Abstract
Background
Left ventricular ejection fraction (EF) and global longitudinal strain (GLS) are widely used for cardiac surveillance in patients receiving potentially cardiotoxic cancer therapy. While GLS is more sensitive for detecting early myocardial dysfunction, the relationship between EF and GLS in routine clinical practice remains incompletely characterized, and discordance between these parameters may complicate clinical interpretation.
Methods
This retrospective observational study included 117 oncology patients undergoing serial echocardiographic assessment at baseline, early follow-up (6–12 weeks), and short-term follow-up (3–6 months). EF was measured by biplane Simpson’s method, and GLS by speckle-tracking echocardiography as absolute values. EF deterioration was defined as a ≥ 10% absolute reduction or EF < 53%, while GLS deterioration was defined as a ≥ 15% relative reduction in absolute GLS magnitude. Concordance between EF and GLS deterioration was assessed, using Cohen’s kappa and McNemar’s test.
Results
Mean EF and GLS values remained stable (EF p = 0.124; GLS p = 0.803). EF deterioration occurred in 32 patients (27.4%), and GLS deterioration in 25 patients (21.4%). Discordance was common, with isolated GLS deterioration in 17 patients (14.5%), and EF deterioration without GLS decline in 24 patients (20.5%), representing discordance in 41% of patients. Agreement was poor (κ = 0.05), and McNemar’s test was not significant (p = 0.27). ΔGLS showed a weak association with ΔEF (r = 0.19, p = 0.036).
Conclusions
Although systolic function remained stable overall, clinically relevant deterioration occurred in a subset. Frequent EF–GLS discordance highlights their complementary but non-interchangeable roles in cardio-oncology surveillance.
Keywords: Cardio-oncology, Ejection fraction, Global longitudinal strain, Echocardiography, Cancer therapy–related cardiac dysfunction, Longitudinal follow-up
Introduction
Advances in oncologic therapies have substantially improved cancer survival, leading to a growing population of patients exposed to potentially cardiotoxic treatments [1]. As survivorship increases, cancer therapy–related cardiac dysfunction (CTRCD) has emerged as an important determinant of long-term morbidity and mortality among oncology patients [2]. Early identification of myocardial dysfunction is therefore a central goal of contemporary cardio-oncology care, as timely recognition of cardiac injury may allow modification of oncologic therapy or initiation of cardioprotective treatment to prevent irreversible cardiac damage [3].
Left ventricular ejection fraction (EF) has historically served as the cornerstone of cardiac monitoring during cancer therapy. However, EF reflects global ventricular performance and may remain within the normal range until myocardial injury has already occurred [4]. Consequently, reliance on EF alone may delay recognition of early cardiotoxicity. Global longitudinal strain (GLS), derived from speckle-tracking echocardiography, has emerged as a more sensitive marker of myocardial deformation and is increasingly incorporated into cardio-oncology surveillance guidelines. Several studies have demonstrated that reductions in GLS may precede overt declines in EF, suggesting that GLS may identify subclinical myocardial dysfunction at an earlier stage [5, 6].
Despite growing adoption of GLS in clinical practice, important uncertainties remain regarding its interpretation during routine surveillance. While guideline recommendations support the use of GLS to detect early cardiotoxicity, the relationship between changes in GLS and subsequent changes in EF has been inconsistent across studies. In addition, many existing investigations have focused on highly selected patient populations, specific chemotherapy regimens, or prospective clinical trial settings. As a result, the longitudinal behavior and concordance of EF and GLS in heterogeneous, real-world oncology populations remain incompletely characterized [7, 8].
A particular clinical challenge arises when EF and GLS provide discordant information. In routine practice, clinicians may encounter patients in whom GLS deteriorates while EF remains preserved, or conversely patients with EF decline without clear GLS changes. The frequency, patterns, and clinical interpretation of such discordance remain incompletely defined, yet they have important implications for surveillance strategies and clinical decision-making in cardio-oncology.
The present study was therefore designed to evaluate longitudinal changes in EF and GLS in a real-world cohort of oncology patients undergoing routine cardiac surveillance. In addition to examining temporal changes in these parameters, we sought to characterize the concordance and discordance between EF and GLS deterioration and to explore the relationship between changes in myocardial deformation and global ventricular function.
Methods
Study design and population
This retrospective observational cohort study included adult oncology patients who underwent serial echocardiographic assessment from 2021 to 2023 during and after cancer therapy. A total of 254 patients were screened for eligibility. Of these, 117 patients met the inclusion criteria and had complete echocardiographic data at baseline, early follow-up (6–12 weeks), and short-term follow-up (3–6 months), and were included in the final analysis. The patient selection process, including the numbers of patients screened, excluded, and included, is summarized in the study flow diagram (Fig. 1).
Fig. 1.
Study flow diagram. Flow diagram of patient selection, showing the number of oncology patients screened for eligibility, the number excluded with reasons for exclusion, and the number included in the final analysis
Patients referred for routine cardiac surveillance were eligible if echocardiographic examinations were available at all three time points. Patients were consecutively included based on availability of complete echocardiographic data.
Patients with pre-existing significant cardiac disease, baseline left ventricular systolic dysfunction, or inadequate echocardiographic image quality were excluded. With respect to oncologic treatment exposure, most patients received anthracycline-based chemotherapy, HER2-targeted therapy (trastuzumab with or without pertuzumab), or a combination of both, consistent with contemporary breast cancer treatment protocols, while the remainder received other systemic anticancer regimens. As detailed regimen-level and cumulative-dose information was not uniformly retrievable from the medical records, exact patient counts for each treatment category could not be reliably determined.
Echocardiographic assessment
Standard transthoracic echocardiography was performed at baseline, first follow-up, and second follow-up according to institutional protocols. Echocardiographic studies were performed using Philips ultrasound systems. GLS analysis was conducted using vendor-specific software (QLAB, Philips Medical Systems, Andover, MA, USA). Images were acquired from standard apical 4-, 2-, and 3-chamber views with frame rates typically between 50 and 80 frames per second. Strain analysis was performed offline by experienced operators according to established guidelines [9]. Left ventricular ejection fraction (EF) was calculated using the biplane Simpson’s method. Echocardiographic measurements were obtained according to the recommendations of the American Society of Echocardiography [10]. GLS was measured from standard apical views and analyzed as absolute magnitudes, such that lower absolute values reflect worsening myocardial deformation.
Definitions of EF and GLS deterioration
Clinically relevant EF deterioration was defined as either:
≥ 10% absolute reduction in EF from baseline, or
EF value < 53% at either follow-up time point.
GLS deterioration was defined as a ≥ 15% relative reduction in absolute GLS magnitude from baseline at either follow-up time point. These definitions are consistent with current guideline recommendations, including the 2022 ESC Cardio-Oncology Guidelines [11].
Statistical analysis
Continuous variables are presented as mean ± standard deviation. Normality was assessed using the Shapiro–Wilk test. Changes in EF and GLS over time were evaluated using repeated-measures analysis of variance (ANOVA), with Greenhouse–Geisser correction applied when sphericity assumptions were violated.
For association analyses, changes in EF (ΔEF) and GLS (ΔGLS) were calculated as the difference between first follow-up and baseline values:
ΔEF = EF at first follow-up − baseline EF.
ΔGLS = absolute GLS at first follow-up − baseline absolute GLS.
The relationship between ΔGLS and ΔEF was assessed using Pearson correlation. Linear regression analysis was performed to evaluate the predictive value of ΔGLS for ΔEF. A two-sided p value < 0.05 was considered statistically significant. All statistical analyses were performed using SPSS software, version 26 (IBM Corp., Armonk, NY, USA).
As this was an exploratory retrospective study, no formal sample size calculation was performed.
Ethical considerations
This study was conducted in accordance with the principles of the Declaration of Helsinki. Ethical approval was obtained from the Institutional Review Board of King Abdullah International Medical Research Center (KAIMRC). Given the retrospective design and use of anonymized data, the requirement for informed consent was waived. All patient data were handled confidentially and stored in password-protected databases accessible only to the study investigators.
Results
Baseline characteristics
The mean age of the study population was 51.2 ± 12.3 years. The cohort was predominantly female (95.7%), and breast cancer was the most common malignancy (89.7%). Almost all patients were in sinus rhythm at baseline. Baseline demographic and clinical characteristics are summarized in Table 1.
Table 1.
Baseline demographic and clinical characteristics
| Variable | Value |
|---|---|
| Sample size | 117 |
| Age (years), mean ± SD | 51.2 ± 12.3 |
| Female sex, n (%) | 112 (95.7%) |
| BMI (kg/m²), mean ± SD | 30.2 ± 9.1 |
| Breast cancer, n (%) | 105 (89.7%) |
| Sinus rhythm on ECG, n (%) | 116 (99.1%) |
Longitudinal changes in EF and GLS
Mean EF values were 57.7% at baseline, 56.7% at first follow-up, and 57.1% at second follow-up. Repeated-measures ANOVA demonstrated no significant change in EF over time (p = 0.124).
Mean GLS values (reported as absolute values) were 20.36 at baseline, 20.54 at first follow-up, and 20.44 at second follow-up, with no significant temporal change observed (p = 0.803). Fig. 2 demonstrates mean EF and GLS values over time. Detailed longitudinal echocardiographic parameters are presented in Table 2.
Fig. 2.
Mean EF and GLS values over time. Mean ± standard error values of left ventricular ejection fraction (EF) and global longitudinal strain (GLS) at baseline, first follow-up, and second follow-up, demonstrating stability of left ventricular systolic function across time points
Table 2.
Longitudinal echocardiographic parameters
| Parameter | Baseline | Follow-up 1 | Follow-up 2 | p-value |
|---|---|---|---|---|
| EF (%) | 57.7 ± 4.6 | 56.7 ± 4.5 | 57.1 ± 5.4 | 0.124 |
| GLS (%) | 20.36 ± 3.57 | 20.54 ± 2.76 | 20.44 ± 2.91 | 0.803 |
Clinically relevant EF and GLS deterioration
Using predefined clinically meaningful cut-offs, EF deterioration (defined as a ≥ 10% absolute reduction from baseline or EF < 53% at follow-up) occurred in 32 patients (27.4%). Of these, 10 patients met the ≥ 10% reduction criterion alone, 14 met the EF < 53% criterion alone, and 8 met both criteria.
GLS deterioration, defined as a ≥ 15% relative reduction from baseline GLS magnitude, was observed in 25 patients (21.4%). Isolated GLS deterioration without concomitant EF deterioration was identified in 17 patients (14.5%), indicating discordance between EF and GLS in a subset of patients. The distribution of EF and GLS deterioration is summarized in Table 3.
Table 3.
EF and GLS deterioration during follow-up
| Outcome | n (%) |
|---|---|
| EF deterioration | 32 (27.4%) |
| GLS deterioration | 25 (21.4%) |
| GLS deterioration without EF decline | 17 (14.5%) |
| EF deterioration without GLS decline | 24 (20.5%) |
Concordance between EF and GLS deterioration
Concordance analysis demonstrated that EF and GLS remained stable in the majority of patients. However, discordant patterns were frequently observed. The distribution of EF values across time points is illustrated in Fig. 3.
Fig. 3.
Distribution of left ventricular ejection fraction over time. Boxplots illustrating the distribution of individual patient left ventricular ejection fraction (EF) measurements at baseline, first follow-up, and second follow-up. Boxes represent the interquartile range with median values, and whiskers indicate overall dispersion. While group-level EF distributions remained stable over time, clinically relevant EF deterioration occurred in a subset of patients, highlighting inter-individual variability despite preserved population-level trends
Overall, discordant EF–GLS patterns were observed in 41% of patients. Specifically, 8 patients (6.8%) exhibited deterioration in both EF and GLS, 17 patients (14.5%) demonstrated isolated GLS deterioration despite preserved EF, and 24 patients (20.5%) showed EF deterioration without concomitant GLS decline. The detailed concordance between EF and GLS deterioration is shown in Table 4.
Table 4.
Concordance between EF and GLS deterioration
| GLS stable | GLS deteriorated | Total | |
|---|---|---|---|
| EF stable | 68 (58.1%) | 17 (14.5%) | 85 |
| EF deteriorated | 24 (20.5%) | 8 (6.8%) | 32 |
| Total | 92 | 25 | 117 |
Agreement between EF and GLS deterioration was low (Cohen’s κ = 0.05), indicating poor concordance. McNemar’s test demonstrated no statistically significant difference between EF and GLS classifications (p = 0.27), suggesting that the two parameters identify different subsets of patients.
Association between ΔGLS and ΔEF
A weak but statistically significant positive correlation was observed between changes in GLS (ΔGLS) and changes in EF (ΔEF) between baseline and first follow-up (r = 0.19, p = 0.036). In linear regression analysis, ΔGLS was a significant predictor of ΔEF (β = 0.19, p = 0.036), explaining 3.8% of the variance in EF change (Fig. 4).
Fig. 4.
Relationship between changes in global longitudinal strain (ΔGLS) and changes in left ventricular ejection fraction (ΔEF) between baseline and first follow-up. ΔGLS was calculated using absolute GLS values. A weak but statistically significant positive association was observed (r = 0.19, p = 0.036)
Discussion
In this longitudinal real-world cohort of oncology patients undergoing routine cardiac surveillance, we found that left ventricular systolic function assessed by both ejection fraction (EF) and global longitudinal strain (GLS) remained stable at the population level during early follow-up. However, clinically meaningful deterioration occurred in a substantial minority of patients, and discordant patterns between EF and GLS were frequently observed. These findings highlight the complexity of interpreting myocardial function during cancer therapy and underscore the complementary roles of EF and GLS in cardio-oncology practice [1, 2].
A key observation of the present study is the discrepancy between population-level stability and individual-level deterioration. Although mean EF and GLS values did not change significantly over time, more than one quarter of patients experienced clinically relevant EF deterioration and approximately one fifth demonstrated GLS deterioration. This finding emphasizes that reliance on group averages may obscure clinically meaningful changes at the individual level, which is particularly relevant in cardio-oncology where early detection of myocardial injury is critical for guiding management [8, 12–14].
An additional important finding is the frequent discordance between EF and GLS. While some patients exhibited deterioration in both parameters, a notable proportion demonstrated isolated GLS impairment despite preserved EF. This pattern supports the concept that myocardial deformation abnormalities may precede detectable reductions in global systolic function. Prior studies, including those by Thavendiranathan et al. and Negishi et al., have demonstrated that reductions in GLS may identify subclinical cancer therapy–related cardiac dysfunction (CTRCD) before overt EF decline [15–17]. However, randomized data from the SUCCOUR trial did not show a significant reduction in EF decline with GLS-guided surveillance compared with standard monitoring, highlighting ongoing uncertainty regarding the clinical impact of GLS-guided management [18]. Current recommendations from the American Society of Echocardiography, the European Association of Cardiovascular Imaging, and the 2022 ESC Cardio-Oncology Guidelines support the use of GLS as an adjunctive tool for early detection of myocardial dysfunction [9, 11].
Conversely, we also observed patients with EF deterioration in the absence of GLS decline. This finding highlights that the relationship between EF and GLS is not strictly linear, and that these parameters reflect distinct physiological aspects of ventricular performance. EF primarily reflects global volumetric pump function, whereas GLS reflects myocardial fiber deformation, particularly within the subendocardial layers that are more vulnerable to early injury. The presence of such discordance underscores the importance of integrating multiple echocardiographic parameters rather than relying on a single metric in clinical practice.
Mechanistically, the earlier impairment of GLS may be explained by the susceptibility of subendocardial longitudinal fibers to cardiotoxic injury. In contrast, EF may remain preserved until more advanced myocardial dysfunction occurs due to compensatory mechanisms and its dependence on loading conditions. These considerations support a cautious interpretation of isolated GLS abnormalities, as such changes may not uniformly translate into subsequent EF decline in all patients.
Despite the statistical association observed between changes in GLS and EF, the strength of this relationship was modest, with GLS explaining only a small proportion of the variance in EF change. This finding reinforces that EF and GLS capture related but distinct aspects of myocardial function and that GLS abnormalities should be interpreted as markers of early myocardial stress rather than definitive predictors of future systolic dysfunction.
From a clinical perspective, these findings highlight an important challenge in cardio-oncology practice: how to interpret and act upon discordant EF–GLS findings. While guideline recommendations define relative GLS reduction as an early marker of cardiotoxicity, the optimal management of such abnormalities remains uncertain [19, 20]. Our results suggest that clinical decisions should incorporate the broader clinical context, including patient risk profile and treatment exposure, rather than relying solely on a single imaging parameter.
Several factors may explain the overall preservation of systolic function observed at the group level. The study population consisted predominantly of women with breast cancer receiving contemporary treatment regimens, which are increasingly associated with improved cardiovascular safety [21, 22]. In addition, the relatively short follow-up period reflects early surveillance intervals and may not capture late cardiotoxic effects that can develop over longer timeframes [6, 9].
These findings underscore the importance of integrating EF and GLS within a comprehensive, patient-centered approach to cardio-oncology surveillance. Rather than viewing these parameters as interchangeable, they should be interpreted as complementary tools that provide distinct and clinically relevant information.
Study limitations
This study has several limitations. First, its retrospective design introduces potential selection bias and limits the ability to control for treatment-related variables. Second, the predominance of female patients with breast cancer restricts generalizability to other malignancies and to male populations. Third, although general treatment categories were identified, detailed information regarding specific chemotherapy regimens, cumulative dosing, treatment duration and exposure frequencies was not consistently available, precluding therapy-specific analyses. Fourth, the relatively short follow-up period limits assessment of long-term cardiotoxic outcomes. Fifth, the absence of clinical cardiovascular outcomes prevents evaluation of the prognostic significance of the observed imaging changes. In addition, intraobserver and interobserver variability were not formally assessed, which may influence interpretation of longitudinal EF and GLS changes. Nevertheless, all strain measurements were performed offline by experienced operators using vendor-specific software and standardized EACVI/ASE acquisition and analysis protocols, which have demonstrated good intra- and interobserver reproducibility in prior validation studies. Future prospective studies incorporating longer follow-up and detailed treatment data will be important to clarify the clinical implications of EF and GLS discordance in oncology populations.
Conclusions
In a real-world cohort of oncology patients undergoing routine cardiac surveillance, EF and GLS frequently demonstrated discordant patterns despite stable group-level systolic function. These findings highlight that EF and GLS provide complementary but non-interchangeable information and should be interpreted together in cardio-oncology surveillance. Integration of both parameters, alongside clinical context, may improve the identification and interpretation of early myocardial dysfunction during cancer therapy.
Acknowledgements
Not applicable.
Abbreviations
- EF
Ejection fraction
- GLS
Global longitudinal strain
- CTRCD
Cancer therapy–related cardiac dysfunction
- BMI
Body mass index
- ECG
Electrocardiogram
- ANOVA
Analysis of variance
- ΔEF
Change in ejection fraction
- ΔGLS
Change in global longitudinal strain
- SD
Standard deviation
- OR
Odds ratio
- CI
Confidence interval
Authors’ contributions
J.A. conceived the study. A.S., R.M., R.J., and N.K. collected the data. J.A. and A.S. drafted the manuscript. R.M. and J.A. prepared Figs. 1, 2 and 3. All authors reviewed and approved the final manuscript.
Funding
This research received no external funding.
Data availability
The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.
Declarations
Ethics approval and consent to participate
This study was conducted in accordance with the principles of the Declaration of Helsinki. Ethical approval was obtained from the Institutional Review Board of King Abdullah International Medical Research Center (KAIMRC), Jeddah, Saudi Arabia. Due to the retrospective nature of the study and the use of anonymized data, the requirement for informed consent was waived.
Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Associated Data
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Data Availability Statement
The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.