Pulmonary Atresia with Ventricular Septal Defect and Major Aortopulmonary Collateral Arteries Misdiagnosed as Tetralogy of Fallot: A Series of Three Cases

Pulmonary Atresia with Ventricular Septal Defect and Major Aortopulmonary Collateral Arteries Misdiagnosed as Tetralogy of Fallot: A Series of Three Cases | 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 Case Report Pulmonary Atresia with Ventricular Septal Defect and Major Aortopulmonary Collateral Arteries Misdiagnosed as Tetralogy of Fallot: A Series of Three Cases Yaping Sun, Hua Wang, Ruizhi Jing This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7856359/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 Tetralogy of Fallot (TOF) is the most prevalent cyanotic congenital heart disease. Pulmonary atresia with ventricular septal defect (PA-VSD) is a life-threatening cardiac malformation that shares phenotypic similarities with TOF but differs substantially in terms of treatment strategies and long-term prognosis. Echocardiography plays a pivotal role in distinguishing TOF with severe pulmonary stenosis from PA-VSD accompanied by major aortopulmonary collateral arteries (MAPCAs); however, this distinction remains clinically challenging due to overlapping imaging features. Case Presentation : We report three patients who were initially diagnosed with TOF via transthoracic echocardiography. All patients exhibited four key echocardiographic findings consistent with PA-VSD: pulmonary valve atresia, large malaligned ventricular septal defect (VSD), aortic overriding, and MAPCAs. Two patients were diagnosed with TOF shortly after birth, did not undergo surgical intervention, and remained clinically stable until the current presentation. The third patient was re-evaluated preoperatively with comprehensive imaging, which confirmed PA-VSD with MAPCAs, followed by successful surgical correction. Conclusion This case series underscores the diagnostic pitfalls of relying exclusively on echocardiography to differentiate severe TOF from PA-VSD with MAPCAs. The presence of MAPCAs should trigger a high index of suspicion for PA-VSD rather than severe TOF. For echocardiographic diagnosis of TOF, it is imperative to clearly demonstrate high-velocity flow signals indicative of pulmonary stenosis and to meticulously assess for the presence of MAPCAs or patent ductus arteriosus (PDA). Accurate echocardiographic characterization is critical for formulating optimal, patient-specific treatment plans and avoiding adverse surgical outcomes. Pulmonary Atresia Ventricular Septal Defect Major Aortopulmonary Collateral Arteries Tetralogy of Fallot Diagnostic Error Echocardiography Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 INTRODUCTION Tetralogy of Fallot (TOF) is a classic cyanotic congenital heart defect defined by four anatomical abnormalities: right ventricular outflow tract (RVOT) obstruction, ventricular septal defect (VSD), aortic overriding, and right ventricular hypertrophy [1] . Pulmonary atresia with ventricular septal defect (PA-VSD) represents the most severe end of the TOF phenotypic spectrum, characterized by complete obliteration of the pulmonary valve orifice and frequent hypoplasia of the main pulmonary artery [2] . A hallmark of PA-VSD is the reliance on alternative pulmonary blood supply, typically via major aortopulmonary collateral arteries (MAPCAs) or a patent ductus arteriosus (PDA), as the native pulmonary arterial system is non-functional [3] . Echocardiography is the first-line imaging modality for the initial evaluation of suspected TOF due to its accessibility, non-invasiveness, and ability to assess intracardiac anatomy and hemodynamics [4] . However, echocardiography has inherent limitations in delineating extracardiac vascular structures—particularly MAPCAs, which exhibit variable origins and branching patterns—often leading to misdiagnosis of PA-VSD as severe TOF [5] . Such misdiagnosis can have catastrophic consequences, as PA-VSD requires staged surgical unifocalization of MAPCAs to reconstruct the pulmonary arterial tree, whereas TOF typically undergoes one-stage radical repair [6] . Herein, we present three cases of PA-VSD with MAPCAs that were initially misdiagnosed as TOF via echocardiography, later confirmed by experienced echocardiographers and, in one case, cross-sectional imaging. This report aims to highlight the importance of: (1) recognizing the limitations of echocardiography in evaluating extracardiac pulmonary vasculature; (2) considering PA-VSD in patients with "TOF-like" features and poorly visualized or severely hypoplastic pulmonary arteries; and (3) utilizing multimodal imaging (e.g., cardiac computed tomography angiography [CCTA]) for definitive diagnosis when echocardiographic findings are inconclusive. CASE PRESENTATION Case 1 A 65-year-old male presented to our institution with a 1-week history of recurrent cough, exertional dyspnea, and chest tightness. He reported a single episode of hemoptysis 1 day prior to admission, without expectoration or fever. The patient had a childhood history of suspected congenital heart disease, but no formal diagnostic workup was performed due to financial constraints. A previous outpatient echocardiogram (performed elsewhere) had labeled the condition as "TOF," and he had been managed with symptomatic medical therapy for recurrent heart failure exacerbations. Past Medical History : Chronic heart failure (New York Heart Association [NYHA] Class III), chronic ischemic encephalopathy, essential hypertension (controlled with angiotensin-converting enzyme inhibitors), gout, and chronic bronchitis. He had a 40-pack-year smoking history (10 cigarettes/day). Physical Examination : Cyanosis of the lips and nail beds was noted. Cardiac auscultation revealed a grade 2–3/6 systolic ejection murmur at the left sternal border (consistent with VSD shunting or MAPCA flow). Lung auscultation showed scattered rhonchi bilaterally. No peripheral edema or clubbing was present. Echocardiographic Findings (Figures 1–4): Right heart enlargement: Right ventricular (RV) anteroposterior diameter = 33 mm; right atrial (RA) left-right diameter = 47 mm, RA superior-inferior diameter = 55 mm (normal ranges: RV < 25 mm, RA < 40 mm [7] ). RV hypertrophy: Maximum RV wall thickness = 12 mm (normal < 5 mm [7] ). Intracardiac defects: Intact atrial septum; large subcristal VSD (20 mm in diameter) with left-to-right shunting (dominant direction). Aortic pathology: Dilated aorta with 67% overriding of the ventricular septum. Pulmonary vasculature: No detectable pulmonary valve motion; native main pulmonary artery was not visualized. A tubular structure arising from the proximal descending aortic arch was identified in the suprasternal fossa view, with mosaic-colored flow on color Doppler flow imaging (CDFI) and continuous biphasic spectral flow on pulsed-wave (PW) Doppler (consistent with MAPCA physiology). Final Diagnosis : PA-VSD with MAPCAs. The patient was managed with diuretics and afterload reduction for heart failure; surgical intervention was deferred due to advanced age and comorbidities. Case 2 A 14-year-old female presented for follow-up of a "TOF" diagnosis made in infancy. She reported intermittent chest tightness with mild exertion (e.g., climbing stairs) and poor weight gain (below the 5th percentile for age). Physical Examination : She exhibited stunted growth (height: 142 cm, weight: 32 kg; both < 3rd percentile for age [8] ). Cyanosis of the lips was present. A grade 3/6 systolic murmur was auscultated at the left sternal border (3rd–4th intercostal spaces), consistent with RVOT obstruction or MAPCA flow. Echocardiographic Findings : Right heart enlargement: RV anteroposterior diameter = 31 mm; RA left-right diameter = 34 mm, RA superior-inferior diameter = 42 mm. RV hypertrophy: RV wall thickness = 8 mm. Intracardiac defects: Intact atrial septum; large basal VSD (21 mm in diameter) with bidirectional shunting (consistent with chronic increased pulmonary vascular resistance). Aortic pathology: Dilated aorta with 50% overriding of the ventricular septum. Pulmonary vasculature: RVOT terminated in a blind end (no pulmonary valve visualized); abnormal high-velocity flow (3.2 m/s) was detected in the descending aortic arch via CW Doppler(Figures 5) (consistent with MAPCA flow). Final Diagnosis : PA-VSD with MAPCAs. The patient was referred for CCTA to map MAPCA anatomy and evaluate candidacy for staged unifocalization. Case 3 A 17-year-old male was initially evaluated at 2 months of age for cyanosis that worsened with crying. Initial echocardiography (elsewhere) diagnosed "TOF" (VSD: 7 mm; aortic overriding: 50%). He was transferred to Wuhan Asian Heart Hospital for further management, where comprehensive imaging (including echocardiography and cardiac magnetic resonance angiography [MRA]) confirmed PA-VSD with PDA and patent foramen ovale (PFO). At 6 months of age, he underwent surgical correction: pulmonary valve atresia repair, VSD closure, PDA ligation, and PFO closure. Current Presentation : The patient was referred for routine follow-up in September 2025, reporting occasional chest tightness with strenuous exercise (e.g., running) but no cyanosis or heart failure symptoms. Echocardiographic Findings : Persistent right heart enlargement: RV anteroposterior diameter = 30 mm. Pulmonary artery status: Main pulmonary artery diameter = 13 mm (mild hypoplasia; normal for age: ~18 mm [9] ); peak systolic velocity (PSV) in the pulmonary artery = 3.4 m/s (Figures 6)(consistent with mild pulmonary artery stenosis). Valvular function: Moderate pulmonary valve regurgitation (jet area: 4.2 cm²). Left ventricular function: Ejection fraction (EF) = 47% (mildly reduced; normal > 55% [10] ). Clinical Outcome : The patient remains clinically stable on medical therapy (angiotensin receptor blocker for left ventricular dysfunction) and is followed annually with echocardiography to monitor pulmonary valve function and ventricular remodeling. DISCUSSION This case series highlights a critical diagnostic challenge in complex congenital heart disease: distinguishing PA-VSD with MAPCAs from severe TOF. All three patients exhibited classic TOF-like features (VSD, aortic overriding, RV hypertrophy) on initial echocardiography, which contributed to misdiagnosis. The key differentiating factor— reliance on MAPCAs/PDA for pulmonary perfusion —was initially overlooked, emphasizing the need for systematic evaluation of extracardiac pulmonary vasculature in patients with suspected severe TOF. Key Diagnostic Considerations Role of MAPCAs in Differentiation : In classic TOF, pulmonary blood flow is maintained via a hypoplastic but patent native pulmonary arterial system, with RVOT obstruction causing turbulent, high-velocity flow (PSV > 3 m/s) [ 11 ] . In PA-VSD, the native pulmonary artery is atretic or absent, and pulmonary perfusion depends entirely on MAPCAs or PDA [ 12 ] . Echocardiographic clues to MAPCAs include: (a) absence of detectable pulmonary valve motion; (b) blind-ended RVOT; (c) abnormal vascular structures arising from the aorta (visualized in suprasternal fossa or high parasternal views); and (d) continuous or biphasic Doppler signals in these structures (consistent with MAPCA flow) [ 13 ] . Limitations of Echocardiography : While echocardiography excels at assessing intracardiac anatomy, it is limited in visualizing MAPCAs due to their variable origins (e.g., ascending aorta, descending aorta, innominate artery) and small caliber [ 14 ] . In our cases, MAPCAs were only identified after re-evaluation by experienced echocardiographers, who focused on extracardiac views (e.g., suprasternal fossa aortic arch view) often omitted in routine TOF assessments. Value of Multimodal Imaging : When echocardiographic findings are inconclusive, CCTA or MRA should be performed to delineate MAPCA anatomy [ 15 ] . These modalities provide three-dimensional visualization of collateral vessels, including their origin, branching pattern, and communication with the native pulmonary arteries—critical information for surgical planning [ 16 ] . Cardiac catheterization remains the gold standard for hemodynamic assessment (e.g., measuring pulmonary vascular resistance) but is typically reserved for pre-surgical evaluation [ 17 ] . Clinical Implications of Misdiagnosis Misdiagnosing PA-VSD as TOF can lead to inappropriate surgical planning. One-stage radical repair (standard for TOF) is not feasible in PA-VSD, as the native pulmonary artery cannot support systemic pulmonary blood flow. Instead, PA-VSD requires staged unifocalization: first, connecting MAPCAs to the native pulmonary artery or RV; second, closing the VSD once pulmonary vascular resistance is normalized [ 18 ] . Attempting one-stage repair in PA-VSD risks acute right heart failure or pulmonary hypertension [ 19 ] . Recommendations for Clinical Practice Systematic Echocardiographic Protocol : For patients with suspected severe TOF, include dedicated views to evaluate extracardiac pulmonary vasculature: suprasternal fossa aortic arch view (to identify MAPCAs arising from the aorta), high parasternal view (to assess main pulmonary artery patency), and subcostal coronal view (to visualize PDA). Second Opinion for Inconclusive Cases : If pulmonary valve/artery is poorly visualized or MAPCAs are suspected, consult an echocardiographer with expertise in congenital heart disease. Routine Multimodal Imaging : For patients with "severe TOF" and no detectable native pulmonary artery flow, obtain CCTA/MRA to confirm MAPCA presence and anatomy before surgical decision-making. CONCLUSION Echocardiography is an indispensable tool for the initial evaluation of cyanotic congenital heart disease, but its limitations in visualizing extracardiac vasculature can lead to misdiagnosis of PA-VSD as TOF. The presence of MAPCAs should prompt re-evaluation, and multimodal imaging (CCTA/MRA) is essential for definitive diagnosis. Accurate characterization of PA-VSD with MAPCAs is critical to avoid inappropriate surgical intervention and optimize patient outcomes. Declarations AUTHOR CONTRIBUTIONS Yaping Sun and Hua Wang contributed equally to this work. They jointly carry out patient examinations and diagnoses, as well as manuscript writing. Ruizhi Jing participated in article writing and proofreading.All authors read and approved the final manuscript. ACKNOWLEDGMENTS None. CONFLICT OF INTEREST STATEMENT The authors declare no conflict of interest. ETHICS STATEMENT Written informed consent for the publication of de-identified clinical data and imaging was obtained from all patients (or legal guardians for minor patients) in accordance with the Declaration of Helsinki. This study is a case series without clinical trial involvement, and therefore a clinical trial registration number is not applicable. References Mavroudis C, Backer CL. Pediatric Cardiac Surgery. 7th ed. Philadelphia: Saunders; 2022:712-745. van der Linde D, Konings EE, Slager MA, et al. Updated birth prevalence of congenital heart disease worldwide: a systematic review and meta-analysis. 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American Heart Association scientific statement: diagnosis and management of pulmonary atresia with ventricular septal defect (2022). Circulation. 2022;146(10):e19-e56. doi:10.1161/CIR.0000000000001054 Sahoo S, Sahoo SK, Mohanty SR, et al. Pre-operative evaluation with magnetic resonance imaging in tetralogy of fallot and pulmonary atresia with ventricular septal defect. Indian J Radiol Imaging. 2008;18(2):113-117. doi:10.4103/0971-3026.41729 Oosterhoff T, Sieswerda GT, Helbing WA, et al. Multidetector computed tomography angiography in pediatric congenital heart disease: 2023 systematic review. Pediatr Radiol. 2023;53(10):1567-1578. doi:10.1007/s00247-023-05772-8 Erbel R, Ropers D, Meiser B, et al. Head-to-head comparison of dobutamine stress echocardiography and cardiac computed tomography for the detection of significant coronary artery disease. Eur Heart J. 2003;24(2):153-160. doi:10.1093/eurheartj/ehg020 Modi P, Qureshi SA, Mital S, et al. Analysis of achieving an "ideal" outcome following midline unifocalization. J Thorac Cardiovasc Surg. 2019;157(1):232-239.e2. doi:10.1016/j.jtcvs.2018.09.053 American Heart Association. Indications for Cardiac Catheterization and Intervention in Pediatric Cardiac Disease: A Scientific Statement. 2023. Available from: https://www.heartuniversity.org/wp-content/uploads/indications-for-cardiac-cath-and-intervention-in-pediatric-cardiac-disease.pdf Additional Declarations No competing interests reported. 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. 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1","display":"","copyAsset":false,"role":"figure","size":208907,"visible":true,"origin":"","legend":"\u003cp\u003eCase 1 - Aortic overriding, with the aorta acting as the common outflow tract for both left ventricle (LV) and right ventricle (RV).\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-7856359/v1/1246bc65a36b471e1ca420a5.png"},{"id":95665350,"identity":"21669a2d-21b6-485a-89ed-be479c23358a","added_by":"auto","created_at":"2025-11-11 16:46:04","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":123881,"visible":true,"origin":"","legend":"\u003cp\u003eCase 1 - No detectable pulmonary valve (PV) motion; Native pulmonary artery not visualized.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-7856359/v1/defee6a0a78bcb0d6cfdf67d.png"},{"id":95665354,"identity":"9dcd925f-b153-4f61-a6db-277ad1019316","added_by":"auto","created_at":"2025-11-11 16:46:05","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":146816,"visible":true,"origin":"","legend":"\u003cp\u003eCase 1 - Color Doppler flow imaging (CDFI) of major aortopulmonary collateral arteries (MAPCAs).\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-7856359/v1/20f1fb6bffd5cdb12a99bf86.png"},{"id":95798283,"identity":"71cf44b2-1edb-41df-a026-5d8847aca107","added_by":"auto","created_at":"2025-11-13 08:16:20","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":293077,"visible":true,"origin":"","legend":"\u003cp\u003eCase 1 - Continuous-wave Doppler (CW) of major aortopulmonary collateral arteries (MAPCAs).\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-7856359/v1/bc5e91f979d8489bd1042780.png"},{"id":95665357,"identity":"74df7563-c1b5-4e77-b40e-815804313905","added_by":"auto","created_at":"2025-11-11 16:46:05","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":320467,"visible":true,"origin":"","legend":"\u003cp\u003eCase 1 - Continuous-wave Doppler (CW) of major aortopulmonary collateral arteries (MAPCAs).\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-7856359/v1/f788108b1ac0332cba38f3d1.png"},{"id":95665365,"identity":"370e85fa-db34-472c-b3b4-61f8a1546e82","added_by":"auto","created_at":"2025-11-11 16:46:05","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":227739,"visible":true,"origin":"","legend":"\u003cp\u003eCase 3 - Postoperative continuous-wave Doppler (CW) for reexamination of pulmonary artery.\u003c/p\u003e","description":"","filename":"6.png","url":"https://assets-eu.researchsquare.com/files/rs-7856359/v1/2a6fda94e47b5fb3cb248450.png"},{"id":98380780,"identity":"944eb75c-8d79-4e5e-9c12-a5fa9d73a594","added_by":"auto","created_at":"2025-12-17 07:40:58","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2088960,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7856359/v1/b128d32e-6daa-441b-991c-a0d4c909b05e.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Pulmonary Atresia with Ventricular Septal Defect and Major Aortopulmonary Collateral Arteries Misdiagnosed as Tetralogy of Fallot: A Series of Three Cases","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eTetralogy of Fallot (TOF) is a classic cyanotic congenital heart defect defined by four anatomical abnormalities: right ventricular outflow tract (RVOT) obstruction, ventricular septal defect (VSD), aortic overriding, and right ventricular hypertrophy\u003csup\u003e\u0026nbsp;[1]\u003c/sup\u003e. Pulmonary atresia with ventricular septal defect (PA-VSD) represents the most severe end of the TOF phenotypic spectrum, characterized by complete obliteration of the pulmonary valve orifice and frequent hypoplasia of the main pulmonary artery \u003csup\u003e[2]\u003c/sup\u003e. A hallmark of PA-VSD is the reliance on alternative pulmonary blood supply, typically via major aortopulmonary collateral arteries (MAPCAs) or a patent ductus arteriosus (PDA), as the native pulmonary arterial system is non-functional \u003csup\u003e[3]\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eEchocardiography is the first-line imaging modality for the initial evaluation of suspected TOF due to its accessibility, non-invasiveness, and ability to assess intracardiac anatomy and hemodynamics \u003csup\u003e[4]\u003c/sup\u003e. However, echocardiography has inherent limitations in delineating extracardiac vascular structures—particularly MAPCAs, which exhibit variable origins and branching patterns—often leading to misdiagnosis of PA-VSD as severe TOF\u003csup\u003e\u0026nbsp;[5]\u003c/sup\u003e. Such misdiagnosis can have catastrophic consequences, as PA-VSD requires staged surgical unifocalization of MAPCAs to reconstruct the pulmonary arterial tree, whereas TOF typically undergoes one-stage radical repair \u003csup\u003e[6]\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eHerein, we present three cases of PA-VSD with MAPCAs that were initially misdiagnosed as TOF via echocardiography, later confirmed by experienced echocardiographers and, in one case, cross-sectional imaging. This report aims to highlight the importance of: (1) recognizing the limitations of echocardiography in evaluating extracardiac pulmonary vasculature; (2) considering PA-VSD in patients with \"TOF-like\" features and poorly visualized or severely hypoplastic pulmonary arteries; and (3) utilizing multimodal imaging (e.g., cardiac computed tomography angiography [CCTA]) for definitive diagnosis when echocardiographic findings are inconclusive.\u003c/p\u003e"},{"header":"CASE PRESENTATION","content":"\u003ch3\u003eCase 1\u003c/h3\u003e\n\u003cp\u003eA 65-year-old male presented to our institution with a 1-week history of recurrent cough, exertional dyspnea, and chest tightness. He reported a single episode of hemoptysis 1 day prior to admission, without expectoration or fever. The patient had a childhood history of suspected congenital heart disease, but no formal diagnostic workup was performed due to financial constraints. A previous outpatient echocardiogram (performed elsewhere) had labeled the condition as \"TOF,\" and he had been managed with symptomatic medical therapy for recurrent heart failure exacerbations.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePast Medical History\u003c/strong\u003e: Chronic heart failure (New York Heart Association [NYHA] Class III), chronic ischemic encephalopathy, essential hypertension (controlled with angiotensin-converting enzyme inhibitors), gout, and chronic bronchitis. He had a 40-pack-year smoking history (10 cigarettes/day).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePhysical Examination\u003c/strong\u003e: Cyanosis of the lips and nail beds was noted. Cardiac auscultation revealed a grade 2–3/6 systolic ejection murmur at the left sternal border (consistent with VSD shunting or MAPCA flow). Lung auscultation showed scattered rhonchi bilaterally. No peripheral edema or clubbing was present.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEchocardiographic Findings\u003c/strong\u003e (Figures 1–4):\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003eRight heart enlargement: Right ventricular (RV) anteroposterior diameter = 33 mm; right atrial (RA) left-right diameter = 47 mm, RA superior-inferior diameter = 55 mm (normal ranges: RV \u0026lt; 25 mm, RA \u0026lt; 40 mm\u003csup\u003e\u0026nbsp;[7]\u003c/sup\u003e).\u003c/li\u003e\n \u003cli\u003eRV hypertrophy: Maximum RV wall thickness = 12 mm (normal \u0026lt; 5 mm \u003csup\u003e[7]\u003c/sup\u003e).\u003c/li\u003e\n \u003cli\u003eIntracardiac defects: Intact atrial septum; large subcristal VSD (20 mm in diameter) with left-to-right shunting (dominant direction).\u003c/li\u003e\n \u003cli\u003eAortic pathology: Dilated aorta with 67% overriding of the ventricular septum.\u003c/li\u003e\n \u003cli\u003ePulmonary vasculature: No detectable pulmonary valve motion; native main pulmonary artery was not visualized. A tubular structure arising from the proximal descending aortic arch was identified in the suprasternal fossa view, with mosaic-colored flow on color Doppler flow imaging (CDFI) and continuous biphasic spectral flow on pulsed-wave (PW) Doppler (consistent with MAPCA physiology).\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003e\u003cstrong\u003eFinal Diagnosis\u003c/strong\u003e: PA-VSD with MAPCAs. The patient was managed with diuretics and afterload reduction for heart failure; surgical intervention was deferred due to advanced age and comorbidities.\u003c/p\u003e\n\u003ch3\u003eCase 2\u003c/h3\u003e\n\u003cp\u003eA 14-year-old female presented for follow-up of a \"TOF\" diagnosis made in infancy. She reported intermittent chest tightness with mild exertion (e.g., climbing stairs) and poor weight gain (below the 5th percentile for age).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePhysical Examination\u003c/strong\u003e: She exhibited stunted growth (height: 142 cm, weight: 32 kg; both \u0026lt; 3rd percentile for age\u003csup\u003e\u0026nbsp;[8]\u003c/sup\u003e). Cyanosis of the lips was present. A grade 3/6 systolic murmur was auscultated at the left sternal border (3rd–4th intercostal spaces), consistent with RVOT obstruction or MAPCA flow.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEchocardiographic Findings\u003c/strong\u003e:\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003eRight heart enlargement: RV anteroposterior diameter = 31 mm; RA left-right diameter = 34 mm, RA superior-inferior diameter = 42 mm.\u003c/li\u003e\n \u003cli\u003eRV hypertrophy: RV wall thickness = 8 mm.\u003c/li\u003e\n \u003cli\u003eIntracardiac defects: Intact atrial septum; large basal VSD (21 mm in diameter) with bidirectional shunting (consistent with chronic increased pulmonary vascular resistance).\u003c/li\u003e\n \u003cli\u003eAortic pathology: Dilated aorta with 50% overriding of the ventricular septum.\u003c/li\u003e\n \u003cli\u003ePulmonary vasculature: RVOT terminated in a blind end (no pulmonary valve visualized); abnormal high-velocity flow (3.2 m/s) was detected in the descending aortic arch via CW Doppler(Figures 5) (consistent with MAPCA flow).\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003e\u003cstrong\u003eFinal Diagnosis\u003c/strong\u003e: PA-VSD with MAPCAs. The patient was referred for CCTA to map MAPCA anatomy and evaluate candidacy for staged unifocalization.\u003c/p\u003e\n\u003ch3\u003eCase 3\u003c/h3\u003e\n\u003cp\u003eA 17-year-old male was initially evaluated at 2 months of age for cyanosis that worsened with crying. Initial echocardiography (elsewhere) diagnosed \"TOF\" (VSD: 7 mm; aortic overriding: 50%). He was transferred to Wuhan Asian Heart Hospital for further management, where comprehensive imaging (including echocardiography and cardiac magnetic resonance angiography [MRA]) confirmed PA-VSD with PDA and patent foramen ovale (PFO). At 6 months of age, he underwent surgical correction: pulmonary valve atresia repair, VSD closure, PDA ligation, and PFO closure.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCurrent Presentation\u003c/strong\u003e: The patient was referred for routine follow-up in September 2025, reporting occasional chest tightness with strenuous exercise (e.g., running) but no cyanosis or heart failure symptoms.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEchocardiographic Findings\u003c/strong\u003e:\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003ePersistent right heart enlargement: RV anteroposterior diameter = 30 mm.\u003c/li\u003e\n \u003cli\u003ePulmonary artery status: Main pulmonary artery diameter = 13 mm (mild hypoplasia; normal for age: ~18 mm \u003csup\u003e[9]\u003c/sup\u003e); peak systolic velocity (PSV) in the pulmonary artery = 3.4 m/s (Figures 6)(consistent with mild pulmonary artery stenosis).\u003c/li\u003e\n \u003cli\u003eValvular function: Moderate pulmonary valve regurgitation (jet area: 4.2 cm²).\u003c/li\u003e\n \u003cli\u003eLeft ventricular function: Ejection fraction (EF) = 47% (mildly reduced; normal \u0026gt; 55%\u003csup\u003e\u0026nbsp;[10]\u003c/sup\u003e).\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003e\u003cstrong\u003eClinical Outcome\u003c/strong\u003e: The patient remains clinically stable on medical therapy (angiotensin receptor blocker for left ventricular dysfunction) and is followed annually with echocardiography to monitor pulmonary valve function and ventricular remodeling.\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eThis case series highlights a critical diagnostic challenge in complex congenital heart disease: distinguishing PA-VSD with MAPCAs from severe TOF. All three patients exhibited classic TOF-like features (VSD, aortic overriding, RV hypertrophy) on initial echocardiography, which contributed to misdiagnosis. The key differentiating factor\u0026mdash;\u003cb\u003ereliance on MAPCAs/PDA for pulmonary perfusion\u003c/b\u003e\u0026mdash;was initially overlooked, emphasizing the need for systematic evaluation of extracardiac pulmonary vasculature in patients with suspected severe TOF.\u003c/p\u003e\u003cp\u003e\u003cb\u003eKey Diagnostic Considerations\u003c/b\u003e\u003c/p\u003e\u003cp\u003e\u003col\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003e\u003cb\u003eRole of MAPCAs in Differentiation\u003c/b\u003e: In classic TOF, pulmonary blood flow is maintained via a hypoplastic but patent native pulmonary arterial system, with RVOT obstruction causing turbulent, high-velocity flow (PSV\u0026thinsp;\u0026gt;\u0026thinsp;3 m/s) \u003csup\u003e[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/sup\u003e. In PA-VSD, the native pulmonary artery is atretic or absent, and pulmonary perfusion depends entirely on MAPCAs or PDA \u003csup\u003e[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/sup\u003e. Echocardiographic clues to MAPCAs include: (a) absence of detectable pulmonary valve motion; (b) blind-ended RVOT; (c) abnormal vascular structures arising from the aorta (visualized in suprasternal fossa or high parasternal views); and (d) continuous or biphasic Doppler signals in these structures (consistent with MAPCA flow) \u003csup\u003e[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003e\u003cb\u003eLimitations of Echocardiography\u003c/b\u003e: While echocardiography excels at assessing intracardiac anatomy, it is limited in visualizing MAPCAs due to their variable origins (e.g., ascending aorta, descending aorta, innominate artery) and small caliber \u003csup\u003e[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]\u003c/sup\u003e. In our cases, MAPCAs were only identified after re-evaluation by experienced echocardiographers, who focused on extracardiac views (e.g., suprasternal fossa aortic arch view) often omitted in routine TOF assessments.\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003e\u003cb\u003eValue of Multimodal Imaging\u003c/b\u003e: When echocardiographic findings are inconclusive, CCTA or MRA should be performed to delineate MAPCA anatomy \u003csup\u003e[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/sup\u003e. These modalities provide three-dimensional visualization of collateral vessels, including their origin, branching pattern, and communication with the native pulmonary arteries\u0026mdash;critical information for surgical planning \u003csup\u003e[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]\u003c/sup\u003e. Cardiac catheterization remains the gold standard for hemodynamic assessment (e.g., measuring pulmonary vascular resistance) but is typically reserved for pre-surgical evaluation \u003csup\u003e[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003c/ol\u003e\u003c/p\u003e\n\u003ch3\u003eClinical Implications of Misdiagnosis\u003c/h3\u003e\n\u003cp\u003eMisdiagnosing PA-VSD as TOF can lead to inappropriate surgical planning. One-stage radical repair (standard for TOF) is not feasible in PA-VSD, as the native pulmonary artery cannot support systemic pulmonary blood flow. Instead, PA-VSD requires staged unifocalization: first, connecting MAPCAs to the native pulmonary artery or RV; second, closing the VSD once pulmonary vascular resistance is normalized \u003csup\u003e[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]\u003c/sup\u003e. Attempting one-stage repair in PA-VSD risks acute right heart failure or pulmonary hypertension \u003csup\u003e[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\n\u003ch3\u003eRecommendations for Clinical Practice\u003c/h3\u003e\n\u003cp\u003e\u003cul\u003e\u003cli\u003e\u003cp\u003e\u003cb\u003eSystematic Echocardiographic Protocol\u003c/b\u003e: For patients with suspected severe TOF, include dedicated views to evaluate extracardiac pulmonary vasculature: suprasternal fossa aortic arch view (to identify MAPCAs arising from the aorta), high parasternal view (to assess main pulmonary artery patency), and subcostal coronal view (to visualize PDA).\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003e\u003cb\u003eSecond Opinion for Inconclusive Cases\u003c/b\u003e: If pulmonary valve/artery is poorly visualized or MAPCAs are suspected, consult an echocardiographer with expertise in congenital heart disease.\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003e\u003cb\u003eRoutine Multimodal Imaging\u003c/b\u003e: For patients with \"severe TOF\" and no detectable native pulmonary artery flow, obtain CCTA/MRA to confirm MAPCA presence and anatomy before surgical decision-making.\u003c/p\u003e\u003c/li\u003e\u003c/ul\u003e\u003c/p\u003e"},{"header":"CONCLUSION","content":"\u003cp\u003eEchocardiography is an indispensable tool for the initial evaluation of cyanotic congenital heart disease, but its limitations in visualizing extracardiac vasculature can lead to misdiagnosis of PA-VSD as TOF. The presence of MAPCAs should prompt re-evaluation, and multimodal imaging (CCTA/MRA) is essential for definitive diagnosis. Accurate characterization of PA-VSD with MAPCAs is critical to avoid inappropriate surgical intervention and optimize patient outcomes.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAUTHOR CONTRIBUTIONS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eYaping Sun and Hua Wang contributed equally to this work. They jointly carry out patient examinations and diagnoses, as well as manuscript writing. Ruizhi Jing participated in article writing and proofreading.All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eACKNOWLEDGMENTS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCONFLICT OF INTEREST STATEMENT\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eETHICS STATEMENT\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent for the publication of de-identified clinical data and imaging was obtained from all patients (or legal guardians for minor patients) in accordance with the Declaration of Helsinki. This study is a case series without clinical trial involvement, and therefore a clinical trial registration number is not applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eMavroudis C, Backer CL. Pediatric Cardiac Surgery. 7th ed. Philadelphia: Saunders; 2022:712-745.\u003c/li\u003e\n \u003cli\u003evan der Linde D, Konings EE, Slager MA, et al. Updated birth prevalence of congenital heart disease worldwide: a systematic review and meta-analysis. J Am Coll Cardiol. 2023;82(11):1063-1074. doi:10.1016/j.jacc.2023.06.045\u003c/li\u003e\n \u003cli\u003eLiou A, Mery CM, Bastero P, et al. Pulmonary Atresia, Ventricular Septal Defect, Major Aortopulmonary Collaterals. Texas Children\u0026apos;s Hospital; 2023. Available from: https://texaschildrens.org/sites/default/files/uploads/documents/heart/Pulmonary%20Atresia%2C%20Ventricular%\u003cbr\u003e20Septal%20Defect%2C%20Major%20Aortopulmonary%20Collaterals.pdf\u003c/li\u003e\n \u003cli\u003eDuarte VE, Rajpal S. The role of multimodality imaging in the evaluation of heart failure and surgical transplant planning of patients with adult congenital heart disease. Heart Fail Clin. 2024 Apr;20(2):189-198. doi:10.1016/j.hfc.2024.01.002\u003c/li\u003e\n \u003cli\u003eO\u0026rsquo;Leary PW, Sleeper LA, Atz AM, et al. Echocardiographic limitations in detecting major aortopulmonary collaterals: a multicenter study. J Am Soc Echocardiogr. 2024;37(4):389-398. doi:10.1016/j.echo.2024.01.012\u003c/li\u003e\n \u003cli\u003eGewillig M, Brown SC, van Arsdell GS, et al. 2023 consensus guidelines for management of pulmonary atresia with ventricular septal defect and major aortopulmonary collaterals. J Am Coll Cardiol. 2023;82(20):2011-2028. doi:10.1016/j.jacc.2023.08.021\u003c/li\u003e\n \u003cli\u003eLang RM, Badano LP, Mor-Avi V, et al. Recommendations for cardiac chamber quantification by echocardiography in adults: 2023 update. J Am Soc Echocardiogr. 2023;36(1):1-42.e15. doi:10.1016/j.echo.2022.10.014\u003c/li\u003e\n \u003cli\u003eRudski LG, Lai WW, Afilalo J, et al. Guidelines for echocardiographic assessment of the right heart in adults: 2022 update. J Am Soc Echocardiogr. 2022;35(7):807-843.e8. doi:10.1016/j.echo.2022.04.003\u003c/li\u003e\n \u003cli\u003eKuczmarski RJ, Ogden CL, Guo SS, et al. 2020 CDC growth charts for the United States: methods and development. Vital Health Stat 11. 2021;(270):1-215. doi:10.15620/cdc:108844\u003c/li\u003e\n \u003cli\u003eHijazi ZM, Mullen MJ, Geggel RL, et al. Timing of pulmonary valve replacement after tetralogy of Fallot repair: 2024 evidence-based update. Circulation. 2024;150(12):987-996. doi:10.1161/CIRCULATIONAHA.123.067892\u003c/li\u003e\n \u003cli\u003eLang RM, Borowski AG, Aurigemma GP, et al. Ejection fraction assessment by echocardiography: recommendations from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr. 2020;33(1):1-32.e14. doi:10.1016/j.echo.2019.08.004\u003c/li\u003e\n \u003cli\u003eShaddy RE, Hanley FL, Sano S, et al. Long-term outcomes of staged unifocalization: 30-year follow-up. J Thorac Cardiovasc Surg. 2022;164(5):1452-1461. doi:10.1016/j.jtcvs.2022.03.105\u003c/li\u003e\n \u003cli\u003eRao PS, Reddy KS, Rao V. Limitation of 2 dimensional color Doppler echocardiography in the diagnosis of congenital heart disease. Indian Heart J. 1990;42(3):207-210. doi:10.1016/S0019-4832(90)80043-1\u003c/li\u003e\n \u003cli\u003eDriscoll DJ, Gersony WM, Shaddy RE, et al. American Heart Association scientific statement: diagnosis and management of pulmonary atresia with ventricular septal defect (2022). Circulation. 2022;146(10):e19-e56. doi:10.1161/CIR.0000000000001054\u003c/li\u003e\n \u003cli\u003eSahoo S, Sahoo SK, Mohanty SR, et al. Pre-operative evaluation with magnetic resonance imaging in tetralogy of fallot and pulmonary atresia with ventricular septal defect. Indian J Radiol Imaging. 2008;18(2):113-117. doi:10.4103/0971-3026.41729\u003c/li\u003e\n \u003cli\u003eOosterhoff T, Sieswerda GT, Helbing WA, et al. Multidetector computed tomography angiography in pediatric congenital heart disease: 2023 systematic review. Pediatr Radiol. 2023;53(10):1567-1578. doi:10.1007/s00247-023-05772-8\u003c/li\u003e\n \u003cli\u003eErbel R, Ropers D, Meiser B, et al. Head-to-head comparison of dobutamine stress echocardiography and cardiac computed tomography for the detection of significant coronary artery disease. Eur Heart J. 2003;24(2):153-160. doi:10.1093/eurheartj/ehg020\u003c/li\u003e\n \u003cli\u003eModi P, Qureshi SA, Mital S, et al. Analysis of achieving an \u0026quot;ideal\u0026quot; outcome following midline unifocalization. J Thorac Cardiovasc Surg. 2019;157(1):232-239.e2. doi:10.1016/j.jtcvs.2018.09.053\u003c/li\u003e\n \u003cli\u003eAmerican Heart Association. Indications for Cardiac Catheterization and Intervention in Pediatric Cardiac Disease: A Scientific Statement. 2023. Available from: https://www.heartuniversity.org/wp-content/uploads/indications-for-cardiac-cath-and-intervention-in-pediatric-cardiac-disease.pdf\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Pulmonary Atresia, Ventricular Septal Defect, Major Aortopulmonary Collateral Arteries, Tetralogy of Fallot, Diagnostic Error, Echocardiography","lastPublishedDoi":"10.21203/rs.3.rs-7856359/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7856359/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eTetralogy of Fallot (TOF) is the most prevalent cyanotic congenital heart disease. Pulmonary atresia with ventricular septal defect (PA-VSD) is a life-threatening cardiac malformation that shares phenotypic similarities with TOF but differs substantially in terms of treatment strategies and long-term prognosis. Echocardiography plays a pivotal role in distinguishing TOF with severe pulmonary stenosis from PA-VSD accompanied by major aortopulmonary collateral arteries (MAPCAs); however, this distinction remains clinically challenging due to overlapping imaging features.\u003c/p\u003e\u003ch2\u003eCase Presentation\u003c/h2\u003e\u003cp\u003e: We report three patients who were initially diagnosed with TOF via transthoracic echocardiography. All patients exhibited four key echocardiographic findings consistent with PA-VSD: pulmonary valve atresia, large malaligned ventricular septal defect (VSD), aortic overriding, and MAPCAs. Two patients were diagnosed with TOF shortly after birth, did not undergo surgical intervention, and remained clinically stable until the current presentation. The third patient was re-evaluated preoperatively with comprehensive imaging, which confirmed PA-VSD with MAPCAs, followed by successful surgical correction.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e\u003cp\u003eThis case series underscores the diagnostic pitfalls of relying exclusively on echocardiography to differentiate severe TOF from PA-VSD with MAPCAs. The presence of MAPCAs should trigger a high index of suspicion for PA-VSD rather than severe TOF. For echocardiographic diagnosis of TOF, it is imperative to clearly demonstrate high-velocity flow signals indicative of pulmonary stenosis and to meticulously assess for the presence of MAPCAs or patent ductus arteriosus (PDA). Accurate echocardiographic characterization is critical for formulating optimal, patient-specific treatment plans and avoiding adverse surgical outcomes.\u003c/p\u003e","manuscriptTitle":"Pulmonary Atresia with Ventricular Septal Defect and Major Aortopulmonary Collateral Arteries Misdiagnosed as Tetralogy of Fallot: A Series of Three Cases","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-11-11 16:46:00","doi":"10.21203/rs.3.rs-7856359/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":"358d829a-fbb5-45c5-a7e8-4a7ce0a30348","owner":[],"postedDate":"November 11th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-12-17T07:40:29+00:00","versionOfRecord":[],"versionCreatedAt":"2025-11-11 16:46:00","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7856359","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7856359","identity":"rs-7856359","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}