Comparison of Left Atrial Strain Parameters After Doxorubicin Therapy in Pediatric Patients With Leukemia and Healthy Children: A Cross-Sectional Case–Control Study

Comparison of Left Atrial Strain Parameters After Doxorubicin Therapy in Pediatric Patients With Leukemia and Healthy Children: A Cross-Sectional Case–Control Study | 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 Comparison of Left Atrial Strain Parameters After Doxorubicin Therapy in Pediatric Patients With Leukemia and Healthy Children: A Cross-Sectional Case–Control Study Şeyma Şebnem ÖN, Hakan KURT, Zülal ÜLGER, Meral YILMAZ, Burcu Büşra ACAR, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8778601/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 Objective: To compare left atrial strain parameters during reservoir, conduit, and contraction phases in pediatric patients with leukemia treated with doxorubicin and age- and sex-matched healthy controls, and to evaluate their potential role in detecting subclinical cardiotoxicity. Methods: This single-center, cross-sectional case–control study included 22 pediatric patients with acute lymphoblastic leukemia who received a cumulative doxorubicin dose of 240 mg/m² and 25 healthy controls. All participants underwent comprehensive echocardiographic evaluation, including two-dimensional speckle-tracking analysis. Left ventricular global longitudinal strain (GLS) and left atrial strain parameters were assessed. Intergroup comparisons and correlation analyses were performed using appropriate statistical methods. Results: The mean follow-up duration after completion of chemotherapy was 4.6 ± 2.6 years. Left atrial reservoir, conduit, and contraction strain values were numerically lower in the leukemia group but did not differ significantly from controls. Mean reservoir strain was 39.4 ± 7.8% in patients and 48.9 ± 6.5% in controls (p = 0.353). Conduit strain showed a trend toward significance (25.1 ± 6.3% vs. 32.4 ± 7.1%, p = 0.078). Contraction strain and GLS were comparable between groups. Left ventricular wall thickness and end-diastolic diameter were significantly lower in patients, while ejection fraction remained preserved. No significant correlations were observed between strain parameters and follow-up duration. Conclusion: At mid-term follow-up after moderate-dose doxorubicin therapy, left atrial strain parameters and GLS remained largely preserved in pediatric leukemia survivors. These findings suggest the absence of overt subclinical myocardial dysfunction at this dose level, emphasizing the importance of long-term strain-based surveillance in this population. Leukemia doxorubicin left atrial strain global longitudinal strain cardiotoxicity Pediatric Cardiology Figures Figure 1 Figure 2 Figure 3 INTRODUCTION Leukemia is one of the most common malignancies of childhood, and survival rates particularly in acute lymphoblastic leukemia (ALL) have improved markedly with modern chemotherapy protocols [ 1 ]. The incorporation of anthracyclines, especially doxorubicin, into treatment regimens has played a major role in increasing cure rates, resulting in a steadily growing population of childhood cancer survivors [ 2 , 3 ]. However, improved survival has also drawn increasing attention to treatment-related late cardiovascular complications, which may significantly affect long-term clinical outcomes [ 1 , 3 ]. Doxorubicin is a cumulative and dose dependent agent with well-established cardiotoxic effects mediated through multiple molecular and cellular mechanisms, including oxidative stress, mitochondrial dysfunction, and cardiomyocyte apoptosis [ 3 – 5 ]. Anthracycline related cardiotoxicity encompasses a broad clinical spectrum, ranging from acute myocardial injury during therapy to late onset cardiomyopathy developing years after completion of treatment [ 5 ]. Importantly, myocardial involvement may remain clinically silent for prolonged periods, emphasizing the need for sensitive methods capable of detecting subclinical cardiac dysfunction. Conventional echocardiographic parameters, particularly left ventricular ejection fraction, have long been used for cardiac surveillance; however, their sensitivity in detecting early myocardial injury is limited. Consequently, myocardial deformation imaging using two-dimensional speckle tracking echocardiography has emerged as a valuable tool for identifying subclinical cardiac involvement in children treated with anthracyclines [ 6 ]. In recent years, the left atrium has been increasingly recognized not merely as a passive filling chamber but as an integral component of cardiac performance, reflecting left ventricular filling dynamics through its reservoir, conduit, and contractile functions. Alterations in left atrial function may occur early in the course of myocardial involvement and may precede overt systolic dysfunction. Although interest in left atrial strain analysis has grown, data regarding its role in detecting anthracycline-related subclinical cardiotoxicity in pediatric leukemia survivors remain limited. [ 7 ]. MATERIALS AND METHODS This study was designed as a single-center, cross-sectional case–control investigation conducted at a tertiary university hospital. The study was conducted in accordance with the principles of the Declaration of Helsinki. Ethical approval was obtained from the local Clinical Research Ethics Committee (Approval No: 2025–6510, Date: November 11, 2025). Written informed consent was obtained from the parents or legal guardians of all participants prior to enrollment. The case group consisted of pediatric patients aged 5–17 years who were followed with a diagnosis of acute lymphoblastic leukemia (ALL) and had received doxorubicin therapy according to the treatment protocol. All patients were in the maintenance phase of therapy. Chemotherapy regimens, cumulative doxorubicin doses, and follow-up durations were retrospectively reviewed from electronic medical records. Exclusion criteria included congenital heart disease, valvular heart disease, known cardiomyopathy, a history of arrhythmia, or inadequate image quality for strain analysis. The control group comprised 25 healthy children with an age- and sex distribution similar to that of the case group, who had been referred to the outpatient clinic for evaluation of a heart murmur or chest pain and were found to have completely normal echocardiographic findings, physical examinations, and electrocardiograms, with no known systemic disease. Participants with insufficient image quality were also excluded from the control group. All participants underwent two-dimensional, M-mode, color, and Doppler echocardiographic examinations during the same session using a Vivid T9 ultrasound system (GE Healthcare, Horten, Norway). All measurements were performed by a single investigator experienced in pediatric cardiology, with the patient in the supine position, in accordance with the guidelines of the American Society of Echocardiography (ASE). Left ventricular ejection fraction was calculated using the modified biplane Simpson method. Left ventricular internal dimensions, wall thicknesses, and diastolic function parameters were recorded according to standard protocols. Each parameter was assessed as the average of three consecutive cardiac cycles. Myocardial deformation analysis was performed using two-dimensional speckle-tracking echocardiography. For left ventricular strain assessment, grayscale images acquired from apical two-, three-, and four-chamber views were analyzed, with frame rates maintained between 50 and 90 frames per second. Endocardial borders were manually traced, automatically generated speckle-tracking contours were visually inspected, and manual adjustments were applied when necessary. Left ventricular global longitudinal strain (GLS) was calculated as the average of peak systolic longitudinal strain values obtained from the three apical views. Left atrial strain analysis was performed using the apical four-chamber view. The left atrial endocardial border was manually delineated, excluding the pulmonary veins and left atrial appendage, and automated tracking was verified. Strain analysis was referenced to the onset of the QRS complex. Left atrial strain values corresponding to the reservoir, conduit, and contraction phases were obtained, and mean values from three consecutive cardiac cycles were calculated for each parameter. In this manner, myocardial deformation parameters reflecting subclinical functional alterations of both the left ventricle and left atrium were comprehensively evaluated. Representative examples of left atrial strain analysis obtained from the apical two and four-chamber view, illustrating region-of-interest delineation and reservoir, conduit, and contraction phases, are shown in Fig. 1 A and 1 B. Statistical Analysis Statistical analysis was performed using SPSS version 25.0 (IBM Corp., Armonk, NY, USA). The distribution of continuous variables was assessed using the Shapiro–Wilk test. Normally distributed variables were expressed as mean ± standard deviation, whereas non-normally distributed variables were presented as median (interquartile range). Intergroup comparisons were conducted using the independent samples t-test for normally distributed variables and the Mann–Whitney U test for non-normally distributed variables. Categorical variables were compared using the chi-square test. In the patient group, relationships between left atrial strain parameters and cumulative doxorubicin dose, follow-up duration, left ventricular GLS, and ejection fraction were evaluated using Spearman correlation analysis. A p value < 0.05 was considered statistically significant. RESULTS A total of 47 children were included in the study, comprising 22 pediatric patients with leukemia and 25 age- and sex-matched healthy controls. Baseline demographic and clinical characteristics of the study population are summarized in Table 1. The mean age did not differ between groups, whereas body weight was significantly lower in the leukemia group. All patients received a cumulative doxorubicin dose of 240 mg/m² according to the treatment protocol, except for two patients who were treated with higher cumulative doses of 420 mg/m² and 480 mg/m² due to classification into a high-risk treatment group. The mean follow-up duration after completion of chemotherapy was 4.6 ± 2.6 years. Left atrial and left ventricular myocardial deformation parameters are presented in Table 2 and illustrated in Fig. 2. Left atrial reservoir strain, left atrial contraction strain, and left ventricular global longitudinal strain were comparable between the leukemia and control groups. Left atrial conduit strain was numerically lower in the leukemia group compared with healthy controls (25.1 ± 6.3% vs. 32.4 ± 7.1%), although this difference did not reach statistical significance. Conventional two-dimensional echocardiographic measurements are detailed in Table 3. Left ventricular wall thickness and left ventricular end-diastolic diameter were significantly lower in the leukemia group compared with controls, whereas left ventricular ejection fraction remained preserved and did not differ between groups. This pattern indicates the presence of structural cardiac differences in the absence of overt systolic dysfunction. To better illustrate the dissociation between structural and functional cardiac findings, a schematic summary of the composite structural–functional cardiac profile is presented in Fig. 3. While ventricular dimensions were reduced in leukemia survivors, myocardial deformation parameters reflecting systolic and atrial function remained largely preserved. Correlation analyses between time since completion of therapy and myocardial deformation parameters are shown in Table 4. No meaningful correlations were observed between follow-up duration and left atrial strain components or GLS, suggesting the absence of a detectable time-dependent deterioration in myocardial deformation within the studied follow-up period. DISCUSSION In the present study, left atrial strain components (reservoir, conduit, and contraction phases) and left ventricular global longitudinal strain (GLS) were evaluated in pediatric patients with leukemia who had received a cumulative doxorubicin dose of 240 mg/m² and were compared with age- and sex-matched healthy controls. Despite a mean follow-up duration of approximately 48 months, left atrial strain parameters and GLS were largely comparable between the two groups. In contrast, conventional two-dimensional echocardiography revealed significantly lower left ventricular wall thickness and end-diastolic diameter in the leukemia group, while left ventricular ejection fraction remained preserved. The left atrium has increasingly been recognized as an integral component of cardiac performance, reflecting left ventricular filling dynamics through its reservoir, conduit, and contractile functions. Left atrial strain assessed by speckle-tracking echocardiography has been proposed as a sensitive, noninvasive marker of early diastolic dysfunction and elevated left ventricular filling pressures [ 8 – 11 ]. In this context, the absence of significant differences in left atrial reservoir and contraction strain parameters in our cohort suggests that overt diastolic dysfunction may not be present during mid-term follow-up after exposure to a cumulative doxorubicin dose of 240 mg/m². However, the borderline reduction observed in conduit strain may indicate subtle early alterations in diastolic function, as this phase is considered particularly sensitive to changes in ventricular relaxation. This finding may reflect an early subclinical effect that could not be confirmed statistically due to the limited sample size. Anthracycline-related cardiotoxicity is mediated through multiple molecular and cellular mechanisms, including oxidative stress, mitochondrial dysfunction, and cardiomyocyte apoptosis, which may lead to myocardial injury before the development of overt systolic dysfunction [ 8 , 12 – 14 ]. Previous studies have demonstrated that GLS may decline before reductions in left ventricular ejection fraction and therefore serve as an early marker of subclinical systolic dysfunction in children treated with anthracyclines [ 15 , 16 ]. In contrast, the preservation of GLS in our study suggests that subclinical systolic impairment may not have developed within the evaluated cumulative dose range and follow-up period. Nevertheless, this finding should be interpreted cautiously, as late-onset anthracycline-related cardiotoxicity has been reported to occur several years after completion of therapy [ 17 ]. In addition to functional parameters, structural echocardiographic measurements revealed significantly lower left ventricular wall thickness and end-diastolic diameter in the leukemia group compared with healthy controls. Similar structural alterations have been reported in childhood cancer survivors exposed to anthracyclines and have been attributed to early myocardial remodeling associated with cardiotoxicity [ 16 , 17 ]. Importantly, these changes may occur in the absence of measurable systolic dysfunction. At the same time, growth impairment and reduced somatic development frequently observed during and after leukemia treatment may also contribute to smaller cardiac dimensions [ 17 ]. Therefore, the observed structural differences in our cohort are likely multifactorial, reflecting both potential anthracycline-related myocardial effects and differences in physical growth. Consistent with this interpretation, body weight was significantly lower in the leukemia group compared with healthy controls. Undernutrition and weight loss are common during the treatment course of childhood leukemia and have been shown to negatively affect growth and development [19]. Reduced body weight and altered body composition may influence cardiac size and geometry, representing important confounding factors in the interpretation of echocardiographic measurements. Accordingly, anthropometric parameters should be carefully considered when evaluating cardiac structure in pediatric oncology survivors. Correlation analyses demonstrated no significant relationship between time since completion of therapy and left atrial strain parameters or GLS. Anthracycline-induced cardiotoxicity is known to follow a progressive course, with clinical manifestations potentially emerging many years after treatment completion [ 17 ]. The absence of a time-dependent association in our study may therefore reflect the relatively limited follow-up duration and does not exclude the possibility of late-onset myocardial involvement. Longer-term prospective studies incorporating serial strain assessments are needed to better characterize temporal changes in myocardial deformation. Only two patients in the leukemia group received cumulative doxorubicin doses exceeding 240 mg/m², and these patients exhibited lower left atrial strain values compared with those who received standard doses, although statistical significance could not be demonstrated. Given the well-established dose-dependent nature of anthracycline-related cardiotoxicity [ 8 , 12 , 17 ], this observation is consistent with existing literature and should be regarded as hypothesis-generating. Confirmation of this trend will require larger cohorts including patients exposed to a wider range of cumulative anthracycline doses. LIMITATIONS Several limitations of this study should be acknowledged. First, the single-center design and relatively small sample size may limit the generalizability of the findings. Second, baseline (pre-treatment) strain measurements were not available, precluding the assessment of within-patient changes over time. Third, because all patients received similar cumulative doses of doxorubicin, a dose–response analysis could not be performed. In addition, potential confounding factors such as exposure to radiotherapy and other cardiotoxic agents were not evaluated in detail. CONCLUSION In conclusion, the finding that left atrial strain parameters and left ventricular GLS were comparable to those of healthy controls in children who received a cumulative doxorubicin dose of 240 mg/m² with a mean follow-up of 48 months suggests the absence of overt subclinical systolic or diastolic dysfunction at this dose level. Nevertheless, because the risk of late-onset anthracycline-related cardiotoxicity cannot be entirely excluded, continued regular echocardiographic follow-up preferably incorporating strain-based imaging remains essential into adulthood. Furthermore, the presence of lower body weight and smaller left ventricular dimensions highlights the impact of cancer therapy on growth and development and underscores the need for a multidisciplinary follow-up approach in this population. Declarations FINANCIAL SUPPORT No specific financial support or funding was received for this study. Conflict of Interest Statement The authors declare no conflict of interest. Funding Statement No specific funding was received for this study. Ethics Approval This study was approved by the Local Clinical Research Ethics Committee of Ege University Faculty of Medicine. Written informed consent was obtained from the parents of all participants. Author Contributions ŞŞÖ, HK, BKB: Study design, data collection, manuscript writing ZÜ, NK, DYK, ED: Data analysis, interpretation EL,MY, BBA, HK: Patient recruitment, data acquisition All authors: Critical revision and final approval (All authors approved the final manuscript.) References Curry HL, Parkes SE, Powell JE, Mann JR (2006) Caring for survivors of childhood cancers: the size of the problem. Eur J Cancer 42(4):501–508 Danesi R, Zucchi R (2003) Cardiac toxicity of antineoplastic anthracyclines. Curr Med Chem Anticancer Agents 3(2):151–171 Minotti G, Menna P, Salvatorelli E, Cairo G, Gianni L (2004) Anthracyclines: molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity. Pharmacol Rev 56(2):185–229 Wouters KA, Kremer LC, Miller TL, Herman EH, Lipshultz SE (2005) Protecting against anthracycline-induced myocardial damage: a review of the most promising strategies. Br J Haematol 131(5):561–578 Arola OJ, Saraste A, Pulkki K et al (2000) Acute doxorubicin cardiotoxicity involves cardiomyocyte apoptosis. Cancer Res 60(7):1789–1792 Al-Biltagi M, Tolba OA, El-Shanshory MR, El-Shitany N, El-Hawary ES (2012) Strain echocardiography in early detection of doxorubicin-induced left ventricular dysfunction in children with acute lymphoblastic leukemia. ISRN Pediatr 2012:1–10 Cameli M, Lisi M, Righini FM, Mondillo S (2009) Left atrial strain: a new parameter for assessment of left atrial function by two-dimensional speckle tracking. Cardiovasc Ultrasound 7:6 Saraiva RM, Demirkol S, Buakhamsri A et al (2010) Left atrial strain measured by two-dimensional speckle tracking represents a new tool to evaluate left atrial function. J Am Soc Echocardiogr 23(2):172–180 Russo C, Jin Z, Homma S et al (2012) Left atrial minimum volume and reservoir function in left ventricular diastolic dysfunction. Heart 98(10):813–820 Wakami K, Ohte N, Asada K et al (2009) Correlation between left atrial wall deformation and left ventricular end-diastolic pressure. J Am Soc Echocardiogr 22(7):847–851 Chatterjee K, Zhang J, Honbo N, Karliner JS (2010) Doxorubicin cardiomyopathy. Cardiology 115(2):155–162 Migrino RQ, Aggarwal D, Konorev E et al (2008) Detection of doxorubicin cardiomyopathy using two-dimensional strain echocardiography. Ultrasound Med Biol 34(2):208–214 Steinherz LJ, Steinherz PG, Tan CTC, Heller G, Murphy ML (1991) Cardiac toxicity 4 to 20 years after completing anthracycline therapy. JAMA 266(12):1672–1677 Lipshultz SE, Landy DC, Lopez-Mitnik G et al (2012) Cardiovascular status of childhood cancer survivors exposed and unexposed to cardiotoxic therapy. J Clin Oncol 30(10):1050–1057 den Hoed MA, Pluijm SM, de Groot-Kruseman HA et al (2015) The negative impact of being underweight and weight loss on survival of children with acute lymphoblastic leukemia. Haematologica 100(1):62–69 Sabatino J, Di Salvo G, Prota C et al (2019) Left atrial strain to identify diastolic dysfunction in children with cardiomyopathies. J Clin Med 8(8):1243 Rique A, Cautela J, Thuny F et al (2024) Left ventricular longitudinal strain abnormalities after childhood exposure to anthracycline chemotherapy. Child (Basel) 11:378 Tables Tables are available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files TABLES.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. 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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-8778601","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":595380238,"identity":"0a8e6b70-7672-4dcd-b2fa-6ffc2bad3042","order_by":0,"name":"Şeyma Şebnem ÖN","email":"","orcid":"","institution":"Ege University","correspondingAuthor":false,"prefix":"","firstName":"Şeyma","middleName":"Şebnem","lastName":"ÖN","suffix":""},{"id":595380239,"identity":"0750c796-6ebe-4d25-ae2e-acfe49bcf0bf","order_by":1,"name":"Hakan KURT","email":"","orcid":"","institution":"Ege 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DOĞAN","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA7klEQVRIiWNgGAWjYNACNhDBfADCOUC8FrYEmBbGBiK18BgQp4Wf//CxDwxlNnb9s3s+PvxSwSDHdyOB/XEFHi2SM9KSZzCcAxJ3zm42ljnDYCx5I4Gx8QweLQY3eIwZGNsOJzPcyN0mLdnGkLgBpAWfy+zPn/8M1iJ/I+f5b8l/DPUEtRgw5DCDtNgZ3MhhY/zYwJBgQEiLxI00Y4aEc2kJhkCGNMMxCcOZZx42zsSnhb//8GOGD2U29nI3kh9+/FFjI893PPnAR3xawCCBgSERpIiZh0ECSBETk0BgDyIYfxCldhSMglEwCkYaAADzalFqANix9QAAAABJRU5ErkJggg==","orcid":"","institution":"Ege University","correspondingAuthor":true,"prefix":"","firstName":"Eser","middleName":"","lastName":"DOĞAN","suffix":""}],"badges":[],"createdAt":"2026-02-03 16:54:01","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8778601/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8778601/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":103439257,"identity":"4d8e05dd-1e82-401e-b1a5-f0f8e0d2bb0f","added_by":"auto","created_at":"2026-02-25 17:01:20","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":2587577,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eRepresentative examples of two-dimensional speckle-tracking echocardiography.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e(A)\u003c/strong\u003e Healthy control demonstrating left left ventricular and aplax view and left atrial strain analysis from the apical two and four-chamber view, with clearly identifiable reservoir, conduit, and contraction phases referenced to the onset of the QRS complex.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e(B)\u003c/strong\u003e Pediatric patient with leukemia following high-dose doxorubicin therapy, illustrating left ventricular and left atrial strain analysis obtained using the same acquisition and analysis protocol.\u003c/p\u003e\n\u003cp\u003eImages are provided to demonstrate the methodology of myocardial deformation assessment and phase identification and are not intended for quantitative comparison.\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-8778601/v1/cfb4ea5e439f6f0de6ab44d0.png"},{"id":103508187,"identity":"10c3409a-12e3-4530-a268-6d8bcf4c3ca3","added_by":"auto","created_at":"2026-02-26 13:47:25","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":28936,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eComparison of left atrial strain components and left ventricular global longitudinal strain between pediatric leukemia survivors and healthy controls.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBars represent mean values with standard deviation. Left atrial conduit strain showed a numerical reduction in the leukemia group without reaching statistical significance.\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-8778601/v1/6f09f55048e68ec2b650d2d2.png"},{"id":103439258,"identity":"546b1bdf-0b4d-4839-a9bb-2cecbd50c6e3","added_by":"auto","created_at":"2026-02-25 17:01:20","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":313662,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eStructural and functional cardiac profile after doxorubicin therapy in pediatric leukemia survivors.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis schematic figure summarizes the dissociation between structural and functional cardiac findings in pediatric leukemia survivors treated with a cumulative doxorubicin dose of 240 mg/m². While left ventricular wall thickness and end-diastolic diameter were reduced, left atrial strain components and left ventricular global longitudinal strain remained largely preserved. A numerical reduction in left atrial conduit strain was observed without reaching statistical significance.\u003c/p\u003e","description":"","filename":"floatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-8778601/v1/a5735433ae804c50e0c2e51e.png"},{"id":105153954,"identity":"13883c3e-9344-4418-8627-f0fef6e715d3","added_by":"auto","created_at":"2026-03-22 16:39:46","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3614858,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8778601/v1/4600c50f-e741-4110-bc4b-0fa2eb33bea1.pdf"},{"id":103439256,"identity":"5e8288be-edbd-452c-97bd-33606c6329c6","added_by":"auto","created_at":"2026-02-25 17:01:20","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":18802,"visible":true,"origin":"","legend":"","description":"","filename":"TABLES.docx","url":"https://assets-eu.researchsquare.com/files/rs-8778601/v1/4afcf877f9404d76a3122429.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Comparison of Left Atrial Strain Parameters After Doxorubicin Therapy in Pediatric Patients With Leukemia and Healthy Children: A Cross-Sectional Case–Control Study","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eLeukemia is one of the most common malignancies of childhood, and survival rates particularly in acute lymphoblastic leukemia (ALL) have improved markedly with modern chemotherapy protocols [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. The incorporation of anthracyclines, especially doxorubicin, into treatment regimens has played a major role in increasing cure rates, resulting in a steadily growing population of childhood cancer survivors [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. However, improved survival has also drawn increasing attention to treatment-related late cardiovascular complications, which may significantly affect long-term clinical outcomes [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eDoxorubicin is a cumulative and dose dependent agent with well-established cardiotoxic effects mediated through multiple molecular and cellular mechanisms, including oxidative stress, mitochondrial dysfunction, and cardiomyocyte apoptosis [\u003cspan additionalcitationids=\"CR4\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Anthracycline related cardiotoxicity encompasses a broad clinical spectrum, ranging from acute myocardial injury during therapy to late onset cardiomyopathy developing years after completion of treatment [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Importantly, myocardial involvement may remain clinically silent for prolonged periods, emphasizing the need for sensitive methods capable of detecting subclinical cardiac dysfunction.\u003c/p\u003e \u003cp\u003eConventional echocardiographic parameters, particularly left ventricular ejection fraction, have long been used for cardiac surveillance; however, their sensitivity in detecting early myocardial injury is limited. Consequently, myocardial deformation imaging using two-dimensional speckle tracking echocardiography has emerged as a valuable tool for identifying subclinical cardiac involvement in children treated with anthracyclines [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn recent years, the left atrium has been increasingly recognized not merely as a passive filling chamber but as an integral component of cardiac performance, reflecting left ventricular filling dynamics through its reservoir, conduit, and contractile functions. Alterations in left atrial function may occur early in the course of myocardial involvement and may precede overt systolic dysfunction. Although interest in left atrial strain analysis has grown, data regarding its role in detecting anthracycline-related subclinical cardiotoxicity in pediatric leukemia survivors remain limited. [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e"},{"header":"MATERIALS AND METHODS","content":"\u003cp\u003eThis study was designed as a single-center, cross-sectional case\u0026ndash;control investigation conducted at a tertiary university hospital. The study was conducted in accordance with the principles of the Declaration of Helsinki. Ethical approval was obtained from the local Clinical Research Ethics Committee (Approval No: 2025\u0026ndash;6510, Date: November 11, 2025). Written informed consent was obtained from the parents or legal guardians of all participants prior to enrollment. The case group consisted of pediatric patients aged 5\u0026ndash;17 years who were followed with a diagnosis of acute lymphoblastic leukemia (ALL) and had received doxorubicin therapy according to the treatment protocol. All patients were in the maintenance phase of therapy. Chemotherapy regimens, cumulative doxorubicin doses, and follow-up durations were retrospectively reviewed from electronic medical records. Exclusion criteria included congenital heart disease, valvular heart disease, known cardiomyopathy, a history of arrhythmia, or inadequate image quality for strain analysis.\u003c/p\u003e \u003cp\u003eThe control group comprised 25 healthy children with an age- and sex distribution similar to that of the case group, who had been referred to the outpatient clinic for evaluation of a heart murmur or chest pain and were found to have completely normal echocardiographic findings, physical examinations, and electrocardiograms, with no known systemic disease. Participants with insufficient image quality were also excluded from the control group.\u003c/p\u003e \u003cp\u003eAll participants underwent two-dimensional, M-mode, color, and Doppler echocardiographic examinations during the same session using a Vivid T9 ultrasound system (GE Healthcare, Horten, Norway). All measurements were performed by a single investigator experienced in pediatric cardiology, with the patient in the supine position, in accordance with the guidelines of the American Society of Echocardiography (ASE). Left ventricular ejection fraction was calculated using the modified biplane Simpson method. Left ventricular internal dimensions, wall thicknesses, and diastolic function parameters were recorded according to standard protocols. Each parameter was assessed as the average of three consecutive cardiac cycles.\u003c/p\u003e \u003cp\u003eMyocardial deformation analysis was performed using two-dimensional speckle-tracking echocardiography. For left ventricular strain assessment, grayscale images acquired from apical two-, three-, and four-chamber views were analyzed, with frame rates maintained between 50 and 90 frames per second. Endocardial borders were manually traced, automatically generated speckle-tracking contours were visually inspected, and manual adjustments were applied when necessary. Left ventricular global longitudinal strain (GLS) was calculated as the average of peak systolic longitudinal strain values obtained from the three apical views.\u003c/p\u003e \u003cp\u003eLeft atrial strain analysis was performed using the apical four-chamber view. The left atrial endocardial border was manually delineated, excluding the pulmonary veins and left atrial appendage, and automated tracking was verified. Strain analysis was referenced to the onset of the QRS complex. Left atrial strain values corresponding to the reservoir, conduit, and contraction phases were obtained, and mean values from three consecutive cardiac cycles were calculated for each parameter.\u003c/p\u003e \u003cp\u003eIn this manner, myocardial deformation parameters reflecting subclinical functional alterations of both the left ventricle and left atrium were comprehensively evaluated. Representative examples of left atrial strain analysis obtained from the apical two and four-chamber view, illustrating region-of-interest delineation and reservoir, conduit, and contraction phases, are shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA and \u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eB.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eStatistical analysis was performed using SPSS version 25.0 (IBM Corp., Armonk, NY, USA). The distribution of continuous variables was assessed using the Shapiro\u0026ndash;Wilk test. Normally distributed variables were expressed as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation, whereas non-normally distributed variables were presented as median (interquartile range). Intergroup comparisons were conducted using the independent samples t-test for normally distributed variables and the Mann\u0026ndash;Whitney U test for non-normally distributed variables. Categorical variables were compared using the chi-square test. In the patient group, relationships between left atrial strain parameters and cumulative doxorubicin dose, follow-up duration, left ventricular GLS, and ejection fraction were evaluated using Spearman correlation analysis. A p value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"RESULTS","content":"\u003cp\u003eA total of 47 children were included in the study, comprising 22 pediatric patients with leukemia and 25 age- and sex-matched healthy controls. Baseline demographic and clinical characteristics of the study population are summarized in Table 1. The mean age did not differ between groups, whereas body weight was significantly lower in the leukemia group. All patients received a cumulative doxorubicin dose of 240 mg/m\u0026sup2; according to the treatment protocol, except for two patients who were treated with higher cumulative doses of 420 mg/m\u0026sup2; and 480 mg/m\u0026sup2; due to classification into a high-risk treatment group. The mean follow-up duration after completion of chemotherapy was 4.6\u0026thinsp;\u0026plusmn;\u0026thinsp;2.6 years.\u003c/p\u003e\n\u003cdiv\u003e\u003c/div\u003e\n\u003cdiv\u003e\n \u003ctable id=\"Tab2\" border=\"1\"\u003e\u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eLeft atrial and left ventricular myocardial deformation parameters are presented in Table 2 and illustrated in Fig. 2. Left atrial reservoir strain, left atrial contraction strain, and left ventricular global longitudinal strain were comparable between the leukemia and control groups. Left atrial conduit strain was numerically lower in the leukemia group compared with healthy controls (25.1\u0026thinsp;\u0026plusmn;\u0026thinsp;6.3% vs. 32.4\u0026thinsp;\u0026plusmn;\u0026thinsp;7.1%), although this difference did not reach statistical significance.\u003c/p\u003e\n\u003cdiv\u003e\u003c/div\u003e\n\u003cdiv\u003e\n \u003ctable id=\"Tab4\" border=\"1\"\u003e\u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eConventional two-dimensional echocardiographic measurements are detailed in Table 3. Left ventricular wall thickness and left ventricular end-diastolic diameter were significantly lower in the leukemia group compared with controls, whereas left ventricular ejection fraction remained preserved and did not differ between groups. This pattern indicates the presence of structural cardiac differences in the absence of overt systolic dysfunction.\u003c/p\u003e\n\u003cdiv\u003e\u003c/div\u003e\n\u003cp\u003eTo better illustrate the dissociation between structural and functional cardiac findings, a schematic summary of the composite structural\u0026ndash;functional cardiac profile is presented in Fig. 3. While ventricular dimensions were reduced in leukemia survivors, myocardial deformation parameters reflecting systolic and atrial function remained largely preserved.\u003c/p\u003e\n\u003cp\u003eCorrelation analyses between time since completion of therapy and myocardial deformation parameters are shown in Table 4. No meaningful correlations were observed between follow-up duration and left atrial strain components or GLS, suggesting the absence of a detectable time-dependent deterioration in myocardial deformation within the studied follow-up period.\u003c/p\u003e\n"},{"header":"DISCUSSION","content":"\u003cp\u003eIn the present study, left atrial strain components (reservoir, conduit, and contraction phases) and left ventricular global longitudinal strain (GLS) were evaluated in pediatric patients with leukemia who had received a cumulative doxorubicin dose of 240 mg/m\u0026sup2; and were compared with age- and sex-matched healthy controls. Despite a mean follow-up duration of approximately 48 months, left atrial strain parameters and GLS were largely comparable between the two groups. In contrast, conventional two-dimensional echocardiography revealed significantly lower left ventricular wall thickness and end-diastolic diameter in the leukemia group, while left ventricular ejection fraction remained preserved.\u003c/p\u003e \u003cp\u003eThe left atrium has increasingly been recognized as an integral component of cardiac performance, reflecting left ventricular filling dynamics through its reservoir, conduit, and contractile functions. Left atrial strain assessed by speckle-tracking echocardiography has been proposed as a sensitive, noninvasive marker of early diastolic dysfunction and elevated left ventricular filling pressures [\u003cspan additionalcitationids=\"CR9 CR10\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. In this context, the absence of significant differences in left atrial reservoir and contraction strain parameters in our cohort suggests that overt diastolic dysfunction may not be present during mid-term follow-up after exposure to a cumulative doxorubicin dose of 240 mg/m\u0026sup2;. However, the borderline reduction observed in conduit strain may indicate subtle early alterations in diastolic function, as this phase is considered particularly sensitive to changes in ventricular relaxation. This finding may reflect an early subclinical effect that could not be confirmed statistically due to the limited sample size.\u003c/p\u003e \u003cp\u003eAnthracycline-related cardiotoxicity is mediated through multiple molecular and cellular mechanisms, including oxidative stress, mitochondrial dysfunction, and cardiomyocyte apoptosis, which may lead to myocardial injury before the development of overt systolic dysfunction [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan additionalcitationids=\"CR13\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Previous studies have demonstrated that GLS may decline before reductions in left ventricular ejection fraction and therefore serve as an early marker of subclinical systolic dysfunction in children treated with anthracyclines [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. In contrast, the preservation of GLS in our study suggests that subclinical systolic impairment may not have developed within the evaluated cumulative dose range and follow-up period. Nevertheless, this finding should be interpreted cautiously, as late-onset anthracycline-related cardiotoxicity has been reported to occur several years after completion of therapy [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn addition to functional parameters, structural echocardiographic measurements revealed significantly lower left ventricular wall thickness and end-diastolic diameter in the leukemia group compared with healthy controls. Similar structural alterations have been reported in childhood cancer survivors exposed to anthracyclines and have been attributed to early myocardial remodeling associated with cardiotoxicity [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Importantly, these changes may occur in the absence of measurable systolic dysfunction. At the same time, growth impairment and reduced somatic development frequently observed during and after leukemia treatment may also contribute to smaller cardiac dimensions [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Therefore, the observed structural differences in our cohort are likely multifactorial, reflecting both potential anthracycline-related myocardial effects and differences in physical growth.\u003c/p\u003e \u003cp\u003eConsistent with this interpretation, body weight was significantly lower in the leukemia group compared with healthy controls. Undernutrition and weight loss are common during the treatment course of childhood leukemia and have been shown to negatively affect growth and development [19]. Reduced body weight and altered body composition may influence cardiac size and geometry, representing important confounding factors in the interpretation of echocardiographic measurements. Accordingly, anthropometric parameters should be carefully considered when evaluating cardiac structure in pediatric oncology survivors.\u003c/p\u003e \u003cp\u003eCorrelation analyses demonstrated no significant relationship between time since completion of therapy and left atrial strain parameters or GLS. Anthracycline-induced cardiotoxicity is known to follow a progressive course, with clinical manifestations potentially emerging many years after treatment completion [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. The absence of a time-dependent association in our study may therefore reflect the relatively limited follow-up duration and does not exclude the possibility of late-onset myocardial involvement. Longer-term prospective studies incorporating serial strain assessments are needed to better characterize temporal changes in myocardial deformation.\u003c/p\u003e \u003cp\u003eOnly two patients in the leukemia group received cumulative doxorubicin doses exceeding 240 mg/m\u0026sup2;, and these patients exhibited lower left atrial strain values compared with those who received standard doses, although statistical significance could not be demonstrated. Given the well-established dose-dependent nature of anthracycline-related cardiotoxicity [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e], this observation is consistent with existing literature and should be regarded as hypothesis-generating. Confirmation of this trend will require larger cohorts including patients exposed to a wider range of cumulative anthracycline doses.\u003c/p\u003e"},{"header":"LIMITATIONS","content":"\u003cp\u003eSeveral limitations of this study should be acknowledged. First, the single-center design and relatively small sample size may limit the generalizability of the findings. Second, baseline (pre-treatment) strain measurements were not available, precluding the assessment of within-patient changes over time. Third, because all patients received similar cumulative doses of doxorubicin, a dose\u0026ndash;response analysis could not be performed. In addition, potential confounding factors such as exposure to radiotherapy and other cardiotoxic agents were not evaluated in detail.\u003c/p\u003e"},{"header":"CONCLUSION","content":"\u003cp\u003eIn conclusion, the finding that left atrial strain parameters and left ventricular GLS were comparable to those of healthy controls in children who received a cumulative doxorubicin dose of 240 mg/m\u0026sup2; with a mean follow-up of 48 months suggests the absence of overt subclinical systolic or diastolic dysfunction at this dose level. Nevertheless, because the risk of late-onset anthracycline-related cardiotoxicity cannot be entirely excluded, continued regular echocardiographic follow-up preferably incorporating strain-based imaging remains essential into adulthood. Furthermore, the presence of lower body weight and smaller left ventricular dimensions highlights the impact of cancer therapy on growth and development and underscores the need for a multidisciplinary follow-up approach in this population.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFINANCIAL SUPPORT\u003c/strong\u003e\u003cbr\u003e\u0026nbsp;No specific financial support or funding was received for this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of Interest Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo specific funding was received for this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics Approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was approved by the Local Clinical Research Ethics Committee of Ege University Faculty of Medicine. Written informed consent was obtained from the parents of all participants.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eŞŞ\u0026Ouml;, HK, BKB: Study design, data collection, manuscript writing\u003cbr\u003e\u0026nbsp;Z\u0026Uuml;, NK, DYK, ED: Data analysis, interpretation\u003cbr\u003e\u0026nbsp;EL,MY, BBA, HK: Patient recruitment, data acquisition\u003cbr\u003e\u0026nbsp;All authors: Critical revision and final approval\u003c/p\u003e\n\u003cp\u003e(All authors approved the final manuscript.)\u003c/p\u003e\n"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eCurry HL, Parkes SE, Powell JE, Mann JR (2006) Caring for survivors of childhood cancers: the size of the problem. Eur J Cancer 42(4):501\u0026ndash;508\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDanesi R, Zucchi R (2003) Cardiac toxicity of antineoplastic anthracyclines. Curr Med Chem Anticancer Agents 3(2):151\u0026ndash;171\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMinotti G, Menna P, Salvatorelli E, Cairo G, Gianni L (2004) Anthracyclines: molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity. Pharmacol Rev 56(2):185\u0026ndash;229\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWouters KA, Kremer LC, Miller TL, Herman EH, Lipshultz SE (2005) Protecting against anthracycline-induced myocardial damage: a review of the most promising strategies. Br J Haematol 131(5):561\u0026ndash;578\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eArola OJ, Saraste A, Pulkki K et al (2000) Acute doxorubicin cardiotoxicity involves cardiomyocyte apoptosis. Cancer Res 60(7):1789\u0026ndash;1792\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAl-Biltagi M, Tolba OA, El-Shanshory MR, El-Shitany N, El-Hawary ES (2012) Strain echocardiography in early detection of doxorubicin-induced left ventricular dysfunction in children with acute lymphoblastic leukemia. ISRN Pediatr 2012:1\u0026ndash;10\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCameli M, Lisi M, Righini FM, Mondillo S (2009) Left atrial strain: a new parameter for assessment of left atrial function by two-dimensional speckle tracking. Cardiovasc Ultrasound 7:6\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSaraiva RM, Demirkol S, Buakhamsri A et al (2010) Left atrial strain measured by two-dimensional speckle tracking represents a new tool to evaluate left atrial function. J Am Soc Echocardiogr 23(2):172\u0026ndash;180\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRusso C, Jin Z, Homma S et al (2012) Left atrial minimum volume and reservoir function in left ventricular diastolic dysfunction. Heart 98(10):813\u0026ndash;820\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWakami K, Ohte N, Asada K et al (2009) Correlation between left atrial wall deformation and left ventricular end-diastolic pressure. J Am Soc Echocardiogr 22(7):847\u0026ndash;851\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChatterjee K, Zhang J, Honbo N, Karliner JS (2010) Doxorubicin cardiomyopathy. Cardiology 115(2):155\u0026ndash;162\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMigrino RQ, Aggarwal D, Konorev E et al (2008) Detection of doxorubicin cardiomyopathy using two-dimensional strain echocardiography. Ultrasound Med Biol 34(2):208\u0026ndash;214\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSteinherz LJ, Steinherz PG, Tan CTC, Heller G, Murphy ML (1991) Cardiac toxicity 4 to 20 years after completing anthracycline therapy. JAMA 266(12):1672\u0026ndash;1677\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLipshultz SE, Landy DC, Lopez-Mitnik G et al (2012) Cardiovascular status of childhood cancer survivors exposed and unexposed to cardiotoxic therapy. J Clin Oncol 30(10):1050\u0026ndash;1057\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eden Hoed MA, Pluijm SM, de Groot-Kruseman HA et al (2015) The negative impact of being underweight and weight loss on survival of children with acute lymphoblastic leukemia. Haematologica 100(1):62\u0026ndash;69\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSabatino J, Di Salvo G, Prota C et al (2019) Left atrial strain to identify diastolic dysfunction in children with cardiomyopathies. J Clin Med 8(8):1243\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRique A, Cautela J, Thuny F et al (2024) Left ventricular longitudinal strain abnormalities after childhood exposure to anthracycline chemotherapy. Child (Basel) 11:378\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables are available in the Supplementary Files section.\u003c/p\u003e\n"}],"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":"Leukemia, doxorubicin, left atrial strain, global longitudinal strain, cardiotoxicity, Pediatric Cardiology","lastPublishedDoi":"10.21203/rs.3.rs-8778601/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8778601/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cb\u003eObjective:\u003c/b\u003e\u003c/p\u003e \u003cp\u003eTo compare left atrial strain parameters during reservoir, conduit, and contraction phases in pediatric patients with leukemia treated with doxorubicin and age- and sex-matched healthy controls, and to evaluate their potential role in detecting subclinical cardiotoxicity.\u003c/p\u003e\u003cp\u003e\u003cb\u003eMethods:\u003c/b\u003e\u003c/p\u003e \u003cp\u003eThis single-center, cross-sectional case\u0026ndash;control study included 22 pediatric patients with acute lymphoblastic leukemia who received a cumulative doxorubicin dose of 240 mg/m\u0026sup2; and 25 healthy controls. All participants underwent comprehensive echocardiographic evaluation, including two-dimensional speckle-tracking analysis. Left ventricular global longitudinal strain (GLS) and left atrial strain parameters were assessed. Intergroup comparisons and correlation analyses were performed using appropriate statistical methods.\u003c/p\u003e\u003cp\u003e\u003cb\u003eResults:\u003c/b\u003e\u003c/p\u003e \u003cp\u003eThe mean follow-up duration after completion of chemotherapy was 4.6\u0026thinsp;\u0026plusmn;\u0026thinsp;2.6 years. Left atrial reservoir, conduit, and contraction strain values were numerically lower in the leukemia group but did not differ significantly from controls. Mean reservoir strain was 39.4\u0026thinsp;\u0026plusmn;\u0026thinsp;7.8% in patients and 48.9\u0026thinsp;\u0026plusmn;\u0026thinsp;6.5% in controls (p\u0026thinsp;=\u0026thinsp;0.353). Conduit strain showed a trend toward significance (25.1\u0026thinsp;\u0026plusmn;\u0026thinsp;6.3% vs. 32.4\u0026thinsp;\u0026plusmn;\u0026thinsp;7.1%, p\u0026thinsp;=\u0026thinsp;0.078). Contraction strain and GLS were comparable between groups. Left ventricular wall thickness and end-diastolic diameter were significantly lower in patients, while ejection fraction remained preserved. No significant correlations were observed between strain parameters and follow-up duration.\u003c/p\u003e\u003cp\u003e\u003cb\u003eConclusion:\u003c/b\u003e\u003c/p\u003e \u003cp\u003eAt mid-term follow-up after moderate-dose doxorubicin therapy, left atrial strain parameters and GLS remained largely preserved in pediatric leukemia survivors. These findings suggest the absence of overt subclinical myocardial dysfunction at this dose level, emphasizing the importance of long-term strain-based surveillance in this population.\u003c/p\u003e","manuscriptTitle":"Comparison of Left Atrial Strain Parameters After Doxorubicin Therapy in Pediatric Patients With Leukemia and Healthy Children: A Cross-Sectional Case–Control Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-02-25 17:01:15","doi":"10.21203/rs.3.rs-8778601/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":"d5674df4-c0e1-41fe-aef7-dc9a4c701d88","owner":[],"postedDate":"February 25th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-03-22T16:39:29+00:00","versionOfRecord":[],"versionCreatedAt":"2026-02-25 17:01:15","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8778601","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8778601","identity":"rs-8778601","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}