Fragmented QRS as an Early Marker of Radiation-Induced Cardiotoxicity in Lung Cancer Patients: A Controlled Observational Study

Fragmented QRS as an Early Marker of Radiation-Induced Cardiotoxicity in Lung Cancer Patients: A Controlled Observational 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 Fragmented QRS as an Early Marker of Radiation-Induced Cardiotoxicity in Lung Cancer Patients: A Controlled Observational Study Hasan Oguz Kapicibasi, Ercan Aksit, Ozgur Yildirim This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8816305/v1 This work is licensed under a CC BY 4.0 License Status: Under Revision Version 1 posted 9 You are reading this latest preprint version Abstract Background Fragmented QRS (fQRS) is an electrocardiographic marker reflecting myocardial scarring and conduction heterogeneity and has been linked to adverse cardiac outcomes. Cardiac exposure during thoracic radiotherapy (RT) may contribute to subclinical myocardial injury. Objectives To assess the incidence and determinants of fragmented QRS development in lung cancer patients undergoing curative-intent radiotherapy. To our knowledge, this study represents the first controlled evaluation of fragmented QRS as an early electrocardiographic marker of radiation-induced cardiotoxicity in lung cancer patients. Methods Between September 2020 and September 2023, 34 lung cancer patients treated with curative-intent radiotherapy were compared with 40 sociodemographically matched controls. Patients were aged ≥ 18 years and had local advanced lung cancer. Individuals with cardiac implantable electronic devices, acute coronary syndrome, systemic connective tissue disease, sarcoidosis, or inadequate electrocardiographic data were excluded. All participants underwent post-treatment assessment using a standard 12-lead electrocardiogram. Controls underwent a single 12-lead ECG at enrollment. Fragmented QRS was identified according to established criteria. Results Fragmented QRS was observed in 9 of 34 patients (26.5%) in the radiotherapy group and in 3 of 40 controls (7.5%). The prevalence of fQRS was significantly higher among patients who received radiotherapy (p = 0.027). Conclusions Fragmented QRS appears to occur with increased frequency in lung cancer patients treated with curative-intent radiotherapy and may represent an early electrocardiographic marker of radiation-induced cardiotoxicity. Careful attention to cardiac dose during treatment planning, routine ECG surveillance, and additional cardiac evaluation should be considered in patients with detected fQRS. fragmented QRS lung cancer radiotherapy cardiotoxicity ECG Figures Figure 1 Introduction Lung cancer is one of the most commonly diagnosed malignancies worldwide and has one of the poorest prognoses (13%). It also accounts for a substantial proportion of cancer-related mortality (26%).( 1 , 2 ) In 2015, 158,040 deaths related to lung cancer were reported ( 2 , 3 ). Globally, the incidence of lung cancer in men is approximately 30–35 per 100,000, whereas it is around 48 per 100,000 in European Union countries. In our country, the incidence of lung cancer is approximately 69 per 100,000 in men and 7–8 per 100,000 in women ( 1 , 4 ). Lung cancer is generally diagnosed at advanced stages of its natural course, and more than 90% of cases are symptomatic at the time of presentation ( 5 ). Radiotherapy (RT) is used in cancer treatment for palliative, curative, adjuvant, neoadjuvant, and prophylactic purposes. The primary goal of radiotherapy is to reduce or completely eradicate tumor burden while preserving normal tissue. However, damage to normal tissue remains a major limitation of RT. To address this challenge, various strategies have been developed over time, including dose–volume modulation, image-guided radiotherapy techniques, involved-field radiotherapy, and the use of agents aimed at preventing radiation-induced lung injury ( 6 , 7 ). Radiotherapy-induced fibrosis may lead to a broad spectrum of cardiovascular complications, including pericarditis, myocardial dysfunction, heart failure, valvular abnormalities, and arrhythmias ( 8 – 10 ). These cardiovascular complications may result in reduced quality of life, increased mortality, and sudden cardiac death ( 11 , 12 ). Fragmented QRS has been shown to be a marker of myocardial fibrosis in various clinical studies ( 13 , 14 ). In light of these findings, to date, no study has specifically evaluated the relationship between regional radiotherapy and the development of fQRS in patients with lung cancer. In this study, we aimed to investigate the association between locoregional radiotherapy and the development of fragmented QRS on electrocardiography (ECG). Patients and Methods This study was conducted at Çanakkale Onsekiz Mart University (COMU) Faculty of Medicine between September 2020 and September 2023. Ethical approval was obtained from the local ethics committee of Çanakkale Onsekiz Mart University (IRB No: 2019-19). A total of 74 participants were included in this case–control study, comprising 34 lung cancer patients receiving curative-intent radiotherapy and 40 individuals in the control group. Inclusion criteria were age ≥ 18 years, stage II–IV lung cancer, and receipt of curative-intent radiotherapy with concurrent chemotherapy. Exclusion criteria included the presence of a permanent pacemaker, implantable cardioverter-defibrillator (ICD), or cardiac resynchronization therapy (CRT); acute coronary syndrome; systemic connective tissue disease; sarcoidosis; and inadequate medical records or poor-quality electrocardiograms. Figure 1. All patients underwent standard surface 12-lead electrocardiography (Nihon Kohden Cardiofax M ECG-1350; filtering range: 0.15–100 Hz; AC filtering: 60 Hz; paper speed: 25 mm/s; calibration: 10 mm/mV).Fragmented QRS was defined as the presence of an additional R wave (R′) within the QRS complex (< 120 ms), notching at the nadir of the R or S wave, or the presence of more than one R′ wave in at least two contiguous leads. Fragmentation of fQRS was also defined as the presence of an additional R wave (R′), notching at the lowest point of the S wave, or the presence of more than one R′ wave in two adjacent leads corresponding to a major coronary artery territory on resting 12-lead ECG. Fragmentation of a wide QRS complex was defined as the presence of various RSR patterns, including more than two R waves (R″), more than two notches in the R wave, or more than two notches in the upward or downward limb of the S wave ( 15 ). All electrocardiograms were evaluated by expert cardiologists who were blinded to the patient and control group assignments. Brugada-like patterns and left bundle branch block were excluded. Two independent cardiologists served as blinded reviewers, and in cases of disagreement, a third expert provided the final decision. Two-dimensional transthoracic Doppler echocardiography was performed by the same cardiology specialist who was blinded to the clinical data of the study participants. Images including at least three cardiac cycles were obtained in the left lateral decubitus and supine positions (Vivid 7, GE Vingmed, 2.5 MHz, USA). Left ventricular ejection fraction (LVEF) was calculated using M-mode measurements from the parasternal long-axis view with the cursor positioned perpendicular to the left ventricle and using the Simpson method from the apical four-chamber view. Pulmonary artery systolic pressure (PASP) was calculated from the apical four-chamber view by applying continuous-wave (CW) Doppler to the tricuspid regurgitation jet. Radiotherapy Protocol for Lung Cancer Patients Radiotherapy for patients with lung cancer was delivered using the Varian RapidArc™ system, which enables highly conformal and intensity-modulated treatment. All treatment plans were generated based on computed tomography (CT) imaging with a slice thickness of 3 mm and were optimized using the Varian treatment planning system (Eclipse™). To minimize motion artifacts, patients were immobilized in the supine position using a dedicated body immobilization system with vacuum cushions. Target volumes, including the gross tumor volume (GTV), clinical target volume (CTV), and planning target volume (PTV), were delineated in accordance with institutional protocols and the ICRU Report 83 guidelines. Organs at risk (OARs), such as the heart, spinal cord, esophagus, and contralateral lung, were carefully contoured and evaluated using dose–volume histograms (DVHs). Patients were treated using the RapidArc volumetric modulated arc therapy (VMAT) technique with 6-MV photons. For curative intent, the standard prescription dose was 60–66 Gy, delivered in once-daily fractions of 2 Gy, five days per week, over a period of 6–6.5 weeks. In patients requiring palliative treatment, hypofractionated regimens such as 30 Gy in 10 fractions or 20 Gy in 5 fractions were planned according to the clinical condition; however, no patient in the present study received palliative radiotherapy. Concurrent chemotherapy with cisplatin-based regimens was administered, particularly in patients with centrally located tumors or mediastinal lymph node involvement. In selected patients, respiratory motion management was performed using four-dimensional computed tomography (4D-CT) or respiratory gating techniques, as deemed clinically appropriate. Dose constraints were defined as follows: a maximum spinal cord dose of < 45 Gy, a mean lung dose of < 20 Gy, V20 (the percentage of lung volume receiving ≥ 20 Gy) of < 35%, a mean esophageal dose of < 34 Gy, and a mean heart dose of < 30 Gy. Adaptive replanning was performed in patients who demonstrated anatomical changes during the course of treatment. All treatment plans were reviewed and approved by a multidisciplinary team consisting of radiation oncologists and medical physicists. To ensure treatment accuracy throughout the course of radiotherapy, daily image-guided radiotherapy (IGRT) was performed using kilovoltage cone-beam computed tomography (kV CBCT). Statistical Analysis Data obtained within the scope of the study were transferred to the JAMOVI statistical software for analysis. This software was selected because it is freely available. Descriptive characteristics of the participants, including demographic variables, were analyzed using descriptive statistics (frequencies and percentages) and presented in tables. For comparisons between patients who received radiotherapy and those who did not, non-normally distributed variables—namely age, left atrium, aortic root, left ventricular diastolic diameter, left ventricular systolic diameter, left ventricular ejection fraction, interventricular septum thickness, posterior wall thickness, and pulmonary artery pressure (PAP)—were analyzed using the Mann–Whitney U test. In the entire study population, the associations between lung cancer development and smoking status, alcohol consumption, hypertension (HT), diabetes mellitus (DM), and chronic obstructive pulmonary disease (COPD) were analyzed using the chi-square test. In the subgroup of patients who received radiotherapy only, the association between radiation dose and the development of fragmented QRS was evaluated using the chi-square test. The association between receipt of radiotherapy and the development of fragmented QRS, as well as the corresponding risk estimation, was assessed using the chi-square test and risk ratio analysis. For all chi-square analyses, when more than 20% of the cells had expected frequencies of five or fewer, exact chi-square results were reported. In all statistical analyses, a p value of < 0.05 was considered statistically significant. Results A total of 74 patients were included in the study, comprising 34 patients with lung cancer and 40 control subjects. Of the lung cancer cases, 7 patients belonged to the group that received curative postoperative radiotherapy (including patients with chest wall resection, multistation N2 disease, positive bronchial surgical margins, local recurrence, and concomitant esophageal carcinoma). The control group was selected to be comparable to the lung cancer group in terms of major risk factors. Among all participants, 49 patients (66.2%) were male, 56 (75.7%) were current or former smokers, and 45 (60.8%) had chronic obstructive pulmonary disease (COPD). Fragmented QRS (fQRS) was detected in 16.2% of the total study population. The demographic and clinical characteristics of the participants are summarized in Table 1 . Although a history of smoking and chronic obstructive pulmonary disease (COPD) was more frequent in the radiotherapy (RT) group, other baseline variables were comparable between the groups. The mean age of the participants was 63.28 ± 10.68 years. Concomitant echocardiographic measurements demonstrated preserved systolic function, with a mean left ventricular ejection fraction of 56.5 ± 6.16%. Comparisons based on receipt of radiotherapy revealed no statistically significant differences between groups in terms of left atrial diameter, aortic root diameter, left ventricular diastolic and systolic diameters, or ejection fraction (p > 0.05). These findings are presented in Table 2 . Fragmented QRS (fQRS) was detected on electrocardiography in 9 of the 34 patients with lung cancer (26.5%), whereas fQRS was identified in 3 of the 40 healthy control subjects (7.5%). A statistically significant difference was observed in the incidence of fragmented QRS between patients who received radiotherapy and those who did not (p < 0.05). The calculated risk ratio was 4.44. These results are summarized in Table 3 . The prevalence of fragmented QRS (fQRS) was significantly higher in patients with lung cancer compared with matched healthy controls. All 34 patients who received radiotherapy were treated with curative-intent radiotherapy, delivered once daily, five days per week, to a total dose of 60–66 Gy (2 Gy per fraction) over 6–6.5 weeks. No statistically significant association was observed between the administered radiotherapy dose and the development of fragmented QRS (p > 0.05). These findings are presented in Table 4 . Discussion Radiation therapy is a fundamental component of cancer treatment and may be administered as adjuvant, neoadjuvant, palliative, or definitive therapy, either with or without concurrent chemotherapy. The adverse effects of radiation therapy are largely determined by the tissues included within the radiation field. Treatment of thoracic malignancies, such as Hodgkin lymphoma, lung cancer, and breast cancer, is associated with an increased risk of radiation-induced cardiovascular toxicity (RICT). ( 16 ) The first scientific descriptions of radiation-induced cardiac disease (RICT) date back to 1924. During the autopsy of a patient who had received radiotherapy for mediastinal lymphoma and subsequently died of heart failure, a German pathologist reported extensive cardiac damage.( 17 ) Fibrosis is considered the principal pathophysiological mechanism underlying radiation-induced cardiovascular injury.( 9 , 18 , 19 ) Therefore, early detection of radiotherapy-induced fibrosis in patients undergoing radiotherapy may facilitate both the management of the underlying disease and the identification and prevention of treatment-related clinical conditions. Fragmented QRS (fQRS) is an electrocardiographic finding characterized by the presence of additional R waves or notching within the QRS complex on a routine 12-lead electrocardiogram (filter range 0.15–100 Hz, AC filter 60 Hz, paper speed 25 mm/s, and amplitude 10 mm/mV). It is defined by the presence or absence of a Q wave and either an additional R wave (R′) in two contiguous leads or notching at the nadir of the R or S wave, corresponding to the territory of a major coronary artery. In contrast, the prevalence of fQRS in the healthy general population is relatively low.( 20 ) The presence of fragmented QRS (fQRS) on electrocardiography (ECG) is considered a marker of myocardial scar and fibrosis and has been shown to be significantly associated with adverse outcomes in patients with cardiovascular disease (CVD).( 21 ) In our study, the frequency of fragmented QRS (fQRS) development was significantly higher in patients with lung cancer who received curative-intent radiotherapy compared with healthy controls. The prevalence of fQRS was 26.5% in the lung cancer group versus 7.5% in the control group, and the risk of developing fQRS was approximately 4.4-fold higher among patients who underwent radiotherapy. These findings suggest that radiotherapy may have a potential impact on the cardiac conduction system and, additionally, on myocardial structural integrity. The role of postoperative curative radiotherapy (PORT) in patients with non–small cell lung cancer (NSCLC) who have undergone complete surgical resection has been clarified by the LungART randomized phase III trial. This study demonstrated that routine PORT did not improve overall survival in patients with completely resected pN2 disease; however, it was associated with an increased risk of cardiopulmonary toxicity. Consequently, PORT is not recommended as a standard approach in R0–pN2 cases. Nevertheless, in the presence of positive surgical margins (R1 or R2 resection), PORT continues to be recommended with curative intent in order to improve locoregional control. Importantly, the decision to administer PORT should be individualized within a multidisciplinary framework, taking into account surgical margin status as well as pathological risk factors ( 22 ). In our study, 7 patients with lung cancer received postoperative curative radiotherapy due to indications such as chest wall resection following surgery, multistation N2 disease, positive bronchial surgical margins, local recurrence, and synchronous esophageal cancer. Nevertheless, in patients exposed to thoracic radiotherapy, increasing cardiac radiation dose has been reported to induce myocardial fibrosis, leading to heterogeneity in electrical conduction, which may be associated with the development of fragmented QRS (fQRS) on electrocardiography.( 23 ) In our study, no statistically significant association was observed between radiotherapy dose and the development of fQRS (p > 0.05). This finding may be attributable to the fact that all patients in our cohort received radiotherapy at curative dose levels, resulting in a relatively narrow dose range. The absence of significant differences in echocardiographic parameters in our study suggests that fQRS may represent an early electrocardiographic marker that precedes overt impairment of mechanical cardiac function. This finding underscores the potential value of routine electrocardiographic monitoring in the follow-up of patients with lung cancer undergoing treatment. Moreover, the widespread availability and low cost of electrocardiography further enhance its clinical utility. Several studies have suggested that fragmented QRS may represent an important electrocardiographic parameter that should be considered in patients with chronic obstructive pulmonary disease (COPD).( 24 ) In our study, the control group was carefully selected to be comparable to the lung cancer group with respect to major cardiovascular risk factors, thereby reducing the likelihood that the observed differences could be explained solely by smoking or comorbidities. Nevertheless, a higher prevalence of COPD and a history of smoking in the radiotherapy-treated lung cancer group is an expected finding and may have constituted an additional burden contributing to cardiac electrical remodeling. Therefore, in this patient population, the effect of radiotherapy on the development of fQRS should be considered in a synergistic manner together with concomitant pulmonary and vascular factors. A key finding of our study is the increased frequency of fQRS despite preserved left ventricular systolic function. This observation supports the notion that fQRS is not merely a marker of advanced cardiac injury but may also serve as an early risk indicator. From a clinical perspective, the presence of fQRS in patients receiving radiotherapy for lung cancer warrants close surveillance for arrhythmias and future cardiovascular events. Although not routinely available in many centers, cardiovascular magnetic resonance (CMR) is considered the gold standard noninvasive imaging modality for the identification and quantification of myocardial fibrosis, owing to its superior native tissue characterization capabilities.( 25 ) However, electrocardiographic monitoring in patients receiving radiotherapy for lung cancer may be useful for the early detection of potential cardiac risk. In this context, larger prospective studies with longer follow-up are warranted to further clarify the prognostic value of fQRS and its role in clinical decision-making. This study has several limitations. The most important limitation is the lack of information regarding the presence of fQRS on electrocardiography prior to radiotherapy. As this was a hypothesis-generating case–control study, two groups with comparable demographic characteristics were analyzed. The single-center design may limit the generalizability of the findings, and the sample size was relatively small, with long-term clinical outcomes remaining unknown. In addition, longitudinal follow-up data to evaluate the temporal dynamics of fQRS development were not available.Potential confounders that may influence cardiotoxicity, such as concomitant chemotherapy, represent additional limitations, as these variables could not be adequately addressed in detailed subgroup analyses. Furthermore, coronary artery disease—one of the most important underlying causes of fQRS—could not be systematically excluded using advanced diagnostic modalities such as coronary computed tomography angiography. The development of fragmented QRS (fQRS) following lung radiotherapy is a noteworthy finding. fQRS may be considered a complementary tool for risk stratification of cardiotoxicity. In conclusion, fQRS occurs significantly more frequently in patients with lung cancer receiving curative-intent radiotherapy, suggesting that radiotherapy may induce early electrical alterations in the myocardial conduction system. To the best of our knowledge, no previous study has specifically evaluated radiotherapy-associated fQRS development in patients with lung cancer.From a clinical standpoint, minimizing cardiac dose during radiotherapy planning, incorporating fQRS screening into electrocardiography-based cardio-oncology surveillance algorithms, and considering additional cardiac evaluation—such as echocardiography, cardiac biomarkers (troponin/BNP), or advanced imaging with cardiac magnetic resonance—in patients with detected fQRS are of particular importance. Declarations Author Contribution Author Contributions: Conceptualization, H.O.K.; methodology, H.O.K., E.A., and O.Y.; formal analysis, E.A. and O.Y.; investigation, H.O.K., E.A., and O.Y.; resources, H.O.K.; data curation, H.O.K., E.A., and O.Y.; writing original draft preparation, H.O.K., E.A., and O.Y.; writing review and editing, H.O.K., E.A., and O.Y.; project administration, H.O.K. All authors have read and agreed to the published version of the manuscript References Republic of Turkey Ministry of Health, General Directorate of Public Health, Department of Cancer Control. Cancer Registry in Turkey. Accessed June 24. 2018. https://hsgm.saglik.gov.tr/tr/kanser-anasayfa Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61(2):69–90. 10.3322/caac.20107 . Siegel RL, Miller KD, Jemal A, Cancer statistics. 2015. CA Cancer J Clin. 2015;65(1):5–29. 10.3322/caac.21254 Kayı Cangır A, Yumuk PF, Dizbay Sak S, et al. Lung cancer in Turkey. J Thorac Oncol. 2022;17(10):1158–70. 10.1016/j.jtho.2022.06.001 . Beckles MA, Spiro SG, Colice GL, Rudd RM. Initial evaluation of the patient with lung cancer: symptoms, signs, laboratory tests, and paraneoplastic syndromes. Chest. 2003;123(1 Suppl):S97–104. 10.1378/chest.123.1_suppl.97s . Machtay M. Pulmonary complications of anticancer treatment. In: Abeloff MD, Armitage JO, Niederhuber JE, Kastan MB, McKenna WG, eds. Abeloff's Clinical Oncology. 4th ed. Elsevier Churchill Livingstone; 2008:969–981. Graves PR, Siddiqui F, Anscher MS, Movsas B. Radiation pulmonary toxicity: from mechanisms to management. Semin Radiat Oncol. 2010;20(3):201–7. 10.1016/j.semradonc.2010.01.009 . Jaworski C, Mariani JA, Wheeler G, Kaye DM. Cardiac complications of thoracic irradiation. J Am Coll Cardiol. 2013;61(23):2319–28. 10.1016/j.jacc.2013.01.090 . Fajardo LF, Stewart JR. Capillary injury preceding radiation-induced myocardial fibrosis. Radiology. 1971;101(2):429–33. 10.1148/101.2.429 . Duma MN, Molls M, Trott KR. From heart to heart for breast cancer patients: cardiovascular toxicities in breast cancer radiotherapy. Strahlenther Onkol. 2014;190(1):5–7. 10.1007/s00066-013-0460-9 . Paszat LF, Mackillop WJ, Groome PA, Boyd C, Schulze K, Holowaty E. Mortality from myocardial infarction after adjuvant radiotherapy for breast cancer. J Clin Oncol. 1998;16(8):2625–31. 10.1200/JCO.1998.16.8.2625 . Cuzick J, Stewart H, Rutqvist L, et al. Cause-specific mortality in long-term survivors of breast cancer who participated in trials of radiotherapy. J Clin Oncol. 1994;12(3):447–53. 10.1200/JCO.1994.12.3.447 . Basaran Y, Tigen K, Karaahmet T, et al. Fragmented QRS complexes are associated with cardiac fibrosis and intraventricular systolic dyssynchrony in nonischemic dilated cardiomyopathy. Echocardiography. 2011;28(1):62–8. 10.1111/j.1540- . Homsi M, Alsayed L, Safadi B, Mahenthiran J, Das MK. Fragmented QRS complexes on 12-lead ECG: a marker of cardiac sarcoidosis. Ann Noninvasive Electrocardiol. 2009;14(4):319–26. 10.1111/j.1542-474X.2009.00320.x . Pietrasik G, Zareba W. QRS fragmentation: diagnostic and prognostic significance. Cardiol J. 2012;19(2):114–21. Hufnagle JJ, Andersen SN, Maani EV. Radiation-Induced Cardiac Toxicity. In: StatPearls. StatPearls Publishing; 2023. Available from: https://www.ncbi.nlm.nih.gov/books/NBK554453 Rössle R. Specific roentgen injury of the heart muscle [in German]. Strahlentherapie. 1924;18:812–28. Lee C, Hahn RT. Valvular heart disease associated with radiation therapy: A contemporary review. Struct Heart. 2023;7(2):100104. 10.1016/j.shj.2022.100104 . Schultz-Hector S, Trott KR. Radiation-induced cardiovascular diseases: is the epidemiologic evidence compatible with the radiobiologic data? Int J Radiat Oncol Biol Phys. 2007;67(1):10–8. 10.1016/j.ijrobp.2006.08.071 . Das MK, Khan B, Jacob S, Kumar A, Mahenthiran J. Significance of a fragmented QRS complex versus a Q wave in patients with coronary artery disease. Circulation. 2006;113(21):2495–501. 10.1161/CIRCULATIONAHA.105.595892 . Jain R, Singh R, Yamini S, Das MK. Fragmented ECG as a risk marker in cardiovascular diseases. Curr Cardiol Rev. 2014;10(3):277–86. 10.2174/1573403x10666140514103651 . Le Pechoux C, Pourel N, Barlesi F, et al. Postoperative radiotherapy versus no postoperative radiotherapy in patients with completely resected non-small-cell lung cancer and proven mediastinal N2 involvement (Lung ART): an open-label, randomised, phase 3 trial. Lancet Oncol. 2022;23(1):104–14. 10.1016/S1470-2045(21)00606-9 . Darby SC, Ewertz M, McGale P, et al. Risk of ischemic heart disease in women after radiotherapy for breast cancer. N Engl J Med. 2013;368(11):987–98. 10.1056/NEJMoa1209825 . Eyuboglu M. Circadian blood pressure patterns and fragmented QRS localization in hypertensive patients. High Blood Press Cardiovasc Prev. 2021;28(1):57–62. 10.1007/s40292-020-00421-x . Zhu L, Wang Y, Zhao S, Lu M. Detection of myocardial fibrosis: Where we stand. Front Cardiovasc Med. 2022;9:926378. 10.3389/fcvm.2022.926378 . Tables Table 1 to 4 are available in the Supplementary Files section. Additional Declarations No competing interests reported. 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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-8816305","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":589768913,"identity":"b1233b48-7aa3-4759-bf96-9b41477edc84","order_by":0,"name":"Hasan Oguz Kapicibasi","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABEklEQVRIiWNgGAWjYDCCA2AygYGBmYHhMJDFww/mF5CiRbIBxDcgRgsDWBcDgwFYBI8WvtuHD7/m+ZMmb87O/PBwQU2djPH51YkfHhgwyPOLHcCqRfJcWpo1D0+O4c5mNoPDM44d5jG78XazBNBhhjNnJ2DVYnCGx8yYR6KCccNhHobDPGwHgFrObgBpSTC4jU+LQYU9RMu/Oh7jGWc3/yCgxfgxT0JOIlgLbxszjwF/7za8tkieYUtjnHMgLRnsl5l9h3kkbvBus0gwkMDpF74zzIc/vPmTbLud//DjzwXf6uz5+89uvvmjwkaeXxq7FiBgkwC7EM6XAKuUwKUcBJg/oGrhP4BP9SgYBaNgFIxAAADIhWCYngsMogAAAABJRU5ErkJggg==","orcid":"","institution":"University of Health Sciences","correspondingAuthor":true,"prefix":"","firstName":"Hasan","middleName":"Oguz","lastName":"Kapicibasi","suffix":""},{"id":589768914,"identity":"6cff3b43-49d2-4ec6-8c0e-29ccac33b236","order_by":1,"name":"Ercan Aksit","email":"","orcid":"","institution":"Canakkale Onsekiz Mart Universitesi Tip Fakultesi Hastanesi","correspondingAuthor":false,"prefix":"","firstName":"Ercan","middleName":"","lastName":"Aksit","suffix":""},{"id":589768915,"identity":"77540c14-6702-4a05-b847-a4f471239961","order_by":2,"name":"Ozgur Yildirim","email":"","orcid":"","institution":"Canakkale Devlet Hastanesi","correspondingAuthor":false,"prefix":"","firstName":"Ozgur","middleName":"","lastName":"Yildirim","suffix":""}],"badges":[],"createdAt":"2026-02-07 14:53:13","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8816305/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8816305/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":102515906,"identity":"0c2564ef-ddfc-4ea6-abfd-3f6c65b2f5b7","added_by":"auto","created_at":"2026-02-12 13:44:50","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":122925,"visible":true,"origin":"","legend":"\u003cp\u003eStudy Flow Chart\u003c/p\u003e","description":"","filename":"figure1300DP.png","url":"https://assets-eu.researchsquare.com/files/rs-8816305/v1/566d65778df811c21274ec03.png"},{"id":102515908,"identity":"ffa0baad-f7aa-449b-8cc3-60654923830b","added_by":"auto","created_at":"2026-02-12 13:44:54","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":526632,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8816305/v1/e3802eda-28d8-4373-97a9-5135adb19403.pdf"},{"id":102515907,"identity":"6d6d2fe8-6d1a-4a05-b1cf-62ced16b87e6","added_by":"auto","created_at":"2026-02-12 13:44:50","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":23748,"visible":true,"origin":"","legend":"","description":"","filename":"Tables.docx","url":"https://assets-eu.researchsquare.com/files/rs-8816305/v1/6e50d532329f40170f45295d.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003eFragmented QRS as an Early Marker of Radiation-Induced Cardiotoxicity in Lung Cancer Patients: A Controlled Observational Study\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eLung cancer is one of the most commonly diagnosed malignancies worldwide and has one of the poorest prognoses (13%). It also accounts for a substantial proportion of cancer-related mortality (26%).(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) In 2015, 158,040 deaths related to lung cancer were reported (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). Globally, the incidence of lung cancer in men is approximately 30\u0026ndash;35 per 100,000, whereas it is around 48 per 100,000 in European Union countries. In our country, the incidence of lung cancer is approximately 69 per 100,000 in men and 7\u0026ndash;8 per 100,000 in women (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). Lung cancer is generally diagnosed at advanced stages of its natural course, and more than 90% of cases are symptomatic at the time of presentation (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). Radiotherapy (RT) is used in cancer treatment for palliative, curative, adjuvant, neoadjuvant, and prophylactic purposes. The primary goal of radiotherapy is to reduce or completely eradicate tumor burden while preserving normal tissue. However, damage to normal tissue remains a major limitation of RT. To address this challenge, various strategies have been developed over time, including dose\u0026ndash;volume modulation, image-guided radiotherapy techniques, involved-field radiotherapy, and the use of agents aimed at preventing radiation-induced lung injury (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). Radiotherapy-induced fibrosis may lead to a broad spectrum of cardiovascular complications, including pericarditis, myocardial dysfunction, heart failure, valvular abnormalities, and arrhythmias (\u003cspan additionalcitationids=\"CR9\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). These cardiovascular complications may result in reduced quality of life, increased mortality, and sudden cardiac death (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). Fragmented QRS has been shown to be a marker of myocardial fibrosis in various clinical studies (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). In light of these findings, to date, no study has specifically evaluated the relationship between regional radiotherapy and the development of fQRS in patients with lung cancer.\u003c/p\u003e \u003cp\u003eIn this study, we aimed to investigate the association between locoregional radiotherapy and the development of fragmented QRS on electrocardiography (ECG).\u003c/p\u003e"},{"header":"Patients and Methods","content":"\u003cp\u003eThis study was conducted at \u0026Ccedil;anakkale Onsekiz Mart University (COMU) Faculty of Medicine between September 2020 and September 2023. Ethical approval was obtained from the local ethics committee of \u0026Ccedil;anakkale Onsekiz Mart University (IRB No: 2019-19). A total of 74 participants were included in this case\u0026ndash;control study, comprising 34 lung cancer patients receiving curative-intent radiotherapy and 40 individuals in the control group.\u003c/p\u003e \u003cp\u003e \u003cb\u003eInclusion criteria\u003c/b\u003e were age\u0026thinsp;\u0026ge;\u0026thinsp;18 years, stage II\u0026ndash;IV lung cancer, and receipt of curative-intent radiotherapy with concurrent chemotherapy. \u003cb\u003eExclusion criteria\u003c/b\u003e included the presence of a permanent pacemaker, implantable cardioverter-defibrillator (ICD), or cardiac resynchronization therapy (CRT); acute coronary syndrome; systemic connective tissue disease; sarcoidosis; and inadequate medical records or poor-quality electrocardiograms. Figure\u0026nbsp;1.\u003c/p\u003e \u003cp\u003eAll patients underwent standard surface 12-lead electrocardiography (Nihon Kohden Cardiofax M ECG-1350; filtering range: 0.15\u0026ndash;100 Hz; AC filtering: 60 Hz; paper speed: 25 mm/s; calibration: 10 mm/mV).Fragmented QRS was defined as the presence of an additional R wave (R\u0026prime;) within the QRS complex (\u0026lt;\u0026thinsp;120 ms), notching at the nadir of the R or S wave, or the presence of more than one R\u0026prime; wave in at least two contiguous leads. Fragmentation of fQRS was also defined as the presence of an additional R wave (R\u0026prime;), notching at the lowest point of the S wave, or the presence of more than one R\u0026prime; wave in two adjacent leads corresponding to a major coronary artery territory on resting 12-lead ECG.\u003c/p\u003e \u003cp\u003eFragmentation of a wide QRS complex was defined as the presence of various RSR patterns, including more than two R waves (R\u0026Prime;), more than two notches in the R wave, or more than two notches in the upward or downward limb of the S wave (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eAll electrocardiograms were evaluated by expert cardiologists who were blinded to the patient and control group assignments. Brugada-like patterns and left bundle branch block were excluded. Two independent cardiologists served as blinded reviewers, and in cases of disagreement, a third expert provided the final decision.\u003c/p\u003e \u003cp\u003eTwo-dimensional transthoracic Doppler echocardiography was performed by the same cardiology specialist who was blinded to the clinical data of the study participants. Images including at least three cardiac cycles were obtained in the left lateral decubitus and supine positions (Vivid 7, GE Vingmed, 2.5 MHz, USA). Left ventricular ejection fraction (LVEF) was calculated using M-mode measurements from the parasternal long-axis view with the cursor positioned perpendicular to the left ventricle and using the Simpson method from the apical four-chamber view. Pulmonary artery systolic pressure (PASP) was calculated from the apical four-chamber view by applying continuous-wave (CW) Doppler to the tricuspid regurgitation jet.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eRadiotherapy Protocol for Lung Cancer Patients\u003c/h2\u003e \u003cp\u003eRadiotherapy for patients with lung cancer was delivered using the Varian RapidArc\u0026trade; system, which enables highly conformal and intensity-modulated treatment. All treatment plans were generated based on computed tomography (CT) imaging with a slice thickness of 3 mm and were optimized using the Varian treatment planning system (Eclipse\u0026trade;). To minimize motion artifacts, patients were immobilized in the supine position using a dedicated body immobilization system with vacuum cushions.\u003c/p\u003e \u003cp\u003e Target volumes, including the gross tumor volume (GTV), clinical target volume (CTV), and planning target volume (PTV), were delineated in accordance with institutional protocols and the ICRU Report 83 guidelines. Organs at risk (OARs), such as the heart, spinal cord, esophagus, and contralateral lung, were carefully contoured and evaluated using dose\u0026ndash;volume histograms (DVHs).\u003c/p\u003e \u003cp\u003ePatients were treated using the RapidArc volumetric modulated arc therapy (VMAT) technique with 6-MV photons. For curative intent, the standard prescription dose was 60\u0026ndash;66 Gy, delivered in once-daily fractions of 2 Gy, five days per week, over a period of 6\u0026ndash;6.5 weeks. In patients requiring palliative treatment, hypofractionated regimens such as 30 Gy in 10 fractions or 20 Gy in 5 fractions were planned according to the clinical condition; however, no patient in the present study received palliative radiotherapy. Concurrent chemotherapy with cisplatin-based regimens was administered, particularly in patients with centrally located tumors or mediastinal lymph node involvement. In selected patients, respiratory motion management was performed using four-dimensional computed tomography (4D-CT) or respiratory gating techniques, as deemed clinically appropriate. Dose constraints were defined as follows: a maximum spinal cord dose of \u0026lt;\u0026thinsp;45 Gy, a mean lung dose of \u0026lt;\u0026thinsp;20 Gy, V20 (the percentage of lung volume receiving\u0026thinsp;\u0026ge;\u0026thinsp;20 Gy) of \u0026lt;\u0026thinsp;35%, a mean esophageal dose of \u0026lt;\u0026thinsp;34 Gy, and a mean heart dose of \u0026lt;\u0026thinsp;30 Gy. Adaptive replanning was performed in patients who demonstrated anatomical changes during the course of treatment. All treatment plans were reviewed and approved by a multidisciplinary team consisting of radiation oncologists and medical physicists. To ensure treatment accuracy throughout the course of radiotherapy, daily image-guided radiotherapy (IGRT) was performed using kilovoltage cone-beam computed tomography (kV CBCT).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003e Data obtained within the scope of the study were transferred to the JAMOVI statistical software for analysis. This software was selected because it is freely available. Descriptive characteristics of the participants, including demographic variables, were analyzed using descriptive statistics (frequencies and percentages) and presented in tables. For comparisons between patients who received radiotherapy and those who did not, non-normally distributed variables\u0026mdash;namely age, left atrium, aortic root, left ventricular diastolic diameter, left ventricular systolic diameter, left ventricular ejection fraction, interventricular septum thickness, posterior wall thickness, and pulmonary artery pressure (PAP)\u0026mdash;were analyzed using the Mann\u0026ndash;Whitney U test.\u003c/p\u003e \u003cp\u003eIn the entire study population, the associations between lung cancer development and smoking status, alcohol consumption, hypertension (HT), diabetes mellitus (DM), and chronic obstructive pulmonary disease (COPD) were analyzed using the chi-square test. In the subgroup of patients who received radiotherapy only, the association between radiation dose and the development of fragmented QRS was evaluated using the chi-square test. The association between receipt of radiotherapy and the development of fragmented QRS, as well as the corresponding risk estimation, was assessed using the chi-square test and risk ratio analysis.\u003c/p\u003e \u003cp\u003eFor all chi-square analyses, when more than 20% of the cells had expected frequencies of five or fewer, exact chi-square results were reported. In all statistical analyses, a p value of \u0026lt;\u0026thinsp;0.05 was considered statistically significant.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eA total of 74 patients were included in the study, comprising 34 patients with lung cancer and 40 control subjects. Of the lung cancer cases, 7 patients belonged to the group that received curative postoperative radiotherapy (including patients with chest wall resection, multistation N2 disease, positive bronchial surgical margins, local recurrence, and concomitant esophageal carcinoma). The control group was selected to be comparable to the lung cancer group in terms of major risk factors.\u003c/p\u003e\n\u003cp\u003eAmong all participants, 49 patients (66.2%) were male, 56 (75.7%) were current or former smokers, and 45 (60.8%) had chronic obstructive pulmonary disease (COPD). Fragmented QRS (fQRS) was detected in 16.2% of the total study population. The demographic and clinical characteristics of the participants are summarized in \u003cstrong\u003eTable 1\u003c/strong\u003e.\u003c/p\u003e\n\u003cp\u003eAlthough a history of smoking and chronic obstructive pulmonary disease (COPD) was more frequent in the radiotherapy (RT) group, other baseline variables were comparable between the groups. The mean age of the participants was 63.28 \u0026plusmn; 10.68 years. Concomitant echocardiographic measurements demonstrated preserved systolic function, with a mean left ventricular ejection fraction of 56.5 \u0026plusmn; 6.16%.\u003c/p\u003e\n\u003cp\u003eComparisons based on receipt of radiotherapy revealed no statistically significant differences between groups in terms of left atrial diameter, aortic root diameter, left ventricular diastolic and systolic diameters, or ejection fraction (p \u0026gt; 0.05). These findings are presented in \u003cstrong\u003eTable 2\u003c/strong\u003e.\u003c/p\u003e\n\u003cp\u003eFragmented QRS (fQRS) was detected on electrocardiography in 9 of the 34 patients with lung cancer (26.5%), whereas fQRS was identified in 3 of the 40 healthy control subjects (7.5%). A statistically significant difference was observed in the incidence of fragmented QRS between patients who received radiotherapy and those who did not (p \u0026lt; 0.05). The calculated risk ratio was 4.44. These results are summarized in \u003cstrong\u003eTable 3\u003c/strong\u003e.\u003c/p\u003e\n\u003cp\u003eThe prevalence of fragmented QRS (fQRS) was significantly higher in patients with lung cancer compared with matched healthy controls. All 34 patients who received radiotherapy were treated with curative-intent radiotherapy, delivered once daily, five days per week, to a total dose of 60\u0026ndash;66 Gy (2 Gy per fraction) over 6\u0026ndash;6.5 weeks. No statistically significant association was observed between the administered radiotherapy dose and the development of fragmented QRS (p \u0026gt; 0.05). These findings are presented in \u003cstrong\u003eTable 4\u003c/strong\u003e.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eRadiation therapy is a fundamental component of cancer treatment and may be administered as adjuvant, neoadjuvant, palliative, or definitive therapy, either with or without concurrent chemotherapy. The adverse effects of radiation therapy are largely determined by the tissues included within the radiation field. Treatment of thoracic malignancies, such as Hodgkin lymphoma, lung cancer, and breast cancer, is associated with an increased risk of radiation-induced cardiovascular toxicity (RICT). (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eThe first scientific descriptions of radiation-induced cardiac disease (RICT) date back to 1924. During the autopsy of a patient who had received radiotherapy for mediastinal lymphoma and subsequently died of heart failure, a German pathologist reported extensive cardiac damage.(\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e) Fibrosis is considered the principal pathophysiological mechanism underlying radiation-induced cardiovascular injury.(\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eTherefore, early detection of radiotherapy-induced fibrosis in patients undergoing radiotherapy may facilitate both the management of the underlying disease and the identification and prevention of treatment-related clinical conditions. Fragmented QRS (fQRS) is an electrocardiographic finding characterized by the presence of additional R waves or notching within the QRS complex on a routine 12-lead electrocardiogram (filter range 0.15\u0026ndash;100 Hz, AC filter 60 Hz, paper speed 25 mm/s, and amplitude 10 mm/mV). It is defined by the presence or absence of a Q wave and either an additional R wave (R\u0026prime;) in two contiguous leads or notching at the nadir of the R or S wave, corresponding to the territory of a major coronary artery. In contrast, the prevalence of fQRS in the healthy general population is relatively low.(\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e) The presence of fragmented QRS (fQRS) on electrocardiography (ECG) is considered a marker of myocardial scar and fibrosis and has been shown to be significantly associated with adverse outcomes in patients with cardiovascular disease (CVD).(\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eIn our study, the frequency of fragmented QRS (fQRS) development was significantly higher in patients with lung cancer who received curative-intent radiotherapy compared with healthy controls. The prevalence of fQRS was 26.5% in the lung cancer group versus 7.5% in the control group, and the risk of developing fQRS was approximately 4.4-fold higher among patients who underwent radiotherapy. These findings suggest that radiotherapy may have a potential impact on the cardiac conduction system and, additionally, on myocardial structural integrity.\u003c/p\u003e \u003cp\u003eThe role of postoperative curative radiotherapy (PORT) in patients with non\u0026ndash;small cell lung cancer (NSCLC) who have undergone complete surgical resection has been clarified by the LungART randomized phase III trial. This study demonstrated that routine PORT did not improve overall survival in patients with completely resected pN2 disease; however, it was associated with an increased risk of cardiopulmonary toxicity. Consequently, PORT is not recommended as a standard approach in R0\u0026ndash;pN2 cases.\u003c/p\u003e \u003cp\u003eNevertheless, in the presence of positive surgical margins (R1 or R2 resection), PORT continues to be recommended with curative intent in order to improve locoregional control. Importantly, the decision to administer PORT should be individualized within a multidisciplinary framework, taking into account surgical margin status as well as pathological risk factors (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn our study, 7 patients with lung cancer received postoperative curative radiotherapy due to indications such as chest wall resection following surgery, multistation N2 disease, positive bronchial surgical margins, local recurrence, and synchronous esophageal cancer.\u003c/p\u003e \u003cp\u003eNevertheless, in patients exposed to thoracic radiotherapy, increasing cardiac radiation dose has been reported to induce myocardial fibrosis, leading to heterogeneity in electrical conduction, which may be associated with the development of fragmented QRS (fQRS) on electrocardiography.(\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e) In our study, no statistically significant association was observed between radiotherapy dose and the development of fQRS (p\u0026thinsp;\u0026gt;\u0026thinsp;0.05). This finding may be attributable to the fact that all patients in our cohort received radiotherapy at curative dose levels, resulting in a relatively narrow dose range.\u003c/p\u003e \u003cp\u003eThe absence of significant differences in echocardiographic parameters in our study suggests that fQRS may represent an early electrocardiographic marker that precedes overt impairment of mechanical cardiac function. This finding underscores the potential value of routine electrocardiographic monitoring in the follow-up of patients with lung cancer undergoing treatment. Moreover, the widespread availability and low cost of electrocardiography further enhance its clinical utility. Several studies have suggested that fragmented QRS may represent an important electrocardiographic parameter that should be considered in patients with chronic obstructive pulmonary disease (COPD).(\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eIn our study, the control group was carefully selected to be comparable to the lung cancer group with respect to major cardiovascular risk factors, thereby reducing the likelihood that the observed differences could be explained solely by smoking or comorbidities. Nevertheless, a higher prevalence of COPD and a history of smoking in the radiotherapy-treated lung cancer group is an expected finding and may have constituted an additional burden contributing to cardiac electrical remodeling.\u003c/p\u003e \u003cp\u003eTherefore, in this patient population, the effect of radiotherapy on the development of fQRS should be considered in a synergistic manner together with concomitant pulmonary and vascular factors. A key finding of our study is the increased frequency of fQRS despite preserved left ventricular systolic function. This observation supports the notion that fQRS is not merely a marker of advanced cardiac injury but may also serve as an early risk indicator. From a clinical perspective, the presence of fQRS in patients receiving radiotherapy for lung cancer warrants close surveillance for arrhythmias and future cardiovascular events.\u003c/p\u003e \u003cp\u003eAlthough not routinely available in many centers, cardiovascular magnetic resonance (CMR) is considered the gold standard noninvasive imaging modality for the identification and quantification of myocardial fibrosis, owing to its superior native tissue characterization capabilities.(\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e) However, electrocardiographic monitoring in patients receiving radiotherapy for lung cancer may be useful for the early detection of potential cardiac risk. In this context, larger prospective studies with longer follow-up are warranted to further clarify the prognostic value of fQRS and its role in clinical decision-making.\u003c/p\u003e \u003cp\u003eThis study has several limitations. The most important limitation is the lack of information regarding the presence of fQRS on electrocardiography prior to radiotherapy. As this was a hypothesis-generating case\u0026ndash;control study, two groups with comparable demographic characteristics were analyzed. The single-center design may limit the generalizability of the findings, and the sample size was relatively small, with long-term clinical outcomes remaining unknown. In addition, longitudinal follow-up data to evaluate the temporal dynamics of fQRS development were not available.Potential confounders that may influence cardiotoxicity, such as concomitant chemotherapy, represent additional limitations, as these variables could not be adequately addressed in detailed subgroup analyses. Furthermore, coronary artery disease\u0026mdash;one of the most important underlying causes of fQRS\u0026mdash;could not be systematically excluded using advanced diagnostic modalities such as coronary computed tomography angiography.\u003c/p\u003e \u003cp\u003eThe development of fragmented QRS (fQRS) following lung radiotherapy is a noteworthy finding. fQRS may be considered a complementary tool for risk stratification of cardiotoxicity. In conclusion, fQRS occurs significantly more frequently in patients with lung cancer receiving curative-intent radiotherapy, suggesting that radiotherapy may induce early electrical alterations in the myocardial conduction system. To the best of our knowledge, no previous study has specifically evaluated radiotherapy-associated fQRS development in patients with lung cancer.From a clinical standpoint, minimizing cardiac dose during radiotherapy planning, incorporating fQRS screening into electrocardiography-based cardio-oncology surveillance algorithms, and considering additional cardiac evaluation\u0026mdash;such as echocardiography, cardiac biomarkers (troponin/BNP), or advanced imaging with cardiac magnetic resonance\u0026mdash;in patients with detected fQRS are of particular importance.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eAuthor Contributions: Conceptualization, H.O.K.; methodology, H.O.K., E.A., and O.Y.; formal analysis, E.A. and O.Y.; investigation, H.O.K., E.A., and O.Y.; resources, H.O.K.; data curation, H.O.K., E.A., and O.Y.; writing original draft preparation, H.O.K., E.A., and O.Y.; writing review and editing, H.O.K., E.A., and O.Y.; project administration, H.O.K. All authors have read and agreed to the published version of the manuscript\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eRepublic of Turkey Ministry of Health, General Directorate of Public Health, Department of Cancer Control. Cancer Registry in Turkey. Accessed June 24. 2018. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://hsgm.saglik.gov.tr/tr/kanser-anasayfa\u003c/span\u003e\u003cspan address=\"https://hsgm.saglik.gov.tr/tr/kanser-anasayfa\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61(2):69\u0026ndash;90. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3322/caac.20107\u003c/span\u003e\u003cspan address=\"10.3322/caac.20107\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSiegel RL, Miller KD, Jemal A, Cancer statistics. 2015. CA Cancer J Clin. 2015;65(1):5\u0026ndash;29. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3322/caac.21254\u003c/span\u003e\u003cspan address=\"10.3322/caac.21254\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKayı Cangır A, Yumuk PF, Dizbay Sak S, et al. Lung cancer in Turkey. J Thorac Oncol. 2022;17(10):1158\u0026ndash;70. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.jtho.2022.06.001\u003c/span\u003e\u003cspan address=\"10.1016/j.jtho.2022.06.001\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBeckles MA, Spiro SG, Colice GL, Rudd RM. Initial evaluation of the patient with lung cancer: symptoms, signs, laboratory tests, and paraneoplastic syndromes. Chest. 2003;123(1 Suppl):S97\u0026ndash;104. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1378/chest.123.1_suppl.97s\u003c/span\u003e\u003cspan address=\"10.1378/chest.123.1_suppl.97s\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMachtay M. Pulmonary complications of anticancer treatment. In: Abeloff MD, Armitage JO, Niederhuber JE, Kastan MB, McKenna WG, eds. Abeloff's Clinical Oncology. 4th ed. Elsevier Churchill Livingstone; 2008:969\u0026ndash;981.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGraves PR, Siddiqui F, Anscher MS, Movsas B. Radiation pulmonary toxicity: from mechanisms to management. Semin Radiat Oncol. 2010;20(3):201\u0026ndash;7. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.semradonc.2010.01.009\u003c/span\u003e\u003cspan address=\"10.1016/j.semradonc.2010.01.009\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJaworski C, Mariani JA, Wheeler G, Kaye DM. Cardiac complications of thoracic irradiation. J Am Coll Cardiol. 2013;61(23):2319\u0026ndash;28. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.jacc.2013.01.090\u003c/span\u003e\u003cspan address=\"10.1016/j.jacc.2013.01.090\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFajardo LF, Stewart JR. Capillary injury preceding radiation-induced myocardial fibrosis. Radiology. 1971;101(2):429\u0026ndash;33. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1148/101.2.429\u003c/span\u003e\u003cspan address=\"10.1148/101.2.429\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDuma MN, Molls M, Trott KR. From heart to heart for breast cancer patients: cardiovascular toxicities in breast cancer radiotherapy. Strahlenther Onkol. 2014;190(1):5\u0026ndash;7. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s00066-013-0460-9\u003c/span\u003e\u003cspan address=\"10.1007/s00066-013-0460-9\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePaszat LF, Mackillop WJ, Groome PA, Boyd C, Schulze K, Holowaty E. Mortality from myocardial infarction after adjuvant radiotherapy for breast cancer. J Clin Oncol. 1998;16(8):2625\u0026ndash;31. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1200/JCO.1998.16.8.2625\u003c/span\u003e\u003cspan address=\"10.1200/JCO.1998.16.8.2625\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCuzick J, Stewart H, Rutqvist L, et al. Cause-specific mortality in long-term survivors of breast cancer who participated in trials of radiotherapy. J Clin Oncol. 1994;12(3):447\u0026ndash;53. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1200/JCO.1994.12.3.447\u003c/span\u003e\u003cspan address=\"10.1200/JCO.1994.12.3.447\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBasaran Y, Tigen K, Karaahmet T, et al. Fragmented QRS complexes are associated with cardiac fibrosis and intraventricular systolic dyssynchrony in nonischemic dilated cardiomyopathy. Echocardiography. 2011;28(1):62\u0026ndash;8. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1111/j.1540-\u003c/span\u003e\u003cspan address=\"10.1111/j.1540-\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHomsi M, Alsayed L, Safadi B, Mahenthiran J, Das MK. Fragmented QRS complexes on 12-lead ECG: a marker of cardiac sarcoidosis. Ann Noninvasive Electrocardiol. 2009;14(4):319\u0026ndash;26. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1111/j.1542-474X.2009.00320.x\u003c/span\u003e\u003cspan address=\"10.1111/j.1542-474X.2009.00320.x\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePietrasik G, Zareba W. QRS fragmentation: diagnostic and prognostic significance. Cardiol J. 2012;19(2):114\u0026ndash;21.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHufnagle JJ, Andersen SN, Maani EV. Radiation-Induced Cardiac Toxicity. In: StatPearls. StatPearls Publishing; 2023. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.ncbi.nlm.nih.gov/books/NBK554453\u003c/span\u003e\u003cspan address=\"https://www.ncbi.nlm.nih.gov/books/NBK554453\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eR\u0026ouml;ssle R. Specific roentgen injury of the heart muscle [in German]. Strahlentherapie. 1924;18:812\u0026ndash;28.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLee C, Hahn RT. Valvular heart disease associated with radiation therapy: A contemporary review. Struct Heart. 2023;7(2):100104. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.shj.2022.100104\u003c/span\u003e\u003cspan address=\"10.1016/j.shj.2022.100104\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSchultz-Hector S, Trott KR. Radiation-induced cardiovascular diseases: is the epidemiologic evidence compatible with the radiobiologic data? Int J Radiat Oncol Biol Phys. 2007;67(1):10\u0026ndash;8. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.ijrobp.2006.08.071\u003c/span\u003e\u003cspan address=\"10.1016/j.ijrobp.2006.08.071\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDas MK, Khan B, Jacob S, Kumar A, Mahenthiran J. Significance of a fragmented QRS complex versus a Q wave in patients with coronary artery disease. Circulation. 2006;113(21):2495\u0026ndash;501. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1161/CIRCULATIONAHA.105.595892\u003c/span\u003e\u003cspan address=\"10.1161/CIRCULATIONAHA.105.595892\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJain R, Singh R, Yamini S, Das MK. Fragmented ECG as a risk marker in cardiovascular diseases. Curr Cardiol Rev. 2014;10(3):277\u0026ndash;86. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.2174/1573403x10666140514103651\u003c/span\u003e\u003cspan address=\"10.2174/1573403x10666140514103651\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLe Pechoux C, Pourel N, Barlesi F, et al. Postoperative radiotherapy versus no postoperative radiotherapy in patients with completely resected non-small-cell lung cancer and proven mediastinal N2 involvement (Lung ART): an open-label, randomised, phase 3 trial. Lancet Oncol. 2022;23(1):104\u0026ndash;14. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/S1470-2045(21)00606-9\u003c/span\u003e\u003cspan address=\"10.1016/S1470-2045(21)00606-9\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDarby SC, Ewertz M, McGale P, et al. Risk of ischemic heart disease in women after radiotherapy for breast cancer. N Engl J Med. 2013;368(11):987\u0026ndash;98. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1056/NEJMoa1209825\u003c/span\u003e\u003cspan address=\"10.1056/NEJMoa1209825\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEyuboglu M. Circadian blood pressure patterns and fragmented QRS localization in hypertensive patients. High Blood Press Cardiovasc Prev. 2021;28(1):57\u0026ndash;62. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s40292-020-00421-x\u003c/span\u003e\u003cspan address=\"10.1007/s40292-020-00421-x\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhu L, Wang Y, Zhao S, Lu M. Detection of myocardial fibrosis: Where we stand. Front Cardiovasc Med. 2022;9:926378. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3389/fcvm.2022.926378\u003c/span\u003e\u003cspan address=\"10.3389/fcvm.2022.926378\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1 to 4 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"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":"cardio-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"caon","sideBox":"Learn more about [Cardio-Oncology](http://cardiooncologyjournal.biomedcentral.com)","snPcode":"40959","submissionUrl":"https://submission.nature.com/new-submission/40959/3","title":"Cardio-Oncology","twitterHandle":"@OncoBioMed","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"fragmented QRS, lung cancer, radiotherapy, cardiotoxicity, ECG","lastPublishedDoi":"10.21203/rs.3.rs-8816305/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8816305/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eFragmented QRS (fQRS) is an electrocardiographic marker reflecting myocardial scarring and conduction heterogeneity and has been linked to adverse cardiac outcomes. Cardiac exposure during thoracic radiotherapy (RT) may contribute to subclinical myocardial injury.\u003c/p\u003e\u003ch2\u003eObjectives\u003c/h2\u003e \u003cp\u003eTo assess the incidence and determinants of fragmented QRS development in lung cancer patients undergoing curative-intent radiotherapy. To our knowledge, this study represents the first controlled evaluation of fragmented QRS as an early electrocardiographic marker of radiation-induced cardiotoxicity in lung cancer patients.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eBetween September 2020 and September 2023, 34 lung cancer patients treated with curative-intent radiotherapy were compared with 40 sociodemographically matched controls. Patients were aged\u0026thinsp;\u0026ge;\u0026thinsp;18 years and had local advanced lung cancer. Individuals with cardiac implantable electronic devices, acute coronary syndrome, systemic connective tissue disease, sarcoidosis, or inadequate electrocardiographic data were excluded. All participants underwent post-treatment assessment using a standard 12-lead electrocardiogram. Controls underwent a single 12-lead ECG at enrollment. Fragmented QRS was identified according to established criteria.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eFragmented QRS was observed in 9 of 34 patients (26.5%) in the radiotherapy group and in 3 of 40 controls (7.5%). The prevalence of fQRS was significantly higher among patients who received radiotherapy (p\u0026thinsp;=\u0026thinsp;0.027).\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eFragmented QRS appears to occur with increased frequency in lung cancer patients treated with curative-intent radiotherapy and may represent an early electrocardiographic marker of radiation-induced cardiotoxicity. Careful attention to cardiac dose during treatment planning, routine ECG surveillance, and additional cardiac evaluation should be considered in patients with detected fQRS.\u003c/p\u003e","manuscriptTitle":"Fragmented QRS as an Early Marker of Radiation-Induced Cardiotoxicity in Lung Cancer Patients: A Controlled Observational Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-02-12 13:44:41","doi":"10.21203/rs.3.rs-8816305/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-05-11T10:27:02+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-05-08T19:26:56+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"122499987805523863647868125337824630371","date":"2026-04-20T21:35:53+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-03-08T17:22:35+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"246002313953290029365105669734155460993","date":"2026-02-24T01:44:09+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-02-15T15:53:19+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-02-11T16:45:16+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-02-10T05:20:17+00:00","index":"","fulltext":""},{"type":"submitted","content":"Cardio-Oncology","date":"2026-02-07T14:32:05+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"cardio-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"caon","sideBox":"Learn more about [Cardio-Oncology](http://cardiooncologyjournal.biomedcentral.com)","snPcode":"40959","submissionUrl":"https://submission.nature.com/new-submission/40959/3","title":"Cardio-Oncology","twitterHandle":"@OncoBioMed","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"332a3928-7751-41fc-ad0e-b7f82153648e","owner":[],"postedDate":"February 12th, 2026","published":true,"recentEditorialEvents":[{"type":"decision","content":"Revision requested","date":"2026-05-11T10:27:02+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-05-08T19:26:56+00:00","index":16,"fulltext":""}],"rejectedJournal":[],"revision":"","amendment":"","status":"in-revision","subjectAreas":[],"tags":[],"updatedAt":"2026-05-11T10:40:13+00:00","versionOfRecord":[],"versionCreatedAt":"2026-02-12 13:44:41","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8816305","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8816305","identity":"rs-8816305","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}