Quantitative assessment of changes in left ventricular myocardial work and energy loss in HER2-positive breast cancer patients undergoing combination therapy with chemotherapy and targeted treatment using pressure-strain loop and vector flow mapping

Introduction

Currently, breast cancer (BC) is the most prevalent malignant tumor among females (1). According to 2022 data from the International Agency for Research on Cancer (1), BC ranks first globally in terms of incidence and mortality among female-specific malignancies. The mortality rate of BC has been progressively increasing over the years, and it is now the leading cause of mortality among the female population (2). Through advancements in the investigation of molecular subtypes, it has been established that human epidermal growth factor receptor 2-positive breast cancer (HER2⁺ BC) accounts for approximately 15–30% of all invasive BC cases (3). In comparison to human epidermal growth factor receptor 2 (HER2)-negative BC, this subtype is characterized by reduced disease-free survival, an elevated risk of metastasis, and shortened overall survival (3,4).

The therapeutic strategy of combining anthracycline drugs with molecular-targeted agents is commonly adopted as the standard first-line treatment to extend patient survival. This approach effectively suppresses tumor growth and metastasis, improving patient outcomes (5). However, the concurrent administration of these two medicines may be correlated with the substantially increased incidence of cardiotoxicity via multiple underlying mechanisms (6). The cardiotoxicity caused by chemotherapy treatment and targeted therapies, which leads to chronic treatment-related cardiac dysfunction (CTRCD), has emerged as the major reason for cancer-related-mortality in malignant tumor patients post-treatment, surpassed only by cancer recurrence (7). This toxicity substantially impairs the prognosis and long-term survival rates of HER2⁺ BC patients, and represents the second most significant factor contributing to adverse outcomes and elevated mortality among cancer survivors (7,8). The early monitoring of the cardiac function of HER2⁺ BC patients receiving combined therapy, coupled with the timely implementation of preventive interventions, can effectively mitigate the risk of cardiotoxicity (9), prevent progression from subclinical cardiac impairment to clinical cardiac failure, enhance the quality of life of cancer patients following combined therapy, and improve patient prognosis (10). This study aimed to use the left ventricular pressure-strain loop (PSL) and blood flow vector analysis to evaluate the effects of chemotherapy combined with targeted therapy on myocardial function, as well as to investigate the clinical relevance of left ventricular myocardial work (LVMW) and energy loss (EL) in the early detection of cardiac functional changes.

The non-invasive left ventricular PSL, which is grounded in a fundamental physics principle of work (W), is calculated as the product of force (F) and distance (S), with calculus applied to refine the calculations. The method employs non-invasive brachial artery pressure measurements as a surrogate for left ventricular pressure (F), and uses two-dimensional (2D) speckle tracking echocardiography to conduct longitudinal strain analysis, where the derived strain values represent distance (S). Using specialized software, the instantaneous myocardial strain values are multiplied by the corresponding instantaneous pressures of the left ventricle (LV), followed by integration to generate the PSL curve for the LV. This process can further obtain the quantified LVMW parameters, including the global and segmental parameters (11). The PSL incorporates the effects of afterload on the systolic function of the LV, making it more precise than the global longitudinal strain (GLS), which is derived from 2D speckle tracking and solely quantifies myocardial fiber deformation. A comprehensive report demonstrated that compared to GLS, myocardial work (MW) is a superior predictor of exercise tolerability in patients with disharmonious contractility across various left ventricular segments and dilated cardiomyopathy (12). Additionally, a study of heart failure patients with preserved ejection fraction states that the increase in GCW after exercise is a more decisive indicator of enhanced cardiac exercise reserve than GLS (13). Notably, several studies conducted by Di Lisi et al. in cohorts of BC patients undergoing cardiotoxic chemotherapy regimens have reported that while both GLS and the myocardial work index (MWI) exhibited significant reductions post-treatment, the MWI showed enhanced sensitivity and earlier detection of CTRCD during the course of therapy than GLS (14,15). A few previous studies have shown that the PSL constructed using non-invasive methods exhibits an excellent correlation with the pressure-volume loops acquired via invasive cardiac catheterization measurements (16,17). Further, using advanced clinical imaging techniques for diagnostic evaluation, Russell et al. showed that MW accurately reflects myocardial metabolic demand and oxygen consumption (11). MW has progressively emerged as the predominant metric for assessing cardiac function, gradually superseding the left ventricular ejection fraction (LVEF) and GLS (18).

Cardiotoxicity induced by chemotherapy agents and targeted therapies may result in alterations in hemodynamics, and thus can be both quantitatively and visually assessed using cardiovascular magnetic resonance imaging (19), vector flow mapping (VFM), and particle imaging velocimetry (PIV) (20). VFM is an emerging technique that quantitatively assesses blood flow vectors in the cardiac chambers by integrating color Doppler and 2D speckle tracking. The accuracy of the blood flow velocity vectors derived from VFM has been validated through comparison with PIV imaging (21). The EL resulting from blood flow viscous friction, as calculated by VFM, serves as a reliable metric for assessing the efficiency of blood flow transmission. It quantifies the energy lost due to viscous friction within the ventricular flow field and dissipated in the form of heat energy within the LV. The underlying principle and its accuracy have been documented in previous studies (22). The occurrence of turbulence results in irreversible EL within the fluid, accompanied by a reduction in kinetic energy. Conversely, the presence of a single larger and more stable vortex contributes to reduced EL in the flow field, thereby promoting the maintenance of a stable energy state. In a study of patients with diffuse large B-cell lymphoma, Yang et al. (23) showed that EL increases progressively during anthracycline-based chemotherapy. This elevation is attributed to turbulent myocardial deformation caused by dyssynchronous myocardial motion, which results from the cardiotoxic effects of the chemotherapeutic agents. Garcia et al. showed that turbulence induced by aortic valve stenosis leads to significantly elevated EL during diastole in individuals diagnosed as suffering from aortic stenosis in comparison with healthy individuals (24). The quantification of EL resulting from blood viscosity friction within the ventricular flow field, which is required to overcome turbulence, offers a novel approach for detecting cardiac dysfunction induced by combination therapy.

Based on the aforementioned two techniques, this study assessed the function of the LV in HER2⁺ BC patients in terms of MW and EL with the aim of more sensitively detecting CTRCDS induced by the combination of anthracycline-based chemotherapy and targeted therapy in a clinical context. We present this article in accordance with the STROBE reporting checklist (available at https://qims.amegroups.com/article/view/10.21037/qims-2025-1138/rc).

Methods

Patients

Initially, 67 patients with invasive HER2⁺ BC, confirmed by clinical pathology and histological examination at the First Affiliated Hospital of Shihezi University, were prospectively enrolled in the study between July 2023 and December 2024. During the follow-up period, eight patients were lost to follow-up, one patient was excluded from the study for failure to adhere to the standard chemotherapy regimen, and three patients were excluded due to suboptimal image quality. Thus, ultimately, a total of 55 patients were included in the final analysis. During the same period, 55 gender- and age- matched healthy individuals who underwent routine physical examinations at the hospital were recruited as the normal controls. Transthoracic echocardiographic and image acquisition examinations were performed at three time points: before treatment initiation (T0), after the second cycle of treatment (T2), and after the fourth cycle of treatment (T4).

Patients were included in the HER2⁺ BC group if they met the following inclusion criteria: (Ⅰ) had a pathologically confirmed diagnosis of BC; (II) were HER2-positive as determined by immunohistochemistry or fluorescence in situ hybridization; (III) were aged between 18 and 65 years; (IV) had a LVEF >50% before treatment initiation; and (V) were scheduled to undergo anthracycline-based chemotherapy combined with either single-target therapy (trastuzumab) or dual-target therapy (trastuzumab and pertuzumab), administered in 21-day cycles for a total of four cycles. Patients were excluded from the study if they met any of the following exclusion criteria: (I) had a history of heart failure, myocarditis, myocardial infarction, serious valvular disease or cardiomyopathy, or any other severe cardiac conditions; (II) had previously undergone chemotherapy or radiotherapy; (III) had persistent atrial fibrillation or severe arrhythmias interfering with the collection and analysis of ultrasound data; (IV) had a cerebrovascular disease, connective tissue disorder, or renal insufficiency that might compromise the assessment of cardiac function; or (V) had thoracic deformities or were pregnant, which could compromise image quality, leading to suboptimal visualization.

This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study was approved by the Ethics Committee of the First Affiliated Hospital of Shihezi University (No. KJ2024-263-01), and all participants signed an informed consent form prior to their enrollment in the study.

Blood pressure (BP)

Right brachial artery BP was measured using the automatic upper arm BP monitoring device (Omron HEM-7312, OMRON Corporation, Kyoto, Japan) prior to each patient’s supine ultrasound examination. During measurement, the position of the sleeve was positioned at the same level as the heart. Three consecutive readings were obtained at 1-minute intervals, and the calculated averages were used for the later computational analysis.

Routine 2D Doppler echocardiography

GE VIVID E9 (GE Vingmed Ultrasound AS, Horten, Norway) and Lisendo 880 sonograph instruments (Hitachi, Ltd., Tokyo, Japan), equipped with M5S-D and S121 probes, respectively, were used for image acquisition. The regular 2D Doppler echocardiography indices and MW metrics calculated using the PSL were obtained using the above-mentioned GE system and the M5S-D sensor. The EL calculated using VFM was obtained using the above-mentioned Lisendo 880 system and S121 sensor. All the participants were instructed to breathe calmly and lie on their left side. Synchronous electrocardiogram (ECG) monitoring was then performed. Once a resting state was achieved, two experienced senior physicians with comparable expertise acquired standard echocardiographic views in accordance with the adult echocardiography guidelines developed by the American Society of Echocardiography (25). The 2D echocardiographic parameters were calculated as the mean of three consecutive cardiac cycles. LVEF was determined using Simpson’s two-plane method (25). On a standard parasternal long-axis view of the LV during the late-diastole period, measurements were obtained for the internal diameter of the cardiac chambers. Using spectral Doppler mode, the peak flow velocities in early and late mitral orifice diastole were recorded. In tissue Doppler imaging mode, the average peak velocity in early and late bicuspid annular diastolic peak velocities on both the lateral wall and septal side of the LV were measured.

Quantified MW

Standard 2D dynamic images of at least three consecutive cardiac cycles in the apical three-chamber (AP3C), apical four-chamber (AP4C), and apical two-chamber (AP2C) views were captured over three consecutive cardiac cycles and stored. These images ensured clear visualization of the epicardium, subendocardial myocardium, and endocardium. The average frame rate of the 2D images exceeded 40 frames per second. Subsequently, the MW indicators were analyzed and obtained using Echo PAC software (GE Healthcare). The timing for the aortic valve closure (AVC) and the aortic valve opening (AVO) were assessed by integrating the left ventricular outflow tract Doppler spectrum with the 2D echocardiographic images. Similarly, the mitral valve closure (MVC) and the mitral valve opening (MVO) time were determined by combining the mitral inflow Doppler spectrum with the corresponding 2D images. The AP3C, AP4C, and AP2C views of the heart were selected. “Measure” was clicked on, followed by “AFI”. The system then delineated the region in the middle of the endocardium and epicardium at the selected views. If the automatic tracking results were unsatisfactory, manual adjustments were made to refine the edges or their width between them, thereby optimizing the region of interest (ROI). Once the adjustments were complete, “Process” was clicked on to calculate the GLS of the LV. After saving the results, “Myocardial Work” and select “Event Timing” were clicked on. The positions of AVO, AVC, MVO, and MVC were then fine-tuned in conjunction with the AP3C view. The participant’s artery pressure value was input, and the software automatically integrated the left ventricular strain data with the BP value to analyze and generate non-invasive left ventricular pressure-strain loop (LVPSL) images, and the global and 17-segmental MW indicators. The global MW parameters primarily included the: (I) global work index (GWI); (II) global constructive work (GCW); (III) global work waste (GWW); and (IV) global work efficiency (GWE), where GWE = GCW/(GCW + GWW) (Figure 1).

Figure 1 Myocardial work parameters. (A) Controls; (B) HER2⁺ BC patients at T0; (C) HER2⁺ BC patients at T2; (D) HER2⁺ BC patients at T4. ANT, anterior; BP, blood pressure; GCW, global constructive work; GLS, global longitudinal strain; GWE, global work efficiency; GWI, global work index; GWW, global waste work; HER2⁺ BC patients, human epidermal growth factor receptor 2-positive breast cancer patients; INF, inferior; LAT, lateral; LVP, left ventricular pressure; POST, posterior; SEPT, septal; T0, before treatment initiation; T2, after the second cycle of treatment; T4, after the fourth cycle of treatment.

EL by VFM

The images for the subsequent blood flow vector analysis were acquired at the standard AP4C, AP3C, and AP2C views. The sampling field clearly depicted the left ventricular cavity and endocardial border. The image sector angle and depth were adjusted to ensure that the color sampling box fully encompassed the entire LV. The frame rate during image acquisition was maintained at ≥40 frames per second, and the velocity scale was set between 66 and 89 cm/s to avoid color flow aliasing. The built-in VFM analysis software was activated for the on-machine analysis. The endocardial boundaries were outlined manually, and the system traced the left ventricular endocardium. The time flow curve (TFC) was plotted 2 cm over the mitral valve. Based on ECG, the TFC, and the valve opening and closing events, the cardiac cycle was separated into the following four periods: rapid-filling (RF), atrial contraction (AC), rapid ejection (RE), and isovolumetric contraction (IVC). The frame exhibiting the most significant changes in each phase was selected to record the left ventricular EL parameter. By entering the EL mode, the ROI was manually delineated (e.g., the entire LV, and the basal, middle, and apical segments), enabling the automatic generation of the specific summation of energy loss (SEL) and average energy loss (AEL) in this ROI. The EL equation, which was developed by Itatani et al., is expressed as follows:

EL=∑i,j∫μ(∂ui∂xj+∂uj∂xi)2dv[1]

This formula evaluates the square for the difference of adjacent velocity vectors. At locations where the magnitude or direction for velocity vector field varies significantly, the value of the EL increases accordingly (26). It can be inferred that EL will significantly increase in the presence of turbulence.

In this study, the specific SEL and AEL of the entire LV, as well as each segment (i.e., the basal, middle, and apical segments) during four periods (i.e., the RF, AC, IVC, and RE periods) were calculated (Figure 2).

Figure 2 SEL and AEL of global and regional left ventricle. (A) Controls; (B) HER2⁺ BC patients at T0; (C) HER2⁺ BC patients at T2; (D) HER2⁺ BC patients at T4. AEL, average energy loss; EL-AVE, average energy loss; EL-SUM, summation of energy loss; HER2⁺ BC patients, human epidermal growth factor receptor 2-positive breast cancer patients; SEL, summation of energy loss; T0, before treatment initiation; T2, after the second cycle of treatment; T4, after the fourth cycle of treatment.

Repeatability test

To evaluate the inter- and intra-observer variabilities in the MW parameters in different segments and EL at various periods, 10 randomly selected images were used. The two repeatability analyses were performed with an interval exceeding 5 days. Intra-observer variability was assessed by having one observer analyze a single set of images on two separate occasions. Inter-observer variability was evaluated by having two observers independently analyze the same set of images.

Statistical analysis

SPSS 27.0 was used for the data analysis. The measurement data that followed a normal distribution and exhibited homogeneity of variance across multiple samples are presented as the mean ± standard deviation (SD). The independent-sample t-test was used to compare two sets of data, while a one-way analysis of variance was used to compare multiple groups. The non-normally distributed data are presented as the median (interquartile range), and the Kruskal-Wallis H test was used for multi-group comparisons. A Bland-Altman analysis was conducted to assess repeatability. A receiver operating characteristic (ROC) curve analysis was conducted on each group of participants using GraphPad Prism software. The area under the curve (AUC) was calculated to assess and compare the diagnostic performance of each index. The maximum Youden index was determined and used as the critical point that offers the optimal balance between sensitivity and specificity, thereby enabling the identification of the optimal diagnostic cut-off value. A P value <0.05 was considered statistically significant.

Results

Baseline and echocardiographic features

The baseline and 2D echocardiographic features of the participants are summarized in Tables 1,2, respectively. No significant differences were observed between the HER2⁺ BC and control groups in terms of the baseline and echocardiographic features (all P>0.05) (Tables 1,2).

Global and segmental MW of the LV

In relation to the global MW, the GWI was significantly reduced at T2 compared with T0, and showed a consistent downward trend throughout the treatment cycle (GWI; 2,106.80±178.82 vs. 1,922.93±218.06 vs. 1,805.09±216.12 mmHg%; P<0.001). GCW, GLS, the GWI, and GWE were significantly decreased at T4 compared with both T0 and T2, while GWW was significantly elevated at T4 (Table 3).

In terms of the segmental GWI, compared with T0, GWI began to decrease significantly at T2 within the following segments: the basal anterior, basal anterolateral, basal inferolateral, basal inferoseptal, mid-anteroseptal, mid-anterolateral, mid-inferolateral, mid-inferior, apical anterior, apical lateral, apical inferior, apical septal, and apex. Further, these differences became progressively more pronounced as the treatment period progressed. The GWI of the basal anteroseptal, basal inferior, mid-anterior, and mid-inferoseptal segments showed a significant decreased beginning at T4 (Table 4).

Left ventricular EL

In terms of global EL, no significant differences in AEL or SEL were observed at T0 between the patient and control groups during the four time phases (i.e., the AC, RF, IVC, and RE periods) (all P>0.05). Compared with T0, both the AEL and SEL at T2 were significantly increased during the AC period [AEL in AC: 6.48 (5.10, 13.67) vs. 12.56 (7.92, 27.92) vs. 19.51 (10.75, 33.96) J/(s·m³), P<0.001; SEL in AC: 2.43 (1.83, 5.21) vs. 6.60 (3.06, 13.35) vs. 9.98 (5.81, 20.10) J/(s·m), P<0.001]. Compared with both T0 and T2, the AEL and SEL at T4 were significantly increased during the RF, IVC, and RE periods (Tables 5,6).

In terms of EL in three different regions of the LV (i.e., the basal, middle, and apical segments), compared with T0, the AEL and SEL of all three regions at T2 were significantly increased during the AC period and displayed a marked upward trend as the treatment progressed, with the apical segment showing the largest increase (all P<0.001). Both the AEL and SEL of these segments at T4 were significantly increased in comparison to those at T0 and T2 during the RF, IVC, and RE periods (P<0.001). Further, both the AEL and SEL at T0, T2, and T4 demonstrated a consistent decreasing gradient from the base of the LV to the apex (Figures 3,4).

Figure 3 Left ventricular regional (base, mid, and apex) AEL in the control and HER2⁺ BC groups (J/s·m³). ^※, P<0.05, compared with T0; *, P<0.05, compared with T2. AC, atrial contraction; AEL, average energy loss; HER2⁺ BC, human epidermal growth factor receptor 2-positive breast cancer; IVC, isovolumetric contraction; RE, rapid ejection; RF, rapid filling; T0, before treatment initiation; T2, after the second cycle of treatment; T4, after the fourth cycle of treatment.

Figure 4 Left ventricular regional (base, mid, and apex) SEL in the control and HER2⁺ BC groups [J/(s·m)]. ^※, P<0.05, compared with T0; *, P<0.05, compared with T2. AC, atrial contraction; HER2⁺ BC, human epidermal growth factor receptor 2-positive breast cancer; IVC, isovolumetric contraction; RE, rapid ejection; RF, rapid filling; SEL, summation of energy loss; T0, before treatment initiation; T2, after the second cycle of treatment; T4, after the fourth cycle of treatment.

ROC curve analysis

A ROC curve analysis was conducted to evaluate the predictive capability of the global MW parameters, as well as the global AEL, for subclinical left ventricular myocardial dysfunction in the HER2⁺ BC patients; all the values are summarized in Table 7 and Figure 5. Based on the ROC curve analysis, after the second cycle of treatment, the GWI had an AUC of 0.7547, a cut-off value of 1,961 mmHg%, a sensitivity of 0.6000, and a specificity of 0.8364, showing the maximum AUC at T2, and the best sensitivity and specificity at T2. No significant differences in the AUC values were observed among the GWW, GWE, and GLS (P>0.05). The AEL-AC had an AUC of 0.7405, a cut-off value of 16.12 J/(s·m³), a sensitivity of 0.4727, and a specificity of 0.9636. Of the four time-phase EL parameters at T2, AEL-AC had the largest AUC. No significant differences in the AUC values were observed among AEL-RF, AEL-IVC, and AEL-RE (P>0.05). After the fourth cycle of treatment, the GWI had an AUC of 0.8645, a cut-off value of 1,889 mmHg%, a sensitivity of 0.6727, and a specificity of 0.9273. The GWI had the largest AUC at T4. No significant differences in the AUC values were observed among GWW, GWE, and GLS (P>0.05). The AEL-AC had an AUC of 0.8605, a cut-off value of 15.41 J/(s·m³), a sensitivity of 0.6909, and a specificity of 0.9455. The AEL-AC had the largest AUC at T2 among AEL-AC, AEL-RF, AEL-IVC, and AEL-RE. No significant differences in the AUC values were observed among AEL-RF, AEL-IVC, and AEL-RE (P>0.05) (Table 7 and Figure 5).

Figure 5 ROC curve analysis for myocardial work and energy loss parameters in HER2⁺ BC patients (A) after the second cycle of treatment, and (B) after the fourth cycle of treatment. AC, atrial contraction; AEL, average energy loss; AUC, area under curve; GCW, global constructive work; GLS, global longitudinal strain; GWE, global work efficiency; GWI, global work index; GWW, global waste work; HER2⁺ BC patients, human epidermal growth factor receptor 2-positive breast cancer patients; IVC, isovolumetric contraction; MW, myocardial work; RE, rapid ejection; RF, rapid filling; ROC, receiver operating characteristic; T2, after the second cycle of treatment; T4, after the fourth cycle of treatment.

Reproducibility and repeatability

The intraclass correlation coefficient (ICC) values for the intra- and inter-observer repeatability assessments of MW and EL were above 0.8, suggesting the MW and EL exhibited excellent reliability and repeatability (Table 8).

Discussion

BC is one of the most lethal malignancies affecting women, representing a significant threat to women’s health and lives (27). The combination of anthracycline drugs and targeted therapies serves as the first-line treatment for HER2⁺ BC, effectively suppressing tumor growth and metastasis while improving patient prognosis. However, cardiotoxicity-induced CTRCD has emerged as a critical factor contributing to mortality in HER2⁺ BC patients post-treatment (8). Thus, the timely monitoring of early cardiac injury is critical for improving patient prognosis.

LVEF exhibits a delayed response to myocardial toxic injury and may not adequately represent normal cardiac function during the early stages of treatment. GLS is influenced by cardiac loading conditions, which are more variable in tumor patients than healthy individuals. Moreover, GLS is associated with several technical limitations in clinical practice; for example, the measurement outcomes may vary due to differences among imaging platforms and vendors. GLS analysis also requires high frame rates and is highly susceptible to motion artifacts. Further, GLS assessment may not be feasible in certain patient populations, particularly those with anterior chest wall deformities or pectus excavatum. In patients with arrhythmias or suboptimal electrocardiographic signal quality, the accurate determination of end systole may be challenging, further limiting the reliability of GLS measurements (28-30). Consequently, GLS may not accurately reflect true myocardial contractility. Currently, there is a paucity of sensitive and reliable indicators for monitoring subclinical cardiac impairment in clinical practice.

Anthracycline-based chemotherapy drugs and monoclonal antibody-targeted therapies promote the generation of reactive oxygen species (ROS), and suppress the expression of antioxidant enzymes in cardiomyocytes, leading to the ineffective clearance of ROS and superoxides in myocardial tissue, and subsequently inducing severe oxidative stress-mediated mitochondrial dysfunction in cardiomyocytes (31). Mitochondria serve as the energy-producing organelles in cells. Thus, myocardial injury induced by combination therapy is closely associated with myocardial oxygen consumption and metabolic activity. ¹⁸F-fluorodeoxy-glucose positron emission tomography has shown that the PSL area accurately indicates the MW, myocardial oxygen consumption, and energy metabolism (11). Thus, the LVMW parameter provides a more direct and precise reflection of myocardial injury following chemotherapy for BC.

The MW parameters include: (I) the GWI, which was defined as the total field surrounded by PSL, representing the cumulative work performed by the LV from mitral valve closing to opening in one cardiac cycle; (II) GCW, which indicates the positive contribution to ejection, specifically during systolic myocardial shortening and isovolumic relaxation; (III) GWW, which represents the work detrimental to ventricular ejection that occurs during systolic myocardial elongation and isovolumic contraction; and (IV) GWE, which is calculated as a ratio, expressed as GWE = GCW/(GCW + GWW) ×100%. The segmental parameters are derived based on a 17-segment left ventricular model, and include each MW parameter for each segment.

The LVEF values of the HER2⁺ BC patients at T0, T2, and T4 were similar, and did not exhibit a significant decrease. This is consistent with the results reported by Thavendiranathan et al., who observed no substantial decrease in LVFE during the early phase of chemotherapy in their cohort (32). These observations suggest that the LVFE remains within normal limits during the initial stages of adjuvant therapy and that any decline progresses gradually. However, LVEF demonstrates limited sensitivity to early subclinical cardiac damage. By the time a reduction in LVEF is detected using conventional methods following combination therapy, the optimal window for early clinical intervention may have been missed, thereby limiting its utility in assessing early cardiac toxicity (32). This may be attributed to the heart’s robust compensatory capacity, as well as the intrinsic limitations of the LVEF measurement, including its reliance on geometric assumptions, load dependence, and inherent measurement variability (12). Patients with ventricular aneurysm exhibit localized bulging of the LV, while those with dilated cardiomyopathy often demonstrate non-ellipsoidal left ventricular geometry. Additionally, conditions such as left ventricular cavity stenosis and congenital left ventricular hypoplasia involve morphological variations that exceed the assumptions of standard volumetric models. Further, acoustic shadowing caused by ventricular assist device implants and structural alterations following cardiac surgery can interfere with accurate volume calculations. These factors collectively contribute to potential inaccuracies or even erroneous measurements when employing Simpson’s two-plane method for LVEF assessment. In our study, despite the LVEF being similar before and after treatment and falling within the regular range, significant difference were observed in terms of the GLS, GWI, GCW, GWW, and GWE. These findings suggest that the MW parameters exhibit greater sensitivity to early myocardial injury during combined therapy compared to LVEF.

We observed that the GWI at T2 and T4 was significantly lower than at T0, exhibiting a downward trend as the number of chemotherapy cycles increased. Additionally, GLS, GCW, and GWE decreased significantly at T4, while GWW increased during the same period. These findings indicate that left ventricular function in HER2⁺ BC patients is compromised following treatment, with the severity of impairment worsening progressively as chemotherapy progresses. Our results support those of Tang Sha et al. (33). Monoclonal antibody drugs and anthracycline drugs induce the production of superoxide anions and a significant amount of ROS, leading to sustained oxidative stress–induced damage to myocardial cells. This results in severe mitochondrial dysfunction and abnormal energy metabolism during myocardial contraction. Consequently, the GWI, which quantifies the PSL area and serves as an indicator of myocardial metabolic oxygen demand, exhibits a significant reduction at T2 (11). Further, anthracyclines exhibit a high affinity for cardiolipin located on the inner mitochondrial membrane (34), leading to their accumulation in myocardial cells and clearance difficulty. This characteristic results in a dose-dependent cumulative effect. Consequently, the GWI at T2 and T4 demonstrates a decreasing trend with the progression of treatment cycles. Cardiotoxicity is significantly potentiated when anthracycline drugs are co-administered with molecular-targeted agents (35). Moreover, upon the patient’s first exposure to the combined treatment regimen, the myocardium exhibits increased vulnerability to the toxic effects of anthracycline-induced myocardial protein damage and monoclonal antibody-mediated myocardial fibrosis via antigen cross-reactivity. This leads to an impaired myocardial deformation capacity and the early-onset dysfunction of myocardial performance. Consequently, GLS, GCW, and GWE show significant decreases at T4, while GWW shows an increase at T4.

Previous studies have shown that GLS is a reliable indicator of systolic function (36-38); however, its application may be limited by the significant disruption of vascular endothelial endocrine function by anthracyclines. This disruption reduces the secretion of nitric oxide by vascular endothelial cells, decreases nitric oxide levels in cardiac vasculature (39,40), increases vascular stiffness (41), alters peripheral vascular wall tension, and induces vascular wall remodeling, thereby affecting both the preload and afterload of the heart. As GLS is load-dependent, it cannot be used to determine whether abnormal GLS values result from reduced intrinsic myocardial contractility or increased left ventricular afterload. Emerging evidence suggests (42) that GLS does not exhibit significant changes during pregnancy. This may be due to the concurrent alterations in both preload and afterload during gestation, as well as the inherent load-dependent characteristics of GLS. Boe et al. (43) observed that in patients with coronary artery disease, an increase in afterload is associated with a further reduction in GLS in ischemic regions. These findings highlight the load-dependent nature of GLS and underscore its limitations in accurately assessing myocardial function in clinical scenarios involving dynamic changes in preload and afterload. Consequently, this may contribute to the misinterpretation of the true LVEF, rendering GLS less reliable in the early detection of cardiac functional changes (44).

The ROC curve analysis conducted in this study to assess the diagnostic performance of each parameter further corroborated these findings. Among the MW parameters, the GWI had the highest sensitivity and specificity, as well as the highest diagnostic accuracy. The AUC of the GWI progressively increased from the second to the fourth treatment cycle, with corresponding cut-off values of 1,961 mmHg% and 1,889 mmHg%. These values may serve as preliminary reference thresholds for identifying subclinical left ventricular dysfunction in HER2⁺ BC patients undergoing combined therapy at T2 and T4. A GWI exceeding 1,961 mmHg% at T2 and 1,889 mmHg% at T4, respectively, suggests the early impairment of left ventricular function in HER2⁺ BC patients. In such cases, further evaluation should be conducted using complementary diagnostic modalities, including ECG, myocardial enzyme panel, and pro-brain natriuretic peptide (proBNP) levels, to assess both objective cardiac changes and clinical symptom progression. If cardiotoxicity is confirmed, the treatment regimen should be promptly modified in accordance with current BC management guidelines. This may include transitioning to agents with lower cardiotoxic potential, reducing the drug dosage, or discontinuing therapy altogether, while initiating cardioprotective interventions. When appropriate, consultation with a cardiology specialist is recommended to prevent progression of myocardial injury and the potential development of heart failure. Conversely, if follow-up assessments including serial cardiac monitoring and comprehensive clinical evaluation confirm the absence of cardiotoxicity, continuation of the current therapeutic regimen may be considered, provided that cardiac function remains under regular surveillance and preventive cardioprotective measures are maintained. The intra- and inter-observer repeatability assessments of MW and EL demonstrated favorable outcomes, indicating high reliability and reproducibility for both methods; however, given the single-center design and limited sample size of this study, these findings should be considered exploratory and may not be generalizable to other patient populations or clinical settings.

We performed a comparative analysis of the MWI across 17 segments of the LV, and observed that the MWI exhibited a gradient distribution from the apex to the base in both the controls and BC patients; specifically, the MWI increased progressively from the base to the apex (27). This is consistent with the results reported by Galli et al. (45). In terms of the underlying mechanism, according to Laplace’s law, peak systolic wall stress is proportional to the radius of curvature of the ventricular wall. A larger radius of curvature corresponds to higher wall stress, which inhibits myocardial fiber shortening during contraction (46). Thus, progressing from the base to the apex of the LV, the radius of curvature of the ventricular cavity gradually decreases, leading to a reduction in ventricular wall stress. During systole, the extent of myocardial fiber shortening increases, which corresponds to an increase in strain. Consequently, the MWI, which is derived by integrating strain with left ventricular pressure, also increases progressively.

We also noted that the MWI of all 13 segments of the left ventricular myocardium exhibited a significant reduction starting at T2, and showed a marked downward trend as the treatment cycle progressed. Nevertheless, the overall gradient from the base to the apex remained consistent. These findings indicate that myocardial function is diffusely compromised in HER2⁺ BC patients undergoing combination therapy. The characteristic of a widespread decrease in the MWI across multiple segments aids in differentiating this condition from the segmental decline in MW observed in ischemic cardiomyopathy and left bundle branch block (11,47-50).

In addition to the MW parameters for assessing ventricular wall mechanics, the hemodynamic state within the cardiac cavity is also intricately linked to overall cardiac function. The interaction between intracavitary blood flow and peripheral myocardial tissue structures contributes to the development of its inherent adaptive capacity. Previous research has shown that left ventricular remodeling is related to a reduction of blood flow kinetic energy (51). The analysis of intraventricular hemodynamics of patients with acute myocardial infarction using PIV technology demonstrated that patients in ST-segment elevation myocardial infarction exhibited significantly higher EL compared to those with natural left ventricular wall segment motion (52).

Anthracycline and monoclonal antibody antitumor drugs induce myocardial cell injury, apoptosis, fibrosis, compensatory collagen fiber proliferation, and collagen deposition in the extracellular matrix (53,54). These pathological changes result in ventricular wall stiffness, reduced myocardial compliance, impaired myocardial deformation capacity, restricted ventricular filling and atrial emptying, elevated pressure within the LV and left atrium (LA), and a lack of coordination between intracardiac blood flow dynamics and myocardial motion. High-speed, directionally disordered turbulent flow begins to emerge, disrupting the previously stable intracardiac blood flow field. The continuous interaction between disordered blood flow and wall shear stress inevitably leads to increased energy dissipation in the cardiac chambers (55). In this study, the AEL-AC and SEL-AC of the HER2⁺ BC patients exhibited significant increases at T2, which were even more pronounced at T4. Additionally, AEL-RF, SEL-RF, AEL-IVC, SEL-IVC, AEL-RE, and SEL-RE demonstrated significant increases at T4. At this time point, the strain and MW parameters derived from the PSL showed significant reductions, but no significant differences were observed in the traditional systolic and diastolic function parameters. This is likely due to the patients compensating by increasing their EL to maintain relatively normal pump function and suction efficiency. These findings indicate that EL parameters, particularly AEL-AC and SEL-AC, exhibit earlier and more significant changes.

Some studies have indicated that alterations in the structural configuration and operational parameters in the LA may serve as early indexes of cardiac damage (56,57). The LA has three primary functions: (I) a reservoir function, wherein it stores blood flowing back from the pulmonary veins; (II) a conduit function, wherein it channels pulmonary venous blood into the LV during diastole; and (III) a booster pump function, wherein active contraction during atrial systole propels residual atrial blood into the LV, thereby enhancing ventricular filling (58). When anthracyclines and monoclonal targeted drugs are administered in combination therapy, they induce myocardial cell damage, leading to ventricular wall stiffness, left ventricular diastolic dysfunction, and reduced passive emptying of the LA. Consequently, the left atrial volume increases, enhancing its reservoir function. According to the Frank-Starling mechanism (59), to augment the booster pump function, left atrial contractility is increased. The physiological vortices present during diastole not only maintain a certain level of kinetic energy for blood flow in the cardiac cavity but also facilitate fluid transformation, reduce fluid collisions, and prevent excessive energy dissipation, representing an energy-conserving mechanism of the heart. This helps avoid turbulence and ensures that EL remains within normal limits. However, under these conditions, left atrial contractility increases, causing intracardiac vortex fluctuations. The rapid changes in vortices and interactions between multiple small vortices lead to turbulence formation, increasing viscous frictional heat generation between blood components and resulting in greater EL. Therefore, AEL-AC and SEL-AC exhibit significant increases and demonstrate earlier changes compared to other phases of AEL and SEL.

This study conducted a ROC curve analysis to evaluate the diagnostic performance of each parameter, thereby providing further validation of the aforementioned conclusions. Among the various strain-derived parameters, AEL-AC showed the highest sensitivity and specificity, as well as the highest diagnostic accuracy. Notably, the AUC of AEL-AC progressively increased from the second to the fourth treatment cycle, with corresponding cut-off values of 16.12 and 15.41 J/(s·m³). These values may serve as preliminary reference thresholds for identifying subclinical left ventricular dysfunction in HER2⁺ BC patients undergoing combined therapy at T2 and T4; AEL-AC values exceeding 16.12 J/(s·m³) at T2 and 15.41 J/(s·m³) at T4, respectively, suggest early impairment of left ventricular function in HER2⁺ BC patients at these time points. The intra- and inter-observer repeatability assessments of MW and EL yielded favorable results, indicating the high reliability and reproducibility of both methods; however, given the single-center design and relatively small sample size of this study, these findings should be interpreted as preliminary and may not be generalizable across broader clinical settings.

EL at different time phases and segments is associated with the left ventricular peak torsion angle, diastolic untwisting velocity and area, respectively, as well as other factors (51,60). Consequently, the distribution of EL within the ventricle follows a specific pattern. In the normal population, AEL and SEL progressively decrease from the base to the apex. In this study, during the same treatment period, the AEL and SEL of the basal segment were significantly higher than those of the middle and apical segments, a finding that is consistent with previous research results (61). We further observed that the AEL-AC and SEL-AC in the apical segment exhibited significant increases at both T2 and T4, with the magnitude of increase being the greatest among the three regions: the basal, middle, and apical segments. This phenomenon corresponds to the reduced ventricular wall strain capacity, diastolic dysfunction, and diminished normal left ventricular suction function observed in HER⁺ BC patients following the combined treatment. Left ventricular filling transitions from being predominantly driven by left ventricular suction to being primarily AC-driven. During this process, the LA contracts forcefully, causing the mitral valve to open widely and resulting in increased and accelerated blood flow into the LV. The high-speed blood flow originating from the basal segment rapidly impacts the apical segment, disrupting the relatively stable fluid dynamics previously present in this region. The abrupt changes in blood flow velocity and direction hinder efficient fluid transformation at the apex and lead to increased fluid collisions. The collision of high-speed blood flows from different directions generates disordered turbulence, which intensifies viscous friction and produces a substantial amount of heat energy in this location. Consequently, the AEL-AC and SEL-AC in the apical region exhibit significant increases.

The observation of the aforementioned phenomenon in this study suggests that the MW and blood flow efficiency in HER2⁺ BC patients are already compromised during the early phase of combination therapy. Further research into MW and EL may offer valuable insights for evaluating left ventricular function in HER2⁺ BC patients following combination therapy.

Study limitations

First, this was a single-center study with a comparatively short follow-up period. The relatively small sample size of the study might have compromised the statistical power and introduced biases into the results. Consequently, the findings should be considered preliminary. Future studies with larger cohorts need to be conducted to validate the changes in MW and EL in HER2⁺ BC patients following combination therapy. Second, this study assessed the changes and underlying causes of MW and EL in HER2⁺ BC patients before combined treatment, after the second cycle of treatment, and after the fourth cycle of treatment. However, given the ongoing absence of long-term cardiac function data and comprehensive patient clinical endpoints measures, we intend to implement a longitudinal follow-up study as part of our future research initiatives, incorporating long-term patient follow-up data and patient disease outcomes, to further investigate the clinical significance of MW and EL alterations in HER2⁺ BC patients. This will help determine whether these parameters influence patient prognosis or elevate the incidence of heart failure. Third, the flow direction of blood within the left ventricular cavity is not pre-defined and remains unconstrained. Thus, hemodynamic research techniques should ideally be based on a three-dimensional spatial stereoscopic design. However, VFM relies on software analysis derived from 2D color Doppler and speckle tracking, which restricted our study to a single plane and cannot accurately represent the true characteristics of the three-dimensional flow field. Further, the PSL technique employs brachial artery BP as a proxy of the left ventricular pressure measured via cardiac catheterization, and uses strain as an approximation of changes in left ventricular volume, which might have introduced a degree of measurement error.

Conclusions

Following combination treatment, the GWI, GCW, GLS and GWE of the HER2⁺ BC patients were significantly decreased, while the GWW was increased; however, LVEF remained within the normal range. The MWI of all 17 left ventricular segments showed a significant decrease, indicating diffuse myocardial injury in the LV. To further investigate the reduction in the MWI from the perspective of intracavitary hemodynamics, we employed VFM and observed that EL increased during four phases: RF, AC, IVC, and RE. Among these, the earliest and most significant change was observed during AC, as the LA underwent excessive contraction to maintain relatively normal diastolic function. Thus, PSL and EL can be used to effectively evaluate the diastolic and systolic myocardial mechanics and hemodynamic function of HER2⁺ BC patients receiving combination therapy. Additionally, among all the MW and EL parameters, the GWI and AEL-AC showed superior early diagnostic performance.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://qims.amegroups.com/article/view/10.21037/qims-2025-1138/rc

Data Sharing Statement: Available at https://qims.amegroups.com/article/view/10.21037/qims-2025-1138/dss

Funding: This study was supported by Science and Technology Program of XPCC (Nos. 2022ZD030, 2023ZD013); National Natural Science Foundation of China (No. 82160338); Shihezi University Independently on University Level Scientific Research Projects (Nos. ZZZC202196, ZZZC2022091, and ZZZC2023056); The Third Batch of the “2+5” Key Talent Program “Tianshan Elite” High-Level Medical and Health Talent Development Project (No. TSYC202401B196).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-2025-1138/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. This study has been approved by the Ethics Committee of the First Affiliated Hospital of Shihezi University (No. KJ2024-263-01), and all subjects signed an informed consent form prior to their involvement.

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/.

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