Early Right Ventricular Injury and Myocardial Metabolic Changes After Contemporary Thoracic Radiotherapy: The CONNECT study

Early Right Ventricular Injury and Myocardial Metabolic Changes After Contemporary Thoracic Radiotherapy: The CONNECT 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 Article Early Right Ventricular Injury and Myocardial Metabolic Changes After Contemporary Thoracic Radiotherapy: The CONNECT study Georgios Ntentas, Eliana Reyes, Kasia Owczarczyk, Vijay Maharajan, and 15 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8604030/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Radiation-related cardiovascular disease (CVD) is a major concern for cancer survivors, yet few methods exist to detect early cardiac injury within the first year of thoracic radiotherapy. Surveillance has largely focused on the left ventricle (LV), with little attention given to the right heart which may be particularly vulnerable to radiation due to its thin wall and anterior anatomical location. We aimed to prospectively evaluate potential early multimodality biomarkers of radiation-related cardiotoxicity and examine their association with radiation dose considering the whole heart and individual chambers. Methods CONNECT was a prospective, longitudinal study enrolling patients receiving thoracic radiotherapy for lymphoma, oesophageal, or lung cancer. Participants had multimodality assessments at baseline, after anthracycline-based chemotherapy (lymphoma only), within 2 weeks after radiotherapy and after 6 months, including simultaneous cardiac 18F- fluoro-2-deoxy-D-glucose (18F-FDG) PET/MRI, serum biomarkers and 12-lead ECG. Associations between findings and radiation doses to the heart were examined. Results Twenty-four patients (72 PET/MRI scans) were analysed. Both LVEF and RVEF declined early, but only RVEF remained persistently reduced at 6 months (−5.9%, p=0.004), with ≥10% decline in 40% of patients. Abnormal 18F-FDG uptake emerged in 35% of patients at 6 months, localised to the basal myocardium. Both reduction in RVEF and abnormal uptake were correlated with cardiac doses. Relative LV global longitudinal strain was impaired (>15%) at 6 months in 35% of patients. Troponin rises were modest, transient, and not predictive of dysfunction at 6 months. T1, T2, late gadolinium enhancement and ECG showed no change. Conclusions CONNECT demonstrates that persistent early radiation-related cardiotoxicity is right sided-predominant, dose-dependent, and accompanied by left ventricular myocardial metabolic changes. These findings identify the right heart as a critical, overlooked area in radiotherapy treatment planning and cardio-oncology surveillance. Health sciences/Diseases/Cancer Health sciences/Diseases/Cardiovascular diseases Health sciences/Medical research/Biomarkers Full Text Additional Declarations There is NO Competing Interest. This study was reviewed and approved by the UK Health Research Authority and Health and Care Research Wales (IRAS 289880 & REC reference 21/YH/0170). Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8604030","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":574731683,"identity":"223e8bae-618f-4b5c-8da5-c29d5bea64be","order_by":0,"name":"Georgios Ntentas","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABBElEQVRIiWNgGAWjYAgACTkGCWLV8jAwMDYwMFgYQ7UYEK2lIrGBkBZ59+ZjH79UMOTZs/cef/Djj0T6dun2B8wFFX9wajE8cyx5tswZhmIennOJjb1tErk755wxYJ5xBrcthjNyjJkl2xgSeyRyDBt4GyRyN9zIYWDmbcOjZf4boJZ/QC3ybwwb/wAdZnAj/QEz7z88fpHgMWb82ACyhcewmYdNIsHgRoIBM28Dbi0GPGnJzAzHJBJ7zuQYzpZtkzAEOszgMM8xY9y2tB8+zPijxiaxvf2Mwcc3f+rkgQ57+JinRg63LQcYGJh50GP8AE71IFsagFH4A5+KUTAKRsEoGAUAntNRm6vSKE0AAAAASUVORK5CYII=","orcid":"","institution":"Guy’s and St Thomas’ NHS Foundation Trust","correspondingAuthor":true,"prefix":"","firstName":"Georgios","middleName":"","lastName":"Ntentas","suffix":""},{"id":574731684,"identity":"e76837ce-85a6-43af-adff-6a307275895a","order_by":1,"name":"Eliana Reyes","email":"","orcid":"","institution":"St Bartholomew’s Hospital","correspondingAuthor":false,"prefix":"","firstName":"Eliana","middleName":"","lastName":"Reyes","suffix":""},{"id":574731685,"identity":"ade6c1bb-abac-47ca-a696-cb1d4af4631b","order_by":2,"name":"Kasia Owczarczyk","email":"","orcid":"","institution":"Guy’s and St Thomas’ NHS Foundation Trust","correspondingAuthor":false,"prefix":"","firstName":"Kasia","middleName":"","lastName":"Owczarczyk","suffix":""},{"id":574731686,"identity":"9575b150-7f61-43af-8002-8d21418b3585","order_by":3,"name":"Vijay Maharajan","email":"","orcid":"","institution":"King’s College London","correspondingAuthor":false,"prefix":"","firstName":"Vijay","middleName":"","lastName":"Maharajan","suffix":""},{"id":574731687,"identity":"8cd38420-42d7-4400-af6f-b0b6a53720f3","order_by":4,"name":"Andrew Bell","email":"","orcid":"https://orcid.org/0009-0005-2560-8172","institution":"King's College London","correspondingAuthor":false,"prefix":"","firstName":"Andrew","middleName":"","lastName":"Bell","suffix":""},{"id":574731688,"identity":"92f80291-e6ad-4a03-854f-8e5d391fb8a4","order_by":5,"name":"Richard Crawley","email":"","orcid":"","institution":"King’s College London","correspondingAuthor":false,"prefix":"","firstName":"Richard","middleName":"","lastName":"Crawley","suffix":""},{"id":574731689,"identity":"39f79432-2ba1-4f58-aaef-8e2fb3405639","order_by":6,"name":"Shahreen Ahmad","email":"","orcid":"","institution":"Guy’s and St Thomas’ NHS Foundation Trust","correspondingAuthor":false,"prefix":"","firstName":"Shahreen","middleName":"","lastName":"Ahmad","suffix":""},{"id":574731690,"identity":"f5245e79-c0cb-4f3c-a050-5830977d41a6","order_by":7,"name":"Daniel Smith","email":"","orcid":"","institution":"Guy’s and St Thomas’ NHS Foundation Trust","correspondingAuthor":false,"prefix":"","firstName":"Daniel","middleName":"","lastName":"Smith","suffix":""},{"id":574731691,"identity":"da7a649c-ea64-4b19-abb4-0f07fe1170c6","order_by":8,"name":"Asad Qureshi","email":"","orcid":"","institution":"Guy’s and St Thomas’ NHS Foundation Trust","correspondingAuthor":false,"prefix":"","firstName":"Asad","middleName":"","lastName":"Qureshi","suffix":""},{"id":574731692,"identity":"ecca7e30-7c12-45a4-bfc9-07ed47c1625b","order_by":9,"name":"Jessica Brady","email":"","orcid":"","institution":"Guy’s and St Thomas’ NHS Foundation Trust","correspondingAuthor":false,"prefix":"","firstName":"Jessica","middleName":"","lastName":"Brady","suffix":""},{"id":574731693,"identity":"641a16b5-26f6-4a20-880c-7d0670a4e709","order_by":10,"name":"Deb Smith","email":"","orcid":"","institution":"Patient representative","correspondingAuthor":false,"prefix":"","firstName":"Deb","middleName":"","lastName":"Smith","suffix":""},{"id":574731694,"identity":"d86ff565-936d-4775-84df-ed5f552b4468","order_by":11,"name":"Tamas Vincze","email":"","orcid":"","institution":"Patient representative","correspondingAuthor":false,"prefix":"","firstName":"Tamas","middleName":"","lastName":"Vincze","suffix":""},{"id":574731695,"identity":"6ac06c67-92bb-430f-8e57-f9e2f59084cb","order_by":12,"name":"Sami Jeljeli","email":"","orcid":"","institution":"PET Centre, St Thomas' Hospital, King's College London \u0026 Guys and St Thomas' NHS Foundation Trust","correspondingAuthor":false,"prefix":"","firstName":"Sami","middleName":"","lastName":"Jeljeli","suffix":""},{"id":574731696,"identity":"1385cbaa-7ca5-4b30-a73e-ad14774bf42c","order_by":13,"name":"Claudia Prieto","email":"","orcid":"","institution":"School of Engineering and the iHEALTH Millenium Institute, Pontificia Universidad Católica de Chile, Santiago, Chile; School of Biomedical Engineering and Imaging Sciences, King’s Coll","correspondingAuthor":false,"prefix":"","firstName":"Claudia","middleName":"","lastName":"Prieto","suffix":""},{"id":574731697,"identity":"12850cef-b20a-4752-84b2-1f7fce0ac09e","order_by":14,"name":"Alexander Lyon","email":"","orcid":"","institution":"Imperial College London","correspondingAuthor":false,"prefix":"","firstName":"Alexander","middleName":"","lastName":"Lyon","suffix":""},{"id":574731698,"identity":"e8ec0152-d41c-4b6f-97df-eda90a22d0a3","order_by":15,"name":"Michael Marber","email":"","orcid":"","institution":"King's College London","correspondingAuthor":false,"prefix":"","firstName":"Michael","middleName":"","lastName":"Marber","suffix":""},{"id":574731699,"identity":"8222b92f-da32-4dc1-8ec1-fa4e19e1cd10","order_by":16,"name":"Sally Barrington","email":"","orcid":"https://orcid.org/0000-0002-2516-5288","institution":"King's College London","correspondingAuthor":false,"prefix":"","firstName":"Sally","middleName":"","lastName":"Barrington","suffix":""},{"id":574731700,"identity":"0fc58283-7811-4a16-8ee6-5f90252d873e","order_by":17,"name":"N. George Mikhaeel","email":"","orcid":"","institution":"Guy’s and St Thomas’ NHS Foundation Trust","correspondingAuthor":false,"prefix":"","firstName":"N.","middleName":"George","lastName":"Mikhaeel","suffix":""},{"id":574731701,"identity":"a86a9d4c-bd91-49a9-aa62-b3ee25c123b2","order_by":18,"name":"Muhummad Nazir","email":"","orcid":"","institution":"King’s College London","correspondingAuthor":false,"prefix":"","firstName":"Muhummad","middleName":"","lastName":"Nazir","suffix":""}],"badges":[],"createdAt":"2026-01-14 17:15:50","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8604030/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8604030/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":104400905,"identity":"2b2b1e8a-5ec8-429e-85de-1f9dc1b85f07","added_by":"auto","created_at":"2026-03-11 12:11:23","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":939178,"visible":true,"origin":"","legend":"Article File","description":"","filename":"CONNECTManuscriptFinalNatureMed.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8604030/v1_covered_478208c8-b430-42db-966b-146b27ea0e15.pdf"}],"financialInterests":"\u003cp\u003eThere is \u003cstrong\u003eNO\u003c/strong\u003e Competing Interest.\u003c/p\u003e\n\u003cp\u003eThis study was reviewed and approved by the UK Health Research Authority and Health and Care Research Wales (IRAS 289880 \u0026amp; REC reference 21/YH/0170).\u003c/p\u003e","formattedTitle":"Early Right Ventricular Injury and Myocardial Metabolic Changes After Contemporary Thoracic Radiotherapy: The CONNECT study","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"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":"","lastPublishedDoi":"10.21203/rs.3.rs-8604030/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8604030/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Background\r\nRadiation-related cardiovascular disease (CVD) is a major concern for cancer survivors, yet few methods exist to detect early cardiac injury within the first year of thoracic radiotherapy. Surveillance has largely focused on the left ventricle (LV), with little attention given to the right heart which may be particularly vulnerable to radiation due to its thin wall and anterior anatomical location. We aimed to prospectively evaluate potential early multimodality biomarkers of radiation-related cardiotoxicity and examine their association with radiation dose considering the whole heart and individual chambers.\r\n\r\nMethods\r\nCONNECT was a prospective, longitudinal study enrolling patients receiving thoracic radiotherapy for lymphoma, oesophageal, or lung cancer. Participants had multimodality assessments at baseline, after anthracycline-based chemotherapy (lymphoma only), within 2 weeks after radiotherapy and after 6 months, including simultaneous cardiac 18F- fluoro-2-deoxy-D-glucose (18F-FDG) PET/MRI, serum biomarkers and 12-lead ECG. Associations between findings and radiation doses to the heart were examined.\r\n\r\nResults\r\nTwenty-four patients (72 PET/MRI scans) were analysed. Both LVEF and RVEF declined early, but only RVEF remained persistently reduced at 6 months (−5.9%, p=0.004), with ≥10% decline in 40% of patients. Abnormal 18F-FDG uptake emerged in 35% of patients at 6 months, localised to the basal myocardium. Both reduction in RVEF and abnormal uptake were correlated with cardiac doses. Relative LV global longitudinal strain was impaired (\u003e15%) at 6 months in 35% of patients. Troponin rises were modest, transient, and not predictive of dysfunction at 6 months. T1, T2, late gadolinium enhancement and ECG showed no change.\r\n\r\nConclusions\r\nCONNECT demonstrates that persistent early radiation-related cardiotoxicity is right sided-predominant, dose-dependent, and accompanied by left ventricular myocardial metabolic changes. These findings identify the right heart as a critical, overlooked area in radiotherapy treatment planning and cardio-oncology surveillance.","manuscriptTitle":"Early Right Ventricular Injury and Myocardial Metabolic Changes After Contemporary Thoracic Radiotherapy: The CONNECT study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-01-22 14:02:58","doi":"10.21203/rs.3.rs-8604030/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":"6367ecdc-629d-4139-8743-0fc5e865cc62","owner":[],"postedDate":"January 22nd, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":61158921,"name":"Health sciences/Diseases/Cancer"},{"id":61158922,"name":"Health sciences/Diseases/Cardiovascular diseases"},{"id":61158923,"name":"Health sciences/Medical research/Biomarkers"}],"tags":[],"updatedAt":"2026-03-03T09:52:54+00:00","versionOfRecord":[],"versionCreatedAt":"2026-01-22 14:02:58","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8604030","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8604030","identity":"rs-8604030","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}