricular (LV) function using two-dimensional (2D) and three-dimensional (3D) speckle tracking echocardiography (STE) for the detection of preclinical diabetic cardiomyopathy, in asymptomatic type 1 diabetic patients, over a 6-year follow-up. DESIGN AND METHODS: Sixty-six asymptomatic type 1 diabetic patients with no cardiovascular risk factors were compared to 26 matched healthy controls. Conventional, 2D and 3D-STE were performed at baseline. A subgroup of 14 patients underwent a 6-year follow-up evaluation. RESULTS: At baseline, diabetic patients had similar LV ejection fraction (60 vs 61%; P = NS), but impaired longitudinal function, as assessed by 2D-global longitudinal strain (GLS) (-18.9 ± 2 vs -20.5 ± 2; P = 0.0002) and 3D-GLS (-17.5 ± 2 vs -19 ± 2; P = 0.003). At follow-up, diabetic patients had worsened longitudinal function compared to baseline (2D-GLS: -18.4 ± 1 vs -19.2 ± 1; P = 0.03). Global circumferential (GCS) and radial (GRS) strains were unchanged at baseline and during follow-up. Metabolic status did not correlate with GLS, whereas GCS and GRS showed a good correlation, suggestive of a compensatory increase of circumferential and radial functions in advanced stages of the disease - long-term diabetes (GCS: -26 ± 3 vs -23.3 ± 3; P = 0.008) and in the presence of microvascular complications (GRS: 38.8 ± 9 vs 34.3 ± 8; P = 0.04). CONCLUSIONS: Subclinical myocardial dysfunction can be detected by 2D and 3D-STE in type 1 diabetic patients, independently of any other cardiovascular risk factors. Diabetic cardiomyopathy progression was suggested by a mild decrease in longitudinal function at the follow-up, but did not extend to a clinical expression of the disease, as no death or over heart failure was reported.

Left Atrial Volume and Mortality in Patients With Aortic Stenosis.

BACKGROUND: Left atrium (LA) enlargement is common in patients with aortic stenosis (AS), yet its prognostic implications are unclear. This study investigates the value of left atrial volume (LAV) and LAV normalized to body size for predicting mortality in AS. METHODS AND RESULTS: We included 1351 patients with AS in sinus rhythm at diagnosis and analyzed the occurrence of all-cause death during follow-up with medical and surgical management. Five parameters of LA enlargement were tested: nonindexed LAV and normalized LAV by ratiometric (LAV/body surface area [BSA] and LAV/height) and allometric (LAV/BSA1.7 and LAV/height2.0) scaling. For each parameter, patients in the highest quartile were at high risk of death, whereas outcome was better and similar for the other quartiles. Five-year survival was lower for patients with LAV >95 mL and LAV/BSA >50 mL/m2 compared with those with no or mild LA enlargement (both P<0.001). After adjustment for established outcome predictors, including surgery, high risk of death was observed with LAV >95 mL (adjusted hazard ratio, 1.40 [95% confidence interval, 1.06-1.88]) and LAV/BSA >50 mL/m2 (adjusted hazard ratio, 1.42 [95% confidence interval, 1.08-1.91]). LAV/BSA and LAV showed good and similar predictive performance, whereas other scaling methods did not show better outcome prediction. In patients with severe AS at baseline, preserved (≥50%) ejection fraction, and no or minimal symptoms, LA enlargement was significantly associated with mortality (adjusted hazard ratio, 1.87 [95% confidence interval, 1.02-3.44] for LAV >95 mL, and adjusted hazard ratio, 1.90 [95% confidence interval, 1.03-3.56] for LAV/BSA >50 mL/m2). CONCLUSIONS: LA enlargement is an important predictor of mortality in AS, incrementally to known predictors of outcome. LAV and LAV/BSA have comparable predictive performance and should be assessed in clinical practice for risk stratification.

Correction: Asymptomatic aortic stenosis: An assessment of patients' and of their general practitioners' knowledge, after an indexed specialized assessment in community practice.

[This corrects the article DOI: 10.1371/journal.pone.0179988.].

Impact of Mean Transaortic Pressure Gradient on Long-Term Outcome in Patients With Severe Aortic Stenosis and Preserved Left Ventricular Ejection Fraction.

BACKGROUND: Mean transaortic pressure gradient (MTPG) has never been validated as a predictor of mortality in patients with severe aortic stenosis. We sought to determine the value of MTPG to predict mortality in a large prospective cohort of severe aortic stenosis patients with preserved left ventricular ejection fraction and to investigate the cutoff of 60 mm Hg, proposed in American guidelines. METHODS AND RESULTS: A total of 1143 patients with severe aortic stenosis defined by aortic valve area ≤1 cm2 and MTPG ≥40 mm Hg were included. The population was divided into 3 groups according to MTPG: between 40 and 49 mm Hg, between 50 and 59 mm Hg, and ≥60 mm Hg. The end point was all-cause mortality. MTPG was ≥60 mm Hg in 392 patients. Patients with MTPG ≥60 mm Hg had a significantly increase risk of mortality compared with patients with MTPG <60 mm Hg (hazard ratio [HR]=1.62 [1.27-2.05] P<0.001), even for the subgroup of asymptomatic or minimally symptomatic patients (HR=1.56 [1.04-2.34] P=0.032). After adjustment for established outcome predictors, patients with MTPG ≥60 mm Hg had a significantly higher risk of mortality than patients with MTPG <60 mm Hg (HR=1.71 [1.33-2.20] P<0.001), even after adjusting for surgery as a time-dependent variable (HR=1.71 [1.43-2.11] P<0.001). Similar results were observed for the subgroup of asymptomatic or minimally symptomatic patients (HR=1.70 [1.10-2.32] P=0.018 and HR=1.68 [1.20-2.36] P=0.003, respectively). CONCLUSIONS: This study shows the negative prognostic impact of high MTPG (≥60 mm Hg), on long-term outcome of patients with severe aortic stenosis with preserved left ventricular ejection fraction, irrespective of symptoms.

Asymptomatic aortic stenosis: An assessment of patients' and of their general practitioners' knowledge, after an indexed specialized assessment in community practice.

BACKGROUND: Clinical and echocardiography follow-up is recommended in patients with aortic stenosis to detect symptom onset, thus a watchful waiting approach has to be safe and effective. For both AS patients and their general practitioners, evaluation of valvular heart disease (VHD) knowledge, after the indexed specialized assessment has never been measured. AIMS: To evaluate the knowledge of clinical symptoms of aortic stenosis by both patients and their general practitioner. METHODS: Sixty-four patients, with moderate to severe and initially asymptomatic AS (median AVA (interquartile range) 1.01(0.80-1.15) cm2) previously referred to a tertiary center and medically managed for at least 6 months after the index echocardiogram, and their primary care doctors were interviewed on the phone and asked to answer specific questions related to knowledge of aortic stenosis symptoms. RESULTS: Fifty-six percent of patients quoted shortness of breath as one of the aortic stenosis symptoms, and only 16% knew the 3 aortic stenosis symptoms. Fifty percent of patients reported having received sufficient information regarding aortic stenosis; only 48% remembered receiving information regarding specific symptoms. Only 14% general practitioners quoted the 3 specific symptoms. According to the initial recommendation, only 41 patients (64%) benefitted from a 6-to-12 month clinical and echocardiography follow up. CONCLUSION: GPs are not sufficiently trained to safely manage AS patients in the community and to ensure adequate follow-up and monitoring. AS patients were not properly informed about their diagnosis and symptomatology. Hence, therapeutic education should be improved for patients with asymptomatic AS and continuous medical education on VHD should be reinforced, for GPs.

Relationship between exercise pressure gradient and haemodynamic progression of aortic stenosis.

BACKGROUND AND AIMS: We hypothesized that large exercise-induced increases in aortic mean pressure gradient can predict haemodynamic progression during follow-up in asymptomatic patients with aortic stenosis. METHODS: We retrospectively identified patients with asymptomatic moderate or severe aortic stenosis (aortic valve area<1.5cm2 or<1cm2) and normal ejection fraction, who underwent an exercise stress echocardiography at baseline with a normal exercise test and a resting echocardiography during follow-up. The relationship between exercise-induced increase in aortic mean pressure gradient and annualised changes in resting mean pressure gradient during follow-up was investigated. RESULTS: Fifty-five patients (mean age 66±15 years; 45% severe aortic stenosis) were included. Aortic mean pressure gradient significantly increased from rest to peak exercise (P<0.001). During a median follow-up of 1.6 [1.1-3.2] years, resting mean pressure gradient increased from 35±13mmHg to 48±16mmHg, P<0.0001. Median annualised change in resting mean pressure gradient during follow-up was 5 [2-11] mmHg. Exercise-induced increase in aortic mean pressure gradient did correlate with annualised changes in mean pressure gradient during follow-up (r=0.35, P=0.01). Hemodynamic progression of aortic stenosis was faster in patients with large exercise-induced increase in aortic mean pressure gradient (≥20mmHg) as compared to those with exercise-induced increase in aortic mean pressure gradient<20mmHg (median annualised increase in mean pressure gradient 19 [6-28] vs. 4 [2-10] mmHg/y respectively, P=0.002). Similar results were found in the subgroup of 30 patients with moderate aortic stenosis. CONCLUSION: Large exercise-induced increases in aortic mean pressure gradient correlate with haemodynamic progression of stenosis during follow-up in patients with asymptomatic aortic stenosis. Further studies are needed to fully establish the role of ESE in the decision-making process in comparison to other prognostic markers in asymptomatic patients with aortic stenosis.

Prognostic Value of Aortic Valve Area by Doppler Echocardiography in Patients With Severe Asymptomatic Aortic Stenosis.

BACKGROUND: The aim of this study was to evaluate the relationship between aortic valve area (AVA) obtained by Doppler echocardiography and outcome in patients with severe asymptomatic aortic stenosis and to define a specific threshold of AVA for identifying asymptomatic patients at very high risk based on their clinical outcome. METHODS AND RESULTS: We included 199 patients with asymptomatic severe aortic stenosis (AVA ≤1.0 cm(2)). The risk of events (death or need for aortic valve replacement) increased linearly on the scale of log hazard with decreased AVA (adjusted hazard ratio 1.17; 95% CI 1.06-1.29 per 0.1 cm(2) AVA decrement; P=0.002). Event-free survival at 12, 24, and 48 months was 63±6%, 51±6%, and 34±6%, respectively, for AVA 0.8 to 1 cm(2); 49±6%, 36±6%, and 26±6%, respectively, for AVA 0.6 to 0.8 cm(2); and 33±8%, 20±7%, and 11±5%, respectively, for AVA ≤0.6 cm(2) (Ptrend=0.002). Patients with AVA ≤0.6 cm(2) had a significantly increased risk of events compared with patients with AVA 0.8 to 1 cm(2) (adjusted hazard ratio 2.22; 95% CI 1.41-3.52; P=0.001), whereas patients with AVA 0.6 to 0.8 cm(2) had an increased risk of events compared with those with AVA 0.8 to 1 cm(2), but the difference was not statistically significant (adjusted hazard ratio 1.38; 95% CI 0.93-2.05; P=0.11). After adjustment for covariates and aortic valve replacement as a time-dependent variable, patients with AVA ≤0.6 cm(2) had a significantly greater risk of all-cause mortality than patients with AVA >0.6 cm(2) (hazard ratio 3.39; 95% CI 1.80-6.40; P<0.0001). CONCLUSIONS: Patients with severe asymptomatic aortic stenosis and AVA ≤0.6 cm(2) displayed an important increase in the risk of adverse events during short-term follow-up. Further studies are needed to determine whether elective aortic valve replacement improves outcome in this high-risk subgroup of patients.