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European Journal of Echocardiography Advance Access published online on September 11, 2008
European Journal of Echocardiography, doi:10.1093/ejechocard/jen235
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org

Minimum vs. maximum left atrial volume for prediction of first atrial fibrillation or flutter in an elderly cohort: a prospective study

Kaniz Fatema1, Marion E. Barnes1, Kent R. Bailey2, Walter P. Abhayaratna3, Steven Cha2, James B. Seward1 and Teresa S.M. Tsang1,*

1 Division of Cardiovascular Diseases and Internal Medicine, Mayo Clinic, 200 First Street, SW, Rochester, MN 55905, USA
2 Division of Biostatistics, Mayo Clinic, Rochester, MN, USA
3 Australian National University, Canberra, Australia, USA

Received 28 May 2008; accepted after revision 23 August 2008.

* Corresponding author. Tel: +1 507 266 4130; fax: +1 507 284 1732. E-mail address: tsang.teresa{at}mayo.edu


   Abstract
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 Abstract
Introduction
 Methods
 Results
 Discussion
 Conclusions
 Funding
 References
 
Aims: We sought to compare the predictive power and reproducibility between minimum and maximum left atrial (LA) volume for the development of first atrial fibrillation (AF)/flutter.

Methods and results: This prospective study included 574 adults, mean age 74 ± 6 years, in sinus rhythm, and had no history or evidence of prior atrial arrhythmias. During a mean follow-up of 1.9 ± 1.2 years, 30 (5.2%) developed first AF/flutter. The 3-year risk estimates of freedom from AF/flutter by tertiles of minimum and maximum LA volumes were, respectively, 97, 87, and 74% (P < 0.0006) and 94, 85, and 78% (P = 0.03). Minimum LA volume was incremental to clinical and other echocardiographic parameters of AF/flutter prediction [per tertile, hazard ratio (HR) 2.4], as was maximum LA volume (per tertile, HR 1.8) in a separate model. When both volumes were entered into the same model and adjusting for covariates, minimum but not maximum LA volume retained significance. However, in terms of interobserver reproducibility, maximum LA volume compared more favourably (mean difference 3.1 ± 7.1 vs. 7.4 ± 7.3 mL/m2).

Conclusion: Minimal LA volume was an independent predictor of first AF/flutter. Although it was marginally superior to maximal LA volume in terms of predictive ability, the interobserver variability was greater.

Keywords: Left atrium; Atrial fibrillation; Prediction


   Introduction
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 Abstract
 Introduction
Methods
 Results
 Discussion
 Conclusions
 Funding
 References
 
Atrial fibrillation (AF) is a highly prevalent age-related condition1 and is associated with adverse cardiovascular outcomes such as stroke,2,3 congestive heart failure,4,5 and premature death.6–10 Maximum left atrial (LA) volume is a barometer of the burden of left ventricular (LV) diastolic dysfunction11 and has been shown to be incremental to clinical risk factors for the prediction of incident AF in older adults.12 In a previous study, minimum LA volume was found to be a stronger correlate of LV filling pressures than maximum LA volume.13 As such, it is possible that minimal LA volume may be a more powerful predictor than maximal LA volume for risk stratification of AF development. In this study, we aimed to assess whether minimum LA volume is an independent predictor of first AF/flutter in older adults, and hypothesized that minimum LA volume is superior to maximum LA volume for such prediction.


   Methods
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 Abstract
 Introduction
 Methods
Results
 Discussion
 Conclusions
 Funding
 References
 
Study design and population
This was a prospective cohort study approved by the Mayo Institutional Review Board. All patients provided written informed consent. The participants of this study resided within a 400-mile radius of the Mayo Clinic. They were largely Olmsted County, MN, USA, residents who were seen within the Department of Medicine and scheduled for a comprehensive echocardiogram. Because of the relative geographical isolation of Olmsted County, MN; Mayo Clinic is the referral centre for the area where these participants resided, and a prior study has shown that 96% of Olmsted County residents were seen at the Mayo Clinic over a 3-year period.14 At the time of enrolment and consent, the participants had to be willing to participate in a survey for follow-up at enrolment. They had to be of age ≥65 years. Exclusion criteria included a history or evidence of atrial arrhythmia, stroke, valvular or congenital heart disease, and cardiac pacemaker implantation.

Clinical and echocardiographic data
Baseline clinical data were obtained from a comprehensive review of each patient’s medical record. The definitions for all clinical conditions have been previously described.12 LA volume was measured offline using the biplane area–length method15 and indexed to body surface area. Minimum and maximum LA volumes were obtained at mitral valve closure and just before mitral valve opening, respectively. Left ventricular ejection fraction and LV mass were determined by standard 2D-echocardiography methods.15 LV diastolic function was classified by Doppler assessment of mitral inflow, pulmonary venous flow, and tissue Doppler imaging of septal mitral annular motion. The grading of diastolic dysfunction is as follows: Grade 1: impaired relaxation; Grade 2: pseudo normal pattern; and Grade 3/4: reversible/irreversible restrictive pattern.16

Outcome ascertainment
Subjects were prospectively followed for the development of first AF or flutter. Ascertainment was accomplished both by survey questionnaires sent to all participants and comprehensive review of their medical records to 2007. The participants were specifically asked whether they had developed symptoms of AF, or incurred a diagnosis of AF, and whether they had been hospitalized and for what reasons. The outcome of AF/flutter was considered to have occurred only if it could be verified by a 12-lead electrocardiogram, whether the event was documented at, or outside of, Mayo Clinic. In our analysis, no distinction was made between AF and atrial flutter, or whether the atrial arrhythmia was paroxysmal or persistent. Ascertainment of death was accomplished through comprehensive review of medical records and the use of the following resources: death certificates; vital status information from Mayo Registration; Minnesota State death tapes; and social security death index.

Statistical analysis
Data were presented as means ± standard deviations (SD) for continuous variables and frequency percentages for categorical data. Differences in baseline characteristics between patients with and without subsequent development of AF/flutter were assessed using rank sum tests for continuous variables and {chi}2 tests for categorical variables. Simple associations between LA volume and clinical or echocardiographic parameters were evaluated using Spearman's correlation tests. Receiver–operator analyses were used to assess the overall performance of minimum and maximum LA volumes for (i) the detection of moderate (Grade 2) or severe (Grade 3/4) diastolic dysfunction and (ii) elevated LV filling pressure (E/e' ≥ 10). Areas under the receiver–operating characteristic curves were compared using the method of DeLong et al.17 Cox proportional hazards modelling was used to determine the association between LA volume and incident AF/flutter, adjusting for clinically relevant covariates. The clinical and echocardiographic parameters in Table 1 were considered in the models. We first assessed the significance of each variable in terms of its relationship with the AF/flutter in the univariable analyses. Then, those variables that were significant at P < 0.05 were entered into Cox proportional hazards multivariable model: (1) without minimal LA volume; (2) without maximal LA volume; and (3) with both maximum and minimum LA volume. The Kaplan–Meier method was used to estimate the 3-year cumulative risk of AF/flutter for the cohort, stratified by LA volume tertiles. Differences across tertiles of minimum and maximum LA volumes were examined using log-rank tests. Statistical significance was defined as two-tailed P < 0.05. The interobserver reproducibility of LA volume was tested with the random selection of 50 patients using Bland–Altman analysis. We reported the mean differences with SDs between the two operators for both minimum and maximum LA volumes. We also assessed the intraclass correlations along with their 95% confidence intervals for both volumes.


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  		Table 1 Baseline characteristics of the study population stratified by subsequent development of new atrial fibrillation (AF)/flutter

 

   Results
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 Abstract
 Introduction
 Methods
 Results
Discussion
 Conclusions
 Funding
 References
 
Of the 574 participants (mean age 74 ± 6 years, 52% men), 30 (5.2%) developed newly diagnosed, electrocardiographically confirmed AF/flutter during a mean follow-up of 1.9 ± 1.2 years. A total of 97 (17%) participants died during the follow-up period. Outcome ascertainment was complete for the cohort. Baseline characteristics of the study population are described in Table 1. Univariable predictors of incident AF/flutter included minimum LA volume (P < 0.0001), maximum LA volume (P = 0.006), body mass index (P = 0.046), E/e' ratio (P = 0.005), and the presence of moderate or severe diastolic dysfunction (P = 0.01) at baseline.

Minimum and maximum LA volumes were strongly correlated with each other (r = 0.85; P < 0.0001), and were positively associated with advancing age; a history of congestive heart failure, coronary artery disease, and hypertension; and LV mass index, diastolic function grade, and filling pressures as estimated by E/e' (Table 2). Both minimum and maximum LA volumes were inversely associated with a measure of LV relaxation (e') and LV ejection fraction. The overall performance of minimum LA volume was marginally greater than maximum LA volume for the detection of moderate or severe diastolic dysfunction and increased LV filling pressures (Figure 1), but the differences were not statistically significant (P = 0.34 and P = 0.49, respectively).


Figure 1
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  		Figure 1 Receiver–operator curves for the detection of (A) moderate or severe diastolic dysfunction and (B) increased left ventricular filling pressure (E/e' ≥ 10).

 


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  		Table 2 Clinical and echocardiographic associations with indexed minimum and maximum left atrial (LA) volume

 
After adjusting for age, both larger minimum and maximum LA volumes were associated with greater risks of first AF/flutter (Figure 2). The Kaplan–Meier 3-year age-adjusted risk estimates of freedom from AF/flutter by tertiles of minimum LA volume (<16, 16–23, and >23 mL/m2) were 97, 87, and 74% (P < 0.0006), and by tertiles of maximum LA volumes (<34, 34–44, and >44 mL/m2) were 94, 85, and 78% (P = 0.03). A stepwise increase in age-adjusted risk of AF/flutter was evident when the cohort was stratified according to tertiles of minimum or maximum LA volume, with the risk association being stronger for minimum LA volume (Figure 3). In separate multivariable models, minimum LA volume (P = 0.003) and maximum LA volume (P = 0.039) were predictive of first AF/flutter, independent of baseline clinical risk factors, LV ejection fraction, and diastolic function grade (Table 3). However, maximum LA volume (P = 0.79) was not incremental to minimum LA volume (P = 0.02) for the prediction of first AF/flutter in a multivariate model when both these parameters were entered into the model, adjusting for age, sex, clinical risk factors, LV ejection fraction, and diastolic function. The interobserver reproducibility was better for maximum LA volume, when compared with minimal LA volume (Figure 4). Mean difference was 3.1 ± 7.1 mL/m2 for maximum LA volume and 7.4 ± 7.3 mL/m2 for minimal LA volume; and intraclass correlations were 0.87 (0.73–0.91) and 0.81 (0.32–0.78), respectively.


Figure 2
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  		Figure 2 Age-adjusted cumulative survival from atrial fibrillation (AF) or flutter by (A) minimum left atrial (LA) volume and (B) maximum LA volume.

 


Figure 3
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  		Figure 3 Age-adjusted associations between minimum and maximum left atrial (LA) volume (LAVmin and LAVmax) for the prediction of atrial fibrillation or flutter.

 


Figure 4
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  		Figure 4 Interobserver reproducibility for (A) minimum left atrial (LA) volume and (B) maximum LA volume.

 


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  		Table 3 Multivariate models for the prediction of first atrial fibrillation/flutter

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
Conclusions
 Funding
 References
 
In this prospective study of older patients without valvular heart disease or a history of atrial arrhythmias, we found that minimum and maximum LA volumes were both predictive of the development of first AF/flutter, independent of clinical risk factors, LV ejection fraction, and the severity of LV diastolic dysfunction. The graded risk association with incident AF/flutter was slightly stronger for minimum LA volume.

That maximum LA volume is a robust predictor of age-related outcomes, including AF,18 stroke,19 heart failure,20 and cardiovascular death,21 is fairly well established. To the best of our knowledge, this is the first study to determine the utility of minimum LA volume, and to compare minimum and maximum LA volume for the prediction of AF/flutter. We found that maximum and minimum LA volumes, which represent the size of the left atrium at the commencement and completion of LA emptying and LV filling, correlated modestly with non-invasive estimates of LV filling pressure. The correlation was stronger for minimum than maximum LA volume, a finding that was consistent with the results from a study using invasive methods to determine LV filling pressure.13 The results of our study, therefore, not only confirm the prognostic utility of maximum LA volume, but also suggest that minimum LA volume may be a slightly more robust predictor of AF/flutter. However, the potential advantage of minimum LA volume for AF/flutter prediction may be offset by its greater interobserver variability.

Our findings also extend the current understanding of the relationship between LA volume and diastolic function grade in the prediction of cardiovascular outcomes. In our multivariable models, minimum and maximum LA volumes, but not diastolic function grade, remained as independent predictors of AF/flutter, underscoring the relative value of these parameters for the prediction of first AF/flutter. In this cohort, LA size which reflects the average effects of LV filling pressures over time with structural remodelling provided a better estimate of risk of an outcome than the instantaneous measurement of diastolic function grade or filling pressure at the time of the study.22

The study was limited by the fact that the population was referral-based and lacked racial-ethnic diversity. As such, the extent to which our results can be applied to the general population or other population groups is unknown. Case ascertainment may have been incomplete if subjects had episodes of silent AF/flutter, and out-stringent requirement for 12-lead electrocardiogram confirmation. In this observational study, we were unable to adequately assess the influence of various medical therapies on study measurements.


   Conclusions
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusions
Funding
 References
 
Minimum LA volume was a robust independent predictor of first AF/flutter in this elderly cohort. Although it was at least as, and probably slightly more powerful than maximum LA volume for such prediction, the potential clinical advantage for its utility in risk stratification was offset by the lower interobserver reproducibility.


   Funding
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusions
 Funding
References
 
This study was supported by a grant from the American Heart Association.

Conflict of interest: none declared.


   References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusions
 Funding
 References
 

  1. Chugh SS, Blackshear JL, Shen WK, Hammill SC, Gersh BJ. Epidemiology and natural history of atrial fibrillation: clinical implications. J Am Coll Cardiol (2001) 37:371–8.[Abstract/Free Full Text]
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This Article
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