Echocardiographic reference ranges for normal left atrial function parameters: results from the EACVI NORRE study

Echocardiographic reference ranges for normal left atrial function parameters: results from the... Abstract Aims To obtain the normal ranges for echocardiographic measurements of left atrial (LA) function from a large group of healthy volunteers accounting for age and gender. Methods and results A total of 371 (median age 45 years) healthy subjects were enrolled at 22 collaborating institutions collaborating in the Normal Reference Ranges for Echocardiography (NORRE) study of the European Association of Cardiovascular Imaging (EACVI). Left atrial data sets were analysed with a vendor-independent software (VIS) package allowing homogeneous measurements irrespective of the echocardiographic equipment used to acquire data sets. The lowest expected values of LA function were 26.1%, 48.7%, and 41.4% for left atrial strain (LAS), 2D left atrial emptying fraction (LAEF), and 3D LAEF (reservoir function); 7.7%, 24.2%, and −0.53/s for LAS-active, LAEF-active, and LA strain rate during LA contraction (SRa) (pump function) and 12.0% and 21.6% for LAS-passive and LAEF-passive (conduit function). Left atrial reservoir and conduit function were decreased with age while pump function was increased. All indices of reservoir function and all LA strains had no difference in both gender and vendor. However, inter-vendor differences were observed in LA SRa despite the use of VIS. Conclusion The NORRE study provides contemporary, applicable echocardiographic reference ranges for LA function. Our data highlight the importance of age-specific reference values for LA functions. adult echocardiography, left atrial function, deformation imaging, reference values Introduction The left atrium is extremely sensitive to sustained volume and pressure overload secondary to increased left ventricular filling pressures,1 and the stepwise backward effects of loss in left atrial (LA) functional properties are a reduction in lung vessel compliance and vascular remodelling that trigger right ventricular overload and dysfunction.2 In contrast to left ventricular measures, there is a strong linear relationship between volumetric and longitudinal deformation indices of left atrium.3 Early detection of subclinical LA dysfunction plays a crucial role in the evaluation of many cardiac diseases.4–9 Although normal ranges of LA function have been reported in recent studies,10–13 age related normal references remain unknown. The Normal Reference Ranges for Echocardiography (NORRE) study is the first European, large, prospective, multicentre study performed in 22 laboratories accredited by the European Association of Cardiovascular Imaging (EACVI) and in one American laboratory. The NORRE study has already provided reference values for all 2D echocardiographic measurements of the four cardiac chambers,14 Doppler parameters,15 aortic dimensions,16 left ventricular strains,17 and 3D echocardiographic measurements of LV volumes and strain.18 This report aimed (i) to establish normal reference limits, using vendor-independent software (VIS), for 2D and 3D measurement of LA function in healthy adults and (ii) to examine the influence of age, gender, and vendor on the reference ranges. Methods Patient population A total of 734 healthy European subjects constituted the final NORRE study population. The local ethics committees approved the study protocol. After the exclusion of patients that had incompatible image format and/or poor image quality, the final study population consisted of 371 normal subjects. Baseline clinical characteristics of patients included in and excluded from this study are shown in Supplementary data online, Table S1. Echocardiographic examination A comprehensive echocardiographic examination was performed using state-of-the-art echocardiographic ultrasound systems (GE Vivid E9; Vingmed Ultrasound, Horten, Norway, and/or iE33; Philips Medical Systems, Andover, MA, USA) following recommended protocols approved by the EACVI.19,20 All echocardiographic images were recorded in a digital raw-data format (native DICOM format) and centralized for further analysis, after anonymization, at the EACVI Central Core Laboratory at the University of Liège, Belgium. LA functions and stiffness analysis Based on previous validated studies and guidelines of the American Society of Echocardiography/EACVI, quantification of LA 2D strain, 2D volume, and 3D volume was performed using commercially available VIS (2D Cardiac Performance Analysis and 4D Cardio-View, TomTec Imaging System, Munich, Germany) (Figure 1).10,21 2D analyses were performed in the apical four- and two-chamber views. The most suitable cardiac cycle was chosen for each view. The reference point was set at the beginning of the QRS complex. Left atrial end-systole was identified as the time point in which the LA cavity was the smallest. The endocardial border was traced in end-systole. The accuracy of tracking was visually confirmed throughout the cardiac cycle and confirmed from the morphology of the strain curves. If necessary, the region of interest was readjusted. In the measurement of LA 3D volumes, end-diastole was identified as the time point in which the LA cavity is the largest and end-systole as the time point at which the cavity was the smallest. The definition of LA reservoir, pump, and conduit function in this study is demonstrated in Figure 2. Left atrial reservoir function was assessed using the left atrial strain curve (LAS), left atrial emptying fraction (LAEF) in both 2D and 3D. As shown in Figure 2, LA pump function was assessed using LAS-active: LA strain at the onset time of the P wave, LAEF-active: (LA volume at the onset time of the P wave − LA minimum volume)/LA volume at the onset time of the P wave and LA strain rate during LA contraction (SRa).10 Left atrial conduit function was assessed by using LAS-passive: LAS − LAS-active, and LAEF-passive: (LA maximum volume − LA volume at the onset time of the P wave)/LA maximum volume. The ratio of mitral inflow E/e’ to LA reservoir function (LAS, LAEF) was used to estimate LA stiffness.22 Figure 1 View largeDownload slide Measurements of LA strain and strain rate by 2D speckle-tracking echocardiography analysis and LA volume by 2D and 3D echocardiography analysis using VIS. VIS, vendor-independent software; LA, left atrial; LAV, left atrial volume. Figure 1 View largeDownload slide Measurements of LA strain and strain rate by 2D speckle-tracking echocardiography analysis and LA volume by 2D and 3D echocardiography analysis using VIS. VIS, vendor-independent software; LA, left atrial; LAV, left atrial volume. Figure 2 View largeDownload slide Assessments of LA reservoir, pump and conduit function using LA strain analysis and LA volume. EF, emptying fraction; LA, left atrial; LAS, left atrial strain; SRa, strain rate. Figure 2 View largeDownload slide Assessments of LA reservoir, pump and conduit function using LA strain analysis and LA volume. EF, emptying fraction; LA, left atrial; LAS, left atrial strain; SRa, strain rate. Statistical analysis Normality of the distribution of continuous variables was tested by the Shapiro–Wilk test. All data are presented as the mean ± standard deviation or median (interquartile range) as appropriate. Group differences were evaluated using the Student’s t-test for normally distributed continuous variables and the Mann–Whitney U test for non-normally distributed continuous variables. Correlation between continuous variables was performed Pearson’s or Spearman’s correlation coefficient as appropriate. The lowest (2.5th percentile) and highest (97.5th percentile) expected values for left atrial parameters were estimated in 1000 bootstrap samples to generate sampling distributions. For each of these values, the mean and standard errors were estimated from the simulated sampling distribution. Multiple linear regression analyses were performed to examine the independent correlates between LA functions and baseline parameters including cardiovascular risk factors (age, gender, body mass index, systolic blood pressure, diastolic blood pressure, glycaemia, and cholesterol level) and vendor. Intra-observer (T.S.) variability was assessed in 20 randomly selected subjects using intraclass correlation coefficient (ICC). A P-value of <0.05 was considered as statistically significant. Data were analysed using open source statistical software, R version 3.3.2 (R Foundation for Statistical Computing, www.R-project.org) and SPSS 19.0 software (SPSS Inc., Chicago, IL, USA). Results Demographic data Table 1 summarizes the demographic data of the cohort of the NORRE population analysed in this study. A total of 165 men and 206 women were included. There was no significant association between age and 3D LA volume index on univariable analysis (R = 0.09, P = 0.07) and no differences in 3D LA volume index for gender. Values for LA reservoir, pump, and conduit function obtained from analysis of LA volume and strain curves for the entire study population are summarized in Table 2. The lowest limits of normality were 26.1%, 48.7%, and 41.4% for LAS, 2D LAEF, and 3D LAEF (reservoir function), respectively; 7.7%, 24.2%, and −0.53/s for LAS-active, LAEF-active, and LA SRa (pump function), respectively; and 12.0% and 21.6% for LAS-passive and LAEF-passive (conduit function), respectively. All LA parameters except SRa were significantly associated with age. Gender differences were observed in LAEF-passive. Vendor differences were observed in 2D LAEF, LAEF-active, and LA SRa. Multivariable analysis for LA functions showed that LAS, 2D LAEF, 3D LAEF, LAS-passive, and LAEF-passive decreased whereas 3D LA volume index and LAS-active increased with age. After adjusting for variables including basic parameters and vendor, LAEF-passive was higher in women than in men and 3D LA volume index was higher and LA SRa was lower when acquired with GE platforms compared with Philips equipment, (Table 3). Figure 3 shows two representative cases of LA functional assessments (middle vs. advanced age). Table 1 Characteristics of the population Parameters Total (n = 371) Male (n = 165, 44%) Female (n = 206, 56%) P-value Age (years) 45 (34–55) 46 (33–57) 44 (34–54) 0.54 Height (cm) 170 ± 9 177 ± 7 165 ± 7 <0.001 Weight (kg) 69 (60–78) 77 (71–84) 63 (57–69) <0.001 Body surface area (m2) 1.79 (1.66–1.94) 1.94 (1.85–2.05) 1.68 (1.61–1.78) <0.001 Body mass index (kg/m2) 23.9 (22.0–26.0) 24.7 (23.2–26.4) 23.2 (21.1–25.4) <0.001 Systolic blood pressure (mmHg) 120 (110–130) 121 (117–130) 116 (108–126) <0.001 Diastolic blood pressure (mmHg) 75 (70–80) 77 (70–80) 73 (68–80) 0.002 Glycaemia (mg/dL) 90 (85–98) 91 (87–98) 90 (83–96) 0.017 Cholesterol level (mg/dL) 181 (163–197) 183 (160–197) 179 (164–196) 0.86 Parameters Total (n = 371) Male (n = 165, 44%) Female (n = 206, 56%) P-value Age (years) 45 (34–55) 46 (33–57) 44 (34–54) 0.54 Height (cm) 170 ± 9 177 ± 7 165 ± 7 <0.001 Weight (kg) 69 (60–78) 77 (71–84) 63 (57–69) <0.001 Body surface area (m2) 1.79 (1.66–1.94) 1.94 (1.85–2.05) 1.68 (1.61–1.78) <0.001 Body mass index (kg/m2) 23.9 (22.0–26.0) 24.7 (23.2–26.4) 23.2 (21.1–25.4) <0.001 Systolic blood pressure (mmHg) 120 (110–130) 121 (117–130) 116 (108–126) <0.001 Diastolic blood pressure (mmHg) 75 (70–80) 77 (70–80) 73 (68–80) 0.002 Glycaemia (mg/dL) 90 (85–98) 91 (87–98) 90 (83–96) 0.017 Cholesterol level (mg/dL) 181 (163–197) 183 (160–197) 179 (164–196) 0.86 Table 1 Characteristics of the population Parameters Total (n = 371) Male (n = 165, 44%) Female (n = 206, 56%) P-value Age (years) 45 (34–55) 46 (33–57) 44 (34–54) 0.54 Height (cm) 170 ± 9 177 ± 7 165 ± 7 <0.001 Weight (kg) 69 (60–78) 77 (71–84) 63 (57–69) <0.001 Body surface area (m2) 1.79 (1.66–1.94) 1.94 (1.85–2.05) 1.68 (1.61–1.78) <0.001 Body mass index (kg/m2) 23.9 (22.0–26.0) 24.7 (23.2–26.4) 23.2 (21.1–25.4) <0.001 Systolic blood pressure (mmHg) 120 (110–130) 121 (117–130) 116 (108–126) <0.001 Diastolic blood pressure (mmHg) 75 (70–80) 77 (70–80) 73 (68–80) 0.002 Glycaemia (mg/dL) 90 (85–98) 91 (87–98) 90 (83–96) 0.017 Cholesterol level (mg/dL) 181 (163–197) 183 (160–197) 179 (164–196) 0.86 Parameters Total (n = 371) Male (n = 165, 44%) Female (n = 206, 56%) P-value Age (years) 45 (34–55) 46 (33–57) 44 (34–54) 0.54 Height (cm) 170 ± 9 177 ± 7 165 ± 7 <0.001 Weight (kg) 69 (60–78) 77 (71–84) 63 (57–69) <0.001 Body surface area (m2) 1.79 (1.66–1.94) 1.94 (1.85–2.05) 1.68 (1.61–1.78) <0.001 Body mass index (kg/m2) 23.9 (22.0–26.0) 24.7 (23.2–26.4) 23.2 (21.1–25.4) <0.001 Systolic blood pressure (mmHg) 120 (110–130) 121 (117–130) 116 (108–126) <0.001 Diastolic blood pressure (mmHg) 75 (70–80) 77 (70–80) 73 (68–80) 0.002 Glycaemia (mg/dL) 90 (85–98) 91 (87–98) 90 (83–96) 0.017 Cholesterol level (mg/dL) 181 (163–197) 183 (160–197) 179 (164–196) 0.86 Table 2 Left atrial reservoir, pump, and conduit function Total Age Differences between gender Differences between vender Mean ± SD or medial (IQR) Limits of normality ± SEa,b R P-value P-value P-value  3D LA volume (mL) 47.7 (40.8 to 57.1) 78.7 ± 2.2a 0.10 0.06 <0.001 0.001  3D LA volume index (mL/m2) 26.3 (23.1 to 31.1) 40.6 ± 1.1a 0.09 0.07 0.07 0.001 Reservoir function  LAS (%) 42.5 (36.1 to 48.0) 26.1 ± 0.7b −0.47 <0.001 0.49 0.47  2D LAEF (%) 68.5 (63.2 to 73.2) 48.7 ± 1.9b −0.31 <0.001 0.42 0.02  3D LAEF (%) 57.3 (52.4 to 61.9) 41.4 ± 1.1b −0.17 <0.001 0.53 0.76 Pump function  LAS-active (%) 16.3 (12.9 to 19.5) 7.7 ± 0.3b 0.15 0.003 0.34 0.35  LAEF-active (%) 43.1 ± 9.4 24.2 ± 1.4b 0.14 0.008 0.13 0.002  LA SRa (/s) −1.31 (−1.99 to −0.95) −0.53 ± 0.03b −0.1 0.054 0.08 <0.001 Conduit function  LAS-passive (%) 25.7 (20.4 to 31.8) 12.0 ± 0.5b −0.61 <0.001 0.06 0.98  LAEF-passive (%) 43.0 ± 10.3 21.6 ± 0.9b −0.55 <0.001 0.008 0.85 Total Age Differences between gender Differences between vender Mean ± SD or medial (IQR) Limits of normality ± SEa,b R P-value P-value P-value  3D LA volume (mL) 47.7 (40.8 to 57.1) 78.7 ± 2.2a 0.10 0.06 <0.001 0.001  3D LA volume index (mL/m2) 26.3 (23.1 to 31.1) 40.6 ± 1.1a 0.09 0.07 0.07 0.001 Reservoir function  LAS (%) 42.5 (36.1 to 48.0) 26.1 ± 0.7b −0.47 <0.001 0.49 0.47  2D LAEF (%) 68.5 (63.2 to 73.2) 48.7 ± 1.9b −0.31 <0.001 0.42 0.02  3D LAEF (%) 57.3 (52.4 to 61.9) 41.4 ± 1.1b −0.17 <0.001 0.53 0.76 Pump function  LAS-active (%) 16.3 (12.9 to 19.5) 7.7 ± 0.3b 0.15 0.003 0.34 0.35  LAEF-active (%) 43.1 ± 9.4 24.2 ± 1.4b 0.14 0.008 0.13 0.002  LA SRa (/s) −1.31 (−1.99 to −0.95) −0.53 ± 0.03b −0.1 0.054 0.08 <0.001 Conduit function  LAS-passive (%) 25.7 (20.4 to 31.8) 12.0 ± 0.5b −0.61 <0.001 0.06 0.98  LAEF-passive (%) 43.0 ± 10.3 21.6 ± 0.9b −0.55 <0.001 0.008 0.85 IQR, interquartile range; SD, standard deviation; SE, standard error; other abbreviations as in Figure 2. a Highest expected values. b Lowest expected values. Table 2 Left atrial reservoir, pump, and conduit function Total Age Differences between gender Differences between vender Mean ± SD or medial (IQR) Limits of normality ± SEa,b R P-value P-value P-value  3D LA volume (mL) 47.7 (40.8 to 57.1) 78.7 ± 2.2a 0.10 0.06 <0.001 0.001  3D LA volume index (mL/m2) 26.3 (23.1 to 31.1) 40.6 ± 1.1a 0.09 0.07 0.07 0.001 Reservoir function  LAS (%) 42.5 (36.1 to 48.0) 26.1 ± 0.7b −0.47 <0.001 0.49 0.47  2D LAEF (%) 68.5 (63.2 to 73.2) 48.7 ± 1.9b −0.31 <0.001 0.42 0.02  3D LAEF (%) 57.3 (52.4 to 61.9) 41.4 ± 1.1b −0.17 <0.001 0.53 0.76 Pump function  LAS-active (%) 16.3 (12.9 to 19.5) 7.7 ± 0.3b 0.15 0.003 0.34 0.35  LAEF-active (%) 43.1 ± 9.4 24.2 ± 1.4b 0.14 0.008 0.13 0.002  LA SRa (/s) −1.31 (−1.99 to −0.95) −0.53 ± 0.03b −0.1 0.054 0.08 <0.001 Conduit function  LAS-passive (%) 25.7 (20.4 to 31.8) 12.0 ± 0.5b −0.61 <0.001 0.06 0.98  LAEF-passive (%) 43.0 ± 10.3 21.6 ± 0.9b −0.55 <0.001 0.008 0.85 Total Age Differences between gender Differences between vender Mean ± SD or medial (IQR) Limits of normality ± SEa,b R P-value P-value P-value  3D LA volume (mL) 47.7 (40.8 to 57.1) 78.7 ± 2.2a 0.10 0.06 <0.001 0.001  3D LA volume index (mL/m2) 26.3 (23.1 to 31.1) 40.6 ± 1.1a 0.09 0.07 0.07 0.001 Reservoir function  LAS (%) 42.5 (36.1 to 48.0) 26.1 ± 0.7b −0.47 <0.001 0.49 0.47  2D LAEF (%) 68.5 (63.2 to 73.2) 48.7 ± 1.9b −0.31 <0.001 0.42 0.02  3D LAEF (%) 57.3 (52.4 to 61.9) 41.4 ± 1.1b −0.17 <0.001 0.53 0.76 Pump function  LAS-active (%) 16.3 (12.9 to 19.5) 7.7 ± 0.3b 0.15 0.003 0.34 0.35  LAEF-active (%) 43.1 ± 9.4 24.2 ± 1.4b 0.14 0.008 0.13 0.002  LA SRa (/s) −1.31 (−1.99 to −0.95) −0.53 ± 0.03b −0.1 0.054 0.08 <0.001 Conduit function  LAS-passive (%) 25.7 (20.4 to 31.8) 12.0 ± 0.5b −0.61 <0.001 0.06 0.98  LAEF-passive (%) 43.0 ± 10.3 21.6 ± 0.9b −0.55 <0.001 0.008 0.85 IQR, interquartile range; SD, standard deviation; SE, standard error; other abbreviations as in Figure 2. a Highest expected values. b Lowest expected values. Table 3 Multivariable analysis for left atrial functions Variables Basic parametersa Basic parametersa + vendor β-coefficients ± SE P-value β-coefficients ± SE P-value 3D LA volume index (mL/m2)  Age (years) 0.07 ± 0.03 0.029  Cholesterol level (mg/dL) −0.03 ± 0.01 0.033 −0.03 ± 0.01 0.009  Male gender 1.62 ± 0.77 0.037  Vendor (GE as referent) −3.94 ± 0.74 <0.001 LAS (%)  Age (years) −0.32 ± 0.04 <0.001 −0.33 ± 0.04 <0.001  Body mass index (kg/m2) −0.39 ± 0.18 0.03 −0.42 ± 0.18 0.02  Glycaemia (mg/dL) −0.09 ± 0.04 0.049 2D LAEF, (%)  Age (years) −0.20 ± 0.04 <0.001 −0.21 ± 0.04 <0.001 3D LAEF (%)  Age (years) −0.11 ± 0.04 0.008 −0.10 ± 0.04 0.013 LAS-active (%)  Age (years) 0.06 ± 0.02 0.02 0.06 ± 0.03 0.02  Glycaemia (mg/dL) −0.07 ± 0.02 0.005 −0.07 ± 0.02 0.006 LAEF-active (%)  Body mass index (kg/m2) 0.40 ± 0.20 0.047  Glycaemia (mg/dL) −0.10 ± 0.05 0.036 −0.10 ± 0.05 0.045 LA SRa (/s)  Age (years) −0.01 ± 0.004 0.01  Vendor (GE as referent) −1.08 ± 0.08 <0.001 LAS-passive (%)  Age (years) −0.37 ± 0.04 <0.001 −0.38 ± 0.04 <0.001  Body mass index (kg/m2) −0.53 ± 0.16 0.001 −0.56 ± 0.16 <0.001 LAEF-passive (%)  Age (years) −0.43 ± 0.05 <0.001 −0.43 ± 0.05 <0.001  Male gender −2.42 ± 1.18 0.04  Body mass index (kg/m2) −0.52 ± 0.19 0.007 −0.55 ± 0.19 0.005 Variables Basic parametersa Basic parametersa + vendor β-coefficients ± SE P-value β-coefficients ± SE P-value 3D LA volume index (mL/m2)  Age (years) 0.07 ± 0.03 0.029  Cholesterol level (mg/dL) −0.03 ± 0.01 0.033 −0.03 ± 0.01 0.009  Male gender 1.62 ± 0.77 0.037  Vendor (GE as referent) −3.94 ± 0.74 <0.001 LAS (%)  Age (years) −0.32 ± 0.04 <0.001 −0.33 ± 0.04 <0.001  Body mass index (kg/m2) −0.39 ± 0.18 0.03 −0.42 ± 0.18 0.02  Glycaemia (mg/dL) −0.09 ± 0.04 0.049 2D LAEF, (%)  Age (years) −0.20 ± 0.04 <0.001 −0.21 ± 0.04 <0.001 3D LAEF (%)  Age (years) −0.11 ± 0.04 0.008 −0.10 ± 0.04 0.013 LAS-active (%)  Age (years) 0.06 ± 0.02 0.02 0.06 ± 0.03 0.02  Glycaemia (mg/dL) −0.07 ± 0.02 0.005 −0.07 ± 0.02 0.006 LAEF-active (%)  Body mass index (kg/m2) 0.40 ± 0.20 0.047  Glycaemia (mg/dL) −0.10 ± 0.05 0.036 −0.10 ± 0.05 0.045 LA SRa (/s)  Age (years) −0.01 ± 0.004 0.01  Vendor (GE as referent) −1.08 ± 0.08 <0.001 LAS-passive (%)  Age (years) −0.37 ± 0.04 <0.001 −0.38 ± 0.04 <0.001  Body mass index (kg/m2) −0.53 ± 0.16 0.001 −0.56 ± 0.16 <0.001 LAEF-passive (%)  Age (years) −0.43 ± 0.05 <0.001 −0.43 ± 0.05 <0.001  Male gender −2.42 ± 1.18 0.04  Body mass index (kg/m2) −0.52 ± 0.19 0.007 −0.55 ± 0.19 0.005 SE, standard error; other abbreviations as in Figure 2. a Age, gender, body mass index, systolic blood pressure, diastolic blood pressure, glycaemia and cholesterol level. Table 3 Multivariable analysis for left atrial functions Variables Basic parametersa Basic parametersa + vendor β-coefficients ± SE P-value β-coefficients ± SE P-value 3D LA volume index (mL/m2)  Age (years) 0.07 ± 0.03 0.029  Cholesterol level (mg/dL) −0.03 ± 0.01 0.033 −0.03 ± 0.01 0.009  Male gender 1.62 ± 0.77 0.037  Vendor (GE as referent) −3.94 ± 0.74 <0.001 LAS (%)  Age (years) −0.32 ± 0.04 <0.001 −0.33 ± 0.04 <0.001  Body mass index (kg/m2) −0.39 ± 0.18 0.03 −0.42 ± 0.18 0.02  Glycaemia (mg/dL) −0.09 ± 0.04 0.049 2D LAEF, (%)  Age (years) −0.20 ± 0.04 <0.001 −0.21 ± 0.04 <0.001 3D LAEF (%)  Age (years) −0.11 ± 0.04 0.008 −0.10 ± 0.04 0.013 LAS-active (%)  Age (years) 0.06 ± 0.02 0.02 0.06 ± 0.03 0.02  Glycaemia (mg/dL) −0.07 ± 0.02 0.005 −0.07 ± 0.02 0.006 LAEF-active (%)  Body mass index (kg/m2) 0.40 ± 0.20 0.047  Glycaemia (mg/dL) −0.10 ± 0.05 0.036 −0.10 ± 0.05 0.045 LA SRa (/s)  Age (years) −0.01 ± 0.004 0.01  Vendor (GE as referent) −1.08 ± 0.08 <0.001 LAS-passive (%)  Age (years) −0.37 ± 0.04 <0.001 −0.38 ± 0.04 <0.001  Body mass index (kg/m2) −0.53 ± 0.16 0.001 −0.56 ± 0.16 <0.001 LAEF-passive (%)  Age (years) −0.43 ± 0.05 <0.001 −0.43 ± 0.05 <0.001  Male gender −2.42 ± 1.18 0.04  Body mass index (kg/m2) −0.52 ± 0.19 0.007 −0.55 ± 0.19 0.005 Variables Basic parametersa Basic parametersa + vendor β-coefficients ± SE P-value β-coefficients ± SE P-value 3D LA volume index (mL/m2)  Age (years) 0.07 ± 0.03 0.029  Cholesterol level (mg/dL) −0.03 ± 0.01 0.033 −0.03 ± 0.01 0.009  Male gender 1.62 ± 0.77 0.037  Vendor (GE as referent) −3.94 ± 0.74 <0.001 LAS (%)  Age (years) −0.32 ± 0.04 <0.001 −0.33 ± 0.04 <0.001  Body mass index (kg/m2) −0.39 ± 0.18 0.03 −0.42 ± 0.18 0.02  Glycaemia (mg/dL) −0.09 ± 0.04 0.049 2D LAEF, (%)  Age (years) −0.20 ± 0.04 <0.001 −0.21 ± 0.04 <0.001 3D LAEF (%)  Age (years) −0.11 ± 0.04 0.008 −0.10 ± 0.04 0.013 LAS-active (%)  Age (years) 0.06 ± 0.02 0.02 0.06 ± 0.03 0.02  Glycaemia (mg/dL) −0.07 ± 0.02 0.005 −0.07 ± 0.02 0.006 LAEF-active (%)  Body mass index (kg/m2) 0.40 ± 0.20 0.047  Glycaemia (mg/dL) −0.10 ± 0.05 0.036 −0.10 ± 0.05 0.045 LA SRa (/s)  Age (years) −0.01 ± 0.004 0.01  Vendor (GE as referent) −1.08 ± 0.08 <0.001 LAS-passive (%)  Age (years) −0.37 ± 0.04 <0.001 −0.38 ± 0.04 <0.001  Body mass index (kg/m2) −0.53 ± 0.16 0.001 −0.56 ± 0.16 <0.001 LAEF-passive (%)  Age (years) −0.43 ± 0.05 <0.001 −0.43 ± 0.05 <0.001  Male gender −2.42 ± 1.18 0.04  Body mass index (kg/m2) −0.52 ± 0.19 0.007 −0.55 ± 0.19 0.005 SE, standard error; other abbreviations as in Figure 2. a Age, gender, body mass index, systolic blood pressure, diastolic blood pressure, glycaemia and cholesterol level. Figure 3 View largeDownload slide Two representative cases of LA functional assessments. LAV, left atrial volume; other abbreviations as in Figure 2. Figure 3 View largeDownload slide Two representative cases of LA functional assessments. LAV, left atrial volume; other abbreviations as in Figure 2. Age and LA functions relationship Left atrial reservoir, pump, and conduit function and stiffness in the three subgroups according to age (20–40, 40–60, and ≥60 years) are displayed in Table 4. The lowest expected values for LAS were 31.1% in 20–40 years of age, 27.7% in 40–60 years, and 22.7% in ≥60 years. The highest expected values for LA stiffness calculated from LAS were 0.22 in 20–40 years of age, 0.42 in 40–60 years, and 0.55 in ≥60 years. Table 4 Left atrial functions and stiffness according to age Age 20–40 (n = 137) Age 40–60 (n = 173) Age ≥60 (n = 61) Medial (IQR) Limits of normality  ± SEa,b Medial (IQR) Limits of normality  ± SEa,b Medial (IQR) Limits of normality  ± SEa,b Reservoir function  LAS (%) 46.8 (42.3–52.4) 31.1 ± 2.6b 40.9 (35.4–46.1) 27.7 ± 1.5b 35.5 (30.9–41.9) 22.7 ± 2.0b  2D LAEF (%) 71.3 (67.3–74.9) 51.7 ± 2.0b 66.7 (62.8–72.4) 49.2 ± 2.7b 64.0 (58.1–69.5) 44.1 ± 1.7b  3D LAEF (%) 58.4 (53.1–63.1) 42.2 ± 2.3b 57.1 (52.2–61.3) 39.4 ± 1.9b 55.6 (50.6–60.4) 38.3 ± 2.5b Pump function  LAS-active (%) 15.6 (11.9–19.0) 7.2 ± 0.5b 16.3 (13.2–19.6) 9.3 ± 0.8b 16.8 (13.6–21.4) 7.7 ± 0.8b Conduit function  LAS-passive (%) 30.6 (26.8–36.5) 16.2 ± 1.6b 24.1 (19.7–29.3) 12.0 ± 1.0b 18.6 (14.7–22.6) 11.5 ± 0.1b Stiffness  E/e’ divided by LAS 0.12 (0.10–0.15) 0.22 ± 0.01a 0.16 (0.13–0.22) 0.42 ± 0.04a 0.24 (0.18–0.29) 0.55 ± 0.09a  E/e’ divided by 2D LAEF 0.08 (0.07–0.09) 0.15 ± 0.01a 0.10 (0.09–0.12) 0.23 ± 0.04a 0.14 (0.11–0.15) 0.24 ± 0.02a  E/e’ divided by 3D LAEF 0.10 (0.08–0.12) 0.19 ± 0.01a 0.11 (0.10–0.15) 0.24 ± 0.04a 0.15 (0.13–0.17) 0.27 ± 0.02a  E/e’ 5.6 (4.8–6.7) 9.0 ± 1.3a 6.8 (5.8–8.3) 13.4 ± 2.4a 8.3 (7.1–9.8) 13.3 ± 0.5a Age 20–40 (n = 137) Age 40–60 (n = 173) Age ≥60 (n = 61) Medial (IQR) Limits of normality  ± SEa,b Medial (IQR) Limits of normality  ± SEa,b Medial (IQR) Limits of normality  ± SEa,b Reservoir function  LAS (%) 46.8 (42.3–52.4) 31.1 ± 2.6b 40.9 (35.4–46.1) 27.7 ± 1.5b 35.5 (30.9–41.9) 22.7 ± 2.0b  2D LAEF (%) 71.3 (67.3–74.9) 51.7 ± 2.0b 66.7 (62.8–72.4) 49.2 ± 2.7b 64.0 (58.1–69.5) 44.1 ± 1.7b  3D LAEF (%) 58.4 (53.1–63.1) 42.2 ± 2.3b 57.1 (52.2–61.3) 39.4 ± 1.9b 55.6 (50.6–60.4) 38.3 ± 2.5b Pump function  LAS-active (%) 15.6 (11.9–19.0) 7.2 ± 0.5b 16.3 (13.2–19.6) 9.3 ± 0.8b 16.8 (13.6–21.4) 7.7 ± 0.8b Conduit function  LAS-passive (%) 30.6 (26.8–36.5) 16.2 ± 1.6b 24.1 (19.7–29.3) 12.0 ± 1.0b 18.6 (14.7–22.6) 11.5 ± 0.1b Stiffness  E/e’ divided by LAS 0.12 (0.10–0.15) 0.22 ± 0.01a 0.16 (0.13–0.22) 0.42 ± 0.04a 0.24 (0.18–0.29) 0.55 ± 0.09a  E/e’ divided by 2D LAEF 0.08 (0.07–0.09) 0.15 ± 0.01a 0.10 (0.09–0.12) 0.23 ± 0.04a 0.14 (0.11–0.15) 0.24 ± 0.02a  E/e’ divided by 3D LAEF 0.10 (0.08–0.12) 0.19 ± 0.01a 0.11 (0.10–0.15) 0.24 ± 0.04a 0.15 (0.13–0.17) 0.27 ± 0.02a  E/e’ 5.6 (4.8–6.7) 9.0 ± 1.3a 6.8 (5.8–8.3) 13.4 ± 2.4a 8.3 (7.1–9.8) 13.3 ± 0.5a CI, confidence interval; SD, standard deviation; other abbreviations as in Figure 2. a Highest expected values. b Lowest expected values. Table 4 Left atrial functions and stiffness according to age Age 20–40 (n = 137) Age 40–60 (n = 173) Age ≥60 (n = 61) Medial (IQR) Limits of normality  ± SEa,b Medial (IQR) Limits of normality  ± SEa,b Medial (IQR) Limits of normality  ± SEa,b Reservoir function  LAS (%) 46.8 (42.3–52.4) 31.1 ± 2.6b 40.9 (35.4–46.1) 27.7 ± 1.5b 35.5 (30.9–41.9) 22.7 ± 2.0b  2D LAEF (%) 71.3 (67.3–74.9) 51.7 ± 2.0b 66.7 (62.8–72.4) 49.2 ± 2.7b 64.0 (58.1–69.5) 44.1 ± 1.7b  3D LAEF (%) 58.4 (53.1–63.1) 42.2 ± 2.3b 57.1 (52.2–61.3) 39.4 ± 1.9b 55.6 (50.6–60.4) 38.3 ± 2.5b Pump function  LAS-active (%) 15.6 (11.9–19.0) 7.2 ± 0.5b 16.3 (13.2–19.6) 9.3 ± 0.8b 16.8 (13.6–21.4) 7.7 ± 0.8b Conduit function  LAS-passive (%) 30.6 (26.8–36.5) 16.2 ± 1.6b 24.1 (19.7–29.3) 12.0 ± 1.0b 18.6 (14.7–22.6) 11.5 ± 0.1b Stiffness  E/e’ divided by LAS 0.12 (0.10–0.15) 0.22 ± 0.01a 0.16 (0.13–0.22) 0.42 ± 0.04a 0.24 (0.18–0.29) 0.55 ± 0.09a  E/e’ divided by 2D LAEF 0.08 (0.07–0.09) 0.15 ± 0.01a 0.10 (0.09–0.12) 0.23 ± 0.04a 0.14 (0.11–0.15) 0.24 ± 0.02a  E/e’ divided by 3D LAEF 0.10 (0.08–0.12) 0.19 ± 0.01a 0.11 (0.10–0.15) 0.24 ± 0.04a 0.15 (0.13–0.17) 0.27 ± 0.02a  E/e’ 5.6 (4.8–6.7) 9.0 ± 1.3a 6.8 (5.8–8.3) 13.4 ± 2.4a 8.3 (7.1–9.8) 13.3 ± 0.5a Age 20–40 (n = 137) Age 40–60 (n = 173) Age ≥60 (n = 61) Medial (IQR) Limits of normality  ± SEa,b Medial (IQR) Limits of normality  ± SEa,b Medial (IQR) Limits of normality  ± SEa,b Reservoir function  LAS (%) 46.8 (42.3–52.4) 31.1 ± 2.6b 40.9 (35.4–46.1) 27.7 ± 1.5b 35.5 (30.9–41.9) 22.7 ± 2.0b  2D LAEF (%) 71.3 (67.3–74.9) 51.7 ± 2.0b 66.7 (62.8–72.4) 49.2 ± 2.7b 64.0 (58.1–69.5) 44.1 ± 1.7b  3D LAEF (%) 58.4 (53.1–63.1) 42.2 ± 2.3b 57.1 (52.2–61.3) 39.4 ± 1.9b 55.6 (50.6–60.4) 38.3 ± 2.5b Pump function  LAS-active (%) 15.6 (11.9–19.0) 7.2 ± 0.5b 16.3 (13.2–19.6) 9.3 ± 0.8b 16.8 (13.6–21.4) 7.7 ± 0.8b Conduit function  LAS-passive (%) 30.6 (26.8–36.5) 16.2 ± 1.6b 24.1 (19.7–29.3) 12.0 ± 1.0b 18.6 (14.7–22.6) 11.5 ± 0.1b Stiffness  E/e’ divided by LAS 0.12 (0.10–0.15) 0.22 ± 0.01a 0.16 (0.13–0.22) 0.42 ± 0.04a 0.24 (0.18–0.29) 0.55 ± 0.09a  E/e’ divided by 2D LAEF 0.08 (0.07–0.09) 0.15 ± 0.01a 0.10 (0.09–0.12) 0.23 ± 0.04a 0.14 (0.11–0.15) 0.24 ± 0.02a  E/e’ divided by 3D LAEF 0.10 (0.08–0.12) 0.19 ± 0.01a 0.11 (0.10–0.15) 0.24 ± 0.04a 0.15 (0.13–0.17) 0.27 ± 0.02a  E/e’ 5.6 (4.8–6.7) 9.0 ± 1.3a 6.8 (5.8–8.3) 13.4 ± 2.4a 8.3 (7.1–9.8) 13.3 ± 0.5a CI, confidence interval; SD, standard deviation; other abbreviations as in Figure 2. a Highest expected values. b Lowest expected values. Vendor and LA functions relationship Multivariable analysis showed that 3D LA volume index was higher [GE, 27.8 (24.2–32.2) mL/m2, n = 189 vs. Philips, 25.5 (22.8–29.3) mL/m2, n = 184, P = 0.001] and LA SRa was lower [GE, −0.98 (−1.16 to −0.73)/s vs. Philips, −1.99 (−2.42 to −1.58)/s, P < 0.001] with GE compared with Philips equipment for the total population. The same tendency was observed for the apical four-chambers [−0.84 (−1.12 to −0.65) vs. −1.81 (−2.28 to −1.32)/s, P < 0.001] and two-chambers [−1.11 (−1.31 to −0.82) vs. −2.25 (−2.65 to −1.70)/s, P < 0.001] LA SRa. The number of patients whose LA SRa could not be identified on LA strain analysis was significantly higher with GE than Philips (8% vs. 0% and 38% vs. 15% in apical four- and two-chambers view, P < 0.001, respectively). The lowest expected values for LA SRa were −0.47/s (GE) and −0.86/s (Philips). The highest expected values for LA volume index were 41.3 mL/m2 (GE) and 39.6 mL/m2 (Philips). Repeatability Intra-observer analysis showed excellent repeatability in LAS, LAS-active, LA SRa, and 3D LA volume (ICC = 0.85, 0.71, 0.79, and 0.90, P < 0.01, respectively). Discussion The present prospective, EACVI multicentre study provides contemporary normal reference values for LA function in a large cohort of healthy volunteers over a wide range of ages. 2DE analyses were performed using a VIS in order to obtain homogeneous measurements irrespective of the echocardiographic equipment used to acquire data. Left atrial reservoir and conduit function decreased with age while pump function increased. All indices of reservoir function and LA strains had no gender and vendor differences. Interestingly, inter-vendor differences were observed in 3D LA volume index and LA SRa despite the use of VIS software. Previous single-centre studies with healthy subjects reported that the highest expected value for 3D LA volume index was: 33 mL/m2 in the study of Wu et al.,23 a Japanese cohort, using Philips equipment and software, 41 mL/m2 in the study of Aune et al.,24 a Norway cohort, using Philips equipment and software, and 43 mL/m2 in the study of Badano et al.,13 an Italian cohort, using GE equipment and TomTec software. This multicentre study with a Caucasian European population showed lower 3D LA volume index compared with single-centre studies in the Norway and Italy. The reasons for this difference may be caused by several factors: (i) lower temporal resolution of 3D echocardiographic data sets caused by a wide-angle 3D acquisition for the LA13; (ii) the difference in baseline blood pressure in male [systolic/diastolic blood pressure: 123/76 mmHg (mean) and 121/77 mmHg (median) in this study vs. 127/79 mmHg (mean) in the Norwegian cohort and 130/80 mmHg (median) in the Italian cohort]; and (iii) inter-vendor differences as demonstrated in this study. A previous multicentre study reporting on a large cohort of healthy subjects showed that LAS and LAEF were negatively associated with age while having no differences in gender.10 A meta-analysis of LA strain using 2D speckle tracking echocardiography has detected no difference in both gender and vendor.11 These finding are consistent with the findings of this study. The mechanism of age-related changes in LA function, in particular pump function, may be explained by age-related changes in left ventricular diastolic performance from normal to diastolic dysfunction grade 1.25 In fact, our data demonstrated the age-related increases in LA stiffness, an index that has been reported as a sensitive marker of diastolic dysfunction.22,26 This study showed that the best concordance between the two major vendors was in LA strain whereas the major discordance was noted in 3D LA volume index and SRa. These data support the use of comparable values independently of the machine used to acquire LA images. Limitations This study presents several limitations. First, only half of the patients included in the study were available for LA function analysis indicating that dependency on image quality is one of the main limitations for strain analysis by speckle tracking. Second, the existence of inter-vendor differences in 3D LA volume index and LA SRa was not confirmed by the direct comparison in the same patients. Further study is warranted to investigate the cause of the inter-vendor differences. Last of all, whether the NORRE study results can be extrapolated to non-Caucasian European individuals is still unknown. Conclusion The NORRE study provides applicable reference ranges for LA functions. Multivariable analysis showed that age is independently associated with all LAS components irrespective of gender and vendor. Our data highlight the importance of age-specific assessment for LA function. Supplementary data Supplementary data are available at European Heart Journal - Cardiovascular Imaging online. Acknowledgements The EACVI Research and Innovation Committee thanks the Heart House for its support. Funding The NORRE Study is supported by GE Healthcare and Philips Healthcare in the form of an unrestricted educational grant. TomTec has provided the software for strain analysis. Sponsor funding has in no way influenced the content or management of this study. Appendix of the list of contributors to the NORRE Study Patrizio Lancellotti, Raluca Dulgheru, Seisyou Kou, Tadafumi Sugimoto, Anne Bernard, Federica Ilardi, Stella Marchetta, Alain Nchimi, Sébastien Robinet, Yun Yun Go, University of Liège hospital, GIGA Cardiovascular Science, Heart Valve Clinic, Imaging Cardiology, Belgium; Daniele Barone, Laboratory of Cardiovascular Ecography Cardiology Department, S. Andrea Hospital, La Spezia, Italy; Monica Baroni, Laboratorio Di Ecocardiografia Adulti, Fondazione Toscana ‘G. Monasterio’-Ospedale Del Cuore, Massa, Italy; Jose Juan Gomez de Diego, Unidad de Imagen Cardiovascular, ICV, Hospital Clinico San Carlos, Madrid, Spain; Andreas Hagendorff, Echokardiographie-Labore des Universitätsklinikums AöR, Department of Cardiology-Angiology, University of Leipzig, Leipzig, Germany; Krasimira Hristova, University National Heart Hospital, Department of Noninvasive Functional Diagnostic and Imaging, Sofia, Bulgaria; Gonzalo de la Morena, Luis Caballero, Daniel Saura, Unidad de Imagen Cardiaca, Servicio de Cardiologia, Hospital Clinico Universitario Virgen de la Arrixaca, IMIB-Arrixaca, Murcia, Spain; Teresa Lopez, Nieves Montoro, La Paz Hospital in Madrid, Spain; Jose Luis Zamorano, Covadonga Fernandez-Golfin, University Hospital Ramón y Cajal, Madrid, Spain; Nuno Cardim, Maria Adelaide Almeida, Hospital da Luz, Lisbon, Portugal; Bogdan A. Popescu, Monica Rosca, Andreea Calin, University of Medicine and Pharmacy ‘Carol Davila’-Euroecolab, Institute of Cardiovascular Diseases ‘Prof. Dr. C. C. Iliescu’, Bucharest, Romania; George Kacharava, Natalia Gonjilashvili, Levan Kurashvili, Natela Akhaladze, Zaza Mgaloblishvili, Echocardiography Laboratory of Adult Cardiology Department of the Joann Medical Center, Tbilisi, GA, USA; María José Oliva, Josefa González-Carrillo, ArrixacaIMIB, Murcia, Spain; George D. Athanassopoulos, Eftychia Demerouti, Noninvasive Diagnostics Department, Onassis Cardiac Surgery Center, Athens, Greece; Dragos Vinereanu, Roxana Rimbas, Andrea Olivia Ciobanu, Cardiovascular Research Unit, University and Emergency Hospital, University of Medicine and Pharmacy Carol Davila, Bucharest, Romania; Luigi P. Badano, Diletta Peluso, Seena Padayattil Jose, Department of Cardiac, Thoracic and Vascular Sciences University of Padova, School of Medicine, Padova, Italy; Nico van de Veire, Johan de Sutter, Echocardiography Unit-AZ Maria Middelares Gent, Belgium; Martin Penicka, Martin Kotrc, Cardiovascular Center Aalst, OLV-Clinic, Belgium; Jens-Uwe Voigt, Echocardiography Laboratory, Department of Cardiovascular Diseases, University Hospital Gasthuisberg, Leuven, Belgium; Tolga Ozyigit, VKV Amerikan Hastanesi, Kardiyoloji Bölümü, Istanbul, Turkey; Jose David Rodrigo Carbonero, Laboratorio de Ecocardiografia Hospital de Cruces–Barakaldo, Spain; Alessandro Salustri, SheikhKhalifa Medical City, PO Box: 51900, Abu Dhabi, United Arab; Ralph Stephan Von Bardeleben, Medical Department Cardiology, Universitätsmedizin of the Johannes Gutenberg University Mainz, Germany; Roberto M. Lang, Karima Addetia, Department of Medicine University of Chicago Medical Center, IL, USA. Conflict of interest: None declared. References 1 Dernellis JM , Stefanadis CI , Zacharoulis AA , Toutouzas PK. Left atrial mechanical adaptation to long-standing hemodynamic loads based on pressure-volume relations . Am J Cardiol 1998 ; 81 : 1138 – 43 . Google Scholar CrossRef Search ADS PubMed 2 Guazzi M , Borlaug BA. Pulmonary hypertension due to left heart disease . Circulation 2012 ; 126 : 975 – 90 . Google Scholar CrossRef Search ADS PubMed 3 Kobayashi Y , Moneghetti KJ , Boralkar K , Amsallem M , Tuzovic M , Liang D et al. Challenging the complementarity of different metrics of left atrial function: insight from a cardiomyopathy-based study . Eur Heart J Cardiovasc Imaging 2017 ; 18 : 1153 – 62 . Google Scholar CrossRef Search ADS PubMed 4 Debonnaire P , Leong DP , Witkowski TG , Al Amri I , Joyce E , Katsanos S et al. Left atrial function by two-dimensional speckle-tracking echocardiography in patients with severe organic mitral regurgitation: association with guidelines-based surgical indication and postoperative (long-term) survival . J Am Soc Echocardiogr 2013 ; 26 : 1053 – 62 . Google Scholar CrossRef Search ADS PubMed 5 Yasuda R , Murata M , Roberts R , Tokuda H , Minakata Y , Suzuki K et al. Left atrial strain is a powerful predictor of atrial fibrillation recurrence after catheter ablation: study of a heterogeneous population with sinus rhythm or atrial fibrillation . Eur Heart J Cardiovasc Imaging 2015 ; 16 : 1008 – 14 . Google Scholar PubMed 6 Santos AB , Kraigher-Krainer E , Gupta DK , Claggett B , Zile MR , Pieske B et al. Impaired left atrial function in heart failure with preserved ejection fraction . Eur J Heart Fail 2014 ; 16 : 1096 – 103 . Google Scholar CrossRef Search ADS PubMed 7 Melenovsky V , Hwang SJ , Redfield MM , Zakeri R , Lin G , Borlaug BA. Left atrial remodeling and function in advanced heart failure with preserved or reduced ejection fraction . Circ Heart Fail 2015 ; 8 : 295 – 303 . Google Scholar CrossRef Search ADS PubMed 8 Sugimoto T , Bandera F , Generati G , Alfonzetti E , Bussadori C , Guazzi M. Left Atrial function dynamics during exercise in heart failure: pathophysiological implications on the right heart and exercise ventilation inefficiency . JACC Cardiovasc Imaging 2017 ; 10 : 1253 – 64 . Google Scholar CrossRef Search ADS PubMed 9 Russo C , Jin Z , Homma S , Rundek T , Elkind MSV , Sacco RL et al. LA Phasic volumes and reservoir function in the elderly by real-time 3D echocardiography: normal values, prognostic significance, and clinical correlates . JACC Cardiovasc Imaging 2017 ; 10 : 976 – 85 . Google Scholar CrossRef Search ADS PubMed 10 Morris DA , Takeuchi M , Krisper M , Köhncke C , Bekfani T , Carstensen T et al. Normal values and clinical relevance of left atrial myocardial function analysed by speckle-tracking echocardiography: multicentre study . Eur Heart J Cardiovasc Imaging 2015 ; 16 : 364 – 72 . Google Scholar CrossRef Search ADS PubMed 11 Pathan F , D’Elia N , Nolan MT , Marwick TH , Negishi K. Normal ranges of left atrial strain by speckle-tracking echocardiography: a systematic review and meta-analysis . J Am Soc Echocardiogr 2017 ; 30 : 59 – 70 . Google Scholar CrossRef Search ADS PubMed 12 Miglioranza MH , Badano LP , Mihăilă S , Peluso D , Cucchini U , Soriani N et al. Physiologic determinants of left atrial longitudinal strain: a two-dimensional speckle-tracking and three-dimensional echocardiographic study in healthy volunteers . J Am Soc Echocardiogr 2016 ; 29 : 1023 – 34 . Google Scholar CrossRef Search ADS PubMed 13 Badano LP , Miglioranza MH , Mihăilă S , Peluso D , Xhaxho J , Marra MP et al. Left atrial volumes and function by three-dimensional echocardiography: reference values, accuracy, reproducibility, and comparison with two-dimensional echocardiographic measurements . Circ Cardiovasc Imaging 2016 ; 9 : e004229 . Google Scholar CrossRef Search ADS PubMed 14 Kou S , Caballero L , Dulgheru R , Voilliot D , De Sousa C , Kacharava G et al. Echocardiographic reference ranges for normal cardiac chamber size: results from the NORRE study . Eur Heart J Cardiovasc Imaging 2014 ; 15 : 680 – 90 . Google Scholar CrossRef Search ADS PubMed 15 Caballero L , Kou S , Dulgheru R , Gonjilashvili N , Athanassopoulos GD , Barone D et al. Echocardiographic reference ranges for normal cardiac Doppler data: results from the NORRE Study . Eur Heart J Cardiovasc Imaging 2015 ; 16 : 1031 – 41 . Google Scholar PubMed 16 Saura D , Dulgheru R , Caballero L , Bernard A , Kou S , Gonjilashvili N et al. Two-dimensional transthoracic echocardiographic normal reference ranges for proximal aorta dimensions: results from the EACVI NORRE study . Eur Heart J Cardiovasc Imaging 2017 ; 18 : 167 – 79 . Google Scholar CrossRef Search ADS PubMed 17 Sugimoto T , Dulgheru R , Bernard A , Ilardi F , Contu L , Addetia K et al. Echocardiographic reference ranges for normal left ventricular 2D strain: results from the EACVI NORRE study . Eur Heart J Cardiovasc Imaging 2017 ; 18 : 833 – 40 . Google Scholar CrossRef Search ADS PubMed 18 Bernard A , Addetia K , Dulgheru R , Caballero L , Sugimoto T , Akhaladze N et al. 3D echocardiographic reference ranges for normal left ventricular volume and strain: results from the EACVI NORRE study . Eur Heart J Cardiovasc Imaging 2017 ; 18 : 475 – 83 . Google Scholar CrossRef Search ADS PubMed 19 Lancellotti P , Badano LP , Lang RM , Akhaladze N , Athanassopoulos GD , Barone D et al. Normal Reference Ranges for Echocardiography: rationale, study design, and methodology (NORRE Study) . Eur Heart J Cardiovasc Imaging 2013 ; 14 : 303 – 8 . Google Scholar CrossRef Search ADS PubMed 20 Cosyns B , Garbi M , Separovic J , Pasquet A , Lancellotti P ; Education Committee of the European Association of Cardiovascular Imaging Association (EACVI) . Update of the echocardiography core syllabus of the European Association of Cardiovascular Imaging (EACVI) . Eur Heart J Cardiovasc Imaging 2013 ; 14 :837–9. 21 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 22 Kurt M , Wang J , Torre-Amione G , Nagueh SF. Left atrial function in diastolic heart failure . Circ Cardiovasc Imaging 2009 ; 2 : 10 – 5 . Google Scholar CrossRef Search ADS PubMed 23 Wu VC , Takeuchi M , Kuwaki H , Iwataki M , Nagata Y , Otani K et al. Prognostic value of LA volumes assessed by transthoracic 3D echocardiography: comparison with 2D echocardiography . JACC Cardiovasc Imaging 2013 ; 6 : 1025 – 35 . Google Scholar CrossRef Search ADS PubMed 24 Aune E , Baekkevar M , Roislien J , Rodevand O , Otterstad JE. Normal reference ranges for left and right atrial volume indexes and ejection fractions obtained with real-time three-dimensional echocardiography . Eur J Echocardiogr 2009 ; 10 : 738 – 44 . Google Scholar CrossRef Search ADS PubMed 25 Singh A , Addetia K , Maffessanti F , Mor-Avi V , Lang RM. LA strain for categorization of LV diastolic dysfunction . JACC Cardiovasc Imaging 2017 ; 10 : 735 – 43 . Google Scholar CrossRef Search ADS PubMed 26 Khurram IM , Maqbool F , Berger RD , Marine JE , Spragg DD , Ashikaga H et al. Association between left atrial stiffness index and atrial fibrillation recurrence in patients undergoing left atrial ablation . Circ Arrhythm Electrophysiol 2016 ; 9 : e003163 . Google Scholar CrossRef Search ADS PubMed Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. 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) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png European Heart Journal – Cardiovascular Imaging Oxford University Press

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Abstract

Abstract Aims To obtain the normal ranges for echocardiographic measurements of left atrial (LA) function from a large group of healthy volunteers accounting for age and gender. Methods and results A total of 371 (median age 45 years) healthy subjects were enrolled at 22 collaborating institutions collaborating in the Normal Reference Ranges for Echocardiography (NORRE) study of the European Association of Cardiovascular Imaging (EACVI). Left atrial data sets were analysed with a vendor-independent software (VIS) package allowing homogeneous measurements irrespective of the echocardiographic equipment used to acquire data sets. The lowest expected values of LA function were 26.1%, 48.7%, and 41.4% for left atrial strain (LAS), 2D left atrial emptying fraction (LAEF), and 3D LAEF (reservoir function); 7.7%, 24.2%, and −0.53/s for LAS-active, LAEF-active, and LA strain rate during LA contraction (SRa) (pump function) and 12.0% and 21.6% for LAS-passive and LAEF-passive (conduit function). Left atrial reservoir and conduit function were decreased with age while pump function was increased. All indices of reservoir function and all LA strains had no difference in both gender and vendor. However, inter-vendor differences were observed in LA SRa despite the use of VIS. Conclusion The NORRE study provides contemporary, applicable echocardiographic reference ranges for LA function. Our data highlight the importance of age-specific reference values for LA functions. adult echocardiography, left atrial function, deformation imaging, reference values Introduction The left atrium is extremely sensitive to sustained volume and pressure overload secondary to increased left ventricular filling pressures,1 and the stepwise backward effects of loss in left atrial (LA) functional properties are a reduction in lung vessel compliance and vascular remodelling that trigger right ventricular overload and dysfunction.2 In contrast to left ventricular measures, there is a strong linear relationship between volumetric and longitudinal deformation indices of left atrium.3 Early detection of subclinical LA dysfunction plays a crucial role in the evaluation of many cardiac diseases.4–9 Although normal ranges of LA function have been reported in recent studies,10–13 age related normal references remain unknown. The Normal Reference Ranges for Echocardiography (NORRE) study is the first European, large, prospective, multicentre study performed in 22 laboratories accredited by the European Association of Cardiovascular Imaging (EACVI) and in one American laboratory. The NORRE study has already provided reference values for all 2D echocardiographic measurements of the four cardiac chambers,14 Doppler parameters,15 aortic dimensions,16 left ventricular strains,17 and 3D echocardiographic measurements of LV volumes and strain.18 This report aimed (i) to establish normal reference limits, using vendor-independent software (VIS), for 2D and 3D measurement of LA function in healthy adults and (ii) to examine the influence of age, gender, and vendor on the reference ranges. Methods Patient population A total of 734 healthy European subjects constituted the final NORRE study population. The local ethics committees approved the study protocol. After the exclusion of patients that had incompatible image format and/or poor image quality, the final study population consisted of 371 normal subjects. Baseline clinical characteristics of patients included in and excluded from this study are shown in Supplementary data online, Table S1. Echocardiographic examination A comprehensive echocardiographic examination was performed using state-of-the-art echocardiographic ultrasound systems (GE Vivid E9; Vingmed Ultrasound, Horten, Norway, and/or iE33; Philips Medical Systems, Andover, MA, USA) following recommended protocols approved by the EACVI.19,20 All echocardiographic images were recorded in a digital raw-data format (native DICOM format) and centralized for further analysis, after anonymization, at the EACVI Central Core Laboratory at the University of Liège, Belgium. LA functions and stiffness analysis Based on previous validated studies and guidelines of the American Society of Echocardiography/EACVI, quantification of LA 2D strain, 2D volume, and 3D volume was performed using commercially available VIS (2D Cardiac Performance Analysis and 4D Cardio-View, TomTec Imaging System, Munich, Germany) (Figure 1).10,21 2D analyses were performed in the apical four- and two-chamber views. The most suitable cardiac cycle was chosen for each view. The reference point was set at the beginning of the QRS complex. Left atrial end-systole was identified as the time point in which the LA cavity was the smallest. The endocardial border was traced in end-systole. The accuracy of tracking was visually confirmed throughout the cardiac cycle and confirmed from the morphology of the strain curves. If necessary, the region of interest was readjusted. In the measurement of LA 3D volumes, end-diastole was identified as the time point in which the LA cavity is the largest and end-systole as the time point at which the cavity was the smallest. The definition of LA reservoir, pump, and conduit function in this study is demonstrated in Figure 2. Left atrial reservoir function was assessed using the left atrial strain curve (LAS), left atrial emptying fraction (LAEF) in both 2D and 3D. As shown in Figure 2, LA pump function was assessed using LAS-active: LA strain at the onset time of the P wave, LAEF-active: (LA volume at the onset time of the P wave − LA minimum volume)/LA volume at the onset time of the P wave and LA strain rate during LA contraction (SRa).10 Left atrial conduit function was assessed by using LAS-passive: LAS − LAS-active, and LAEF-passive: (LA maximum volume − LA volume at the onset time of the P wave)/LA maximum volume. The ratio of mitral inflow E/e’ to LA reservoir function (LAS, LAEF) was used to estimate LA stiffness.22 Figure 1 View largeDownload slide Measurements of LA strain and strain rate by 2D speckle-tracking echocardiography analysis and LA volume by 2D and 3D echocardiography analysis using VIS. VIS, vendor-independent software; LA, left atrial; LAV, left atrial volume. Figure 1 View largeDownload slide Measurements of LA strain and strain rate by 2D speckle-tracking echocardiography analysis and LA volume by 2D and 3D echocardiography analysis using VIS. VIS, vendor-independent software; LA, left atrial; LAV, left atrial volume. Figure 2 View largeDownload slide Assessments of LA reservoir, pump and conduit function using LA strain analysis and LA volume. EF, emptying fraction; LA, left atrial; LAS, left atrial strain; SRa, strain rate. Figure 2 View largeDownload slide Assessments of LA reservoir, pump and conduit function using LA strain analysis and LA volume. EF, emptying fraction; LA, left atrial; LAS, left atrial strain; SRa, strain rate. Statistical analysis Normality of the distribution of continuous variables was tested by the Shapiro–Wilk test. All data are presented as the mean ± standard deviation or median (interquartile range) as appropriate. Group differences were evaluated using the Student’s t-test for normally distributed continuous variables and the Mann–Whitney U test for non-normally distributed continuous variables. Correlation between continuous variables was performed Pearson’s or Spearman’s correlation coefficient as appropriate. The lowest (2.5th percentile) and highest (97.5th percentile) expected values for left atrial parameters were estimated in 1000 bootstrap samples to generate sampling distributions. For each of these values, the mean and standard errors were estimated from the simulated sampling distribution. Multiple linear regression analyses were performed to examine the independent correlates between LA functions and baseline parameters including cardiovascular risk factors (age, gender, body mass index, systolic blood pressure, diastolic blood pressure, glycaemia, and cholesterol level) and vendor. Intra-observer (T.S.) variability was assessed in 20 randomly selected subjects using intraclass correlation coefficient (ICC). A P-value of <0.05 was considered as statistically significant. Data were analysed using open source statistical software, R version 3.3.2 (R Foundation for Statistical Computing, www.R-project.org) and SPSS 19.0 software (SPSS Inc., Chicago, IL, USA). Results Demographic data Table 1 summarizes the demographic data of the cohort of the NORRE population analysed in this study. A total of 165 men and 206 women were included. There was no significant association between age and 3D LA volume index on univariable analysis (R = 0.09, P = 0.07) and no differences in 3D LA volume index for gender. Values for LA reservoir, pump, and conduit function obtained from analysis of LA volume and strain curves for the entire study population are summarized in Table 2. The lowest limits of normality were 26.1%, 48.7%, and 41.4% for LAS, 2D LAEF, and 3D LAEF (reservoir function), respectively; 7.7%, 24.2%, and −0.53/s for LAS-active, LAEF-active, and LA SRa (pump function), respectively; and 12.0% and 21.6% for LAS-passive and LAEF-passive (conduit function), respectively. All LA parameters except SRa were significantly associated with age. Gender differences were observed in LAEF-passive. Vendor differences were observed in 2D LAEF, LAEF-active, and LA SRa. Multivariable analysis for LA functions showed that LAS, 2D LAEF, 3D LAEF, LAS-passive, and LAEF-passive decreased whereas 3D LA volume index and LAS-active increased with age. After adjusting for variables including basic parameters and vendor, LAEF-passive was higher in women than in men and 3D LA volume index was higher and LA SRa was lower when acquired with GE platforms compared with Philips equipment, (Table 3). Figure 3 shows two representative cases of LA functional assessments (middle vs. advanced age). Table 1 Characteristics of the population Parameters Total (n = 371) Male (n = 165, 44%) Female (n = 206, 56%) P-value Age (years) 45 (34–55) 46 (33–57) 44 (34–54) 0.54 Height (cm) 170 ± 9 177 ± 7 165 ± 7 <0.001 Weight (kg) 69 (60–78) 77 (71–84) 63 (57–69) <0.001 Body surface area (m2) 1.79 (1.66–1.94) 1.94 (1.85–2.05) 1.68 (1.61–1.78) <0.001 Body mass index (kg/m2) 23.9 (22.0–26.0) 24.7 (23.2–26.4) 23.2 (21.1–25.4) <0.001 Systolic blood pressure (mmHg) 120 (110–130) 121 (117–130) 116 (108–126) <0.001 Diastolic blood pressure (mmHg) 75 (70–80) 77 (70–80) 73 (68–80) 0.002 Glycaemia (mg/dL) 90 (85–98) 91 (87–98) 90 (83–96) 0.017 Cholesterol level (mg/dL) 181 (163–197) 183 (160–197) 179 (164–196) 0.86 Parameters Total (n = 371) Male (n = 165, 44%) Female (n = 206, 56%) P-value Age (years) 45 (34–55) 46 (33–57) 44 (34–54) 0.54 Height (cm) 170 ± 9 177 ± 7 165 ± 7 <0.001 Weight (kg) 69 (60–78) 77 (71–84) 63 (57–69) <0.001 Body surface area (m2) 1.79 (1.66–1.94) 1.94 (1.85–2.05) 1.68 (1.61–1.78) <0.001 Body mass index (kg/m2) 23.9 (22.0–26.0) 24.7 (23.2–26.4) 23.2 (21.1–25.4) <0.001 Systolic blood pressure (mmHg) 120 (110–130) 121 (117–130) 116 (108–126) <0.001 Diastolic blood pressure (mmHg) 75 (70–80) 77 (70–80) 73 (68–80) 0.002 Glycaemia (mg/dL) 90 (85–98) 91 (87–98) 90 (83–96) 0.017 Cholesterol level (mg/dL) 181 (163–197) 183 (160–197) 179 (164–196) 0.86 Table 1 Characteristics of the population Parameters Total (n = 371) Male (n = 165, 44%) Female (n = 206, 56%) P-value Age (years) 45 (34–55) 46 (33–57) 44 (34–54) 0.54 Height (cm) 170 ± 9 177 ± 7 165 ± 7 <0.001 Weight (kg) 69 (60–78) 77 (71–84) 63 (57–69) <0.001 Body surface area (m2) 1.79 (1.66–1.94) 1.94 (1.85–2.05) 1.68 (1.61–1.78) <0.001 Body mass index (kg/m2) 23.9 (22.0–26.0) 24.7 (23.2–26.4) 23.2 (21.1–25.4) <0.001 Systolic blood pressure (mmHg) 120 (110–130) 121 (117–130) 116 (108–126) <0.001 Diastolic blood pressure (mmHg) 75 (70–80) 77 (70–80) 73 (68–80) 0.002 Glycaemia (mg/dL) 90 (85–98) 91 (87–98) 90 (83–96) 0.017 Cholesterol level (mg/dL) 181 (163–197) 183 (160–197) 179 (164–196) 0.86 Parameters Total (n = 371) Male (n = 165, 44%) Female (n = 206, 56%) P-value Age (years) 45 (34–55) 46 (33–57) 44 (34–54) 0.54 Height (cm) 170 ± 9 177 ± 7 165 ± 7 <0.001 Weight (kg) 69 (60–78) 77 (71–84) 63 (57–69) <0.001 Body surface area (m2) 1.79 (1.66–1.94) 1.94 (1.85–2.05) 1.68 (1.61–1.78) <0.001 Body mass index (kg/m2) 23.9 (22.0–26.0) 24.7 (23.2–26.4) 23.2 (21.1–25.4) <0.001 Systolic blood pressure (mmHg) 120 (110–130) 121 (117–130) 116 (108–126) <0.001 Diastolic blood pressure (mmHg) 75 (70–80) 77 (70–80) 73 (68–80) 0.002 Glycaemia (mg/dL) 90 (85–98) 91 (87–98) 90 (83–96) 0.017 Cholesterol level (mg/dL) 181 (163–197) 183 (160–197) 179 (164–196) 0.86 Table 2 Left atrial reservoir, pump, and conduit function Total Age Differences between gender Differences between vender Mean ± SD or medial (IQR) Limits of normality ± SEa,b R P-value P-value P-value  3D LA volume (mL) 47.7 (40.8 to 57.1) 78.7 ± 2.2a 0.10 0.06 <0.001 0.001  3D LA volume index (mL/m2) 26.3 (23.1 to 31.1) 40.6 ± 1.1a 0.09 0.07 0.07 0.001 Reservoir function  LAS (%) 42.5 (36.1 to 48.0) 26.1 ± 0.7b −0.47 <0.001 0.49 0.47  2D LAEF (%) 68.5 (63.2 to 73.2) 48.7 ± 1.9b −0.31 <0.001 0.42 0.02  3D LAEF (%) 57.3 (52.4 to 61.9) 41.4 ± 1.1b −0.17 <0.001 0.53 0.76 Pump function  LAS-active (%) 16.3 (12.9 to 19.5) 7.7 ± 0.3b 0.15 0.003 0.34 0.35  LAEF-active (%) 43.1 ± 9.4 24.2 ± 1.4b 0.14 0.008 0.13 0.002  LA SRa (/s) −1.31 (−1.99 to −0.95) −0.53 ± 0.03b −0.1 0.054 0.08 <0.001 Conduit function  LAS-passive (%) 25.7 (20.4 to 31.8) 12.0 ± 0.5b −0.61 <0.001 0.06 0.98  LAEF-passive (%) 43.0 ± 10.3 21.6 ± 0.9b −0.55 <0.001 0.008 0.85 Total Age Differences between gender Differences between vender Mean ± SD or medial (IQR) Limits of normality ± SEa,b R P-value P-value P-value  3D LA volume (mL) 47.7 (40.8 to 57.1) 78.7 ± 2.2a 0.10 0.06 <0.001 0.001  3D LA volume index (mL/m2) 26.3 (23.1 to 31.1) 40.6 ± 1.1a 0.09 0.07 0.07 0.001 Reservoir function  LAS (%) 42.5 (36.1 to 48.0) 26.1 ± 0.7b −0.47 <0.001 0.49 0.47  2D LAEF (%) 68.5 (63.2 to 73.2) 48.7 ± 1.9b −0.31 <0.001 0.42 0.02  3D LAEF (%) 57.3 (52.4 to 61.9) 41.4 ± 1.1b −0.17 <0.001 0.53 0.76 Pump function  LAS-active (%) 16.3 (12.9 to 19.5) 7.7 ± 0.3b 0.15 0.003 0.34 0.35  LAEF-active (%) 43.1 ± 9.4 24.2 ± 1.4b 0.14 0.008 0.13 0.002  LA SRa (/s) −1.31 (−1.99 to −0.95) −0.53 ± 0.03b −0.1 0.054 0.08 <0.001 Conduit function  LAS-passive (%) 25.7 (20.4 to 31.8) 12.0 ± 0.5b −0.61 <0.001 0.06 0.98  LAEF-passive (%) 43.0 ± 10.3 21.6 ± 0.9b −0.55 <0.001 0.008 0.85 IQR, interquartile range; SD, standard deviation; SE, standard error; other abbreviations as in Figure 2. a Highest expected values. b Lowest expected values. Table 2 Left atrial reservoir, pump, and conduit function Total Age Differences between gender Differences between vender Mean ± SD or medial (IQR) Limits of normality ± SEa,b R P-value P-value P-value  3D LA volume (mL) 47.7 (40.8 to 57.1) 78.7 ± 2.2a 0.10 0.06 <0.001 0.001  3D LA volume index (mL/m2) 26.3 (23.1 to 31.1) 40.6 ± 1.1a 0.09 0.07 0.07 0.001 Reservoir function  LAS (%) 42.5 (36.1 to 48.0) 26.1 ± 0.7b −0.47 <0.001 0.49 0.47  2D LAEF (%) 68.5 (63.2 to 73.2) 48.7 ± 1.9b −0.31 <0.001 0.42 0.02  3D LAEF (%) 57.3 (52.4 to 61.9) 41.4 ± 1.1b −0.17 <0.001 0.53 0.76 Pump function  LAS-active (%) 16.3 (12.9 to 19.5) 7.7 ± 0.3b 0.15 0.003 0.34 0.35  LAEF-active (%) 43.1 ± 9.4 24.2 ± 1.4b 0.14 0.008 0.13 0.002  LA SRa (/s) −1.31 (−1.99 to −0.95) −0.53 ± 0.03b −0.1 0.054 0.08 <0.001 Conduit function  LAS-passive (%) 25.7 (20.4 to 31.8) 12.0 ± 0.5b −0.61 <0.001 0.06 0.98  LAEF-passive (%) 43.0 ± 10.3 21.6 ± 0.9b −0.55 <0.001 0.008 0.85 Total Age Differences between gender Differences between vender Mean ± SD or medial (IQR) Limits of normality ± SEa,b R P-value P-value P-value  3D LA volume (mL) 47.7 (40.8 to 57.1) 78.7 ± 2.2a 0.10 0.06 <0.001 0.001  3D LA volume index (mL/m2) 26.3 (23.1 to 31.1) 40.6 ± 1.1a 0.09 0.07 0.07 0.001 Reservoir function  LAS (%) 42.5 (36.1 to 48.0) 26.1 ± 0.7b −0.47 <0.001 0.49 0.47  2D LAEF (%) 68.5 (63.2 to 73.2) 48.7 ± 1.9b −0.31 <0.001 0.42 0.02  3D LAEF (%) 57.3 (52.4 to 61.9) 41.4 ± 1.1b −0.17 <0.001 0.53 0.76 Pump function  LAS-active (%) 16.3 (12.9 to 19.5) 7.7 ± 0.3b 0.15 0.003 0.34 0.35  LAEF-active (%) 43.1 ± 9.4 24.2 ± 1.4b 0.14 0.008 0.13 0.002  LA SRa (/s) −1.31 (−1.99 to −0.95) −0.53 ± 0.03b −0.1 0.054 0.08 <0.001 Conduit function  LAS-passive (%) 25.7 (20.4 to 31.8) 12.0 ± 0.5b −0.61 <0.001 0.06 0.98  LAEF-passive (%) 43.0 ± 10.3 21.6 ± 0.9b −0.55 <0.001 0.008 0.85 IQR, interquartile range; SD, standard deviation; SE, standard error; other abbreviations as in Figure 2. a Highest expected values. b Lowest expected values. Table 3 Multivariable analysis for left atrial functions Variables Basic parametersa Basic parametersa + vendor β-coefficients ± SE P-value β-coefficients ± SE P-value 3D LA volume index (mL/m2)  Age (years) 0.07 ± 0.03 0.029  Cholesterol level (mg/dL) −0.03 ± 0.01 0.033 −0.03 ± 0.01 0.009  Male gender 1.62 ± 0.77 0.037  Vendor (GE as referent) −3.94 ± 0.74 <0.001 LAS (%)  Age (years) −0.32 ± 0.04 <0.001 −0.33 ± 0.04 <0.001  Body mass index (kg/m2) −0.39 ± 0.18 0.03 −0.42 ± 0.18 0.02  Glycaemia (mg/dL) −0.09 ± 0.04 0.049 2D LAEF, (%)  Age (years) −0.20 ± 0.04 <0.001 −0.21 ± 0.04 <0.001 3D LAEF (%)  Age (years) −0.11 ± 0.04 0.008 −0.10 ± 0.04 0.013 LAS-active (%)  Age (years) 0.06 ± 0.02 0.02 0.06 ± 0.03 0.02  Glycaemia (mg/dL) −0.07 ± 0.02 0.005 −0.07 ± 0.02 0.006 LAEF-active (%)  Body mass index (kg/m2) 0.40 ± 0.20 0.047  Glycaemia (mg/dL) −0.10 ± 0.05 0.036 −0.10 ± 0.05 0.045 LA SRa (/s)  Age (years) −0.01 ± 0.004 0.01  Vendor (GE as referent) −1.08 ± 0.08 <0.001 LAS-passive (%)  Age (years) −0.37 ± 0.04 <0.001 −0.38 ± 0.04 <0.001  Body mass index (kg/m2) −0.53 ± 0.16 0.001 −0.56 ± 0.16 <0.001 LAEF-passive (%)  Age (years) −0.43 ± 0.05 <0.001 −0.43 ± 0.05 <0.001  Male gender −2.42 ± 1.18 0.04  Body mass index (kg/m2) −0.52 ± 0.19 0.007 −0.55 ± 0.19 0.005 Variables Basic parametersa Basic parametersa + vendor β-coefficients ± SE P-value β-coefficients ± SE P-value 3D LA volume index (mL/m2)  Age (years) 0.07 ± 0.03 0.029  Cholesterol level (mg/dL) −0.03 ± 0.01 0.033 −0.03 ± 0.01 0.009  Male gender 1.62 ± 0.77 0.037  Vendor (GE as referent) −3.94 ± 0.74 <0.001 LAS (%)  Age (years) −0.32 ± 0.04 <0.001 −0.33 ± 0.04 <0.001  Body mass index (kg/m2) −0.39 ± 0.18 0.03 −0.42 ± 0.18 0.02  Glycaemia (mg/dL) −0.09 ± 0.04 0.049 2D LAEF, (%)  Age (years) −0.20 ± 0.04 <0.001 −0.21 ± 0.04 <0.001 3D LAEF (%)  Age (years) −0.11 ± 0.04 0.008 −0.10 ± 0.04 0.013 LAS-active (%)  Age (years) 0.06 ± 0.02 0.02 0.06 ± 0.03 0.02  Glycaemia (mg/dL) −0.07 ± 0.02 0.005 −0.07 ± 0.02 0.006 LAEF-active (%)  Body mass index (kg/m2) 0.40 ± 0.20 0.047  Glycaemia (mg/dL) −0.10 ± 0.05 0.036 −0.10 ± 0.05 0.045 LA SRa (/s)  Age (years) −0.01 ± 0.004 0.01  Vendor (GE as referent) −1.08 ± 0.08 <0.001 LAS-passive (%)  Age (years) −0.37 ± 0.04 <0.001 −0.38 ± 0.04 <0.001  Body mass index (kg/m2) −0.53 ± 0.16 0.001 −0.56 ± 0.16 <0.001 LAEF-passive (%)  Age (years) −0.43 ± 0.05 <0.001 −0.43 ± 0.05 <0.001  Male gender −2.42 ± 1.18 0.04  Body mass index (kg/m2) −0.52 ± 0.19 0.007 −0.55 ± 0.19 0.005 SE, standard error; other abbreviations as in Figure 2. a Age, gender, body mass index, systolic blood pressure, diastolic blood pressure, glycaemia and cholesterol level. Table 3 Multivariable analysis for left atrial functions Variables Basic parametersa Basic parametersa + vendor β-coefficients ± SE P-value β-coefficients ± SE P-value 3D LA volume index (mL/m2)  Age (years) 0.07 ± 0.03 0.029  Cholesterol level (mg/dL) −0.03 ± 0.01 0.033 −0.03 ± 0.01 0.009  Male gender 1.62 ± 0.77 0.037  Vendor (GE as referent) −3.94 ± 0.74 <0.001 LAS (%)  Age (years) −0.32 ± 0.04 <0.001 −0.33 ± 0.04 <0.001  Body mass index (kg/m2) −0.39 ± 0.18 0.03 −0.42 ± 0.18 0.02  Glycaemia (mg/dL) −0.09 ± 0.04 0.049 2D LAEF, (%)  Age (years) −0.20 ± 0.04 <0.001 −0.21 ± 0.04 <0.001 3D LAEF (%)  Age (years) −0.11 ± 0.04 0.008 −0.10 ± 0.04 0.013 LAS-active (%)  Age (years) 0.06 ± 0.02 0.02 0.06 ± 0.03 0.02  Glycaemia (mg/dL) −0.07 ± 0.02 0.005 −0.07 ± 0.02 0.006 LAEF-active (%)  Body mass index (kg/m2) 0.40 ± 0.20 0.047  Glycaemia (mg/dL) −0.10 ± 0.05 0.036 −0.10 ± 0.05 0.045 LA SRa (/s)  Age (years) −0.01 ± 0.004 0.01  Vendor (GE as referent) −1.08 ± 0.08 <0.001 LAS-passive (%)  Age (years) −0.37 ± 0.04 <0.001 −0.38 ± 0.04 <0.001  Body mass index (kg/m2) −0.53 ± 0.16 0.001 −0.56 ± 0.16 <0.001 LAEF-passive (%)  Age (years) −0.43 ± 0.05 <0.001 −0.43 ± 0.05 <0.001  Male gender −2.42 ± 1.18 0.04  Body mass index (kg/m2) −0.52 ± 0.19 0.007 −0.55 ± 0.19 0.005 Variables Basic parametersa Basic parametersa + vendor β-coefficients ± SE P-value β-coefficients ± SE P-value 3D LA volume index (mL/m2)  Age (years) 0.07 ± 0.03 0.029  Cholesterol level (mg/dL) −0.03 ± 0.01 0.033 −0.03 ± 0.01 0.009  Male gender 1.62 ± 0.77 0.037  Vendor (GE as referent) −3.94 ± 0.74 <0.001 LAS (%)  Age (years) −0.32 ± 0.04 <0.001 −0.33 ± 0.04 <0.001  Body mass index (kg/m2) −0.39 ± 0.18 0.03 −0.42 ± 0.18 0.02  Glycaemia (mg/dL) −0.09 ± 0.04 0.049 2D LAEF, (%)  Age (years) −0.20 ± 0.04 <0.001 −0.21 ± 0.04 <0.001 3D LAEF (%)  Age (years) −0.11 ± 0.04 0.008 −0.10 ± 0.04 0.013 LAS-active (%)  Age (years) 0.06 ± 0.02 0.02 0.06 ± 0.03 0.02  Glycaemia (mg/dL) −0.07 ± 0.02 0.005 −0.07 ± 0.02 0.006 LAEF-active (%)  Body mass index (kg/m2) 0.40 ± 0.20 0.047  Glycaemia (mg/dL) −0.10 ± 0.05 0.036 −0.10 ± 0.05 0.045 LA SRa (/s)  Age (years) −0.01 ± 0.004 0.01  Vendor (GE as referent) −1.08 ± 0.08 <0.001 LAS-passive (%)  Age (years) −0.37 ± 0.04 <0.001 −0.38 ± 0.04 <0.001  Body mass index (kg/m2) −0.53 ± 0.16 0.001 −0.56 ± 0.16 <0.001 LAEF-passive (%)  Age (years) −0.43 ± 0.05 <0.001 −0.43 ± 0.05 <0.001  Male gender −2.42 ± 1.18 0.04  Body mass index (kg/m2) −0.52 ± 0.19 0.007 −0.55 ± 0.19 0.005 SE, standard error; other abbreviations as in Figure 2. a Age, gender, body mass index, systolic blood pressure, diastolic blood pressure, glycaemia and cholesterol level. Figure 3 View largeDownload slide Two representative cases of LA functional assessments. LAV, left atrial volume; other abbreviations as in Figure 2. Figure 3 View largeDownload slide Two representative cases of LA functional assessments. LAV, left atrial volume; other abbreviations as in Figure 2. Age and LA functions relationship Left atrial reservoir, pump, and conduit function and stiffness in the three subgroups according to age (20–40, 40–60, and ≥60 years) are displayed in Table 4. The lowest expected values for LAS were 31.1% in 20–40 years of age, 27.7% in 40–60 years, and 22.7% in ≥60 years. The highest expected values for LA stiffness calculated from LAS were 0.22 in 20–40 years of age, 0.42 in 40–60 years, and 0.55 in ≥60 years. Table 4 Left atrial functions and stiffness according to age Age 20–40 (n = 137) Age 40–60 (n = 173) Age ≥60 (n = 61) Medial (IQR) Limits of normality  ± SEa,b Medial (IQR) Limits of normality  ± SEa,b Medial (IQR) Limits of normality  ± SEa,b Reservoir function  LAS (%) 46.8 (42.3–52.4) 31.1 ± 2.6b 40.9 (35.4–46.1) 27.7 ± 1.5b 35.5 (30.9–41.9) 22.7 ± 2.0b  2D LAEF (%) 71.3 (67.3–74.9) 51.7 ± 2.0b 66.7 (62.8–72.4) 49.2 ± 2.7b 64.0 (58.1–69.5) 44.1 ± 1.7b  3D LAEF (%) 58.4 (53.1–63.1) 42.2 ± 2.3b 57.1 (52.2–61.3) 39.4 ± 1.9b 55.6 (50.6–60.4) 38.3 ± 2.5b Pump function  LAS-active (%) 15.6 (11.9–19.0) 7.2 ± 0.5b 16.3 (13.2–19.6) 9.3 ± 0.8b 16.8 (13.6–21.4) 7.7 ± 0.8b Conduit function  LAS-passive (%) 30.6 (26.8–36.5) 16.2 ± 1.6b 24.1 (19.7–29.3) 12.0 ± 1.0b 18.6 (14.7–22.6) 11.5 ± 0.1b Stiffness  E/e’ divided by LAS 0.12 (0.10–0.15) 0.22 ± 0.01a 0.16 (0.13–0.22) 0.42 ± 0.04a 0.24 (0.18–0.29) 0.55 ± 0.09a  E/e’ divided by 2D LAEF 0.08 (0.07–0.09) 0.15 ± 0.01a 0.10 (0.09–0.12) 0.23 ± 0.04a 0.14 (0.11–0.15) 0.24 ± 0.02a  E/e’ divided by 3D LAEF 0.10 (0.08–0.12) 0.19 ± 0.01a 0.11 (0.10–0.15) 0.24 ± 0.04a 0.15 (0.13–0.17) 0.27 ± 0.02a  E/e’ 5.6 (4.8–6.7) 9.0 ± 1.3a 6.8 (5.8–8.3) 13.4 ± 2.4a 8.3 (7.1–9.8) 13.3 ± 0.5a Age 20–40 (n = 137) Age 40–60 (n = 173) Age ≥60 (n = 61) Medial (IQR) Limits of normality  ± SEa,b Medial (IQR) Limits of normality  ± SEa,b Medial (IQR) Limits of normality  ± SEa,b Reservoir function  LAS (%) 46.8 (42.3–52.4) 31.1 ± 2.6b 40.9 (35.4–46.1) 27.7 ± 1.5b 35.5 (30.9–41.9) 22.7 ± 2.0b  2D LAEF (%) 71.3 (67.3–74.9) 51.7 ± 2.0b 66.7 (62.8–72.4) 49.2 ± 2.7b 64.0 (58.1–69.5) 44.1 ± 1.7b  3D LAEF (%) 58.4 (53.1–63.1) 42.2 ± 2.3b 57.1 (52.2–61.3) 39.4 ± 1.9b 55.6 (50.6–60.4) 38.3 ± 2.5b Pump function  LAS-active (%) 15.6 (11.9–19.0) 7.2 ± 0.5b 16.3 (13.2–19.6) 9.3 ± 0.8b 16.8 (13.6–21.4) 7.7 ± 0.8b Conduit function  LAS-passive (%) 30.6 (26.8–36.5) 16.2 ± 1.6b 24.1 (19.7–29.3) 12.0 ± 1.0b 18.6 (14.7–22.6) 11.5 ± 0.1b Stiffness  E/e’ divided by LAS 0.12 (0.10–0.15) 0.22 ± 0.01a 0.16 (0.13–0.22) 0.42 ± 0.04a 0.24 (0.18–0.29) 0.55 ± 0.09a  E/e’ divided by 2D LAEF 0.08 (0.07–0.09) 0.15 ± 0.01a 0.10 (0.09–0.12) 0.23 ± 0.04a 0.14 (0.11–0.15) 0.24 ± 0.02a  E/e’ divided by 3D LAEF 0.10 (0.08–0.12) 0.19 ± 0.01a 0.11 (0.10–0.15) 0.24 ± 0.04a 0.15 (0.13–0.17) 0.27 ± 0.02a  E/e’ 5.6 (4.8–6.7) 9.0 ± 1.3a 6.8 (5.8–8.3) 13.4 ± 2.4a 8.3 (7.1–9.8) 13.3 ± 0.5a CI, confidence interval; SD, standard deviation; other abbreviations as in Figure 2. a Highest expected values. b Lowest expected values. Table 4 Left atrial functions and stiffness according to age Age 20–40 (n = 137) Age 40–60 (n = 173) Age ≥60 (n = 61) Medial (IQR) Limits of normality  ± SEa,b Medial (IQR) Limits of normality  ± SEa,b Medial (IQR) Limits of normality  ± SEa,b Reservoir function  LAS (%) 46.8 (42.3–52.4) 31.1 ± 2.6b 40.9 (35.4–46.1) 27.7 ± 1.5b 35.5 (30.9–41.9) 22.7 ± 2.0b  2D LAEF (%) 71.3 (67.3–74.9) 51.7 ± 2.0b 66.7 (62.8–72.4) 49.2 ± 2.7b 64.0 (58.1–69.5) 44.1 ± 1.7b  3D LAEF (%) 58.4 (53.1–63.1) 42.2 ± 2.3b 57.1 (52.2–61.3) 39.4 ± 1.9b 55.6 (50.6–60.4) 38.3 ± 2.5b Pump function  LAS-active (%) 15.6 (11.9–19.0) 7.2 ± 0.5b 16.3 (13.2–19.6) 9.3 ± 0.8b 16.8 (13.6–21.4) 7.7 ± 0.8b Conduit function  LAS-passive (%) 30.6 (26.8–36.5) 16.2 ± 1.6b 24.1 (19.7–29.3) 12.0 ± 1.0b 18.6 (14.7–22.6) 11.5 ± 0.1b Stiffness  E/e’ divided by LAS 0.12 (0.10–0.15) 0.22 ± 0.01a 0.16 (0.13–0.22) 0.42 ± 0.04a 0.24 (0.18–0.29) 0.55 ± 0.09a  E/e’ divided by 2D LAEF 0.08 (0.07–0.09) 0.15 ± 0.01a 0.10 (0.09–0.12) 0.23 ± 0.04a 0.14 (0.11–0.15) 0.24 ± 0.02a  E/e’ divided by 3D LAEF 0.10 (0.08–0.12) 0.19 ± 0.01a 0.11 (0.10–0.15) 0.24 ± 0.04a 0.15 (0.13–0.17) 0.27 ± 0.02a  E/e’ 5.6 (4.8–6.7) 9.0 ± 1.3a 6.8 (5.8–8.3) 13.4 ± 2.4a 8.3 (7.1–9.8) 13.3 ± 0.5a Age 20–40 (n = 137) Age 40–60 (n = 173) Age ≥60 (n = 61) Medial (IQR) Limits of normality  ± SEa,b Medial (IQR) Limits of normality  ± SEa,b Medial (IQR) Limits of normality  ± SEa,b Reservoir function  LAS (%) 46.8 (42.3–52.4) 31.1 ± 2.6b 40.9 (35.4–46.1) 27.7 ± 1.5b 35.5 (30.9–41.9) 22.7 ± 2.0b  2D LAEF (%) 71.3 (67.3–74.9) 51.7 ± 2.0b 66.7 (62.8–72.4) 49.2 ± 2.7b 64.0 (58.1–69.5) 44.1 ± 1.7b  3D LAEF (%) 58.4 (53.1–63.1) 42.2 ± 2.3b 57.1 (52.2–61.3) 39.4 ± 1.9b 55.6 (50.6–60.4) 38.3 ± 2.5b Pump function  LAS-active (%) 15.6 (11.9–19.0) 7.2 ± 0.5b 16.3 (13.2–19.6) 9.3 ± 0.8b 16.8 (13.6–21.4) 7.7 ± 0.8b Conduit function  LAS-passive (%) 30.6 (26.8–36.5) 16.2 ± 1.6b 24.1 (19.7–29.3) 12.0 ± 1.0b 18.6 (14.7–22.6) 11.5 ± 0.1b Stiffness  E/e’ divided by LAS 0.12 (0.10–0.15) 0.22 ± 0.01a 0.16 (0.13–0.22) 0.42 ± 0.04a 0.24 (0.18–0.29) 0.55 ± 0.09a  E/e’ divided by 2D LAEF 0.08 (0.07–0.09) 0.15 ± 0.01a 0.10 (0.09–0.12) 0.23 ± 0.04a 0.14 (0.11–0.15) 0.24 ± 0.02a  E/e’ divided by 3D LAEF 0.10 (0.08–0.12) 0.19 ± 0.01a 0.11 (0.10–0.15) 0.24 ± 0.04a 0.15 (0.13–0.17) 0.27 ± 0.02a  E/e’ 5.6 (4.8–6.7) 9.0 ± 1.3a 6.8 (5.8–8.3) 13.4 ± 2.4a 8.3 (7.1–9.8) 13.3 ± 0.5a CI, confidence interval; SD, standard deviation; other abbreviations as in Figure 2. a Highest expected values. b Lowest expected values. Vendor and LA functions relationship Multivariable analysis showed that 3D LA volume index was higher [GE, 27.8 (24.2–32.2) mL/m2, n = 189 vs. Philips, 25.5 (22.8–29.3) mL/m2, n = 184, P = 0.001] and LA SRa was lower [GE, −0.98 (−1.16 to −0.73)/s vs. Philips, −1.99 (−2.42 to −1.58)/s, P < 0.001] with GE compared with Philips equipment for the total population. The same tendency was observed for the apical four-chambers [−0.84 (−1.12 to −0.65) vs. −1.81 (−2.28 to −1.32)/s, P < 0.001] and two-chambers [−1.11 (−1.31 to −0.82) vs. −2.25 (−2.65 to −1.70)/s, P < 0.001] LA SRa. The number of patients whose LA SRa could not be identified on LA strain analysis was significantly higher with GE than Philips (8% vs. 0% and 38% vs. 15% in apical four- and two-chambers view, P < 0.001, respectively). The lowest expected values for LA SRa were −0.47/s (GE) and −0.86/s (Philips). The highest expected values for LA volume index were 41.3 mL/m2 (GE) and 39.6 mL/m2 (Philips). Repeatability Intra-observer analysis showed excellent repeatability in LAS, LAS-active, LA SRa, and 3D LA volume (ICC = 0.85, 0.71, 0.79, and 0.90, P < 0.01, respectively). Discussion The present prospective, EACVI multicentre study provides contemporary normal reference values for LA function in a large cohort of healthy volunteers over a wide range of ages. 2DE analyses were performed using a VIS in order to obtain homogeneous measurements irrespective of the echocardiographic equipment used to acquire data. Left atrial reservoir and conduit function decreased with age while pump function increased. All indices of reservoir function and LA strains had no gender and vendor differences. Interestingly, inter-vendor differences were observed in 3D LA volume index and LA SRa despite the use of VIS software. Previous single-centre studies with healthy subjects reported that the highest expected value for 3D LA volume index was: 33 mL/m2 in the study of Wu et al.,23 a Japanese cohort, using Philips equipment and software, 41 mL/m2 in the study of Aune et al.,24 a Norway cohort, using Philips equipment and software, and 43 mL/m2 in the study of Badano et al.,13 an Italian cohort, using GE equipment and TomTec software. This multicentre study with a Caucasian European population showed lower 3D LA volume index compared with single-centre studies in the Norway and Italy. The reasons for this difference may be caused by several factors: (i) lower temporal resolution of 3D echocardiographic data sets caused by a wide-angle 3D acquisition for the LA13; (ii) the difference in baseline blood pressure in male [systolic/diastolic blood pressure: 123/76 mmHg (mean) and 121/77 mmHg (median) in this study vs. 127/79 mmHg (mean) in the Norwegian cohort and 130/80 mmHg (median) in the Italian cohort]; and (iii) inter-vendor differences as demonstrated in this study. A previous multicentre study reporting on a large cohort of healthy subjects showed that LAS and LAEF were negatively associated with age while having no differences in gender.10 A meta-analysis of LA strain using 2D speckle tracking echocardiography has detected no difference in both gender and vendor.11 These finding are consistent with the findings of this study. The mechanism of age-related changes in LA function, in particular pump function, may be explained by age-related changes in left ventricular diastolic performance from normal to diastolic dysfunction grade 1.25 In fact, our data demonstrated the age-related increases in LA stiffness, an index that has been reported as a sensitive marker of diastolic dysfunction.22,26 This study showed that the best concordance between the two major vendors was in LA strain whereas the major discordance was noted in 3D LA volume index and SRa. These data support the use of comparable values independently of the machine used to acquire LA images. Limitations This study presents several limitations. First, only half of the patients included in the study were available for LA function analysis indicating that dependency on image quality is one of the main limitations for strain analysis by speckle tracking. Second, the existence of inter-vendor differences in 3D LA volume index and LA SRa was not confirmed by the direct comparison in the same patients. Further study is warranted to investigate the cause of the inter-vendor differences. Last of all, whether the NORRE study results can be extrapolated to non-Caucasian European individuals is still unknown. Conclusion The NORRE study provides applicable reference ranges for LA functions. Multivariable analysis showed that age is independently associated with all LAS components irrespective of gender and vendor. Our data highlight the importance of age-specific assessment for LA function. Supplementary data Supplementary data are available at European Heart Journal - Cardiovascular Imaging online. Acknowledgements The EACVI Research and Innovation Committee thanks the Heart House for its support. Funding The NORRE Study is supported by GE Healthcare and Philips Healthcare in the form of an unrestricted educational grant. TomTec has provided the software for strain analysis. Sponsor funding has in no way influenced the content or management of this study. Appendix of the list of contributors to the NORRE Study Patrizio Lancellotti, Raluca Dulgheru, Seisyou Kou, Tadafumi Sugimoto, Anne Bernard, Federica Ilardi, Stella Marchetta, Alain Nchimi, Sébastien Robinet, Yun Yun Go, University of Liège hospital, GIGA Cardiovascular Science, Heart Valve Clinic, Imaging Cardiology, Belgium; Daniele Barone, Laboratory of Cardiovascular Ecography Cardiology Department, S. Andrea Hospital, La Spezia, Italy; Monica Baroni, Laboratorio Di Ecocardiografia Adulti, Fondazione Toscana ‘G. Monasterio’-Ospedale Del Cuore, Massa, Italy; Jose Juan Gomez de Diego, Unidad de Imagen Cardiovascular, ICV, Hospital Clinico San Carlos, Madrid, Spain; Andreas Hagendorff, Echokardiographie-Labore des Universitätsklinikums AöR, Department of Cardiology-Angiology, University of Leipzig, Leipzig, Germany; Krasimira Hristova, University National Heart Hospital, Department of Noninvasive Functional Diagnostic and Imaging, Sofia, Bulgaria; Gonzalo de la Morena, Luis Caballero, Daniel Saura, Unidad de Imagen Cardiaca, Servicio de Cardiologia, Hospital Clinico Universitario Virgen de la Arrixaca, IMIB-Arrixaca, Murcia, Spain; Teresa Lopez, Nieves Montoro, La Paz Hospital in Madrid, Spain; Jose Luis Zamorano, Covadonga Fernandez-Golfin, University Hospital Ramón y Cajal, Madrid, Spain; Nuno Cardim, Maria Adelaide Almeida, Hospital da Luz, Lisbon, Portugal; Bogdan A. Popescu, Monica Rosca, Andreea Calin, University of Medicine and Pharmacy ‘Carol Davila’-Euroecolab, Institute of Cardiovascular Diseases ‘Prof. Dr. C. C. Iliescu’, Bucharest, Romania; George Kacharava, Natalia Gonjilashvili, Levan Kurashvili, Natela Akhaladze, Zaza Mgaloblishvili, Echocardiography Laboratory of Adult Cardiology Department of the Joann Medical Center, Tbilisi, GA, USA; María José Oliva, Josefa González-Carrillo, ArrixacaIMIB, Murcia, Spain; George D. Athanassopoulos, Eftychia Demerouti, Noninvasive Diagnostics Department, Onassis Cardiac Surgery Center, Athens, Greece; Dragos Vinereanu, Roxana Rimbas, Andrea Olivia Ciobanu, Cardiovascular Research Unit, University and Emergency Hospital, University of Medicine and Pharmacy Carol Davila, Bucharest, Romania; Luigi P. Badano, Diletta Peluso, Seena Padayattil Jose, Department of Cardiac, Thoracic and Vascular Sciences University of Padova, School of Medicine, Padova, Italy; Nico van de Veire, Johan de Sutter, Echocardiography Unit-AZ Maria Middelares Gent, Belgium; Martin Penicka, Martin Kotrc, Cardiovascular Center Aalst, OLV-Clinic, Belgium; Jens-Uwe Voigt, Echocardiography Laboratory, Department of Cardiovascular Diseases, University Hospital Gasthuisberg, Leuven, Belgium; Tolga Ozyigit, VKV Amerikan Hastanesi, Kardiyoloji Bölümü, Istanbul, Turkey; Jose David Rodrigo Carbonero, Laboratorio de Ecocardiografia Hospital de Cruces–Barakaldo, Spain; Alessandro Salustri, SheikhKhalifa Medical City, PO Box: 51900, Abu Dhabi, United Arab; Ralph Stephan Von Bardeleben, Medical Department Cardiology, Universitätsmedizin of the Johannes Gutenberg University Mainz, Germany; Roberto M. Lang, Karima Addetia, Department of Medicine University of Chicago Medical Center, IL, USA. 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Association between left atrial stiffness index and atrial fibrillation recurrence in patients undergoing left atrial ablation . Circ Arrhythm Electrophysiol 2016 ; 9 : e003163 . Google Scholar CrossRef Search ADS PubMed Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. 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: Feb 23, 2018

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