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Functional and Anatomic Responses of the Left Atrium to Change in Estimated Left Ventricular Filling Pressure
Functional and Anatomic Responses of the Left Atrium to Change in Estimated Left Ventricular Filling Pressure Quan L. Huynh, MB, PhD, Kashif Kalam, MBBS, Andrea Iannaccone, MD, Kazuaki Negishi, MD, PhD, Liza Thomas, MBBS, PhD, and Thomas H. Marwick, MBBS, PhD, MPH, Hobart and Sydney, Australia
Background: Left atrial (LA) remodeling and dysfunction reflect chronic exposure to elevated left ventricular (LV) filling pressures. The aim of this longitudinal cohort study was to define the effect of reducing LV filling pressures on reverse remodeling of LA volume (LAV) and function. Methods: This retrospective cohort included 195 patients (52% men; mean age, 64 6 14 years) in sinus rhythm with LA dilatation and sequential echocardiograms (median interval, 1 year; interquartile range, 0.5–2.0 years). One hundred seventy-four patients underwent medical therapy (82 with reduced E/e0 ratios), and 21 underwent surgery for valvular heart disease. Biplane LAV (normal value, #68 mL for men, #62 mL for women), LA strain (ε) (normal value, >32%) and LV filling pressures (assessed as E/e0 ratio; normal value, <13) were measured. Results: Although LAV at baseline and follow-up were 88 6 27 and 81 6 24 mL, LA ε and E/e0 ratio remained stable at 26 6 11% and 14 6 7, respectively. Changes in E/e0 ratio were associated with changes in LAV (r = 0.37, P < .001) and LA ε (r = 0.51 P < .001). Although reduced E/e0 ratio or improved LA ε at follow-up occurred in about 50% of the patients, only 26% (51 of 195) had normalized LAV. Compared with surgery, successful reduction of E/e0 with medical therapy was less effective in reducing LAV (P < .001) but produced similar improvement in LA ε. Having normal or improved E/e0 ratio at follow-up was not associated with normalization of LAV (relative risk, 1.29 [P = .326] and 1.22 [P = .421], respectively) but was associated with normalized LA ε (relative risk, 2.04 [P = .011] and 1.86 [P = .017], respectively) independently of LAV. Conclusions: Reduction in LV filling pressures reduces but rarely normalizes LAV. The strong association of reduced LV filling pressure with improved LA function indicated by LA longitudinal ε supports the increasing interest of LA ε measurement. (J Am Soc Echocardiogr 2015;28:1428-33.) Keywords: Echocardiography, Doppler, Strain, Volume
There is convincing evidence that left atrial (LA) enlargement, as determined by echocardiography, strongly and independently predicts many cardiovascular outcomes, including atrial fibrillation,1 stroke,2,3 heart failure,4,5 and mortality.2 Although LA size may be influenced by many factors,6 LA enlargement correlates well with the severity of diastolic dysfunction and usually reflects chronic exposure to elevated left ventricular (LV) filling pressure.7 LA remodeling is accompanied by deterioration in LA function, which may be important, as the left atrium maintains cardiac performance by modulating LV filling. Impaired LA function is therefore associated with many cardiovascular adverse events, including atrial fibrillation, stroke, and mortality.8-10 From the Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia (Q.L.H., K.K., A.I., K.N., T.H.M.); and South Western Sydney Clinical School, The University of New South Wales, Liverpool Hospital, Sydney, Australia (L.T.). Reprint requests: Thomas H. Marwick, MBBS, PhD, MPH, Menzies Institute for Medical Research, University of Tasmania, 17 Liverpool Street (Private Bag 23), Hobart TAS 7000, Australia (E-mail: [email protected]). 0894-7317/$36.00 Copyright 2015 by the American Society of Echocardiography. http://dx.doi.org/10.1016/j.echo.2015.07.028
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Fortunately, reversal of LA remodeling is possible, particularly during the early stages of LA structural and functional alteration. Restoring sinus rhythm from atrial fibrillation11,12 and repairing the mitral valve among patients with severe mitral regurgitation13 have been reported to reduce LA size. The reduction in LV filling pressures with medical therapy may also lead to reverse structural and functional remodeling of the left atrium. In this study, we hypothesized that reduction in LV filling pressures by medical and surgical management would lead to reduced LA volume (LAV) and improved LA function. All parameters were assessed noninvasively, using LA strain (ε) to assess LA function and E/e0 ratio to estimate LV filling pressures.14-17
METHODS Study Population This retrospective cohort study included 195 patients (52% men; mean age, 64 6 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
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no histories of heart transplantation at baseline, and had an interε = Strain val of $4 weeks between echocardiographic studies. LA = Left atrial Those who had severe valvular LAV = Left atrial volume heart disease at both baseline and follow-up without any surgiLV = Left ventricular cal intervention were also LVEF = Left ventricular excluded from the study. Of the ejection fraction 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/e0 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. Abbreviations
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.16,18 End-systolic LAV was measured using the biplane area-length method.18-20 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 guidelines19 but align with the new cutoff to define normal LAV in the 2015 updated guidelines.18 Alternative cutoffs for normalization of LAV were defined by a 15% reduction in LAV from baseline, as previously suggested.13 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.21 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.22 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 (e0 ) ve-
locities were obtained, and the mean E/e0 ratio was used for analysis. Normal LV filling pressure was defined as an E/e0 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/e0 to LA ε, as previously suggested.23 Ten patients were randomly chosen for 20 repeated measurements (10 at baseline and 10 at follow-up) of LA ε and E/e0 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/e0 ratio (DE/e’), LAV (DLAV), and LA ε (Dε) 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/e0 ratio. Stata versuin 12.0 (StataCorp LP, College Station, TX) was used for analyses.
RESULTS 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/e0 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/e0 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 6 2.23% (LA ε) and 0.05 6 1.55 (E/e0 ratio). Echocardiographic Follow-Up Approximately 50% of the patients had improved E/e0 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/e0 ratio were due to changes in both E and e0 . Among patients with DE/e0 < 0, their E reduced from
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Table 1 Patient characteristics Variable
Baseline
Follow-up
P
84.8 6 22.5
86.8 6 24.3
.028
Systolic pressure (mm Hg)
140.1 6 18.7
138.5 6 17.1
.723
Diastolic pressure (mm Hg)
81.3 6 11.1
81.8 6 13.5
.684
LVEF (%)
52 6 12
54 6 11
.004
E/A ratio
1.3 6 0.8
1.3 6 0.8
.594 .613
Weight (kg)
E/e0 ratio
13.5 6 6.6
13.8 6 6.8
E (m/sec)
0.87 6 0.26
0.85 6 0.29
.397
e0 (m/sec)
0.07 6 0.02
0.07 6 0.03
.882
LAV (mL)
88.2 6 27.3
81.6 6 24.0
.001
Total LA ε (%)
26.4 6 11.1
26.3 6 11.0
.466
Contraction proportion (%)
44.7 6 20.0
44.5 6 19.2
.619
Conduit proportion (%)
55.3 6 20.2
55.5 6 19.2
.424
0.70 6 0.66
0.77 6 0.93
.234
LA wall stiffness b-blocker use
40% (78)
42% (82)
.564
ACE inhibitor/ARB use
72% (140)
75% (146)
.231
Diuretic use
60% (117)
65% (127)
.100
Aldosterone use
25% (49)
25% (49)
.889
Statin use
35% (68)
34% (67)
.870
ACE, Angiotensin converting enzyme; ARB, angiotensin receptor blocker. Data are expressed as mean 6 SD or as percentage (number).
0.92 6 0.24 m/sec at baseline to 0.79 6 0.28 m/sec at follow-up (P < .001), and their e0 increased from 0.07 6 0.03 m/sec at baseline to 0.09 6 0.04 m/sec at follow-up (P < .001). Similarly, among those with DE/e0 $ 0, E increased from 0.80 6 0.24 m/sec at baseline to 0.87 6 0.27 m/sec at follow-up (P = .007) and their e0 decreased from 0.07 6 0.02 m/sec at baseline to 0.06 6 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/e0 (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 (DE/e0 ) 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. Changes of Filling Pressure and LA Changes Table 2 shows the differences in echocardiographic parameters between patients who showed reduced LV filling pressure (DE/e0 < 0)
Figure 1 Relationship between change in LAV and change in LA ε. and those with stable or increased LV filling pressures (DE/e0 $ 0) during follow-up. Patients whose LAVs normalized at follow-up had lower LAVs at baseline and had greater DLAV and DE/e0 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/e0 (by 3.8), to a similar degree as those with normalized LAVs. Although patients with DE/e0 < 0 had reduced LAVs and improved LA ε and LVEF at follow-up, those with DE/ e0 $ 0 maintained similar LVEFs and LAVs from baseline but demonstrated impairment of LA ε. Table 3 summarizes the changes in E/e0 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 DE/e0 with Dε than with DLAV, as shown in Figure 2. Finally, a normal or improved E/e0 ratio at follow-up predicted normal LA ε (relative risk, 2.04 [95% CI, 1.18–3.53] and 1.87 [95% CI, 1.12–3.11], respectively), after adjusting for LAV changes. In contrast, a normal or improved E/e0 ratio at follow-up did not predict normalization of LAV at follow-up (relative risk, 1.29 [95% CI, 0.77–2.16] and relative risk, 1.22 [95% CI, 0.76–1.96], respectively), and similar results were found when we used lower cut points to define normalization of LAV (#58 mL for men, #52 mL for women). Neither was an association identified when normal or improved E/e0 ratio at follow-up was used to predict a 15% reduction in LAV (relative risk, 1.27 [95% CI, 0.78–2.09] and relative risk, 1.16 [95% CI, 0.70–1.93], respectively).
Impact of Different Types of Intervention Supplemental Table 1 compares the effects of medical and surgical therapy on changes in LAV and LA ε. Average values of changes in LAV and LA ε were compared among three groups of patients (group 1, medical therapy with stable or increased E/e0 ratio; group 2, medical therapy with successful reduction in E/e0 ratio; and group 3, surgical therapy). Compared with surgery, successful reduction of E/e0 ratio with medical therapy was less effective in reducing LAV (model
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Journal of the American Society of Echocardiography Volume 28 Number 12
Figure 2 Relationship of change in E/e0 ratio with changes in LAV (A) and LA ε (B).
Table 2 Comparison between patients with increased LV filling pressures (DE/e0 $ 0) and those with reduced LV filling pressures (DE/e0 < 0)
Table 3 Change in E/e0 ratio and cross-classification of changes in LAV and ε LAV remained enlarged
Variable
Change in LAV (mL) Change in LA ε (%) Change in LVEF (%)
DE/e0 $ 0 (n = 90)
0.5 6 26.4 3.9 6 9.5 066
DE/e0 < 0 (n = 84)
P
9.0 6 21.8
.002
5.5 6 11.7
<.001
469
.006
Data are expressed as mean 6 SD.
1, 9.0 vs 32.6 mL; P < .001) but resulted in similar improvements in LA ε (model 3, 5.8% vs 3.9%; P = .48). These results were adjusted for age, sex, length of follow-up, blood pressure, and changes in body weight, resting heart rate, pulmonary artery systolic pressure, and diuretic dose. Further adjustment for Dε (if the outcome was DLAV; model 2) or DLAV (if the outcome was Dε; model 4) provided different results. Adjustment for Dε substantially reduced the effects of medical therapy on DLAV and partially reduced the effects of surgery on DLAV. On the other hand, adjusting for DLAV (model 4) only marginally altered the effects of both medical and surgical therapy on Dε. These results suggest a mediating effect of Dε on DLAV but not the opposite.
DISCUSSION We investigated the effects of changing LV filling pressures on LA structure and function in patients with LA dilatation at baseline. However, decreases in LAV due to the reduction in LV filling pressures were small, and normalization of the dilated left atrium was rare. Changes in LV filling pressures were strongly associated with changes in LA ε and significantly predicted normalization of LA ε independently of changes in LAV. LA Anatomic Remodeling Because the LA modulates LV filling through its reservoir, conduit, and pump function,24 the left atrium is directly exposed to the pressure in the left ventricle during diastole.25 As diastolic dysfunction
DE/e0
LAV normalized n
DE/e0
Change
n
LA ε remained abnormal (n = 89)
71
1.0 6 4.5
18
0.1 6 3.1
LA ε became abnormal (n = 21)
18
6.9 6 9.7
3
5.4 6 4.0
LA ε normalized (n = 32)
18
4.3 6 6.8
14 5.5 6 5.9
LA ε remained normal (n = 32)
21
0.2 6 3.0
11
0.2 6 2.1
Data are expressed as mean 6 SD.
progresses, the elevation in LV filling pressure becomes more severe.26,27 The consequent increase in LA wall tension leads to LA remodeling and dilatation. It appears from our study that reducing LV filling pressures may have only modest effects on LAV and that normalization or even 15% reduction in LAV is rare. In our study, patients with normalized LAVs at follow-up had lower LAVs at baseline and had greater DLAV and DE/e0 than those whose left atria remained enlarged. Although patients with less severe LA dilatation were more likely to normalize,28 a similar degree of reduction of LAV (by 23 mL) and E/e0 (by 3.8) in patients in whom LAVs remained enlarged suggests that reverse remodeling may be achievable for patients at any level of LAV and that longer followup may be required to observe a normalization in patients with severely enlarged LAV. This is consistent with the linear relationship between DE/e0 and DLAV shown in Figure 2. LA Functional Remodeling The association between acute changes in LA ε and increased venous return or resting filling pressure has been reported recently,29 but to our knowledge, this is the first study to demonstrate long-term recovery of LA ε due to reduction in LV filling pressures. Because LV filling pressure was moderately associated with both LA conduit function (r = 0.48) and contractile function (r = 0.35), changes in global LA ε due to reduction in LV filling pressures should have been
1432 Huynh et al
contributed to by changes in both the conduit and contractile function of the left atrium. In this study, changes in LV filling pressures were strongly associated with Dε, and the association with normalization of LA ε was independent of DLAV. Despite being less effective in reducing LAV, decreasing LV filling pressures by medical therapy produced similar improvements of LA ε to those achieved with surgery. These findings suggest that LA functional recovery may happen independently of (and perhaps precede) structural reverse remodeling. This dissociation between atrial enlargement and function in recovery of the atrium mirrors similar differential changes as the atrium becomes impaired in the first place.30 These findings suggest that when LV filling pressure increases, deterioration in LA function may also happen independently and precede structural remodeling. This notion is supported by our data: patients with DE/e0 $ 0 had increased LAVs by only 0.5 mL on average but had already reduced LA ε by 3.9% (Table 2). It is plausible to assume that improvement in LA function is associated with more favorable outcomes, especially in relation to atrial fibrillation. LA ε has an independent association with new-onset atrial fibrillation,8,9 with a discriminatory power for prediction of atrial fibrillation that is the highest among all clinical and echocardiographic parameters—much stronger than that of LAV.8 For patients with paroxysmal atrial fibrillation, LA ε at baseline is related to rhythm outcome after catheter ablation.31 Furthermore, LA ε can provide incremental value over the CHA2DS2-VASc score for stratifying risk for embolism in patients with atrial fibrillation and independently predict poststroke mortality.10 LAV is currently recommended as one of the criteria for facilitating interpretation of E/e0 ratio measurement. However, our results suggest that LAV may not be a reliable predictor of LV diastolic pressures in the setting of changing hemodynamic conditions associated with medical or surgical intervention and support the increasing interest in measuring LA function in these circumstances. Medical and Surgical Treatment One possible explanation for the different effects of medical and surgical therapy observed in our study is that the anatomic remodeling of the left atrium may be more quickly responsive to mechanical intervention (surgery) because the LA wall is no longer exposed to a regurgitation jet after the mitral valve is fixed. Conservative treatment, on the other hand, may take more time to induce anatomic remodeling of the left atrium by reducing LV filling pressures. A reduction in LV filling pressure, however, induces an improvement in LA conduit and contractile function, which leads to similar effects in LA functional remodeling between medical and surgical therapy. Limitations LAV reflects the chronic effect of LV filling pressure over time,32 and although LA remodeling is not a rapid process, reverse remodeling might even be slower. Therefore, our findings from 1-year median follow-up may have underestimated the long-term effects of reducing LV filling pressures on the reverse remodeling of the left atrium. It is possible that higher rates of normalization might have been revealed with longer observation. Because of the retrospective nature of this study, patients’ duration of disease was not recorded. This additional information (if available) could have provided more insight into the time course of the remodeling and reverse remodeling processes. Not being able to use indexed LAV for analysis was another limitation of this study. This was because height was not always measured for every patient in hospital. For the purpose of simplified analysis, we
Journal of the American Society of Echocardiography December 2015
used E/e0 < 13 as the cutoff to define normal LV filling pressure. This may have misclassified patients who had E/e0 ratios ranging between 8 and 13 and increased LV filling pressures. Measuring LA ε only from the four-chamber apical view was also a limitation of this study. An average value of measurements from the four-chamber and two-chamber views would have been a more robust indicator. This study included a relatively homogenous population of patients. Although these patients did not have atrial fibrillation at baseline, we did not have a means of verifying the absence of asymptomatic, paroxysmal atrial fibrillation. The majority of the patients included in this study had preserved LVEFs (75% with LVEFs $ 45%). Furthermore, our cohort contained mostly Caucasians, and we were therefore unable to investigate if there were any ethnicityrelated differences in cardiac function and geometry.33 Although E/e0 ratio is a robust marker of LV filling pressures, it has been suggested to be unreliable in certain groups of patients, such as those with decompensated advanced systolic heart failure.34 These groups were not represented in this study, and limitations in the accuracy of E/e0 would be expected to weaken rather than strengthen associations. Likewise, the use of two-dimensional instead of three-dimensional echocardiography may have led to underestimation of change in LAV. However, this would also tend to bias toward the null hypothesis, so the association of change in estimated filling pressure with change in LA structural and functional remodeling is likely to be valid.
CONCLUSIONS The results of this study provide evidence of structural and functional LA reverse remodeling due to reduction in LV filling pressures. Although the magnitude of reduction in LAV is small and normalization is rare, reducing LV filling pressures may significantly improve LA function independent of LAV changes. These findings suggest a measurement of LA function in the interpretation of LV diastolic pressure in circumstances of changing hemodynamic condition due to medical or surgical treatment.
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7. Tsang TS, Barnes ME, Gersh BJ, Bailey KR, Seward JB. Left atrial volume as a morphophysiologic expression of left ventricular diastolic dysfunction and relation to cardiovascular risk burden. Am J Cardiol 2002;90:1284-9. 8. Cameli M, Lisi M, Reccia R, Bennati E, Malandrino A, Solari M, et al. Preoperative left atrial strain predicts post-operative atrial fibrillation in patients undergoing aortic valve replacement for aortic stenosis. Int J Cardiovasc Imaging 2014;30:279-86. 9. Her AY, Kim JY, Kim YH, Choi EY, Min PK, Yoon YW, et al. Left atrial strain assessed by speckle tracking imaging is related to new-onset atrial fibrillation after coronary artery bypass grafting. Can J Cardiol 2013;29:377-83. 10. Obokata M, Negishi K, Kurosawa K, Tateno R, Tange S, Arai M, et al. Left atrial strain provides incremental value for embolism risk stratification over CHA(2)DS(2)-VASc score and indicates prognostic impact in patients with atrial fibrillation. J Am Soc Echocardiogr 2014;27:709-7164. 11. Hagens VE, Van Veldhuisen DJ, Kamp O, Rienstra M, Bosker HA, Veeger NJ, et al. Effect of rate and rhythm control on left ventricular function and cardiac dimensions in patients with persistent atrial fibrillation: results from the Rate Control versus Electrical Cardioversion for Persistent Atrial Fibrillation (RACE) study. Heart Rhythm 2005;2:19-24. 12. Reant P, Lafitte S, Jais P, Serri K, Weerasooriya R, Hocini M, et al. Reverse remodeling of the left cardiac chambers after catheter ablation after 1 year in a series of patients with isolated atrial fibrillation. Circulation 2005;112: 2896-903. 13. Westenberg JJ, van der Geest RJ, Lamb HJ, Versteegh MI, Braun J, Doornbos J, et al. MRI to evaluate left atrial and ventricular reverse remodeling after restrictive mitral annuloplasty in dilated cardiomyopathy. Circulation 2005;112:I437-42. 14. Kuroda T, Shiina A, Suzuki O, Fujita T, Noda T, Tsuchiya M, et al. Prediction of prognosis of patients with idiopathic dilated cardiomyopathy: a comparison of echocardiography with cardiac catheterization. Jpn J Med 1989;28:180-8. 15. Liang HY, Cauduro SA, Pellikka PA, Bailey KR, Grossardt BR, Yang EH, et al. Comparison of usefulness of echocardiographic Doppler variables to left ventricular end-diastolic pressure in predicting future heart failure events. Am J Cardiol 2006;97:866-71. 16. Nagueh SF, Appleton CP, Gillebert TC, Marino PN, Oh JK, Smiseth OA, et al. Recommendations for the evaluation of left ventricular diastolic function by echocardiography. J Am Soc Echocardiogr 2009;22:107-33. 17. Park JH, Marwick TH. Use and limitations of E/e0 to assess left ventricular filling pressure by echocardiography. J Cardiovasc Ultrasound 2011;19: 169-73. 18. Lang RM, Badano LP, Mor-Avi V, Afilalo J, Armstrong A, Ernande L, et al. Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr 2015;28:1-39. 19. Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Pellikka PA, et al. Recommendations for chamber quantification: a report from the American Society of Echocardiography’s Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch
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32. 33.
34.
of the European Society of Cardiology. J Am Soc Echocardiogr 2005;18: 1440-63. Jenkins C, Bricknell K, Marwick TH. Use of real-time three-dimensional echocardiography to measure left atrial volume: comparison with other echocardiographic techniques. J Am Soc Echocardiogr 2005;18:991-7. Mor-Avi V, Lang RM, Badano LP, Belohlavek M, Cardim NM, Derumeaux G, et al. Current and evolving echocardiographic techniques for the quantitative evaluation of cardiac mechanics: ASE/EAE consensus statement on methodology and indications endorsed by the Japanese Society of Echocardiography. J Am Soc Echocardiogr 2011;24:277-313. Cameli M, Caputo M, Mondillo S, Ballo P, Palmerini E, Lisi M, et al. Feasibility and reference values of left atrial longitudinal strain imaging by twodimensional speckle tracking. Cardiovasc Ultrasound 2009;7:6. Kurt M, Wang J, Torre-Amione G, Nagueh SF. Left atrial function in diastolic heart failure. Circ Cardiovasc Imaging 2009;2:10-5. Ling D, Rankin JS, Edwards CH 2nd, McHale PA, Anderson RW. Regional diastolic mechanics of the left ventricle in the conscious dog. Am J Physiol 1979;236:H323-30. Prioli A, Marino P, Lanzoni L, Zardini P. Increasing degrees of left ventricular filling impairment modulate left atrial function in humans. Am J Cardiol 1998;82:756-61. Cheng CP, Freeman GL, Santamore WP, Constantinescu MS, Little WC. Effect of loading conditions, contractile state, and heart rate on early diastolic left ventricular filling in conscious dogs. Circ Res 1990;66:814-23. Rovner A, Greenberg NL, Thomas JD, Garcia MJ. Relationship of diastolic intraventricular pressure gradients and aerobic capacity in patients with diastolic heart failure. Am J Physiol Heart Circ Physiol 2005;289: H2081-8. Casaclang-Verzosa G, Gersh BJ, Tsang TS. Structural and functional remodeling of the left atrium: clinical and therapeutic implications for atrial fibrillation. J Am Coll Cardiol 2008;51:1-11. Obokata M, Negishi K, Kurosawa K, Arima H, Tateno R, Ui G, et al. Incremental diagnostic value of la strain with leg lifts in heart failure with preserved ejection fraction. JACC Cardiovasc Imaging 2013;6:749-58. Boyd AC, Richards DA, Marwick T, Thomas L. Atrial strain rate is a sensitive measure of alterations in atrial phasic function in healthy ageing. Heart 2011;97:1513-9. Motoki H, Negishi K, Kusunose K, Popovic ZB, Bhargava M, Wazni OM, et al. Global left atrial strain in the prediction of sinus rhythm maintenance after catheter ablation for atrial fibrillation. J Am Soc Echocardiogr 2014; 27:1184-92. Douglas PS. The left atrium: a biomarker of chronic diastolic dysfunction and cardiovascular disease risk. J Am Coll Cardiol 2003;42:1206-7. Chahal NS, Lim TK, Jain P, Chambers JC, Kooner JS, Senior R. Ethnicityrelated differences in left ventricular function, structure and geometry: a population study of UK Indian Asian and European white subjects. Heart 2010;96:466-71. Mullens W, Borowski AG, Curtin RJ, Thomas JD, Tang WH. Tissue Doppler imaging in the estimation of intracardiac filling pressure in decompensated patients with advanced systolic heart failure. Circulation 2009;119:62-70.
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Journal of the American Society of Echocardiography December 2015
Supplementary Table 1 Comparing the effects of changing LV filling pressures and valve surgery in LAV and ε Changes in LA ε (%)
Changes in LAV (mL) Group
Group 1: medical—stable/increased E/e0 (n = 92) Group 2: medical—decreased E/e0 (n = 82) Group 3: valve surgery (n = 21) P (group 2 vs group 3)
Model 1
†
Model 2
1.8 6 2.3
‡
Model 3†
1.5 6 7.6
9.0 6 2.3*
2.3 6 9.2
32.6 6 2.5* <.001
*
3.9 6 0.9
Model 4§
4.0 6 3.4
5.8 6 1.0**
5.9 6 3.0**
23.2 6 9.5*
3.9 6 1.1*
4.5 6 3.2*
<.001
=.48
=.798
*
Data are expressed as mean 6 SD. *P < .01 and **P < .001 versus group 1 (reference group). † Adjusted for age, sex, length of follow-up, blood pressure, and changes in body weight, resting heart rate, pulmonary artery systolic pressure and diuretic dose. ‡ Model 1 with further adjustment for Dε. § Model 3 with further adjustment for DLAV.
Background: Left atrial (LA) remodeling and dysfunction reflect chronic exposure to elevated left ventricular (LV) filling pressures. The aim of this longitudinal cohort study was to define the effect of reducing LV filling pressures on reverse remodeling of LA volume (LAV) and function. Methods: This retrospective cohort included 195 patients (52% men; mean age, 64 6 14 years) in sinus rhythm with LA dilatation and sequential echocardiograms (median interval, 1 year; interquartile range, 0.5–2.0 years). One hundred seventy-four patients underwent medical therapy (82 with reduced E/e0 ratios), and 21 underwent surgery for valvular heart disease. Biplane LAV (normal value, #68 mL for men, #62 mL for women), LA strain (ε) (normal value, >32%) and LV filling pressures (assessed as E/e0 ratio; normal value, <13) were measured. Results: Although LAV at baseline and follow-up were 88 6 27 and 81 6 24 mL, LA ε and E/e0 ratio remained stable at 26 6 11% and 14 6 7, respectively. Changes in E/e0 ratio were associated with changes in LAV (r = 0.37, P < .001) and LA ε (r = 0.51 P < .001). Although reduced E/e0 ratio or improved LA ε at follow-up occurred in about 50% of the patients, only 26% (51 of 195) had normalized LAV. Compared with surgery, successful reduction of E/e0 with medical therapy was less effective in reducing LAV (P < .001) but produced similar improvement in LA ε. Having normal or improved E/e0 ratio at follow-up was not associated with normalization of LAV (relative risk, 1.29 [P = .326] and 1.22 [P = .421], respectively) but was associated with normalized LA ε (relative risk, 2.04 [P = .011] and 1.86 [P = .017], respectively) independently of LAV. Conclusions: Reduction in LV filling pressures reduces but rarely normalizes LAV. The strong association of reduced LV filling pressure with improved LA function indicated by LA longitudinal ε supports the increasing interest of LA ε measurement. (J Am Soc Echocardiogr 2015;28:1428-33.) Keywords: Echocardiography, Doppler, Strain, Volume
There is convincing evidence that left atrial (LA) enlargement, as determined by echocardiography, strongly and independently predicts many cardiovascular outcomes, including atrial fibrillation,1 stroke,2,3 heart failure,4,5 and mortality.2 Although LA size may be influenced by many factors,6 LA enlargement correlates well with the severity of diastolic dysfunction and usually reflects chronic exposure to elevated left ventricular (LV) filling pressure.7 LA remodeling is accompanied by deterioration in LA function, which may be important, as the left atrium maintains cardiac performance by modulating LV filling. Impaired LA function is therefore associated with many cardiovascular adverse events, including atrial fibrillation, stroke, and mortality.8-10 From the Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia (Q.L.H., K.K., A.I., K.N., T.H.M.); and South Western Sydney Clinical School, The University of New South Wales, Liverpool Hospital, Sydney, Australia (L.T.). Reprint requests: Thomas H. Marwick, MBBS, PhD, MPH, Menzies Institute for Medical Research, University of Tasmania, 17 Liverpool Street (Private Bag 23), Hobart TAS 7000, Australia (E-mail: [email protected]). 0894-7317/$36.00 Copyright 2015 by the American Society of Echocardiography. http://dx.doi.org/10.1016/j.echo.2015.07.028
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Fortunately, reversal of LA remodeling is possible, particularly during the early stages of LA structural and functional alteration. Restoring sinus rhythm from atrial fibrillation11,12 and repairing the mitral valve among patients with severe mitral regurgitation13 have been reported to reduce LA size. The reduction in LV filling pressures with medical therapy may also lead to reverse structural and functional remodeling of the left atrium. In this study, we hypothesized that reduction in LV filling pressures by medical and surgical management would lead to reduced LA volume (LAV) and improved LA function. All parameters were assessed noninvasively, using LA strain (ε) to assess LA function and E/e0 ratio to estimate LV filling pressures.14-17
METHODS Study Population This retrospective cohort study included 195 patients (52% men; mean age, 64 6 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
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Journal of the American Society of Echocardiography Volume 28 Number 12
no histories of heart transplantation at baseline, and had an interε = Strain val of $4 weeks between echocardiographic studies. LA = Left atrial Those who had severe valvular LAV = Left atrial volume heart disease at both baseline and follow-up without any surgiLV = Left ventricular cal intervention were also LVEF = Left ventricular excluded from the study. Of the ejection fraction 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/e0 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. Abbreviations
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.16,18 End-systolic LAV was measured using the biplane area-length method.18-20 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 guidelines19 but align with the new cutoff to define normal LAV in the 2015 updated guidelines.18 Alternative cutoffs for normalization of LAV were defined by a 15% reduction in LAV from baseline, as previously suggested.13 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.21 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.22 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 (e0 ) ve-
locities were obtained, and the mean E/e0 ratio was used for analysis. Normal LV filling pressure was defined as an E/e0 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/e0 to LA ε, as previously suggested.23 Ten patients were randomly chosen for 20 repeated measurements (10 at baseline and 10 at follow-up) of LA ε and E/e0 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/e0 ratio (DE/e’), LAV (DLAV), and LA ε (Dε) 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/e0 ratio. Stata versuin 12.0 (StataCorp LP, College Station, TX) was used for analyses.
RESULTS 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/e0 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/e0 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 6 2.23% (LA ε) and 0.05 6 1.55 (E/e0 ratio). Echocardiographic Follow-Up Approximately 50% of the patients had improved E/e0 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/e0 ratio were due to changes in both E and e0 . Among patients with DE/e0 < 0, their E reduced from
1430 Huynh et al
Journal of the American Society of Echocardiography December 2015
Table 1 Patient characteristics Variable
Baseline
Follow-up
P
84.8 6 22.5
86.8 6 24.3
.028
Systolic pressure (mm Hg)
140.1 6 18.7
138.5 6 17.1
.723
Diastolic pressure (mm Hg)
81.3 6 11.1
81.8 6 13.5
.684
LVEF (%)
52 6 12
54 6 11
.004
E/A ratio
1.3 6 0.8
1.3 6 0.8
.594 .613
Weight (kg)
E/e0 ratio
13.5 6 6.6
13.8 6 6.8
E (m/sec)
0.87 6 0.26
0.85 6 0.29
.397
e0 (m/sec)
0.07 6 0.02
0.07 6 0.03
.882
LAV (mL)
88.2 6 27.3
81.6 6 24.0
.001
Total LA ε (%)
26.4 6 11.1
26.3 6 11.0
.466
Contraction proportion (%)
44.7 6 20.0
44.5 6 19.2
.619
Conduit proportion (%)
55.3 6 20.2
55.5 6 19.2
.424
0.70 6 0.66
0.77 6 0.93
.234
LA wall stiffness b-blocker use
40% (78)
42% (82)
.564
ACE inhibitor/ARB use
72% (140)
75% (146)
.231
Diuretic use
60% (117)
65% (127)
.100
Aldosterone use
25% (49)
25% (49)
.889
Statin use
35% (68)
34% (67)
.870
ACE, Angiotensin converting enzyme; ARB, angiotensin receptor blocker. Data are expressed as mean 6 SD or as percentage (number).
0.92 6 0.24 m/sec at baseline to 0.79 6 0.28 m/sec at follow-up (P < .001), and their e0 increased from 0.07 6 0.03 m/sec at baseline to 0.09 6 0.04 m/sec at follow-up (P < .001). Similarly, among those with DE/e0 $ 0, E increased from 0.80 6 0.24 m/sec at baseline to 0.87 6 0.27 m/sec at follow-up (P = .007) and their e0 decreased from 0.07 6 0.02 m/sec at baseline to 0.06 6 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/e0 (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 (DE/e0 ) 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. Changes of Filling Pressure and LA Changes Table 2 shows the differences in echocardiographic parameters between patients who showed reduced LV filling pressure (DE/e0 < 0)
Figure 1 Relationship between change in LAV and change in LA ε. and those with stable or increased LV filling pressures (DE/e0 $ 0) during follow-up. Patients whose LAVs normalized at follow-up had lower LAVs at baseline and had greater DLAV and DE/e0 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/e0 (by 3.8), to a similar degree as those with normalized LAVs. Although patients with DE/e0 < 0 had reduced LAVs and improved LA ε and LVEF at follow-up, those with DE/ e0 $ 0 maintained similar LVEFs and LAVs from baseline but demonstrated impairment of LA ε. Table 3 summarizes the changes in E/e0 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 DE/e0 with Dε than with DLAV, as shown in Figure 2. Finally, a normal or improved E/e0 ratio at follow-up predicted normal LA ε (relative risk, 2.04 [95% CI, 1.18–3.53] and 1.87 [95% CI, 1.12–3.11], respectively), after adjusting for LAV changes. In contrast, a normal or improved E/e0 ratio at follow-up did not predict normalization of LAV at follow-up (relative risk, 1.29 [95% CI, 0.77–2.16] and relative risk, 1.22 [95% CI, 0.76–1.96], respectively), and similar results were found when we used lower cut points to define normalization of LAV (#58 mL for men, #52 mL for women). Neither was an association identified when normal or improved E/e0 ratio at follow-up was used to predict a 15% reduction in LAV (relative risk, 1.27 [95% CI, 0.78–2.09] and relative risk, 1.16 [95% CI, 0.70–1.93], respectively).
Impact of Different Types of Intervention Supplemental Table 1 compares the effects of medical and surgical therapy on changes in LAV and LA ε. Average values of changes in LAV and LA ε were compared among three groups of patients (group 1, medical therapy with stable or increased E/e0 ratio; group 2, medical therapy with successful reduction in E/e0 ratio; and group 3, surgical therapy). Compared with surgery, successful reduction of E/e0 ratio with medical therapy was less effective in reducing LAV (model
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Journal of the American Society of Echocardiography Volume 28 Number 12
Figure 2 Relationship of change in E/e0 ratio with changes in LAV (A) and LA ε (B).
Table 2 Comparison between patients with increased LV filling pressures (DE/e0 $ 0) and those with reduced LV filling pressures (DE/e0 < 0)
Table 3 Change in E/e0 ratio and cross-classification of changes in LAV and ε LAV remained enlarged
Variable
Change in LAV (mL) Change in LA ε (%) Change in LVEF (%)
DE/e0 $ 0 (n = 90)
0.5 6 26.4 3.9 6 9.5 066
DE/e0 < 0 (n = 84)
P
9.0 6 21.8
.002
5.5 6 11.7
<.001
469
.006
Data are expressed as mean 6 SD.
1, 9.0 vs 32.6 mL; P < .001) but resulted in similar improvements in LA ε (model 3, 5.8% vs 3.9%; P = .48). These results were adjusted for age, sex, length of follow-up, blood pressure, and changes in body weight, resting heart rate, pulmonary artery systolic pressure, and diuretic dose. Further adjustment for Dε (if the outcome was DLAV; model 2) or DLAV (if the outcome was Dε; model 4) provided different results. Adjustment for Dε substantially reduced the effects of medical therapy on DLAV and partially reduced the effects of surgery on DLAV. On the other hand, adjusting for DLAV (model 4) only marginally altered the effects of both medical and surgical therapy on Dε. These results suggest a mediating effect of Dε on DLAV but not the opposite.
DISCUSSION We investigated the effects of changing LV filling pressures on LA structure and function in patients with LA dilatation at baseline. However, decreases in LAV due to the reduction in LV filling pressures were small, and normalization of the dilated left atrium was rare. Changes in LV filling pressures were strongly associated with changes in LA ε and significantly predicted normalization of LA ε independently of changes in LAV. LA Anatomic Remodeling Because the LA modulates LV filling through its reservoir, conduit, and pump function,24 the left atrium is directly exposed to the pressure in the left ventricle during diastole.25 As diastolic dysfunction
DE/e0
LAV normalized n
DE/e0
Change
n
LA ε remained abnormal (n = 89)
71
1.0 6 4.5
18
0.1 6 3.1
LA ε became abnormal (n = 21)
18
6.9 6 9.7
3
5.4 6 4.0
LA ε normalized (n = 32)
18
4.3 6 6.8
14 5.5 6 5.9
LA ε remained normal (n = 32)
21
0.2 6 3.0
11
0.2 6 2.1
Data are expressed as mean 6 SD.
progresses, the elevation in LV filling pressure becomes more severe.26,27 The consequent increase in LA wall tension leads to LA remodeling and dilatation. It appears from our study that reducing LV filling pressures may have only modest effects on LAV and that normalization or even 15% reduction in LAV is rare. In our study, patients with normalized LAVs at follow-up had lower LAVs at baseline and had greater DLAV and DE/e0 than those whose left atria remained enlarged. Although patients with less severe LA dilatation were more likely to normalize,28 a similar degree of reduction of LAV (by 23 mL) and E/e0 (by 3.8) in patients in whom LAVs remained enlarged suggests that reverse remodeling may be achievable for patients at any level of LAV and that longer followup may be required to observe a normalization in patients with severely enlarged LAV. This is consistent with the linear relationship between DE/e0 and DLAV shown in Figure 2. LA Functional Remodeling The association between acute changes in LA ε and increased venous return or resting filling pressure has been reported recently,29 but to our knowledge, this is the first study to demonstrate long-term recovery of LA ε due to reduction in LV filling pressures. Because LV filling pressure was moderately associated with both LA conduit function (r = 0.48) and contractile function (r = 0.35), changes in global LA ε due to reduction in LV filling pressures should have been
1432 Huynh et al
contributed to by changes in both the conduit and contractile function of the left atrium. In this study, changes in LV filling pressures were strongly associated with Dε, and the association with normalization of LA ε was independent of DLAV. Despite being less effective in reducing LAV, decreasing LV filling pressures by medical therapy produced similar improvements of LA ε to those achieved with surgery. These findings suggest that LA functional recovery may happen independently of (and perhaps precede) structural reverse remodeling. This dissociation between atrial enlargement and function in recovery of the atrium mirrors similar differential changes as the atrium becomes impaired in the first place.30 These findings suggest that when LV filling pressure increases, deterioration in LA function may also happen independently and precede structural remodeling. This notion is supported by our data: patients with DE/e0 $ 0 had increased LAVs by only 0.5 mL on average but had already reduced LA ε by 3.9% (Table 2). It is plausible to assume that improvement in LA function is associated with more favorable outcomes, especially in relation to atrial fibrillation. LA ε has an independent association with new-onset atrial fibrillation,8,9 with a discriminatory power for prediction of atrial fibrillation that is the highest among all clinical and echocardiographic parameters—much stronger than that of LAV.8 For patients with paroxysmal atrial fibrillation, LA ε at baseline is related to rhythm outcome after catheter ablation.31 Furthermore, LA ε can provide incremental value over the CHA2DS2-VASc score for stratifying risk for embolism in patients with atrial fibrillation and independently predict poststroke mortality.10 LAV is currently recommended as one of the criteria for facilitating interpretation of E/e0 ratio measurement. However, our results suggest that LAV may not be a reliable predictor of LV diastolic pressures in the setting of changing hemodynamic conditions associated with medical or surgical intervention and support the increasing interest in measuring LA function in these circumstances. Medical and Surgical Treatment One possible explanation for the different effects of medical and surgical therapy observed in our study is that the anatomic remodeling of the left atrium may be more quickly responsive to mechanical intervention (surgery) because the LA wall is no longer exposed to a regurgitation jet after the mitral valve is fixed. Conservative treatment, on the other hand, may take more time to induce anatomic remodeling of the left atrium by reducing LV filling pressures. A reduction in LV filling pressure, however, induces an improvement in LA conduit and contractile function, which leads to similar effects in LA functional remodeling between medical and surgical therapy. Limitations LAV reflects the chronic effect of LV filling pressure over time,32 and although LA remodeling is not a rapid process, reverse remodeling might even be slower. Therefore, our findings from 1-year median follow-up may have underestimated the long-term effects of reducing LV filling pressures on the reverse remodeling of the left atrium. It is possible that higher rates of normalization might have been revealed with longer observation. Because of the retrospective nature of this study, patients’ duration of disease was not recorded. This additional information (if available) could have provided more insight into the time course of the remodeling and reverse remodeling processes. Not being able to use indexed LAV for analysis was another limitation of this study. This was because height was not always measured for every patient in hospital. For the purpose of simplified analysis, we
Journal of the American Society of Echocardiography December 2015
used E/e0 < 13 as the cutoff to define normal LV filling pressure. This may have misclassified patients who had E/e0 ratios ranging between 8 and 13 and increased LV filling pressures. Measuring LA ε only from the four-chamber apical view was also a limitation of this study. An average value of measurements from the four-chamber and two-chamber views would have been a more robust indicator. This study included a relatively homogenous population of patients. Although these patients did not have atrial fibrillation at baseline, we did not have a means of verifying the absence of asymptomatic, paroxysmal atrial fibrillation. The majority of the patients included in this study had preserved LVEFs (75% with LVEFs $ 45%). Furthermore, our cohort contained mostly Caucasians, and we were therefore unable to investigate if there were any ethnicityrelated differences in cardiac function and geometry.33 Although E/e0 ratio is a robust marker of LV filling pressures, it has been suggested to be unreliable in certain groups of patients, such as those with decompensated advanced systolic heart failure.34 These groups were not represented in this study, and limitations in the accuracy of E/e0 would be expected to weaken rather than strengthen associations. Likewise, the use of two-dimensional instead of three-dimensional echocardiography may have led to underestimation of change in LAV. However, this would also tend to bias toward the null hypothesis, so the association of change in estimated filling pressure with change in LA structural and functional remodeling is likely to be valid.
CONCLUSIONS The results of this study provide evidence of structural and functional LA reverse remodeling due to reduction in LV filling pressures. Although the magnitude of reduction in LAV is small and normalization is rare, reducing LV filling pressures may significantly improve LA function independent of LAV changes. These findings suggest a measurement of LA function in the interpretation of LV diastolic pressure in circumstances of changing hemodynamic condition due to medical or surgical treatment.
REFERENCES 1. Tsang TS, Barnes ME, Bailey KR, Leibson CL, Montgomery SC, Takemoto Y, et al. Left atrial volume: important risk marker of incident atrial fibrillation in 1655 older men and women. Mayo Clin Proc 2001; 76:467-75. 2. 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;92:835-41. 3. Barnes ME, Miyasaka Y, Seward JB, Gersh BJ, Rosales AG, Bailey KR, et al. Left atrial volume in the prediction of first ischemic stroke in an elderly cohort without atrial fibrillation. Mayo Clin Proc 2004;79:1008-14. 4. Takemoto Y, Barnes ME, Seward JB, Lester SJ, Appleton CA, Gersh BJ, et al. Usefulness of left atrial volume in predicting first congestive heart failure in patients > or = 65 years of age with well-preserved left ventricular systolic function. Am J Cardiol 2005;96:832-6. 5. Gottdiener JS, Kitzman DW, Aurigemma GP, Arnold AM, Manolio TA. Left atrial volume, geometry, and function in systolic and diastolic heart failure of persons > or =65 years of age (the cardiovascular health study). Am J Cardiol 2006;97:83-9. 6. Abhayaratna WP, Seward JB, Appleton CP, Douglas PS, Oh JK, Tajik AJ, et al. Left atrial size: physiologic determinants and clinical applications. J Am Coll Cardiol 2006;47:2357-63.
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Supplementary Table 1 Comparing the effects of changing LV filling pressures and valve surgery in LAV and ε Changes in LA ε (%)
Changes in LAV (mL) Group
Group 1: medical—stable/increased E/e0 (n = 92) Group 2: medical—decreased E/e0 (n = 82) Group 3: valve surgery (n = 21) P (group 2 vs group 3)
Model 1
†
Model 2
1.8 6 2.3
‡
Model 3†
1.5 6 7.6
9.0 6 2.3*
2.3 6 9.2
32.6 6 2.5* <.001
*
3.9 6 0.9
Model 4§
4.0 6 3.4
5.8 6 1.0**
5.9 6 3.0**
23.2 6 9.5*
3.9 6 1.1*
4.5 6 3.2*
<.001
=.48
=.798
*
Data are expressed as mean 6 SD. *P < .01 and **P < .001 versus group 1 (reference group). † Adjusted for age, sex, length of follow-up, blood pressure, and changes in body weight, resting heart rate, pulmonary artery systolic pressure and diuretic dose. ‡ Model 1 with further adjustment for Dε. § Model 3 with further adjustment for DLAV.