Cardiotoxicity surveillance via myocardial work among cancer patients treated with immunotherapy

Cardiotoxicity surveillance via myocardial work among cancer patients treated with immunotherapy | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Cardiotoxicity surveillance via myocardial work among cancer patients treated with immunotherapy Juliana Goes Martins Fagundes, Matheus Coelho Torres, Thiago Lins Fagundes Sousa, and 12 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6406754/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment; however, the risk of cardiotoxicity has increased due to inadequate data for improving management and prevention strategies. Methods In this single-centre, prospective observational study, ICI-treated patients underwent biomarker assessments and echocardiography to measure global longitudinal strain (GLS) and myocardial work (MW) at baseline, 2 months, and every 3 months for one year or until treatment was discontinued. Cardiotoxicity was defined as a ≥ 10% reduction in left ventricular ejection fraction (LVEF) to < 50%, troponin elevation of ≥ 0.30 ng/ml, or ≥ 15% relative reduction in GLS. Results Among 63 patients, 39 (62%) completed at least two evaluations (56% male, 61% smokers, and 54% lung cancer patients). The overall incidence of cancer therapy-related cardiac dysfunction (CTRCD) was 26%, with half of these patients experiencing a ≥ 10% reduction in LVEF. The CTRCD group presented a lower baseline LVEF (67% vs. 62%, p = 0.014). Concurrent chemotherapy and higher baseline coronary calcium scores were not linked to CTRCD risk, and no CTRCD cases were noted in patients on beta-blockers. Additionally, significant reductions in MW parameters were observed in the CTRCD group at 2 months. Conclusions Our findings highlight an unexpectedly high incidence of noninflammatory left ventricular dysfunction when sensitive measurement tools are used. These findings underscore the need for further studies to validate MW as a tool for cardiological surveillance and early diagnosis of CTRCD in patients receiving ICIs. Cancer Cardiotoxicity Immune checkpoint inhibitors Figures Figure 1 Figure 2 Figure 3 Background Cardiovascular diseases and cancer are the leading causes of death worldwide and share common risk factors. Growing evidence suggests that cancer survivors have a greater risk of developing cardiovascular diseases and that patients with cardiovascular diseases are more likely to develop cancer [ 1 , 2 ]. Given this interplay between cancer and cardiovascular diseases, it is crucial to understand the impact of cancer therapies on the cardiovascular health of cancer survivors. Currently, immune checkpoint inhibitors (ICIs) are an essential component of the systemic treatment of several types of cancer. ICIs are generally well tolerated; however, immune-related adverse events of any grade (irAEs) appear in 54–95% of all patients, and grade ≥ 3 irAEs appear in up to 24% of these individuals [ 3 , 4 ]. Cardiotoxicity has different clinical presentations, and the incidence varies; the incidence ranges from 0.3–1% for myocarditis, and it is 0.9% for heart failure and up to 1% for arrhythmias. It is associated with high mortality rates, which reach 50% in patients with myocarditis [ 5 ]. A meta-analysis published in 2022 revealed that the overall incidence of cardiovascular adverse events reached 8.32%, with 4.28% of cases categorized as grade 5 [ 5 ]. The suggested pathophysiology for the occurrence of cardiotoxicity after ICI therapy involves the development of immune cross-reactivity between cardiac and tumour cells, the formation of autoantibodies, high production of inflammatory cytokines, loss of self-immune tolerance, and accelerated atherosclerosis [ 6 ]. Current guidelines for managing irAEs recommend performing an electrocardiogram and collecting troponin and brain natriuretic peptide before the initiation of ICI treatment. The timing and frequency of cardiovascular monitoring should be based on the patient's risk factors and the therapeutic protocol; however, the criteria for cardiotoxicity or cancer therapy-related cardiac dysfunction (CTRCD) screening are not clear [ 4 , 7 , 8 ]. Global longitudinal strain (GLS) is a tool that offers high sensitivity (frequently greater than 90%) for detecting early myocardial dysfunction and has been shown to be useful for guiding cardioprotective therapies in randomized trials. However, GLS results are influenced by blood pressure, and patients with cancer usually experience weight loss associated with cachexia or treatment-related adverse events, which are reflected in blood pressure fluctuations during the course of the disease, which may impact ventricular and GLS test performance [ 9 – 11 ]. The myocardial work (MW) tool, which was derived from longitudinal strain analysis, incorporates blood pressure into the model and has the advantages of being less influenced by load fluctuations and analysing all cardiac cycles, consequently generating more reliable data [ 12 – 14 ]. Indeed, MW was able to rule out myocardial dysfunction in the presence of GLS alterations in a cohort of patients treated with anthracyclines [ 15 ]. Here, we aimed to perform prospective cardiovascular monitoring in patients receiving ICIs to estimate the incidence of clinical and subclinical changes via the use of myocardial deformation and MW tools. Methods Study design and patients This prospective, single-center, observational cohort study included patients who were eligible for treatment with ICIs (anti-CTLA4, anti-PD1, and/or anti-PDL1 inhibitors) as monotherapy or in combination strategies (chemotherapy and antiangiogenic) in (neo)adjuvant or palliative settings, regardless of tumour histology, from January 2020 to April 2022. Patients who were pregnant, whose ultrasound window was inadequate, or who had previous decompensated heart disease were excluded. Patients were referred for a cardiological evaluation before the initiation of ICI therapy, after 2 months of ICI therapy, and every 3 months thereafter until the end of their participation in the protocol, with such termination expected to occur after one year of follow-up or in cases of treatment discontinuation owing to toxicity or disease progression and/or death. Ethics approval and consent to participate The study design and implementation followed all applicable regulations concerning the involvement of human study participants and were carried out in adherence to the criteria established by the Declaration of Helsinki and Brazilian law. All patients provided signed informed consent forms. This study was approved by the Ethics Committee of Lauro Wanderley University Hospital of the Federal University of Paraíba under the number CAAE 16621419.6.0000.5183. Cardiovascular procedures Patients were initially asked about comorbidities, medication use, and lifestyle habits. When staging exams (e.g., computed tomography or 18 FDG positron emission tomography) were available, we used the ordinal scale of the calcium score, measured through high-resolution chest computed tomography, with division of the coronary territory into 4 vessels (the left main coronary artery, left anterior descending artery, circumflex artery, and right coronary artery). Each coronary segment received a score from 0 to 3 according to the extent of calcification in the length of the vessel in the axial plane: absent, 2/3. The final score was defined as the sum of the 4 vessels (0 to 12) and was divided into 3 severity categories, 0, 1-3, and 4-12, which classified the patients in relation to the extent of coronary disease [16]. Patients underwent two-dimensional transthoracic echocardiography in the left lateral decubitus position by a dedicated echocardiography examiner at each/every predefined timepoint. Morphometric, Doppler , and myocardial function measurements were performed according to the “Recommendations for Cardiac Chamber Quantification by Echocardiography in Adults” [11]. Delta GLS was calculated via data from the subsequent echocardiography in comparison with the pretreatment exam. Myocardial strain and MW were calculated noninvasively, with the final generation of data regarding the global myocardial work index (GWI), constructive myocardial work (GWC), wasted myocardial work (GWW), and myocardial work efficiency (GWE). Myocardial strain, which assesses the ability of the heart to contract, is useful for evaluating cardiac function more sensitively than other measures, such as the ejection fraction [17]. GCW quantifies the total work done by the heart throughout the cardiac cycle, considering both the pressure generated by the heart and the volume of blood ejected. GCW is often assessed via pressure‒volume loops generated during transthoracic echocardiography. GWE is a measurement that reflects the efficiency of the contractile function of the heart. It is calculated on the basis of global cardiac work relative to energy expenditure or the total work performed by the heart during the cardiac cycle. Higher values suggest better efficiency. The GWI is a calculated index that combines parameters related to the area under the pressure‒volume curve, which reflects the cardiac workload during systole. The GWI serves as an indicator of the overall performance of the heart. GWW quantifies the amount of energy that is wasted during the cardiac cycle, primarily during periods of isovolumetric contraction and relaxation when the heart generates pressure without effectively ejecting blood. Lower values indicate better cardiac efficiency. Similarly, prospective collection of blood samples enabled the evaluation of clinical biomarkers such as brain natriuretic peptide and troponin I, which were analysed via an immunometric assay via the Lumina Teck Micropoint system from Lumina Teck, São Paulo, Brazil. The values were considered positive when the troponin level was ≥ 0.30 ng/ml and the brain natriuretic peptide level was ≥ 100 pg/ml, according to the normal reference values of the methodology used [17]. At each cycle, noninvasive blood pressure measurements, peripheral pulse measurements, and symptoms were assessed during clinical visits. CTRCD was defined either as a reduction ≥10% in the left ventricular ejection fraction (LVEF) for a final value below 50% troponin elevation ≥0.30 ng/ml or a relative reduction in GLS ≥15%. If either brain natriuretic peptide or troponin were positive, CTRCD was defined by transthoracic echocardiography, or if new cardiovascular symptoms were present, the patient was referred for evaluation by a cardiologist [17]. Case management was not standardized to include an evaluation with a cardio-oncologist, but the patient could choose to be evaluated by their cardiologist if they were already under the cardiologist’s care. Statistical analysis The data are presented herein as the means ± standard deviations, medians with lower and upper quartiles (95% confidence intervals), and categorical variables as frequencies and percentages. For continuous variables, one sample Shapiro‒Wilk test was used to assess the normal distribution of all variables. Independent Student’s t tests and Mann–Whitney U tests were used for parametric and nonparametric variables, respectively. The chi-square test was used for categorical variables. One-way analysis of variance or the Kruskal–Wallis test was used to test differences in continuous variables between time points (0, 2, 5 and 11 months). Data analyses were performed via the Statistical Package for the Social Sciences Version 23 for Windows (SPSS Inc., Chicago, IL, USA). A P value lower than 0.05 was considered statistically significant for all analyses. Survival curves were estimated via the Kaplan‒Meier method and compared via the log-rank test. Cox multivariate analysis was performed to evaluate prognostic factors for event-free survival. No sample size calculation was performed. Results High incidence of CTRCD using speckle tracking and the MW tool From January 2020 to April 2022, 63 patients consented to participate in the study, and 39 patients underwent at least 2 echocardiographs and were included in the final analysis (Fig. S1 in the Supplementary Appendix). The baseline characteristics are described in Table 1. The patients were predominantly men (n=22; 56%), smokers (n=24; 61%), and individuals with lung cancer (n=21; 54%). Table 1. Baseline characteristics Overall (n=39) CTRCD (n=10) No-CTRCD (n=29) p value Age (years) 68 (45-89) 63 (56-84) 71 (45-89) 0.584 Weight (kg) 70.0 (41.9–117.0) 73.5 (41.9–117.0) 69.9 (43.0–110.5) 0.416 BMI (kg/m 2 ) 26.8 (16-42) 26.2 (16-42) 26.8 (17-35) 0.721 Sex, n (%) Female Male 17 (44) 22 (56) 3 (30) 7 (70) 14 (48) 15 (52) 0.464 Type of Neoplasm, n (%) Lung Head and Neck Gastrointestinal Tract Skin/Melanoma Genitourinary Tract 21 (54) 2 (5) 6 (15) 7 (18) 3 (8) 7 (70) 1 (10) 0 (0) 2 (20) 0 (0) 14 (48) 1 (3) 6 (21) 5 (17) 3 (10) 0.377 Stage, n (%) I III IV 1 (2) 6 (15) 32 (82) 0 (0) 1 (10) 9 (90) 1 (3) 5 (17) 23 (80) 1.000 New York Heart Association score, n (%) 0 1 2 21 (54) 13 (33) 5 (13) 4 (40) 3 (30) 3 (30) 17 (59) 10 (34) 2 (7) 0.252 Comorbidities, n (%) Smoking Diabetes Mellitus Hypertension Coronary Artery Disease Heart Disease 24 (61) 14 (36) 26 (67) 5 (13) 2 (5) 7 (70) 4 (40) 7 (70) 3 (30) 0 (0) 17 (59) 10 (34) 19 (65) 2 (7) 2 (7) 0.711 1.000 1.000 0.096 1.000 Medication, n (%) ACE Inhibitors/ARBs Antiplatelets Beta-blockers Statins Anticoagulants Metformin 18 (46) 3 (8) 9 (23) 11 (28) 2 (5) 9 (23) 5 (50) 1 (10) 0 (0) 4 (40) 0 (0) 3 (30) 13 (45) 2 (7) 9 (31) 7 (24) 2 (7) 6 (21) 1.000 1.000 0.402 0.424 1.000 0.669 Calcium Score Classification, n (%) 0 1-3 4-12 9 (23) 14 (36) 11 (28) 3 (30) 3 (30) 3 (30) 6 (21) 11 (38) 8 (27) 0.972 Radiation Therapy, n (%) Previous Concurrent Thorax 12 (31) 5 (13) 8 (21) 4 (40) 1 (10) 2 (20) 8 (27) 4 (14) 6 (21) 1.000 Immunotherapy, n (%) Atezolizumab Avelumab Durvalumab Ipilimumab Nivolumab Pembrolizumab 5 (13) 1 (3) 3 (8) 2 (5) 4 (10) 26 (67) 1 (10) 1 (10) 0 (0) 0 (0) 0 (0) 8 (80) 4 (14) 0 (0) 3 (10) 2 (7) 4 (14) 18 (62) Type of Treatment, n (%) Chemoimmunotherapy Immunotherapy–Immunotherapy Anti-angiogenic. 18 (46) 2 (5) 4 (10) 5 (50) 0 (0) 1 (10) 13 (45) 2 (7) 3 (10) 1.000 0.556 1.000 Baseline characteristics of the total cohort and when classified into the CTRCD and non-CTRCD groups ACE - angiotensin-converting enzyme inhibitors; ARBs - angiotensin receptor blockers; BMI – body mass index; CTRCD - cancer therapy-related cardiac dysfunction; The incidence of global CTRCD was 25% (n=10), with 5 (13%) patients meeting the criteria for LVEF reduction (possibly with additional fulfilment of the GLS criteria) and 5 (13%) meeting the criteria for GLS reduction only. There was a 69,23% adherence to biomarker collection up to the second month, with a decrease in adherence at the subsequent timepoints (Table S1 in the Supplementary Appendix). No patient tested positive for troponin or brain natriuretic peptide. In addition to the classic CTRCD criteria, 2 patients (5%) developed new segmental dysfunction, and the other 2 patients (5%) developed new diastolic dysfunction at the echocardiography evaluation (Fig. 1). All patients were referred to a cardio-oncologist or returned to their usual cardiologist for specialized evaluation at the time of the event. No patient had evidence of myocarditis on cardiac magnetic resonance imaging. The baseline characteristics according to the diagnosis of CTRCD are also described in Table 1. Patients in the CTRCD group were predominantly men (n=7; 70%), smokers (n=7; 70%), and individuals with lung cancer (n=7; 70%) and had a higher classification of cardiac symptoms (e.g., New York Heart Association score 2; 30%) (Table 1). The use of beta-blockers at the start of ICI therapy was reported only by patients in the non-CTRCD group (0% vs. 31%, p=0.402). Echocardiographic findings With respect to the baseline echocardiographic characteristics, the CTRCD group had a lower LVEF than the non-CTRCD group did (63 vs. 67%, p=0.014, respectively), accompanied by no statistically significant lower MW values (GWI 2142 vs. 2417, p=0.174), as well as a lower E/A ratio, an echocardiography measure used to assess the diastolic function of the heart, particularly of the left ventricle (0.82 vs. 1.02, p=0.449). Despite these changes, the size of the chambers and cardiac mass were similar in the CTRCD group (Table S2 in the Supplementary Appendix). Compared with patients in the non-CTRCD group, patients in the CTRCD group had a reduction in the median GLS from - 21% to - 16% (p<0.01), which was observed by echocardiography at the second month. The median systolic blood pressure was similar between the groups, and the heart rate was numerically greater in the CTRCD group (78 vs. 69 bpm, p=0.200), as measured by echocardiography at the second month. The echocardiography evaluation at 2 months post-ICI initiation revealed reductions in GWI (1833 vs. 2334 mmHg, p= 0.006), GWC (2299 vs. 2683 mmHg, p=0.040), and GWE (83% vs. 95%, p=0.025) and a trend towards an increase in GWW (286 vs. 116 mmHg, p= 0.064) (Fig. 2 and table 2). When multivariate analyses were performed to compare the parameters of myocardial function (strain, MW, and ejection fraction) between groups, logistic regression revealed that delta GLS was the strongest predictor of the outcome (OR 0.491; 95% CI, 0.293–0.822; P = 0.007) (Table S3 in the Supplementary Appendix). There were no significant changes in cardiac dimensions or Doppler findings at the second-month exam (Table S4 in the Supplementary Appendix). Examples of GLS changes are demonstrated in Figure 3. Evolution of GCW (A), GWI (B), GWW (C), GWE (D), GLS (E), and LVEF (F) in the CTCRD group (orange) compared with those in the non-CTRCD group (blue) from baseline to 11 months of immunotherapy. CTRCD - cancer therapy-related cardiac dysfunction; LVEF - left ventricular ejection fraction. GLS - global longitudinal strain; GCW - global cardiac work; GWE - global work efficiency; GWI - global work index; GWW - global wasted work Table 2. Evaluation of cardiac function by echocardiogram after 2 months CTRCD (n=10) N-CTRCD (n=29) p value LVEF (%) 59.5 (40.0-70.0) 66.0 (60.0-82.0) 0.006 GLS (%) -16 (8-21) -21 (15-25) <0.001 GCW (mmHg) 2299 (1115-2725) 2683 (711-3633) 0.040 GWE (%) 83 (75-98) 95 (82-98) 0.025 GWI (mmHg) 1833 (832-2222) 2334 (598-3301) 0.006 GWW (mmHg) 286 (43-852) 116 (21-516) 0.064 transthoracic echocardiography evaluation at 2nd month post ICI start, showing significant lower values in LVEF (59,5 vs. 66%, p=0.006), GLS (-16 vs. -21, p<0.001), GWI (1833 vs. 2334 mmHg, p= 0.006), GWC (2299 vs. 2683 mmHg, p=0.040), GWE (83% vs. 95%, p=0.025) and a tendency towards an increase in GWW (286 vs. 116 mmHg, p= 0.064) in CTRCD group. LVEF - left ventricular ejection fraction. GLS - Global Longitudinal Strain; GCW - Global Cardiac Work; GWE - Global Work Efficiency; GWI - Global Work Index; GWW - Global Wasted Work. Considering the changes throughout the protocol, the moment of most marked echocardiography difference and with the highest incidence of CTRCD was at the second-month evaluation, followed by a reduction in the echocardiography difference between groups (Fig. 2 and Table S7 in the Supplementary Appendix). It was not possible to predict the occurrence of cardiotoxicity through echocardiography because the events occurred during the first follow-up examination (second month). Of the 10 patients meeting the CTRCD criteria, 6 continued ICI treatment without medication, and 1 began treatment with beta-blockers under a cardio-oncologist's supervision after exhibiting a decrease in GLS. Three patients discontinued ICI treatment (1 death, 1 protocol change, and 1 loss to follow-up), which potentially affected the subsequent evaluations. Incidence of CTRCD in patients with lung cancer Since a significant portion of the patients included were undergoing treatment for lung cancer (n=21), we chose to analyse these patients specifically. The results revealed a greater incidence of CTRCD (n=7; 35%), in which 14% had LVEF reduction (n=3) and 19% had isolated GLS reduction (n=4) (Fig. 2). In terms of baseline characteristics, both groups were similar, except for a greater number of patients who previously used statins in the CTRCD group (57 vs. 28%, p=0.424) (Table S5 in the Supplementary Appendix). The CTRCD group tended to have a higher calcium score for coronary atherosclerotic disease (score 4–12 43 vs. 29%, p=0.574), which was consistent with the greater number of patients receiving statins in this group. Similar to the overall population, patients with lung cancer also had a lower baseline LVEF (64 vs. 67%, p=0.043), as well as a trend towards reduced MW and Doppler parameters (Table S6 in the Supplementary Appendix). The decreases in myocardial function parameters at the second month were similar to the findings in the general cohort: LVEF (54 vs. 69%, p=0.024), GLS (- 15 vs. - 21%, p=0.006), and GCI (1706 vs. 2393, p=0.011), except for the loss of statistical significance in the GCW (2323 vs. 2694, p=0.052), GWE (82 vs. 95 p= 0.127) and GWW (299 vs. 108, p= 0.263) analyses. CTRCD does not impact treatment outcomes Among those patients with available tumour response data (80% (n=8) in the CTRCD group patients and 86% (n=25) in the non-CTRCD group patients), the disease control rate was 80% in the CTRCD group. In the non-CTRCD group, 65% of patients had a disease control rate, and 24% had progressive disease as the best response. There was a higher incidence of irAEs in the CTRCD group (50% vs. 38%). The overall survival time, which was similar between the groups, was 12 months in the CTRCD group (the IC was not calculated because of insufficient events) versus 11.3 months in the non-CTRD group (95% CI, 7.1 to 15.5 months, p=0.85). Finally, we assessed overall survival according to several baseline characteristics, such as the use of beta-blockers, metformin or irAEs. Patients who were taking beta-blockers had an overall survival time of 20.7 months (the IC was not calculated due to insufficient events), whereas nonusers of beta-blockers had an overall survival of 8.8 months (95% CI, 4.2 to 13.5). Additionally, the overall survival time in the group that experienced irAEs was 11.3 months (95% CI, 10.4 to 12.3) versus 8.7 months (95% CI, 2.4 to 14.9) for those who did not experience these complications (Fig. S2 in the Supplementary Appendix). Discussion We performed this prospective study to evaluate cardiac function via myocardial deformation and MW in patients receiving ICIs. We found an unexpectedly high incidence of CTRCD with 25% cardiac impairment without a significant decrease in the LVEF. Our data align with the findings published by Andres et al. [18], who retrospectively evaluated 89 patients who had been treated with ICIs and referred for cardiotoxicity. In this study, myocarditis was more strongly associated with ICI combination therapy (anti-PD1 + anti-CTLA4), whereas noninflammatory left ventricular dysfunction was more strongly related to the use of pembrolizumab [19]. Noninflammatory left ventricular dysfunction is a novel definition for LV dysfunction associated with ICI use and was identified in this study as a new diagnosis of asymptomatic reduction in the LVEF to a value < 50% confirmed by transthoracic echocardiography or cardiac magnetic resonance (CMR) or symptomatic heart failure with LVEF 50–53% with a reduced GLS and/or natriuretic peptide elevation, without other causes of cardiac dysfunction, inflammation on CRM or troponin elevation. In our study, the most commonly used ICI was pembrolizumab, and the cancers most frequently included were lung cancer and genitourinary cancers, which share risk factors with cardiovascular diseases, such as smoking [18]. There were also no biomarker changes, and we did not find any cases of myocarditis. We hypothesized that the CTRCD was mild enough not to alter the biomarkers and that the mechanisms of myocardial lesions presented had a nonmyocarditis aetiology, such as noninflammatory left ventricular dysfunction [18]. Noninflammatory left ventricular dysfunction is already described as a category of CTRCD by the European Society of Cardiology, with no indication for immunosuppression and a recommendation to resume ICI therapy on the basis of disease severity [7, 20]. From 2022 to 2024, four Chinese studies were conducted to assess clinical and subclinical changes in cardiac function during ICI treatment. The first study prospectively evaluated 36 patients with lung cancer over the first three months of ICI treatment via cardiac magnetic resonance and was performed at baseline and then at 3 weeks and 3 months after the initiation of ICI therapy. This study revealed an incidence of CTRCD in 19% of cases. The cardiac alterations were more pronounced in the 3 rd evaluation, with a reduction in GLS in the 2 nd evaluation that was able to predict the occurrence of CTRCD. Similar to our findings, no troponin alterations were detected in the entire group [21]. The second study prospectively assessed 55 patients who were primarily diagnosed with bladder cancer; these individuals were evaluated both before and after treatment with ICIs. The incidence of CTRCD was not reported, but there was a statistically significant decrease in the LV-GLS and RV-GLS values, among other changes in cardiac size and mechanics, when the baseline and post-ICI exams were compared [22]. In 2023, 52 patients with advanced lung cancer who received PD-1 inhibitor therapy were enrolled. Cardiac markers, noninvasive left ventricular (LV) myocardial work, and conventional echocardiographic parameters were measured before therapy (T0) and after the first (T1), second (T2), third (T3), and fourth (T4) cycles of treatment. Analysis revealed that LV global waste work (GWW) increased and that global work efficiency (GWE) decreased from T2 onwards. Specifically, GWW increased significantly from T1 to T4, whereas GLS, the global work index (GWI), and global constructive work (GCW) decreased. Interestingly, the incidence of immune-related adverse events (irAEs) was associated with changes in myocardial work parameters, with patients experiencing two or more irAEs showing increased GWW and decreased GLS and GWE [23]. In 2024, a case‒control study assessed 43 immunotherapy patients and 43 healthy controls at three stages: pretreatment (T0), after three cycles (T3), and after six cycles (T6). No significant differences in baseline echocardiographic parameters or left ventricular strain were found between T0 patients and controls. However, after treatment, significant changes were observed in myocardial work indices, with decreases in GLS, the GWI, GCW, and GWE and an increase in global work waste (GWW) at T3 and T6 [24]. In our study of ICI-treated real-life patients, the finding of 13% cardiotoxicity using criteria with a decrease in LVEF and 25% cardiotoxicity considering broader criteria (subclinical CTRCD) demonstrated an unexpected incidence of cardiotoxicity. We included a greater proportion of patients with lung cancer whose risk factors coincided with those of cardiovascular disease/atherosclerosis and could explain the higher rates of CTRCD than those reported in prospective clinical trials evaluating ICIs. Indeed, these patients had a numerically higher incidence of CTRCD. To evaluate the baseline cardiovascular profile, the calcium score was calculated via routine staging images, and a similar baseline calcium score was found in both groups [16]. The data presented herein suggest a greater incidence of subclinical events, which were predominantly characterized by findings considered noninflammatory in terms of aetiology. This contrasts with the data regarding the incidence of clinical myocardial events. A published meta-analysis revealed that myocardial events represent <5% of all irAEs, and most of these events were related to the use of nivolumab, followed by pembrolizumab [19]. However, considering that the meta-analysis was conducted with reported clinical toxicity data, these subclinical alterations were not reported and were not considered myocardial events. The current recommendations by the European Society of Cardiology include an evaluation of baseline electrocardiogram and serum markers in all patients, adding baseline echocardiography to those with high cardiovascular risk. If available, an assessment of strain should be performed. However, to date, there is no recommendation for follow-up with echocardiography even for patients who have an elevated cardiovascular risk, as prospective studies have not demonstrated clinical value thus far [25]. In cases of suspected CTRCD, patients should be promptly referred for evaluation by a cardio-oncologist [20]. In our study, in agreement with the changes in LVEF and GLS, there was a reduction in MW, with changes in all the parameters. As most of the CTRCD diagnoses were found in the second evaluation, it is not possible to affirm whether the reduction in strain and MW can predict the decrease in ejection fraction, although studies may have demonstrated such a prediction with anthracycline use [26]. In our study, GLS was the strongest predictor of CTRCD. A large American retrospective study analysing patients who underwent clinically indicated echocardiographic evaluations revealed that changes in MW indices were associated with posterior reduced GLS in patients with CTRCD [27]. A European prospective study evaluating patients exposed to anthracyclines and trastuzumab revealed that GWI, GWE, and GCW (but not GWW or GLS) predict the occurrence of moderate CTRCD (a reduction in LVEF to values less than 50% associated with a reduction in GLS greater than 15%) [28]. In contrast, two Chinese studies reported that MW indices demonstrated lower sensitivity than GLS in predicting CTRCD [29, 30]. Another advantage of MW is that it excludes myocardial dysfunction in the presence of GLS changes in patients with blood pressure alterations greater than 20 mmHg, as demonstrated in a multicentre case‒control study [15]. The improvement in MW parameters after the second evaluation in our study can be explained by ICI interruption and/or the initiation of beta-blockers prescribed by the referring cardiologist. However, these changes may be self-limited and therefore may not have sustained repercussions that are significant enough to be reported in the literature; this explains why the incidence reported in this study differs from that reported in the majority of toxicity studies [8]. In the evaluation conducted by Andres et al. [18], more than 70% of patients who developed noninflammatory left ventricular dysfunction were able to safely resume treatment, which was similar to our findings. Some studies have indicated better outcomes in patients who experience irAEs [31, 32]. The response rates in our study were higher in the CTRCD group but did not impact survival. A higher incidence of toxicity has been described as a predictor of the response to some classes of antineoplastic drugs and immunotherapy. Therefore, we believe that greater activation of the immune system could be responsible for both higher response rates and overall survival, as well as a higher incidence of adverse events [33], and that permissive cardiotoxicity is achievable in many cases [34, 35]. In our study, no patient using beta-blockers presented with CTRCD, supporting the hypothesis that this drug has a protective effect against CTRCD [36, 37]. Limitations Our study had several limitations, such as being a small-sample and single-centre study with a heterogeneous population, with a single evaluator for echocardiographic examinations, and inadequate adherence to biomarker collection. Referring to a cardio-oncologist was not centralized, as the patients could be referred to their attending cardiologists, resulting in a lack of standardized management in the handling of cases. Conclusions Our study prospectively evaluated cardiovascular toxicity in patients receiving ICIs via highly sensitive tools for screening. This assessment yielded unexpected findings of a significant incidence of CTRCD (26%), which is likely not associated with immune events, and a reduction in MW parameters (GWI; 1833 vs. 2334 mmHg, p = 0.006; GCW; 2299 vs. 2683 mmHg, p = 0.040; and GWE; 83 vs. 95%, p = 0.025), with a trend towards increased GWW; 286 vs. 116 mmHg, p = 0.064). Additional studies are necessary to validate the higher incidence of subclinical CTRCD and assess the clinical relevance of this sensitive screening, as well as to identify which subgroup of patients would benefit from this approach. Additionally, we need to enhance our understanding of the clinical impact of MW changes and the utility of this tool as a sensitive and more reliable method for diagnosis, which would provide evidence for appropriate management and the need for specific pharmacological treatment for cardiotoxicity. Abbreviations Cancer therapy-related cardiac dysfunction (CTRCD); Constructive myocardial work (GCW); Global myocardial work index (GWI); Global longitudinal strain (GLS); Wasted myocardial work (GWW); Myocardial work efficiency (GWE); Immune checkpoint inhibitors (ICIs); Immune-related adverse events (irAEs); Left ventricular ejection fraction (LVEF); Myocardial work (MW). Declarations Ethics approval and consent to participate The study design and implementation followed all applicable regulations concerning the involvement of human study participants and were carried out in adherence to the criteria established by the Declaration of Helsinki and Brazilian law. All patients provided signed informed consent forms. This study was approved by the Ethics Committee of Lauro Wanderley University Hospital of the Federal University of Paraíba under the number CAAE 16621419.6.0000.5183. Consent for publication The consent was obtained upon signing the Informed Consent Form (ICF) during the study recruitment. This consent was approved by the Ethics Committee of the Lauro Wanderley University Hospital - UFPB. Availability of data and materials The tabulated data and examination images may be obtained upon direct contact with the corresponding author . Competing interests There are no conflicts of interest related to the data presented. Funding The research was conducted with the researchers' own sponsorship. Authors’ contributions Conception and design: Juliana Goes Martins Fagundes, Marcelo Dantas Tavares de Melo, Silvia Moreira Ayub Ferreira. Provision of study materials or patients: Juliana Goes Martins Fagundes, Matheus Coelho Torres, Thiago Lins Fagundes de Sousa, Eudanusia Guilherme de Figueiredo, Emilio Carlos De Arruda Lacerda, Jean Fabrício De Lima Pereira, Igor Lemos Duarte, Marcelo Dantas Tavares de Melo. Collection and assembly of data: Juliana Goes Martins Fagundes, Matheus Coelho Torres, Rodrigo de Carvalho Flamini, Alline Fernanda Amaral Verçosa, Marcelo Dantas Tavares de Melo. Data analysis and interpretation: Juliana Goes Martins Fagundes, Matheus Coelho Torres, Thiago Lins Fagundes de Sousa, Luís Fabio Botelho, Marcelo Dantas Tavares de Melo, Silvia Moreira Ayub Ferreira, and Guilherme Wesley Peixoto da Fonseca. Manuscript writing: All authors Final approval of the manuscript: All authors Accountability for all aspects of the work: All authors Acknowledgements This research received nonfinancial support from the Oncoclínicas, Maurílio de Almeida, Cardiovida, and Nova diagnóstica companies, as well as support from the Heart Institute of the University of São Paulo Medical School (INCOR-FMUSP) and the Federal University of Paraíba (UFPB). References Armenian SH, Xu L, Ky B, Sun C, Farol LT, Pal SK, et al. Cardiovascular disease among survivors of adult-onset cancer: a community-based retrospective cohort study. J Clin Oncol. 2016;34:1122-30. Hasin T, Gerber Y, McNallan SM, Weston SA, Kushwaha SS, Nelson TJ, et al. Patients with heart failure have an increased risk of incident cancer. J Am Coll Cardiol. 2013;62:881-6. Feng Y, Guo K, Jin H, Jiang J, Wang M, Lin S. Adverse events of neoadjuvant combination immunotherapy for resectable cancer patients: a systematic review and meta-analysis. 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Prospective cardiovascular surveillance of immune checkpoint inhibitor-based combination therapy in patients with advanced renal cell cancer: data from the phase III JAVELIN renal 101 trial. J Clin Oncol. 2022;40:1929-38. Pudil R, Horacek JM, Strasova A, Jebavy L, Vojacek J. Monitoring of the very early changes of left ventricular diastolic function in patients with acute leukemia treated with anthracyclines. Exp Oncol. 2008;30:160-2. Zhan J, Van den Eynde J, Cordrey K, Long R, Danford DA, Hays AG, et al. Deterioration in myocardial work indices precedes changes in global longitudinal strain following anthracycline chemotherapy. Int J Cardiol. 2022;363:171-8. Moya A, Buytaert D, Beles M, Paolisso P, Duchenne J, Huygh G, et al. Serial non-invasive myocardial work measurements for patient risk stratification and early detection of cancer therapeutics-related cardiac dysfunction in breast cancer patients: a single-centre observational study. J Clin Med. 2023;12:1652. Chen J, Cheng C, Fan L, Xu X, Chen J, Feng Y, et al. Assessment of left heart dysfunction to predict doxorubicin cardiotoxicity in children with lymphoma. Front Pediatr. 2023;11:1163664. Guan J, Bao W, Xu Y, Yang W, Li M, Xu M, et al. Assessment of myocardial work in cancer therapy-related cardiac dysfunction and analysis of CTRCD prediction by echocardiography. Front Pharmacol. 2021;12:770580. Liang Y, Xu H, Liu F, Li L, Lin C, Zhang Y, et al. Immune-related adverse events and their effects on survival outcomes in patients with non-small cell lung cancer treated with immune checkpoint inhibitors: a systematic review and meta-analysis. Front Oncol. 2024;14:1281645. Ma S, Nie H, Wei C, Jin C, Wang L. Association between immune-related adverse events and prognosis in patients with advanced non-small cell lung cancer: a systematic review and meta-analysis. Front Oncol. 2024;14:1402017. Socinski MA, Jotte RM, Cappuzzo F, Nishio M, Mok TSK, Reck M, et al. Association of immune-related adverse events with efficacy of atezolizumab in patients with non-small cell lung cancer: pooled analyses of the phase 3 IMpower130, IMpower132, and IMpower150 randomized clinical trials. JAMA Oncol. 2023;9:527-35. Porter C, Azam TU, Mohananey D, Kumar R, Chu J, Lenihan D, et al. Permissive cardiotoxicity: the clinical crucible of cardio-oncology. JACC CardioOncol. 2022;4:302-12. Tan K, Wang A, Zheng Y, Wang S, Wang C, Li J, et al. Safety and efficacy of restarting immune checkpoint inhibitors in non-small cell lung cancer patients following immune-related adverse events: a systematic review and meta-analysis. Clin Transl Oncol. 2024;27:196-203. Avila MS, Ayub-Ferreira SM, de Barros Wanderley MR, das Dores Cruz F, Brandão SMG, Rigaud VOC, et al. Carvedilol for prevention of chemotherapy-related cardiotoxicity. J Am Coll Cardiol. 2018;71:2281-90. Attar A, Behnagh AK, Hosseini M, Amanollahi F, Shafiekhani P, Kabir A. Beta-blockers for primary prevention of anthracycline-induced cardiac toxicity: an updated meta-analysis of randomized clinical trials. Cardiovasc Ther. 2022;2022:8367444. Additional Declarations No competing interests reported. Supplementary Files figureS1.pdf figureS2.pdf supplementaryfile.pdf captionfigures.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6406754","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":447227089,"identity":"edb92c01-10cc-4891-8244-892b417b7750","order_by":0,"name":"Juliana Goes Martins 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Tavares","lastName":"Melo","suffix":""},{"id":447227105,"identity":"ad01be3a-d903-4fe4-ba78-528f66fb7c92","order_by":14,"name":"Silvia Moreira Ayub Ferreira","email":"","orcid":"","institution":"Federal University of Paraíba","correspondingAuthor":false,"prefix":"","firstName":"Silvia","middleName":"Moreira Ayub","lastName":"Ferreira","suffix":""}],"badges":[],"createdAt":"2025-04-09 00:23:07","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6406754/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6406754/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":82133758,"identity":"c88027d4-20c7-48d7-afa1-a63032617757","added_by":"auto","created_at":"2025-05-07 06:00:28","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":352330,"visible":true,"origin":"","legend":"\u003cp\u003eHigh incidence of cancer therapy-related cardiac dysfunction (CTRCD).\u003c/p\u003e\n\u003cp\u003ePie chart depicting the incidence of CTRCD using only the classic criteria—left ventricular ejection fraction (LVEF) and strain.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-6406754/v1/122d303174117ed15d22a46b.png"},{"id":82133759,"identity":"eb3dd426-edea-4871-8e25-34e5f34940f2","added_by":"auto","created_at":"2025-05-07 06:00:28","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":232218,"visible":true,"origin":"","legend":"\u003cp\u003eEvolution of myocardial parameters during immunotherapy.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-6406754/v1/c2c7c375601483757bf1973f.png"},{"id":82135178,"identity":"ebd394f4-2f76-49d1-a248-f6428c0157b7","added_by":"auto","created_at":"2025-05-07 06:08:28","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":526151,"visible":true,"origin":"","legend":"\u003cp\u003eCTRCD in patients with LVEF criteria (3A1-4) and isolation strain criteria (3B 1-4). This figure shows two cases of CTRCD that were diagnosed during the study. Fig a1 and a2 report the baseline GLS and MW parameters. Fig a3 and a4 show a significant reduction in GLS and GWI. This patient developed clinical heart failure, with improvement in TTE parameters and initiation of cardioprotective medications, and did not show any suggestive signs of myocarditis on MRI or changes on coronary angiography. Fig B1-2 shows the baseline examinations of a patient who was diagnosed with CTRCD solely on the basis of GLS and who was asymptomatic, with less pronounced changes in GLS and GWI than in the other parameters.\u003c/p\u003e\n\u003cp\u003eTTE – transthoracic echocardiography. GLS - global longitudinal strain; GCW - global cardiac work; GWE - global work efficiency; GWI - global work index; GWW - global wasted work.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-6406754/v1/fa0d42cc7677b47f646e0649.png"},{"id":84330712,"identity":"6f3600b3-b0c3-4e97-9204-32a1593b0f8e","added_by":"auto","created_at":"2025-06-10 15:54:17","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2046237,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6406754/v1/b9377c3a-e84b-454f-a6e1-36b595225e9e.pdf"},{"id":82133757,"identity":"50647a87-0455-4549-b5bd-2af1b6bd5172","added_by":"auto","created_at":"2025-05-07 06:00:28","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":65281,"visible":true,"origin":"","legend":"","description":"","filename":"figureS1.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6406754/v1/5489714f146c880830a51525.pdf"},{"id":82135176,"identity":"f1b97dec-1b7b-4fd6-b165-f6ea28413b31","added_by":"auto","created_at":"2025-05-07 06:08:28","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":517062,"visible":true,"origin":"","legend":"","description":"","filename":"figureS2.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6406754/v1/479d0c47049a6725e444259d.pdf"},{"id":82137116,"identity":"6f69fe7d-43e4-4845-81e3-9daefe0b4cde","added_by":"auto","created_at":"2025-05-07 06:16:28","extension":"pdf","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":259097,"visible":true,"origin":"","legend":"","description":"","filename":"supplementaryfile.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6406754/v1/56ec44ae2fd5a96e7e230844.pdf"},{"id":82133761,"identity":"dda96697-c2ed-4bc9-8200-937506d0cc6a","added_by":"auto","created_at":"2025-05-07 06:00:28","extension":"docx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":14002,"visible":true,"origin":"","legend":"","description":"","filename":"captionfigures.docx","url":"https://assets-eu.researchsquare.com/files/rs-6406754/v1/953707e0f26613676a216dea.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Cardiotoxicity surveillance via myocardial work among cancer patients treated with immunotherapy","fulltext":[{"header":"Background","content":"\u003cp\u003eCardiovascular diseases and cancer are the leading causes of death worldwide and share common risk factors. Growing evidence suggests that cancer survivors have a greater risk of developing cardiovascular diseases and that patients with cardiovascular diseases are more likely to develop cancer [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Given this interplay between cancer and cardiovascular diseases, it is crucial to understand the impact of cancer therapies on the cardiovascular health of cancer survivors.\u003c/p\u003e \u003cp\u003eCurrently, immune checkpoint inhibitors (ICIs) are an essential component of the systemic treatment of several types of cancer. ICIs are generally well tolerated; however, immune-related adverse events of any grade (irAEs) appear in 54\u0026ndash;95% of all patients, and grade\u0026thinsp;\u0026ge;\u0026thinsp;3 irAEs appear in up to 24% of these individuals [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Cardiotoxicity has different clinical presentations, and the incidence varies; the incidence ranges from 0.3\u0026ndash;1% for myocarditis, and it is 0.9% for heart failure and up to 1% for arrhythmias. It is associated with high mortality rates, which reach 50% in patients with myocarditis [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. A meta-analysis published in 2022 revealed that the overall incidence of cardiovascular adverse events reached 8.32%, with 4.28% of cases categorized as grade 5 [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. The suggested pathophysiology for the occurrence of cardiotoxicity after ICI therapy involves the development of immune cross-reactivity between cardiac and tumour cells, the formation of autoantibodies, high production of inflammatory cytokines, loss of self-immune tolerance, and accelerated atherosclerosis [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e \u003cp\u003e Current guidelines for managing irAEs recommend performing an electrocardiogram and collecting troponin and brain natriuretic peptide before the initiation of ICI treatment. The timing and frequency of cardiovascular monitoring should be based on the patient's risk factors and the therapeutic protocol; however, the criteria for cardiotoxicity or cancer therapy-related cardiac dysfunction (CTRCD) screening are not clear [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Global longitudinal strain (GLS) is a tool that offers high sensitivity (frequently greater than 90%) for detecting early myocardial dysfunction and has been shown to be useful for guiding cardioprotective therapies in randomized trials. However, GLS results are influenced by blood pressure, and patients with cancer usually experience weight loss associated with cachexia or treatment-related adverse events, which are reflected in blood pressure fluctuations during the course of the disease, which may impact ventricular and GLS test performance [\u003cspan additionalcitationids=\"CR10\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. The myocardial work (MW) tool, which was derived from longitudinal strain analysis, incorporates blood pressure into the model and has the advantages of being less influenced by load fluctuations and analysing all cardiac cycles, consequently generating more reliable data [\u003cspan additionalcitationids=\"CR13\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Indeed, MW was able to rule out myocardial dysfunction in the presence of GLS alterations in a cohort of patients treated with anthracyclines [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eHere, we aimed to perform prospective cardiovascular monitoring in patients receiving ICIs to estimate the incidence of clinical and subclinical changes via the use of myocardial deformation and MW tools.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cstrong\u003e\u003cem\u003eStudy design and patients\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis prospective, single-center, observational cohort study included patients who were eligible for treatment with ICIs (anti-CTLA4, anti-PD1, and/or anti-PDL1 inhibitors) as monotherapy or in combination strategies (chemotherapy and antiangiogenic) in (neo)adjuvant or palliative settings, regardless of tumour histology, from January 2020 to April 2022. Patients who were pregnant, whose ultrasound window was inadequate, or who had previous decompensated heart disease were excluded. Patients were referred for a cardiological evaluation before the initiation of ICI therapy, after 2 months of ICI therapy, and every 3 months thereafter until the end of their participation in the protocol, with such termination expected to occur after one year of follow-up or in cases of treatment discontinuation owing to toxicity or disease progression and/or death.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eEthics approval and consent to participate\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study design and implementation followed all applicable regulations concerning the involvement of human study participants and were carried out in adherence to the criteria established by the Declaration of Helsinki and Brazilian law. All patients provided signed informed consent forms. This study was approved by the Ethics Committee of Lauro Wanderley University Hospital of the Federal University of Paraíba under the number CAAE 16621419.6.0000.5183.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eCardiovascular procedures\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePatients were initially asked about comorbidities, medication use, and lifestyle habits. When staging exams (e.g., computed tomography or \u003csup\u003e18\u003c/sup\u003eFDG positron emission tomography) were available, we used the ordinal scale of the calcium score, measured through high-resolution chest computed tomography, with division of the coronary territory into 4 vessels (the left main coronary artery, left anterior descending artery, circumflex artery, and right coronary artery). Each coronary segment received a score from 0 to 3 according to the extent of calcification in the length of the vessel in the axial plane: absent, \u0026lt;1/3; 1/3–2/3; and \u0026gt; 2/3. The final score was defined as the sum of the 4 vessels (0 to 12) and was divided into 3 severity categories, 0, 1-3, and 4-12, which classified the patients in relation to the extent of coronary disease [16].\u003c/p\u003e\n\u003cp\u003ePatients underwent two-dimensional transthoracic echocardiography in the left lateral decubitus position by a dedicated echocardiography examiner at each/every predefined timepoint. Morphometric, \u003cem\u003eDoppler\u003c/em\u003e, and myocardial function measurements were performed according to the “Recommendations for Cardiac Chamber Quantification by Echocardiography in Adults” [11]. Delta GLS was calculated via data from the subsequent echocardiography in comparison with the pretreatment exam. Myocardial strain and MW were calculated noninvasively, with the final generation of data regarding the global myocardial work index (GWI), constructive myocardial work (GWC), wasted myocardial work (GWW), and myocardial work efficiency (GWE).\u003c/p\u003e\n\u003cp\u003eMyocardial strain, which assesses the ability of the heart to contract, is useful for evaluating cardiac function more sensitively than other measures, such as the ejection fraction [17]. GCW quantifies the total work done by the heart throughout the cardiac cycle, considering both the pressure generated by the heart and the volume of blood ejected. GCW is often assessed via pressure‒volume loops generated during transthoracic echocardiography. GWE is a measurement that reflects the efficiency of the contractile function of the heart. It is calculated on the basis of global cardiac work relative to energy expenditure or the total work performed by the heart during the cardiac cycle. Higher values suggest better efficiency. The GWI is a calculated index that combines parameters related to the area under the pressure‒volume curve, which reflects the cardiac workload during systole. The GWI serves as an indicator of the overall performance of the heart. GWW quantifies the amount of energy that is wasted during the cardiac cycle, primarily during periods of isovolumetric contraction and relaxation when the heart generates pressure without effectively ejecting blood. Lower values indicate better cardiac efficiency.\u003c/p\u003e\n\u003cp\u003eSimilarly, prospective collection of blood samples enabled the evaluation of clinical biomarkers such as brain natriuretic peptide and troponin I, which were analysed via an immunometric assay via the Lumina Teck Micropoint system from Lumina Teck, São Paulo, Brazil. The values were considered positive when the troponin level was ≥ 0.30 ng/ml and the brain natriuretic peptide level was ≥ 100 pg/ml, according to the normal reference values of the methodology used [17].\u003c/p\u003e\n\u003cp\u003eAt each cycle, noninvasive blood pressure measurements, peripheral pulse measurements, and symptoms were assessed during clinical visits. CTRCD was defined either as a reduction ≥10% in the left ventricular ejection fraction (LVEF) for a final value below 50% troponin elevation ≥0.30 ng/ml or a relative reduction in GLS ≥15%. If either brain natriuretic peptide or troponin were positive, CTRCD was defined by transthoracic echocardiography, or if new cardiovascular symptoms were present, the patient was referred for evaluation by a cardiologist [17].\u0026nbsp;Case management was not standardized to include an evaluation with a cardio-oncologist, but the patient could choose to be evaluated by their cardiologist if they were already under the cardiologist’s care.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eStatistical analysis\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data are presented herein as the means ± standard deviations, medians with lower and upper quartiles (95% confidence intervals), and categorical variables as frequencies and percentages. For continuous variables, one sample Shapiro‒Wilk test was used to assess the normal distribution of all variables. Independent Student’s t tests and Mann–Whitney U tests were used for parametric and nonparametric variables, respectively. The chi-square test was used for categorical variables. One-way analysis of variance or the Kruskal–Wallis test was used to test differences in continuous variables between time points (0, 2, 5 and 11 months). Data analyses were performed via the Statistical Package for the Social Sciences Version 23 for Windows (SPSS Inc., Chicago, IL, USA). A P value lower than 0.05 was considered statistically significant for all analyses. Survival curves were estimated via the Kaplan‒Meier method and compared via the log-rank test. Cox multivariate analysis was performed to evaluate prognostic factors for event-free survival. No sample size calculation was performed.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003e\u003cem\u003eHigh incidence of\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cem\u003eCTRCD\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cem\u003eusing speckle tracking and the MW tool\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFrom January 2020 to April 2022, 63 patients consented to participate in the study, and 39 patients underwent at least 2 echocardiographs and were included in the final analysis (Fig. S1 in the Supplementary Appendix). The baseline characteristics are described in Table 1. The patients were predominantly men (n=22; 56%), smokers (n=24; 61%), and individuals with lung cancer (n=21; 54%).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 1.\u003c/strong\u003e Baseline characteristics\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eOverall (n=39)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eCTRCD (n=10)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eNo-CTRCD (n=29)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ep value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge (years)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e68 (45-89)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e63 (56-84)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e71 (45-89)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.584\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eWeight (kg)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e70.0 (41.9\u0026ndash;117.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e73.5 (41.9\u0026ndash;117.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e69.9 (43.0\u0026ndash;110.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.416\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eBMI (kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e26.8 (16-42)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e26.2 (16-42)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e26.8 (17-35)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.721\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eSex, n (%)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e17 (44)\u003c/p\u003e\n \u003cp\u003e22 (56)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e3 (30)\u003c/p\u003e\n \u003cp\u003e7 (70)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e14 (48)\u003c/p\u003e\n \u003cp\u003e15 (52)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.464\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eType of Neoplasm, n (%)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eLung\u003c/p\u003e\n \u003cp\u003eHead and Neck\u003c/p\u003e\n \u003cp\u003eGastrointestinal Tract\u003c/p\u003e\n \u003cp\u003eSkin/Melanoma\u003c/p\u003e\n \u003cp\u003eGenitourinary Tract\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e21 (54)\u003c/p\u003e\n \u003cp\u003e2 (5)\u003c/p\u003e\n \u003cp\u003e6 (15)\u003c/p\u003e\n \u003cp\u003e7 (18)\u003c/p\u003e\n \u003cp\u003e3 (8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e7 (70)\u003c/p\u003e\n \u003cp\u003e1 (10)\u003c/p\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003cp\u003e2 (20)\u003c/p\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e14 (48)\u003c/p\u003e\n \u003cp\u003e1 (3)\u003c/p\u003e\n \u003cp\u003e6 (21)\u003c/p\u003e\n \u003cp\u003e5 (17)\u003c/p\u003e\n \u003cp\u003e3 (10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.377\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eStage, n (%)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eI\u003c/p\u003e\n \u003cp\u003eIII\u003c/p\u003e\n \u003cp\u003eIV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e1 (2)\u003c/p\u003e\n \u003cp\u003e6 (15)\u003c/p\u003e\n \u003cp\u003e32 (82)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003cp\u003e1 (10)\u003c/p\u003e\n \u003cp\u003e9 (90)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e1 (3)\u003c/p\u003e\n \u003cp\u003e5 (17)\u003c/p\u003e\n \u003cp\u003e23 (80)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1.000\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eNew York Heart Association score, n (%)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e0\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e1\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e2\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e21 (54)\u003c/p\u003e\n \u003cp\u003e13 (33)\u003c/p\u003e\n \u003cp\u003e5 (13)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e4 (40)\u003c/p\u003e\n \u003cp\u003e3 (30)\u003c/p\u003e\n \u003cp\u003e3 (30)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e17 (59)\u003c/p\u003e\n \u003cp\u003e10 (34)\u003c/p\u003e\n \u003cp\u003e2 (7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.252\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eComorbidities, n (%)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eSmoking\u003c/p\u003e\n \u003cp\u003eDiabetes Mellitus\u003c/p\u003e\n \u003cp\u003eHypertension\u003c/p\u003e\n \u003cp\u003eCoronary Artery Disease\u003c/p\u003e\n \u003cp\u003eHeart Disease\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e24 (61)\u003c/p\u003e\n \u003cp\u003e14 (36)\u003c/p\u003e\n \u003cp\u003e26 (67)\u003c/p\u003e\n \u003cp\u003e5 (13)\u003c/p\u003e\n \u003cp\u003e2 (5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e7 (70)\u003c/p\u003e\n \u003cp\u003e4 (40)\u003c/p\u003e\n \u003cp\u003e7 (70)\u003c/p\u003e\n \u003cp\u003e3 (30)\u003c/p\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e17 (59)\u003c/p\u003e\n \u003cp\u003e10 (34)\u003c/p\u003e\n \u003cp\u003e19 (65)\u003c/p\u003e\n \u003cp\u003e2 (7)\u003c/p\u003e\n \u003cp\u003e2 (7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.711\u003c/p\u003e\n \u003cp\u003e1.000\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;1.000\u003c/p\u003e\n \u003cp\u003e0.096\u003c/p\u003e\n \u003cp\u003e1.000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eMedication, n (%)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eACE Inhibitors/ARBs\u003c/p\u003e\n \u003cp\u003eAntiplatelets\u003c/p\u003e\n \u003cp\u003eBeta-blockers\u003c/p\u003e\n \u003cp\u003eStatins\u003c/p\u003e\n \u003cp\u003eAnticoagulants\u003c/p\u003e\n \u003cp\u003eMetformin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e18 (46)\u003c/p\u003e\n \u003cp\u003e3 (8)\u003c/p\u003e\n \u003cp\u003e9 (23)\u003c/p\u003e\n \u003cp\u003e11 (28)\u003c/p\u003e\n \u003cp\u003e2 (5)\u003c/p\u003e\n \u003cp\u003e9 (23)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e5 (50)\u003c/p\u003e\n \u003cp\u003e1 (10)\u003c/p\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003cp\u003e4 (40)\u003c/p\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003cp\u003e3 (30)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e13 (45)\u003c/p\u003e\n \u003cp\u003e2 (7)\u003c/p\u003e\n \u003cp\u003e9 (31)\u003c/p\u003e\n \u003cp\u003e7 (24)\u003c/p\u003e\n \u003cp\u003e2 (7)\u003c/p\u003e\n \u003cp\u003e6 (21)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e1.000\u003c/p\u003e\n \u003cp\u003e1.000\u003c/p\u003e\n \u003cp\u003e0.402\u003c/p\u003e\n \u003cp\u003e0.424\u003c/p\u003e\n \u003cp\u003e1.000\u003c/p\u003e\n \u003cp\u003e0.669\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eCalcium Score Classification, n (%)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003cp\u003e1-3\u003c/p\u003e\n \u003cp\u003e4-12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e9 (23)\u003c/p\u003e\n \u003cp\u003e14 (36)\u003c/p\u003e\n \u003cp\u003e11 (28)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e3 (30)\u003c/p\u003e\n \u003cp\u003e3 (30)\u003c/p\u003e\n \u003cp\u003e3 (30)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e6 (21)\u003c/p\u003e\n \u003cp\u003e11 (38)\u003c/p\u003e\n \u003cp\u003e8 (27)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.972\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eRadiation Therapy, n (%)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003ePrevious\u003c/p\u003e\n \u003cp\u003eConcurrent\u003c/p\u003e\n \u003cp\u003eThorax\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e12 (31)\u003c/p\u003e\n \u003cp\u003e5 (13)\u003c/p\u003e\n \u003cp\u003e8 (21)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e4 (40)\u003c/p\u003e\n \u003cp\u003e1 (10)\u003c/p\u003e\n \u003cp\u003e2 (20)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e8 (27)\u003c/p\u003e\n \u003cp\u003e4 (14)\u003c/p\u003e\n \u003cp\u003e6 (21)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1.000\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eImmunotherapy, n (%)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eAtezolizumab\u003c/p\u003e\n \u003cp\u003eAvelumab\u003c/p\u003e\n \u003cp\u003eDurvalumab\u003c/p\u003e\n \u003cp\u003eIpilimumab\u003c/p\u003e\n \u003cp\u003eNivolumab\u003c/p\u003e\n \u003cp\u003ePembrolizumab\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e5 (13)\u003c/p\u003e\n \u003cp\u003e1 (3)\u003c/p\u003e\n \u003cp\u003e3 (8)\u003c/p\u003e\n \u003cp\u003e2 (5)\u003c/p\u003e\n \u003cp\u003e4 (10)\u003c/p\u003e\n \u003cp\u003e26 (67)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e1 (10)\u003c/p\u003e\n \u003cp\u003e1 (10)\u003c/p\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003cp\u003e8 (80)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e4 (14)\u003c/p\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003cp\u003e3 (10)\u003c/p\u003e\n \u003cp\u003e2 (7)\u003c/p\u003e\n \u003cp\u003e4 (14)\u003c/p\u003e\n \u003cp\u003e18 (62)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eType of Treatment, n (%)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eChemoimmunotherapy\u003c/p\u003e\n \u003cp\u003eImmunotherapy\u0026ndash;Immunotherapy\u003c/p\u003e\n \u003cp\u003eAnti-angiogenic.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e18 (46)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e2 (5)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e4 (10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e5 (50)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e1 (10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e13 (45)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e2 (7)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e3 (10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e1.000\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.556\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e1.000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\" valign=\"top\"\u003e\n \u003cp\u003eBaseline characteristics of the total cohort and when classified into the CTRCD and non-CTRCD groups\u003c/p\u003e\n \u003cp\u003eACE - angiotensin-converting enzyme inhibitors; ARBs - angiotensin receptor blockers; BMI \u0026ndash; body mass index; CTRCD - cancer therapy-related cardiac dysfunction;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;The incidence of global CTRCD was 25% (n=10), with 5 (13%) patients meeting the criteria for LVEF reduction (possibly with additional fulfilment of the GLS criteria) and 5 (13%) meeting the criteria for GLS reduction only. There was a 69,23% adherence to biomarker collection up to the second month, with a decrease in adherence at the subsequent timepoints (Table S1 in the Supplementary Appendix). No patient tested positive for troponin or brain natriuretic peptide. In addition to the classic CTRCD criteria, 2 patients (5%) developed new segmental dysfunction, and the other 2 patients (5%) developed new diastolic dysfunction at the echocardiography evaluation (Fig. 1). All patients were referred to a cardio-oncologist or returned to their usual cardiologist for specialized evaluation at the time of the event. No patient had evidence of myocarditis on cardiac magnetic resonance imaging.\u003c/p\u003e\n\u003cp\u003eThe baseline characteristics according to the diagnosis of CTRCD are also described in Table 1. Patients in the CTRCD group were predominantly men (n=7; 70%), smokers (n=7; 70%), and individuals with lung cancer (n=7; 70%) and had a higher classification of cardiac symptoms (e.g., New York Heart Association score 2; 30%) (Table 1). The use of beta-blockers at the start of ICI therapy was reported only by patients in the non-CTRCD group (0% vs. 31%, p=0.402).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eEchocardiographic findings\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWith respect to the baseline echocardiographic characteristics, the CTRCD group had a lower LVEF than the non-CTRCD group did (63 vs. 67%, p=0.014, respectively), accompanied by no statistically significant lower MW values (GWI 2142 vs. 2417, p=0.174), as well as a lower E/A ratio, an echocardiography measure used to assess the diastolic function of the heart, particularly of the left ventricle (0.82 vs. 1.02, p=0.449). Despite these changes, the size of the chambers and cardiac mass were similar in the CTRCD group (Table S2 in the Supplementary Appendix). Compared with patients in the non-CTRCD group, patients in the CTRCD group had a reduction in the median GLS from - 21% to - 16% (p\u0026lt;0.01), which was observed by echocardiography at the second month.\u003c/p\u003e\n\u003cp\u003eThe median systolic blood pressure was similar between the groups, and the heart rate was numerically greater in the CTRCD group (78 vs. 69 bpm, p=0.200), as measured by echocardiography at the second month.\u003c/p\u003e\n\u003cp\u003eThe echocardiography evaluation at 2 months post-ICI initiation revealed reductions in GWI (1833 vs. 2334 mmHg, p= 0.006), GWC (2299 vs. 2683 mmHg, p=0.040), and GWE (83% vs. 95%, p=0.025) and a trend towards an increase in GWW (286 vs. 116 mmHg, p= 0.064) (Fig. 2 and table 2). When multivariate analyses were performed to compare the parameters of myocardial function (strain, MW, and ejection fraction) between groups, logistic regression revealed that delta GLS was the strongest predictor of the outcome (OR 0.491; 95% CI, 0.293\u0026ndash;0.822; P = 0.007) (Table S3 in the Supplementary Appendix). There were no significant changes in cardiac dimensions \u003cem\u003eor Doppler\u003c/em\u003e findings at the second-month exam (Table S4 in the Supplementary Appendix). Examples of GLS changes are demonstrated in Figure 3.\u003c/p\u003e\n\u003cp\u003eEvolution of GCW (A), GWI (B), GWW (C), GWE (D), GLS (E), and LVEF (F) in the CTCRD group (orange) compared with those in the non-CTRCD group (blue) from baseline to 11 months of immunotherapy.\u003c/p\u003e\n\u003cp\u003eCTRCD - cancer therapy-related cardiac dysfunction; LVEF - left ventricular ejection fraction. GLS - global longitudinal strain; GCW - global cardiac work; GWE - global work efficiency; GWI - global work index; GWW - global wasted work\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2.\u0026nbsp;\u003c/strong\u003eEvaluation of cardiac function by echocardiogram after 2 months\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eCTRCD (n=10)\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eN-CTRCD (n=29)\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ep value\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eLVEF (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e59.5 (40.0-70.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e66.0 (60.0-82.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.006\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eGLS (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-16 (8-21)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-21 (15-25)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eGCW (mmHg)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2299 (1115-2725)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2683 (711-3633)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.040\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eGWE (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e83 (75-98)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e95 (82-98)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.025\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eGWI (mmHg)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1833 (832-2222)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2334 (598-3301)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.006\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eGWW (mmHg)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e286 (43-852)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e116 (21-516)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.064\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" valign=\"top\"\u003e\n \u003cp\u003etransthoracic echocardiography evaluation at 2nd month post ICI start, showing significant lower values in LVEF (59,5 vs. 66%, p=0.006), GLS (-16 vs. -21, p\u0026lt;0.001), GWI (1833 vs. 2334 mmHg, p= 0.006), GWC (2299 vs. 2683 mmHg, p=0.040), GWE (83% vs. 95%, p=0.025) and a tendency towards an increase in GWW (286 vs. 116 mmHg, p= 0.064) in CTRCD group.\u003c/p\u003e\n \u003cp\u003eLVEF - left ventricular ejection fraction. GLS - Global Longitudinal Strain; GCW - Global Cardiac Work; GWE - Global Work Efficiency; GWI - Global Work Index; GWW - Global Wasted Work.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eConsidering the changes throughout the protocol, the moment of most marked echocardiography difference and with the highest incidence of CTRCD was at the second-month evaluation, followed by a reduction in the echocardiography difference between groups (Fig. 2 and Table S7 in the Supplementary Appendix). It was not possible to predict the occurrence of cardiotoxicity through echocardiography because the events occurred during the first follow-up examination (second month). Of the 10 patients meeting the CTRCD criteria, 6 continued ICI treatment without medication, and 1 began treatment with beta-blockers under a cardio-oncologist\u0026apos;s supervision after exhibiting a decrease in GLS. Three patients discontinued ICI treatment (1 death, 1 protocol change, and 1 loss to follow-up), which potentially affected the subsequent evaluations.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eIncidence of CTRCD in patients with lung cancer\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSince a significant portion of the patients included were undergoing treatment for lung cancer (n=21), we chose to analyse these patients specifically. The results revealed a greater incidence of CTRCD (n=7; 35%), in which 14% had LVEF reduction (n=3) and 19% had isolated GLS reduction (n=4) (Fig. 2).\u003c/p\u003e\n\u003cp\u003eIn terms of baseline characteristics, both groups were similar, except for a greater number of patients who previously used statins in the CTRCD group (57 vs. 28%, p=0.424) (Table S5 in the Supplementary Appendix). The CTRCD group tended to have a higher calcium score for coronary atherosclerotic disease (score 4\u0026ndash;12 43 vs. 29%, p=0.574), which was consistent with the greater number of patients receiving statins in this group.\u003c/p\u003e\n\u003cp\u003eSimilar to the overall population, patients with lung cancer also had a lower baseline LVEF (64 vs. 67%, p=0.043), as well as a trend towards reduced MW and \u003cem\u003eDoppler\u003c/em\u003e parameters (Table S6 in the Supplementary Appendix). The decreases in myocardial function parameters at the second month were similar to the findings in the general cohort: LVEF (54 vs. 69%, p=0.024), GLS (- 15 vs. - 21%, p=0.006), and GCI (1706 vs. 2393, p=0.011), except for the loss of statistical significance in the GCW (2323 vs. 2694, p=0.052), GWE (82 vs. 95 p= 0.127) and GWW (299 vs. 108, p= 0.263) analyses.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eCTRCD does not impact treatment outcomes\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAmong those patients with available tumour response data (80% (n=8) in the CTRCD group patients and 86% (n=25) in the non-CTRCD group patients), the disease control rate was 80% in the CTRCD group. In the non-CTRCD group, 65% of patients had a disease control rate, and 24% had progressive disease as the best response. There was a higher incidence of irAEs in the CTRCD group (50% vs. 38%). The overall survival time, which was similar between the groups, was 12 months in the CTRCD group (the IC was not calculated because of insufficient events) versus 11.3 months in the non-CTRD group (95% CI, 7.1 to 15.5 months, p=0.85).\u003c/p\u003e\n\u003cp\u003eFinally, we assessed overall survival according to several baseline characteristics, such as the use of beta-blockers, metformin or irAEs. Patients who were taking beta-blockers had an overall survival time of 20.7 months (the IC was not calculated due to insufficient events), whereas nonusers of beta-blockers had an overall survival of 8.8 months (95% CI, 4.2 to 13.5). Additionally, the overall survival time in the group that experienced irAEs was 11.3 months (95% CI, 10.4 to 12.3) versus 8.7 months (95% CI, 2.4 to 14.9) for those who did not experience these complications (Fig. S2 in the Supplementary Appendix).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eWe performed this prospective study to evaluate cardiac function via myocardial deformation and MW in patients receiving ICIs. We found an unexpectedly high incidence of CTRCD with 25% cardiac impairment without a significant decrease in the LVEF.\u003c/p\u003e\n\u003cp\u003eOur data align with the findings published by Andres et al. [18], who retrospectively evaluated 89 patients who had been treated with ICIs and referred for cardiotoxicity.\u0026nbsp;In this study, myocarditis was more strongly associated with ICI combination therapy (anti-PD1 + anti-CTLA4), whereas noninflammatory left ventricular dysfunction was more strongly related to the use of pembrolizumab [19]. Noninflammatory left ventricular dysfunction is a novel definition for LV dysfunction associated with ICI use and was identified in this study as a new diagnosis of asymptomatic reduction in the LVEF to a value \u0026lt; 50% confirmed by transthoracic echocardiography or cardiac magnetic resonance (CMR) or symptomatic heart failure with LVEF 50–53% with a reduced GLS and/or natriuretic peptide elevation, without other causes of cardiac dysfunction, inflammation on CRM or troponin elevation. In our study, the most commonly used ICI was pembrolizumab, and the cancers most frequently included were lung cancer and genitourinary cancers, which share risk factors with cardiovascular diseases, such as smoking [18]. There were also no biomarker changes, and we did not find any cases of myocarditis. We hypothesized that the CTRCD was mild enough not to alter the biomarkers and that the mechanisms of myocardial lesions presented had a nonmyocarditis aetiology, such as noninflammatory left ventricular dysfunction [18].\u003c/p\u003e\n\u003cp\u003eNoninflammatory left ventricular dysfunction is already described as a category of CTRCD by the European Society of Cardiology, with no indication for immunosuppression and a recommendation to resume ICI therapy on the basis of disease severity [7, 20].\u003c/p\u003e\n\u003cp\u003eFrom 2022 to 2024, four Chinese studies were conducted to assess clinical and subclinical changes in cardiac function during ICI treatment. The first study prospectively evaluated 36 patients with lung cancer over the first three months of ICI treatment via cardiac magnetic resonance and was performed at baseline and then at 3 weeks and 3 months after the initiation of ICI therapy. This study revealed an incidence of CTRCD in 19% of cases. The cardiac alterations were more pronounced in the 3\u003csup\u003erd\u003c/sup\u003e evaluation, with a reduction in GLS in the 2\u003csup\u003end\u003c/sup\u003e evaluation that was able to predict the occurrence of CTRCD. Similar to our findings, no troponin alterations were detected in the entire group [21].\u003c/p\u003e\n\u003cp\u003eThe second study prospectively assessed 55 patients who were primarily diagnosed with bladder cancer; these individuals were evaluated both before and after treatment with ICIs. The incidence of CTRCD was not reported, but there was a statistically significant decrease in the LV-GLS and RV-GLS values, among other changes in cardiac size and mechanics, when the baseline and post-ICI exams were compared [22].\u003c/p\u003e\n\u003cp\u003eIn 2023, 52 patients with advanced lung cancer who received PD-1 inhibitor therapy were enrolled. Cardiac markers, noninvasive left ventricular (LV) myocardial work, and conventional echocardiographic parameters were measured before therapy (T0) and after the first (T1), second (T2), third (T3), and fourth (T4) cycles of treatment. Analysis revealed that LV global waste work (GWW) increased and that global work efficiency (GWE) decreased from T2 onwards. Specifically, GWW increased significantly from T1 to T4, whereas GLS, the global work index (GWI), and global constructive work (GCW) decreased. Interestingly, the incidence of immune-related adverse events (irAEs) was associated with changes in myocardial work parameters, with patients experiencing two or more irAEs showing increased GWW and decreased GLS and GWE [23].\u003c/p\u003e\n\u003cp\u003eIn 2024, a case‒control study assessed 43 immunotherapy patients and 43 healthy controls at three stages: pretreatment (T0), after three cycles (T3), and after six cycles (T6). No significant differences in baseline echocardiographic parameters or left ventricular strain were found between T0 patients and controls. However, after treatment, significant changes were observed in myocardial work indices, with decreases in GLS, the GWI, GCW, and GWE and an increase in global work waste (GWW) at T3 and T6 [24].\u003c/p\u003e\n\u003cp\u003eIn our study of ICI-treated real-life patients, the finding of 13% cardiotoxicity using criteria with a decrease in LVEF and 25% cardiotoxicity considering broader criteria (subclinical CTRCD) demonstrated an unexpected incidence of cardiotoxicity. We included a greater proportion of patients with lung cancer whose risk factors coincided with those of cardiovascular disease/atherosclerosis and could explain the higher rates of CTRCD than those reported in prospective clinical trials evaluating ICIs. Indeed, these patients had a numerically higher incidence of CTRCD. To evaluate the baseline cardiovascular profile, the calcium score was calculated via routine staging images, and a similar baseline calcium score was found in both groups [16].\u003c/p\u003e\n\u003cp\u003eThe data presented herein suggest a greater incidence of subclinical events, which were predominantly characterized by findings considered noninflammatory in terms of aetiology. This contrasts with the data regarding the incidence of clinical myocardial events. A published meta-analysis revealed that myocardial events represent \u0026lt;5% of all irAEs, and most of these events were related to the use of nivolumab, followed by pembrolizumab [19].\u0026nbsp;However, considering that the meta-analysis was conducted with reported clinical toxicity data, these subclinical alterations were not reported and were not considered myocardial events.\u003c/p\u003e\n\u003cp\u003eThe current recommendations by the European Society of Cardiology include an evaluation of baseline electrocardiogram and serum markers in all patients, adding baseline echocardiography to those with high cardiovascular risk. If available, an assessment of strain should be performed. However, to date, there is no recommendation for follow-up with echocardiography even for patients who have an elevated cardiovascular risk, as prospective studies have not demonstrated clinical value thus far [25]. In cases of suspected CTRCD, patients should be promptly referred for evaluation by a cardio-oncologist [20].\u003c/p\u003e\n\u003cp\u003eIn our study, in agreement with the changes in LVEF and GLS, there was a reduction in MW, with changes in all the parameters. As most of the CTRCD diagnoses were found\u0026nbsp;in the second evaluation, it is not possible to affirm whether the reduction in strain and MW can predict the decrease in ejection fraction, although studies may have demonstrated such a prediction with anthracycline use [26].\u0026nbsp;In our study, GLS was the\u0026nbsp;strongest predictor of CTRCD.\u003c/p\u003e\n\u003cp\u003eA large American retrospective study analysing patients who underwent clinically indicated echocardiographic evaluations revealed that changes in MW indices were associated with posterior reduced GLS in patients with CTRCD [27]. A European prospective study evaluating patients exposed to anthracyclines and trastuzumab revealed that GWI, GWE, and GCW (but not GWW or GLS) predict the occurrence of moderate CTRCD (a reduction in LVEF to values less than 50% associated with a reduction in GLS greater than 15%) [28]. In contrast, two Chinese studies reported that MW indices demonstrated lower sensitivity than GLS in predicting CTRCD [29, 30]. Another advantage of MW is that it excludes myocardial dysfunction in the presence of GLS changes in patients with blood pressure alterations greater than 20 mmHg, as demonstrated in a multicentre case‒control study [15].\u003c/p\u003e\n\u003cp\u003eThe improvement in MW parameters after the second evaluation in our study can be explained by ICI interruption and/or the initiation of beta-blockers prescribed by the referring cardiologist. However, these changes may be self-limited and therefore may not have sustained repercussions that are significant enough to be reported in the literature; this explains why the incidence reported in this study differs from that reported in the majority of toxicity studies [8].\u0026nbsp;In the evaluation conducted by Andres et al. [18], more than 70% of patients who developed noninflammatory left ventricular dysfunction were able to safely resume treatment, which was similar to our findings.\u003c/p\u003e\n\u003cp\u003eSome studies have indicated better outcomes in patients who experience irAEs [31, 32]. The response rates in our study were higher in the CTRCD group but did not impact survival. A higher incidence of toxicity has been described as a predictor of the response to some classes of antineoplastic drugs and immunotherapy. Therefore, we believe that greater activation of the immune system could be responsible for both higher response rates and overall survival, as well as a higher incidence of adverse events [33], and that permissive cardiotoxicity is achievable in many cases [34, 35]. In our study, no patient using beta-blockers presented with CTRCD, supporting the hypothesis that this drug has a protective effect against CTRCD [36, 37].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eLimitations\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOur study had several limitations, such as being a small-sample and single-centre study with a heterogeneous population, with a single evaluator for echocardiographic examinations, and inadequate adherence to biomarker collection. Referring to a cardio-oncologist was not centralized, as the patients could be referred to their attending cardiologists, resulting in a lack of standardized management in the handling of cases.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eOur study prospectively evaluated cardiovascular toxicity in patients receiving ICIs via highly sensitive tools for screening. This assessment yielded unexpected findings of a significant incidence of CTRCD (26%), which is likely not associated with immune events, and a reduction in MW parameters (GWI; 1833 vs. 2334 mmHg, p = 0.006; GCW; 2299 vs. 2683 mmHg, p = 0.040; and GWE; 83 vs. 95%, p = 0.025), with a trend towards increased GWW; 286 vs. 116 mmHg, p = 0.064).\u003c/p\u003e\n\u003cp\u003eAdditional studies are necessary to validate the higher incidence of subclinical CTRCD and assess the clinical relevance of this sensitive screening, as well as to identify which subgroup of patients would benefit from this approach. Additionally, we need to enhance our understanding of the clinical impact of MW changes and the utility of this tool as a sensitive and more reliable method for diagnosis, which would provide evidence for appropriate management and the need for specific pharmacological treatment for cardiotoxicity.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eCancer therapy-related cardiac dysfunction (CTRCD); Constructive myocardial work (GCW); Global myocardial work index (GWI); Global longitudinal strain (GLS); Wasted myocardial work (GWW); Myocardial work efficiency (GWE); Immune checkpoint inhibitors (ICIs); Immune-related adverse events (irAEs); Left ventricular ejection fraction (LVEF); Myocardial work (MW).\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003e\u003cem\u003eEthics approval and consent to participate\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study design and implementation followed all applicable regulations concerning the involvement of human study participants and were carried out in adherence to the criteria established by the Declaration of Helsinki and Brazilian law. All patients provided signed informed consent forms. This study was approved by the Ethics Committee of Lauro Wanderley University Hospital of the Federal University of Paraíba under the number CAAE 16621419.6.0000.5183.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eConsent for publication\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe consent was obtained upon signing the Informed Consent Form (ICF) during the study recruitment. This consent was approved by the Ethics Committee of the Lauro Wanderley University Hospital - UFPB.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eAvailability of data and materials\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe tabulated data and examination images may be obtained upon direct contact with the corresponding author\u003cstrong\u003e\u003cem\u003e.\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eCompeting interests\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThere are no conflicts of interest related to the data presented.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eFunding\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe research was conducted with the researchers' own sponsorship.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eAuthors’ contributions\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConception and design: Juliana Goes Martins Fagundes, Marcelo Dantas Tavares de Melo, Silvia Moreira Ayub Ferreira.\u003c/p\u003e\n\u003cp\u003eProvision of study materials or patients: Juliana Goes Martins Fagundes, Matheus Coelho Torres, Thiago Lins Fagundes de Sousa, Eudanusia Guilherme de Figueiredo, Emilio Carlos De Arruda Lacerda, Jean Fabrício De Lima Pereira, Igor Lemos Duarte, Marcelo Dantas Tavares de Melo.\u003c/p\u003e\n\u003cp\u003eCollection and assembly of data: Juliana Goes Martins Fagundes, Matheus Coelho Torres, Rodrigo de Carvalho Flamini, Alline Fernanda Amaral Verçosa, Marcelo Dantas Tavares de Melo.\u003c/p\u003e\n\u003cp\u003eData analysis and interpretation: Juliana Goes Martins Fagundes, Matheus Coelho Torres, Thiago Lins Fagundes de Sousa, Luís Fabio Botelho, Marcelo Dantas Tavares de Melo, Silvia Moreira Ayub Ferreira, and Guilherme Wesley Peixoto da Fonseca.\u003c/p\u003e\n\u003cp\u003eManuscript writing: All authors\u003c/p\u003e\n\u003cp\u003eFinal approval of the manuscript: All authors\u003c/p\u003e\n\u003cp\u003eAccountability for all aspects of the work: All authors\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eAcknowledgements\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research received nonfinancial support from the Oncoclínicas, Maurílio de Almeida, Cardiovida, and Nova diagnóstica companies, as well as support from the Heart Institute of the University of São Paulo Medical School (INCOR-FMUSP) and the Federal University of Paraíba (UFPB).\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eArmenian SH, Xu L, Ky B, Sun C, Farol LT, Pal SK, et al. 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Curr Probl Cardiol. 2021;46:100818.\u003c/li\u003e\n \u003cli\u003eMoya A, Buytaert D, Penicka M, Bartunek J, Vanderheyden M. State-of-the-art: noninvasive assessment of left ventricular function through myocardial work. J Am Soc Echocardiogr. 2023;36:1027-42.\u003c/li\u003e\n \u003cli\u003eKosmala W, Negishi T, Thavendiranathan P, Penicka M, De Blois J, Murbr\u0026aelig;ch K, et al. Incremental value of myocardial work over global longitudinal strain in the surveillance for cancer-treatment-related cardiac dysfunction: a case-control study. J Clin Med. 2022;11:912.\u003c/li\u003e\n \u003cli\u003eHecht HS, Cronin P, Blaha MJ, Budoff MJ, Kazerooni EA, Narula J, et al. SCCT/STR guidelines for coronary artery calcium scoring of noncontrast noncardiac chest CT scans: a report of the society of cardiovascular computed tomography and society of thoracic radiology. J Cardiovasc Comput Tomogr. 2016;11:74-84.\u003c/li\u003e\n \u003cli\u003eHajjar LA, Costa I, Lopes M, Hoff PMG, Diz M, Fonseca SMR, et al. Brazilian cardio-oncology guideline - 2020. Arq Bras Cardiol. 2020;115:1006-43.\u003c/li\u003e\n \u003cli\u003eAndres MS, Ramalingam S, Rosen SD, Baksi J, Khattar R, Kirichenko Y, et al. The spectrum of cardiovascular complications related to immune-checkpoint inhibitor treatment: including myocarditis and the new entity of non inflammatory left ventricular dysfunction. Cardio-Oncology. 2022;8:21.\u003c/li\u003e\n \u003cli\u003eLessomo FYN, Wang Z, Mukuka C. Comparative cardiotoxicity risk of pembrolizumab versus nivolumab in cancer patients undergoing immune checkpoint inhibitor therapy: a meta-analysis. Front Oncol. 2023;13:1080998.\u003c/li\u003e\n \u003cli\u003eLyon AR, Lopez-Fernandez T, Couch LS, Asteggiano R, Aznar MC, Bergler-Klein J, et al. 2022 ESC guidelines on cardio-oncology developed in collaboration with the European Hematology Association (EHA), the European Society for Therapeutic Radiology and Oncology (ESTRO) and the International Cardio-Oncology Society (IC-OS). Eur Heart J. 2022;43:4229-361.\u003c/li\u003e\n \u003cli\u003eLiu J, Cao Y, Zhu K, Yao S, Yuan M, Kong X, et al. Early evaluation of subclinical cardiotoxicity in patients with lung cancer receiving immune checkpoint inhibitors by cardiovascular magnetic resonance: a prospective observational study. Quant Imaging Med Surg. 2022;12:4771-85.\u003c/li\u003e\n \u003cli\u003eXu A, Yuan M, Zhan X, Zhao G, Mu G, Wang T, et al. Early detection of immune checkpoint inhibitor-related subclinical cardiotoxicity: a pilot study by using speckle tracking imaging and three-dimensional echocardiography. Front Cardiovasc Med. 2022;9:1087287.\u003c/li\u003e\n \u003cli\u003eLi X, Wang C, Kang R, Zhao Y, Chen L, Liu F, et al. Evaluating the effect of PD-1 inhibitors on left ventricular function in lung cancer with noninvasive myocardial work. Quant Imaging Med Surg. 2023;13:3241-54.\u003c/li\u003e\n \u003cli\u003eChunlan S, Bing Y, Xi W. Study of stress‐strain loops on cardiotoxicity related to immune checkpoint inhibitors. Echocardiography. 2024;41:e15746.\u003c/li\u003e\n \u003cli\u003eRini BI, Moslehi JJ, Bonaca M, Schmidinger M, Albiges L, Choueiri TK, et al. Prospective cardiovascular surveillance of immune checkpoint inhibitor-based combination therapy in patients with advanced renal cell cancer: data from the phase III JAVELIN renal 101 trial. J Clin Oncol. 2022;40:1929-38.\u003c/li\u003e\n \u003cli\u003ePudil R, Horacek JM, Strasova A, Jebavy L, Vojacek J. Monitoring of the very early changes of left ventricular diastolic function in patients with acute leukemia treated with anthracyclines. Exp Oncol. 2008;30:160-2.\u003c/li\u003e\n \u003cli\u003eZhan J, Van den Eynde J, Cordrey K, Long R, Danford DA, Hays AG, et al. Deterioration in myocardial work indices precedes changes in global longitudinal strain following anthracycline chemotherapy. Int J Cardiol. 2022;363:171-8.\u003c/li\u003e\n \u003cli\u003eMoya A, Buytaert D, Beles M, Paolisso P, Duchenne J, Huygh G, et al. Serial non-invasive myocardial work measurements for patient risk stratification and early detection of cancer therapeutics-related cardiac dysfunction in breast cancer patients: a single-centre observational study. J Clin Med. 2023;12:1652.\u003c/li\u003e\n \u003cli\u003eChen J, Cheng C, Fan L, Xu X, Chen J, Feng Y, et al. Assessment of left heart dysfunction to predict doxorubicin cardiotoxicity in children with lymphoma. Front Pediatr. 2023;11:1163664.\u003c/li\u003e\n \u003cli\u003eGuan J, Bao W, Xu Y, Yang W, Li M, Xu M, et al. Assessment of myocardial work in cancer therapy-related cardiac dysfunction and analysis of CTRCD prediction by echocardiography. Front Pharmacol. 2021;12:770580.\u003c/li\u003e\n \u003cli\u003eLiang Y, Xu H, Liu F, Li L, Lin C, Zhang Y, et al. Immune-related adverse events and their effects on survival outcomes in patients with non-small cell lung cancer treated with immune checkpoint inhibitors: a systematic review and meta-analysis. Front Oncol. 2024;14:1281645.\u003c/li\u003e\n \u003cli\u003eMa S, Nie H, Wei C, Jin C, Wang L. Association between immune-related adverse events and prognosis in patients with advanced non-small cell lung cancer: a systematic review and meta-analysis. Front Oncol. 2024;14:1402017.\u003c/li\u003e\n \u003cli\u003eSocinski MA, Jotte RM, Cappuzzo F, Nishio M, Mok TSK, Reck M, et al. Association of immune-related adverse events with efficacy of atezolizumab in patients with non-small cell lung cancer: pooled analyses of the phase 3 IMpower130, IMpower132, and IMpower150 randomized clinical trials. JAMA Oncol. 2023;9:527-35.\u003c/li\u003e\n \u003cli\u003ePorter C, Azam TU, Mohananey D, Kumar R, Chu J, Lenihan D, et al. Permissive cardiotoxicity: the clinical crucible of cardio-oncology. JACC CardioOncol. 2022;4:302-12.\u003c/li\u003e\n \u003cli\u003eTan K, Wang A, Zheng Y, Wang S, Wang C, Li J, et al. Safety and efficacy of restarting immune checkpoint inhibitors in non-small cell lung cancer patients following immune-related adverse events: a systematic review and meta-analysis. Clin Transl Oncol. 2024;27:196-203.\u003c/li\u003e\n \u003cli\u003eAvila MS, Ayub-Ferreira SM, de Barros Wanderley MR, das Dores Cruz F, Brand\u0026atilde;o SMG, Rigaud VOC, et al. Carvedilol for prevention of chemotherapy-related cardiotoxicity. J Am Coll Cardiol. 2018;71:2281-90.\u003c/li\u003e\n \u003cli\u003eAttar A, Behnagh AK, Hosseini M, Amanollahi F, Shafiekhani P, Kabir A. Beta-blockers for primary prevention of anthracycline-induced cardiac toxicity: an updated meta-analysis of randomized clinical trials. Cardiovasc Ther. 2022;2022:8367444.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Cancer, Cardiotoxicity, Immune checkpoint inhibitors","lastPublishedDoi":"10.21203/rs.3.rs-6406754/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6406754/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cb\u003eBackground\u003c/b\u003e\u003c/p\u003e \u003cp\u003eImmune checkpoint inhibitors (ICIs) have revolutionized cancer treatment; however, the risk of cardiotoxicity has increased due to inadequate data for improving management and prevention strategies.\u003c/p\u003e\u003cp\u003e\u003cb\u003eMethods\u003c/b\u003e\u003c/p\u003e \u003cp\u003eIn this single-centre, prospective observational study, ICI-treated patients underwent biomarker assessments and echocardiography to measure global longitudinal strain (GLS) and myocardial work (MW) at baseline, 2 months, and every 3 months for one year or until treatment was discontinued. Cardiotoxicity was defined as a\u0026thinsp;\u0026ge;\u0026thinsp;10% reduction in left ventricular ejection fraction (LVEF) to \u0026lt;\u0026thinsp;50%, troponin elevation of \u0026ge;\u0026thinsp;0.30 ng/ml, or \u0026ge;\u0026thinsp;15% relative reduction in GLS.\u003c/p\u003e\u003cp\u003e\u003cb\u003eResults\u003c/b\u003e\u003c/p\u003e \u003cp\u003eAmong 63 patients, 39 (62%) completed at least two evaluations (56% male, 61% smokers, and 54% lung cancer patients). The overall incidence of cancer therapy-related cardiac dysfunction (CTRCD) was 26%, with half of these patients experiencing a\u0026thinsp;\u0026ge;\u0026thinsp;10% reduction in LVEF. The CTRCD group presented a lower baseline LVEF (67% vs. 62%, p\u0026thinsp;=\u0026thinsp;0.014). Concurrent chemotherapy and higher baseline coronary calcium scores were not linked to CTRCD risk, and no CTRCD cases were noted in patients on beta-blockers. Additionally, significant reductions in MW parameters were observed in the CTRCD group at 2 months.\u003c/p\u003e\u003cp\u003e\u003cb\u003eConclusions\u003c/b\u003e\u003c/p\u003e \u003cp\u003eOur findings highlight an unexpectedly high incidence of noninflammatory left ventricular dysfunction when sensitive measurement tools are used. These findings underscore the need for further studies to validate MW as a tool for cardiological surveillance and early diagnosis of CTRCD in patients receiving ICIs.\u003c/p\u003e","manuscriptTitle":"Cardiotoxicity surveillance via myocardial work among cancer patients treated with immunotherapy","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-05-07 06:00:21","doi":"10.21203/rs.3.rs-6406754/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"096373c9-af4b-4b85-ab4e-636f9c7228b8","owner":[],"postedDate":"May 7th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-06-10T15:53:58+00:00","versionOfRecord":[],"versionCreatedAt":"2025-05-07 06:00:21","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6406754","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6406754","identity":"rs-6406754","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}