Comparative reproducibility of myocardial work and left ventricular ejection fraction in patients after an acute coronary syndrome

Purpose: To assess reproducibility (interobserver variability and agreement) of Global Work Efficiency (GWE) and left ventricular ejection fraction (LVEF), assessed by 2D-echocardiography (2-DE) and 3D-echocardiography (3-DE), in patients with acute coronary syndrome (ACS), through measurements performed by operators with different levels of experience. Methods: Echocardiographers with three levels of experience were involved in offline processing: advanced, who performed image acquisition – Reader 1 (5 years of training in 2-DE, 3 years in 3-DE); intermediate – Reader 2 (3 years of training in 2-DE, 1 year in 3-DE); beginner – Reader 3 (1 year of training in 2-DE, 3 months in 3-DE). Measurements of GWE and LVEF were performed independently. Interobserver variability and agreement between readers were compared using Bland-Altman plots, as bias and limits of agreement (LOA), and Pearson correlations. Results: 90 patients (54±9 years, 75 males) with ACS were analyzed. Comparing measurements of GWE, following bias and limits of agreement (LOA) were obtained: R1 vs R2: bias -0.6, LOA -3;2 (r=0.98, p<0.001); R2 vs R3: bias -0.3, LOA -3;5 (r=0.96, p<0.001); R1 vs R3: bias -1, LOA -5;4 (r=0.94, p<0.001). Interobserver variability and agreement of GWE were comparable with LVEF by 3-DE: R1 vs R2: bias 0.6, -2, and -1.4; LOA -3;4, -7;4, and -6;4, respectively (r=0.96, 0.91, 0.94, respectively, all p<0.001); however, for LVEF by 2-DE interobserver variability was higher, while agreement was lower. Conclusion: Reproducibility of GWE in patients after an ACS is independent of experience of the operator, and similar with the reproducibility of LVEF by 3-DE. 1. INTRODUCTION Cardiovascular imaging provides an accurate, accessible, and non-invasive assessment of left ventricular (LV) function in patients after an acute coronary syndrome (ACS).(1) Due to its availability, reproducibility, and low costs, the main imaging tool for analyzing left ventricular volumes and function is 2-dimensional echocardiography (2-DE). However, the method has its downfalls: measurements are performed using assumptions on LV geometry and are vulnerable to acquisition errors, such as foreshortening or inappropriate estimation of endocardial borders.(2) Conversely, guidelines on echocardiographic chamber quantifications recommend a 3-dimensional assessment of LV volumes and ejection fraction, since 3-dimensional echocardiography (3-DE) offers a more accurate analysis of LV morphology, with good reproducibility and without being affected by errors in geometric assumptions.(3) Meanwhile, results obtained by 3-DE are comparable to the current “gold standard”, cardiac magnetic resonance (CMR).(4) Unfortunately, 3-DE is not widely available and is highly dependent on the image acquisition. Noninvasive myocardial work (MW) is a new echocardiographic tool derived from speckle-tracking (STE), used to assess global and regional myocardial performance. The method integrates myocardial deformation and afterload, estimated by left ventricular pressure during a cardiac cycle, using timing of valvular events and systolic brachial artery pressure.(1) There is little data regarding MW use and its clinical significance in the first days after an ACS. Recent studies have shown that this is a better predictor of LV recovery, compared to the global longitudinal strain (GLS), emerging as an important prognostic marker and therapeutic target.(5) However, in order to be used in clinical practice, reproducibility of MW should be better analyzed in dedicated studies. Thus, our main objective was to analyze reproducibility of MW for assessing LV performance in an ACS setting, compared to reproducibility of parameters of LV function by 2-DE and 3-DE, when used by operators with different levels of experience. 2. MATERIALS AND METHODS 2.1. Study population and design. This is a single-center, prospective study, enrolling patients with an ACS (with or without ST-segment elevation), who underwent coronary angiography, and were treated according to the current guidelines.(6,7) The local ethics committee approved the study, and all patients signed the informed consent before being included. Inclusion criteria were: (i) age over 18 years; (ii) hospitalization for ACS, as diagnosed by the most recent guidelines (6,7); (iii) good echocardiographic windows. Exclusion criteria were: (i) irregular rhythm that could not allow 3-DE acquisition; (ii) severe valvular heart disease; and (iii) hemodynamic instability. Patients who were technically unsuitable for STE analysis or 3-DE acquisition were excluded. 2.2. Echocardiography . 2-DE and 3-DE acquisitions were performed by an advanced echocardiographer, with 5 years of training in 2-DE, and 3 years of training in 3-DE and STE. A comprehensive precordial echocardiography was performed according to the current guidelines(8), using a state-of-the-art echocardiographic ultrasound system (Vivid E9 or Vivid E95, GE Healthcare), equipped with an M5 S probe for 2-DE and a 4V probe for 3-DE. All images were collected within the first 48 hours after admission. Apical four- and two-chamber views were used to assess 2D LV volumes, while apical four-chamber view, with multibeat full-volume acquisition, was used to assess 3D LV volumes. Data were analyzed offline on a workstation EchoPac™ (EchoPAC version 203, GE Healthcare). Echocardiographers with three levels of experience were involved: advanced, who was also in charge of image acquisition, labelled as Reader 1 (R1), with 5 years of training in 2-DE, and 3 years of training in 3-DE and STE; intermediate, labelled as Reader 2 (R2), with 3 years of training in 2-DE, and 1 year of training in 3-DE and STE; and beginner, labelled as Reader 3, with 1 year of training in 2-DE, and 3 months of training in 3-DE and STE. All 3 echocardiographers performed the measurements in a blinded fashion on the same echocardiographic images. All measurements for each patient were independently performed in sequential order by the three readers, with Reader 1 conducting the initial assessment, followed by Reader 2, and subsequently by Reader 3. LV end-diastolic and end-systolic volumes were measured, and LVEF was calculated, using the biplane Simpson method applied to apical four- and two-chamber views for 2-DE. 3-DE volumes and LVEF were calculated using the dedicated software (4D Auto LVQ, GE Vingmed Ultrasound), as shown in Figure 1. GLS was obtained from two-dimensional grayscale images in apical four-, three-, and two-chamber views at a frame rate of 60–70 frames per second, as shown in Figure 2. Myocardial motion was automatically tracked in the region of interest, and adjusted by correcting the endocardial widths or boundaries, as necessary. MW was analyzed, using a dedicated vendor-specific software (GE Healthcare). Valvular events were defined using pulsed-wave Doppler acquisition. This software is based on the theoretical ventricular pressure curve, which is adjusted for each patient based on valvular timing events and peak systolic blood pressure, measured with an arm cuff immediately before the acquisition.(9) Parameter of myocardial work which was assessed was GWE (Global Work Efficiency), which is the total work of the myocardium within the pressure-strain loops, from mitral closure to mitral opening (Figure 2). Figure 1. Left ventricular (LV) volume measurements and LV ejection fraction calculation, using the dedicated software. The 3D shape of LV and the volumetric curve were automatically obtained, after tracing the endocardial border of the LV. Figure 2. A. Myocardial motion automatically tracked and adjusted by correcting the endocardial widths or boundaries; B. GLS (Global Longitudinal Strain) and bull’s eye, generated by a dedicated software; C. GWE (Global Work Efficiency) obtained from GLS by integrating the arterial pressure. 2.3. Statistical analysis. Continuous data are expressed as mean ± standard deviation, while categorical variables are presented as absolute numbers and percentages. Inter-observer variability and agreements between methods were obtained through Bland-Almand plots by quantifying their systematic differences (bias) and the limits of agreement (LOA), respectively . LOA was calculated as the mean difference ±1.96 times the standard deviation of the differences, defining the range within which 95% of the individual differences are expected to lie. If bias approaches zero, systematic discrepancies are negligible, reducing the likelihood of consistent overestimation or underestimation by one reader relative to the other. Additionally, if the LOA are narrow, it further supports good inter-observer variability. Pearson correlations were also used to compare agreement between measurements. An R-value above 0.90 was labeled as a very good correlation. P-value <0.5 was considered statistically significant. Statistics were performed using IBM SPSS Statistics for Windows, 29.0. Armonk, NY, USA. 3. RESULTS 3.1. Study Population. 90 patients (54 ± 9 years, 75 men) admitted with ACS (21.1% with non-ST elevation ACS and 78.9% with ST-elevation ACS) were analyzed. Time spent for calculating 2-DE LVEF was 128 ± 20 s for the advanced reader, 138 ± 15 s for the intermediate reader, and 140 ± 21 s for the beginner, whereas time spent for calculating 3-DE LVEF was 153 ± 10 s for the advanced reader, 172 ± 18 s for the intermediate reader, and 190 ± s for the beginner. Time spent for measuring GWE was 130 ± 17 s for the advanced reader, 139 ± 23 s for the intermediate reader, and 142 ± 18 s for the beginner. 3.2. Comparison between 2-DE measurements provided by operators with different levels of experience. Bland-Altman plots showed a bias of -0.9 between advanced and intermediate readers, with LOA -5;4, bias of -4 between intermediate and beginner readers, with LOA -10;4, and bias of -5 between advanced and beginner readers, with LOA -8;4 (Figure 3). All correlations were very good (R > 0.90; p < 0.001) (Figure 4). Figure 3. Bland-Altman plots for measurements of 2-DE left ventricular ejection fraction (LVEF) by advanced (R1), intermediate (R2), and beginner (R3) readers. Figure 4. Correlations between 2-DE left ventricular ejection fraction (LVEF), measured by advanced (R1), intermediate (R2), and beginner (R3) readers. 3.3. Comparison between 3-DE measurements provided by operators with different levels of experience. Bland-Altman plots showed a bias of -0.6 between advanced and intermediate readers, with LOA -3;4, bias of -2 between intermediate and beginner readers with LOA -7;4, and bias of -1.4 between advanced and beginner readers with LOA -6;4 (Figure 5). 3-DE measurements provided systematically lower bias values and narrower LOA intervals compared to 2-DE measurements. All correlations were very good (R > 0.90; p < 0.001) (Figure 6). Figure 5. Bland-Altman plots for measurements of 3-DE left ventricular ejection fraction (LVEF) by advanced (R1), intermediate (R2), and beginner (R3) readers. Figure 6. Correlations between 3-DE left ventricular ejection fraction (LVEF), measured by advanced (R1), intermediate (R2), and beginner (R3) readers. 3.4. Comparison between Global Work Efficiency (GWE) measurements provided by operators with different levels of experience . Bland-Altman plots showed a bias of -0.6 between advanced and intermediate readers, with LOA -3;2, bias of -0.3 between intermediate and beginner readers with LOA -3;5, and bias of -1.0 between advanced and beginner readers with LOA of -5;4 (Figure 7). All correlations were also very good (R > 0.94; p < 0.001) (Figure 8). Figure 7. Bland-Altman plots for measurements of GWE (Global Work Efficiency) by advanced (R1), intermediate (R2), and beginner (R3) readers. Figure 8. Correlations between GWE (Global Work Efficiency), measured by advanced (R1), intermediate (R2), and beginner (R3) readers. 3.4. Comparison of interobserver variability and agreement between echocardiographers with different levels of experience for GWE, and 2-DE and 3-DE measurements of LVEF are summarized in Table 1. Bias values are closer to zero for both GWE and LVEF by 3-DE across all comparisons, suggesting very good interobserver variability, lower than for LVEF by 2-DE. Similarly, LOA are consistently narrower for GWE and LVEF by 3-DE, suggesting very good agreement, whereas 2-DE shows the widest LOA ranges across all comparisons. Table 1. Interobserver variability and agreement between echocardiographers with different levels of experience for GWE, and 2-DE and 3-DE measurements of LVEF. 2-DE -- 2D echocardiography, 3-DE -- 3D echocardiography, GWE -- Global Work Efficiency, LOA -- limits of agreement, LVEF -- left ventricular ejection fraction, R1 -- advanced reader, R2 -- intermediate reader, R3 -- beginner reader, 4. DISCUSSION We showed that reproducibility of GWE in patients after an ACS is independent of experience of the operator, and similar with the reproducibility of LVEF by 3-DE. Meanwhile, LVEF by 2-DE has higher interobserver variability and lower agreement. This is an important message, since identifying reproducible and time-efficient echocardiographic parameters for assessing left ventricular function in patients after an acute coronary syndrome is essential, as they have a key role in prognostic stratification, risk of heart failure, and in optimizing follow-up strategies to improve patient outcomes. To the best of our knowledge, this is the first study assessing comparative reproducibility of parameters of LV function, measured by myocardial work (GWE) and LVEF by 2-DE and 3-DE, between users with different levels of experience. 3-DE for assessment of left ventricular function in patients with ACS. Our results are consistent with previously reported data. A meta-analysis including twenty-three studies that aimed to investigate 3-DE performance and reproducibility showed that 3-DE offers an advantage over 2-DE in providing better accuracy, precision, and reproducibility for LV volume and LVEF measurements, with interobserver bias of 5.8%.(10) Similarly, Medvedofsky et al confirmed that 3-DE provides more consistent LVEF measurements, with bias closer to zero and very good agreement between readers. The analysis included one hundred eighty patients from different clinical centers with all ranges of chamber size and function and showed no clear differences in the agreement between measurements performed by the participating sites (11) . Thus, an interobserver bias of <2% and an LOA within ±5 and ±7% is considered good for LVEF assessment using 3-DE, reflecting superior reproducibility compared to 2-DE(8), which was confirmed in our study. Previous research has also highlighted the advantages of (3-DE) across users with varying levels of expertise(2,12). Hien et al. reported good reproducibility of 3-DE measurements between experienced and non-experienced observers; however, their analysis focused on transesophageal echocardiography in patients with organic mitral regurgitation(12). Similarly, a study by Baldea et al. demonstrated that 3-DE is a method that can be efficiently learned and applied, showing high reproducibility for LV assessment even among operators with limited experience following just one month of training.(2) Our findings highlight the reliability of 3-DE for LVEF assessment in patients with ACS. The significance of these findings is further emphasized by the established prognostic value of 3-DE, which has demonstrated superior predictive power for cardiovascular mortality compared to two-dimensional echocardiography. In a study conducted by Medvedofsky et al., involving over four hundred patients with both ischemic and non-ischemic cardiovascular disease, 3DE-derived parameters outperformed 2DE in predicting cardiovascular death(13). When feasible and accessible, 3-DE should be used, even by practitioners with 3 months of experience. Myocardial work in patients with ACS. Although data on reproducibility of myocardial work are limited, our results are consistent with previous studies that analyzed interobserver variability between users with the same level of experience.(1) As the bias is close to zero, systematic discrepancies become minimal, with a low risk of consistent overestimation or underestimation by one reader compared to another. Furthermore, narrow limits of agreement reinforce the method’s reproducibility and interchangeability. We used GWE as the target parameter for the assessment of myocardial work, since this is the most important functional parameter and was proved to be an independent prognostic factor in patients with acute coronary syndromes. A comprehensive analysis on more than five hundred patients with STEMI and a median follow-up of 80 months, conducted by Lustosa et al. found that those with reduced GWE (<86%) showed more impacting cardiac damage than patients with preserved GWE (≥86%).(14) Moreover, GWE showed a more significant incremental benefit than LVEF, and higher values of GWE were associated with better outcome, independent of other parameters like age, troponin levels or LVEF. Thus reduced GWE measured by transthoracic echocardiography within 48 hours of admission in ST-segment–elevation myocardial infarction patients is associated with worse long-term survival. (14) In a more recent study on patients with ACS (with and without ST-segment elevation), in which major events (ME) like cardiovascular death, heart failure, and unplanned coronary revascularization were observed, GWE was the only transthoracic parameter independently associated with the long-term occurrence of ME. This analysis suggests that GWE might be the best non-invasive parameter of myocardial function to predict adverse outcomes after an ACS(1) Mahdiui et al showed that patients with STEMI had lower values of GWE, compared to healthy subjects and compared to patients who associated cardiovascular risk factors, since acute coronary syndromes can result in LV dyssynchrony, regional impairments in longitudinal LV strain, and fluctuations in LV afterload, all of which contribute to a reduction in overall LV mechanical efficiency.(15)GWE might also be used to detect patients whose initial LV dysfunction was related to myocardial stunning and not permanent myocyte damage, since it has been shown that its values can significantly improve over three months after an acute coronary syndrome. A recent analysis performed on 350 patients with STEMI undergoing primary PCI and who also received optimal medical therapy showed a significant improvement of GWE after three months, which may reflect the presence of myocardial stunning and may be used to discriminate viable (stunned) myocardium from scar tissue (16) Our findings demonstrated very good reproducibility of GWE measurements among operators with varying experience levels, comparable to 3-DE reproducibility, suggesting that GWE is a reliable tool for assessing LV function in patients with acute coronary syndromes.

of the study Some limitations of this study should be acknowledged. First, since a correct evaluation of MW parameters is not feasible in patients with poor-quality acquisitions, patients with atrial fibrillation, severe valvular disease, and unsatisfactory echocardiographic windows were excluded. In addition, images were obtained by a single operator, so extending the data to acquisitions made by multiple operators should be cautiously made. Finally, the results were not compared with measurements made with CMR, considered to be the gold standard of LV assessment.

This study demonstrates that myocardial work offers highly reproducible measurements of left ventricular performance in patients with acute coronary syndrome, comparable to 3-DE LVEF, independent of experience of the operator. This could support its use in clinical practice for patients with acute coronary syndrome, in order to adapt medical treatment, monitoring visits, and screening for residual subclinical myocardial ischemia. Conflicts of Interest: The authors declare no conflict of interest. Funding: Public grant(s) – EU funding – UEFISCDI. Project number grant 5/2018; INNATE- IM: Targeting innate immune system mechanisms for a better risk stratification and identification of new therapeutic options in acute myocardial infarction.

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Authors Metrics & Citations Metrics Article Usage 375views 192downloads Citations Download citation R. Copciag, V. Bratu, Roxana Rimbas(Sisu), et al. Comparative reproducibility of myocardial work and left ventricular ejection fraction in patients after an acute coronary syndrome. Authorea. 14 April 2025. DOI: https://doi.org/10.22541/au.174465412.20077507/v1 DOI: https://doi.org/10.22541/au.174465412.20077507/v1 If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download. For more information or tips please see 'Downloading to a citation manager' in the Help menu.