Published online May 26, 2020.
https://doi.org/10.4250/jcvi.2020.0043
Normal Reference Values for Left Atrial Strain and Its Determinants from a Large Korean Multicenter Registry
, MD, PhD,1
Jae-Hyeong Park, MD, PhD,1
Minyeong Lee, BSc,2
Jin-Oh Choi, MD, PhD,3
Ju-Hee Lee, MD, PhD,4
Mi-Seung Shin, MD, PhD,5
Mi-Jeong Kim, MD, PhD,6
Hae Ok Jung, MD, PhD,7
Jeong Rang Park, MD, PhD,8
Il Suk Sohn, MD, PhD,9
Hyungseop Kim, MD, PhD,10
Hyung-Kwan Kim, MD, PhD,11
Goo-Yeong Cho, MD, PhD,12
Jin-Sun Park, MD, PhD,13
Chi Young Shim, MD, PhD,14
Sung Hee Shin, MD, PhD,15
Kye Hun Kim, MD, PhD,16
Woo-Shik Kim, MD, PhD,17
and Seung Woo Park, MD, PhD3
Abstract
BACKGROUND
Left atrial (LA) strain is a novel parameter of LA function. However, its reference value has not been established, and the determining factors for LA strain remain elusive. We aimed to present LA strain with reservoir, conduit, and contractile components and associated parameters in a large-sized group of healthy individuals.
METHODS
The present study was from a prospective multicenter registry in South Korea. Subjects who had no history of cardiovascular disease with adequate images were eligible for inclusion. LA reservoir, conduit, and contractile strains (LASRES, LASCD and LASCT, respectively) were measured. Left ventricular global longitudinal strain (LV GLS) and early and late diastolic strain rates (DSRe and DSRa, respectively) were also evaluated.
RESULTS
Among a total of 324 subjects (mean age: 49 ± 16 years, 167 females), the mean LASRES, LASCD, and LASCT values were 35.9% ± 10.6%, 21.9% ± 9.3%, and 13.9% ± 3.6%, respectively. Mean LV GLS was -20.4% ± 2.2%, and mean DSRe and DSRa were 1.6 ± 0.4 s-1 and 0.8 ± 0.3 s-1, respectively. With aging, LASRES and LASCD showed significant decreases. Factors showing independent associations with LASRES were age (B = -0.425, p < 0.001), DSRe (B = 4.706, p = 0.001), and LV GLS (B = -1.081, p < 0.001). Age (B = -0.319, p < 0.001), DSRe (B = 4.140, p = 0.002), DSRa (B = -3.409, p = 0.018), and LV GLS (B = -0.783, p < 0.001) showed associations with LASCD. With LASCT, only DSRa showed a correlation (R = 0.277, p < 0.001).
CONCLUSIONS
We presented LA strain in a large-sized group of healthy subjects. Age is a significant determinant of LA function. Associations of LA strain with diastolic strain rates and LV GLS reflect cardiac mechanics.
INTRODUCTION
The clinical significance of left atrial (LA) remodeling has been shown in a variety of cardiovascular diseases. However, the dynamic feature of LA has been recently highlighted.1), 2) These studies showed that LA is not simply a conduit chamber but that it has sophisticated actions during a cardiac cycle that performs in close interplay with the left ventricular (LV) mechanics.1) Currently, LA volume index (LAVI) is a main parameter of LA remodeling.1) However, as LAVI is based on a static volumetric measurement, it has inherent limitations with respect to reflecting the dynamic aspects of LA.2) With this background, a novel speckle tracking echocardiography derived index, ‘LA strain,’ was recently introduced. LA strain may be more suitable to represent LA function.2) LA strain has been tested in several clinical studies and shown to be a more useful diagnostic tool than conventional parameters.3), 4), 5) However, the clinical evidence for using LA strain as a diagnostic tool is insufficient. In addition, applying LA strain in clinical practice is difficult because its reference value has not yet been established for a variety of subject groups. In the present study, we aimed to identify a reference value for LA strain with reservoir, conduit, and contractile components in a large group of healthy Koreans. We also aimed to elucidate determining factors for LA strain.
METHODS
Study outline
Our research group from the Korean Society of Echocardiography recently conducted a prospective nation-wide registry (Normal echOcardiogRaphic Measurements in KoreAn popuLation, NORMAL) including 23 tertiary-referral hospitals in South Korea and constructed a large-sized echocardiographic database of healthy individuals.6) The primary objective of the study was to present normal reference values of echocardiography in a Korean population. The eligibility criteria were as follows: 1) an adult aged 20–79 years, and 2) no history of cardiovascular diseases such as hypertension, diabetes mellitus, coronary/peripheral arterial disease, and atrial fibrillation. The NORMAL study required only two-dimensional and Doppler echocardiographic images. The overall database included 1,003 subjects. In a sub-study focusing on strain analysis, 501 subjects (50%) whose exams were performed using a single-vendor machine (GE Medical Systems, Horten, Norway) were selected.7) In the present study, LA strain analysis was finally available for 324 subjects (32%) for whom LA images included the whole LA roof in both apical four-chamber and two-chamber views. The subject clinical characteristics, conventional echocardiographic data, LV systolic strain, and diastolic strain rate were analyzed, with the main focus on LA strain. This study conformed to the ethical guidelines of the Declaration of Helsinki, and the study protocol was approved by the Ethics Committees of all participating centers. Written informed consent was waived because of the non-invasiveness of this study protocol.
Echocardiographic analysis
All routine echocardiographic studies were performed according to current recommendations.8), 9) Images for strain analysis were obtained with 60–90 frames/sec from two consecutive cardiac beats.10) All image data were digitally stored for analysis in the core laboratory of Chungnam National University Hospital. Two dedicated researchers (SBJ and PJH) who were blinded to clinical information analyzed all strain images using EchoPAC® and BT 201 device (GE Medical Systems, Horten, Norway). LV global longitudinal strain (GLS) and early and late diastolic strain rates (DSRe and DSRa) were evaluated according to previously described methods.10), 11)
To measure LA strain, we manually traced the LA endocardium and thus the software automatically tracked the region of interest on the LA wall. A LA strain curve cycle was generated with a configuration by R-R gating that began with the onset of systole.12) We then defined the following three components of LA function: LA reservoir, conduit, and contractile strains (LASRES, LASCD, and LASCT, respectively). The first peak point was defined as LASRES (Figure 1). Another peak point after the P wave on electrocardiography was defined as LASCT. We also defined variables LASCD (LASRES - LASCT) and LASCD/LASCT ratio. We performed this process in both apical 4-chamber and 2-chamber images and calculated average LA strain values.
Figure 1
Demonstration of LA strain measurement. ECG: electrocardiography, LA: left atrium.
Statistical analysis
We presented categorical variables as numbers (%) and continuous variables as mean ± standard deviation (SD). We used independent Student's t-tests to compare numeric data between sex groups. To evaluate differences in LA strain values among age groups defined by decade, we used one-way analysis of variance (ANOVA) with Bonferroni correction with non-parametric means as needed. To determine variables associated with LA stain parameters, Pearson's bivariate correlation test and multiple linear regression analysis were performed. We evaluated intra- and inter-observer measurement variabilities based on intraclass correlation coefficients (ICCs). All reported p-values were two-tailed and a p-value of < 0.05 was accepted as statistically significant. SPSS software version 22 (IBM Corp, Armonk, NY, USA) was used for all statistical analyses.
RESULTS
Subject characteristics
This study included a total of 324 subjects; the mean age was 49 ± 16 years, and there were 167 females (52%) (Table 1). The mean systolic and diastolic blood pressures were 120 ± 13 mmHg and 72 ± 10 mmHg, respectively. The mean pulse rate was 68 ± 10 beats/min. For the echocardiographic parameters, the mean LV ejection fraction (LVEF) was 62 ± 4%, the mean LV mass index (LVMI) was 75 ± 14 g/m2, and the mean LAVI was 27 ± 6 mL/m2. For Doppler parameters, septal and lateral mitral annular E′ velocity were 9.3 ± 2.9 cm/s and 12.6 ± 3.7 cm/s, respectively. Septal and lateral E/E′ ratios were 7.9 ± 2.3 and 5.9 ± 1.8, respectively. There was no significant difference in age between the male and female groups. The male group showed a higher body surface area, blood pressure, and LV volumes compared to the female group. However, LVEF and LAVI were not significantly different between male and female groups. The female group presented higher mitral E velocity and E/A ratio without showing significant differences in mitral annular E′ velocity and E/E′ ratios compared to the male group.
Table 1
Clinical and echocardiographic parameters
LA and LV strain values
In the total subjects, the mean LASRES, LASCD, and LASCT values were 35.9% ± 10.6%, 21.9% ± 9.3% and 13.9% ± 3.6%, respectively, and the mean LASCD/LASCT ratio was 1.7 ± 0.8 (Table 2). The mean LV GLS was -20.4% ± 2.2%. The mean DSRe and DSRa were 1.6 ± 0.4 s-1 and 0.8 ± 0.3 s-1, respectively. The female group showed significantly higher LASRES (37.3% ± 11.0% vs. 34.3% ± 10.0%, p = 0.009) and LASCD (23.5% ± 9.8% vs. 20.3% ± 8.5%, p = 0.002) than the male group, whereas there was no significant difference in LASCT between sex groups. The female group showed significantly higher LASCD/LASCT ratio (1.8% ± 0.8% vs. 1.5% ± 0.7%, p = 0.001). The female group also showed higher LV GLS (-21.2% ± 2.1% vs. -19.5% ± 2.1%, p < 0.001) and DSRe (1.7 ± 0.4 s-1 vs. 1.4 ± 0.3 s-1, p < 0.001), whereas DSRa did not differ between female and male groups. LASRES, LASCD, and LASCD/LASCT ratio showed significant decreases with increasing age (Figures 2A, 2B, and 2D, respectively; all p < 0.001). However, there was no age-related trend for LASCT (Figure 2C). These trends according to age were observed in both male and female groups (Figure 3).
Table 2
Strain parameter values
Figure 2
LA strain values according to age groups. LA: left atrium.
Figure 3
LA strain values according to age and sex groups. LA: left atrium.
Factors associated with LA strain
In Pearson's bivariate analysis, LASRES showed significant correlations with age (R = -0.705, p < 0.001), LVMI (R = -0.310, p < 0.001), E′ velocity (R = 0.603, p < 0.001), E/E′ ratio (R = -0.304, p < 0.001), DSRe (R = 0.585, p < 0.001), DSRa (R = -0.337, p < 0.001), and LV GLS (R = -0.359, p < 0.001) (Table 3). In multiple linear regression analysis, factors showing significant associations with LASRES were age (B = -0.425, p < 0.001), DSRe (B = 4.706, p = 0.001), and LV GLS (B = -1.081, p < 001). With LASCD, age (B = -0.319, p < 0.001), DSRe (B = 4.140, p = 0.002), DSRa (B = -3.409, p = 0.018), and LV GLS (B = -0.783, p < 0.001) showed independent associations while septal E′ velocity showed a trend without statistical significance (Table 4). With LASCT, only DSRa showed a weak correlation (R = 0.277, p < 0.001). However, there was no other feasible variable for test of independent association (Supplementary Table 1). With LASCD/LASCT ratio, age (B = -0.011, p < 0.001), diastolic blood pressure (B = -0.010, p = 0.002), DSRe (B = 0.602, p < 0.001), and DSRa (B = -1.158, p < 0.001) showed independent associations (Table 5).
Table 3
Parameters associated with LA reservoir strain
Table 4
Parameters associated with LA conduit strain
Table 5
Parameters associated with LA conduit/contractile strain ratio
Measurement variability
Intra- and inter-observer ICCs for LASRES were 0.974 (95% confidence interval [CI], 0.946–0.988) and 0.948 (95% CI, 0.889–0.976), respectively (Table 6). Intra- and inter-observer ICCs for LASCD were 0.978 (95% CI, 0.953–0.990) and 0.930 (95% CI, 0.852–0.967), respectively. For LASCT, intra- and inter-observer ICCs were 0.976 (95% CI, 0.949–0.989) and 0.942 (95% CI, 0.876–0.973), respectively.
Table 6
Measurement variabilities for strain values
DISCUSSION
LA remodeling means cumulative structural and functional alterations due to hemodynamic stress.1) Given the absence of other structural abnormalities, the major cause of LA remodeling is elevated LV filling pressure. Therefore, the presence of LA remodeling reflects long-term progression of various cardiovascular diseases.1) Currently, LAVI is the main parameter of LA remodeling and has advantages of simple measurement and clinical evidence from a variety of cardiovascular disease.1) However, LAVI essentially represents a static volume. Thus, LAVI has limitations to reflect the unique LA mechanics during the cardiac cycle including reservoir, conduit, and contractile functions.1), 2) The diagnostic sensitivity of LAVI has been shown to be limited to detection of subtle changes in LA function.4), 13)
LA strain, a new parameter of LA remodeling
With this background, a recently introduced parameter, ‘LA strain,’ has potential advantages to surpass conventional diagnostic tools. Its usefulness has been presented in a few clinical cardiovascular disease entities.3), 4), 5) However, LA strain is still not applied in clinical practice to date. The major limitation of LA strain as a clinical metric is the lack of an established normal reference value.12) In response to this practical need, here we present reference values for LA strain derived from a large-sized group of healthy subjects and age and sex-specified subgroups.
The mean LASRES in our study was 36.3% ± 8.4%. A few previous studies have reported LASRES values (also described as peak LA strain) in healthy groups.12), 14), 15), 16) Pathan et al.12) performed a meta-analysis of 2,542 healthy subjects and found that the mean LASRES was 39.4% (95% CI: 38.0%–40.8%). D'Ascenzi et al.16) also performed a meta-analysis of 2,087 subjects and reported a mean LASRES of 38% ± 3% (95% CI: 32%–43%). Kim et al.14) reported a mean LASRES of 35.7% ± 5.8% in a study of 54 healthy Korean subjects. Although these studies presented LASRES values similar to our results, one recent international multicenter study by Morris et al.15) reported a mean LASRES of 45.5% ± 11.4% from 329 healthy subjects, which is substantially different from our results. For such a variation in values, different clinical features of study subjects might be the major cause. For example, the mean subject age in our study was 49 ± 16 years in contrast to 36.1 ± 12.7 years in the study of Morris et al.15) In addition, the definitions of ‘healthy subject' were not specific. Thus, clinical profiles might differ according to studies. There could be a technical bias because different methods for measuring LA strain have been used.2) Pathan et al.12) reported significant heterogeneity in LASRES values between studies, especially according to the size of study groups (n > 100 vs. n < 100). This suggests that technical fluency might matter. In this regard, our present study examined a large-sized subject group (n = 324). Pathan et al.12) performed a meta-analysis and reported that mean LASCD and LASCT were 23.0% (range of 15.7%–33.4%) and 17.4% (range of 14.0%–25.0%), respectively. However, the numbers of original studies examining LASCD and LASCT are limited (14 and 18 studies, respectively). In addition, all of these studies included small numbers of subjects (n = 30–64). In addition, measurement values showed a wide variability. Therefore, more data are required to obtain reliable reference values for LASCD and LASCT. The present study is one of the largest original researches to investigate LASCD and LASCT.
Determinant factors for LA strain
In the present study, common factors that were associated with LA strain parameters were age, diastolic strain rates, and LV GLS. In particular, the effect of age was evident. Thus, LASRES and LASCD presented significant attenuations with aging. Although LASCT itself showed no significant difference between age groups, considering the significant decrease of LASRES with age, the contribution of LASCT seemed to be augmented by age, which was evident by the parameter LASCD/LASCT. Liao et al.17) previously reported that LA contractile strain rate was significantly increased when associated with aging and higher blood pressure. This result was interpreted as a compensatory mechanism due to decreased LA mechanical function. Our study results are consistent with their findings, suggesting that dominant LASCD in early diastole is the core of intact LA function. A gradual reverse of that pattern with age would be interpreted as a physiologic decline in LA function. A decrease in LA strain means an increase in LA stiffness, indicating an increase in LA fibrous content from a pathological view point.18) Cumulative myocardial fibrosis with aging has been revealed in various cardiovascular diseases.19) The impact of age on LA function has also been shown in previous studies.15), 20), 21) However, we did not observe any sex-difference in any LA strain parameter. This pattern (a significant association of LA strain with age but not with sex) has also been shown in a previous study.21) Conversely, sex differences regarding LV systolic and diastolic functions have been previously described, with some studies reporting that females present higher LV systolic strain22) and mitral annular E′ velocity.23) The different impact of sex on LV and LA functions may have interesting implications and should be reevaluated in future studies.
Our data show an association between LA function and LV diastolic function. This finding has also been described in several previous studies.24), 25), 26) Singh et al.27) showed that LA strain could be a discriminator regarding the class of diastolic dysfunction. However, a new finding in our data is the relationship between novel strain parameters. That is, LASRES, LASCD, and LASCD/LASCT each presented a significant association with diastolic strain rates in multivariate analysis, but not with mitral E′ velocity or E/E′ ratio. Our subject group was distinctive from that of previous studies dealing with diastolic dysfunction20), 27) in that our study subjects had no history of cardiovascular disease. Thus, this study group might have a low probability of clinical diastolic dysfunction. Considering the different subject characteristics, we suggest that the significant association between LA strain parameters and diastolic strain rates in our data might come from the better sensitivity of strain parameters over Doppler indices, although this should be evaluated in future studies.
Another interesting finding was the significant association between LA strain and LV GLS. As mentioned above, LV diastolic dysfunction is the main driver of LA remodeling.24), 25), 26) Certainly, LV GLS is a representative parameter of systolic function. However, in a previous clinical study regarding heart failure with preserved EF, decreased LV GLS was also associated with diastolic dysfunction.28) From a physiologic point of view, LV systole and diastole are not independent functions, but are phasic motions converting to each other.1) In addition, intact LV systolic function can induce apical displacement of mitral annulus and full expansion of LA.1), 2) Thus, the association between LA strain and LV GLS seems reasonable. However, LVEF did not show a significant association, and thus our finding again emphasized the usefulness of strain parameters for evaluating cardiac mechanics.
Technical aspects of LA strain
The advantages of LA strain measurement are its non-invasiveness, feasibility in routine examinations, and simple post-processing,2) which are beneficial for clinical application and data accumulation. Compared with Doppler parameters, LA strain has freedom from angle-dependency, which is the biggest advantage. In addition, LA strain is relatively less affected by loading conditions.29) However, there are also limitations in LA strain analysis. Currently, several techniques such as speckle-tracking, velocity vector imaging, and edge tracking are available, and technical standardization has not been achieved.2) As the LA is located at the far field of imaging, the limited acoustic window could be problematic.1) Tracking for thin-wall LA produces a low signal-to-noise ratio, which is another technical challenge.1) Nonetheless, as previous studies have reported the high feasibility of LA strain,14), 15) the technical merits of LA strain seem to outweigh its drawbacks.
Limitations
Since the NORMAL registry was originally not intended for LA strain analysis, our present study included only 32% of overall subjects with suitable images, which could be a source of selection bias. In addition, the clinical information for study subjects was limited to basic characteristics. Thus, there was a limitation with respect to evaluating the clinical meaning of LA strain. Although age showed significant associations with LA strain parameters in this cross-sectional analysis, the true chronological change in LA strain should be evaluated prospectively with a serial echocardiographic follow-up. Furthermore, as we used images obtained by a single-vendor machine (GE Medical Systems, Horten, Norway), the present study results would not be directly applicable to those using different systems.
Conclusions
We presented a reference value for LA strain with reservoir, conduit, and contractile components in a large-sized group of healthy subjects. Age was a physiologic determinant of LA function. However, the impact of sex was not evident. Significant associations between LA strain and diastolic strain rates and LV GLS reflect cardiac mechanics. They might emphasize the usefulness of strain parameters over conventional metrics such as mitral E′ and LVEF.
SUPPLEMENTARY MATERIAL
Parameters associated with LA contractile strainSupplementary Table 1
Conflict of Interest:The authors have no financial conflicts of interest.
ACKNOWLEDGMENTS
This work was supported by the NORMAL research group of the Korean Society of Echocardiography.
References
-
Morris DA, Parwani A, Huemer M, et al. Clinical significance of the assessment of the systolic and diastolic myocardial function of the left atrium in patients with paroxysmal atrial fibrillation and low CHADS(2) index treated with catheter ablation therapy. Am J Cardiol 2013;111:1002–1011.
-
-
Kim DG, Lee KJ, Lee S, et al. Feasibility of two-dimensional global longitudinal strain and strain rate imaging for the assessment of left atrial function: a study in subjects with a low probability of cardiovascular disease and normal exercise capacity. Echocardiography 2009;26:1179–1187.
-
-
D'Ascenzi F, Piu P, Capone V, et al. Reference values of left atrial size and function according to age: should we redefine the normal upper limits? Int J Cardiovasc Imaging 2019;35:41–48.
-
MeSH Terms
Figures
1 / 3
Tables
1 / 6
