Study Population

This retrospective cohort study included 195 patients (52% men; mean age, 64 ± 13 years) with LA dilatation (>68 mL for men, >62 mL for women) who were admitted to the Royal Hobart Hospital (Australia) and underwent sequential transthoracic echocardiographic examinations as routine follow-up from 2005 through 2013. All subjects were >18 years of age, were in sinus rhythm, had no histories of heart transplantation at baseline, and had an interval of ≥4 weeks between echocardiographic studies. Those who had severe valvular heart disease at both baseline and follow-up without any surgical intervention were also excluded from the study. Of the total of 195 patients included in this study, 93 (48%) were diagnosed with heart failure with New York Heart Association functional classification I ( n = 23), II ( n = 29), III ( n = 33), or IV ( n = 8). Seven patients had moderate to severe mitral regurgitation, 11 had moderate to severe aortic stenosis, and three had moderate mitral regurgitation and moderate to severe aortic regurgitation or stenosis. All these patients underwent surgery (not including a maze procedure) at some time within the follow-up period of this study. Because E/e′ ratio may not be a reliable measurement of LV filling pressure in patients with mitral valve disease or surgically repaired mitral valves, surgical patients were excluded from the main analyses of this study. The results of comparing LA structure and function between these surgical patients and those who underwent medical management are reported in the supplemental information. The median follow-up period was 1 year (interquartile range, 0.5–2 years). The study was approved by the Tasmanian Human Research Ethics Committee.

Echocardiographic Measurements

All echocardiographic studies were performed in a single echocardiographic laboratory by experienced clinical sonographers. Two-dimensional and Doppler measurements were obtained using standard techniques and procedures following the American Society of Echocardiography guideline. End-systolic LAV was measured using the biplane area-length method. Normal LAV was defined as ≤68 mL (men) or ≤62 mL (women), as recommended in the guidelines. These cutoffs were used to distinguish between “mildly abnormal” and “moderately abnormal” in the 2005 guidelines but align with the new cutoff to define normal LAV in the 2015 updated guidelines. Alternative cutoffs for normalization of LAV were defined by a 15% reduction in LAV from baseline, as previously suggested.

Peak LA longitudinal ε was measured using two-dimensional speckle-tracking software (Research Arena; TomTec Medical Imaging, Unterschleissheim, Germany) by a single rater who was blinded to clinical information, following standard methodologies for speckle-tracking reported in the guidelines. After the observer manually traced the LA endocardial surface in the four-chamber view using a point-and-click approach, the software automatically tracked the LA endocardial borders throughout the cardiac cycle. We took the onset of the QRS complex on the electrocardiogram as a reference point and measured positive peak LA longitudinal ε. The region of interest was divided into six segments. Peak LA longitudinal ε was obtained by averaging the peak values of all segments. The normal range of LA ε was defined as >32%, as previously recommended. LA contractile function was assessed by averaging the increment in ε after the onset of the P wave. LA conduit function was calculated as the difference between global LA ε and LA contractile function.

Pulsed-wave Doppler derived mitral inflow early (E) and late (A) velocities and medial and lateral tissue Doppler derived early (e′) velocities were obtained, and the mean E/e′ ratio was used for analysis. Normal LV filling pressure was defined as an E/e′ ratio < 13. LV ejection fraction (LVEF) was calculated using the biplane modified Simpson method. An index of LA wall stiffness was calculated as the ratio of E/e′ to LA ε, as previously suggested.

Ten patients were randomly chosen for 20 repeated measurements (10 at baseline and 10 at follow-up) of LA ε and E/e′ ratio to calculate intrarater variability. These measurements were repeated again by another expert to calculate interrater variability. These measurements were conducted ≥4 weeks apart. The raters were blinded to patients’ clinical information and the original measurements and were allowed to pick the best cardiac cycle each time of remeasurement.

Other Clinical Factors

Body weight, blood pressure, and medication use were obtained from medical records at both baseline and follow-up.

Statistical Analyses

Paired t tests were used to compare data at baseline and follow-up, and standard t tests were used to compare the mean values of clinical and echocardiographic parameters between groups. Log-binomial regression was used to calculate relative risks. Pearson correlation and linear regression were used to estimate the strengths and effect sizes of linear relationships. Changes in E/e′ ratio (ΔE/e’), LAV (ΔLAV), and LA ε (Δε) were calculated by taking the differences between baseline and follow-up values. Intraclass correlation and absolute mean and SD of the differences between repeated measurements were used to quantify intra- and interrater variability of LA ε and E/e′ ratio. Stata versuin 12.0 (StataCorp LP, College Station, TX) was used for analyses.

Patient Characteristics

Clinical characteristics at baseline and follow-up are shown in Table 1 . Most patients had preserved LVEFs and elevated LV filling pressures at both baseline and follow-up. Compared with baseline, patients had increased body weight and LVEFs and reduced LAVs but maintained their blood pressure, E/A ratios, E/e′ ratios, LA ε, and medication use at follow-up. Two patients (1%) developed paroxysmal atrial fibrillation during follow-up.

The intrarater intraclass correlations were 0.89 (95% CI, 0.76–0.97), 0.92 (95% CI, 0.80–0.98), and 0.83 (95% CI, 0.73–0.96) for global LA ε, conduit function, and contractile function, respectively. The interrater intraclass correlations were 0.86 (95% CI, 0.68–0.94), 0.84 (95% CI, 0.64–0.93), and 0.76 (95% CI, 0.47–0.90) for global LA ε, conduit function, and contractile function, respectively. The intra- and interrater intraclass correlations for E/e′ were 0.98 (95% CI, 0.95–0.99) and 0.96 (95% CI, 0.90–0.98), respectively. The interrater absolute difference was −0.94 ± 2.23% (LA ε) and −0.05 ± 1.55 (E/e′ ratio).

Echocardiographic Follow-Up

Approximately 50% of the patients had improved E/e′ ratios (92 of 174) or LA ε (97 of 174) during the follow-up period, but only 25% (47 of 174) showed reverse remodeling resulting in normalization of LAV. The changes in E/e′ ratio were due to changes in both E and e′. Among patients with ΔE/e′ < 0, their E reduced from 0.92 ± 0.24 m/sec at baseline to 0.79 ± 0.28 m/sec at follow-up ( P < .001), and their e′ increased from 0.07 ± 0.03 m/sec at baseline to 0.09 ± 0.04 m/sec at follow-up ( P < .001). Similarly, among those with ΔE/e′ ≥ 0, E increased from 0.80 ± 0.24 m/sec at baseline to 0.87 ± 0.27 m/sec at follow-up ( P = .007) and their e′ decreased from 0.07 ± 0.02 m/sec at baseline to 0.06 ± 0.02 m/sec at follow-up ( P = .016).

Compared with patients in whom the left atrium remained enlarged ( n = 141), those whose LAVs normalized ( n = 47) included a similar proportion undergoing surgery (10% vs 11%, P = .87) and had similar length of follow-up (median, 1.0 vs 1.1 years; P = .701) but had lower LAVs at baseline (77 vs 92 mL, P < .001) and greater magnitude of changes in E/e′ (−3.5 vs 0.5, P = .04).

Baseline LAV was negatively associated with changes in LAV ( r = −0.43 P < .001). That is, patients with very large LAVs to begin with were likely to reduce greater absolute values of LAV. Enlargement in LAV was moderately associated with reduction in LA ε; this negative association ( r = −0.30, P < .001) between changes in LA structure (LAV) and function (ε) is shown in Figure 1 . Similarly, the moderate associations of contrary directions between changes in LV filling pressures (ΔE/e′) and LAV ( r = 0.33 P < .001) and LA ε ( r = −0.52, P < .001) are shown in Figure 2 . Changes in filling pressures were moderately associated with both the conduit ( r = −0.48, P < .001) and the contractile ( r = −0.35, P < .001) function of the left atrium and strongly associated with changes in LA wall stiffness ( r = 0.71, P < .001). These results were adjusted for age, sex, length of follow-up, body weight at baseline, changes in body weight, blood pressure, and respective outcome (LAV or LA ε) at baseline.

Relationship between change in LAV and change in LA ε.

Relationship of change in E/e′ ratio with changes in LAV (A) and LA ε (B) .

Changes of Filling Pressure and LA Changes

Table 2 shows the differences in echocardiographic parameters between patients who showed reduced LV filling pressure (ΔE/e′ < 0) and those with stable or increased LV filling pressures (ΔE/e′ ≥ 0) during follow-up. Patients whose LAVs normalized at follow-up had lower LAVs at baseline and had greater ΔLAV and ΔE/e′ than those whose LAVs remained enlarged. However, 15% (21 of 141) of the patients in whom LAV remained enlarged showed reductions of LAV (by −23 mL) and E/e′ (by −3.8), to a similar degree as those with normalized LAVs. Although patients with ΔE/e′ < 0 had reduced LAVs and improved LA ε and LVEF at follow-up, those with ΔE/e′ ≥ 0 maintained similar LVEFs and LAVs from baseline but demonstrated impairment of LA ε.

Table 3 summarizes the changes in E/e′ on the basis of the changes in LAV and LA ε between baseline and follow-up. Although there were only minimal changes in LV filling pressures among patients who maintained similar LA ε from baseline to follow-up, LV filling pressures increased among patients whose LA ε became abnormal and decreased among patients whose LA ε normalized. These results were regardless of LAV and independent of whether LAV normalized or remained enlarged and were consistent with the stronger association of ΔE/e′ with Δε than with ΔLAV, as shown in Figure 2 .

Table 3

Change in E/e′ ratio and cross-classification of changes in LAV and ε

Change	LAV remained enlarged		LAV normalized
	n	ΔE/e′	n	ΔE/e′
LA ε remained abnormal ( n = 89)	71	1.0 ± 4.5	18	0.1 ± 3.1
LA ε became abnormal ( n = 21)	18	6.9 ± 9.7	3	5.4 ± 4.0
LA ε normalized ( n = 32)	18	−4.3 ± 6.8	14	−5.5 ± 5.9
LA ε remained normal ( n = 32)	21	−0.2 ± 3.0	11	0.2 ± 2.1

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