There are different types of chemotherapy and radiotherapy agents, and some of them are considered more cardiotoxic than others (Figure S1) [8].

Among them are anthracyclines, such as doxorubicin and epirubicin, which are used in the treatment of different types of cancer, including breast cancer, lymphoma, and leukemia [9]. These chemotherapeutic agents can cause both acute and chronic cardiotoxicity, including congestive heart failure and cardiac arrhythmias.

Another chemotherapy regimen associated with cardiotoxicity is tyrosine kinase inhibitors, such as Ibrutinib, which is available orally for the treatment of chronic lymphocytic leukemia, lymphoma, and Waldenstrom’s macroglobulinemia [10].

Monoclonal antibodies like trastuzumab, used in the treatment of HER2-positive breast cancer, also carry the risk of left ventriculfar dysfunction, which may be reversible or irreversible [11].

Transthoracic echocardiography is a non-invasive technique that can be performed at all stages of cancer to evaluate and detect coronary, myocardial, valvular, and pericardial disease, as well as complications secondary to therapy (chemotherapy/radiotherapy). Transthoracic echocardiography remains the first-line imaging modality in evaluation, diagnosis, and surveillance [12, 13].

Currently, validated methods for detecting cardiotoxicity include measurement of left ventricular ejection fraction (LVEF) and global longitudinal strain (GLS). Regarding LVEF, a reduction > 10% (10 absolute percentage points) from the baseline evaluation or an LVEF < 50% is considered significant, or a reduction > 15% with an LVEF > 50%. The European Society of Cardiovascular Imaging defines cardiotoxicity as a reduction of more than 10 absolute percentage points to a value less than 50% At the same time, degrees of cardiotoxicity have also been established (Table S1).

An LVEF between 50–54% is considered borderline and requires further investigation before labeling a patient with normal or abnormal systolic function [14–16].

There are different tools to evaluate cardiotoxicity which can help us with the limitations of performing only LVEF [17] (variability inter an intra-observer, geometric assumptions, lack of capability to show early systolic dysfunction), which includes advanced echocardiography techniques [three dimensional reconstruction (3D), two dimensional images (2D) Strain and Myocardial Work], Multigated Acquisition Scan (MUGA) and magnetic resonance imaging (MRI) are available. All these methods help assess the presence of cardiotoxicity (Figure 2).

If the possibility of evaluating LVEF by 3D reconstruction is available, it has better reproducibility than the conventional 2D method in patients undergoing cancer treatment [18]. It is recommended to use the same technique in patient follow-up.

The introduction of software in echocardiography machines capable of acquiring deformation of cardiac fibers (longitudinal) through speckle tracking (acoustic markers in the myocardium) can detect subclinical dysfunction.

A reduction > 15% from the baseline value establishes the diagnosis of cardiotoxicity, or a strain of –16% without prior evaluation. Its better reproducibility compared to 2D LVEF has been demonstrated [19–21].

The major limitation of GLS is that values are highly influenced by loading conditions. Patients receiving cancer treatment may experience alterations in blood pressure, vomiting, and diarrhea secondary to chemotherapy, hence the suggestion of using new parameters that can detect myocardial dysfunction early and do not have these limitations [22–24].

The non-invasive evaluation of strain curves and blood pressure correlates with myocardial oxygen consumption and metabolism. Global myocardial work index (GWI) combines strain deformation with hemodynamics (non-invasive left ventricular systolic pressure: systemic arterial pressure) [25]. Since 2012, the correlation of invasive and non-invasive pressure-strain curves has been demonstrated.

GWI represents the work performed by the myocardium from the closure of the mitral valve to the opening of the mitral valve, reflecting the metabolism and oxygen consumption of the left ventricle. Its advantage lies in the correction of afterload [26–29].

The parameters that have been established as normal for myocardial work are mentioned below in (Table S2).

This study aims to evaluate the role of myocardial work by echocardiography and determine its utility as an early diagnosis of cardiotoxicity.

Prior to the study, the patient’s blood pressure was measured following international standards for proper blood pressure recording. An E95 device from General Electric with a sectorial 5S transducer was used for echocardiographic measurements, adhering to the practice guidelines of the American Society of Echocardiography.

For performing myocardial work 2D images of apical 4-chamber, 3-chamber, and 2-chamber views were obtained with a depth of around 15 cm to frame the left ventricle, observe the mitral annulus, and approximately one centimeter of the left atrium. These images were acquired with a frame rate of at least 85% of the patient’s heart rate at the time of the study and/or between 40 frame rates and 90 frame rates per second. Aortic valve opening and closing were obtained by marking the reference points on pulsed Doppler of the left ventricular outflow tract. Mitral valve opening and closing were obtained by marking with pulsed Doppler in an apical 4-chamber view at the tips of the mitral valve leaflets, marking the opening at the onset of the Doppler flow of the E-wave and the closing at the end of the Doppler flow of the A-wave. After obtaining the images, myocardial longitudinal deformation was processed using automated functional imaging (AFI) software on the equipment. Each view was labeled, and the region of interest (ROI) was adjusted to involve the entire myocardium, 1 mm above the mitral annulus, and not involve the epicardium. This provided the values of GLS. Subsequently, systolic blood pressure was input to analyze, the myocardial work index, and its derivatives.

Through advanced deformation analysis via transthoracic echocardiography, the following parameters are obtained:

1)

Global myocardial work: This is the amount of energy the myocardium needs to contract and relax (mmHg%).

For this work, we defined cardiotoxicity as follows: a GLS value < 16% (absolute values) and or LVEF < 50%.

Qualitative variables were described in percentages and proportions, while the distribution of quantitative variables was explored using histograms and Kolmogorov-Smirnov test. Those with a normal distribution were reported as means with their respective standard deviations, and those not following a normal distribution were reported as medians with interquartile ranges.

For assessing statistical differences between categorical variables, we performed the χ² test, and for quantitative variables, we made student T test.

Inferential statistics were performed using ROC curves to determine the cutoff point of myocardial work that best identifies the presence of cardiotoxicity. Additionally, other parameters derived from the analysis of myocardial work index were evaluated, such as constructive work, wasted work, and myocardial efficiency. For each value in the ROC curves, 2 × 2 tables were generated to calculate sensitivity, specificity, as well as positive and negative predictive values for identifying the presence of cardiotoxicity. Data analysis was performed using SPSS version 29 software.

Myocardial work indexes are only available on General Electric echo machines, which not all healthcare services have access to. Other limitation in our study is that we used as a golden standard for the diagnostic test echocardiograms parameters that can be less accurate than myocardial work, instead of ventricular ejection fraction through magnetic resonance. That’s because we don’t have the MRI available for every patient.

- GWI having good specificity and negative predictive value, serves as a tool for early diagnosis of cardiotoxicity in individuals receiving chemotherapy.

- Similarly, GCW and GWE are parameters that support the GWI as confirmatory tests for cardiotoxicity due to their good specificity, diagnostic accuracy, and negative predictive value.

- We propose the measurement of myocardial work as an echocardiographic tool for the early diagnosis of cardiotoxicity (without waiting for a decrease in LVEF) and without being a marker that may be influenced by loading conditions, in patients undergoing antineoplastic treatment.