Abstract
Background
While left atrial (LA) enlargement is a recognized risk factor for adverse cardiovascular (CV) outcomes, emerging evidence supports the importance of LA function. We examined LA emptying fraction (LAEF) across the spectrum of CV disease burden in a large cohort of elderly adults living in the community.
Methods and Results
We studied 1,142 participants in the Atherosclerosis Risk in Communities (ARIC) Study who were in sinus rhythm, free of valvular disease, and had acceptable quality 3D-echocardiograms (mean age 76±5 years, 59% women). We determined the cross-sectional correlates of LAEF and compared LAEF among elderly adults without CV disease or CV risk factors (n=201), those with hypertension (n=734), and those with overt heart failure (HF) (n=207). In multivariable analysis, lower LAEF was associated with higher LA volumes, worse LV systolic and diastolic function. Elderly participants free of CV disease or risk factors had smaller LA volumes than those with hypertension (LAV max/BSA 30.2 ± 6.6 ml/m2 vs. 33.0 ± 9.0ml/m2, p =0.001), but similar LAEF (55.2 ± 10.3% vs. 53.8 ± 11.5% respectively, p=0.357). Participants with HF had higher LA volume (39.8 ± 13.3 ml/m2) and worse LAEF (47.6 ± 14.6%) than participants with hypertension or participants free of CV disease or risk factors (all p values <0.001).
Conclusions
In a community-based cohort, LA function was impaired in participants with prevalent HF, but there were no significant differences in LA function between participants with hypertension and those free of CV disease or risk factors, despite greater LA size in the former.
Keywords: left atrium, cardiovascular disease risk factors, echocardiography, 3-dimensional, epidemiology, heart failure, left atrium function, hypertension
Left atrial (LA) enlargement is a robust predictor of cardiovascular outcomes in the general population1 and a marker of poor prognosis in patients with various cardiovascular (CV) diseases.2, 3 However, LA function measured by emptying fraction (LAEF) 4 or by global peak LA longitudinal strain (LA GLS) may provide incremental value to LA volume in predicting CV outcomes. 5-7
Recent technical advances have increased accessibility and usability of new imaging methods such as three dimensional echocardiography (3DE) and cardiac magnetic resonance imaging8 and this has motivated interest in more sophisticated study of LA morphology and its function.4 Nevertheless, there are few population-based studies of LA structure and function and little is known about LA function across the spectrum of cardiovascular (CV) risk, particularly among older adults. Therefore, we used both two dimensional echocardiography (2DE) and 3DE measures to comprehensively assess LA structure and function in a large biracial cohort of elderly men and women. Our aim is to examinethe cross-sectional correlates of LAEF as a measure of LA function, and to compared LA structure and function across the spectrum of CV disease, including elderly adults without evidence of CV disease or CV risk factors, those with hypertension, and those with overt heart failure (HF), from the Atherosclerosis Risk in Communities (ARIC) Study.
Methods
Study population
The ARIC Study is an ongoing, prospective observational study. Detailed study rationale, design, and procedures have been previously published.9 The original cohort included 15 792 men and women aged 45 to 64 years recruited between 1987 and 1989 (visit 1), selected from 4 communities in the United States: Forsyth County, North Carolina; Jackson, Mississippi; Minneapolis, Minnesota; and Washington County, Maryland. Subsequently, three follow-up visits (visit 2 to 4) occurred at 3-year intervals, with annual telephone interviews conducted between visits. Between 2011 and 2013, 6101 surviving participants underwent visit 5, when echocardiography was performed in all 4 ARIC field centers. Our analyses were restricted to a subset of 3,035 ARIC participants who attended at the first half of visit 5 until December 2012. Among those were excluded participants with insufficient 3DE image quality for LA assessment or with atrial fibrillation or other arrhythmia, as ventricular extrasystoles, at the time of the echocardiogram (n=1779), those with moderate or severe mitral, aortic or tricuspid valvular heart disease or who underwent valvular replacement surgery (n=64), participants with non-white or non-black race (n=16), and those with missing data on body mass index (BMI) or body surface area (BSA) (n=34). A total of 1,142 participants constitute the sample for the present analysis.
Institutional review boards from each site approved the study, and informed consent was obtained from all participants. Information on demographics, anthropomorphic measures, and blood pressure was obtained at the time of echocardiography. Standardized and validated interviewer-administered questionnaires included assessment of current medication, the presence of coronary artery disease (CAD) or diabetes mellitus (DM). Established definitions for DM, CAD, and smoking status were used as previously described in the ARIC study.10 Hypertension was defined as systolic blood pressure ≥140 or diastolic blood pressure ≥90 or medication being taken for high blood pressure during the last 4 weeks prior to visit, but 82% participants were taking antihypertensive medication and also fulfilled the high blood pressure criteria. Prevalent HF was defined by history of HF hospitalization, according to the International Classification of Diseases- Ninth Revision (ICD-9), code 410 in any position, obtained by ARIC Study retrospective surveillance of hospital discharges.11, 12 Total cholesterol, high-density lipoprotein cholesterol (HDL) and triglycerides levels were measured in a centralized laboratory. NT-proBNP was measured using electrochemiluminescent immunoassay (Roche Diagnostics) with a lower detection limit of 5pg/mL. The assays and their performance have been previously reported.13 Glomerular filtration rate (GFR) was estimated by the Modification of Diet in Renal Disease (MDRD) Study equation. For the purpose of this study, we defined three groups by CV profile: Group 1 (n=201) – “healthy” elderly participants without evidence of CAD, HF, hypertension, diabetes mellitus or obesity (BMI≥30 kg/m2); Group 2 (n=734) - participants with hypertension without CAD or HF, and Group 3 (n=207) - participants with HF.
Two-dimensional Echocardiography Protocol
The two-dimensional (2D) echocardiographic imaging and analysis protocol has been previously described in detail.14 All echocardiograms were performed using dedicated Philips iE33 Ultrasound systems with Vision 2011, using a preprogrammed acquisition protocol. All studies were acquired and stored digitally and transferred from field centers to a secure server at the Echocardiography Reading Center (ERC; Brigham and Women's Hospital, Boston, MA), where echocardiographic measures were performed and over read, using proprietary validated echocardiographic analysis software, blindly to participants' clinical characteristics.
Left ventricular (LV) dimensions, wall thickness and anterior-posterior LA dimension were measured from the parasternal long-axis view according to the recommendations of the American Society of Echocardiography (ASE).15 LV mass was calculated from LV linear dimensions and indexed to BSA as recommended by ASE guidelines. LV volumes and LV ejection fraction were calculated by the modified Simpson method using the apical 4- and 2-chamber views. 2D echocardiography LA volume was measured by the method of disks using apical 4- and 2-chamber views at an end-systolic frame preceding mitral valve opening. LV diastolic function classified according to Olmsted criteria.16, 17 Right ventricular (RV) function was assessed by RV fractional area change, calculated as the percent change in cavity area from end-diastolic to end-systolic tracings of the RV cavity in the apical 4-chamber view. Deformation analysis was performed on 2D images throughout the cardiac cycle, acquired at a frame rate of 50 to 80 frames per second, using the TomTec Cardiac Performance Analysis package.
Three-dimensional echocardiography
3DE acquisition was performed using X3-1 transducer iE33 (Philips Medical Systems) on wide-angled mode, with 4-wedged shaped pyramidal sub-volumes (93° × 21°) acquired during a single breath hold over 4 consecutive cardiac cycles, at a frame rate of 15-25Hz, depending on the selected line density. Proper gain settings were chosen by the operator to optimize endocardial border detection and to avoid echo images dropout. Imaging volumes were adjusted in size as appropriate to increase volume rate while maintaining spatial resolution. Image quality was judged on the basis of stitch/artifacts and quality resolution of LA segments throughout the whole cardiac cycle, and in presence of stitching artifacts or dropout of more than two LA segments the image was excluded of the analysis.
Three-dimensional models of the LA were generated by semi-automated quantification software (4D LV analyses 2.0, TomTec, Unterschleissheim, Germany). All 3DE images were analyzed by a single operator (AG) with expertise in 3DE, at the core laboratory at the BWH, blind to participants' characteristics. The 2-, 3- and 4-chamber views were automatically selected by the software from the real-time 3DE pyramidal dataset obtained from 4 consecutive cardiac cycles. The off-line contour-tracking algorithm automatically detected blood–tissue interface, but manual correction of the endocardial border was systematically applied. The LA appendage and the orifices of the pulmonary vein were excluded from the tracing (Figure 1). Then, LA endocardial surface was reconstructed throughout the cardiac cycle, resulting in a dynamic cast of LA cavity; for each consecutive frame, the voxel count inside the 3-dimensional surface was used to measure LA volume (LAV), resulting in a smooth interpolated LAV time curve allowing detection of the maximal (LAV max) and minimal (LAV min) LA volumes. LA emptying fraction, an estimate of LA reservoir function was calculated as [(LAV max – LAV min)/LAV max × 100]. In addition, 3DE LA speckle-tracking analysis was automatically performed throughout the cardiac cycle, using P wave as the reference point, and LA GLS, also a surrogate of LA reservoir function was determined.
Figure 1. Left atrium function measurement by 3D echocardiography.
Reproducibility analysis
3DE LAV measurements were repeated in a randomly selected group of 40 participants by an additional investigator (KN) as well as by the same primary reader at least 1 month later, both blinded to the results of all previous measurements.
Statistical methods
Summary statistics for covariates were calculated as counts and percentages or means and standard deviation for categorical and continuous data, respectively. Comparisons of clinical and echocardiographic characteristics between LAEF quartiles were made using trend tests by regression methods and chi-squared tests for trend for continuous and dichotomous variables, respectively. NT-proBNP was assessed using Cuzick's non-parametric trend test.18 The correlation between LAEF and other variables were assessed by Pearson coefficients. Log transformation of NT-proBNP was used to satisfy the model assumptions. Using multivariate linear models, we examined the association between LAEF (independent variable) and measures of cardiac structure and function (dependent variables), adjusted for Framingham risk score covariates (age, sex, systolic blood pressure, total cholesterol, HDL cholesterol and smoking), race, diabetes, left ventricular ejection fraction (LVEF),heart rate and NT-proBNP. The analyses were performed overall and separately for subgroups (Group 1, 2 and 3). In order to assess whether the relationships between LAEF and echocardiographic characteristics were dependent on CV disease group, tests for interaction were performed using the likelihood ratio test comparing models with and without interaction terms between the categorical classification of CV disease Groups, and LAEF. The ability of LA measurements to discriminate between participants with and without HF was assessed using receiver-operating characteristic (ROC) curves. The area under the curve (AUC) was estimated for each parameter along with its 95% confidence interval.
2DE and 3DE derived values of the LAV were compared using linear regression with Pearson correlation (Supplementary Figure 1). Interobserver and intraobserver variability of 3DE LA measurements were calculated as an absolute difference in the corresponding pair of repeated measurements. For all analyses, two-sided p values <0.05 were considered significant. Analyses were performed using Stata version 13.1 (Stata Corp., College Station, Texas).
Results
The final analysis dataset included 1,142 participants with a mean age of 76±5 years, 674 (59%) were women and 967 (85%) were white. When comparing the subset of ARIC participants included in this analysis with those who attended at visit 5, but who were not included in this study, there were no differences in age or gender, but the former were more likely to be white, to have lower BMI and lower prevalence of hypertension (Supplementary Table 1).
Participants in the lowest quartile of LAEF (median 38.6 %, range 4.1% - 45.8 %) were older, more likely to be hypertensive, to have HF, lower heart rate and higher NT-proBNP (Table 1). There were no significant differences regarding sex, race, BMI, cholesterol level, or the presence of diabetes or CAD by LAEF quartiles. In univariate and multivariate linear regression analysis LAEF was inversely related to NT-proBNP (r=-0.29, p<0.01) (Table 2).
Table 1. Characteristics of the study population by quartiles of left atrial emptying fraction (LAEF).
| LAEF Quartile 1 | LAEF Quartile 2 | LAEF Quartile 3 | LAEF Quartile 4 | ||
|---|---|---|---|---|---|
|
| |||||
| Range | 4.1 - 45.8 | 45.9 - 54.8 | 54.9 - 61.2 | 61.3- 83.3 | |
| n=287 | n=287 | n=286 | n=282 | P value* | |
| Demographic and Clinical | |||||
|
| |||||
| LAEF | 36.3 ± 8.3 | 50.8 ± 2.6 | 57.9 ± 1.8 | 66.9 ± 4.1 | NA |
| Age (years) | 77.0 ± 5.2 | 76.3 ± 5.4 | 75.8 ± 5.2 | 75.2 ± 5.0 | <0.001 |
| Men (n, %) | 130 (45.3) | 112 (39.0) | 106 (37.1) | 120 (42.6) | 0.428 |
| White (n, %) | 235 (81.9) | 241 (84.0) | 246 (86.0) | 245 (86.9) | 0.074 |
| Centre (n, %) | <0.001 | ||||
| Forsyth County, NC | 136 (47.4) | 137 (47.7) | 122 (42.7) | 94 (33.3) | |
| Jackson, MS | 41 (14.3) | 34 (11.8) | 34 (11.9) | 29 (10.3) | |
| Minneapolis, MN | 62 (21.6) | 42 (14.6) | 55 (19.2) | 66 (23.4) | |
| Washington County, MD | 48 (16.7) | 74 (25.8) | 75 (26.2) | 93 (33.0) | |
| BMI (kg/m2) | 27.4 ± 5.0 | 27.1 ± 4.7 | 27.3 ± 5.1 | 27.7 ± 5.3 | 0.371 |
| Current smoker (n, %) | 18 (6.4) | 12 (4.3) | 17 (6.1) | 17 (6.2) | 0.866 |
| Hypertension (n, %) | 251 (87.5) | 229 (79.8) | 227 (79.4) | 223 (79.1) | 0.012 |
| Diabetes (n, %) | 87 (30.4) | 68 (23.8) | 80 (28.1) | 85 (30.2) | 0.756 |
| CAD (n, %) | 6 (2.1) | 3 (1.1) | 6 (2.1) | 4 (1.4) | 0.782 |
| HF (n, %) | 84 (29.3) | 43 (15.0) | 43 (15.0) | 37 (13.1) | <0.001 |
| HR (bpm) | 60.3 ± 10.6 | 60.1 ± 9.5 | 61.7 ± 9.3 | 62.4 ± 9.2 | 0.002 |
| Total Cholesterol (mg/dl) | 176.4 ± 39.7 | 180.1 ± 40.8 | 179.4 ± 40.5 | 181.7 ± 40.8 | 0.158 |
| HDL Cholesterol (mg/dl) | 51.2 ± 13.4 | 52.6 ± 13.8 | 53.6 ± 13.3 | 52.3 ± 14.5 | 0.245 |
| eGFR (mL/min/1.73 m2) | 71.5 ± 19.4 | 75.8 ± 19.3 | 74.0 ± 19.6 | 73.8 ± 21.0 | 0.353 |
| Hemoglobin (g/dl) | 13.2 ± 1.3 | 13.2 ± 1.3 | 13.1 ± 1.3 | 13.2 ± 1.3 | 0.688 |
| NT-proBNP (mmol/l) | 200.5 [102.2, 432.4] | 156.8 [80.8, 274.9] | 119.8 [67.8, 212.5] | 112.3 [67.3, 177.2] | <0.001 |
|
| |||||
| 2D Echocardiography | |||||
|
| |||||
| EDV/index (ml/m2) | 46.8 ± 12.2 | 46.7 ± 11.6 | 45.4 ± 10.4 | 44.6 ± 10.1 | 0.006 |
| ESV (ml) | 31.2 ± 14.9 | 29.4 ± 12.1 | 28.0 ± 10.9 | 26.9 ± 10.6 | 0.0001 |
| EF (%) | 65.1 ± 6.7 | 66.3 ± 5.7 | 66.6 ± 5.1 | 67.7 ± 5.4 | 0.0001 |
| LV mass/index (g/m2) | 83.0 ± 22.4 | 83.8 ± 20.7 | 78.0 ± 19.0 | 77.5 ± 17.4 | 0.0001 |
| LA diameter (cm) | 3.6 ± 0.5 | 3.5 ± 0.5 | 3.4 ± 0.5 | 3.4 ± 0.4 | 0.0001 |
| 2D LA vol/index (ml/m2) | 30.5 ± 11.5 | 28.0 ± 8.2 | 26.3 ± 7.8 | 24.8 ± 6.2 | 0.0001 |
| Peak E wave (cm/s) | 73.6 ± 21.3 | 68.8 ± 17.4 | 68.8 ± 17.7 | 68.5 ± 18.1 | 0.002 |
| E/A | 0.9 ± 0.4 | 0.9 ± 0.2 | 0.8 ± 0.2 | 0.8 ± 0.2 | 0.0001 |
| E/e′ | 11.3 ± 4.7 | 10.5 ± 3.9 | 10.4 ± 3.8 | 10.0 ± 3.5 | 0.0002 |
| S′ septum (cm/s) | 6.0 ± 1.2 | 6.3 ± 1.1 | 6.5 ± 1.3 | 6.7 ± 1.2 | 0.0001 |
| Peak LV log strain (%) | -17.4 ± 2.7 | -17.9 ± 2.4 | -18.0 ± 2.4 | -18.1 ± 2.2 | 0.0003 |
| RV diastolic area (cm2) | 20.6 ± 5.8 | 20.5 ± 5.3 | 19.7 ± 5.0 | 19.7 ± 5.4 | 0.014 |
| RV FAC | 0.53 ± 0.08 | 0.54 ± 0.08 | 0.54 ± 0.07 | 0.53 ± 0.08 | 0.749 |
| Diastolic function | 0.303 | ||||
| Unclassified | 53 (20.3) | 50 (17.5) | 43 (15.1) | 48 (17.0) | 0.239 |
| Normal (n, %) | 72 (27.6) | 88 (30.9) | 83 (29.1) | 95 (33.7) | 0.186 |
| Mild DD (n, %) | 34 (13.0) | 52 (18.2) | 68 (23.9) | 62 (22.0) | 0.002 |
| Moderate DD (n, %) | 102 (39.1) | 95 (33.3) | 91 (31.9) | 77 (27.3) | 0.004 |
|
| |||||
| Other 3D Echocardiography data | |||||
|
| |||||
| LAV max/BSA (ml/m2) | 35.5 ± 12.6 | 34.1 ± 9.6 | 32.8 ± 8.6 | 32.5 ± 8.6 | 0.0001 |
| LAV max/ht2.7 (ml/ht2.7) | 16.5 ± 6.1 | 15.9 ± 4.7 | 15.5 ± 4.6 | 15.3 ± 4.4 | 0.0034 |
| LAV min/BSA (ml/m2) | 22.7 ± 10.0 | 16.8 ± 4.8 | 13.8 ± 3.7 | 10.7 ± 3.3 | <0.0001 |
| LAV min/ht2.7 (ml/ht2.7) | 10.6 ± 4.8 | 7.8 ± 2.3 | 6.5 ± 2.0 | 5.1 ± 1.6 | <0.0001 |
| LA GLS (%) | 12.7 ± 4.5 | 17.5 ± 4.3 | 20.8 ± 4.2 | 25.5 ± 4.8 | <0.0001 |
BMI, body mass index; CAD, coronary artery disease; eGFR, glomerular filtration rate; HF, heart failure; HR, heart rate; EDV, end diastolic volume; ESV, end systolic volume; LV, left ventricle, RV, right ventricle; LAV, left atrial volume; GLS, Global longitudinal strain; Data are described as mean (SD) for quantitative variables and counts (proportions) for categorical variables
P value for trend across LAEF categories
Table 2. Associations between left atrial emptying fraction (LAEF) and clinical and echocardiographic characteristics.
| Univariate Analysis | Multivariate Analysis | |||||
|---|---|---|---|---|---|---|
|
| ||||||
| Correlation Coefficient | Coefficient (95% CI)* | P value | Coefficient (95% CI)* | P value | ||
| Demographic and Clinical | ||||||
| Age (years) | -0.14 | -0.34 (-0.47, -0.21) | <0.0001 | -0.10 (-0.24, 0.04) | 0.163 | |
| Hypertension (n, %) | -0.01 | -2.32(-4.14, -0.50) | 0.01 | -1.00 (-2.97, 0.97) | 0.319 | |
| HF (n, %) | -0.20 | -6.41(-8.21,-4.60) | <0.0001 | -2.80 (-4.88, -0.71) | 0.009 | |
| HR (bpm) | 0.07 | 0.09 (0.01, 0.16) | 0.01 | 0.10(0.03, 0.17) | 0.005 | |
| NT-proBNP (mmol/l)# | -0.29 | -3.41(-4.08,-2.74) | <0.0001 | -3.08 (-4.08, -2.74) | <0.0001 | |
|
| ||||||
| 2D Echocardiography | ||||||
|
| ||||||
| EDV/index (ml/m2) | -0.10 | -0.10(-0.17,-0.04) | 0.0007 | 0.04 (-0.03, -0.12) | 0.242 | |
| LVEF (%) | 0.17 | 0.37 (0.25, 0.49) | <0.0001 | 0.28 (0.16, 0.41) | <0.0001 | |
| LV mass/index (g/m2) | -0.15 | -0.09 (-0.12,-0.05) | <0.0001 | -0.02 (-0.05, 0.02) | 0.359 | |
| LA diameter (cm) | -0.18 | -4.13 (-5.44,-2.82) | <0.0001 | -2.02 (-3.57, -0.47) | 0.010 | |
| 2D LA vol/index (ml/m2) | -0.29 | -0.40 (-0.48,-0.33) | <0.0001 | -0.22 (-0.32, -0.13) | <0.0001 | |
| Peak E wave (cm/s) | -0.13 | -0.08 (-0.12,-0.04) | <0.0001 | -0.08 (-0.12,-0.04) | <0.0001 | |
| E/A | -0.20 | -7.28 (-9.34, -5.22) | <0.0001 | -6.66 (-8.91,-4.41) | <0.0001 | |
| E/e′ | -0.11 | -0.33 (-0.51, -0.16) | <0.0001 | -0.22 (-0.41,-0.04) | 0.016 | |
| S′ septum (cm/s) | 0.21 | 2.07 (1.52, 2.62) | <0.0001 | 1.13 (0.52, 1.74) | <0.0001 | |
| Peak LV log strain (%) | -0.16 | -0.80 (-1.08, -0.52) | <0.0001 | -0.63 (-0.96,-0.29) | <0.0001 | |
| RV diastolic area (cm2) | -0.08 | -0.18 (-0.31, -0.04) | 0.007 | -0.10 (-0.25, -0.03) | 0.149 | |
| Diastolic function | -0.02 | -0.23 (-0.84, 0.38) | 0.462 | -0.31(-0.94, 0.31) | 0.332 | |
| Normal | 0.03 | 0.98 (-0.49, 2.46) | 0.192 | 0.60(-0.97, 2.18) | 0.455 | |
| Mild DD | 0.09 | 2.80 (1.09, 4.51) | 0.001 | 2.37(0.64, 4.10) | 0.007 | |
| Moderate DD | -0.08 | -2.06 (-3.5, -0.62) | 0.005 | -1.98(-3.48, -0.47) | 0.010 | |
|
| ||||||
| Other 3D Echocardiography data | ||||||
|
| ||||||
| LAV max/BSA (ml/m2) | -0.15 | -0.19 (-0.26, -0.12) | <0.0001 | -0.01 (-0.08, 0.07) | 0.876 | |
| LAV max/ht2.7 (ml/ht2.7) | -0.13 | -0.32 (-0.46, -0.18) | <0.0001 | 0.02 (-0.13, 0.18) | 0.764 | |
| LAV min/BSA (ml/m2) | -0.68 | -1.10 (-1.17, -1.03) | <0.0001 | -1.18(-1.26, -1.09) | <0.001 | |
| LAV min/ht2.7 (ml/ht2.7) | -0.65 | -2.21(-2.36,-2.07) | <0.0001 | -2.31(-2.49,-2.12) | <0.001 | |
| LA GLS (%) | 0.76 | -1.43 (-1.51,-1.36) | <0.0001 | 1.37(-1.45,-1.29) | <0.001 | |
Multiple linear regression analysis models adjusted for Framingham risk score covariates (age, sex, systolic blood pressure, total cholesterol, HDL cholesterol and smoking) + race + diabetes + LVEF + HR+ NT-proBNP
Log transformation has been used for correlations and multivariate analysis
Regression coefficient from unadjusted and adjusted model
Associations between LAEF and measures of cardiac structure and function
In univariable analyses, lower LAEF was significantly associated with larger LV, RV and LA volumes, greater LV mass, higher peak E wave velocity, higher E/E′ and E/A ratio, lower LVEF, lower mitral annulus peak systolic velocity and worse peak longitudinal LV strain, and with higher prevalence of moderate diastolic dysfunction (Tables 1 and 2). After adjusting for Framingham risk score covariates, race, diabetes, LVEF, heart rate and NT-proBNP, lower LAEF was significantly associated with larger LA volumes, higher E/E′ and E/A ratio, higher prevalence of moderate diastolic dysfunction and worse LV systolic function.
LAEF by cardiovascular groups'categories
Participants with HF (Group 3) had the lowest LAEF, worst LA GLS, largest LAV max/BSA and LAV min/BSA (Figure 2 and 3). All 3DE LA measurements of volume or function could contribute to discriminate participants with HF from among all the participants included (Figure 4).
Figure 2. Distribution of LAEF, LA GLS, LAV max/BSA, and LAV min/BSA, by subgroups.
Figure 3. Box plot of LAEF, LA GLS, LAV max/BSA, and LAV min/BSA, by subgroups, Group Definitions.
Group 1- Green (n=201) – elderly participants without evidence of CAD, HF, hypertension, diabetes or obesity (BMI≥30 kg/m2)
Group 2 - Gray (n=734) - participants with hypertension without CAD or HF
Group 3 – Red (n=207) - participants with HF
P values for linear regression analysis models with Bonferroni correction
Figure 4. Receiver-operating-characteristic (ROC) curves of LAEF, LA GLS, LAV max/BSA and LAV min/BSA for heart failure.
Participants with hypertension (Group 2) had larger LAV max/BSA and LAV min/BSA than participants from Group 1, but there were no significant differences on LAEF or LA GLS between Group 1 and 2 (LAEF: 55.2% ± 10.3 vs 53.8% ± 11.5, LA GLS: 20.1 ± 5.9 vs 19.5 ± 6.3, respectively, Table 3). We observed a significant interaction between the predefined CV Groups categories and LAEF in respect to 3D measurements of LA volumes and LA GLS (p < 0.01 for all; Table 3). There was a poor correlation between LAEF and LAV max in the overall population, and an inverse association between LAEF and LA max in participants with HF. Additional potential interactions that were not significant at the p<0.05 level, but were significant at the p<0.10 level are shown in Supplemental Table 2. Participants with HF (Group 3) had larger LV, RV and LA size, and worst measurements of systolic and diastolic function, compared to those with hypertension (Group 2). The later presented higher LV mass, higher E/E′ and lower prevalence of normal diastolic function, compared with Group 1 participants (Table 4).
Table 3. Multivariate linear regression evaluating the associations between LAEF and other parameters of LA structure and function, by subgroups.
| Group 1 (n=201) (“Healthy”) | Group 2 (n=734) (Hypertensive) | Group 3 (n=207) (Heart Failure) | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| LAEF (%) | 55.2 ± 10.3 | 53.8 ± 11.5 | 47.6 ± 14.6 | |||||||
|
| ||||||||||
| Coefficient (SE) | P value | Coefficient (SE) | P value | Coefficient (SE) | P value | P value for Interaction | ||||
| 3D Echocardiography data | ||||||||||
| LAV max/BSA (ml/m2) | 30.2 ± 6.6 | 0.14 (0.11) | 0.202 | 33.0 ± 9.0 | 0.10 (0.05) | 0.043 | 39.8 ± 13.3 | -0.160 (0.08) | 0.073 | 0.001 |
| LAV max/ht2.7 (ml/ht2.7) | 13.4 ± 3.1 | 0.28 (0.24) | 0.243 | 15.5 ± 4.4 | 0.24 (0.10) | 0.022 | 19.2 ± 6.7 | - 0.194 (0.17) | 0.269 | 0.008 |
| LAV min/BSA (ml/m2) | 13.5 ± 4.4 | -1.64 (0.13) | <0.001 | 15.3 ± 5.8 | -1.37 (0.06) | <0.001 | 21.5 ± 11.2 | -0.944 (0.07) | <0.001 | <0.001 |
| LAV min/ht2.7 (ml/ht2.7) | 5.9 ± 2.0 | -3.43 (0.30) | <0.001 | 7.1 ± 2.7 | -2.76 (0.14) | <0.001 | 10.3 ± 5.6 | -1.81 (0.16) | <0.001 | <0.001 |
| LA GLS (%) | 20.1 ± 5.9 | 1.28 (0.08) | <0.001 | 19.5 ± 6.3 | 1.32 (0.04) | <0.001 | 16.9 ± 6.7 | 1.589 (0.10) | <0.001 | 0.004 |
Group Definitions: Group 1- elderly participants without evidence of CAD, HF, hypertension, diabetes or obesity (BMI≥30 kg/m2); Group 2 - participants with hypertension without CAD or HF; Group 3 - participants with HF. Multiple linear regression analysis models adjusted for Framingham risk score covariates (age, sex, systolic blood pressure, total cholesterol, HDL cholesterol and smoking) + race +diabetes + LVEF + HR+ NT-proBNP.
Log transformation has been used for correlations and multivariate analysis
Table 4. Echocardiographic characteristics of the study population, by subgroups.
| Group 1 (n=201) | Group 2 (n=734) | P value1 | Group 3 (n=207) | P value2 | |
|---|---|---|---|---|---|
| (“Healthy”) | (Hypertensive) | (Heart Failure) | |||
| 2D Echocardiography | |||||
|
| |||||
| EDV/index (ml/m2) | 44.4± 8.8 | 45.0± 10.3 | 0.449 | 50.5± 14.5 | < 0.001 |
| ESV (ml) | 26.4± 8.8 | 27.5± 10.6 | 0.159 | 36.1± 17.4 | < 0.001 |
| EF (%) | 66.4 ± 5.2 | 67.2± 5.4 | 0.047 | 63.7± 7.0 | < 0.001 |
| LV mass/index (g/m2) | 72.4± 15.8 | 79.5± 18.1 | <0.001 | 92.4± 25.1 | < 0.001 |
| LA diameter (cm) | 3.2± 0.4 | 3.5± 0.4 | <0.000 | 3.8± 0.6 | < 0.001 |
| 2D LA vol/index (ml/m2) | 23.9± 6.1 | 26.8± 7.4 | <0.001 | 33.2± 12.7 | < 0.001 |
| Peak E wave (cm/s) | 67.6± 17.3 | 69.2± 17.6 | 0.254 | 74.7± 23.0 | 0.002 |
| E/A | 0.9± 0.3 | 0.8± 0.3 | 0.001 | 0.9± 0.4 | 0.043 |
| E/e′ | 9.4± 3.4 | 10.6± 3.8 | <0.001 | 11.5± 5.0 | 0.009 |
| S′ septum (cm/s) | 6.5± 1.1 | 6.5± 1.2 | 0.774 | 5.9± 1.1 | <0.001 |
| Peak LV log strain (%) | 18.2± 2.3 | 18.1± 2.3 | 0.776 | 16.7± 2.8 | <0.001 |
| RV diastolic area (cm2) | 19.7± 5.17 | 20.0± 5.36 | 0.412 | 21.0± 5.7 | 0.031 |
| RV FAC | 0.5± 0.07 | 0.5± 0.08 | 0.318 | 0.5± 0.08 | 0.002 |
| Diastolic function | <0.001 | 0.278 | |||
| Unclassified | 20 (10.0) | 131 (17.9) | 43 (23.6) | 0.239 | |
| Normal (n, %) | 89 (44.3) | 205 (28.1) | <0.001 | 44 (24.2) | 0.289 |
| Mild DD (n, %) | 36 (17.9) | 148 (20.3) | 0.456 | 32 (17.6) | 0.414 |
| Moderate DD (n, %) | 56 (27.9) | 246 (33.7) | 0.117 | 63 (34.6) | 0.815 |
EDV, end diastolic volume; ESV, end systolic volume; LV, left ventricle, RV, right ventricle; LAV, left atrial volume; GLS, Global longitudinal strain;
P value for the differences between Group 1 and Group 2;
P value for the differences between Group 2 and Group 3. Group 1- elderly participants without evidence of CAD, HF, hypertension, diabetes or obesity; Group 2 - participants with hypertension without CAD or HF; Group 3 - participants with HF.
Discussion
We found that lower LA function was associated with worse LV systolic and diastolic function, and higher plasma levels of NT-proBNP. LAEF was lowest in participants with HF but there were no significant differences in mean LAEF between participants with hypertension and those free of CV disease or risk factors.
Our results corroborate prior studies showing an association between LA dysfunction and measures of LV systolic (LVEF, peak LV longitudinal strain and S′), LV mass and diastolic dysfunction (E/E′ and E/A ratio).19, 20 In addition, we found a poor correlation between LAEF and LAV max in the overall population, and we demonstrated an inverse association between LAEF and LA max in participants with HF. The decreasing LAEF among HF participants with largest LAV max parallels LV volume response in HF, where the decreased contractility is observed in consequence of significant LV remodeling. However, while the LV functional changes in the progressive stages of HF have been extensively described, the role of LA dysfunction so far has received little attention.5 Furthermore, our results show that participants with hypertension had significantly higher LA volumes (both LAV max and min) higher LV mass and worse diastolic function than elderly without CV disease or risk factors, but no significant differences in LA function were found. One explanation for LA enlargement in hypertensive participants is the Frank–Starling mechanism, as the LA dilates in response to the increased LV end-diastolic pressure and may initially improve its ejection performance. 21, 22 However, in cases of sustained increases in LA and LV pressure, as observed among patients with HF, the LA contractile reserve becomes exhausted, LAEF drops and LA turns into a passive conduct dictated by ventricular distensibility.23 Nevertheless, due to the cross-sectional nature of this study we cannot discern whether the LA dysfunction observed among participants with HF is a consequence of hypertension. Previous studies in patients with mild essential hypertension, showed a reduction in LA conduit volume and early diastolic strain, without changes in maximal LA volume or systolic strain compared with controls,24 while others have described LA enlargement along with LVH.25 In this study, in spite of the overall negative association between LA function and diastolic dysfunction, in the subset of hypertensive participants there were no significant differences in LA volume or function by diastolic dysfunction grading (Supplemental Table 3). However, our sample consists of elderly participants, who mostly presented elevated blood pressure, though taking antihypertensive medication. Thus, compared to previous reports, our results likely represent an older and homogeneous population with more severe stages of hypertension.
Left atrial dysfunction has previously been described in HF patients with preserved19, 26 or reduced LVEF,20 but so far LAEF has not been considered for HF echocardiographic recognition. However, the diagnosis of HF with preserved EF (HFpEF) is particularly challenging as diastolic dysfunction, LV hypertrophy and LA enlargement coexist in patients with HFpEF and in those with hypertension. Thus, our findings showing lower LAEF in participants with HF (47.6% ± 14.6) compared to those with hypertension and free of CV disease or risk factors (55.2% ± 10.3) might contribute as an additional discriminating feature to the diagnosis of HF with preserved EF (HFpEF). However, the discriminative accuracy of any single measurement is limited and additional studies will be required, to assertively present cut off values for the determination of LAEF abnormality.
A number of limitations of this analysis should be noted. Our population sample considers the evaluation of elderly subjects from a longitudinal study over 24 years, being limited by the survival bias of this population. Moreover, we only included a subset of ARIC participants and the proportion of images suitable for the 3D LA analysis was limited. This is partly explained by the fact that at the time of 3DE acquisition, the latest 3D technology, which has higher image quality, was not yet available and the focus was LV analysis. Thus, participants were frequently excluded from this study by the absence of the LA roof in the 3D volume pyramid. We were unable to assess phasic atrial function, using gated 3DE, in consequence, variations on passive and active LA emptying were not considered. The subset of ARIC participants included in this study was more likely to be white, to have lower BMI and lower prevalence of hypertension, when compared with those who attended to visit 5, but were not included in this study. We attempted to address these issues by using LA measures indexed to body size, stratifying results by hypertension status, and adjusting for race in our multivariate models. Most hypertensive participants were taking antihypertensive medication (89%) and presented high blood pressure (82%). Thus, we present a well establish and homogeneous hypertensive group, but no further associations between categories of hypertension severity and LAEF can be provided. The definition for prevalent HF was based upon Gothenburg criteria and unadjudicated hospitalization ICD-9 codes, this approach captures participants with prior or current symptoms of HF, as recommended by ACC/AHA staging of HF,27 but the echocardiography evaluation was not assessed at the time of incident HF. Finally, this is an observational cross-sectional study and long-term studies are needed to assess the prognostic value of LAEF assessment.
Notwithstanding these limitations, our study had several strengths. The study was large in size, the sample was derived from a community-cohort comprising elderly adults from multiple sites and included whites and African-Americans with a wide range of CV risk profiles. To date, most studies on LA structure and function used 2DE, but 3DE has been shown to be more accurate,28 reproducible and with superior clinical value than 2DE.29 To our knowledge, this is the largest 3DE study assessing LA function in elderly from the community. These findings contribute to a fuller understanding of LA function and contribute to normative data on 3DE LA volumes and function.30
In summary, we observed that LAEF was lowest in participants with HF but, despite increases in LA size, there were no significant differences in mean LAEF between participants with hypertension and those free of CV disease or risk factors. In addition, lower LAEF was associated with higher NT-proBNP and worse LV systolic and diastolic function. These results highlight for the potential of LAEF as an imaging biomarker and suggest that impairment in LA function may play a role in the pathophysiology of heart failure.
Supplementary Material
Clinical Perspective.
In this community-based cohort, LA function was impaired in elderly with prevalent HF, but there were no significant differences in LA function between participants with hypertension and those free of CV disease or risk factors, despite greater LA size in the former. In addition, worse LA function was associated with worse LV systolic and diastolic function, and higher plasma levels of NT-proBNP. The diagnosis of HF with preserved EF (HFpEF) is challenging as diastolic dysfunction, LV hypertrophy and LA enlargement coexist in patients with HFpEF and in those with hypertension. Our findings highlight for the potential of LAEF as an imaging biomarker and suggest that impairment in LA function may play a role in the pathophysiology of heart failure.
Acknowledgments
The authors thank the staff and participants of the ARIC study for their important contributions.
Sources of Funding: The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C). This work was also supported by NHLBI cooperative agreement NHLBI-HC-11-08 (SDS), grants R00-HL-107642 (SC) and K08-HL-116792 (AMS), and a grant from the Ellison Foundation (SC).Dr. Kitzman is supported partly by NIH grant R01AG18915. Dr. Gonçalves receives funds from Portuguese Foundation for Science and Technology Grant HMSP-ICS/007/2012.
Footnotes
Disclosures: None
References
- 1.Benjamin EJ, D'Agostino RB, Belanger AJ, Wolf PA, Levy D. Left atrial size and the risk of stroke and death. The framingham heart study. Circulation. 1995;92:835–841. doi: 10.1161/01.cir.92.4.835. [DOI] [PubMed] [Google Scholar]
- 2.Patel DA, Lavie CJ, Milani RV, Ventura HO. Left atrial volume index predictive of mortality independent of left ventricular geometry in a large clinical cohort with preserved ejection fraction. Mayo Clinic proceedings Mayo Clinic. 2011;86:730–737. doi: 10.4065/mcp.2010.0682. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Moller JE, Hillis GS, Oh JK, Seward JB, Reeder GS, Wright RS, Park SW, Bailey KR, Pellikka PA. Left atrial volume: A powerful predictor of survival after acute myocardial infarction. Circulation. 2003;107:2207–2212. doi: 10.1161/01.CIR.0000066318.21784.43. [DOI] [PubMed] [Google Scholar]
- 4.Pellicori P, Zhang J, Lukaschuk E, Joseph AC, Bourantas CV, Loh H, Bragadeesh T, Clark AL, Cleland JG. Left atrial function measured by cardiac magnetic resonance imaging in patients with heart failure: Clinical associations and prognostic value. European heart journal. 2015;36:733–42. doi: 10.1093/eurheartj/ehu405. [DOI] [PubMed] [Google Scholar]
- 5.Gupta S, Matulevicius SA, Ayers CR, Berry JD, Patel PC, Markham DW, Levine BD, Chin KM, de Lemos JA, Peshock RM, Drazner MH. Left atrial structure and function and clinical outcomes in the general population. European heart journal. 2013;34:278–285. doi: 10.1093/eurheartj/ehs188. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Welles CC, Ku IA, Kwan DM, Whooley MA, Schiller NB, Turakhia MP. Left atrial function predicts heart failure hospitalization in subjects with preserved ejection fraction and coronary heart disease: Longitudinal data from the heart and soul study. Journal of the American College of Cardiology. 2012;59:673–680. doi: 10.1016/j.jacc.2011.11.012. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Abhayaratna WP, Fatema K, Barnes ME, Seward JB, Gersh BJ, Bailey KR, Casaclang-Verzosa G, Tsang TS. Left atrial reservoir function as a potent marker for first atrial fibrillation or flutter in persons > or = 65 years of age. The American journal of cardiology. 2008;101:1626–1629. doi: 10.1016/j.amjcard.2008.01.051. [DOI] [PubMed] [Google Scholar]
- 8.Habibi M, Chahal H, Opdahl A, Gjesdal O, Helle-Valle TM, Heckbert SR, McClelland R, Wu C, Shea S, Hundley G, Bluemke DA, Lima JA. Association of cmr-measured la function with heart failure development: Results from the mesa study. JACC Cardiovascular imaging. 2014;7:570–579. doi: 10.1016/j.jcmg.2014.01.016. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.The atherosclerosis risk in communities (aric) study: Design and objectives. The aric investigators. American journal of epidemiology. 1989;129:687–702. [PubMed] [Google Scholar]
- 10.Folsom AR, Yamagishi K, Hozawa A, Chambless LE Atherosclerosis Risk in Communities Study I. Absolute and attributable risks of heart failure incidence in relation to optimal risk factors. Circulation Heart failure. 2009;2:11–17. doi: 10.1161/CIRCHEARTFAILURE.108.794933. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Loehr LR, Rosamond WD, Chang PP, Folsom AR, Chambless LE. Heart failure incidence and survival (from the atherosclerosis risk in communities study) The American journal of cardiology. 2008;101:1016–1022. doi: 10.1016/j.amjcard.2007.11.061. [DOI] [PubMed] [Google Scholar]
- 12.Rosamond WD, Chang PP, Baggett C, Johnson A, Bertoni AG, Shahar E, Deswal A, Heiss G, Chambless LE. Classification of heart failure in the atherosclerosis risk in communities (aric) study: A comparison of diagnostic criteria. Circulation Heart failure. 2012;5:152–159. doi: 10.1161/CIRCHEARTFAILURE.111.963199. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Sharrett AR, Patsch W, Sorlie PD, Heiss G, Bond MG, Davis CE. Associations of lipoprotein cholesterols, apolipoproteins a-i and b, and triglycerides with carotid atherosclerosis and coronary heart disease. The atherosclerosis risk in communities (aric) study. Arteriosclerosis and thrombosis : a journal of vascular biology / American Heart Association. 1994;14:1098–1104. doi: 10.1161/01.atv.14.7.1098. [DOI] [PubMed] [Google Scholar]
- 14.Shah AM, Cheng S, Skali H, Wu J, Mangion JR, Kitzman D, Matsushita K, Konety S, Butler KR, Fox ER, Cook N, Ni H, Coresh J, Mosley TH, Heiss G, Folsom AR, Solomon SD. Rationale and design of a multicenter echocardiographic study to assess the relationship between cardiac structure and function and heart failure risk in a biracial cohort of community-dwelling elderly persons: The atherosclerosis risk in communities study. Circulation Cardiovascular imaging. 2014;7:173–181. doi: 10.1161/CIRCIMAGING.113.000736. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Pellikka PA, Picard MH, Roman MJ, Seward J, Shanewise J, Solomon S, Spencer KT, St John Sutton M, Stewart W American Society of Echocardiography's N, Standards C, Task Force on Chamber Q, American College of Cardiology Echocardiography C, American Heart A, European Association of Echocardiography ESoC. Recommendations for chamber quantification. European journal of echocardiography : the journal of the Working Group on Echocardiography of the European Society of Cardiology. 2006;7:79–108. doi: 10.1016/j.euje.2005.12.014. [DOI] [PubMed] [Google Scholar]
- 16.Redfield MM, Jacobsen SJ, Burnett JC, Jr, Mahoney DW, Bailey KR, Rodeheffer RJ. Burden of systolic and diastolic ventricular dysfunction in the community: Appreciating the scope of the heart failure epidemic. JAMA : the journal of the American Medical Association. 2003;289:194–202. doi: 10.1001/jama.289.2.194. [DOI] [PubMed] [Google Scholar]
- 17.Bursi F, Weston SA, Redfield MM, Jacobsen SJ, Pakhomov S, Nkomo VT, Meverden RA, Roger VL. Systolic and diastolic heart failure in the community. JAMA : the journal of the American Medical Association. 2006;296:2209–2216. doi: 10.1001/jama.296.18.2209. [DOI] [PubMed] [Google Scholar]
- 18.Cuzick J. A wilcoxon-type test for trend. Statistics in medicine. 1985;4:87–90. doi: 10.1002/sim.4780040112. [DOI] [PubMed] [Google Scholar]
- 19.Santos AB, Kraigher-Krainer E, Gupta DK, Claggett B, Zile MR, Pieske B, Voors AA, Lefkowitz M, Bransford T, Shi V, Packer M, McMurray JJ, Shah AM, Solomon SD Investigators P. Impaired left atrial function in heart failure with preserved ejection fraction. European journal of heart failure. 2014;16:1096–1103. doi: 10.1002/ejhf.147. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.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. Circulation Heart failure. 2015;8:295–303. doi: 10.1161/CIRCHEARTFAILURE.114.001667. [DOI] [PubMed] [Google Scholar]
- 21.Cioffi G, Mureddu GF, Stefenelli C, de Simone G. Relationship between left ventricular geometry and left atrial size and function in patients with systemic hypertension. Journal of hypertension. 2004;22:1589–1596. doi: 10.1097/01.hjh.0000125454.28861.76. [DOI] [PubMed] [Google Scholar]
- 22.Eshoo S, Ross DL, Thomas L. Impact of mild hypertension on left atrial size and function. Circulation Cardiovascular imaging. 2009;2:93–99. doi: 10.1161/CIRCIMAGING.108.793190. [DOI] [PubMed] [Google Scholar]
- 23.Prioli A, Marino P, Lanzoni L, Zardini P. Increasing degrees of left ventricular filling impairment modulate left atrial function in humans. The American journal of cardiology. 1998;82:756–761. doi: 10.1016/s0002-9149(98)00452-4. [DOI] [PubMed] [Google Scholar]
- 24.Eshoo S, Boyd AC, Ross DL, Marwick TH, Thomas L. Strain rate evaluation of phasic atrial function in hypertension. Heart. 2009;95:1184–1191. doi: 10.1136/hrt.2008.156208. [DOI] [PubMed] [Google Scholar]
- 25.Kokubu N, Yuda S, Tsuchihashi K, Hashimoto A, Nakata T, Miura T, Ura N, Nagao K, Tsuzuki M, Wakabayashi C, Shimamoto K. Noninvasive assessment of left atrial function by strain rate imaging in patients with hypertension: A possible beneficial effect of renin-angiotensin system inhibition on left atrial function. Hypertension research : official journal of the Japanese Society of Hypertension. 2007;30:13–21. doi: 10.1291/hypres.30.13. [DOI] [PubMed] [Google Scholar]
- 26.Obokata M, Negishi K, Kurosawa K, Arima H, Tateno R, Ui G, Tange S, Arai M, Kurabayashi M. Incremental diagnostic value of la strain with leg lifts in heart failure with preserved ejection fraction. JACC Cardiovascular imaging. 2013;6:749–758. doi: 10.1016/j.jcmg.2013.04.006. [DOI] [PubMed] [Google Scholar]
- 27.Hunt SA, Abraham WT, Chin MH, Feldman AM, Francis GS, Ganiats TG, Jessup M, Konstam MA, Mancini DM, Michl K, Oates JA, Rahko PS, Silver MA, Stevenson LW, Yancy CW. 2009 focused update incorporated into the acc/aha 2005 guidelines for the diagnosis and management of heart failure in adults: A report of the american college of cardiology foundation/american heart association task force on practice guidelines: Developed in collaboration with the international society for heart and lung transplantation. Circulation. 2009;119:e391–479. doi: 10.1161/CIRCULATIONAHA.109.192065. [DOI] [PubMed] [Google Scholar]
- 28.Mor-Avi V, Yodwut C, Jenkins C, Kuhl H, Nesser HJ, Marwick TH, Franke A, Weinert L, Niel J, Steringer-Mascherbauer R, Freed BH, Sugeng L, Lang RM. Real-time 3d echocardiographic quantification of left atrial volume: Multicenter study for validation with cmr. JACC Cardiovascular imaging. 2012;5:769–777. doi: 10.1016/j.jcmg.2012.05.011. [DOI] [PubMed] [Google Scholar]
- 29.Suh IW, Song JM, Lee EY, Kang SH, Kim MJ, Kim JJ, Kang DH, Song JK. Left atrial volume measured by real-time 3-dimensional echocardiography predicts clinical outcomes in patients with severe left ventricular dysfunction and in sinus rhythm. Journal of the American Society of Echocardiography : official publication of the American Society of Echocardiography. 2008;21:439–445. doi: 10.1016/j.echo.2007.09.002. [DOI] [PubMed] [Google Scholar]
- 30.Lang RM, Badano LP, Mor-Avi V, Afilalo J, Armstrong A, Ernande L, Flachskampf FA, Foster E, Goldstein SA, Kuznetsova T, Lancellotti P, Muraru D, Picard MH, Rietzschel ER, Rudski L, Spencer KT, Tsang W, Voigt JU. Recommendations for cardiac chamber quantification by echocardiography in adults: An update from the american society of echocardiography and the european association of cardiovascular imaging. Journal of the American Society of Echocardiography : official publication of the American Society of Echocardiography. 2015;28:1–39 e14. doi: 10.1016/j.echo.2014.10.003. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.