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European Heart Journal Advance Access originally published online on June 11, 2007
European Heart Journal 2007 28(14):1773-1781; doi:10.1093/eurheartj/ehm199
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© The European Society of Cardiology 2007. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Left atrial remodelling in mitral regurgitation—methodologic approach, physiological determinants, and outcome implications: a prospective quantitative Doppler-echocardiographic and electron beam-computed tomographic study

David Messika-Zeitoun1,2, Michael Bellamy1, Jean-Francois Avierinos1, Jerome Breen3, Christian Eusemann4, Andrea Rossi5, Thomas Behrenbeck1, Christopher Scott6, Jamil A. Tajik1 and Maurice Enriquez-Sarano1,*

1 Division of Cardiovascular Diseases and Internal Medicine, Mayo Clinic, 200 First Street S.W., Rochester, MN 55905, USA
2 Cardiovascular Department, Hopital Bichat, 46 rue H Huchard, Paris 75018, France
3 Department of Radiology, Mayo Clinic, Rochester, MN, USA
4 Biomedical Imaging Resource Department, Mayo Clinic, Rochester, MN, USA
5 Department of Biomedical and Surgical Sciences, University of Verona, Italy
6 Section of Biostatistics, Mayo Clinic, Rochester, MN, USA

Received 27 February 2007; accepted 13 April 2007; online publish-ahead-of-print 11 June 2007.

* Corresponding author. E-mail address: sarano.maurice{at}mayo.edu


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 Acknowledgements
 References
 
Aims: To define accurate and normal range of echocardiographic left atrial (LA) volume measurement and to assess the prevalence, determinants, and outcome implications of LA enlargement in mitral regurgitation (MR).

Methods and results: We prospectively compared LA volume obtained simultaneously by electron beam-computed tomography (EBCT) and by four echocardiographic methods in 33 test patients. Accurate echocardiographic LA volume measurements were obtained only by biplane area–length method with vertical longitudinal-length (r = 0.95, P < 0.0001; 145 ± 57 vs. 143 ± 55 mL, P = 0.57). Using this method, the normal range in 100 normal subjects, the physiological determinants and outcome implications of LA enlargement in 320 patients with organic MR were analysed. In normal subjects, indexed to body surface area, LA index (27 ± 6 mL/m2) was not influenced by age or gender and values ≥ 40 mL/m2 were beyond the upper limit of normal. In MR, the most powerful determinants of LA enlargement were higher regurgitant volume (RVol) and atrial fibrillation (AF) (P < 0.0001), followed by older age, female gender, higher left ventricular end-systolic volume, and mass (all P < 0.001). After diagnosis in sinus rhythm, LA index ≥ 40 mL/m2 predicted superiorly and independently to LA diameter the occurrence of AF [adjusted RR 1.48 (1.06–2.16), P < 0.01] and the combined endpoint of death or need for mitral surgery [adjusted RR 1.61 (1.3–2.0), P < 0.0001].

Conclusion: LA remodelling can be accurately assessed by echocardiography and LA index ≥ 40 mL/m2 is beyond the normal range. In organic MR, higher LA index is the combined result of multiple physiological effects, provides independent prognostic information, and therefore should be part of a comprehensive echocardiographic examination.

Key Words: Atrium • Echocardiography • Mitral valve • Computed tomography • Outcome


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 Acknowledgements
 References
 
Left atrial (LA) enlargement is part of cardiac remodelling observed in various cardiovascular diseases and appears to be associated with poor clinical outcome.1–4 Furthermore, in the general population, LA enlargement is associated with increased risk of cardiac death.5 Therefore, detecting and quantifying LA enlargement is an important goal in the evaluation of cardiac remodelling. Quantifying LA enlargement is of particular importance in patients with mitral regurgitation (MR) as the disease directly impacts on the LA.6 LA enlargement in MR has been described either as a compensatory mechanism preventing pulmonary congestion,7 or conversely, as a marker of poor prognosis,2 even after successful surgery.3 These uncertainties regarding the clinical and outcome significance of LA enlargement also reflect limited knowledge of the physiological mechanisms leading to LA enlargement, which may reach giant proportions8 for unclear reasons. Another confounding factor is atrial fibrillation (AF), which independently of any volume overload is associated with LA enlargement,9 and the interactions between physiological determinants of LA remodelling and AF are unknown. These gaps in knowledge assume particular importance as cumulative data suggest that LA enlargement may play an important role in the indication of surgery.2,3

However, important methodological concerns limit the utilization of measures of LA remodelling in clinical practice. Echocardiography is widely available for LA size assessment. The M-mode LA diameter measures the antero-posterior LA dimension, which has the advantage of simplicity but assumes concentric LA remodelling.10 Direct measurement of LA volume is more globally descriptive but pioneering methodological studies raised concerns about accuracy of this approach.11–13 Hence, a sound clinical approach to assessment of LA remodelling is uncertain.

Therefore, in regard to LA volume measurement, our aims were to define the accuracy of echocardiographic methods in comparison with simultaneous electron beam-computed tomography (EBCT), to define the normal range, to define the determinants of LA enlargement and its prognosis implications with regard to subsequent AF, in patients with organic MR, in whom we also prospectively quantified the degree of MR, and of left ventricular (LV) remodelling.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 Acknowledgements
 References
 
Study patients
Three patient subsets were prospectively and concurrently enrolled after informed consent:

Validation set
Thirty-three patients with various degrees of LA enlargement, without renal dysfunction (creatinine < 2 mg/dL), underwent prospective LA volume measurement by echocardiography and immediately consecutive (within 1 h without haemodynamic change) by EBCT with complete LA imaging.

Normal group
One hundred subjects with no known heart disease, no detectable comorbidity by history and by clinical and laboratory assessment, normal chest radiography, electrocardiogram, and echocardiography (normal valves, systolic and diastolic function, wall thickness, and haemodynamics) and complete LA imaging were enrolled to define the normal range of LA volume. To minimize the possibility of referral bias, half of these patients were recruited from a population-based sample (Olmsted County, MN, USA), whereas the other patients of this normal group were enrolled irrespective of their geographic origin among those referred for echocardiography for cardiac murmur or general physical examination.

Mitral regurgitation group
To define LA volume, physiological determinants, and outcome implications, we prospectively and consecutively enrolled from 1991 to 1997, 320 patients with organic MR. Eligibility required pure (no stenosis), isolated (no aortic, congenital, or pericardial heart disease), organic MR, and prospective triple quantitation of MR (by at least two methods), of LV remodelling and of LA remodelling using Doppler-echocardiography. Follow-up information was obtained from clinical records, death certificates, postal survey, and telephone calls to patients, relatives, or physicians. AF occurrence during follow-up of patients with baseline sinus rhythm was diagnosed by electrocardiogram.

Doppler-echocardiographic methods
Measurements of left atrial volume
LA volume was calculated by four different echocardiographic methods. LA measurements were performed off-line in end-systole with the largest LA size immediately before mitral opening.

Two methods use LA diameters. The method of cube ({pi} D3/6) is derived from the M-mode diameter (D) obtained from the parasternal long-axis (LAx) view assuming a spherical LA shape. The two-dimensional diameters method uses direct measurement of three diameters, antero-posterior (D1) and transverse (D2) in the four-chamber (4C) view, and supero-inferior (D3) in the apical LAx view.14 LA volume is calculated as [{pi}x(D1 x D2 x D3)/6].

Two methods used the LA contour traced on magnified LA images obtained by apical 4C and LAx views (Figure 1A and B). We traced the inner LA borders, excluding pulmonary veins and LA appendage with a straight line at the mitral annulus (Figure 1C and D). The longitudinal LA length was then positioned manually on this contour. Three different positioning were used (Figure 1): (i) major length (maximal length between lateral annulus extremity and posterior LA wall); (ii) symmetry length (length between annulus center and posterior LA wall); and (iii) vertical length (vertical length between annulus and posterior LA wall). Using these contours and lengths, the biplane area–length method calculates LA volume using planimetered LA areas (A1 and A2, respectively) as (0.85 x A1 x A2)/L where L is the longitudinal length. For the biplane method of disks, the LA is divided into a pile of disks perpendicular to the longitudinal length direction, the radii from the longitudinal axis to the LA contour, and the volume of each disk is calculated and LA volume is calculated by summation of the disks' volumes.15


Figure 1
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  		Figure 1 Apical four-chamber (A, C) and long-axis (B, D) views of the left atrium (LA) without (A, B) and with traced (C, D) contour with three different longitudinal lengths indicated: major (dotted line), symmetry (dashed line), and vertical (solid line). Ao, Aorta; LV, left ventricle; RA, right atrium.

 
Quantitation of mitral regurgitation
The degree of MR was quantified by at least two of three methods which were averaged to calculate regurgitant volume (RVol) and effective regurgitant orifice area (ERO). These methods were quantitative Doppler, based on measurement of mitral and aortic stroke volumes, quantitative two-dimensional echocardiography,15 based on LV stroke volume measurement and PISA method,16 based on analysis of proximal flow convergence. Severe MR was defined by an RVol ≥ 60 mL.17

Quantitation of LV remodelling
LV volumes, mass, and ejection fraction (EF) were measured as recommended by the American Society of Echocardiography.15

Electron beam-computed tomography
EBCT studies were performed with an Imatron C-150 (San Francisco, CA, USA) with acquisition in cine mode triggered by ECG (R wave). Two sequences without overlap of eight slices (8 mm-thick) at 17 images per second starting at the R wave were acquired after injection of intravenous contrast (Iopamidol®) to encompass the entire LA. Cross-sectional tomographic images (360 x 360) were reconstructed using a filtered back-projection algorithm. LA contour was manually traced at end-systole with atrial appendage and pulmonary veins excluded (Figure 2). Summation of LA slice-volume provided total LA volume. To verify EBCT accuracy, similar imaging was performed on a phantom (full cylinder placed in a tub filled with water). The difference true-EBCT volume was only 3%.


Figure 2
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  		Figure 2 Electron beam-computed tomography views showing untraced (A) and traced (B) left atrium. Pulmonary veins and left appendage are excluded.

 
Statistical analysis
Data are presented as mean ± SD, percent, and 95% CI determined for normal distributions or by bootstrapping methods assuming non-normal distributions. Echocardiographic and EBCT methods were compared using linear regressions and paired t-tests. Bland and Altman analysis method was used to assess for error and bias.18 Inter- and intra-observer variability of LA volume measurements was determined as the mean difference ± SD. LA enlargement was defined as the LA index value above the 97.5th percentile in the normal group. Association of M-mode diameter and LA volume was studied using linear and non-linear regressions and the 95% CI of estimated LA volume was used to assess closeness-of-fit and its trends for change with increasing M-mode diameters. Comparison between groups used Student's t-test or {chi}2 test as appropriate. Univariate and stepwise multiple linear regression analysis was used to identify determinants of LA volume. Only variables significantly correlated to LA index (P < 0.05) were tested and in the stepwise multivariable analysis, variables with a P < 0.10 were removed from the model. Determinants of LA enlargement were also evaluated in subgroups stratified by age, sex, and mitral lesions (classified as restricted vs. excessive motion). Rates of AF and of the combined endpoint of death or need for mitral surgery, were estimated by the Kaplan–Meier method, and the log-rank test was used for comparison of rates in patients with and without LA enlargement. Cox proportional hazards analyses were performed to evaluate the predictive value of LA size after adjustment for several variables known to impact on occurrence of events (age, gender, EF, LV mass, and RVol). For these analyses at least 265 patients followed 5 years were requested. Tests were all two-sided and a P < 0.05 was considered significant.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 Acknowledgements
 References
 
Comparison of echocardiographic and EBCT LA volume
All the 33 patients of the validation set had organic MR with variable amount of regurgitation (RVol 68 ± 24 mL/beat, range 31–111) and were subsequently enrolled in a therapeutic clinical trial so that they did not participate in the physiological or outcome analysis. As baseline characteristics, age was 65 ± 13 years, 30% were females, 6% were in AF. LA size was highly variable by M-mode (48 ± 8 mm, range 29–75) and by EBCT (LA volume 143 ± 55 mL, range 55–324 mL). All methods of LA volume determination showed significant correlations with EBCT measurements (all r > 0.80, P < 0.0001) (Table 1). However, accuracy of LA volume measurement was dependent on the method and longitudinal length used (Table 1). Compared with EBCT, the cube method markedly underestimated LA volume as well as the two-dimensional diameters method, although to a lesser degree. Accuracy of biplane methods (disks and area–length) improved with use of the vertical length. However, only the area–length method using the vertical length showed no difference with EBCT (145 ± 58 mL, P = 0.57). Quality control plots (Bland and Altman analysis) showed no trend for under- or over-estimation (mean difference 2 ± 18 mL, Figure 3). Of note, single-plane area–length method systematically overestimated LA volume (161 ± 64 mL, P = 0.0004; mean difference + 18 ± 25 mL).


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  		Table 1 Comparison of LA volume measured by echocardiographic methods to that measured by electron beam-computed tomography (EBCT) in the validation set population

 

Figure 3
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  		Figure 3 Plots of LA volume by echocardiography (biplane area–length method with vertical longitudinal-length) and electron beam-computed tomography (EBCT) in the validation set (n = 33 patients). (A) Scatter plot (x-axis echocardiography, y-axis EBCT) with solid line indicating the regression line and (B) quality control plot (x-axis mean of LA volume by EBCT and echocardiography, y-axis difference echocardiography-EBCT) with solid line indicating the mean difference and grey zone indicating ± 2SD (Bland and Altman method).

 
Intra- and inter-observer variability of LA volume measurements, performed in 10 random patients, was respectively, 2 ± 1% and 11 ± 7% for EBCT and 8 ± 5% and 8 ± 8% for echocardiography using the biplane area–length method.

Left atrial volume normal range
LA volume in the 100 normal subjects enrolled (mean age 53 ± 17 years, 40% female) was measured using the area–length method and is presented in the upper part of Table 2, while clinical characteristics are presented in the left part of Table 3. This group was characterized by lack of symptom and of arrhythmia and normal haemodynamics and LV characteristics.


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  		Table 2 LA measurements in normal subjects and patients with MR

 

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  		Table 3 Association of clinical and echocardiographic characteristics to LA enlargement

 
The LA M-mode diameter was 38 ± 5 mm. LA volume was 50 ± 13 mL (Table 2) and was similar in the referred (n = 50; 50 ± 15 mL) and population-based (n = 50; 50 ± 12 mL) subsets (P = 0.98). LA volume showed no association with age (r = 0.14, P = 0.16) but correlated positively with body surface area (BSA, r = 0.44, P < 0.0001). Although LA volume was larger in men than in women, this difference disappeared after indexation to BSA (27 ± 6 vs. 26 ± 7 mL/m2, P = 0.47).

The 2.5th and 97.5th percentile of LA index were 15 and 40 mL/m2 and we defined an LA enlargement as the LA index value > 97.5th percentile. LA index was not associated with age or sex but a weak association (r2 = 0.21) was noted for larger LA index with larger end-systolic LV size (P < 0.01) and higher mean blood pressure (P = 0.06).

Left atrial volume in patients with mitral regurgitation
The LA size of the 320 patients with organic MR prospectively enrolled is indicated in the lower part of Table 2, whereas clinical characteristics are indicated in Table 3. Age was 64 ± 14 years, 64% were male, 85% in functional class NYHA I or II and 13% in AF. Medications used were digoxin in 21%, angiotensin-converting enzyme-inhibitors in 29%, diuretics in 22%, calcium channel-blockers in 13%, and beta-blockers in 11%. MR showed wide range with RVol was 70 ± 45 mL and 177 patients (55%) having severe MR (RVol ≥ 60 mL).

Left atrial M-mode diameter
This was available in 251 and not measurable in 69. LA diameter and volume, respectively 48 ± 9 mm and 110 ± 59 mL, showed significant correlation (r = 0.74, P < 0.0001) (Figure 4A). However, the relation was curvilinear and the 95% CI increased with LA diameter (32–136 mL at 40 mm and 82–348 mL at 60 mm) as shown by widening of residuals scatter with increasing diameter (Figure 4B, P < 0.0001).


Figure 4
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  		Figure 4 Plots of LA diameter and volume (biplane area–length) in patients with MR. (A) Scatter plot showing the curvilinear regression and widening 95% CI between LA diameter (x-axis) and volume (y-axis) and (B) scatter plot of residuals (y-axis) vs. LA diameter (x-axis) showing the widening residual range. The solid lines indicate the regression line and the grey zones indicate the confidence interval.

 
Left atrial volume
LA volume assessed in the entire organic MR cohort (320 patients) varied widely (114 ± 59, from 23 to 351 mL; LA index, 61 ± 30, from 14 to 173 mL/m2). LA enlargement (LA index ≥ 40 mL/m2) was noted in 70% of patients. Baseline characteristics of patients with and without LA enlargement (Table 3) show numerous clinical and echocardiographic variables differences.

By multivariable analysis, the strongest independent determinant of higher LA index was higher RVol (F = 110, P < 0.0001). RVol normalized to BSA showed only marginally higher correlation with LA index (r = 0.66 vs. 0.63, both P < 0.0001) and did not improve the predictive model. Severe vs. non-severe MR had higher LA index (77 ± 29 vs. 43 ± 20 mL/m2, P < 0.0001) (Table 2) and after adjustment, each 10 mL of RVol was associated with LA index increase of 4 mL/m2. Among patients with severe MR, 93% had LA index ≥ 40 mL/m2, whereas without severe MR 42% also had enlarged LA, so that the positive predictive value of enlarged LA for severe MR was only 73%.

The second strongest determinant of LA index was the presence of AF (F = 37, P < 0.0001). Patients with vs. without AF had LA index of 83 ± 35 vs. 57 ± 28 mL/m2, P < 0.0001, and after adjustment AF was associated with LA index increase of 22 mL/m2. Importantly, the correlation between LA index and RVol remained as strong in patients in AF (r = 0.74, P < 0.001) as in patients in sinus rhythm (r = 0.68, P < 0.001, Figure 5).


Figure 5
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  		Figure 5 Scatter plot of LA index (biplane area–length, y-axis) and regurgitant volume (RVol) (y-axis) in the 320 patients with MR. The open dots are for patients in sinus rhythm and the solid dots for those in atrial fibrillation (AF). The solid lines indicate the regression lines.

 
The other determinants of higher LA index were increasing age (F = 18, P < 0.0001), female gender (F = 14, P = 0.0002), higher LV end-systolic volume (F = 15, P = 0.0001), index higher LV mass (F = 15, P = 0.0001), and lower mean blood pressure (F = 12, P = 0.0006). When the Doppler-measured systolic pulmonary artery pressure (obtained in 264 patients) was added to the model, it was an independent determinant of LA index (F = 13, P = 0.0004), whereas all previously defined determinants remained significant and the model improved slightly (from r2 of 0.63 to 0.67).

Subgroup analysis
Subgroup analysis was stratified by cardiac rhythm, the same determinants of LA index were found in patients' in sinus rhythm. In AF patients, with limited power, higher RVol (P < 0.001) and higher LV end-systolic volume index (P < 0.049) determined higher LA index. When the analysis was stratified by the mechanism of regurgitation, patients with normal or restricted motion (n = 118) compared with those with excessive valve motion (n = 202) showed similar predictive models.

Prognostic implications—incidence of atrial fibrillation
In patients with MR in sinus rhythm at baseline, during follow-up (median 6.8 years, interquartile range 5.0–9.4 years), 58 patients experienced AF (at 10 years 28 ± 4%). Patients with baseline LA index ≥ 40 mL/m2 incurred a higher AF incidence than those with normal LA (at 10 years 38 ± 6 vs. 13 ± 4%, P = 0.002) (Figure 6A). Baseline LA diameter and index were both predictors [RR (95% CI)] of subsequent AF [respectively, RR/mm = 1.04 (1.001–1.075), P = 0.04 and RR/mL/m2 = 1.016 (1.008–1.024), P = 0.003]. However, when considered simultaneously, LA index captured the entire predictive power of LA enlargement (P < 0.01) on occurrence of AF while LA diameter did not maintain statistical significance (P = 0.65). In multivariable analysis, adjusting for age, gender, EF, and LV mass, LA index ≥ 40 mL/m2 remained independently highly predictive of AF occurrence during follow-up [RR = 1.48 (1.06–2.16), P < 0.01].


Figure 6
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  		Figure 6 Rates of atrial fibrillation (A) and of combined endpoint of death or need for mitral surgery (B) after diagnosis in patients with organic MR in sinus rhythm at baseline according to baseline LA index (classified as normal <40 mL/m2 or enlarged ≥ 40 mL/m2).

 
Combined endpoint of death or mitral surgery
Combined endpoint of death or mitral surgery occurred during follow-up in 197 patients in sinus rhythm at baseline (80 ± 3% at 10 years), with a higher incidence in patients with than without LA index ≥ 40 mL/m2 (at 10 years 92 ± 2 vs. 53 ± 6%, P < 0.0001, Figure 6B). In multivariable analysis, LA index was predictive of higher rates of events [adjusted RR 1.6 (1.3–2.0), P < 0.0001) adjusting for age, sex, EF, and RVol.


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
Acknowledgements
 References
 
The present prospective simultaneous EBCT and echocardiographic study shows that LA volume is accurately measured by the area–length method with a vertical longitudinal-length, whereas other methods underestimate LA volume. For normal range, normalizing for BSA, LA index is similar in normal men and women and LA index ≥ 40 mL/m2 are beyond the upper limit of normal LA size. M-mode diameter estimates LA volume imprecisely with a range of error which is wide and increasing with LA size. In organic MR, our study, using prospective triple quantitation of LA and LV remodelling and of MR severity, demonstrates the complex determinants of LA remodelling. The most powerful determinant of LA remodelling is RVol but it is compounded by effects of increasing age, female sex, and AF. LV remodelling, with increasing LV mass and LV end-systolic volume index, is associated with LA enlargement. Baseline LA index is also an independent predictor of outcome after diagnosis, superior to LA diameter.

Assessment of left atrial remodelling—need for improved methodology
LA enlargement is an emerging prognostic marker in varied populations,1,19,20 raising renewed interest in defining LA normalcy21,22 and in assessing LA remodelling.22 LA size assessed by M-mode echocardiography using a single diameter has limited accuracy, apparent in the present study, with underestimation of LA volume10,11 and wide range of error.23 Thus, it is essential to critically examine the echocardiographic LA assessment, to select an approach measuring LA volume accurately.

Concerns about echocardiographic LA volume accuracy in pioneering studies,11–13 create obvious doubts on normal range21 and physiological determinants.22 The present study examined various approaches and showed that accurate LA assessment is possible. EBCT serves as a sound reference for cardiac chamber volumes measurement,11,24,25 confirmed in our phantom comparison and in LA casts studies.13 Compared with simultaneous EBCT, biplane area–length method with vertical longitudinal-length measured accurate LA volumes. LA is asymmetric26 with shape irregularities such as great vessels impingements. The method of disks is accurate with EBCT because it is based on the entire LA contour for all slices. Conversely, echocardiography interpolates data between the only two tomographic planes recorded and may exaggerate the impact of localized impingements. Area–length methodology uses global averaging, less affected by local irregularities probably explaining better LA assessment. This method is simple, reproducible, and accurate, allowing routine LA volume measurement and physiological determinants of LA remodelling assessment. Real-time three-dimensional echocardiography seems promising but requires dedicated software and hardware. Its comparison with standard area–length method27 is justified in future studies.

Normalcy of left atrial volume
In normal subjects, as shown by others, BSA normalization as LA index eliminated differences between men and women.28 Importantly, the identity of measures obtained in referred subjects and those from Olmsted County suggest that, for normal range there was no trend for bias.

In the present study, normal LA index (27 ± 6 mL/m2) and thus definition of LA enlargement (LA index > 97.5th percentile i.e. ≥ 40 mL/m2) are slightly larger than those recommended29 (22 ± 6 mL/m2 and ≥ 29 mL/m2, respectively) or commonly used in previous papers (32 mL/m2 for LA enlargement)28,30,31 deserving several comments. First, our methodology is validated against sound reference (EBCT) and we demonstrate that accurate LA volume measurements can be achieved using the area–length method and a vertical longitudinal-length, whereas all previous studies tended to underestimate LA volume.10–12 Secondly, all echocardiographic methods are not equivalent. The two-dimensional diameters method, used in the largest study aiming at defining normalcy of LA volume,28 underestimates LA index by 10–20%, as shown by the present study and a recent paper.32 Finally, in contrast to others, we used the apical LAx view which avoids LA foreshortening commonly observed with two-chamber views.33

Determinants of left atrial remodelling in mitral regurgitation
In MR, LA enlargement compensates the volume overload,7 but is also a marker for future heart failure,4 AF under conservative management,2 or after mitral valve surgery,34 and possibly excess mortality after surgery.3 Defining physiological determinants of LA remodelling is paramount to interpreting LA enlargement. To our knowledge, the present study, with triple quantitation of MR and of LV and LA remodelling, is the first to address this issue.

In patients with MR, MR degree (RVol) was the major determinant of LA remodelling,35 but LA index cannot be a surrogate for RVol, which should be independently quantified. LA enlargement increases LA compliance, minimizes LA pressure, and may explain why most patients with severe MR present asymptomatically.4 The second determinant of LA index is AF. LA enlargement leads to AF,2 and AF leads to LA enlargement.14 However, in MR contrary to non-valvular AF, the rhythm disturbance leads to orderly and not haphazard LA enlargement, strongly determined by RVol (Figure 5). LV remodelling causes LA enlargement, possibly through higher LV diastolic pressures or myocardial alterations. Irrespective of physiological mechanisms, these associations show that LA enlargement reveals advanced haemodynamic alterations.

Associations between ageing, female gender, and LA enlargement, absent in normal population,5,36 were observed in MR similarly to other diseases.37 Whether age and sex affect LA response to volume overload will require future studies with sequential measurements of LA volume and RVol. Of note, an opposite relation between LA volume and blood pressure was found in the normal and MR groups and may be related to the association of lower blood pressure with more severe haemodynamic impairment in patients with MR.

Impact of left atrial remodelling on outcome
The role of LA enlargement as a harbinger of subsequent AF has been reported in patients without valve disease38 and in those with organic MR.2 AF occurrence leads to increased cardiac morbidity and mortality.2 In the present prospective study, we observed that, LA index is an independent and powerful predictor of subsequent AF. Furthermore, LA index is also a predictor of the combined endpoint of death or need for mitral surgery, independently of RVol. Thus, LA index, which integrates multiple determinants in one variable, provides in one measurement major prognostic information and is essential in the risk-stratification of patients with MR. Although both LA diameter and volume are individually predictive of AF, LA index carries the entire predictive power of LA enlargement. Thus, accurate LA volume measurement translates into additional prognostic information and should be part of comprehensive echocardiographic assessment of patients with MR so that LA enlargement may be taken into account in asymptomatic patients when surgery is considered.

Study limitations
Reference methods in validation studies may be disputed. LA angiography was used in the past,39 but is rarely performed. EBCT determines accurately absolute volumes as shown by our phantom measurements and by previous cardiac volumetric studies.24,25 Absolutely, simultaneous measurement would be ideal but are impossible and the 1 h delay ensured haemodynamic stability.

The strength of associations in present predictive models, suggests that main determinants of LA size were identified. However, LV and LA compliance and pressure are not measurable non-invasively in MR. Their impact on LA enlargement, suggested by the adjunct predictive value of pulmonary pressure, will require complex future invasive studies.

Conclusion
Simultaneous EBCT and echocardiography show that LA volume is accurately measured by two-dimensional echocardiographic area–length method with vertical longitudinal-length. LA index of 40 mL/m2 is the upper limit of normal range. In organic MR, the most powerful determinant of LA remodelling is RVol but it is compounded by effects of increasing age, female sex, AF, and LV remodelling. However, LA remodelling as the recipient of combined effects of these physiological determinants provides strong prognostic information. Therefore, its assessment should be part of comprehensive echocardiographic examination of patients with MR and the development of interventions aiming at preventing LA enlargement is a major therapeutic goal.


   Acknowledgements
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgements
References
 
D.M.-Z. was supported by a grant from the Federation Française de Cardiologie. The study was supported in part by grants HL 64928 and M01-RR00585 of the National Institute of Health.

Conflict of interest: none declared.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgements
 References
 

  1. Vaziri SM, Larson MG, Lauer MS, Benjamin EJ, Levy D. Influence of blood pressure on left atrial size. The Framingham Heart Study. Hypertension (1995) 25:1155–1160.[Abstract/Free Full Text]
  2. Grigioni F, Avierinos JF, Ling LH, Scott CG, Bailey KR, Tajik AJ, Frye RL, Enriquez-Sarano M. Atrial fibrillation complicating the course of degenerative mitral regurgitation: determinants and long-term outcome. J Am Coll Cardiol (2002) 40:84–92.[Abstract/Free Full Text]
  3. Reed D, Abbott R, Smucker M, Kaul S. Prediction of outcome after mitral valve replacement in patients with symptomatic chronic mitral regurgitation. The importance of left atrial size. Circulation (1991) 84:23–34.[Abstract/Free Full Text]
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