Validation of E/e′ Using the Index-Beat Method as an Estimate of Left Atrial Pressure in Patients with Atrial Fibrillation

Introduction: Echocardiographic assessment of diastolic function during atrial fibrillation (AF) remains challenging due to the irregular cardiac cycle length. We sought to assess whether the index-beat method, the beat following two preceding cardiac cycles of equal duration, could provide a more reliable measurement of E/e′ (mitral E wave/diastolic tissue Doppler velocity) than the conventional averaging of consecutive beats and hence facilitate the noninvasive estimation of elevated left atrial pressure (LAP) in patients with AF. Methods: We prospectively studied 35 patients with persistent AF who had preserved left ventricular ejection fraction and underwent radiofrequency ablation. LAP was measured in conjunction with transseptal puncture during catheter ablation. Echocardiography was performed 24 h before ablation and E/e′ was determined using the recommended averaging of 10 beats and the index-beat method, with the observers blinded to the clinical details and LAP measurements. Results: Correlation analysis showed a strong positive correlation between two methods in terms of both septal E/e′ (r = 0.841, p < 0.001) and lateral E/e′ (r = 0.930, p < 0.001). Bland-Altman analysis also showed a good agreement between the two measurement methods in terms of E/e′. E/e′ determined using both conventional averaging and the index-beat method was significantly correlated with LAP (p < 0.05). After Fisher Z transformation, we found that the index-beat septal E/e′ had a better correlation with LAP than did the conventional averaging E/e′ (r = 0.736 vs. r = 0.392, Zr = −2.110, p = 0.035). Furthermore, the index-beat method took significantly less time to measure E/e′ (mean 33.6 s; 95% confidence intervals [CIs]: 32.1 s–36.2 s) than did conventional averaging method (mean 96.2 s; 95% CI: 90.2 s–102.3 s; p < 0.001). Receiver operating characteristic curve analysis revealed that the optimal cut-off for predicting mean LAP >12 mm Hg was 11 (sensitivity 100%; specificity 77.3%) for index-beat septal E/e′ and 16 (sensitivity 61.5%; specificity 95.5%) for index-beat lateral E/e′. Conclusions: Good correlations were found between E/e′ and LAP in patients with AF, particularly with the index-beat method. Moreover, the index-beat method can easily measure E/e′ at an accuracy similar to that for the conventional averaging of consecutive beats, which can therefore be applied to assess the diastolic dysfunction and potentially improve the diagnosis of heart failure in patients with AF.


Introduction
Atrial fibrillation (AF), the most common type of cardiac arrhythmia, has continued to impose an increasingly heavy burden on public health [1].Left ventricular (LV) diastolic function plays an important role in the development, maintenance, and mortality attributable to AF.Early detection and accurate assessment of concurrent diastolic dysfunction are essential for AF management [2][3][4][5].Echocardiography has been routinely used to evaluate diastolic function, but its utility in patients with persistent AF remains challenging owing to the beat-to-beat variability in the cycle length [6][7][8].
The ratio of early diastolic transmitral flow velocity (E) to early diastolic mitral annular velocity (e′), E/e′, has been widely used to estimate the LV filling pressure in both sinus and AF rhythms.In clinical practice, multiple beats are averaged during AF, which is time-consuming with limited evidence.Previous studies have shown that the index-beat method, whereby measurements are taken after two cycles with a similar RR interval, may achieve a more physiologically appropriate measurement in AF [9][10][11].The current study therefore sought to assess whether the index-beat method, the beat following two preceding cardiac cycles of equal duration, could provide a more reliable measurement of E/e′ than the conventional averaging of consecutive beats and hence facilitate the noninvasive estimation of elevated left atrial pressure (LAP) in patients with AF.

Ethics
This study complied with the Declaration of Helsinki and was reviewed and approved by the Ethics Committee of Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China (approval number S-K1994).
Catheter-based LAP was measured during the ablation procedure and echocardiography was routinely performed 24 h before ablation.All clinical and procedural data were prospectively recorded.Written informed consent was obtained from all patients who participated in our study.

Echocardiography
Standard echocardiography was performed in the left lateral decubitus position by a single experienced physician within 24 h before ablation using a GE Vivid E9 instrument equipped with a 1.6-3.2MHz sector transducer.All images were stored digitally for subsequent analysis.LV end-diastolic and end-systolic dimensions were measured using M-mode echocardiography under two-dimensional guidance in the parasternal long-axis view.LVEF was calculated using the modified biplane Simpson method.Left atrial (LA) volume was assessed using the prolate ellipse method in the apical four-chamber and parasternal long-axis view.LA volume index was calculated based on body surface area.Pulmonary arterial systolic pressure was estimated as the sum of the tricuspid regurgitation gradient and estimated right atrial (RA) pressure, provided that the pulmonary valve flow velocity did not increase.Maximal tricuspid regurgitation velocity was measured using continuous wave Doppler echocardiography to evaluate the pressure gradient between the right ventricle and RA.RA pressure was calculated based on inferior vena cava size and inspiratory collapse.Mitral inflow measurements using pulsed-wave spectral Doppler included peak early flow velocity (E).Tissue Doppler imaging using spectral Doppler, including the determination of early velocities from the septal and lateral mitral annulus (e′ sep and e′ lat , respectively), was performed in the apical four-chamber view.E/e′ was calculated for both lateral and septal annular sites (E/e′ lat and E/e′ sep , respectively).
The ratio of peak E to peak e′ was calculated using two different methods of index-beat and conventional averaging method: (1) the index beat was identified as the cardiac cycle following two preceding beats with identical RR intervals, allowing for a maximal difference of 60 ms between the preceding (RR1) and prepreceding (RR2) cardiac cycles as reference (Fig. 1a) [5,12]; (2) conventional E/e′ was calculated by averaging separately measured E and e′ from 10 consecutive cardiac cycles (Fig. 1b).RR intervals were measured using a calliper in the reporting software.Index beats were selected consecutively from the beginning of each echocardiogram data set to avoid selection bias.All Doppler measurements and estimations were performed without knowledge of LAP.

LAP Measurements
Transseptal LAP was measured as described previously [13,14].For the ablation procedure, access was achieved from the femoral veins.After fluoroscopically guided transseptal puncture, a SL1 sheath (St.Jude Medical, St. Paul, USA) was inserted into the body of the left atrium.At this moment, LAP was measured through the sheath that was connected to a single-use pressure transducer (Utah Medical Products, USA) and recorded using a Sensis hemodynamic monitoring system (AXIOM Sensis XP system, Siemens, Germany).Reference for calibration was the supine midchest level.LAP was measured on end expiration at an average of 5 cycles as previous described [15,16].The maximum LAP (LAP max ) was defined as the maximum height of the v wave, and the minimum LAP (LAP min ) pressure was defined as the minimum of the x trough.Mean LAP (LAP mean) was defined as [LAP min + 1/3 (LAP max −LAP min )].

Reproducibility
Interobserver and intra-observer variability for E/e′ were examined.Accordingly, 10 randomly selected patients underwent reanalysis of their index-beat and conventional averaging E/e′ by one observer at 2 separate days, whereas another 10 patients were chosen at random for reanalysis of E/e′ by 2 observers who were blinded to the previously recorded measurements and all clinical Echocardiographic Assessment of Left Atrial Pressure in Atrial Fibrillation Cardiology 2023;148:418-426 DOI: 10.1159/000532071 echocardiography data.Bland-Altman analyses were performed to determine interobserver and intra-observer variability and obtain the 95% upper and lower limits of agreement, bias, and 95% confidence intervals (CIs) of bias.

Statistical Analysis
Student's t test was used to compare normally distributed continuous variables, which are expressed as mean ± SD.The Mann-Whitney U test was used to compare skewed data.The χ 2 test was used to compare categorical variables, which are expressed as frequencies and percentages.Correlation analysis was used to determine correlations between LAP and echocardiographic variables.The diagnostic utility of E/e′ in predicting LAP >12 mm Hg was determined using receiver operating characteristic (ROC) curve analysis.Bland-Altman analysis was used to assess the agreement between the indexbeat E/e′ and conventional averaging E/e′.All tests were two tailed and p values <0.05 indicated a statistically significant difference.All statistical analyses were performed using SPSS for Windows (version 20.0, SPSS Inc., Chicago, IL, USA).

Patient Selection and Baseline Characteristics
A total of 41 patients were screened, after which 6 patients were excluded for poor quality echocardiographic images (2 patients), previous catheter ablation of AF (2 patients) and use of diuretics within the past 7-10 days with a LVEF <50% (2 patients).Online supplementary Figure 1 (for all online suppl.material, see https://doi.org/10.1159/000532071) shows a flowchart of the patient selection.
The baseline characteristics of all 35 patients are summarized in Table 1.The mean age of the included patients was 61 ± 12 years.Among all 35 patients, 26 (74.3%) and 9 (25.7%) were men and women, respectively.Average heart rate was 94 ± 20 beats per minute.The patients were then classified into two groups: those with LAP ≤12 mm Hg (n = 22) and those with LAP >12 mm Hg (n = 13).No significant differences in gender, BMI, and heart rate were noted between the two groups.Compared to patients with LAP ≤12 mm Hg, those with LAP >12 mm Hg were older (66 ± 10 years vs. 58 ± 12 years, respectively; p = 0.036) and had a higher CHA 2 DS 2 -VASc score (3.1 ± 1.6 vs. 1.8 ± 1.5, respectively; p = 0.026).
Regarding the echocardiographic parameters, no significant differences in LA volume index and pulmonary arterial systolic were observed between the two groups.Regardless of whether the conventional averaging of consecutive beats or index-beat approach was used, E/e′ was significantly higher in patients with LAP >12 mm Hg than in those with LAP ≤12 mm Hg (p < 0.05).

Correlation Analysis between the Two Measurement Methods for E/e′
Bland-Altman analysis revealed that among the 35 points, only 2 points (2/35, 5.7%) were outside the 95% limits of agreement for septal E/e′, whereas only 1 point (1/35, 2.9%) was outside the 95% limits of agreement for lateral E/e′, showing a good agreement between the two measurement methods for E/e′ (Fig. 2a, b).Spearman correlation analysis showed a strong positive correlation between two methods in terms of both septal E/e′ (r = 0.841, p < 0.001) and lateral E/e′ (r = 0.930, p < 0.001; Fig. 2c, d).

Relationship between Echocardiographic Parameters and Mean LAP
Conventional averaging E/e′ was correlated with LAP (E/e′ sep , r = 0.392, p = 0.02; E/e′ lat , r = 0.450, p = 0.007); however, the index-beat E/e′ Ma/Fang/Lin/Gao/Fang  seemed to have better correlation with LAP than did conventional averaging E/e′ (E/e′ single-beat sep , r = 0.736, p < 0.001; E/e′ single-beat lat , r = 0.676, p < 0.001) (Fig. 3).Thereafter, we statistically compared the two correlation coefficients (conventional averaging E/e′ and LAP vs. index-beat E/e′ and LAP).After Fisher Z transformation, we found a significant differences between the two correlation coefficients for septal E/e′ and LAP (Zr = −2.110,p = 0.035: r = 0.392 for conventional averaging method vs. r = 0.736 for the indexbeat method); however, no significant differences were observed between the two correlation coefficients for lateral E/e′ and LAP (Zr = −1.348,p = 0.178: r = 0.450 for conventional averaging method vs. r = 0.676 for the index-beat method).
Using ROC curve analysis, we determined that singlebeat septal E/e′ had an area under the ROC curve of 0.920 (95% CI: 0.832-1.000,p < 0.001) for differentiating between LAP >12 mm Hg and LAP ≤12 mm Hg.At a cut-off of >11, single-beat septal E/e′ had a sensitivity and specificity of 100% and 77.3% for predicting LAP >12 mm Hg, respectively.Meanwhile, single-beat lateral E/e′ had an area under the ROC curve of 0.850 (95% CI: 0.719-0.980,p = 0.001) for differentiating between LAP >12 mm Hg and LAP ≤12 mm Hg.At a cut-off of >16, single-beat lateral E/e′ had a 61.5% sensitivity and 95.5% specificity for predicting a LAP of >12 mm Hg (Fig. 4).

Intra-Operator and Inter-Operator Reproducibility
A comparison of the intra-and inter-operator reproducibility for E/e′ between the index-beat method and the conventional averaging method was conducted in 10 randomly selected patients.For intraoperator reproducibility, the index-beat had the smallest bias at −0.2 with narrow limits of agreement to the average of 10 beats (−2.1 to 2.8) and the highest ICC of 0.923 (95% CI: 0.901-0.945).Similar findings were seen for inter-operator reproducibility, with the index-beat method having the smallest bias at −1.1 with similar limits of agreement to the average of 10 beats (−4.8 to 4.6) and the highest ICC of 0.887 (95% CI: 0.833-0.923)(Table 2).Furthermore, the index-beat method took significantly less time to measure E/e′ (mean 33.6 s; 95% CI 32.1-36.2),compared with averaging 10 consecutive beats (96.2 s; 90.2-102.3;p < 0.001).Using the index-beat method saved 62.6 s compared with averaging 10 consecutive beats (absolute difference in means).

Main Findings
The present study demonstrated the feasibility of E/e′ in the evaluation of LAP in patients with AF with preserved LVEF.The main findings of our study were as follows: (1) E/e′ determined using the index-beat approach, whereby measurements are taken after two cycles with similar RR intervals, was compared to that determined using the conventional averaging of consecutive beats; (2) good correlations were found between E/e′ and LAP in patients with AF, particularly with the index-beat method.The index-beat E/e′ can be easily performed and is as accurate as and less time-consuming than the conventional averaging of consecutive beats, thereby suggesting its applicability in assessing diastolic dysfunction in patients with AF.
AF is characterized by the loss of mechanical atrial function due to LA contractile asynchrony, an inability to augment LV filling and a highly variable cycle length, which poses challenges to echocardiographic assessment of cardiac function.As such, predicting LV filling pressure or LA pressure using classic echocardiographic parameters, such as mitral E/A ratio and LA volume index, remains difficult in patients with persistent AF.E/ e′, as a Tissue Doppler imaging-derived index of LV filling that is independent of atrial contraction, has been proven useful for diastolic function assessment.A number of studies have shown that E/e′ is important in patients with non-valvular AF and that it may be useful for the estimation of elevated LV filling pressure/LAP in patients with AF [17,18].However, beat-to-beat variations producing cycle length variability in AF warrant multiple measurements for accuracy.In clinical practice, multiple beats are averaged during AF, which is timeconsuming and also lacks evidence.
Previous studies have confirmed that the LV contractility in AF is influenced by the relative length of the preceding cycle (RR1/RR2), which is caused by the preload and uptake of calcium during the relaxation phase [19].Given that ventricular filling and stroke volume for a particular beat are determined by the previous two RR intervals, the index-beat method, whereby measurements are taken after two cycles with a similar RR interval, could potentially be a more physiologically appropriate measurement.Some small studies have evaluated the use of the index-beat approach in the assessment of systolic and diastolic function among patients with AF.Previous studies assessing echocardiographic parameters have found a strong correlation between the index-beat and average values of multiple beats with high levels of agreement, including strain rate [20,21], stroke volume [12], ejection fraction [9], and E/e′ [22,23].In the current study, we demonstrated that the calculated values of E/e′ at RR1/RR2 = 1 were quite similar to the average values of 10 consecutive beats, which was consistent with the results presented in previous studies.Furthermore, we found that the index-beat E/e′ had a better correlation with LAP than did the conventional averaging E/e′ in patients with AF, and that the index-beat E/e′ had good sensitivity and specificity for predicting LAP >12 mm Hg.We also demonstrated that the index-beat approach improved reproducibility and was less time-consuming than the conventional averaging approach, which was consistent with the findings re-ported in a previous study by Bunting et al. [5].In study of Bunting et al. [5], they also demonstrated that the indexbeat method took significantly less time to measure E/e′ (mean 35.4 s; 95% CI: 33.1-37.8),compared with averaging 5 consecutive beats (mean 44.7 s; 95% CI: 41.8-47.5;p < 0.001).Thus, in clinical settings, the indexbeat E/e′ determined after two preceding cycles with identical RR intervals can be expected to be an alternative for estimating elevated LAP in patients with AF.
In 2008, Senechal et al. [24] used the E/e′ measured via the one-beat method using the longest RR interval to estimate the wedge pressure in patients with AF, with their findings also showing the potential value of echocardiographic assessment in determining diastolic function among patients with AF.However, given that this was a relatively small study of only 24 patients and did not include a clear definition of the longest RR interval, further studies are still needed to determine the value of this one-beat method.In addition, several studies have shown that the synchronous E/e′ index measured by the dual-Doppler method could be more reliable than the conventional E/e′ in patients with AF; however, dual-Doppler echocardiography has still not been widely used in actual clinical practice [25,26].

Clinical Implications
AF and HF are among the most common cardiac diseases encountered in clinical practice, and their incidence only increases with age.Patients with concurrent AF and chronic HF, including those with preserved ejection fraction, have worse prognosis than do patients with AF alone.LV diastolic dysfunction plays an important role in the development, maintenance, and mortality attributable to AF. Accurate diagnosis of coexisting diseases is essential for the initiation of appropriate therapy.As an easily obtainable echocardiographic parameter, E/e′ has been commonly used in evaluating diastolic function in clinical practice.The current study found good correlations between E/e′ and LAP in patients with AF, particularly with the index-beat method.The indexbeat E/e′ can easily be performed and is as accurate as and less time-consuming than the conventional averaging of consecutive beats, which can therefore be applied to assess diastolic dysfunction in patients with AF and potentially improve the diagnosis of heart failure in patients with AF.

Study Limitations
The main limitation of this study is the nonsimultaneous recording of LAP measurements and echocardiography assessment of diastolic function.Echocardiography was performed within 24 h of cardiac catheterization studies.Although we confirmed that the hemodynamic conditions did not differ significantly during catheterization echocardiography recordings and that the medications were not altered between two studies, the possibility of variations could not be excluded.Another limitation was the small number of patients.Finally, we need to highlight that this study included a relatively homogeneous and selective population of patients with AF with preserved LVEF and controlled heart rate; hence, further studies should be conducted before our findings can be extrapolated to other clinical settings.

Conclusions
E/e′ correlated well with LAP in patients with AF, particularly in the method of index beat.E/e′ measured by index beat can easily be performed and is as accurate as and less time-consuming than the conventional averaging of consecutive beats, which can therefore be applied to assess diastolic dysfunction in patients with AF and potentially improve the diagnosis of heart failure in patients with AF.Further studies with more participants are needed to confirm our conclusions.

Fig. 1 .
Fig.1.Index-beat approach versus conventional averaging of consecutive beats.a Pulsed-wave mitral inflow Doppler using the index-beat method, with identical RR intervals of the preceding two beats indicated by the white arrows.b 10 consecutive beats.

Fig. 2 .
Fig. 2. Agreement and correlation between index-beat approach and conventional averaging of consecutive beats for E/e′ (a and b, Bland-Altman analysis, the middle line indicates the mean difference and the two dashed side lines indicate the 95% limits of agreement; c and d, correlation analysis).

Table 1 .
Comparison of clinical, echocardiographic, and hemodynamic characteristics between two groups BMI, body mass index; LAP, left atrial pressure; LAVI, left atrial volume index; PASP, pulmonary artery systolic pressure.

Table 2 .
Interobserver and intraobserver variability and time efficiency for E/e′