Left ventricular global longitudinal strain is predictive of all-cause mortality independent of aortic stenosis severity and ejection fraction

Left ventricular global longitudinal strain is predictive of all-cause mortality independent of... Abstract Aims Left ventricular (LV) global longitudinal strain (GLS) may identify subclinical myocardial dysfunction in patients with aortic stenosis (AS). The aims of the present retrospective single centre study were to determine the independent prognostic value of LV GLS over LV ejection fraction (EF) and the role of LV GLS to further risk stratify severe AS patients before aortic valve replacement. Methods and results A total of 688 patients (median age 72 years, 61.2% men) with mild (n = 130), moderate (n = 264) and severe AS (n = 294) were included. LV GLS was determined by 2D speckle tracking echocardiography. A total of 114 (16.6%) patients died before surgery during the study. When patients with severe AS and normal LVEF were dichotomized based on the median LV GLS value (−14.0%), patients with normal LVEF and ‘preserved’ LV GLS of ≤ −14% had significantly higher survival than patients with ‘impaired’ LV GLS of > −14%. There was no difference in survival between patients with normal LVEF but ‘impaired’ LV GLS ( > −14%) and patients with impaired LVEF (log-rank P = 0.34). LV GLS was independently associated with all-cause mortality on multivariable Cox regression analysis (hazard ratio 1.17, 95% confidence interval 1.09–1.26; P < 0.001). Conclusion LV GLS is independently associated with all-cause mortality in AS patients. It can further risk stratify severe AS patients and may influence the optimal timing of aortic valve replacement. left ventricle, aortic stenosis, prognosis Introduction Aortic stenosis (AS) is one of the most common valvular heart diseases in the general population.1 Often, prognosis for symptomatic severe AS is poor without surgery. Known predictors of poor outcome include older age, significant valvular calcification, rapid hemodynamic progression and impaired left ventricular (LV) ejection fraction (EF).2,3 Often, patients can develop impaired LVEF due to afterload mismatch4 or from true depression of myocardial contractility due to myocardial fibrosis.5 Upon development of an overtly impaired LVEF, aortic valve replacement is associated with higher operative risk and may be less beneficial in cases where the LV dysfunction is not due to afterload mismatch.6 However, conventional measures of global LV systolic function such as LVEF can be preserved until end-stage disease due to development of concentric hypertrophy, and thus lacks accuracy in identifying subtle changes in myocardial contractility. We previously demonstrated that 2D-LV global longitudinal strain (GLS) can detect early subtle myocardial dysfunction in AS patients.7 Although subsequent studies have evaluated the prognostic value of LV GLS in AS patients, they were variously limited by relatively small number of patients with severe AS, few mortality endpoints and short follow-up duration.8–12 In addition, majority of these studies recruited patients with preserved LVEF (≥50%),9–11 whereas only two small studies specifically recruited patients with LVEF ≤ 40%.8,12 Therefore, it is unclear if LV GLS can risk stratify all patients independent of AS severity and LVEF, and identify subgroups of severe AS patients who might benefit from early aortic valve replacement. Hence, the aims of the present study were to examine the independent prognostic value of LV GLS in a large cohort of AS patients with a wide range of LVEF, and determine if LV GLS can further risk stratify severe AS patients before aortic valve replacement. Methods Patient population From the departmental echocardiographic database, patients with the diagnosis of AS between November 1997 and September 2009 were identified. Patients with echocardiographic data allowing offline 2D speckle tracking analysis were selected, leaving 688 patients with AS in this retrospective analysis. All patients underwent clinical history, physical examination, and transthoracic echocardiography. Exclusion criteria included rhythm other than sinus rhythm, moderate or severe coexisting aortic regurgitation, moderate or severe mitral regurgitation, subvalvular or supravalvular AS, dynamic subaortic obstruction, and active endocarditis. All clinical data were prospectively entered in the departmental Cardiology Information System (EPD-Vision®, Leiden University Medical Center). Baseline clinical variables recorded included AS symptom status, New York Heart Association (NYHA) functional class, cardiac risk factors, and medications. Echocardiographic variables recorded included aortic valve area, mean transvalvular gradient, and peak jet velocity, LV volumes, LVEF, wall motion score index, and LV GLS. AS severity was classified into mild, moderate, and severe based on the calculated aortic valve area, mean gradient, and peak velocity as recommended by the European Association of Echocardiography and American Society of Echocardiography.13 All patients were followed up after the baseline echocardiographic examination for the occurrence of aortic valve replacement and death. To determine if LV GLS is associated with all-cause mortality before aortic valve replacement, patients were censored at the time of surgery or transcatheter aortic valve replacement. The prognostic significance of AS severity was first explored by stratifying all AS patients into three groups of mild, moderate, and severe AS. Next, the prognostic value of LVEF was explored by dichotomizing all severe AS patients into two groups based on the presence of normal (≥55%) vs. impaired (<55%) LVEF. Current guidelines define abnormal LVEF as <52% in men and <54% in women based on two standard deviations from the mean.14 For simplicity, the authors defined abnormal LVEF as <55% in all patients in the current study. As patients with impaired LVEF already have reduced LV GLS, the additional incremental prognostic value of LV GLS in severe AS patients with normal LVEF was explored by dichotomizing them into two groups based on the median LV GLS value (−14%). Thus, three groups of severe AS patients were identified and compared: Group 1—normal LVEF with ‘preserved’ LV GLS of ≤ −14%; Group 2—normal LVEF and ‘impaired’ LV GLS of > −14%; and Group 3—impaired LVEF. Finally, the independent prognostic value of LV GLS was determined in multivariable analyses with significant clinical and echocardiographic associates entered as covariates. Echocardiography Transthoracic echocardiography was performed with the subjects at rest using commercially available ultrasound systems (System 5 and Vivid 7, GE-Vingmed, Horten, Norway). All images were digitally stored on hard disks for offline analysis (EchoPAC version 108.1.5, GE-Vingmed, Horten, Norway). A complete 2D, colour, pulsed and continuous-wave Doppler echocardiogram was performed. LV end-diastolic volume index and end-systolic volume index were calculated using Simpson’s biplane method of discs and corrected for body surface area. LVEF was calculated and expressed as a percentage. LV mass index was calculated from the formula as recommended by the American Society of Echocardiography and the European Association of Cardiovascular Imaging.14 Wall motion was assessed using the 16 myocardial segment model as recommended by the American Society of Echocardiography and European Association of Cardiovascular Imaging.14 Briefly, the LV was divided into 12 basal and mid (septal, anteroseptal, anterior, lateral, posterior, inferior) segments and 4 (septal, anterior, lateral, inferior) apical segments. A semi-quantitative scoring system (1 = normal; 2 = hypokinesia; 3 = akinesia; 4 = dyskinesia) was used to analyse each segment, and a global wall motion score index was calculated according to standard formula.14 Definition of AS and classification of its severity were based on recommendations by the European Association of Echocardiography and American Society of Echocardiography.13 Briefly, severe AS was defined as peak velocity > 4.0 m/s, mean gradient > 40 mmHg, or aortic valve area < 1.0cm2; moderate AS was defined as peak velocity 3.0–4.0 m/s, mean gradient 30–40 mmHg, or aortic valve area 1.0–1.5 cm2; and mild AS was defined as peak velocity 2.6–2.9 m/s, mean gradient < 20 mmHg or aortic valve area > 1.5cm2.13 Aortic valve area calculation was performed by the continuity equation using velocity time integrals of the aorta and LV outflow tract.13 Peak and mean aortic transvalvular gradients were calculated using the modified Bernoulli equation. Mitral inflow velocities were recorded using conventional pulsed-wave Doppler echocardiography in the apical 4-chamber view using a 2 mm sample volume. Transmitral early (E wave) and late (A wave) diastolic velocities as well as deceleration time were recorded at the mitral leaflet tips. The pulmonary venous flow velocities were recorded with the sample volume positioned 1 cm below the orifice of the right superior pulmonary vein in the left atrium. The peak systolic (S) and peak diastolic (D) venous flow velocities were recorded. 2D speckle tracking Previous work from our laboratory has demonstrated early impairment in LV GLS in patients with AS which progressively worsened with increasing AS severity.7 In contrast, short-axis LV circumferential and radial functions were preserved until the latter stages of severity.7 Thus, the prognostic value of LV GLS for survival was examined in the present study. To quantify LV GLS, 2D speckle tracking analyses were performed on standard routine grey scale images of the apical 2-, 3-, and 4-chamber views. During analysis, the endocardial border was manually traced at end-systole and the region of interest width adjusted to include the entire myocardium. The software then automatically tracks and accepts segments of good tracking quality and rejects poorly tracked segments, while allowing the observer to manually override its decisions based on visual assessments of tracking quality. Mean LV GLS was calculated from the three individual apical GLS curves. LV diastolic function was presented as mean LV global early diastolic strain rate velocity (SRe). All strain and SRe measurements were exported to a spreadsheet (Microsoft ® Excel 2002, Microsoft Corporation, Redmond, WA, USA). The intra- and inter-observer variabilities (expressed as mean absolute difference ± 1 standard deviation and intraclass correlation coefficient) for LV GLS were 1.2 ± 0.5% and 0.939 and 0.9 ± 1.0% and 0.942, respectively.15 Follow-up and outcome definition All patients were clinically followed up for the occurrence of aortic valve replacement and death. The primary outcome was all-cause mortality after diagnosis of AS starting from baseline echocardiography and up to last follow-up (censored at time of aortic valve replacement). Patient death was ascertained by using data linkages with the governmental death registry database. Statistical analysis All continuous variables were tested for Gaussian distribution using the Kolmogorov–Smirnov test for normality. Normally distributed variables were presented as mean ± 1 standard deviation and non-normally distributed variables were presented as median and interquartile ranges (IQR). Categorical variables were presented as frequencies and percentages, and were compared using χ2 test. Unpaired Student’s t-test and Mann–Whitney U test were used to compare two groups of continuous variables of Gaussian and non-Gaussian distribution, respectively. One-way analysis of variance and Kruskal–Wallis H-tests were used to compare three groups of continuous variables of Gaussian and non-Gaussian distribution, respectively, and multiple comparisons for significant results were performed with Bonferroni corrections. Cumulative event rates were calculated using the Kaplan–Meier method and between group comparisons were made using the log rank tests with respect to the primary outcome of all-cause mortality.16 Cumulative survival rates were presented as a percentage and standard error (SE). Multivariate Cox proportional-hazards models were then constructed to identify independent clinical and echocardiographic associates of the all-cause mortality with significant univariate variables entered as covariates.17 The Cox proportional-hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for all independent predictors of all-cause mortality. To avoid multicollinearity between the univariate predictors, a tolerance level of > 0.5 was set. Validity of the Cox regression assumption of proportionality was confirmed for all continuous covariates by scaled Schoenfeld residuals. For categorical variables, the assumption of proportionality was confirmed by log minus log plots. Harrell’s C-statistic was used to compare the incremental prognostic value of LV GLS associated with all-cause mortality in the multivariable Cox regression model for severe AS patients. A two-tailed P-value of < 0.05 was considered significant. All statistical analyses were performed using SPSS for Windows (SPSS Inc, Chicago, IL, USA), version 17, and Stata version 10.1 (StataCorp LP, TX, USA). Results There were a total of 688 patients (61.2% men) with a median age of 72 years (IQR 63–79 years). Tables 1and2 summarize the clinical and echocardiographic characteristics of the patients. A respective 130 (18.9%), 264 (38.4%), and 294 (42.7%) patients had mild, moderate, and severe AS. The mechanisms underlying AS were degenerative in 90.7%, congenital in 6.1%, rheumatic in 1.7%, and uncertain in 1.5%. Patients with severe AS were more likely to be older (P < 0.001) and at a worse NYHA functional class (P < 0.001). There were no significant differences in the usage of cardiac medications between the three groups. Patients with severe AS had significantly larger LV volumes, higher LV mass index, and more impaired LV GLS. Table 1 Clinical characteristics of the total population and according to aortic stenosis severity Variable Total population (n = 688) Mild aortic stenosis (n = 130) Moderate aortic stenosis (n = 264) Severe aortic stenosis (n = 294) P-valuea Demographic characteristics  Age (years) 72 (63, 79) 71 (62, 77) 71 (60, 78) 74 (66, 80)b <0.001  Male gender (%) 61.2 62.3 62.9 59.2 0.64  Body mass index (kg/m2) 25.9 ± 4.1 26.1 ± 4.6 26.3 ± 4.2 25.5 ± 3.7 0.08  Body surface area (m2) 1.89 ± 0.21 1.90 ± 0.22 1.90 ± 0.21 1.86 ± 0.20b 0.03 Medical history  New York Heart Association class (%) <0.001   I 55.2 78.0 60.7 41.3   II 22.5 11.9 22.6 26.5   III 21.2 10.1 15.6 30.7   IV 1.1 0 1.1 1.5  Hypertension (%) 52.4 50.9 52.7 52.8 0.94  Diabetes (%) 17.6 18.4 14.9 19.8 0.32  Hyperlipidaemia (%) 28.6 22.7 28.8 30.9 0.28  Previous myocardial infarction (%) 13.6 13.0 10.3 16.8 0.08  Systolic blood pressure (mmHg) 145 ± 25 148 ± 28 145 ± 24 144 ± 25 0.41  Diastolic blood pressure (mmHg) 80 ± 13 81 ± 13 81 ± 13 79 ± 13 0.32 Medications  Beta-blocker (%) 39.1 37.5 36.9 41.8 0.48  Calcium channel blockers (%) 21.5 23.2 25.0 17.5 0.09  ACE inhibitor/ARB (%) 40.8 39.3 41.9 40.4 0.88  Diuretic (%) 29.6 23.2 29.3 32.5 0.19  Statins (%) 40.3 32.1 40.4 43.6 0.11 Variable Total population (n = 688) Mild aortic stenosis (n = 130) Moderate aortic stenosis (n = 264) Severe aortic stenosis (n = 294) P-valuea Demographic characteristics  Age (years) 72 (63, 79) 71 (62, 77) 71 (60, 78) 74 (66, 80)b <0.001  Male gender (%) 61.2 62.3 62.9 59.2 0.64  Body mass index (kg/m2) 25.9 ± 4.1 26.1 ± 4.6 26.3 ± 4.2 25.5 ± 3.7 0.08  Body surface area (m2) 1.89 ± 0.21 1.90 ± 0.22 1.90 ± 0.21 1.86 ± 0.20b 0.03 Medical history  New York Heart Association class (%) <0.001   I 55.2 78.0 60.7 41.3   II 22.5 11.9 22.6 26.5   III 21.2 10.1 15.6 30.7   IV 1.1 0 1.1 1.5  Hypertension (%) 52.4 50.9 52.7 52.8 0.94  Diabetes (%) 17.6 18.4 14.9 19.8 0.32  Hyperlipidaemia (%) 28.6 22.7 28.8 30.9 0.28  Previous myocardial infarction (%) 13.6 13.0 10.3 16.8 0.08  Systolic blood pressure (mmHg) 145 ± 25 148 ± 28 145 ± 24 144 ± 25 0.41  Diastolic blood pressure (mmHg) 80 ± 13 81 ± 13 81 ± 13 79 ± 13 0.32 Medications  Beta-blocker (%) 39.1 37.5 36.9 41.8 0.48  Calcium channel blockers (%) 21.5 23.2 25.0 17.5 0.09  ACE inhibitor/ARB (%) 40.8 39.3 41.9 40.4 0.88  Diuretic (%) 29.6 23.2 29.3 32.5 0.19  Statins (%) 40.3 32.1 40.4 43.6 0.11 ACE, angiotensin-converting enzyme; ANOVA, analysis of variance; ARB, angiotensin receptor blocker. a P-value by ANOVA and Kruskal–Wallis H test for continuous variables of Gaussian and non-Gaussian distribution respectively, and by χ2 test for categorical variables. b P-value < 0.05 vs. preceding aortic stenosis severity with Bonferroni corrections for multiple pairwise comparisons. Table 1 Clinical characteristics of the total population and according to aortic stenosis severity Variable Total population (n = 688) Mild aortic stenosis (n = 130) Moderate aortic stenosis (n = 264) Severe aortic stenosis (n = 294) P-valuea Demographic characteristics  Age (years) 72 (63, 79) 71 (62, 77) 71 (60, 78) 74 (66, 80)b <0.001  Male gender (%) 61.2 62.3 62.9 59.2 0.64  Body mass index (kg/m2) 25.9 ± 4.1 26.1 ± 4.6 26.3 ± 4.2 25.5 ± 3.7 0.08  Body surface area (m2) 1.89 ± 0.21 1.90 ± 0.22 1.90 ± 0.21 1.86 ± 0.20b 0.03 Medical history  New York Heart Association class (%) <0.001   I 55.2 78.0 60.7 41.3   II 22.5 11.9 22.6 26.5   III 21.2 10.1 15.6 30.7   IV 1.1 0 1.1 1.5  Hypertension (%) 52.4 50.9 52.7 52.8 0.94  Diabetes (%) 17.6 18.4 14.9 19.8 0.32  Hyperlipidaemia (%) 28.6 22.7 28.8 30.9 0.28  Previous myocardial infarction (%) 13.6 13.0 10.3 16.8 0.08  Systolic blood pressure (mmHg) 145 ± 25 148 ± 28 145 ± 24 144 ± 25 0.41  Diastolic blood pressure (mmHg) 80 ± 13 81 ± 13 81 ± 13 79 ± 13 0.32 Medications  Beta-blocker (%) 39.1 37.5 36.9 41.8 0.48  Calcium channel blockers (%) 21.5 23.2 25.0 17.5 0.09  ACE inhibitor/ARB (%) 40.8 39.3 41.9 40.4 0.88  Diuretic (%) 29.6 23.2 29.3 32.5 0.19  Statins (%) 40.3 32.1 40.4 43.6 0.11 Variable Total population (n = 688) Mild aortic stenosis (n = 130) Moderate aortic stenosis (n = 264) Severe aortic stenosis (n = 294) P-valuea Demographic characteristics  Age (years) 72 (63, 79) 71 (62, 77) 71 (60, 78) 74 (66, 80)b <0.001  Male gender (%) 61.2 62.3 62.9 59.2 0.64  Body mass index (kg/m2) 25.9 ± 4.1 26.1 ± 4.6 26.3 ± 4.2 25.5 ± 3.7 0.08  Body surface area (m2) 1.89 ± 0.21 1.90 ± 0.22 1.90 ± 0.21 1.86 ± 0.20b 0.03 Medical history  New York Heart Association class (%) <0.001   I 55.2 78.0 60.7 41.3   II 22.5 11.9 22.6 26.5   III 21.2 10.1 15.6 30.7   IV 1.1 0 1.1 1.5  Hypertension (%) 52.4 50.9 52.7 52.8 0.94  Diabetes (%) 17.6 18.4 14.9 19.8 0.32  Hyperlipidaemia (%) 28.6 22.7 28.8 30.9 0.28  Previous myocardial infarction (%) 13.6 13.0 10.3 16.8 0.08  Systolic blood pressure (mmHg) 145 ± 25 148 ± 28 145 ± 24 144 ± 25 0.41  Diastolic blood pressure (mmHg) 80 ± 13 81 ± 13 81 ± 13 79 ± 13 0.32 Medications  Beta-blocker (%) 39.1 37.5 36.9 41.8 0.48  Calcium channel blockers (%) 21.5 23.2 25.0 17.5 0.09  ACE inhibitor/ARB (%) 40.8 39.3 41.9 40.4 0.88  Diuretic (%) 29.6 23.2 29.3 32.5 0.19  Statins (%) 40.3 32.1 40.4 43.6 0.11 ACE, angiotensin-converting enzyme; ANOVA, analysis of variance; ARB, angiotensin receptor blocker. a P-value by ANOVA and Kruskal–Wallis H test for continuous variables of Gaussian and non-Gaussian distribution respectively, and by χ2 test for categorical variables. b P-value < 0.05 vs. preceding aortic stenosis severity with Bonferroni corrections for multiple pairwise comparisons. Table 2 Echocardiographic characteristics of the total population and according to aortic stenosis severity Variable Total population (n = 688) Mild aortic stenosis (n = 130) Moderate aortic stenosis (n = 264) Severe aortic stenosis (n = 294) P-valuea Heart rate (beats/min) 72.2 ± 12.9 72.4 ± 15.0 72.3 ± 12.8 74.5 ± 14.1 0.15 AVA (cm2) 1.09 (0.82, 1.40) 1.74 (1.62, 1.96) 1.22 (1.12, 1.36)b 0.78 (0.64, 0.90)b <0.001 Mean gradient (mmHg) 25.0 (15.3, 40.8) 12.1 (9.4, 16.1) 21.2 (15.1, 28.7)b 41.0 (31.2, 51.6)b <0.001 Peak gradient (mmHg) 41.3 (25.7, 64.9) 21.4 (17.0, 27.4) 35.0 (25.1, 48.2)b 65.8 (51.0, 82.5)b <0.001 LV mass index (g/m2) 119.1 (97.5, 146.9) 110.1 (97.5, 127.3) 107.3 (92.7, 131.7) 133.8 (110.0, 160.8)b <0.001 LVEDVI (mL/m2) 51.3 (41.7, 63.1) 46.9 (39.2, 58.3) 50.3 (40.7, 59.4) 53.9 (44.1, 69.0)b <0.001 LVESVI (mL/m2) 20.5 (16.1, 27.1) 19.1 (14.9, 24.6) 19.7 (15.4, 25.0) 22.7 (17.0, 31.5)b <0.001 LVEF (%) 58.7 (53.4, 63.8) 59.9 (54.9, 63.5) 60.0 (54.7, 64.4) 57.3 (51.2, 62.9)b <0.001 LVEF < 55% (%) 32.8 26.2 27.7 40.5b 0.001 Stroke volume index (mL/m2) 42.9 ± 11.4 48.7 ± 13.0 44.8 ± 9.9b 38.7 ± 10.4b <0.001 Wall motion score index 1.07 ± 0.24 1.01 ± 0.11 1.04 ± 0.15 1.18 ± 0.39b <0.001 Transmitral E/A ratio 0.94 ± 0.49 0.90 ± 0.44 0.93 ± 0.38 1.05 ± 0.74b 0.01 Transmitral deceleration time (ms) 240 ± 88 242 ± 86 232 ± 79 233 ± 92 0.52 Pulmonary S/D ratio 1.41 ± 0.44 1.46 ± 0.46 1.43 ± 0.42 1.36 ± 0.47 0.10 Septal E’ velocity (cm/s) 4.52 ± 1.96 4.82 ± 1.67 4.89 ± 1.95 4.00 ± 2.00b <0.001 Septal E/e’ ratio 19.4 ± 12.0 16.4 ± 7.3 16.7 ± 8.1 23.8 ± 15.5b <0.001 Left atrial volume index (mL/m2) 35.4 ± 15.1 32.5 ± 13.0 32.1 ± 13.3 39.7 ± 16.5b <0.001 LV GLS (%) −15.8 ± 3.1 −18.2 ± 2.1 −16.4 ± 2.3b −13.3 ± 3.7b <0.001 LV global longitudinal SRe (s−1) 0.82 ± 0.30 0.99 ± 0.31 0.88 ± 0.26b 0.69 ± 0.26b <0.001 Variable Total population (n = 688) Mild aortic stenosis (n = 130) Moderate aortic stenosis (n = 264) Severe aortic stenosis (n = 294) P-valuea Heart rate (beats/min) 72.2 ± 12.9 72.4 ± 15.0 72.3 ± 12.8 74.5 ± 14.1 0.15 AVA (cm2) 1.09 (0.82, 1.40) 1.74 (1.62, 1.96) 1.22 (1.12, 1.36)b 0.78 (0.64, 0.90)b <0.001 Mean gradient (mmHg) 25.0 (15.3, 40.8) 12.1 (9.4, 16.1) 21.2 (15.1, 28.7)b 41.0 (31.2, 51.6)b <0.001 Peak gradient (mmHg) 41.3 (25.7, 64.9) 21.4 (17.0, 27.4) 35.0 (25.1, 48.2)b 65.8 (51.0, 82.5)b <0.001 LV mass index (g/m2) 119.1 (97.5, 146.9) 110.1 (97.5, 127.3) 107.3 (92.7, 131.7) 133.8 (110.0, 160.8)b <0.001 LVEDVI (mL/m2) 51.3 (41.7, 63.1) 46.9 (39.2, 58.3) 50.3 (40.7, 59.4) 53.9 (44.1, 69.0)b <0.001 LVESVI (mL/m2) 20.5 (16.1, 27.1) 19.1 (14.9, 24.6) 19.7 (15.4, 25.0) 22.7 (17.0, 31.5)b <0.001 LVEF (%) 58.7 (53.4, 63.8) 59.9 (54.9, 63.5) 60.0 (54.7, 64.4) 57.3 (51.2, 62.9)b <0.001 LVEF < 55% (%) 32.8 26.2 27.7 40.5b 0.001 Stroke volume index (mL/m2) 42.9 ± 11.4 48.7 ± 13.0 44.8 ± 9.9b 38.7 ± 10.4b <0.001 Wall motion score index 1.07 ± 0.24 1.01 ± 0.11 1.04 ± 0.15 1.18 ± 0.39b <0.001 Transmitral E/A ratio 0.94 ± 0.49 0.90 ± 0.44 0.93 ± 0.38 1.05 ± 0.74b 0.01 Transmitral deceleration time (ms) 240 ± 88 242 ± 86 232 ± 79 233 ± 92 0.52 Pulmonary S/D ratio 1.41 ± 0.44 1.46 ± 0.46 1.43 ± 0.42 1.36 ± 0.47 0.10 Septal E’ velocity (cm/s) 4.52 ± 1.96 4.82 ± 1.67 4.89 ± 1.95 4.00 ± 2.00b <0.001 Septal E/e’ ratio 19.4 ± 12.0 16.4 ± 7.3 16.7 ± 8.1 23.8 ± 15.5b <0.001 Left atrial volume index (mL/m2) 35.4 ± 15.1 32.5 ± 13.0 32.1 ± 13.3 39.7 ± 16.5b <0.001 LV GLS (%) −15.8 ± 3.1 −18.2 ± 2.1 −16.4 ± 2.3b −13.3 ± 3.7b <0.001 LV global longitudinal SRe (s−1) 0.82 ± 0.30 0.99 ± 0.31 0.88 ± 0.26b 0.69 ± 0.26b <0.001 AVA, aortic valve area; ANOVA, analysis of variance; EDVI, end-diastolic volume index; EF, ejection fraction; ESVI, end-systolic volume index; GLS, global longitudinal strain; LV, left ventricular; SRe, early diastolic strain rate velocity; ANOVA, analysis of variance. a P-value by ANOVA and Kruskal–Wallis H test for continuous variables of Gaussian and non-Gaussian distribution respectively, and χ2 for categorical variable. b P-value < 0.05 vs. preceding aortic stenosis severity with Bonferroni corrections. Table 2 Echocardiographic characteristics of the total population and according to aortic stenosis severity Variable Total population (n = 688) Mild aortic stenosis (n = 130) Moderate aortic stenosis (n = 264) Severe aortic stenosis (n = 294) P-valuea Heart rate (beats/min) 72.2 ± 12.9 72.4 ± 15.0 72.3 ± 12.8 74.5 ± 14.1 0.15 AVA (cm2) 1.09 (0.82, 1.40) 1.74 (1.62, 1.96) 1.22 (1.12, 1.36)b 0.78 (0.64, 0.90)b <0.001 Mean gradient (mmHg) 25.0 (15.3, 40.8) 12.1 (9.4, 16.1) 21.2 (15.1, 28.7)b 41.0 (31.2, 51.6)b <0.001 Peak gradient (mmHg) 41.3 (25.7, 64.9) 21.4 (17.0, 27.4) 35.0 (25.1, 48.2)b 65.8 (51.0, 82.5)b <0.001 LV mass index (g/m2) 119.1 (97.5, 146.9) 110.1 (97.5, 127.3) 107.3 (92.7, 131.7) 133.8 (110.0, 160.8)b <0.001 LVEDVI (mL/m2) 51.3 (41.7, 63.1) 46.9 (39.2, 58.3) 50.3 (40.7, 59.4) 53.9 (44.1, 69.0)b <0.001 LVESVI (mL/m2) 20.5 (16.1, 27.1) 19.1 (14.9, 24.6) 19.7 (15.4, 25.0) 22.7 (17.0, 31.5)b <0.001 LVEF (%) 58.7 (53.4, 63.8) 59.9 (54.9, 63.5) 60.0 (54.7, 64.4) 57.3 (51.2, 62.9)b <0.001 LVEF < 55% (%) 32.8 26.2 27.7 40.5b 0.001 Stroke volume index (mL/m2) 42.9 ± 11.4 48.7 ± 13.0 44.8 ± 9.9b 38.7 ± 10.4b <0.001 Wall motion score index 1.07 ± 0.24 1.01 ± 0.11 1.04 ± 0.15 1.18 ± 0.39b <0.001 Transmitral E/A ratio 0.94 ± 0.49 0.90 ± 0.44 0.93 ± 0.38 1.05 ± 0.74b 0.01 Transmitral deceleration time (ms) 240 ± 88 242 ± 86 232 ± 79 233 ± 92 0.52 Pulmonary S/D ratio 1.41 ± 0.44 1.46 ± 0.46 1.43 ± 0.42 1.36 ± 0.47 0.10 Septal E’ velocity (cm/s) 4.52 ± 1.96 4.82 ± 1.67 4.89 ± 1.95 4.00 ± 2.00b <0.001 Septal E/e’ ratio 19.4 ± 12.0 16.4 ± 7.3 16.7 ± 8.1 23.8 ± 15.5b <0.001 Left atrial volume index (mL/m2) 35.4 ± 15.1 32.5 ± 13.0 32.1 ± 13.3 39.7 ± 16.5b <0.001 LV GLS (%) −15.8 ± 3.1 −18.2 ± 2.1 −16.4 ± 2.3b −13.3 ± 3.7b <0.001 LV global longitudinal SRe (s−1) 0.82 ± 0.30 0.99 ± 0.31 0.88 ± 0.26b 0.69 ± 0.26b <0.001 Variable Total population (n = 688) Mild aortic stenosis (n = 130) Moderate aortic stenosis (n = 264) Severe aortic stenosis (n = 294) P-valuea Heart rate (beats/min) 72.2 ± 12.9 72.4 ± 15.0 72.3 ± 12.8 74.5 ± 14.1 0.15 AVA (cm2) 1.09 (0.82, 1.40) 1.74 (1.62, 1.96) 1.22 (1.12, 1.36)b 0.78 (0.64, 0.90)b <0.001 Mean gradient (mmHg) 25.0 (15.3, 40.8) 12.1 (9.4, 16.1) 21.2 (15.1, 28.7)b 41.0 (31.2, 51.6)b <0.001 Peak gradient (mmHg) 41.3 (25.7, 64.9) 21.4 (17.0, 27.4) 35.0 (25.1, 48.2)b 65.8 (51.0, 82.5)b <0.001 LV mass index (g/m2) 119.1 (97.5, 146.9) 110.1 (97.5, 127.3) 107.3 (92.7, 131.7) 133.8 (110.0, 160.8)b <0.001 LVEDVI (mL/m2) 51.3 (41.7, 63.1) 46.9 (39.2, 58.3) 50.3 (40.7, 59.4) 53.9 (44.1, 69.0)b <0.001 LVESVI (mL/m2) 20.5 (16.1, 27.1) 19.1 (14.9, 24.6) 19.7 (15.4, 25.0) 22.7 (17.0, 31.5)b <0.001 LVEF (%) 58.7 (53.4, 63.8) 59.9 (54.9, 63.5) 60.0 (54.7, 64.4) 57.3 (51.2, 62.9)b <0.001 LVEF < 55% (%) 32.8 26.2 27.7 40.5b 0.001 Stroke volume index (mL/m2) 42.9 ± 11.4 48.7 ± 13.0 44.8 ± 9.9b 38.7 ± 10.4b <0.001 Wall motion score index 1.07 ± 0.24 1.01 ± 0.11 1.04 ± 0.15 1.18 ± 0.39b <0.001 Transmitral E/A ratio 0.94 ± 0.49 0.90 ± 0.44 0.93 ± 0.38 1.05 ± 0.74b 0.01 Transmitral deceleration time (ms) 240 ± 88 242 ± 86 232 ± 79 233 ± 92 0.52 Pulmonary S/D ratio 1.41 ± 0.44 1.46 ± 0.46 1.43 ± 0.42 1.36 ± 0.47 0.10 Septal E’ velocity (cm/s) 4.52 ± 1.96 4.82 ± 1.67 4.89 ± 1.95 4.00 ± 2.00b <0.001 Septal E/e’ ratio 19.4 ± 12.0 16.4 ± 7.3 16.7 ± 8.1 23.8 ± 15.5b <0.001 Left atrial volume index (mL/m2) 35.4 ± 15.1 32.5 ± 13.0 32.1 ± 13.3 39.7 ± 16.5b <0.001 LV GLS (%) −15.8 ± 3.1 −18.2 ± 2.1 −16.4 ± 2.3b −13.3 ± 3.7b <0.001 LV global longitudinal SRe (s−1) 0.82 ± 0.30 0.99 ± 0.31 0.88 ± 0.26b 0.69 ± 0.26b <0.001 AVA, aortic valve area; ANOVA, analysis of variance; EDVI, end-diastolic volume index; EF, ejection fraction; ESVI, end-systolic volume index; GLS, global longitudinal strain; LV, left ventricular; SRe, early diastolic strain rate velocity; ANOVA, analysis of variance. a P-value by ANOVA and Kruskal–Wallis H test for continuous variables of Gaussian and non-Gaussian distribution respectively, and χ2 for categorical variable. b P-value < 0.05 vs. preceding aortic stenosis severity with Bonferroni corrections. Survival outcome for all patients A total of 114 (16.6%) patients died before aortic valve replacement after a median follow-up duration of 8.2 months (IQR 1.9–23.9 months). Of those patients who died, 54 patients had severe AS. The cumulative survival for patients with mild/moderate AS at 6 months and 1 year were 96.9% (SE 1.0%) and 92.8% (SE 1.5%), respectively. In contrast, the cumulative survival for patients with severe AS at 6 months and 1 year were 88.6% (SE 2.4%) and 83.1% (SE 3.3%), respectively (both log rank P < 0.001 vs. moderate and mild AS). LVEF and LV GLS in severe AS To determine if LV GLS can further risk stratify severe AS patients, all patients with severe AS were initially dichotomized based on the presence of normal (≥55%) vs. impaired (<55%) LVEF (Figure 1). Of the 294 patients with severe AS in the study, 176 (59.9%) had normal LVEF on echocardiography. Severe AS patients with impaired LVEF had significantly higher all-cause mortality compared with patients normal LVEF (log rank P = 0.006). Figure 1 View largeDownload slide Flow chart outlining patients with severe AS divided into three groups based on LVEF and LV GLS. Figure 1 View largeDownload slide Flow chart outlining patients with severe AS divided into three groups based on LVEF and LV GLS. Next, all 176 patients with severe AS and normal LVEF were further dichotomized into two groups based on the median value of LV GLS of −14.0%. Thus, three groups of severe AS patients were identified: 88 (29.9%) patients with normal LVEF and ‘preserved’ LV GLS (≤−14%), 88 (29.9%) patients with normal LVEF but ‘impaired’ LV GLS (>−14%), and 118 (40.1%) patients with impaired LVEF (Figure 1). Tables 3 and 4 summarize the clinical and echocardiographic characteristics of the three groups of severe AS patients. The median LVEF for these three groups were 63.0% (IQR 59.7–67.4%), 59.5% (IQR 57.6–64.4%), and 47.5% (IQR 33.9–52.5%), respectively, (P < 0.001). Similarly, their mean LV GLS values were −17.0 ± 1.6%, −13.2 ± 1.8%, and −10.7 ± 3.6%, respectively, (P < 0.001) (Table 4). Table 3 Clinical characteristics of patients with severe aortic stenosis Variable Normal EF ‘Preserved’ LV GLS ( ≤ −14%) (n = 88) Normal EF ‘Impaired’ LV GLS ( > −14%) (n = 88) Impaired LVEF (n = 118) P-valuea Demographic characteristics  Age (years) 71 (62, 80) 76 (67, 80) 76 (67, 81) 0.13  Male gender (%) 51.1 51.1 71.2 0.003  Body mass index (kg/m2) 25.7 ± 3.8 25.1 ± 3.7 25.7 ± 3.8 0.42  Body surface area (m2) 1.85 ± 0.18 1.83 ± 0.21 1.89 ± 0.19 0.11 Medical history  New York Heart Association class (%) 0.043   I 50.6 34.2 39.3   II 31.0 27.8 22.2   III 18.4 36.7 35.9   IV 0 1.3 2.6  Hypertension (%) 55.3 54.2 50.0 0.73  Diabetes (%) 15.3 22.2 21.4 0.46  Hyperlipidaemia (%) 41.7 23.7 27.7 0.031  Previous myocardial infarction (%) 11.6 9.9 25.4 0.005  Systolic blood pressure (mmHg) 147 ± 25 148 ± 26 139 ± 24 0.024  Diastolic blood pressure (mmHg) 80 ± 13 80 ± 13 78 ± 12 0.36 Medications  Beta-blocker (%) 54.8 41.3 32.8 0.008  Calcium channel blockers (%) 13.1 20.0 19.0 0.44  ACE inhibitor/ARB (%) 46.4 37.5 37.9 0.40  Diuretic (%) 21.4 35.0 38.8 0.030  Statins (%) 48.8 37.5 44.0 0.34 Variable Normal EF ‘Preserved’ LV GLS ( ≤ −14%) (n = 88) Normal EF ‘Impaired’ LV GLS ( > −14%) (n = 88) Impaired LVEF (n = 118) P-valuea Demographic characteristics  Age (years) 71 (62, 80) 76 (67, 80) 76 (67, 81) 0.13  Male gender (%) 51.1 51.1 71.2 0.003  Body mass index (kg/m2) 25.7 ± 3.8 25.1 ± 3.7 25.7 ± 3.8 0.42  Body surface area (m2) 1.85 ± 0.18 1.83 ± 0.21 1.89 ± 0.19 0.11 Medical history  New York Heart Association class (%) 0.043   I 50.6 34.2 39.3   II 31.0 27.8 22.2   III 18.4 36.7 35.9   IV 0 1.3 2.6  Hypertension (%) 55.3 54.2 50.0 0.73  Diabetes (%) 15.3 22.2 21.4 0.46  Hyperlipidaemia (%) 41.7 23.7 27.7 0.031  Previous myocardial infarction (%) 11.6 9.9 25.4 0.005  Systolic blood pressure (mmHg) 147 ± 25 148 ± 26 139 ± 24 0.024  Diastolic blood pressure (mmHg) 80 ± 13 80 ± 13 78 ± 12 0.36 Medications  Beta-blocker (%) 54.8 41.3 32.8 0.008  Calcium channel blockers (%) 13.1 20.0 19.0 0.44  ACE inhibitor/ARB (%) 46.4 37.5 37.9 0.40  Diuretic (%) 21.4 35.0 38.8 0.030  Statins (%) 48.8 37.5 44.0 0.34 ACE, angiotensin-converting enzyme; ANOVA, analysis of variance; ARB, angiotensin receptor blocker; EF, ejection fraction; GLS, global longitudinal strain; LV, left ventricular. a P-value by ANOVA and Kruskal–Wallis H test for continuous variables of Gaussian and non-Gaussian distribution respectively, and by χ2 test for categorical variables. Table 3 Clinical characteristics of patients with severe aortic stenosis Variable Normal EF ‘Preserved’ LV GLS ( ≤ −14%) (n = 88) Normal EF ‘Impaired’ LV GLS ( > −14%) (n = 88) Impaired LVEF (n = 118) P-valuea Demographic characteristics  Age (years) 71 (62, 80) 76 (67, 80) 76 (67, 81) 0.13  Male gender (%) 51.1 51.1 71.2 0.003  Body mass index (kg/m2) 25.7 ± 3.8 25.1 ± 3.7 25.7 ± 3.8 0.42  Body surface area (m2) 1.85 ± 0.18 1.83 ± 0.21 1.89 ± 0.19 0.11 Medical history  New York Heart Association class (%) 0.043   I 50.6 34.2 39.3   II 31.0 27.8 22.2   III 18.4 36.7 35.9   IV 0 1.3 2.6  Hypertension (%) 55.3 54.2 50.0 0.73  Diabetes (%) 15.3 22.2 21.4 0.46  Hyperlipidaemia (%) 41.7 23.7 27.7 0.031  Previous myocardial infarction (%) 11.6 9.9 25.4 0.005  Systolic blood pressure (mmHg) 147 ± 25 148 ± 26 139 ± 24 0.024  Diastolic blood pressure (mmHg) 80 ± 13 80 ± 13 78 ± 12 0.36 Medications  Beta-blocker (%) 54.8 41.3 32.8 0.008  Calcium channel blockers (%) 13.1 20.0 19.0 0.44  ACE inhibitor/ARB (%) 46.4 37.5 37.9 0.40  Diuretic (%) 21.4 35.0 38.8 0.030  Statins (%) 48.8 37.5 44.0 0.34 Variable Normal EF ‘Preserved’ LV GLS ( ≤ −14%) (n = 88) Normal EF ‘Impaired’ LV GLS ( > −14%) (n = 88) Impaired LVEF (n = 118) P-valuea Demographic characteristics  Age (years) 71 (62, 80) 76 (67, 80) 76 (67, 81) 0.13  Male gender (%) 51.1 51.1 71.2 0.003  Body mass index (kg/m2) 25.7 ± 3.8 25.1 ± 3.7 25.7 ± 3.8 0.42  Body surface area (m2) 1.85 ± 0.18 1.83 ± 0.21 1.89 ± 0.19 0.11 Medical history  New York Heart Association class (%) 0.043   I 50.6 34.2 39.3   II 31.0 27.8 22.2   III 18.4 36.7 35.9   IV 0 1.3 2.6  Hypertension (%) 55.3 54.2 50.0 0.73  Diabetes (%) 15.3 22.2 21.4 0.46  Hyperlipidaemia (%) 41.7 23.7 27.7 0.031  Previous myocardial infarction (%) 11.6 9.9 25.4 0.005  Systolic blood pressure (mmHg) 147 ± 25 148 ± 26 139 ± 24 0.024  Diastolic blood pressure (mmHg) 80 ± 13 80 ± 13 78 ± 12 0.36 Medications  Beta-blocker (%) 54.8 41.3 32.8 0.008  Calcium channel blockers (%) 13.1 20.0 19.0 0.44  ACE inhibitor/ARB (%) 46.4 37.5 37.9 0.40  Diuretic (%) 21.4 35.0 38.8 0.030  Statins (%) 48.8 37.5 44.0 0.34 ACE, angiotensin-converting enzyme; ANOVA, analysis of variance; ARB, angiotensin receptor blocker; EF, ejection fraction; GLS, global longitudinal strain; LV, left ventricular. a P-value by ANOVA and Kruskal–Wallis H test for continuous variables of Gaussian and non-Gaussian distribution respectively, and by χ2 test for categorical variables. Table 4 Echocardiographic characteristics of patients with severe aortic stenosis Variable Normal EF ‘Preserved’ LV GLS ( ≤ −14%) (n = 88) Normal EF ‘Impaired’ LV GLS ( > −14%) (n = 88) Impaired LVEF (n = 118) P-valuea Heart rate (beats/min) 70.2 ± 12.6 73.0 ± 12.0 78.7 ± 15.6bc <0.001 AVA (cm2) 0.84 (0.75, 0.93) 0.75 (0.62, 0.86)b 0.74 (0.59, 0.87)b <0.001 Mean gradient (mmHg) 42.3 (36.6, 54.3) 46.4 (32.5, 56.4) 35.8 (24.4, 45.7)bc <0.001 Peak gradient (mmHg) 69.9 (57.5, 85.6) 72.3 (54.9, 87.0) 58.5 (40.4, 70.9)bc <0.001 LV mass index (g/m2) 120.0 (93.6, 141.3) 129.2 (108.2, 160.8)b 150.6 (124.1, 170.6)bc <0.001 LVEDVI (mL/m2) 48.6 (39.9, 55.7) 49.6 (40.7, 59.6) 69.1 (54.2, 94.5)bc <0.001 LVESVI (mL/m2) 17.8 (14.2, 22.2) 19.4 (15.9, 23.0) 36.8 (26.5, 60.0)bc <0.001 LVEF (%) 63.0 (59.7, 67.4) 59.5 (57.6, 64.4)b 47.5 (33.9, 52.5)bc <0.001 Stroke volume index (mL/m2) 46.1 ± 7.8 39.4 ± 8.9b 32.8 ± 9.6bc <0.001 Wall motion score index 1.01 ± 0.04 1.02 ± 0.13 1.44 ± 0.50bc <0.001 Transmitral E/A ratio 0.91 ± 0.50 1.00 ± 0.81 1.21 ± 0.83b 0.02 Transmitral deceleration time (ms) 252 ± 83 244 ± 78 209 ± 104bc 0.002 Pulmonary S/D ratio 1.45 ± 0.32 1.45 ± 0.47 1.20 ± 0.55bc 0.001 Septal E’ velocity (cm/s) 4.46 ± 2.25 4.02 ± 1.87 3.63 ± 1.84b 0.03 Septal E/e’ ratio 21.3 ± 11.2 25.4 ± 21.7 24.8 ± 12.7 0.25 Left atrial volume index (mL/m2) 36.6 ± 14.8 40.0 ± 18.1 41.7 ± 16.4 0.12 LV GLS (%) −17.0 ± 1.6 −13.2 ± 1.8b −10.7 ± 3.6bc <0.001 LV global longitudinal SRe (s−1) 0.84 ± 0.24 0.65 ± 0.24b 0.60 ± 0.24bc <0.001 Variable Normal EF ‘Preserved’ LV GLS ( ≤ −14%) (n = 88) Normal EF ‘Impaired’ LV GLS ( > −14%) (n = 88) Impaired LVEF (n = 118) P-valuea Heart rate (beats/min) 70.2 ± 12.6 73.0 ± 12.0 78.7 ± 15.6bc <0.001 AVA (cm2) 0.84 (0.75, 0.93) 0.75 (0.62, 0.86)b 0.74 (0.59, 0.87)b <0.001 Mean gradient (mmHg) 42.3 (36.6, 54.3) 46.4 (32.5, 56.4) 35.8 (24.4, 45.7)bc <0.001 Peak gradient (mmHg) 69.9 (57.5, 85.6) 72.3 (54.9, 87.0) 58.5 (40.4, 70.9)bc <0.001 LV mass index (g/m2) 120.0 (93.6, 141.3) 129.2 (108.2, 160.8)b 150.6 (124.1, 170.6)bc <0.001 LVEDVI (mL/m2) 48.6 (39.9, 55.7) 49.6 (40.7, 59.6) 69.1 (54.2, 94.5)bc <0.001 LVESVI (mL/m2) 17.8 (14.2, 22.2) 19.4 (15.9, 23.0) 36.8 (26.5, 60.0)bc <0.001 LVEF (%) 63.0 (59.7, 67.4) 59.5 (57.6, 64.4)b 47.5 (33.9, 52.5)bc <0.001 Stroke volume index (mL/m2) 46.1 ± 7.8 39.4 ± 8.9b 32.8 ± 9.6bc <0.001 Wall motion score index 1.01 ± 0.04 1.02 ± 0.13 1.44 ± 0.50bc <0.001 Transmitral E/A ratio 0.91 ± 0.50 1.00 ± 0.81 1.21 ± 0.83b 0.02 Transmitral deceleration time (ms) 252 ± 83 244 ± 78 209 ± 104bc 0.002 Pulmonary S/D ratio 1.45 ± 0.32 1.45 ± 0.47 1.20 ± 0.55bc 0.001 Septal E’ velocity (cm/s) 4.46 ± 2.25 4.02 ± 1.87 3.63 ± 1.84b 0.03 Septal E/e’ ratio 21.3 ± 11.2 25.4 ± 21.7 24.8 ± 12.7 0.25 Left atrial volume index (mL/m2) 36.6 ± 14.8 40.0 ± 18.1 41.7 ± 16.4 0.12 LV GLS (%) −17.0 ± 1.6 −13.2 ± 1.8b −10.7 ± 3.6bc <0.001 LV global longitudinal SRe (s−1) 0.84 ± 0.24 0.65 ± 0.24b 0.60 ± 0.24bc <0.001 ANOVA, analysis of variance; AVA, aortic valve area; EDVI, end-diastolic volume index; EF, ejection fraction; ESVI, end-systolic volume index; GLS, global longitudinal strain; LV, left ventricular; SRe, early diastolic strain rate velocity. a P-value by ANOVA and Kruskal–Wallis H test for continuous variables of Gaussian and non-Gaussian distribution respectively. b P-value < 0.05 vs. severe AS patients with normal LVEF and ‘preserved’ LV GLS with Bonferroni corrections. c P-value < 0.05 vs. severe AS patients with normal LVEF but ‘impaired’ LV GLS with Bonferroni corrections. Table 4 Echocardiographic characteristics of patients with severe aortic stenosis Variable Normal EF ‘Preserved’ LV GLS ( ≤ −14%) (n = 88) Normal EF ‘Impaired’ LV GLS ( > −14%) (n = 88) Impaired LVEF (n = 118) P-valuea Heart rate (beats/min) 70.2 ± 12.6 73.0 ± 12.0 78.7 ± 15.6bc <0.001 AVA (cm2) 0.84 (0.75, 0.93) 0.75 (0.62, 0.86)b 0.74 (0.59, 0.87)b <0.001 Mean gradient (mmHg) 42.3 (36.6, 54.3) 46.4 (32.5, 56.4) 35.8 (24.4, 45.7)bc <0.001 Peak gradient (mmHg) 69.9 (57.5, 85.6) 72.3 (54.9, 87.0) 58.5 (40.4, 70.9)bc <0.001 LV mass index (g/m2) 120.0 (93.6, 141.3) 129.2 (108.2, 160.8)b 150.6 (124.1, 170.6)bc <0.001 LVEDVI (mL/m2) 48.6 (39.9, 55.7) 49.6 (40.7, 59.6) 69.1 (54.2, 94.5)bc <0.001 LVESVI (mL/m2) 17.8 (14.2, 22.2) 19.4 (15.9, 23.0) 36.8 (26.5, 60.0)bc <0.001 LVEF (%) 63.0 (59.7, 67.4) 59.5 (57.6, 64.4)b 47.5 (33.9, 52.5)bc <0.001 Stroke volume index (mL/m2) 46.1 ± 7.8 39.4 ± 8.9b 32.8 ± 9.6bc <0.001 Wall motion score index 1.01 ± 0.04 1.02 ± 0.13 1.44 ± 0.50bc <0.001 Transmitral E/A ratio 0.91 ± 0.50 1.00 ± 0.81 1.21 ± 0.83b 0.02 Transmitral deceleration time (ms) 252 ± 83 244 ± 78 209 ± 104bc 0.002 Pulmonary S/D ratio 1.45 ± 0.32 1.45 ± 0.47 1.20 ± 0.55bc 0.001 Septal E’ velocity (cm/s) 4.46 ± 2.25 4.02 ± 1.87 3.63 ± 1.84b 0.03 Septal E/e’ ratio 21.3 ± 11.2 25.4 ± 21.7 24.8 ± 12.7 0.25 Left atrial volume index (mL/m2) 36.6 ± 14.8 40.0 ± 18.1 41.7 ± 16.4 0.12 LV GLS (%) −17.0 ± 1.6 −13.2 ± 1.8b −10.7 ± 3.6bc <0.001 LV global longitudinal SRe (s−1) 0.84 ± 0.24 0.65 ± 0.24b 0.60 ± 0.24bc <0.001 Variable Normal EF ‘Preserved’ LV GLS ( ≤ −14%) (n = 88) Normal EF ‘Impaired’ LV GLS ( > −14%) (n = 88) Impaired LVEF (n = 118) P-valuea Heart rate (beats/min) 70.2 ± 12.6 73.0 ± 12.0 78.7 ± 15.6bc <0.001 AVA (cm2) 0.84 (0.75, 0.93) 0.75 (0.62, 0.86)b 0.74 (0.59, 0.87)b <0.001 Mean gradient (mmHg) 42.3 (36.6, 54.3) 46.4 (32.5, 56.4) 35.8 (24.4, 45.7)bc <0.001 Peak gradient (mmHg) 69.9 (57.5, 85.6) 72.3 (54.9, 87.0) 58.5 (40.4, 70.9)bc <0.001 LV mass index (g/m2) 120.0 (93.6, 141.3) 129.2 (108.2, 160.8)b 150.6 (124.1, 170.6)bc <0.001 LVEDVI (mL/m2) 48.6 (39.9, 55.7) 49.6 (40.7, 59.6) 69.1 (54.2, 94.5)bc <0.001 LVESVI (mL/m2) 17.8 (14.2, 22.2) 19.4 (15.9, 23.0) 36.8 (26.5, 60.0)bc <0.001 LVEF (%) 63.0 (59.7, 67.4) 59.5 (57.6, 64.4)b 47.5 (33.9, 52.5)bc <0.001 Stroke volume index (mL/m2) 46.1 ± 7.8 39.4 ± 8.9b 32.8 ± 9.6bc <0.001 Wall motion score index 1.01 ± 0.04 1.02 ± 0.13 1.44 ± 0.50bc <0.001 Transmitral E/A ratio 0.91 ± 0.50 1.00 ± 0.81 1.21 ± 0.83b 0.02 Transmitral deceleration time (ms) 252 ± 83 244 ± 78 209 ± 104bc 0.002 Pulmonary S/D ratio 1.45 ± 0.32 1.45 ± 0.47 1.20 ± 0.55bc 0.001 Septal E’ velocity (cm/s) 4.46 ± 2.25 4.02 ± 1.87 3.63 ± 1.84b 0.03 Septal E/e’ ratio 21.3 ± 11.2 25.4 ± 21.7 24.8 ± 12.7 0.25 Left atrial volume index (mL/m2) 36.6 ± 14.8 40.0 ± 18.1 41.7 ± 16.4 0.12 LV GLS (%) −17.0 ± 1.6 −13.2 ± 1.8b −10.7 ± 3.6bc <0.001 LV global longitudinal SRe (s−1) 0.84 ± 0.24 0.65 ± 0.24b 0.60 ± 0.24bc <0.001 ANOVA, analysis of variance; AVA, aortic valve area; EDVI, end-diastolic volume index; EF, ejection fraction; ESVI, end-systolic volume index; GLS, global longitudinal strain; LV, left ventricular; SRe, early diastolic strain rate velocity. a P-value by ANOVA and Kruskal–Wallis H test for continuous variables of Gaussian and non-Gaussian distribution respectively. b P-value < 0.05 vs. severe AS patients with normal LVEF and ‘preserved’ LV GLS with Bonferroni corrections. c P-value < 0.05 vs. severe AS patients with normal LVEF but ‘impaired’ LV GLS with Bonferroni corrections. Figure 2 shows that severe AS patients with normal LVEF and ‘preserved’ LV GLS had significantly lower all-cause mortality compared with patients with normal LVEF but ‘impaired’ LV GLS (log rank P = 0.024) and patients with impaired LVEF (log rank P = 0.001). There was no significant difference in survival between severe AS patients with normal LVEF but ‘impaired’ LV GLS and patients with impaired LVEF (log rank P = 0.34). The cumulative survival for severe AS patients with normal LVEF and ‘preserved’ LV GLS at 6 months and 1 year were 98.2% (SE 1.8%) and 92.3% (SE 4.4%), respectively. The cumulative survival for severe AS patients with preserved LVEF but ‘impaired’ LV GLS at 6 months and 1 year were 84.7% (SE 5.5%) and 77.7% (SE 8.5%), respectively. Finally, the cumulative survival for severe AS patients with impaired LVEF at 6 months and 1 year were 83.2% (SE 4.3%) and 75.0% (SE 6.0%), respectively. Not unexpectedly due to the lower event rates in severe AS patients with normal LVEF and ‘preserved’ LV GLS, there was a difference in the follow up duration between the three groups of patients (P = 0.013 by Kruskal–Wallis H-test). Severe AS patients with normal LVEF and ‘preserved’ LV GLS had significantly longer follow up duration compared with patients with normal LVEF but ‘impaired’ LV GLS (P = 0.016 with Bonferroni correction) and against patients with impaired LVEF (P = 0.026 with Bonferroni correction). Figure 2 View largeDownload slide Kaplan–Meier estimates of cumulative survival in severe AS patients with impaired LVEF, normal LVEF with ‘impaired’ LV GLS ( > −14%), and normal LVEF with ‘preserved’ LV GLS ( ≤ −14%). Patients with normal LVEF and ‘preserved’ LV GLS had superior survival compared with patients with normal LVEF but ‘impaired’ LV GLS (log rank P = 0.007), and compared with patients with impaired LVEF (log rank P < 0.001). There was no significant difference in survival between patients with impaired LVEF and patients with normal LVEF but ‘impaired’ LV GLS (log rank P = 0.42). Figure 2 View largeDownload slide Kaplan–Meier estimates of cumulative survival in severe AS patients with impaired LVEF, normal LVEF with ‘impaired’ LV GLS ( > −14%), and normal LVEF with ‘preserved’ LV GLS ( ≤ −14%). Patients with normal LVEF and ‘preserved’ LV GLS had superior survival compared with patients with normal LVEF but ‘impaired’ LV GLS (log rank P = 0.007), and compared with patients with impaired LVEF (log rank P < 0.001). There was no significant difference in survival between patients with impaired LVEF and patients with normal LVEF but ‘impaired’ LV GLS (log rank P = 0.42). Determinants of all-cause mortality in severe AS Table 5 outlines all significant univariable associates of all-cause mortality for patients with severe AS. Patients who died before aortic valve replacement were more likely to be older, male, had a higher LV mass index, larger LV volumes, lower LVEF and stroke volume index, and more impaired LV GLS. Since patients who develop symptomatic AS often undergo aortic valve replacement based on current guidelines recommendations,18 the presence or absence of symptoms was not significantly associated with all-cause mortality before aortic valve replacement (HR 0.91; 95% CI 0.52–1.59; P = 0.75). Table 5 Univariable and multivariable Cox proportional hazard models for all-cause mortality for severe aortic stenosis patients before aortic valve replacement surgery Variable Univariate Multivariatea HR (95% CI) P-value HR (95% CI) P-value Age 1.03 (1.00–1.06) 0.040 Male gender 1.92 (1.06–3.46) 0.031 Previous myocardial infarction 2.59 (1.43–4.71) 0.002 1.97 (1.05–3.69) 0.034 LV mass index (per 10g increase) 1.09 (1.02–1.17) 0.011 LVEDVI 1.01 (1.00–1.02) 0.023 LVESVI 1.02 (1.01–1.03) <0.001 LVEF 0.97 (0.95–0.98) <0.001 Stroke volume index 0.93 (0.91–0.96) <0.001 Wall motion score index (per 0.1 increase) 1.10 (1.04–1.16) 0.001 LV GLS (per 1% absolute change) 1.20 (1.12–1.28) <0.001 1.17 (1.09–1.26) <0.001 Variable Univariate Multivariatea HR (95% CI) P-value HR (95% CI) P-value Age 1.03 (1.00–1.06) 0.040 Male gender 1.92 (1.06–3.46) 0.031 Previous myocardial infarction 2.59 (1.43–4.71) 0.002 1.97 (1.05–3.69) 0.034 LV mass index (per 10g increase) 1.09 (1.02–1.17) 0.011 LVEDVI 1.01 (1.00–1.02) 0.023 LVESVI 1.02 (1.01–1.03) <0.001 LVEF 0.97 (0.95–0.98) <0.001 Stroke volume index 0.93 (0.91–0.96) <0.001 Wall motion score index (per 0.1 increase) 1.10 (1.04–1.16) 0.001 LV GLS (per 1% absolute change) 1.20 (1.12–1.28) <0.001 1.17 (1.09–1.26) <0.001 CI, confidence interval; EDVI, end-diastolic volume index; EF, ejection fraction; ESVI, end-systolic volume index; GLS, global longitudinal strain; HR, hazard ratio; LV, ventricular. a Variables included in the multivariable Cox regression model included age, gender, previous history of myocardial infarction., LV mass index, LVESVI, WMSI, and LV GLS. Table 5 Univariable and multivariable Cox proportional hazard models for all-cause mortality for severe aortic stenosis patients before aortic valve replacement surgery Variable Univariate Multivariatea HR (95% CI) P-value HR (95% CI) P-value Age 1.03 (1.00–1.06) 0.040 Male gender 1.92 (1.06–3.46) 0.031 Previous myocardial infarction 2.59 (1.43–4.71) 0.002 1.97 (1.05–3.69) 0.034 LV mass index (per 10g increase) 1.09 (1.02–1.17) 0.011 LVEDVI 1.01 (1.00–1.02) 0.023 LVESVI 1.02 (1.01–1.03) <0.001 LVEF 0.97 (0.95–0.98) <0.001 Stroke volume index 0.93 (0.91–0.96) <0.001 Wall motion score index (per 0.1 increase) 1.10 (1.04–1.16) 0.001 LV GLS (per 1% absolute change) 1.20 (1.12–1.28) <0.001 1.17 (1.09–1.26) <0.001 Variable Univariate Multivariatea HR (95% CI) P-value HR (95% CI) P-value Age 1.03 (1.00–1.06) 0.040 Male gender 1.92 (1.06–3.46) 0.031 Previous myocardial infarction 2.59 (1.43–4.71) 0.002 1.97 (1.05–3.69) 0.034 LV mass index (per 10g increase) 1.09 (1.02–1.17) 0.011 LVEDVI 1.01 (1.00–1.02) 0.023 LVESVI 1.02 (1.01–1.03) <0.001 LVEF 0.97 (0.95–0.98) <0.001 Stroke volume index 0.93 (0.91–0.96) <0.001 Wall motion score index (per 0.1 increase) 1.10 (1.04–1.16) 0.001 LV GLS (per 1% absolute change) 1.20 (1.12–1.28) <0.001 1.17 (1.09–1.26) <0.001 CI, confidence interval; EDVI, end-diastolic volume index; EF, ejection fraction; ESVI, end-systolic volume index; GLS, global longitudinal strain; HR, hazard ratio; LV, ventricular. a Variables included in the multivariable Cox regression model included age, gender, previous history of myocardial infarction., LV mass index, LVESVI, WMSI, and LV GLS. Of the 294 severe AS patients, 222 patients (76%) underwent invasive coronary angiography. Of these 222 patients, 125 patients (56%) did not have obstructive disease as defined as > 50% stenosis. On multivariable analysis, the presence or absence of any obstructive coronary artery disease was not associated with all-cause mortality in severe AS patients before aortic valve replacement (P > 0.99). Similarly, the number of vessels with obstructive disease was also not a determinant of all-cause mortality in severe AS patients before aortic valve replacement (P = 0.96). To identify independent correlates of all-cause mortality on follow-up, significant univariable associates in Table 5 (age, gender, previous history of myocardial infarction, LV mass index, LV end-systolic volume index, wall motion score index, and LV GLS) were entered into the Cox proportional-hazard model as covariates. On multivariable analysis, previous myocardial infarction (HR 1.97; 95% CI 1.05–3.69; P = 0.034), and every 1% absolute worsening in LV GLS (HR 1.17; 95% CI 1.09–1.26; P < 0.001) were independently associated with increased all-cause mortality on follow-up for severe AS patients. Therefore, considering that LV GLS ranged from −2.9% to −22.3% in patients with severe AS in the present study, the odds that a patient with severe AS and LV GLS of −3% dying on follow-up is nearly 20 times higher compared with a patient with severe AS and LV GLS of −22%. The inclusion of LV GLS incrementally improved the multivariable Cox regression model’s discriminatory value by significantly increasing the Harrell’s C-statistic from 0.728 to 0.783, P = 0.003. To determine if LV stroke volume index was also independently associated with all-cause mortality on follow up, it was forced into the multivariable Cox regression model even though it was significantly correlated with LV GLS (r = −0.68, P < 0.001). However, the results did not change and only LV GLS, not LV stroke volume index, was independently associated with all-cause mortality in severe AS patients on follow-up. Discussion The present study demonstrated the independent prognostic value of LV GLS in a large cohort of patients with a wide range of LVEF and AS severity. LV GLS analysis was able to identify subtle myocardial dysfunction in patients with severe AS and normal LVEF, and could further risk stratify these patients into a higher mortality risk category equivalent to patients with severe AS and impaired LVEF. LV dysfunction in AS Degenerative calcific AS is a chronic progressive disease whose natural history is characterized by a prolonged latent period where patients remain relatively asymptomatic and has a low morbidity and mortality risk.2,19 However, upon development of symptomatic severe AS, the risk of sudden cardiac death increases and can occur even within months of symptom onset.2 Known determinants of poor outcome include older age, significant aortic valvular calcification, rapid hemodynamic progression, and an impaired LVEF.2,3,20 The development of an impaired LVEF in patients with severe AS can be due to either afterload mismatch or from a true depression of myocardial contractility.21 With progressive reduction in the aortic valve area, the resultant increase in afterload is usually accompanied by compensatory concentric LV hypertrophy. This results in normalization of LV wall stress and maintenance of normal LVEF.21 Afterload mismatch occurs in the context of ‘inadequate compensatory’ LV hypertrophy, resulting in an increased wall stress and reduced LVEF.21 Despite an impaired pre-operative LVEF, these patients often recover their LV function after aortic valve replacement.20 However, LV concentric hypertrophy is not compensatory in all patients as some may develop a true depression of myocardial contractility in response to the chronic pressure overload. The mechanism underlying the contractile dysfunction is likely to be multifactorial, ranging from reduced subendocardial perfusion with concomitant increase in myocardial oxygen consumption, neurohumoral upregulation, myocytes degeneration, and eventual replacement fibrosis.5,22–24 Importantly, it is now recognized that early subtle myocardial contractile dysfunction may be present in AS patients despite a normal LVEF.7 Accordingly, Hein et al.24 reported increased interstitial myocardial fibrosis in patients with AS and normal LVEF. Similarly, Weidemann et al.5 reported increased myocardial fibrosis and impaired longitudinal systolic function in patients with symptomatic severe AS that failed to improve at 9 months follow-up after surgical aortic valve replacement. Finally, a recent study demonstrated that the presence of late-gadolinium enhancement on cardiac magnetic resonance imaging (reflecting replacement fibrosis) was predictive of mortality in severe AS patients undergoing aortic valve replacement.25 Previous studies have demonstrated LV diastolic dysfunction in AS patients.26,27 Compared with LVEF, LV GLS by 2D speckle tracking is a more sensitive measure of systolic function and permits identification of patients with underlying impaired myocardial function due to increased fibrosis despite normal LVEF.7 Furthermore, the present study showed that LV GLS was independently associated with all-cause mortality in a large cohort of AS patients with a wide range of LVEF. There are two recent studies that demonstrated LV stroke volume index, as a marker of LV systolic function, is prognostic for all-cause mortality in severe AS patients.28,29 However, both studies did not evaluate the prognostic value of LV GLS. In the present study, we demonstrated only LV GLS was independently associated with all-cause mortality when LV stroke volume was forced into the multivariable Cox regression model. Prognostic value of GLS We have previously demonstrated a progressive decline in longitudinal myocardial function in patients with increasing AS severity despite the presence of a normal LVEF.7 Although 2D speckle tracking LV GLS analysis is a more sensitive measure of myocardial systolic function than LVEF, its prognostic value in all AS patients with a wide range of LVEF was unclear. Several recent studies have attempted to evaluate the prognostic value of LV GLS in severe AS patients with normal LVEF.9–11,30 The largest published study to date by Kusunose et al.30 included 161 severe AS patients, and demonstrated that LV GLS was an independent determinant of mortality in patients with normal LVEF. By virtue of their study design, the results cannot be generalized to AS patients with impaired LVEF. Two small studies specifically evaluated the prognostic value of LV GLS in AS patients with impaired LVEF.8,12 Dahou et al.12 included 126 severe AS patients and demonstrated that both rest and stress LV GLS were independent determinants of mortality on multivariable analyses. In contrast, Bartko et al.8 included only 47 AS patients with impaired LVEF (≤40%) and could not demonstrate an independent association between LV GLS and other variables with mortality outcomes. However, both study patients were derived from the same multicentre True or Pseudo-Severe Aortic Stenosis (TOPAS) study cohorts.8,12 In contrast, the present study is the largest to date to include 688 AS patients, of which 294 patients had severe AS. It also included patients with a wide range of LVEF and AS severity, and is first to demonstrate LV GLS as an independent determinant of all-cause mortality and was a superior prognosticator compared with LVEF. Furthermore, the present study also further risk stratified severe AS patients with normal LVEF into those with and without evidence of subclinical myocardial dysfunction based on the median LV GLS. These two groups were compared with AS patients with an impaired LVEF. Consistent with previous publications, severe AS patients with impaired LVEF had significantly higher all-cause mortality compared with patients with normal LVEF.20 However, the present study is first to demonstrate that severe AS patients with normal LVEF but ‘impaired’ LV GLS had similar increased all-cause mortality risk as patients with impaired LVEF. Clinical implications Patients with severe AS and impaired LVEF have a dismal prognosis without aortic valve replacement.31 Previous study has demonstrated severe AS patients have evidence of macroscopic myocardial fibrosis on delayed contrast-enhanced magnetic resonance imaging that persists after aortic valve replacement.5 Therefore, detection of subtle myocardial dysfunction by speckle tracking echocardiography may permit earlier identification of patients at risk of irreversible myocardial damage. The present study is the largest to date to demonstrate the independent prognostic value of LV GLS in patients with AS, and it is superior to LVEF as a prognosticator. Furthermore, patients with severe AS with normal LVEF but ‘impaired’ LV GLS had similar poor long term prognosis as severe AS patients with impaired LVEF. Patients with ‘impaired’ LV GLS had an increased mortality risk, independent of LVEF and AS severity. This may have implications on the optimal timing of aortic valve replacement in patients with severe AS. Study limitations The present study was a single centre retrospective study. The number of patients with asymptomatic severe AS was relatively low and precluded us to perform a multivariable Cox proportional hazard model analysis to assess the prognostic influence of LV GLS in this specific subpopulation. Sub-analyses based on cardiovascular and non-cardiovascular mortality were not performed. Finally, by virtue of the study design, there were no data on rate of AS progression on prognosis. Conclusions Left ventricular GLS is an independent and superior prognosticator compared with LVEF in patients with AS. Severe AS patients with normal LVEF may have evidence of myocardial dysfunction, and have increased mortality risk similar to that of severe AS patients with impaired LVEF. Therefore, LV GLS can further risk stratify severe AS patients and may influence the optimal timing of aortic valve replacement. Conflict of interest: The department of Cardiology of Leiden University Medical Centre received grants from Biotronik, Medtronic, Boston Scientific Corporation and Edwards Lifesciences. The remaining authors have no conflicts of interest to disclose. Reference 1 Iung B , Baron G , Butchart EG , Delahaye F , Gohlke-Barwolf C , Levang OW et al. A prospective survey of patients with valvular heart disease in Europe: the Euro Heart Survey on Valvular Heart Disease . Eur Heart J 2003 ; 24 : 1231 – 43 . Google Scholar CrossRef Search ADS PubMed 2 Pellikka PA , Sarano ME , Nishimura RA , Malouf JF , Bailey KR , Scott CG et al. Outcome of 622 adults with asymptomatic, hemodynamically significant aortic stenosis during prolonged follow-up . Circulation 2005 ; 111 : 3290 – 5 . Google Scholar CrossRef Search ADS PubMed 3 Rosenhek R , Binder T , Porenta G , Lang I , Christ G , Schemper M et al. Predictors of outcome in severe, asymptomatic aortic stenosis . N Engl J Med 2000 ; 343 : 611 – 7 . Google Scholar CrossRef Search ADS PubMed 4 Krayenbuehl H , Hess OM , Ritter M , Monrad ES , Hoppeler H. Left ventricular systolic function in aortic stenosis . Eur Heart J 1988 ; 9(Suppl. E) : 19 – 23 . Google Scholar CrossRef Search ADS PubMed 5 Weidemann F , Herrmann S , Stork S , Niemann M , Frantz S , Lange V et al. Impact of myocardial fibrosis in patients with symptomatic severe aortic stenosis . Circulation 2009 ; 120 : 577 – 84 . Google Scholar CrossRef Search ADS PubMed 6 Nishimura RA , Otto CM , Bonow RO , Carabello BA , Erwin JP III , Guyton RA et al. 2014 AHA/ACC Guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines . Circulation 2014 ; 129 : e521 – 643 . Google Scholar CrossRef Search ADS PubMed 7 Ng AC , Delgado V , Bertini M , Antoni ML , van Bommel RJ , van Rijnsoever EP et al. Alterations in multidirectional myocardial functions in patients with aortic stenosis and preserved ejection fraction: a two-dimensional speckle tracking analysis . Eur Heart J 2011 ; 32 : 1542 – 50 . Google Scholar CrossRef Search ADS PubMed 8 Bartko PE , Heinze G , Graf S , Clavel MA , Khorsand A , Bergler-Klein J et al. Two-dimensional strain for the assessment of left ventricular function in low flow-low gradient aortic stenosis, relationship to hemodynamics, and outcome: a substudy of the multicenter TOPAS study . Circ Cardiovasc Imaging 2013 ; 6 : 268 – 76 . Google Scholar CrossRef Search ADS PubMed 9 Yingchoncharoen T , Gibby C , Rodriguez LL , Grimm RA , Marwick TH. Association of myocardial deformation with outcome in asymptomatic aortic stenosis with normal ejection fraction . Circ Cardiovasc Imaging 2012 ; 5 : 719 – 25 . Google Scholar CrossRef Search ADS PubMed 10 Kearney LG , Lu K , Ord M , Patel SK , Profitis K , Matalanis G et al. Global longitudinal strain is a strong independent predictor of all-cause mortality in patients with aortic stenosis . Eur Heart J Cardiovasc Imaging 2012 ; 13 : 827 – 33 . Google Scholar CrossRef Search ADS PubMed 11 Lee HF , Hsu LA , Chan YH , Wang CL , Chang CJ , Kuo CT. Prognostic value of global left ventricular strain for conservatively treated patients with symptomatic aortic stenosis . J Cardiol 2013 ; 62 : 301 – 6 . Google Scholar CrossRef Search ADS PubMed 12 Dahou A , Bartko PE , Capoulade R , Clavel MA , Mundigler G , Grondin SL et al. Usefulness of global left ventricular longitudinal strain for risk stratification in low ejection fraction, low-gradient aortic stenosis: results from the multicenter True or Pseudo-Severe Aortic Stenosis study . Circ Cardiovasc Imaging 2015 ; 8 : e002117. Google Scholar CrossRef Search ADS PubMed 13 Baumgartner H , Hung J , Bermejo J , Chambers JB , Evangelista A , Griffin BP et al. Echocardiographic assessment of valve stenosis: EAE/ASE recommendations for clinical practice . Eur J Echocardiogr 2009 ; 10 : 1 – 25 . Google Scholar CrossRef Search ADS PubMed 14 Lang RM , Badano LP , Mor-Avi V , Afilalo J , Armstrong A , Ernande L et al. Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging . Eur Heart J Cardiovasc Imaging 2015 ; 16 : 233 – 70 . Google Scholar CrossRef Search ADS PubMed 15 Ng ACT , Delgado V , Bertini M , van der Meer RW , Rijzewijk LJ , Shanks M et al. Findings from left ventricular strain and strain rate imaging in asymptomatic patients with type 2 diabetes mellitus . Am J Cardiol 2009 ; 104 : 1398 – 401 . Google Scholar CrossRef Search ADS PubMed 16 Kaplan E , Meier P. Nonparametric estimation from incomplete observations . J Am Stat Assoc 1958 ; 53 : 457 – 81 . Google Scholar CrossRef Search ADS 17 Cox D. Regression models and life-tables . J R Stat Soc 1972 ; 34 : 187 – 220 . 18 Vahanian A , Alfieri O , Andreotti F , Antunes MJ , Baron-Esquivias G , Baumgartner H et al. Guidelines on the management of valvular heart disease (version 2012) . Eur Heart J 2012 ; 33 : 2451 – 96 . Google Scholar CrossRef Search ADS PubMed 19 Dal-Bianco JP , Khandheria BK , Mookadam F , Gentile F , Sengupta PP. Management of asymptomatic severe aortic stenosis . J Am Coll Cardiol 2008 ; 52 : 1279 – 92 . Google Scholar CrossRef Search ADS PubMed 20 Carabello BA , Green LH , Grossman W , Cohn LH , Koster JK , Collins JJ Jr. Hemodynamic determinants of prognosis of aortic valve replacement in critical aortic stenosis and advanced congestive heart failure . Circulation 1980 ; 62 : 42 – 8 . Google Scholar CrossRef Search ADS PubMed 21 Carabello BA , Paulus WJ. Aortic stenosis . Lancet 2009 ; 373 : 956 – 66 . Google Scholar CrossRef Search ADS PubMed 22 Marcus ML , Doty DB , Hiratzka LF , Wright CB , Eastham CL. Decreased coronary reserve: a mechanism for angina pectoris in patients with aortic stenosis and normal coronary arteries . N Engl J Med 1982 ; 307 : 1362 – 6 . Google Scholar CrossRef Search ADS PubMed 23 Rajappan K , Rimoldi OE , Dutka DP , Ariff B , Pennell DJ , Sheridan DJ et al. Mechanisms of coronary microcirculatory dysfunction in patients with aortic stenosis and angiographically normal coronary arteries . Circulation 2002 ; 105 : 470 – 6 . Google Scholar CrossRef Search ADS PubMed 24 Hein S , Arnon E , Kostin S , Schonburg M , Elsasser A , Polyakova V et al. Progression from compensated hypertrophy to failure in the pressure-overloaded human heart: structural deterioration and compensatory mechanisms . Circulation 2003 ; 107 : 984 – 91 . Google Scholar CrossRef Search ADS PubMed 25 Barone-Rochette G , Pierard S , De Meester de RC , Seldrum S , Melchior J , Maes F et al. Prognostic significance of LGE by CMR in aortic stenosis patients undergoing valve replacement . J Am Coll Cardiol 2014 ; 64 : 144 – 54 . Google Scholar CrossRef Search ADS PubMed 26 Dahl JS , Barros-Gomes S , Videbaek L , Poulsen MK , Issa IF , Carter-Storch R et al. Early diastolic strain rate in relation to systolic and diastolic function and prognosis in aortic stenosis . JACC Cardiovasc Imaging 2016 ; 9 : 519 – 28 . Google Scholar CrossRef Search ADS PubMed 27 Popovic ZB , Cremer PC. Assessing diastology in aortic stenosis: should we stress about strain rate? JACC Cardiovasc Imaging 2016 ; 9 : 529 – 31 . Google Scholar CrossRef Search ADS PubMed 28 Capoulade R , Le Ven F , Clavel MA , Dumesnil JG , Dahou A , Thebault C et al. Echocardiographic predictors of outcomes in adults with aortic stenosis . Heart 2016 ; 102 : 934 – 42 . Google Scholar CrossRef Search ADS PubMed 29 Lonnebakken MT , de Simone G , Saeed S , Boman K , Rossebo AB , Bahlmann E et al. Impact of stroke volume on cardiovascular risk during progression of aortic valve stenosis . Heart 2017 ; doi: 10.1136/heartjnl-2016-310917. 30 Kusunose K , Goodman A , Parikh R , Barr T , Agarwal S , Popovic ZB et al. Incremental prognostic value of left ventricular global longitudinal strain in patients with aortic stenosis and preserved ejection fraction . Circ Cardiovasc Imaging 2014 ; 7 : 938 – 45 . Google Scholar CrossRef Search ADS PubMed 31 Pereira JJ , Lauer MS , Bashir M , Afridi I , Blackstone EH , Stewart WJ et al. Survival after aortic valve replacement for severe aortic stenosis with low transvalvular gradients and severe left ventricular dysfunction . J Am Coll Cardiol 2002 ; 39 : 1356 – 63 . Google Scholar CrossRef Search ADS PubMed Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. 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Left ventricular global longitudinal strain is predictive of all-cause mortality independent of aortic stenosis severity and ejection fraction

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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions, please email: journals.permissions@oup.com.
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Abstract

Abstract Aims Left ventricular (LV) global longitudinal strain (GLS) may identify subclinical myocardial dysfunction in patients with aortic stenosis (AS). The aims of the present retrospective single centre study were to determine the independent prognostic value of LV GLS over LV ejection fraction (EF) and the role of LV GLS to further risk stratify severe AS patients before aortic valve replacement. Methods and results A total of 688 patients (median age 72 years, 61.2% men) with mild (n = 130), moderate (n = 264) and severe AS (n = 294) were included. LV GLS was determined by 2D speckle tracking echocardiography. A total of 114 (16.6%) patients died before surgery during the study. When patients with severe AS and normal LVEF were dichotomized based on the median LV GLS value (−14.0%), patients with normal LVEF and ‘preserved’ LV GLS of ≤ −14% had significantly higher survival than patients with ‘impaired’ LV GLS of > −14%. There was no difference in survival between patients with normal LVEF but ‘impaired’ LV GLS ( > −14%) and patients with impaired LVEF (log-rank P = 0.34). LV GLS was independently associated with all-cause mortality on multivariable Cox regression analysis (hazard ratio 1.17, 95% confidence interval 1.09–1.26; P < 0.001). Conclusion LV GLS is independently associated with all-cause mortality in AS patients. It can further risk stratify severe AS patients and may influence the optimal timing of aortic valve replacement. left ventricle, aortic stenosis, prognosis Introduction Aortic stenosis (AS) is one of the most common valvular heart diseases in the general population.1 Often, prognosis for symptomatic severe AS is poor without surgery. Known predictors of poor outcome include older age, significant valvular calcification, rapid hemodynamic progression and impaired left ventricular (LV) ejection fraction (EF).2,3 Often, patients can develop impaired LVEF due to afterload mismatch4 or from true depression of myocardial contractility due to myocardial fibrosis.5 Upon development of an overtly impaired LVEF, aortic valve replacement is associated with higher operative risk and may be less beneficial in cases where the LV dysfunction is not due to afterload mismatch.6 However, conventional measures of global LV systolic function such as LVEF can be preserved until end-stage disease due to development of concentric hypertrophy, and thus lacks accuracy in identifying subtle changes in myocardial contractility. We previously demonstrated that 2D-LV global longitudinal strain (GLS) can detect early subtle myocardial dysfunction in AS patients.7 Although subsequent studies have evaluated the prognostic value of LV GLS in AS patients, they were variously limited by relatively small number of patients with severe AS, few mortality endpoints and short follow-up duration.8–12 In addition, majority of these studies recruited patients with preserved LVEF (≥50%),9–11 whereas only two small studies specifically recruited patients with LVEF ≤ 40%.8,12 Therefore, it is unclear if LV GLS can risk stratify all patients independent of AS severity and LVEF, and identify subgroups of severe AS patients who might benefit from early aortic valve replacement. Hence, the aims of the present study were to examine the independent prognostic value of LV GLS in a large cohort of AS patients with a wide range of LVEF, and determine if LV GLS can further risk stratify severe AS patients before aortic valve replacement. Methods Patient population From the departmental echocardiographic database, patients with the diagnosis of AS between November 1997 and September 2009 were identified. Patients with echocardiographic data allowing offline 2D speckle tracking analysis were selected, leaving 688 patients with AS in this retrospective analysis. All patients underwent clinical history, physical examination, and transthoracic echocardiography. Exclusion criteria included rhythm other than sinus rhythm, moderate or severe coexisting aortic regurgitation, moderate or severe mitral regurgitation, subvalvular or supravalvular AS, dynamic subaortic obstruction, and active endocarditis. All clinical data were prospectively entered in the departmental Cardiology Information System (EPD-Vision®, Leiden University Medical Center). Baseline clinical variables recorded included AS symptom status, New York Heart Association (NYHA) functional class, cardiac risk factors, and medications. Echocardiographic variables recorded included aortic valve area, mean transvalvular gradient, and peak jet velocity, LV volumes, LVEF, wall motion score index, and LV GLS. AS severity was classified into mild, moderate, and severe based on the calculated aortic valve area, mean gradient, and peak velocity as recommended by the European Association of Echocardiography and American Society of Echocardiography.13 All patients were followed up after the baseline echocardiographic examination for the occurrence of aortic valve replacement and death. To determine if LV GLS is associated with all-cause mortality before aortic valve replacement, patients were censored at the time of surgery or transcatheter aortic valve replacement. The prognostic significance of AS severity was first explored by stratifying all AS patients into three groups of mild, moderate, and severe AS. Next, the prognostic value of LVEF was explored by dichotomizing all severe AS patients into two groups based on the presence of normal (≥55%) vs. impaired (<55%) LVEF. Current guidelines define abnormal LVEF as <52% in men and <54% in women based on two standard deviations from the mean.14 For simplicity, the authors defined abnormal LVEF as <55% in all patients in the current study. As patients with impaired LVEF already have reduced LV GLS, the additional incremental prognostic value of LV GLS in severe AS patients with normal LVEF was explored by dichotomizing them into two groups based on the median LV GLS value (−14%). Thus, three groups of severe AS patients were identified and compared: Group 1—normal LVEF with ‘preserved’ LV GLS of ≤ −14%; Group 2—normal LVEF and ‘impaired’ LV GLS of > −14%; and Group 3—impaired LVEF. Finally, the independent prognostic value of LV GLS was determined in multivariable analyses with significant clinical and echocardiographic associates entered as covariates. Echocardiography Transthoracic echocardiography was performed with the subjects at rest using commercially available ultrasound systems (System 5 and Vivid 7, GE-Vingmed, Horten, Norway). All images were digitally stored on hard disks for offline analysis (EchoPAC version 108.1.5, GE-Vingmed, Horten, Norway). A complete 2D, colour, pulsed and continuous-wave Doppler echocardiogram was performed. LV end-diastolic volume index and end-systolic volume index were calculated using Simpson’s biplane method of discs and corrected for body surface area. LVEF was calculated and expressed as a percentage. LV mass index was calculated from the formula as recommended by the American Society of Echocardiography and the European Association of Cardiovascular Imaging.14 Wall motion was assessed using the 16 myocardial segment model as recommended by the American Society of Echocardiography and European Association of Cardiovascular Imaging.14 Briefly, the LV was divided into 12 basal and mid (septal, anteroseptal, anterior, lateral, posterior, inferior) segments and 4 (septal, anterior, lateral, inferior) apical segments. A semi-quantitative scoring system (1 = normal; 2 = hypokinesia; 3 = akinesia; 4 = dyskinesia) was used to analyse each segment, and a global wall motion score index was calculated according to standard formula.14 Definition of AS and classification of its severity were based on recommendations by the European Association of Echocardiography and American Society of Echocardiography.13 Briefly, severe AS was defined as peak velocity > 4.0 m/s, mean gradient > 40 mmHg, or aortic valve area < 1.0cm2; moderate AS was defined as peak velocity 3.0–4.0 m/s, mean gradient 30–40 mmHg, or aortic valve area 1.0–1.5 cm2; and mild AS was defined as peak velocity 2.6–2.9 m/s, mean gradient < 20 mmHg or aortic valve area > 1.5cm2.13 Aortic valve area calculation was performed by the continuity equation using velocity time integrals of the aorta and LV outflow tract.13 Peak and mean aortic transvalvular gradients were calculated using the modified Bernoulli equation. Mitral inflow velocities were recorded using conventional pulsed-wave Doppler echocardiography in the apical 4-chamber view using a 2 mm sample volume. Transmitral early (E wave) and late (A wave) diastolic velocities as well as deceleration time were recorded at the mitral leaflet tips. The pulmonary venous flow velocities were recorded with the sample volume positioned 1 cm below the orifice of the right superior pulmonary vein in the left atrium. The peak systolic (S) and peak diastolic (D) venous flow velocities were recorded. 2D speckle tracking Previous work from our laboratory has demonstrated early impairment in LV GLS in patients with AS which progressively worsened with increasing AS severity.7 In contrast, short-axis LV circumferential and radial functions were preserved until the latter stages of severity.7 Thus, the prognostic value of LV GLS for survival was examined in the present study. To quantify LV GLS, 2D speckle tracking analyses were performed on standard routine grey scale images of the apical 2-, 3-, and 4-chamber views. During analysis, the endocardial border was manually traced at end-systole and the region of interest width adjusted to include the entire myocardium. The software then automatically tracks and accepts segments of good tracking quality and rejects poorly tracked segments, while allowing the observer to manually override its decisions based on visual assessments of tracking quality. Mean LV GLS was calculated from the three individual apical GLS curves. LV diastolic function was presented as mean LV global early diastolic strain rate velocity (SRe). All strain and SRe measurements were exported to a spreadsheet (Microsoft ® Excel 2002, Microsoft Corporation, Redmond, WA, USA). The intra- and inter-observer variabilities (expressed as mean absolute difference ± 1 standard deviation and intraclass correlation coefficient) for LV GLS were 1.2 ± 0.5% and 0.939 and 0.9 ± 1.0% and 0.942, respectively.15 Follow-up and outcome definition All patients were clinically followed up for the occurrence of aortic valve replacement and death. The primary outcome was all-cause mortality after diagnosis of AS starting from baseline echocardiography and up to last follow-up (censored at time of aortic valve replacement). Patient death was ascertained by using data linkages with the governmental death registry database. Statistical analysis All continuous variables were tested for Gaussian distribution using the Kolmogorov–Smirnov test for normality. Normally distributed variables were presented as mean ± 1 standard deviation and non-normally distributed variables were presented as median and interquartile ranges (IQR). Categorical variables were presented as frequencies and percentages, and were compared using χ2 test. Unpaired Student’s t-test and Mann–Whitney U test were used to compare two groups of continuous variables of Gaussian and non-Gaussian distribution, respectively. One-way analysis of variance and Kruskal–Wallis H-tests were used to compare three groups of continuous variables of Gaussian and non-Gaussian distribution, respectively, and multiple comparisons for significant results were performed with Bonferroni corrections. Cumulative event rates were calculated using the Kaplan–Meier method and between group comparisons were made using the log rank tests with respect to the primary outcome of all-cause mortality.16 Cumulative survival rates were presented as a percentage and standard error (SE). Multivariate Cox proportional-hazards models were then constructed to identify independent clinical and echocardiographic associates of the all-cause mortality with significant univariate variables entered as covariates.17 The Cox proportional-hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for all independent predictors of all-cause mortality. To avoid multicollinearity between the univariate predictors, a tolerance level of > 0.5 was set. Validity of the Cox regression assumption of proportionality was confirmed for all continuous covariates by scaled Schoenfeld residuals. For categorical variables, the assumption of proportionality was confirmed by log minus log plots. Harrell’s C-statistic was used to compare the incremental prognostic value of LV GLS associated with all-cause mortality in the multivariable Cox regression model for severe AS patients. A two-tailed P-value of < 0.05 was considered significant. All statistical analyses were performed using SPSS for Windows (SPSS Inc, Chicago, IL, USA), version 17, and Stata version 10.1 (StataCorp LP, TX, USA). Results There were a total of 688 patients (61.2% men) with a median age of 72 years (IQR 63–79 years). Tables 1and2 summarize the clinical and echocardiographic characteristics of the patients. A respective 130 (18.9%), 264 (38.4%), and 294 (42.7%) patients had mild, moderate, and severe AS. The mechanisms underlying AS were degenerative in 90.7%, congenital in 6.1%, rheumatic in 1.7%, and uncertain in 1.5%. Patients with severe AS were more likely to be older (P < 0.001) and at a worse NYHA functional class (P < 0.001). There were no significant differences in the usage of cardiac medications between the three groups. Patients with severe AS had significantly larger LV volumes, higher LV mass index, and more impaired LV GLS. Table 1 Clinical characteristics of the total population and according to aortic stenosis severity Variable Total population (n = 688) Mild aortic stenosis (n = 130) Moderate aortic stenosis (n = 264) Severe aortic stenosis (n = 294) P-valuea Demographic characteristics  Age (years) 72 (63, 79) 71 (62, 77) 71 (60, 78) 74 (66, 80)b <0.001  Male gender (%) 61.2 62.3 62.9 59.2 0.64  Body mass index (kg/m2) 25.9 ± 4.1 26.1 ± 4.6 26.3 ± 4.2 25.5 ± 3.7 0.08  Body surface area (m2) 1.89 ± 0.21 1.90 ± 0.22 1.90 ± 0.21 1.86 ± 0.20b 0.03 Medical history  New York Heart Association class (%) <0.001   I 55.2 78.0 60.7 41.3   II 22.5 11.9 22.6 26.5   III 21.2 10.1 15.6 30.7   IV 1.1 0 1.1 1.5  Hypertension (%) 52.4 50.9 52.7 52.8 0.94  Diabetes (%) 17.6 18.4 14.9 19.8 0.32  Hyperlipidaemia (%) 28.6 22.7 28.8 30.9 0.28  Previous myocardial infarction (%) 13.6 13.0 10.3 16.8 0.08  Systolic blood pressure (mmHg) 145 ± 25 148 ± 28 145 ± 24 144 ± 25 0.41  Diastolic blood pressure (mmHg) 80 ± 13 81 ± 13 81 ± 13 79 ± 13 0.32 Medications  Beta-blocker (%) 39.1 37.5 36.9 41.8 0.48  Calcium channel blockers (%) 21.5 23.2 25.0 17.5 0.09  ACE inhibitor/ARB (%) 40.8 39.3 41.9 40.4 0.88  Diuretic (%) 29.6 23.2 29.3 32.5 0.19  Statins (%) 40.3 32.1 40.4 43.6 0.11 Variable Total population (n = 688) Mild aortic stenosis (n = 130) Moderate aortic stenosis (n = 264) Severe aortic stenosis (n = 294) P-valuea Demographic characteristics  Age (years) 72 (63, 79) 71 (62, 77) 71 (60, 78) 74 (66, 80)b <0.001  Male gender (%) 61.2 62.3 62.9 59.2 0.64  Body mass index (kg/m2) 25.9 ± 4.1 26.1 ± 4.6 26.3 ± 4.2 25.5 ± 3.7 0.08  Body surface area (m2) 1.89 ± 0.21 1.90 ± 0.22 1.90 ± 0.21 1.86 ± 0.20b 0.03 Medical history  New York Heart Association class (%) <0.001   I 55.2 78.0 60.7 41.3   II 22.5 11.9 22.6 26.5   III 21.2 10.1 15.6 30.7   IV 1.1 0 1.1 1.5  Hypertension (%) 52.4 50.9 52.7 52.8 0.94  Diabetes (%) 17.6 18.4 14.9 19.8 0.32  Hyperlipidaemia (%) 28.6 22.7 28.8 30.9 0.28  Previous myocardial infarction (%) 13.6 13.0 10.3 16.8 0.08  Systolic blood pressure (mmHg) 145 ± 25 148 ± 28 145 ± 24 144 ± 25 0.41  Diastolic blood pressure (mmHg) 80 ± 13 81 ± 13 81 ± 13 79 ± 13 0.32 Medications  Beta-blocker (%) 39.1 37.5 36.9 41.8 0.48  Calcium channel blockers (%) 21.5 23.2 25.0 17.5 0.09  ACE inhibitor/ARB (%) 40.8 39.3 41.9 40.4 0.88  Diuretic (%) 29.6 23.2 29.3 32.5 0.19  Statins (%) 40.3 32.1 40.4 43.6 0.11 ACE, angiotensin-converting enzyme; ANOVA, analysis of variance; ARB, angiotensin receptor blocker. a P-value by ANOVA and Kruskal–Wallis H test for continuous variables of Gaussian and non-Gaussian distribution respectively, and by χ2 test for categorical variables. b P-value < 0.05 vs. preceding aortic stenosis severity with Bonferroni corrections for multiple pairwise comparisons. Table 1 Clinical characteristics of the total population and according to aortic stenosis severity Variable Total population (n = 688) Mild aortic stenosis (n = 130) Moderate aortic stenosis (n = 264) Severe aortic stenosis (n = 294) P-valuea Demographic characteristics  Age (years) 72 (63, 79) 71 (62, 77) 71 (60, 78) 74 (66, 80)b <0.001  Male gender (%) 61.2 62.3 62.9 59.2 0.64  Body mass index (kg/m2) 25.9 ± 4.1 26.1 ± 4.6 26.3 ± 4.2 25.5 ± 3.7 0.08  Body surface area (m2) 1.89 ± 0.21 1.90 ± 0.22 1.90 ± 0.21 1.86 ± 0.20b 0.03 Medical history  New York Heart Association class (%) <0.001   I 55.2 78.0 60.7 41.3   II 22.5 11.9 22.6 26.5   III 21.2 10.1 15.6 30.7   IV 1.1 0 1.1 1.5  Hypertension (%) 52.4 50.9 52.7 52.8 0.94  Diabetes (%) 17.6 18.4 14.9 19.8 0.32  Hyperlipidaemia (%) 28.6 22.7 28.8 30.9 0.28  Previous myocardial infarction (%) 13.6 13.0 10.3 16.8 0.08  Systolic blood pressure (mmHg) 145 ± 25 148 ± 28 145 ± 24 144 ± 25 0.41  Diastolic blood pressure (mmHg) 80 ± 13 81 ± 13 81 ± 13 79 ± 13 0.32 Medications  Beta-blocker (%) 39.1 37.5 36.9 41.8 0.48  Calcium channel blockers (%) 21.5 23.2 25.0 17.5 0.09  ACE inhibitor/ARB (%) 40.8 39.3 41.9 40.4 0.88  Diuretic (%) 29.6 23.2 29.3 32.5 0.19  Statins (%) 40.3 32.1 40.4 43.6 0.11 Variable Total population (n = 688) Mild aortic stenosis (n = 130) Moderate aortic stenosis (n = 264) Severe aortic stenosis (n = 294) P-valuea Demographic characteristics  Age (years) 72 (63, 79) 71 (62, 77) 71 (60, 78) 74 (66, 80)b <0.001  Male gender (%) 61.2 62.3 62.9 59.2 0.64  Body mass index (kg/m2) 25.9 ± 4.1 26.1 ± 4.6 26.3 ± 4.2 25.5 ± 3.7 0.08  Body surface area (m2) 1.89 ± 0.21 1.90 ± 0.22 1.90 ± 0.21 1.86 ± 0.20b 0.03 Medical history  New York Heart Association class (%) <0.001   I 55.2 78.0 60.7 41.3   II 22.5 11.9 22.6 26.5   III 21.2 10.1 15.6 30.7   IV 1.1 0 1.1 1.5  Hypertension (%) 52.4 50.9 52.7 52.8 0.94  Diabetes (%) 17.6 18.4 14.9 19.8 0.32  Hyperlipidaemia (%) 28.6 22.7 28.8 30.9 0.28  Previous myocardial infarction (%) 13.6 13.0 10.3 16.8 0.08  Systolic blood pressure (mmHg) 145 ± 25 148 ± 28 145 ± 24 144 ± 25 0.41  Diastolic blood pressure (mmHg) 80 ± 13 81 ± 13 81 ± 13 79 ± 13 0.32 Medications  Beta-blocker (%) 39.1 37.5 36.9 41.8 0.48  Calcium channel blockers (%) 21.5 23.2 25.0 17.5 0.09  ACE inhibitor/ARB (%) 40.8 39.3 41.9 40.4 0.88  Diuretic (%) 29.6 23.2 29.3 32.5 0.19  Statins (%) 40.3 32.1 40.4 43.6 0.11 ACE, angiotensin-converting enzyme; ANOVA, analysis of variance; ARB, angiotensin receptor blocker. a P-value by ANOVA and Kruskal–Wallis H test for continuous variables of Gaussian and non-Gaussian distribution respectively, and by χ2 test for categorical variables. b P-value < 0.05 vs. preceding aortic stenosis severity with Bonferroni corrections for multiple pairwise comparisons. Table 2 Echocardiographic characteristics of the total population and according to aortic stenosis severity Variable Total population (n = 688) Mild aortic stenosis (n = 130) Moderate aortic stenosis (n = 264) Severe aortic stenosis (n = 294) P-valuea Heart rate (beats/min) 72.2 ± 12.9 72.4 ± 15.0 72.3 ± 12.8 74.5 ± 14.1 0.15 AVA (cm2) 1.09 (0.82, 1.40) 1.74 (1.62, 1.96) 1.22 (1.12, 1.36)b 0.78 (0.64, 0.90)b <0.001 Mean gradient (mmHg) 25.0 (15.3, 40.8) 12.1 (9.4, 16.1) 21.2 (15.1, 28.7)b 41.0 (31.2, 51.6)b <0.001 Peak gradient (mmHg) 41.3 (25.7, 64.9) 21.4 (17.0, 27.4) 35.0 (25.1, 48.2)b 65.8 (51.0, 82.5)b <0.001 LV mass index (g/m2) 119.1 (97.5, 146.9) 110.1 (97.5, 127.3) 107.3 (92.7, 131.7) 133.8 (110.0, 160.8)b <0.001 LVEDVI (mL/m2) 51.3 (41.7, 63.1) 46.9 (39.2, 58.3) 50.3 (40.7, 59.4) 53.9 (44.1, 69.0)b <0.001 LVESVI (mL/m2) 20.5 (16.1, 27.1) 19.1 (14.9, 24.6) 19.7 (15.4, 25.0) 22.7 (17.0, 31.5)b <0.001 LVEF (%) 58.7 (53.4, 63.8) 59.9 (54.9, 63.5) 60.0 (54.7, 64.4) 57.3 (51.2, 62.9)b <0.001 LVEF < 55% (%) 32.8 26.2 27.7 40.5b 0.001 Stroke volume index (mL/m2) 42.9 ± 11.4 48.7 ± 13.0 44.8 ± 9.9b 38.7 ± 10.4b <0.001 Wall motion score index 1.07 ± 0.24 1.01 ± 0.11 1.04 ± 0.15 1.18 ± 0.39b <0.001 Transmitral E/A ratio 0.94 ± 0.49 0.90 ± 0.44 0.93 ± 0.38 1.05 ± 0.74b 0.01 Transmitral deceleration time (ms) 240 ± 88 242 ± 86 232 ± 79 233 ± 92 0.52 Pulmonary S/D ratio 1.41 ± 0.44 1.46 ± 0.46 1.43 ± 0.42 1.36 ± 0.47 0.10 Septal E’ velocity (cm/s) 4.52 ± 1.96 4.82 ± 1.67 4.89 ± 1.95 4.00 ± 2.00b <0.001 Septal E/e’ ratio 19.4 ± 12.0 16.4 ± 7.3 16.7 ± 8.1 23.8 ± 15.5b <0.001 Left atrial volume index (mL/m2) 35.4 ± 15.1 32.5 ± 13.0 32.1 ± 13.3 39.7 ± 16.5b <0.001 LV GLS (%) −15.8 ± 3.1 −18.2 ± 2.1 −16.4 ± 2.3b −13.3 ± 3.7b <0.001 LV global longitudinal SRe (s−1) 0.82 ± 0.30 0.99 ± 0.31 0.88 ± 0.26b 0.69 ± 0.26b <0.001 Variable Total population (n = 688) Mild aortic stenosis (n = 130) Moderate aortic stenosis (n = 264) Severe aortic stenosis (n = 294) P-valuea Heart rate (beats/min) 72.2 ± 12.9 72.4 ± 15.0 72.3 ± 12.8 74.5 ± 14.1 0.15 AVA (cm2) 1.09 (0.82, 1.40) 1.74 (1.62, 1.96) 1.22 (1.12, 1.36)b 0.78 (0.64, 0.90)b <0.001 Mean gradient (mmHg) 25.0 (15.3, 40.8) 12.1 (9.4, 16.1) 21.2 (15.1, 28.7)b 41.0 (31.2, 51.6)b <0.001 Peak gradient (mmHg) 41.3 (25.7, 64.9) 21.4 (17.0, 27.4) 35.0 (25.1, 48.2)b 65.8 (51.0, 82.5)b <0.001 LV mass index (g/m2) 119.1 (97.5, 146.9) 110.1 (97.5, 127.3) 107.3 (92.7, 131.7) 133.8 (110.0, 160.8)b <0.001 LVEDVI (mL/m2) 51.3 (41.7, 63.1) 46.9 (39.2, 58.3) 50.3 (40.7, 59.4) 53.9 (44.1, 69.0)b <0.001 LVESVI (mL/m2) 20.5 (16.1, 27.1) 19.1 (14.9, 24.6) 19.7 (15.4, 25.0) 22.7 (17.0, 31.5)b <0.001 LVEF (%) 58.7 (53.4, 63.8) 59.9 (54.9, 63.5) 60.0 (54.7, 64.4) 57.3 (51.2, 62.9)b <0.001 LVEF < 55% (%) 32.8 26.2 27.7 40.5b 0.001 Stroke volume index (mL/m2) 42.9 ± 11.4 48.7 ± 13.0 44.8 ± 9.9b 38.7 ± 10.4b <0.001 Wall motion score index 1.07 ± 0.24 1.01 ± 0.11 1.04 ± 0.15 1.18 ± 0.39b <0.001 Transmitral E/A ratio 0.94 ± 0.49 0.90 ± 0.44 0.93 ± 0.38 1.05 ± 0.74b 0.01 Transmitral deceleration time (ms) 240 ± 88 242 ± 86 232 ± 79 233 ± 92 0.52 Pulmonary S/D ratio 1.41 ± 0.44 1.46 ± 0.46 1.43 ± 0.42 1.36 ± 0.47 0.10 Septal E’ velocity (cm/s) 4.52 ± 1.96 4.82 ± 1.67 4.89 ± 1.95 4.00 ± 2.00b <0.001 Septal E/e’ ratio 19.4 ± 12.0 16.4 ± 7.3 16.7 ± 8.1 23.8 ± 15.5b <0.001 Left atrial volume index (mL/m2) 35.4 ± 15.1 32.5 ± 13.0 32.1 ± 13.3 39.7 ± 16.5b <0.001 LV GLS (%) −15.8 ± 3.1 −18.2 ± 2.1 −16.4 ± 2.3b −13.3 ± 3.7b <0.001 LV global longitudinal SRe (s−1) 0.82 ± 0.30 0.99 ± 0.31 0.88 ± 0.26b 0.69 ± 0.26b <0.001 AVA, aortic valve area; ANOVA, analysis of variance; EDVI, end-diastolic volume index; EF, ejection fraction; ESVI, end-systolic volume index; GLS, global longitudinal strain; LV, left ventricular; SRe, early diastolic strain rate velocity; ANOVA, analysis of variance. a P-value by ANOVA and Kruskal–Wallis H test for continuous variables of Gaussian and non-Gaussian distribution respectively, and χ2 for categorical variable. b P-value < 0.05 vs. preceding aortic stenosis severity with Bonferroni corrections. Table 2 Echocardiographic characteristics of the total population and according to aortic stenosis severity Variable Total population (n = 688) Mild aortic stenosis (n = 130) Moderate aortic stenosis (n = 264) Severe aortic stenosis (n = 294) P-valuea Heart rate (beats/min) 72.2 ± 12.9 72.4 ± 15.0 72.3 ± 12.8 74.5 ± 14.1 0.15 AVA (cm2) 1.09 (0.82, 1.40) 1.74 (1.62, 1.96) 1.22 (1.12, 1.36)b 0.78 (0.64, 0.90)b <0.001 Mean gradient (mmHg) 25.0 (15.3, 40.8) 12.1 (9.4, 16.1) 21.2 (15.1, 28.7)b 41.0 (31.2, 51.6)b <0.001 Peak gradient (mmHg) 41.3 (25.7, 64.9) 21.4 (17.0, 27.4) 35.0 (25.1, 48.2)b 65.8 (51.0, 82.5)b <0.001 LV mass index (g/m2) 119.1 (97.5, 146.9) 110.1 (97.5, 127.3) 107.3 (92.7, 131.7) 133.8 (110.0, 160.8)b <0.001 LVEDVI (mL/m2) 51.3 (41.7, 63.1) 46.9 (39.2, 58.3) 50.3 (40.7, 59.4) 53.9 (44.1, 69.0)b <0.001 LVESVI (mL/m2) 20.5 (16.1, 27.1) 19.1 (14.9, 24.6) 19.7 (15.4, 25.0) 22.7 (17.0, 31.5)b <0.001 LVEF (%) 58.7 (53.4, 63.8) 59.9 (54.9, 63.5) 60.0 (54.7, 64.4) 57.3 (51.2, 62.9)b <0.001 LVEF < 55% (%) 32.8 26.2 27.7 40.5b 0.001 Stroke volume index (mL/m2) 42.9 ± 11.4 48.7 ± 13.0 44.8 ± 9.9b 38.7 ± 10.4b <0.001 Wall motion score index 1.07 ± 0.24 1.01 ± 0.11 1.04 ± 0.15 1.18 ± 0.39b <0.001 Transmitral E/A ratio 0.94 ± 0.49 0.90 ± 0.44 0.93 ± 0.38 1.05 ± 0.74b 0.01 Transmitral deceleration time (ms) 240 ± 88 242 ± 86 232 ± 79 233 ± 92 0.52 Pulmonary S/D ratio 1.41 ± 0.44 1.46 ± 0.46 1.43 ± 0.42 1.36 ± 0.47 0.10 Septal E’ velocity (cm/s) 4.52 ± 1.96 4.82 ± 1.67 4.89 ± 1.95 4.00 ± 2.00b <0.001 Septal E/e’ ratio 19.4 ± 12.0 16.4 ± 7.3 16.7 ± 8.1 23.8 ± 15.5b <0.001 Left atrial volume index (mL/m2) 35.4 ± 15.1 32.5 ± 13.0 32.1 ± 13.3 39.7 ± 16.5b <0.001 LV GLS (%) −15.8 ± 3.1 −18.2 ± 2.1 −16.4 ± 2.3b −13.3 ± 3.7b <0.001 LV global longitudinal SRe (s−1) 0.82 ± 0.30 0.99 ± 0.31 0.88 ± 0.26b 0.69 ± 0.26b <0.001 Variable Total population (n = 688) Mild aortic stenosis (n = 130) Moderate aortic stenosis (n = 264) Severe aortic stenosis (n = 294) P-valuea Heart rate (beats/min) 72.2 ± 12.9 72.4 ± 15.0 72.3 ± 12.8 74.5 ± 14.1 0.15 AVA (cm2) 1.09 (0.82, 1.40) 1.74 (1.62, 1.96) 1.22 (1.12, 1.36)b 0.78 (0.64, 0.90)b <0.001 Mean gradient (mmHg) 25.0 (15.3, 40.8) 12.1 (9.4, 16.1) 21.2 (15.1, 28.7)b 41.0 (31.2, 51.6)b <0.001 Peak gradient (mmHg) 41.3 (25.7, 64.9) 21.4 (17.0, 27.4) 35.0 (25.1, 48.2)b 65.8 (51.0, 82.5)b <0.001 LV mass index (g/m2) 119.1 (97.5, 146.9) 110.1 (97.5, 127.3) 107.3 (92.7, 131.7) 133.8 (110.0, 160.8)b <0.001 LVEDVI (mL/m2) 51.3 (41.7, 63.1) 46.9 (39.2, 58.3) 50.3 (40.7, 59.4) 53.9 (44.1, 69.0)b <0.001 LVESVI (mL/m2) 20.5 (16.1, 27.1) 19.1 (14.9, 24.6) 19.7 (15.4, 25.0) 22.7 (17.0, 31.5)b <0.001 LVEF (%) 58.7 (53.4, 63.8) 59.9 (54.9, 63.5) 60.0 (54.7, 64.4) 57.3 (51.2, 62.9)b <0.001 LVEF < 55% (%) 32.8 26.2 27.7 40.5b 0.001 Stroke volume index (mL/m2) 42.9 ± 11.4 48.7 ± 13.0 44.8 ± 9.9b 38.7 ± 10.4b <0.001 Wall motion score index 1.07 ± 0.24 1.01 ± 0.11 1.04 ± 0.15 1.18 ± 0.39b <0.001 Transmitral E/A ratio 0.94 ± 0.49 0.90 ± 0.44 0.93 ± 0.38 1.05 ± 0.74b 0.01 Transmitral deceleration time (ms) 240 ± 88 242 ± 86 232 ± 79 233 ± 92 0.52 Pulmonary S/D ratio 1.41 ± 0.44 1.46 ± 0.46 1.43 ± 0.42 1.36 ± 0.47 0.10 Septal E’ velocity (cm/s) 4.52 ± 1.96 4.82 ± 1.67 4.89 ± 1.95 4.00 ± 2.00b <0.001 Septal E/e’ ratio 19.4 ± 12.0 16.4 ± 7.3 16.7 ± 8.1 23.8 ± 15.5b <0.001 Left atrial volume index (mL/m2) 35.4 ± 15.1 32.5 ± 13.0 32.1 ± 13.3 39.7 ± 16.5b <0.001 LV GLS (%) −15.8 ± 3.1 −18.2 ± 2.1 −16.4 ± 2.3b −13.3 ± 3.7b <0.001 LV global longitudinal SRe (s−1) 0.82 ± 0.30 0.99 ± 0.31 0.88 ± 0.26b 0.69 ± 0.26b <0.001 AVA, aortic valve area; ANOVA, analysis of variance; EDVI, end-diastolic volume index; EF, ejection fraction; ESVI, end-systolic volume index; GLS, global longitudinal strain; LV, left ventricular; SRe, early diastolic strain rate velocity; ANOVA, analysis of variance. a P-value by ANOVA and Kruskal–Wallis H test for continuous variables of Gaussian and non-Gaussian distribution respectively, and χ2 for categorical variable. b P-value < 0.05 vs. preceding aortic stenosis severity with Bonferroni corrections. Survival outcome for all patients A total of 114 (16.6%) patients died before aortic valve replacement after a median follow-up duration of 8.2 months (IQR 1.9–23.9 months). Of those patients who died, 54 patients had severe AS. The cumulative survival for patients with mild/moderate AS at 6 months and 1 year were 96.9% (SE 1.0%) and 92.8% (SE 1.5%), respectively. In contrast, the cumulative survival for patients with severe AS at 6 months and 1 year were 88.6% (SE 2.4%) and 83.1% (SE 3.3%), respectively (both log rank P < 0.001 vs. moderate and mild AS). LVEF and LV GLS in severe AS To determine if LV GLS can further risk stratify severe AS patients, all patients with severe AS were initially dichotomized based on the presence of normal (≥55%) vs. impaired (<55%) LVEF (Figure 1). Of the 294 patients with severe AS in the study, 176 (59.9%) had normal LVEF on echocardiography. Severe AS patients with impaired LVEF had significantly higher all-cause mortality compared with patients normal LVEF (log rank P = 0.006). Figure 1 View largeDownload slide Flow chart outlining patients with severe AS divided into three groups based on LVEF and LV GLS. Figure 1 View largeDownload slide Flow chart outlining patients with severe AS divided into three groups based on LVEF and LV GLS. Next, all 176 patients with severe AS and normal LVEF were further dichotomized into two groups based on the median value of LV GLS of −14.0%. Thus, three groups of severe AS patients were identified: 88 (29.9%) patients with normal LVEF and ‘preserved’ LV GLS (≤−14%), 88 (29.9%) patients with normal LVEF but ‘impaired’ LV GLS (>−14%), and 118 (40.1%) patients with impaired LVEF (Figure 1). Tables 3 and 4 summarize the clinical and echocardiographic characteristics of the three groups of severe AS patients. The median LVEF for these three groups were 63.0% (IQR 59.7–67.4%), 59.5% (IQR 57.6–64.4%), and 47.5% (IQR 33.9–52.5%), respectively, (P < 0.001). Similarly, their mean LV GLS values were −17.0 ± 1.6%, −13.2 ± 1.8%, and −10.7 ± 3.6%, respectively, (P < 0.001) (Table 4). Table 3 Clinical characteristics of patients with severe aortic stenosis Variable Normal EF ‘Preserved’ LV GLS ( ≤ −14%) (n = 88) Normal EF ‘Impaired’ LV GLS ( > −14%) (n = 88) Impaired LVEF (n = 118) P-valuea Demographic characteristics  Age (years) 71 (62, 80) 76 (67, 80) 76 (67, 81) 0.13  Male gender (%) 51.1 51.1 71.2 0.003  Body mass index (kg/m2) 25.7 ± 3.8 25.1 ± 3.7 25.7 ± 3.8 0.42  Body surface area (m2) 1.85 ± 0.18 1.83 ± 0.21 1.89 ± 0.19 0.11 Medical history  New York Heart Association class (%) 0.043   I 50.6 34.2 39.3   II 31.0 27.8 22.2   III 18.4 36.7 35.9   IV 0 1.3 2.6  Hypertension (%) 55.3 54.2 50.0 0.73  Diabetes (%) 15.3 22.2 21.4 0.46  Hyperlipidaemia (%) 41.7 23.7 27.7 0.031  Previous myocardial infarction (%) 11.6 9.9 25.4 0.005  Systolic blood pressure (mmHg) 147 ± 25 148 ± 26 139 ± 24 0.024  Diastolic blood pressure (mmHg) 80 ± 13 80 ± 13 78 ± 12 0.36 Medications  Beta-blocker (%) 54.8 41.3 32.8 0.008  Calcium channel blockers (%) 13.1 20.0 19.0 0.44  ACE inhibitor/ARB (%) 46.4 37.5 37.9 0.40  Diuretic (%) 21.4 35.0 38.8 0.030  Statins (%) 48.8 37.5 44.0 0.34 Variable Normal EF ‘Preserved’ LV GLS ( ≤ −14%) (n = 88) Normal EF ‘Impaired’ LV GLS ( > −14%) (n = 88) Impaired LVEF (n = 118) P-valuea Demographic characteristics  Age (years) 71 (62, 80) 76 (67, 80) 76 (67, 81) 0.13  Male gender (%) 51.1 51.1 71.2 0.003  Body mass index (kg/m2) 25.7 ± 3.8 25.1 ± 3.7 25.7 ± 3.8 0.42  Body surface area (m2) 1.85 ± 0.18 1.83 ± 0.21 1.89 ± 0.19 0.11 Medical history  New York Heart Association class (%) 0.043   I 50.6 34.2 39.3   II 31.0 27.8 22.2   III 18.4 36.7 35.9   IV 0 1.3 2.6  Hypertension (%) 55.3 54.2 50.0 0.73  Diabetes (%) 15.3 22.2 21.4 0.46  Hyperlipidaemia (%) 41.7 23.7 27.7 0.031  Previous myocardial infarction (%) 11.6 9.9 25.4 0.005  Systolic blood pressure (mmHg) 147 ± 25 148 ± 26 139 ± 24 0.024  Diastolic blood pressure (mmHg) 80 ± 13 80 ± 13 78 ± 12 0.36 Medications  Beta-blocker (%) 54.8 41.3 32.8 0.008  Calcium channel blockers (%) 13.1 20.0 19.0 0.44  ACE inhibitor/ARB (%) 46.4 37.5 37.9 0.40  Diuretic (%) 21.4 35.0 38.8 0.030  Statins (%) 48.8 37.5 44.0 0.34 ACE, angiotensin-converting enzyme; ANOVA, analysis of variance; ARB, angiotensin receptor blocker; EF, ejection fraction; GLS, global longitudinal strain; LV, left ventricular. a P-value by ANOVA and Kruskal–Wallis H test for continuous variables of Gaussian and non-Gaussian distribution respectively, and by χ2 test for categorical variables. Table 3 Clinical characteristics of patients with severe aortic stenosis Variable Normal EF ‘Preserved’ LV GLS ( ≤ −14%) (n = 88) Normal EF ‘Impaired’ LV GLS ( > −14%) (n = 88) Impaired LVEF (n = 118) P-valuea Demographic characteristics  Age (years) 71 (62, 80) 76 (67, 80) 76 (67, 81) 0.13  Male gender (%) 51.1 51.1 71.2 0.003  Body mass index (kg/m2) 25.7 ± 3.8 25.1 ± 3.7 25.7 ± 3.8 0.42  Body surface area (m2) 1.85 ± 0.18 1.83 ± 0.21 1.89 ± 0.19 0.11 Medical history  New York Heart Association class (%) 0.043   I 50.6 34.2 39.3   II 31.0 27.8 22.2   III 18.4 36.7 35.9   IV 0 1.3 2.6  Hypertension (%) 55.3 54.2 50.0 0.73  Diabetes (%) 15.3 22.2 21.4 0.46  Hyperlipidaemia (%) 41.7 23.7 27.7 0.031  Previous myocardial infarction (%) 11.6 9.9 25.4 0.005  Systolic blood pressure (mmHg) 147 ± 25 148 ± 26 139 ± 24 0.024  Diastolic blood pressure (mmHg) 80 ± 13 80 ± 13 78 ± 12 0.36 Medications  Beta-blocker (%) 54.8 41.3 32.8 0.008  Calcium channel blockers (%) 13.1 20.0 19.0 0.44  ACE inhibitor/ARB (%) 46.4 37.5 37.9 0.40  Diuretic (%) 21.4 35.0 38.8 0.030  Statins (%) 48.8 37.5 44.0 0.34 Variable Normal EF ‘Preserved’ LV GLS ( ≤ −14%) (n = 88) Normal EF ‘Impaired’ LV GLS ( > −14%) (n = 88) Impaired LVEF (n = 118) P-valuea Demographic characteristics  Age (years) 71 (62, 80) 76 (67, 80) 76 (67, 81) 0.13  Male gender (%) 51.1 51.1 71.2 0.003  Body mass index (kg/m2) 25.7 ± 3.8 25.1 ± 3.7 25.7 ± 3.8 0.42  Body surface area (m2) 1.85 ± 0.18 1.83 ± 0.21 1.89 ± 0.19 0.11 Medical history  New York Heart Association class (%) 0.043   I 50.6 34.2 39.3   II 31.0 27.8 22.2   III 18.4 36.7 35.9   IV 0 1.3 2.6  Hypertension (%) 55.3 54.2 50.0 0.73  Diabetes (%) 15.3 22.2 21.4 0.46  Hyperlipidaemia (%) 41.7 23.7 27.7 0.031  Previous myocardial infarction (%) 11.6 9.9 25.4 0.005  Systolic blood pressure (mmHg) 147 ± 25 148 ± 26 139 ± 24 0.024  Diastolic blood pressure (mmHg) 80 ± 13 80 ± 13 78 ± 12 0.36 Medications  Beta-blocker (%) 54.8 41.3 32.8 0.008  Calcium channel blockers (%) 13.1 20.0 19.0 0.44  ACE inhibitor/ARB (%) 46.4 37.5 37.9 0.40  Diuretic (%) 21.4 35.0 38.8 0.030  Statins (%) 48.8 37.5 44.0 0.34 ACE, angiotensin-converting enzyme; ANOVA, analysis of variance; ARB, angiotensin receptor blocker; EF, ejection fraction; GLS, global longitudinal strain; LV, left ventricular. a P-value by ANOVA and Kruskal–Wallis H test for continuous variables of Gaussian and non-Gaussian distribution respectively, and by χ2 test for categorical variables. Table 4 Echocardiographic characteristics of patients with severe aortic stenosis Variable Normal EF ‘Preserved’ LV GLS ( ≤ −14%) (n = 88) Normal EF ‘Impaired’ LV GLS ( > −14%) (n = 88) Impaired LVEF (n = 118) P-valuea Heart rate (beats/min) 70.2 ± 12.6 73.0 ± 12.0 78.7 ± 15.6bc <0.001 AVA (cm2) 0.84 (0.75, 0.93) 0.75 (0.62, 0.86)b 0.74 (0.59, 0.87)b <0.001 Mean gradient (mmHg) 42.3 (36.6, 54.3) 46.4 (32.5, 56.4) 35.8 (24.4, 45.7)bc <0.001 Peak gradient (mmHg) 69.9 (57.5, 85.6) 72.3 (54.9, 87.0) 58.5 (40.4, 70.9)bc <0.001 LV mass index (g/m2) 120.0 (93.6, 141.3) 129.2 (108.2, 160.8)b 150.6 (124.1, 170.6)bc <0.001 LVEDVI (mL/m2) 48.6 (39.9, 55.7) 49.6 (40.7, 59.6) 69.1 (54.2, 94.5)bc <0.001 LVESVI (mL/m2) 17.8 (14.2, 22.2) 19.4 (15.9, 23.0) 36.8 (26.5, 60.0)bc <0.001 LVEF (%) 63.0 (59.7, 67.4) 59.5 (57.6, 64.4)b 47.5 (33.9, 52.5)bc <0.001 Stroke volume index (mL/m2) 46.1 ± 7.8 39.4 ± 8.9b 32.8 ± 9.6bc <0.001 Wall motion score index 1.01 ± 0.04 1.02 ± 0.13 1.44 ± 0.50bc <0.001 Transmitral E/A ratio 0.91 ± 0.50 1.00 ± 0.81 1.21 ± 0.83b 0.02 Transmitral deceleration time (ms) 252 ± 83 244 ± 78 209 ± 104bc 0.002 Pulmonary S/D ratio 1.45 ± 0.32 1.45 ± 0.47 1.20 ± 0.55bc 0.001 Septal E’ velocity (cm/s) 4.46 ± 2.25 4.02 ± 1.87 3.63 ± 1.84b 0.03 Septal E/e’ ratio 21.3 ± 11.2 25.4 ± 21.7 24.8 ± 12.7 0.25 Left atrial volume index (mL/m2) 36.6 ± 14.8 40.0 ± 18.1 41.7 ± 16.4 0.12 LV GLS (%) −17.0 ± 1.6 −13.2 ± 1.8b −10.7 ± 3.6bc <0.001 LV global longitudinal SRe (s−1) 0.84 ± 0.24 0.65 ± 0.24b 0.60 ± 0.24bc <0.001 Variable Normal EF ‘Preserved’ LV GLS ( ≤ −14%) (n = 88) Normal EF ‘Impaired’ LV GLS ( > −14%) (n = 88) Impaired LVEF (n = 118) P-valuea Heart rate (beats/min) 70.2 ± 12.6 73.0 ± 12.0 78.7 ± 15.6bc <0.001 AVA (cm2) 0.84 (0.75, 0.93) 0.75 (0.62, 0.86)b 0.74 (0.59, 0.87)b <0.001 Mean gradient (mmHg) 42.3 (36.6, 54.3) 46.4 (32.5, 56.4) 35.8 (24.4, 45.7)bc <0.001 Peak gradient (mmHg) 69.9 (57.5, 85.6) 72.3 (54.9, 87.0) 58.5 (40.4, 70.9)bc <0.001 LV mass index (g/m2) 120.0 (93.6, 141.3) 129.2 (108.2, 160.8)b 150.6 (124.1, 170.6)bc <0.001 LVEDVI (mL/m2) 48.6 (39.9, 55.7) 49.6 (40.7, 59.6) 69.1 (54.2, 94.5)bc <0.001 LVESVI (mL/m2) 17.8 (14.2, 22.2) 19.4 (15.9, 23.0) 36.8 (26.5, 60.0)bc <0.001 LVEF (%) 63.0 (59.7, 67.4) 59.5 (57.6, 64.4)b 47.5 (33.9, 52.5)bc <0.001 Stroke volume index (mL/m2) 46.1 ± 7.8 39.4 ± 8.9b 32.8 ± 9.6bc <0.001 Wall motion score index 1.01 ± 0.04 1.02 ± 0.13 1.44 ± 0.50bc <0.001 Transmitral E/A ratio 0.91 ± 0.50 1.00 ± 0.81 1.21 ± 0.83b 0.02 Transmitral deceleration time (ms) 252 ± 83 244 ± 78 209 ± 104bc 0.002 Pulmonary S/D ratio 1.45 ± 0.32 1.45 ± 0.47 1.20 ± 0.55bc 0.001 Septal E’ velocity (cm/s) 4.46 ± 2.25 4.02 ± 1.87 3.63 ± 1.84b 0.03 Septal E/e’ ratio 21.3 ± 11.2 25.4 ± 21.7 24.8 ± 12.7 0.25 Left atrial volume index (mL/m2) 36.6 ± 14.8 40.0 ± 18.1 41.7 ± 16.4 0.12 LV GLS (%) −17.0 ± 1.6 −13.2 ± 1.8b −10.7 ± 3.6bc <0.001 LV global longitudinal SRe (s−1) 0.84 ± 0.24 0.65 ± 0.24b 0.60 ± 0.24bc <0.001 ANOVA, analysis of variance; AVA, aortic valve area; EDVI, end-diastolic volume index; EF, ejection fraction; ESVI, end-systolic volume index; GLS, global longitudinal strain; LV, left ventricular; SRe, early diastolic strain rate velocity. a P-value by ANOVA and Kruskal–Wallis H test for continuous variables of Gaussian and non-Gaussian distribution respectively. b P-value < 0.05 vs. severe AS patients with normal LVEF and ‘preserved’ LV GLS with Bonferroni corrections. c P-value < 0.05 vs. severe AS patients with normal LVEF but ‘impaired’ LV GLS with Bonferroni corrections. Table 4 Echocardiographic characteristics of patients with severe aortic stenosis Variable Normal EF ‘Preserved’ LV GLS ( ≤ −14%) (n = 88) Normal EF ‘Impaired’ LV GLS ( > −14%) (n = 88) Impaired LVEF (n = 118) P-valuea Heart rate (beats/min) 70.2 ± 12.6 73.0 ± 12.0 78.7 ± 15.6bc <0.001 AVA (cm2) 0.84 (0.75, 0.93) 0.75 (0.62, 0.86)b 0.74 (0.59, 0.87)b <0.001 Mean gradient (mmHg) 42.3 (36.6, 54.3) 46.4 (32.5, 56.4) 35.8 (24.4, 45.7)bc <0.001 Peak gradient (mmHg) 69.9 (57.5, 85.6) 72.3 (54.9, 87.0) 58.5 (40.4, 70.9)bc <0.001 LV mass index (g/m2) 120.0 (93.6, 141.3) 129.2 (108.2, 160.8)b 150.6 (124.1, 170.6)bc <0.001 LVEDVI (mL/m2) 48.6 (39.9, 55.7) 49.6 (40.7, 59.6) 69.1 (54.2, 94.5)bc <0.001 LVESVI (mL/m2) 17.8 (14.2, 22.2) 19.4 (15.9, 23.0) 36.8 (26.5, 60.0)bc <0.001 LVEF (%) 63.0 (59.7, 67.4) 59.5 (57.6, 64.4)b 47.5 (33.9, 52.5)bc <0.001 Stroke volume index (mL/m2) 46.1 ± 7.8 39.4 ± 8.9b 32.8 ± 9.6bc <0.001 Wall motion score index 1.01 ± 0.04 1.02 ± 0.13 1.44 ± 0.50bc <0.001 Transmitral E/A ratio 0.91 ± 0.50 1.00 ± 0.81 1.21 ± 0.83b 0.02 Transmitral deceleration time (ms) 252 ± 83 244 ± 78 209 ± 104bc 0.002 Pulmonary S/D ratio 1.45 ± 0.32 1.45 ± 0.47 1.20 ± 0.55bc 0.001 Septal E’ velocity (cm/s) 4.46 ± 2.25 4.02 ± 1.87 3.63 ± 1.84b 0.03 Septal E/e’ ratio 21.3 ± 11.2 25.4 ± 21.7 24.8 ± 12.7 0.25 Left atrial volume index (mL/m2) 36.6 ± 14.8 40.0 ± 18.1 41.7 ± 16.4 0.12 LV GLS (%) −17.0 ± 1.6 −13.2 ± 1.8b −10.7 ± 3.6bc <0.001 LV global longitudinal SRe (s−1) 0.84 ± 0.24 0.65 ± 0.24b 0.60 ± 0.24bc <0.001 Variable Normal EF ‘Preserved’ LV GLS ( ≤ −14%) (n = 88) Normal EF ‘Impaired’ LV GLS ( > −14%) (n = 88) Impaired LVEF (n = 118) P-valuea Heart rate (beats/min) 70.2 ± 12.6 73.0 ± 12.0 78.7 ± 15.6bc <0.001 AVA (cm2) 0.84 (0.75, 0.93) 0.75 (0.62, 0.86)b 0.74 (0.59, 0.87)b <0.001 Mean gradient (mmHg) 42.3 (36.6, 54.3) 46.4 (32.5, 56.4) 35.8 (24.4, 45.7)bc <0.001 Peak gradient (mmHg) 69.9 (57.5, 85.6) 72.3 (54.9, 87.0) 58.5 (40.4, 70.9)bc <0.001 LV mass index (g/m2) 120.0 (93.6, 141.3) 129.2 (108.2, 160.8)b 150.6 (124.1, 170.6)bc <0.001 LVEDVI (mL/m2) 48.6 (39.9, 55.7) 49.6 (40.7, 59.6) 69.1 (54.2, 94.5)bc <0.001 LVESVI (mL/m2) 17.8 (14.2, 22.2) 19.4 (15.9, 23.0) 36.8 (26.5, 60.0)bc <0.001 LVEF (%) 63.0 (59.7, 67.4) 59.5 (57.6, 64.4)b 47.5 (33.9, 52.5)bc <0.001 Stroke volume index (mL/m2) 46.1 ± 7.8 39.4 ± 8.9b 32.8 ± 9.6bc <0.001 Wall motion score index 1.01 ± 0.04 1.02 ± 0.13 1.44 ± 0.50bc <0.001 Transmitral E/A ratio 0.91 ± 0.50 1.00 ± 0.81 1.21 ± 0.83b 0.02 Transmitral deceleration time (ms) 252 ± 83 244 ± 78 209 ± 104bc 0.002 Pulmonary S/D ratio 1.45 ± 0.32 1.45 ± 0.47 1.20 ± 0.55bc 0.001 Septal E’ velocity (cm/s) 4.46 ± 2.25 4.02 ± 1.87 3.63 ± 1.84b 0.03 Septal E/e’ ratio 21.3 ± 11.2 25.4 ± 21.7 24.8 ± 12.7 0.25 Left atrial volume index (mL/m2) 36.6 ± 14.8 40.0 ± 18.1 41.7 ± 16.4 0.12 LV GLS (%) −17.0 ± 1.6 −13.2 ± 1.8b −10.7 ± 3.6bc <0.001 LV global longitudinal SRe (s−1) 0.84 ± 0.24 0.65 ± 0.24b 0.60 ± 0.24bc <0.001 ANOVA, analysis of variance; AVA, aortic valve area; EDVI, end-diastolic volume index; EF, ejection fraction; ESVI, end-systolic volume index; GLS, global longitudinal strain; LV, left ventricular; SRe, early diastolic strain rate velocity. a P-value by ANOVA and Kruskal–Wallis H test for continuous variables of Gaussian and non-Gaussian distribution respectively. b P-value < 0.05 vs. severe AS patients with normal LVEF and ‘preserved’ LV GLS with Bonferroni corrections. c P-value < 0.05 vs. severe AS patients with normal LVEF but ‘impaired’ LV GLS with Bonferroni corrections. Figure 2 shows that severe AS patients with normal LVEF and ‘preserved’ LV GLS had significantly lower all-cause mortality compared with patients with normal LVEF but ‘impaired’ LV GLS (log rank P = 0.024) and patients with impaired LVEF (log rank P = 0.001). There was no significant difference in survival between severe AS patients with normal LVEF but ‘impaired’ LV GLS and patients with impaired LVEF (log rank P = 0.34). The cumulative survival for severe AS patients with normal LVEF and ‘preserved’ LV GLS at 6 months and 1 year were 98.2% (SE 1.8%) and 92.3% (SE 4.4%), respectively. The cumulative survival for severe AS patients with preserved LVEF but ‘impaired’ LV GLS at 6 months and 1 year were 84.7% (SE 5.5%) and 77.7% (SE 8.5%), respectively. Finally, the cumulative survival for severe AS patients with impaired LVEF at 6 months and 1 year were 83.2% (SE 4.3%) and 75.0% (SE 6.0%), respectively. Not unexpectedly due to the lower event rates in severe AS patients with normal LVEF and ‘preserved’ LV GLS, there was a difference in the follow up duration between the three groups of patients (P = 0.013 by Kruskal–Wallis H-test). Severe AS patients with normal LVEF and ‘preserved’ LV GLS had significantly longer follow up duration compared with patients with normal LVEF but ‘impaired’ LV GLS (P = 0.016 with Bonferroni correction) and against patients with impaired LVEF (P = 0.026 with Bonferroni correction). Figure 2 View largeDownload slide Kaplan–Meier estimates of cumulative survival in severe AS patients with impaired LVEF, normal LVEF with ‘impaired’ LV GLS ( > −14%), and normal LVEF with ‘preserved’ LV GLS ( ≤ −14%). Patients with normal LVEF and ‘preserved’ LV GLS had superior survival compared with patients with normal LVEF but ‘impaired’ LV GLS (log rank P = 0.007), and compared with patients with impaired LVEF (log rank P < 0.001). There was no significant difference in survival between patients with impaired LVEF and patients with normal LVEF but ‘impaired’ LV GLS (log rank P = 0.42). Figure 2 View largeDownload slide Kaplan–Meier estimates of cumulative survival in severe AS patients with impaired LVEF, normal LVEF with ‘impaired’ LV GLS ( > −14%), and normal LVEF with ‘preserved’ LV GLS ( ≤ −14%). Patients with normal LVEF and ‘preserved’ LV GLS had superior survival compared with patients with normal LVEF but ‘impaired’ LV GLS (log rank P = 0.007), and compared with patients with impaired LVEF (log rank P < 0.001). There was no significant difference in survival between patients with impaired LVEF and patients with normal LVEF but ‘impaired’ LV GLS (log rank P = 0.42). Determinants of all-cause mortality in severe AS Table 5 outlines all significant univariable associates of all-cause mortality for patients with severe AS. Patients who died before aortic valve replacement were more likely to be older, male, had a higher LV mass index, larger LV volumes, lower LVEF and stroke volume index, and more impaired LV GLS. Since patients who develop symptomatic AS often undergo aortic valve replacement based on current guidelines recommendations,18 the presence or absence of symptoms was not significantly associated with all-cause mortality before aortic valve replacement (HR 0.91; 95% CI 0.52–1.59; P = 0.75). Table 5 Univariable and multivariable Cox proportional hazard models for all-cause mortality for severe aortic stenosis patients before aortic valve replacement surgery Variable Univariate Multivariatea HR (95% CI) P-value HR (95% CI) P-value Age 1.03 (1.00–1.06) 0.040 Male gender 1.92 (1.06–3.46) 0.031 Previous myocardial infarction 2.59 (1.43–4.71) 0.002 1.97 (1.05–3.69) 0.034 LV mass index (per 10g increase) 1.09 (1.02–1.17) 0.011 LVEDVI 1.01 (1.00–1.02) 0.023 LVESVI 1.02 (1.01–1.03) <0.001 LVEF 0.97 (0.95–0.98) <0.001 Stroke volume index 0.93 (0.91–0.96) <0.001 Wall motion score index (per 0.1 increase) 1.10 (1.04–1.16) 0.001 LV GLS (per 1% absolute change) 1.20 (1.12–1.28) <0.001 1.17 (1.09–1.26) <0.001 Variable Univariate Multivariatea HR (95% CI) P-value HR (95% CI) P-value Age 1.03 (1.00–1.06) 0.040 Male gender 1.92 (1.06–3.46) 0.031 Previous myocardial infarction 2.59 (1.43–4.71) 0.002 1.97 (1.05–3.69) 0.034 LV mass index (per 10g increase) 1.09 (1.02–1.17) 0.011 LVEDVI 1.01 (1.00–1.02) 0.023 LVESVI 1.02 (1.01–1.03) <0.001 LVEF 0.97 (0.95–0.98) <0.001 Stroke volume index 0.93 (0.91–0.96) <0.001 Wall motion score index (per 0.1 increase) 1.10 (1.04–1.16) 0.001 LV GLS (per 1% absolute change) 1.20 (1.12–1.28) <0.001 1.17 (1.09–1.26) <0.001 CI, confidence interval; EDVI, end-diastolic volume index; EF, ejection fraction; ESVI, end-systolic volume index; GLS, global longitudinal strain; HR, hazard ratio; LV, ventricular. a Variables included in the multivariable Cox regression model included age, gender, previous history of myocardial infarction., LV mass index, LVESVI, WMSI, and LV GLS. Table 5 Univariable and multivariable Cox proportional hazard models for all-cause mortality for severe aortic stenosis patients before aortic valve replacement surgery Variable Univariate Multivariatea HR (95% CI) P-value HR (95% CI) P-value Age 1.03 (1.00–1.06) 0.040 Male gender 1.92 (1.06–3.46) 0.031 Previous myocardial infarction 2.59 (1.43–4.71) 0.002 1.97 (1.05–3.69) 0.034 LV mass index (per 10g increase) 1.09 (1.02–1.17) 0.011 LVEDVI 1.01 (1.00–1.02) 0.023 LVESVI 1.02 (1.01–1.03) <0.001 LVEF 0.97 (0.95–0.98) <0.001 Stroke volume index 0.93 (0.91–0.96) <0.001 Wall motion score index (per 0.1 increase) 1.10 (1.04–1.16) 0.001 LV GLS (per 1% absolute change) 1.20 (1.12–1.28) <0.001 1.17 (1.09–1.26) <0.001 Variable Univariate Multivariatea HR (95% CI) P-value HR (95% CI) P-value Age 1.03 (1.00–1.06) 0.040 Male gender 1.92 (1.06–3.46) 0.031 Previous myocardial infarction 2.59 (1.43–4.71) 0.002 1.97 (1.05–3.69) 0.034 LV mass index (per 10g increase) 1.09 (1.02–1.17) 0.011 LVEDVI 1.01 (1.00–1.02) 0.023 LVESVI 1.02 (1.01–1.03) <0.001 LVEF 0.97 (0.95–0.98) <0.001 Stroke volume index 0.93 (0.91–0.96) <0.001 Wall motion score index (per 0.1 increase) 1.10 (1.04–1.16) 0.001 LV GLS (per 1% absolute change) 1.20 (1.12–1.28) <0.001 1.17 (1.09–1.26) <0.001 CI, confidence interval; EDVI, end-diastolic volume index; EF, ejection fraction; ESVI, end-systolic volume index; GLS, global longitudinal strain; HR, hazard ratio; LV, ventricular. a Variables included in the multivariable Cox regression model included age, gender, previous history of myocardial infarction., LV mass index, LVESVI, WMSI, and LV GLS. Of the 294 severe AS patients, 222 patients (76%) underwent invasive coronary angiography. Of these 222 patients, 125 patients (56%) did not have obstructive disease as defined as > 50% stenosis. On multivariable analysis, the presence or absence of any obstructive coronary artery disease was not associated with all-cause mortality in severe AS patients before aortic valve replacement (P > 0.99). Similarly, the number of vessels with obstructive disease was also not a determinant of all-cause mortality in severe AS patients before aortic valve replacement (P = 0.96). To identify independent correlates of all-cause mortality on follow-up, significant univariable associates in Table 5 (age, gender, previous history of myocardial infarction, LV mass index, LV end-systolic volume index, wall motion score index, and LV GLS) were entered into the Cox proportional-hazard model as covariates. On multivariable analysis, previous myocardial infarction (HR 1.97; 95% CI 1.05–3.69; P = 0.034), and every 1% absolute worsening in LV GLS (HR 1.17; 95% CI 1.09–1.26; P < 0.001) were independently associated with increased all-cause mortality on follow-up for severe AS patients. Therefore, considering that LV GLS ranged from −2.9% to −22.3% in patients with severe AS in the present study, the odds that a patient with severe AS and LV GLS of −3% dying on follow-up is nearly 20 times higher compared with a patient with severe AS and LV GLS of −22%. The inclusion of LV GLS incrementally improved the multivariable Cox regression model’s discriminatory value by significantly increasing the Harrell’s C-statistic from 0.728 to 0.783, P = 0.003. To determine if LV stroke volume index was also independently associated with all-cause mortality on follow up, it was forced into the multivariable Cox regression model even though it was significantly correlated with LV GLS (r = −0.68, P < 0.001). However, the results did not change and only LV GLS, not LV stroke volume index, was independently associated with all-cause mortality in severe AS patients on follow-up. Discussion The present study demonstrated the independent prognostic value of LV GLS in a large cohort of patients with a wide range of LVEF and AS severity. LV GLS analysis was able to identify subtle myocardial dysfunction in patients with severe AS and normal LVEF, and could further risk stratify these patients into a higher mortality risk category equivalent to patients with severe AS and impaired LVEF. LV dysfunction in AS Degenerative calcific AS is a chronic progressive disease whose natural history is characterized by a prolonged latent period where patients remain relatively asymptomatic and has a low morbidity and mortality risk.2,19 However, upon development of symptomatic severe AS, the risk of sudden cardiac death increases and can occur even within months of symptom onset.2 Known determinants of poor outcome include older age, significant aortic valvular calcification, rapid hemodynamic progression, and an impaired LVEF.2,3,20 The development of an impaired LVEF in patients with severe AS can be due to either afterload mismatch or from a true depression of myocardial contractility.21 With progressive reduction in the aortic valve area, the resultant increase in afterload is usually accompanied by compensatory concentric LV hypertrophy. This results in normalization of LV wall stress and maintenance of normal LVEF.21 Afterload mismatch occurs in the context of ‘inadequate compensatory’ LV hypertrophy, resulting in an increased wall stress and reduced LVEF.21 Despite an impaired pre-operative LVEF, these patients often recover their LV function after aortic valve replacement.20 However, LV concentric hypertrophy is not compensatory in all patients as some may develop a true depression of myocardial contractility in response to the chronic pressure overload. The mechanism underlying the contractile dysfunction is likely to be multifactorial, ranging from reduced subendocardial perfusion with concomitant increase in myocardial oxygen consumption, neurohumoral upregulation, myocytes degeneration, and eventual replacement fibrosis.5,22–24 Importantly, it is now recognized that early subtle myocardial contractile dysfunction may be present in AS patients despite a normal LVEF.7 Accordingly, Hein et al.24 reported increased interstitial myocardial fibrosis in patients with AS and normal LVEF. Similarly, Weidemann et al.5 reported increased myocardial fibrosis and impaired longitudinal systolic function in patients with symptomatic severe AS that failed to improve at 9 months follow-up after surgical aortic valve replacement. Finally, a recent study demonstrated that the presence of late-gadolinium enhancement on cardiac magnetic resonance imaging (reflecting replacement fibrosis) was predictive of mortality in severe AS patients undergoing aortic valve replacement.25 Previous studies have demonstrated LV diastolic dysfunction in AS patients.26,27 Compared with LVEF, LV GLS by 2D speckle tracking is a more sensitive measure of systolic function and permits identification of patients with underlying impaired myocardial function due to increased fibrosis despite normal LVEF.7 Furthermore, the present study showed that LV GLS was independently associated with all-cause mortality in a large cohort of AS patients with a wide range of LVEF. There are two recent studies that demonstrated LV stroke volume index, as a marker of LV systolic function, is prognostic for all-cause mortality in severe AS patients.28,29 However, both studies did not evaluate the prognostic value of LV GLS. In the present study, we demonstrated only LV GLS was independently associated with all-cause mortality when LV stroke volume was forced into the multivariable Cox regression model. Prognostic value of GLS We have previously demonstrated a progressive decline in longitudinal myocardial function in patients with increasing AS severity despite the presence of a normal LVEF.7 Although 2D speckle tracking LV GLS analysis is a more sensitive measure of myocardial systolic function than LVEF, its prognostic value in all AS patients with a wide range of LVEF was unclear. Several recent studies have attempted to evaluate the prognostic value of LV GLS in severe AS patients with normal LVEF.9–11,30 The largest published study to date by Kusunose et al.30 included 161 severe AS patients, and demonstrated that LV GLS was an independent determinant of mortality in patients with normal LVEF. By virtue of their study design, the results cannot be generalized to AS patients with impaired LVEF. Two small studies specifically evaluated the prognostic value of LV GLS in AS patients with impaired LVEF.8,12 Dahou et al.12 included 126 severe AS patients and demonstrated that both rest and stress LV GLS were independent determinants of mortality on multivariable analyses. In contrast, Bartko et al.8 included only 47 AS patients with impaired LVEF (≤40%) and could not demonstrate an independent association between LV GLS and other variables with mortality outcomes. However, both study patients were derived from the same multicentre True or Pseudo-Severe Aortic Stenosis (TOPAS) study cohorts.8,12 In contrast, the present study is the largest to date to include 688 AS patients, of which 294 patients had severe AS. It also included patients with a wide range of LVEF and AS severity, and is first to demonstrate LV GLS as an independent determinant of all-cause mortality and was a superior prognosticator compared with LVEF. Furthermore, the present study also further risk stratified severe AS patients with normal LVEF into those with and without evidence of subclinical myocardial dysfunction based on the median LV GLS. These two groups were compared with AS patients with an impaired LVEF. Consistent with previous publications, severe AS patients with impaired LVEF had significantly higher all-cause mortality compared with patients with normal LVEF.20 However, the present study is first to demonstrate that severe AS patients with normal LVEF but ‘impaired’ LV GLS had similar increased all-cause mortality risk as patients with impaired LVEF. Clinical implications Patients with severe AS and impaired LVEF have a dismal prognosis without aortic valve replacement.31 Previous study has demonstrated severe AS patients have evidence of macroscopic myocardial fibrosis on delayed contrast-enhanced magnetic resonance imaging that persists after aortic valve replacement.5 Therefore, detection of subtle myocardial dysfunction by speckle tracking echocardiography may permit earlier identification of patients at risk of irreversible myocardial damage. The present study is the largest to date to demonstrate the independent prognostic value of LV GLS in patients with AS, and it is superior to LVEF as a prognosticator. Furthermore, patients with severe AS with normal LVEF but ‘impaired’ LV GLS had similar poor long term prognosis as severe AS patients with impaired LVEF. Patients with ‘impaired’ LV GLS had an increased mortality risk, independent of LVEF and AS severity. This may have implications on the optimal timing of aortic valve replacement in patients with severe AS. Study limitations The present study was a single centre retrospective study. The number of patients with asymptomatic severe AS was relatively low and precluded us to perform a multivariable Cox proportional hazard model analysis to assess the prognostic influence of LV GLS in this specific subpopulation. Sub-analyses based on cardiovascular and non-cardiovascular mortality were not performed. Finally, by virtue of the study design, there were no data on rate of AS progression on prognosis. Conclusions Left ventricular GLS is an independent and superior prognosticator compared with LVEF in patients with AS. Severe AS patients with normal LVEF may have evidence of myocardial dysfunction, and have increased mortality risk similar to that of severe AS patients with impaired LVEF. Therefore, LV GLS can further risk stratify severe AS patients and may influence the optimal timing of aortic valve replacement. Conflict of interest: The department of Cardiology of Leiden University Medical Centre received grants from Biotronik, Medtronic, Boston Scientific Corporation and Edwards Lifesciences. The remaining authors have no conflicts of interest to disclose. Reference 1 Iung B , Baron G , Butchart EG , Delahaye F , Gohlke-Barwolf C , Levang OW et al. A prospective survey of patients with valvular heart disease in Europe: the Euro Heart Survey on Valvular Heart Disease . Eur Heart J 2003 ; 24 : 1231 – 43 . Google Scholar CrossRef Search ADS PubMed 2 Pellikka PA , Sarano ME , Nishimura RA , Malouf JF , Bailey KR , Scott CG et al. Outcome of 622 adults with asymptomatic, hemodynamically significant aortic stenosis during prolonged follow-up . Circulation 2005 ; 111 : 3290 – 5 . 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For permissions, please email: journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

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European Heart Journal – Cardiovascular ImagingOxford University Press

Published: Jul 28, 2017

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