Prognostic implications of left ventricular mechanical dispersion in comparison with QRS duration in heart failure with reduced ejection fraction

Introduction

Heart failure (HF) with reduced ejection fraction (HFrEF) is a major public health concern that results in poor outcomes (1). Left ventricular (LV) reverse remodeling (LVRR), characterized by a decrease in LV dimensions, the normalization of shape, and a significant improvement of cardiac function, has been linked to better prognosis in individuals with HFrEF (2,3). Further investigation is warranted regarding the early prediction of LVRR, as this may contribute significantly to risk stratification and clinical decision-making in HF management.

In the current guidelines, QRS duration and morphology are the established primary determinants of cardiac resynchronization therapy (CRT) indication for patients with HFrEF (4). Among patients with HFrEF receiving CRT, those with left bundle branch block (LBBB) and wide QRS demonstrate greater LVRR and functional improvement (5). In contrast, prolonged QRS duration has been associated with a lower likelihood of LVRR in patients with HFrEF receiving medical therapy (6,7). The underlying explanation for this is that LV electrical dyssynchrony, reflected in prolonged QRS duration, may trigger a vicious cycle of progressive LV remodeling and dysfunction, which can be reversed with CRT (4). However, the use of QRS criteria alone may not be sufficiently adequate for accurate prognostic prediction as LV dyssynchrony on echocardiography is frequently observed in patients with HF and a narrow QRS complex (8-10).

LV mechanical dispersion (LV-MD), measured by speckle-tracking echocardiography (STE), reflects LV contraction heterogeneity. Prolonged LV-MD indicates worse mechanical dyssynchrony, which has been associated with sudden cardiac death and ventricular arrhythmias in various cardiovascular diseases including HF (11-14). Moreover, recent studies have demonstrated that LV-MD may be a predictor of CRT response (15,16). However, the interrelationships between QRS duration, LV-MD, and LVRR have not been extensively characterized. This study thus aimed to evaluate the determinants of LV-MD, particularly its association with QRS duration. Furthermore, the prognostic role of LV-MD and whether LV-MD provides additional value over QRS duration in predicting LVRR were investigated in a cohort of patients with HFrEF receiving medical therapy. We present this article in accordance with the STROBE reporting checklist (available at https://qims.amegroups.com/article/view/10.21037/qims-24-2324/rc).

Methods

Study design and population

A analysis of a single-center prospective observational cohort was conducted in which patients hospitalized for HFrEF from January 2020 to December 2022 in Tongji Hospital (Wuhan, China) were consecutively recruited. The inclusion criteria were the presence of symptoms and/or signs of HF, LV ejection fraction (LVEF) ≤40%, and available baseline and follow-up echocardiographic imaging data. Meanwhile, the exclusion criteria were myocarditis; congenital heart disease; severe primary valvular heart disease; cardiomyopathy with specific etiologies, including hyperthyroidism and tachycardia-induced and peripartum cardiomyopathy; and CRT implantation and inadequate image quality for strain analysis. Ultimately, 234 patients were enrolled for analysis (Figure S1).

All patients received tailored medical therapy according to the relevant HF guidelines (17), and were followed up at our outpatient clinic for at least 12 months after discharge. Baseline demographic, clinical, electrocardiographic, and echocardiographic characteristics were obtained. The QRS duration was determined by automated, digital algorithms from a 12-lead electrocardiogram. LBBB was defined according to conventional criteria (18).

Echocardiography

At baseline and during follow-up, all patients underwent a comprehensive transthoracic echocardiographic study performed with a Vivid E95 ultrasound systems (GE HealthCare, Chicago, IL, USA). Data were stored offline and analyzed with commercially available software (EchoPac version 204; GE HealthCare) by an investigator blinded to clinical data.

Conventional echocardiographic measurements were performed according to established guidelines (19). LV linear dimensions were measured from the parasternal long-axis view. LV volumes and LVEF were measured from the apical two- and four-chamber views via the modified Simpson’s biplane method. LV mass was calculated according to the Devereux formula. The transmitral early diastolic velocity (E velocity) was acquired in the apical four-chamber view through pulsed-wave Doppler ultrasound at the level of the mitral valve tips during diastole. Early diastolic mitral annular velocity of the septal mitral annulus (eʹ velocity) was obtained by Doppler tissue imaging, and the E/eʹ ratio was calculated. The severity of mitral regurgitation was characterized as mild, moderate, or severe when the jet area/left atrial area was <20%, 20% to 40%, and >40%, respectively (20).

The apical long-axis, two- and four-chamber views were used for strain analysis. The endocardial border was automatically tracked, and the region of interest was assessed and then manually corrected, if necessary, to ensure optimal tracking. LV global longitudinal strain (LV-GLS) was defined as the average of peak systolic longitudinal strain values of 17 LV segments. LV-MD was calculated as the standard deviation of time from the onset of the QRS complex on electrocardiography to peak negative longitudinal strain in the 17 LV segments (Figure 1).

Figure 1 Speckle tracking echocardiograms and electrocardiograms in a patient with LVRR and another without LVRR. Representative examples of a patient with (upper panel) and another without LVRR (lower panel). (A,D) Bull’s-eye display of GLS. (B,E) Longitudinal strain curves and LV-MD. (C,F) Electrocardiograms. The patient with a lower LV-MD (67 ms) experienced LVRR but had a wide QRS complex (132 ms) at baseline. In contrast, the patient with a higher LV-MD (111 ms) did not experience LVRR although he had a narrow QRS complex (94 ms) at baseline. Yellow vertical lines indicate the onset of the QRS complex on the electrocardiogram. White horizontal arrows indicate contract duration (time to peak negative strain) in each LV segment. ANT, anterior; GLS, global longitudinal strain; GS, global strain; INF, inferior; LAT, lateral; LVRR, left ventricular reverse remodeling; LV, left ventricular; MD, mechanical dispersion; QRS, Q, R, and S waves of an electrocardiogram; SEPT, septal.

Outcomes

The primary outcome was LVRR assessed by baseline and follow-up echocardiography. LVRR was defined as the combined presence of 1) an absolute increase in LVEF of at least 10% and 2) a relative decrease in LV end-diastolic diameter index (LVEDDi) of at least 10% or LVEDDi ≤33 mm/m² (3,21).

Statistical analysis

Continuous variables are expressed as the mean ± standard deviation when normally distributed and as the median and interquartile range (IQR) when not normally distributed. Categorical variables are expressed as absolute numbers and percentages. Continuous variables were compared between groups via the Student t-test or Mann-Whitney test, and categorical variables were compared with the Pearson Chi-squared test or Fisher exact test. According to the cutoffs of QRS duration (120 ms) and LV-MD (median value of 72 ms), patients were classified into groups of wide or narrow QRS complex and into groups of high or low LV-MD. Linear regression analysis was used to identify the clinical, electrocardiographic, and echocardiographic correlates of LV-MD. To investigate the independent predictors of LVRR, variables with P<0.05 in univariable logistic regression analysis and no significant collinearity were selected for inclusion in stepwise multivariable regression analysis, and the odds ratios (ORs) and 95% confidence intervals (CIs) were determined. To check for multicollinearity, the variance inflation factor was calculated between the baseline variables, with no significant multicollinearity being assumed when this value was <5. The nonlinear associations of LV-MD and QRS duration with LVRR were evaluated through use of restricted cubic splines in logistic regression models. Subgroup analysis was further performed to validate the association of LV-MD with LVRR in different clinical settings, and the interactions with age (≤55 vs. >55 years), sex (male vs. female), HF etiology (ischemic vs. nonischemic), QRS duration (<120 vs. ≥120 ms), and LBBB (yes vs. no) were determined. Missing data were imputed using multiple imputation. Intra- and interobserver reproducibility of strain parameters was assessed through calculation of the intraclass correlation coefficients (ICCs) among 20 randomly selected patients. A two-tailed P value <0.05 was considered to indicate statistical significance. Statistical analyses were performed with SPSS version 26.0 (IBM Corp., Armonk, NY, USA) and R version 4.4.1 (The R Foundation for Statistical Computing, Vienna, Austria).

Ethical statement

This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments and was approved by the Ethics Committee of Tongji Hospital (No. TJ-IRB20230717). Informed consent was obtained from all individual participants.

Results

Baseline characteristics

Among the 234 patients in our cohort, the median age was 52 (IQR, 39–63) years, 80% (n=187) were men, 72% (n=168) had a New York Heart Association (NYHA) functional class of III/IV, and 35% (n=82) had an ischemic etiology. LBBB was present in 6% (n=15) of patients, and the median QRS duration was 104 (IQR, 94–112) ms. The median LVEF and LV-GLS were 26% (IQR, 20–30%) and –6.5% (IQR, –8.2% to –5.0%), respectively. The median LV-MD was 72 (IQR, 57–102) and ranged from 30 to 202 ms. The distributions of baseline LV-MD and QRS duration are displayed in Figure 2. Among the patients, 212 (91%) were prescribed an angiotensin receptor-neprilysin inhibitor (ARNI) or renin-angiotensin system inhibitor for treatment, 205 (88%) a β-blocker, 190 (81%) a mineralocorticoid receptor antagonist, and 82 (35%) a sodium-glucose cotransporter-2 inhibitor (SGLT2i). Additionally, 72 (88%) of the 82 patients with an ischemic etiology underwent percutaneous coronary intervention. The baseline clinical and echocardiographic characteristics of the study population are provided in Table 1.

Figure 2 Restricted cubic spline curves for the associations of LV-MD and QRS duration with LVRR. Restricted cubic spline curves showing the unadjusted odds ratios (solid curves) with 95% confidence intervals (dashed curves) according to LV-MD (A) and QRS duration (B) for the incidence of LVRR in patients with HFrEF. The background histograms (light blue color) represent the distributions of LV-MD (A) and QRS duration (B) in the study population (right y-axis). The horizontal dotted lines represent the odds ratio of 1.0. HFrEF, heart failure with reduced ejection fraction; LV, left ventricular; MD, mechanical dispersion; LVRR, left ventricular reverse remodeling; QRS, Q, R, and S waves of an electrocardiogram.

Determinants of LV-MD in HFrEF

Table S1 shows univariable and multivariable linear regression analysis for the association of log₁₀-transformed LV-MD. In univariable linear regression analysis, the significant correlates of LV-MD (log₁₀) were age, body mass index, heart rate, systolic and diastolic blood pressure, HF duration, NYHA functional class III/IV, chronic kidney disease, QRS duration, LBBB, N-terminal pro-B-type natriuretic peptide (NT-proBNP), LVEF, LVEDDi, LV end-systolic volume index, LV mass index, eʹ velocity, E/eʹ ratio, and LV-GLS. After inclusion of significant variables in the multivariable regression analysis, age (β=0.17, P=0.002), HF duration (β=0.15, P=0.011), QRS duration (β=0.38, P<0.001), and LV-GLS (β=0.24, P<0.001) were positively associated with LV-MD, while systolic blood pressure (SBP) (β=−0.14, P=0.013) was negatively associated with LV-MD.

Disagreement between QRS duration and LV-MD

In our cohort of patients with HFrEF, 40 (17%) had a wide QRS complex (≥120 ms), and 117 (50%) had an LV-MD >72 ms. A total of 35 patients (88%) with a wide QRS complex (≥120 ms) and 82 (42%) with a narrow complex (<120 ms) exhibited LV-MD >72 ms, respectively (Figure 3). 14 patients (93%) with LBBB and 103 (47%) without LBBB had LV-MD >72 ms, respectively. Of the 117 patients with LV-MD >72 ms, 70% (n=82) had a narrow QRS complex.

Figure 3 Differences in QRS duration and LV-MD in the study population. The proportions of LV-MD >72 ms and LV-MD ≤72 ms in patients with QRS duration ≥120 ms (A) and a QRS duration <120 ms (B). Among the patients with HFrEF and a wide QRS complex, 12% did not have an LV-MD >72 ms, while 42% of those with a narrow QRS complex had an LV-MD >72 ms. HFrEF, heart failure with reduced ejection fraction; LV, left ventricular; MD, mechanical dispersion; QRS, Q, R, and S waves of an electrocardiogram.

Associations of LV-MD and QRS duration with LVRR

During a median follow-up period of 19 (IQR 14–25) months, 149 (64%) patients achieved LVRR at a median time of 7 (IQR, 6–13) months. Figure 4 shows the incidence of LVRR according to QRS duration and LV-MD. Patients with a narrow QRS complex (<120 ms) had a higher likelihood of achieving LVRR than did those with a wide QRS complex (66% vs. 50%; P=0.048). Similarly, patients with a below-median LV-MD (≤72 ms) also had higher likelihood of achieving LVRR than did those with an above-median LV-MD (84% vs. 44%; P<0.001). Moreover, among patients with a narrow QRS complex (<120 ms), the incidence of LVRR was significantly higher in those with LV-MD ≤72 ms than in those with LV-MD >72 ms (84% vs. 43%; P<0.001). Patients with LV-MD ≤72 ms and a QRS duration <120 ms were significantly more likely to achieve LVRR than were those with a narrow QRS alone (84% vs. 66%; P<0.001). Notably, as shown in Figure 5, the baseline LV-MD was significantly lower in patients with LVRR than in those without LVRR irrespective of QRS duration (≤110 vs. >110 ms), LVEF (<30% vs. ≥30%), and LV-GLS (≤−5.5% vs. >−5.5%) (all P values <0.001).

Figure 4 LVRR in subgroups according to baseline QRS duration and LV-MD. The incidence of LVRR was significantly higher in patients with a QRS duration <120 ms and in those with an LV-MD ≤72 ms. Moreover, in the narrow QRS complex group, patients with LV-MD ≤72 ms had a higher likelihood of achieving LVRR than did those with LV-MD >72 ms. LV, left ventricular; LVRR, left ventricular reverse remodeling; MD, mechanical dispersion; QRS, Q, R, and S waves of an electrocardiogram.

Figure 5 Baseline LV-MD in patients with LVRR and without LVRR. The LV-MD in patients with LVRR (red box) and without LVRR (blue box) in subgroups according to baseline QRS duration (A), LVEF (B), and LV-GLS (C), which were categorized based on the optimal cutoff values as determined by ROC analysis. Data are presented as box (25th percentile, median, and 75th percentile) and whisker (minimum to maximum). According to the Mann-Whitney test, the baseline LV-MD was significantly lower in patients with LVRR than in those without LVRR irrespective of QRS duration, LVEF, and LV-GLS (all P values <0.001). GLS, global longitudinal strain; LV, left ventricular; LVRR, left ventricular reverse remodeling; LVEF, left ventricular ejection fraction; MD, mechanical dispersion; QRS, Q, R, and S waves of an electrocardiogram; ROC, receiver operating characteristic.

Receiver operating characteristic (ROC) analysis was applied to determine the optimal cutoff values of QRS duration ≤110 ms and LV-MD ≤76 ms in predicting LVRR, and LV-MD was found to have a greater area under the curve (AUC) value as compared to QRS duration (0.78 vs. 0.60; P<0.001) (Figure 6). In the restricted cubic spline curves, negative linear associations with LVRR were observed for LV-MD (P for nonlinear=0.172) and QRS duration (P for nonlinear =0.790) (Figure 2). The likelihood of LVRR increased markedly with the decrease in LV-MD and QRS duration. After adjustment, QRS duration was a significant clinical predictor of LVRR (per 1-ms increase: OR 0.98; 95% CI: 0.97–1.00; P=0.048), while LV-MD was a significant echocardiographic predictor of LVRR (per 1-ms increase: OR 0.97; 95% CI: 0.96–0.98; P<0.001) (Table S2). Moreover, QRS duration ceased to be an independent predictor when LV-MD was added to a clinical model containing age, SBP, HF duration, QRS duration, and ARNI use (Table 2).

Figure 6 ROC curves for the prediction of LVRR. Comparison of ROC curves for the prediction of LVRR between baseline LV-MD (red solid curve) and QRS duration (green dashed curve). The DeLong test was used to compare the AUCs. AUC, area under the curve; LVRR, left ventricular reverse remodeling; LV, left ventricular; MD, mechanical dispersion; QRS, Q, R, and S waves of an electrocardiogram; ROC, receiver operating characteristic.

Subgroup analysis

We further performed subgroup analysis to validate the association of LV-MD with LVRR in different clinical settings (Figure 7). A significant inverse relationship between LV-MD and LVRR was found in patients without LBBB (per 1-ms increase: OR 0.96; 95% CI: 0.95–0.98; P<0.001) but not in those with LBBB (per 1-ms increase: OR 1.00; 95% CI: 0.97–1.02; P=0.762) (P for interaction =0.044). The association between LV-MD and LVRR was not modified by age (≤55 vs. >55 years: P for interaction =0.503), sex (male vs. female: P for interaction =0.307), HF etiology (ischemic vs. nonischemic: P for interaction =0.317), or QRS duration (<120 vs. ≥120 ms; P for interaction =0.448).

Figure 7 Forest plot for the subgroup analysis. Forest plot showing the association between LV-MD and LVRR in different subgroups and the significance of the corresponding interaction terms. Unadjusted ORs and 95% CIs of LV-MD were determined via logistic regression analysis. CI, confidence interval; LBBB, left bundle branch block; LV, left ventricular; LVRR, left ventricular reverse remodeling; MD, mechanical dispersion; OR, odds ratio; Pts, patients; QRS, Q, R, and S waves of an electrocardiogram.

Reproducibility

The ICC for intra- and interobserver reproducibility of LV-GLS was 0.97 (95% CI: 0.94–0.99; P<0.001) and 0.95 (95% CI: 0.82–0.98; P<0.001), indicating excellent agreement. LV-MD showed good intraobserver (ICC: 0.87; 95% CI: 0.67–0.95; P<0.001) and interobserver agreement (ICC: 0.85; 95% CI: 0.67–0.94; P<0.001).

Discussion

This work built upon previous studies by demonstrating that STE-derived LV-MD provides incremental information on LV mechanical dyssynchrony as compared with QRS duration or morphology (LBBB) alone in patients with HFrEF. In addition, a strong correlation between LV-MD and LVRR was established after the exclusion of patients with LBBB, and LV-MD had additional value to QRS duration in predicting LVRR in patients with HFrEF receiving medical therapy.

A wide QRS complex indicates LV electrical dyssynchrony and is used as a criterion for selecting patients suitable for CRT in the current guidelines (4). However, using QRS widening as a surrogate for mechanical dyssynchrony remains controversial. Studies suggest that 20% to 30% of patients with chronic HF and a QRS duration ≥120 ms do not have LV dyssynchrony on echocardiography; meanwhile, 20% to 65% of patients with a narrow QRS complex also exhibit LV dyssynchrony (8-10). Recently, STE has provided a new window into assessing myocardial mechanics (22). LV-MD on STE reflects LV contraction heterogeneity and is recognized as an imaging marker of dyssynchrony. In our HFrEF cohort, the median LV-MD was 72 ms, which was greater than that previously reported in healthy individuals (64 ms) (23,24). In line with previous research evaluating dyssynchrony on Doppler tissue imaging and radial strain (8-10), our study found that LV mechanical dyssynchrony as assessed by LV-MD was observed in patients without LBBB or without QRS widening, and 42% patients with a narrow QRS complex (<120 ms) had a greater LV-MD (>72 ms). Therefore, dyssynchrony may be missed when the QRS complex criterion is applied in isolation. Indeed, QRS widening, while traditionally used as an indicator, is an imperfect surrogate for mechanical dyssynchrony, as shown both in our findings and those of previous work (8-10). In the absence of significant electrical dyssynchrony, assessment of dyssynchrony by STE may further identify a high-risk subgroup of patients with poorer outcomes. Accordingly, LV dyssynchrony as assessed by STE may provide complementary value in selecting candidates for CRT, particularly in borderline cases for whom QRS criteria are inconclusive; it thus warrants further investigation.

In HFrEF, the determinants and significance of LV-MD, as well as its association with QRS duration or morphology, have not been extensively examined. In our cohort, in addition to greater QRS duration, older age and worse systolic function (LV-GLS) were significantly associated with increased LV-MD, which has been reported in previous work on patients with HF and preserved ejection fraction and the general population (23-25). In addition, longer HF duration and lower SBP were also significant correlates of prolonged LV-MD. Although LBBB was a significant determinant of LV-MD in univariable analysis, it was not in multivariable analysis. This was likely due to the collinearity of LBBB with QRS duration. Both aging and prolonged HF duration can cause an increase in interstitial collagen deposition and myocardial fibrosis (24,26), which have been shown to affect mechanical dyssynchrony (27,28). As for LV-GLS and SBP, they were both negatively influenced by inefficient contraction due to LV mechanical dyssynchrony. Our results provide additional evidence that LV-MD as assessed by STE may be indicative of underlying LV mechanical dyssynchrony and could better represent mechanical dyssynchrony in comparison with QRS duration alone.

Despite the conflicting results and lack of evidence-based data, echocardiographic parameters of mechanical dyssynchrony, including time differences based on radial strain, patterns of regional longitudinal strain, LV myocardial work (4,29-32), and LV-MD on STE (15) may serve as a supplement to QRS duration and morphology for selecting patients suitable for CRT. However, little is known about the impact of LV-MD on LVRR in patients with HFrEF receiving medical therapy relative to QRS duration and morphology.

QRS duration and morphology are recognized as strong prognostic markers in HFrEF and are linked to LVRR. In several cohorts of patients with HFrEF administered medical therapy, a narrow QRS complex and the absence of LBBB predicted a higher incidence of LVRR (3,6,7). In our study, a narrower QRS complex at baseline was also predictive of subsequent LVRR, with 110 ms being the optimal cutoff value, which is similar to a 116-ms cutoff reported previously (6). However, we did not find that LBBB was significantly predictive of LVRR, likley because the small number of patients with LBBB in the cohort did not provide sufficient power for detecting a difference.

With respect to the potential value of LV-MD in predicting LVRR, we found there to be a negative linear correlation between LV-MD and LVRR in HFrEF patients with medical therapy. When LV-MD was added to the model including QRS duration and clinical parameters, the prognostic value of LV-MD remained significant, but QRS duration ceased to be an independent predictor. Further ROC analysis indicated that LV-MD was superior to QRS duration in predicting LVRR. To the best of our knowledge, these are the first reported findings indicating that LV-MD is a stronger predictor of LVRR than is QRS duration—providing additional prognostic value—in patients treated for HFrEF.

We also evaluated the association of LV-MD with LVRR in different subgroups stratified by age, sex, HF etiology, and QRS duration and morphology (LBBB). Interestingly, LV-MD was found to be a predictor of LVRR, and its predictive value remained consistent among these subgroups except for LBBB. Prolonged LV-MD was significantly correlated with lower probability of attaining LVRR in patients with HFrEF and without LBBB but not in those with LBBB. One possible explanation for this is that patients with LBBB may already have advanced dyssynchrony beyond reversible thresholds or a more fixed fibrosis (33), and thus baseline LV-MD magnitude offers no incremental stratification value. Another possible explanation for this finding is the limited sample size of patients with LBBB in our study reduced the statistical power and precluded the detection of a significant association between LV-MD and LVRR in this subgroup. The predictive value of LV-MD for LVRR in patients with LBBB requires further validation in larger cohorts.

Both prolonged LV-MD and widened QRS have been associated with myocardial fibrosis on cardiac magnetic resonance (CMR) (27,34), and a positive correlation between LV-MD and QRS duration was found in our and other investigations (25). Besides cardiac conduction disturbances, myocardial fibrosis represents a key pathophysiological substrate for LV dyssynchrony in HFrEF, causing electromechanical activation delays and subsequent contraction heterogeneity (22). Mechanical dyssynchrony may represent different pathophysiological phenomena between patients with a wide or narrow QRS complex (35). An increased burden of myocardial fibrosis may be present in patients with a narrow QRS complex but prolonged LV-MD, which is associated with a reduced likelihood of LVRR. Notably, recent evidence has increasingly supported LBBB as being a causative driver of HF progression, inducing immediate electrical and mechanical LV dyssynchrony in the Purkinje cells and myocardium and subsequent gradual structural damages (33). Thus, early detection and treatment of LV dyssynchrony is critical. Moreover, animal models of human cardiomyopathy have demonstrated that mechanical dyssynchrony precedes QRS widening, thus serving as an early marker of disease progression (36). Hence, we speculated that QRS duration with LV-MD could provide additive and complementary value for predicting LVRR, and this was confirmed in our study.

Our findings suggest that LV-MD on STE not only identifies mechanical dyssynchrony more precisely but also outperforms QRS duration in predicting LVRR in patients with HFrEF. Moreover, LV-MD can further refine risk stratification and outcome prediction, particularly in the absence of significant electrical dyssynchrony. Based on our findings and those of previous works (27,28), we speculate that LV-MD may serve as an indirect surrogate of myocardial fibrosis in the absence of CMR, supporting its practical clinical utility. Reliable prediction of both forward and reverse remodeling is pivotal for clinical decision-making and tailored management in HF. Patients with prolonged LV-MD, even without electrical dyssynchrony, exhibit a higher risk for persistent LV dilation and functional decline. In these individuals, more frequent follow-up is necessary to avoid inappropriate delays in therapy; in the future, if the requisite amount of evidence accumulates, more aggressive therapy including CRT may be considered in viable. In contrast, among patients with a higher likelihood of achieving LVRR, delays may be warranted to avoid untimely device implantation or heart transplantation.

Study limitations

This study involved several limitations which should be addressed. First, we employed a single-center observational design with a relatively small sample size. Second, the study population was enrolled in a tertiary referral center for HFrEF, and the final analysis was performed in patients who completed 12-month follow-up, thus limiting the generalizability of our results. Further studies are needed to validate our findings in broader HF populations. Third, LVRR may occur as late as 2 years after the initiation of treatments (37). Thus, the median follow-up of 19 months in our study might have been insufficient for some patients to achieve LVRR, and a longer follow-up might have produced different results. However, our unpublished data with extended follow-up shows that only a small percentage of patients experience LVRR after 2 years, and we believe that extended follow-up would not have substantially altered our conclusions. Fourth, myocardial fibrosis as detected via CMR is not systematically available and was thus not part of this study. Fifth, more studies are needed to identify the exact threshold of LV-MD. Finally, SGLT2is, which have been demonstrated to improve HF outcomes, were used in a minority of our patients (35%), and this might have affected the predictive ability of LV-MD in patients receiving guideline-recommended optimal clinical therapy.

Conclusions

In our cohort, LV mechanical dyssynchrony as assessed by LV-MD was observed when electrical dyssynchrony was absent. Greater LV-MD was independently associated with a lower likelihood of LVRR in patients with HFrEF receiving medical therapy, especially in those without LBBB. LV-MD provides additive and superior value over QRS duration in predicting LVRR and can aid in decision-making for HF management.

Acknowledgments

The authors would like to thank all the patients who participated in this study.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://qims.amegroups.com/article/view/10.21037/qims-24-2324/rc

Data Sharing Statement: Available at https://qims.amegroups.com/article/view/10.21037/qims-24-2324/dss

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-24-2324/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments and was approved by the Ethics Committee of Tongji Hospital (No. TJ-IRB20230717). Informed consent was obtained from all individual participants.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Mensah GA, Fuster V, Murray CJL, Roth GA. Global Burden of Cardiovascular Diseases and Risks Collaborators. Global Burden of Cardiovascular Diseases and Risks, 1990-2022. J Am Coll Cardiol 2023;82:2350-473. [Crossref] [PubMed]
2. Lupón J, Díez-López C, de Antonio M, Domingo M, Zamora E, Moliner P, González B, Santesmases J, Troya MI, Bayés-Genís A. Recovered heart failure with reduced ejection fraction and outcomes: a prospective study. Eur J Heart Fail 2017;19:1615-23. [Crossref] [PubMed]
3. Merlo M, Pyxaras SA, Pinamonti B, Barbati G, Di Lenarda A, Sinagra G. Prevalence and prognostic significance of left ventricular reverse remodeling in dilated cardiomyopathy receiving tailored medical treatment. J Am Coll Cardiol 2011;57:1468-76. [Crossref] [PubMed]
4. Glikson M, Nielsen JC, Kronborg MB, Michowitz Y, Auricchio A, Barbash IM, et al. 2021 ESC Guidelines on cardiac pacing and cardiac resynchronization therapy. Eur Heart J 2021;42:3427-520. [Crossref] [PubMed]
5. van der Bijl P, Khidir M, Leung M, Mertens B, Ajmone Marsan N, Delgado V, Bax JJ. Impact of QRS complex duration and morphology on left ventricular reverse remodelling and left ventricular function improvement after cardiac resynchronization therapy. Eur J Heart Fail 2017;19:1145-51. [Crossref] [PubMed]
6. Kimura Y, Okumura T, Morimoto R, Kazama S, Shibata N, Oishi H, Araki T, Mizutani T, Kuwayama T, Hiraiwa H, Kondo T, Murohara T. A clinical score for predicting left ventricular reverse remodelling in patients with dilated cardiomyopathy. ESC Heart Fail 2021;8:1359-68. [Crossref] [PubMed]
7. Sze E, Samad Z, Dunning A, Campbell KB, Loring Z, Atwater BD, Chiswell K, Kisslo JA, Velazquez EJ, Daubert JP. Impaired Recovery of Left Ventricular Function in Patients With Cardiomyopathy and Left Bundle Branch Block. J Am Coll Cardiol 2018;71:306-17. [Crossref] [PubMed]
8. Perry R, De Pasquale CG, Chew DP, Aylward PE, Joseph MX. QRS duration alone misses cardiac dyssynchrony in a substantial proportion of patients with chronic heart failure. J Am Soc Echocardiogr 2006;19:1257-63. [Crossref] [PubMed]
9. Yu CM, Lin H, Zhang Q, Sanderson JE. High prevalence of left ventricular systolic and diastolic asynchrony in patients with congestive heart failure and normal QRS duration. Heart 2003;89:54-60. [Crossref] [PubMed]
10. Tanaka H, Tanabe M, Simon MA, Starling RC, Markham D, Thohan V, Mather P, McNamara DM, Gorcsan J 3rd. Left ventricular mechanical dyssynchrony in acute onset cardiomyopathy: association of its resolution with improvements in ventricular function. JACC Cardiovasc Imaging 2011;4:445-56. [Crossref] [PubMed]
11. Melichova D, Nguyen TM, Salte IM, Klaeboe LG, Sjøli B, Karlsen S, Dahlslett T, Leren IS, Edvardsen T, Brunvand H, Haugaa KH. Strain echocardiography improves prediction of arrhythmic events in ischemic and non-ischemic dilated cardiomyopathy. Int J Cardiol 2021;342:56-62. [Crossref] [PubMed]
12. Haugaa KH, Grenne BL, Eek CH, Ersbøll M, Valeur N, Svendsen JH, Florian A, Sjøli B, Brunvand H, Køber L, Voigt JU, Desmet W, Smiseth OA, Edvardsen T. Strain echocardiography improves risk prediction of ventricular arrhythmias after myocardial infarction. JACC Cardiovasc Imaging 2013;6:841-50. [Crossref] [PubMed]
13. Haugaa KH, Goebel B, Dahlslett T, Meyer K, Jung C, Lauten A, Figulla HR, Poerner TC, Edvardsen T. Risk assessment of ventricular arrhythmias in patients with nonischemic dilated cardiomyopathy by strain echocardiography. J Am Soc Echocardiogr 2012;25:667-73. [Crossref] [PubMed]
14. Kawakami H, Nerlekar N, Haugaa KH, Edvardsen T, Marwick TH. Prediction of Ventricular Arrhythmias With Left Ventricular Mechanical Dispersion: A Systematic Review and Meta-Analysis. JACC Cardiovasc Imaging 2020;13:562-72. [Crossref] [PubMed]
15. Pujol-López M, Jiménez-Arjona R, Garcia-Ribas C, Borràs R, Guasch E, Regany-Closa M, Graterol FR, Niebla M, Carro E, Roca-Luque I, Guichard JB, Castel MÁ, Arbelo E, Porta-Sánchez A, Brugada J, Sitges M, Tolosana JM, Doltra A, Mont L. Longitudinal comparison of dyssynchrony correction and 'strain' improvement by conduction system pacing: LEVEL-AT trial secondary findings. Eur Heart J Cardiovasc Imaging 2024;25:1394-404. [Crossref] [PubMed]
16. Zhu M, Chen H, Fulati Z, Liu Y, Su Y, Shu X. Left ventricular global longitudinal strain and mechanical dispersion predict response to multipoint pacing for cardiac resynchronization therapy. J Clin Ultrasound 2019;47:356-65. [Crossref] [PubMed]
17. McDonagh TA, Metra M, Adamo M, Gardner RS, Baumbach A, Böhm M, et al. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J 2021;42:3599-726. [Crossref] [PubMed]
18. Surawicz B, Childers R, Deal BJ, Gettes LS, Bailey JJ, Gorgels A, Hancock EW, Josephson M, Kligfield P, Kors JA, Macfarlane P, Mason JW, Mirvis DM, Okin P, Pahlm O, Rautaharju PM, van Herpen G, Wagner GS, Wellens HAmerican Heart Association Electrocardiography and Arrhythmias Committee, Council on Clinical Cardiology. American College of Cardiology Foundation; Heart Rhythm Society. AHA/ACCF/HRS recommendations for the standardization and interpretation of the electrocardiogram: part III: intraventricular conduction disturbances: a scientific statement from the American Heart Association Electrocardiography and Arrhythmias Committee, Council on Clinical Cardiology; the American College of Cardiology Foundation; and the Heart Rhythm Society: endorsed by the International Society for Computerized Electrocardiology. Circulation 2009;119:e235-40. [Crossref] [PubMed]
19. Lang RM, Badano LP, Mor-Avi V, Afilalo J, Armstrong A, Ernande L, Flachskampf FA, Foster E, Goldstein SA, Kuznetsova T, Lancellotti P, Muraru D, Picard MH, Rietzschel ER, Rudski L, Spencer KT, Tsang W, Voigt JU. 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.e14. [Crossref] [PubMed]
20. Zoghbi WA, Adams D, Bonow RO, Enriquez-Sarano M, Foster E, Grayburn PA, Hahn RT, Han Y, Hung J, Lang RM, Little SH, Shah DJ, Shernan S, Thavendiranathan P, Thomas JD, Weissman NJ. Recommendations for Noninvasive Evaluation of Native Valvular Regurgitation: A Report from the American Society of Echocardiography Developed in Collaboration with the Society for Cardiovascular Magnetic Resonance. J Am Soc Echocardiogr 2017;30:303-71. [Crossref] [PubMed]
21. Verdonschot JAJ, Hazebroek MR, Wang P, Sanders-van Wijk S, Merken JJ, Adriaansen YA, van den Wijngaard A, Krapels IPC, Brunner-La Rocca HP, Brunner HG, Heymans SRB. Clinical Phenotype and Genotype Associations With Improvement in Left Ventricular Function in Dilated Cardiomyopathy. Circ Heart Fail 2018;11:e005220. [Crossref] [PubMed]
22. Smiseth OA, Torp H, Opdahl A, Haugaa KH, Urheim S. Myocardial strain imaging: how useful is it in clinical decision making? Eur Heart J 2016;37:1196-207. [Crossref] [PubMed]
23. Aagaard EN, Kvisvik B, Pervez MO, Lyngbakken MN, Berge T, Enger S, Orstad EB, Smith P, Omland T, Tveit A, Røsjø H, Steine K. Left ventricular mechanical dispersion in a general population: Data from the Akershus Cardiac Examination 1950 study. Eur Heart J Cardiovasc Imaging 2020;21:183-90. [Crossref] [PubMed]
24. Rodríguez-Zanella H, Haugaa K, Boccalini F, Secco E, Edvardsen T, Badano LP, Muraru D. Physiological Determinants of Left Ventricular Mechanical Dispersion: A 2-Dimensional Speckle Tracking Echocardiographic Study in Healthy Volunteers. JACC Cardiovasc Imaging 2018;11:650-1. [Crossref] [PubMed]
25. Biering-Sørensen T, Shah SJ, Anand I, Sweitzer N, Claggett B, Liu L, Pitt B, Pfeffer MA, Solomon SD, Shah AM. Prognostic importance of left ventricular mechanical dyssynchrony in heart failure with preserved ejection fraction. Eur J Heart Fail 2017;19:1043-52. [Crossref] [PubMed]
26. Rubiś P, Wiśniowska-Śmialek S, Wypasek E, Biernacka-Fijalkowska B, Rudnicka-Sosin L, Dziewiecka E, Faltyn P, Khachatryan L, Karabinowska A, Kozanecki A, Tomkiewicz-Pająk L, Podolec P. Fibrosis of extracellular matrix is related to the duration of the disease but is unrelated to the dynamics of collagen metabolism in dilated cardiomyopathy. Inflamm Res 2016;65:941-9. [Crossref] [PubMed]
27. Haland TF, Almaas VM, Hasselberg NE, Saberniak J, Leren IS, Hopp E, Edvardsen T, Haugaa KH. Strain echocardiography is related to fibrosis and ventricular arrhythmias in hypertrophic cardiomyopathy. Eur Heart J Cardiovasc Imaging 2016;17:613-21. [Crossref] [PubMed]
28. Abou R, Prihadi EA, Goedemans L, van der Geest R, El Mahdiui M, Schalij MJ, Ajmone Marsan N, Bax JJ, Delgado V. Left ventricular mechanical dispersion in ischaemic cardiomyopathy: association with myocardial scar burden and prognostic implications. Eur Heart J Cardiovasc Imaging 2020;21:1227-34. [Crossref] [PubMed]
29. Layec J, Decroocq M, Delelis F, Appert L, Guyomar Y, Riolet C, Dumortier H, Mailliet A, Tribouilloy C, Maréchaux S, Menet A. Dyssynchrony and Response to Cardiac Resynchronization Therapy in Heart Failure Patients With Unfavorable Electrical Characteristics. JACC Cardiovasc Imaging 2023;16:873-84. [Crossref] [PubMed]
30. Galli E, Leclercq C, Fournet M, Hubert A, Bernard A, Smiseth OA, Mabo P, Samset E, Hernandez A, Donal E. Value of Myocardial Work Estimation in the Prediction of Response to Cardiac Resynchronization Therapy. J Am Soc Echocardiogr 2018;31:220-30. [Crossref] [PubMed]
31. Gorcsan J 3rd, Anderson CP, Tayal B, Sugahara M, Walmsley J, Starling RC, Lumens J. Systolic Stretch Characterizes the Electromechanical Substrate Responsive to Cardiac Resynchronization Therapy. JACC Cardiovasc Imaging 2019;12:1741-52. [Crossref] [PubMed]
32. Beela AS, Ünlü S, Duchenne J, Ciarka A, Daraban AM, Kotrc M, Aarones M, Szulik M, Winter S, Penicka M, Neskovic AN, Kukulski T, Aakhus S, Willems R, Fehske W, Faber L, Stankovic I, Voigt JU. Assessment of mechanical dyssynchrony can improve the prognostic value of guideline-based patient selection for cardiac resynchronization therapy. Eur Heart J Cardiovasc Imaging 2019;20:66-74. [Crossref] [PubMed]
33. Lau EW, Bonnemeier H, Baldauf B. Left bundle branch block-Innocent bystander, silent menace, or both. Heart Rhythm 2025;22:e229-36. [Crossref] [PubMed]
34. Marume K, Noguchi T, Tateishi E, Morita Y, Kamakura T, Ishibashi K, Noda T, Miura H, Nishimura K, Nakai M, Yamada N, Tsujita K, Anzai T, Kusano K, Ogawa H, Yasuda S. Mortality and Sudden Cardiac Death Risk Stratification Using the Noninvasive Combination of Wide QRS Duration and Late Gadolinium Enhancement in Idiopathic Dilated Cardiomyopathy. Circ Arrhythm Electrophysiol 2018;11:e006233. [Crossref] [PubMed]
35. Gorcsan J 3rd, Sogaard P, Bax JJ, Singh JP, Abraham WT, Borer JS, Dickstein K, Gras D, Krum H, Brugada J, Robertson M, Ford I, Holzmeister J, Ruschitzka F. Association of persistent or worsened echocardiographic dyssynchrony with unfavourable clinical outcomes in heart failure patients with narrow QRS width: a subgroup analysis of the EchoCRT trial. Eur Heart J 2016;37:49-59. [Crossref] [PubMed]
36. Yamada S, Arrell DK, Kane GC, Nelson TJ, Perez-Terzic CM, Behfar A, Purushothaman S, Prinzen FW, Auricchio A, Terzic A. Mechanical dyssynchrony precedes QRS widening in ATP-sensitive K⁺ channel-deficient dilated cardiomyopathy. J Am Heart Assoc 2013;2:e000410. [Crossref] [PubMed]
37. Hnat T, Veselka J, Honek J. Left ventricular reverse remodelling and its predictors in non-ischaemic cardiomyopathy. ESC Heart Fail 2022;9:2070-83. [Crossref] [PubMed]