Embryological Determinants of Right Ventricular Morphogenesis in Pulmonary Atresia: The Role of Bipartite and Tripartite Configurations

Embryological Determinants of Right Ventricular Morphogenesis in Pulmonary Atresia: The Role of Bipartite and Tripartite Configurations | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL This is a preprint and has not been peer reviewed. Data may be preliminary. 10 October 2025 V1 Latest version Share on Embryological Determinants of Right Ventricular Morphogenesis in Pulmonary Atresia: The Role of Bipartite and Tripartite Configurations Author : Ghassan Al-Naami 0009-0003-0636-3478 [email protected] Authors Info & Affiliations https://doi.org/10.22541/au.176009604.43965635/v1 187 views 135 downloads Contents Abstract Introduction Embryological Development of the Right Ventricle Pathogenesis of Pulmonary Atresia Clinical Implications and Outcomes Conclusion References Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Pulmonary atresia is a complex congenital heart defect with marked morphological and clinical heterogeneity. Central to this variability is the embryological development of the right ventricle (RV) and its subcomponents. This review explores the embryological basis of RV development, emphasizing the bipartite and tripartite configurations and their clinical relevance in pulmonary atresia. Recent advances in human embryology, including high-resolution reconstructions from the Human Developmental Biology Resource (HDBR) and the work of Hikspoors and colleagues, provide an updated framework for understanding RV morphogenesis 1-2 . We highlight how disruption of ventricular partitioning, mural hypertrophy, and conotruncal malalignment contribute to the phenotypic spectrum of pulmonary atresia 3-4 . Finally, we examine the impact of RV morphology on surgical strategy and long-term prognosis. Introduction Pulmonary atresia (PA) encompasses a group of congenital malformations characterized by complete obstruction of the right ventricular outflow to the pulmonary artery. Two major subtypes are recognized: - PA with intact ventricular septum (PA/IVS) - PA with ventricular septal defect (PA/VSD) The clinical presentation and surgical options depend on the morphology of the right ventricle and its capacity to sustain pulmonary circulation. Contemporary embryology, informed by three-dimensional reconstructions from the HDBR Atlas and detailed descriptions from Hikspoors and colleagues, has reshaped our understanding of RV development and the morphogenetic basis of these lesions. Embryological Development of the Right Ventricle Table 1: Embryological parts of the RV, their origin, and function (modified)‎ 5 Inlet Atrioventricular canal myocardium (becomes atrial vestibules and ventricular inlet) Receives blood from right atrium Trabecular Apical part ballooning from outer curvature of the ventricular loop Main pumping chamber Outlet (Infundibulum) Proximal outflow tract (persists as RV infundibulum after aortic root commitment to LV) Directs blood into pulmonary artery The right ventricle develops from the primary heart tube with looping and chamber ballooning between the 4th and 8th weeks of embryonic life, with inlet, trabecular, and outlet components becoming morphologically distinct ‎6-‎9. Serially sectioned datasets from the HDBR Atlas demonstrate that the outlet component represents the persisting part of the proximal outflow tract after the aortic root has committed to the left ventricle ‎ 1 . Proper septation of the common outflow tract into aorta and pulmonary artery requires coordinated migration of neural crest cells into the conotruncal cushions ‎3-‎4 . Figure : Timeline (CS15–CS17): bipartite RV (inlet + trabecular) at CS15–CS16; proximal outflow tract incorporation begins at CS17 forming the RV infundibulum. The red bar denotes the vulnerability window (CS15–CS16) predisposing to outlet defects (e.g., pulmonary atresia). ‎1, ‎10 Temporal window of vulnerability: By human Carnegie stage 15 (≈36 days), the right‑ventricular inlet is morphologically evident, whereas incorporation of the proximal outflow tract to form the distal, non‑trabeculated outlet (future RV infundibulum) begins around CS17 (Figure 1). Insults occurring between CS14–16 can therefore arrest outlet formation, leaving a bipartite RV (inlet + trabecular components) and predisposing to outflow‑tract defects such as pulmonary atresia ‎1‎-2, ‎11-‎14 . Pathogenesis of Pulmonary Atresia PA with Intact Ventricular Septum (PA/IVS) Recent evidence suggests that PA/IVS is not solely a failure of canalization but rather an acquired lesion of fetal life, evolving from mural hypertrophy and overgrowth of ventricular components. The resulting right ventricle is often hypoplastic, most commonly bipartite (inlet + trabecular, absent outlet). Associated features include: - Coronary sinusoids and RV-to-coronary fistulas - Tricuspid valve abnormalities - Elevated RV pressures with limited growth potential ‎15‎-17 . Timing: when the insult precedes proximal outflow‑tract incorporation (approximately CS15–16), the RV remains bipartite and outlet formation fails or is severely curtailed, favoring PA/IVS ‎1‎-2, ‎11-‎14 . PA with Ventricular Septal Defect (PA/VSD) PA/VSD represents a spectrum of conotruncal anomalies. In this setting, the right ventricle is usually tripartite, since blood flow across the VSD promotes RV growth. However, misalignment of the outflow tract and abnormal septation of the common outflow tract lead to pulmonary obstruction. This variant is closely related to the tetralogy of Fallot spectrum, though it also coexists with other complex conotruncal combinations. Conversely, if flow across a VSD sustains RV growth beyond CS17, the RV more often attains a tripartite state, yet conotruncal malalignment or valvar/arterial obstruction can still yield PA/VSD ‎1-‎3, ‎18-‎19 . Right Ventricular Partitions: Bipartite vs. Tripartite Morphology Table 2 contrasts the two principal RV phenotypes relevant to PA/IVS. The bipartite and tripartite distinctions remain clinically valuable for surgical decision-making: - Tripartite RV: Contains inlet, trabecular, and outlet → more favorable for biventricular repair. - Bipartite RV: Lacks a developed outlet → often necessitates univentricular palliation, particularly if coronary sinusoids are present. Table 2: Comparison between tripartite and bipartite RV Tripartite RV Inlet, trabecular, outlet Generally associated with better RV development and function Bipartite RV Inlet, trabecular (outlet absent) Seen in severe PA/IVS; associated with RV hypoplasia Clinical Implications and Outcomes Management is anchored in the right-ventricular (RV) partition ( Table 3 ). After confirming pulmonary atresia anatomy, the RV is classified as tripartite or bipartite. In a tripartite RV, favorable modifiers—tricuspid annulus z-score ≥ −2, adequate RV size, preserved RVOT continuity, and absence of RV–coronary sinusoids—support a biventricular (BV) approach; when these metrics are borderline, a staged BV or 1.5-ventricle strategy is preferred ‎16-‎17 . In a bipartite RV, the presence of RV–coronary sinusoids argues against RV decompression and favors a univentricular pathway. If sinusoids are absent, tricuspid z-score and RV size are reassessed: adequate dimensions favor staged BV/1.5-ventricle, whereas clearly inadequate dimensions favor univentricular palliation. Advances in imaging—particularly high-resolution echocardiography and fetal MRI—now permit early, accurate recognition of RV morphology and coronary patterns, thereby guiding timely selection of BV, 1.5-ventricle, or univentricular management ‎16, ‎19-‎22 . Table 3: Possible procedures and clinical outcomes for PA in relation to RV morphology Surgical Options Biventricular repair feasible Often requires univentricular pathway RV Growth Potential Preserved with pulmonary flow restoration Limited, especially with coronary sinusoids Long-Term Outcome Better functional prognosis Higher risk of arrhythmias and failure Figure : Algorithmic, stepwise management of pulmonary atresia (PA/IVS) guided by right-ventricular (RV) partition and coronary findings. Biventricular repair aims to establish or maintain two-ventricle circulation with the RV handling the full systemic venous return. Depending on presentation, it may be performed primarily or after initial palliation and typically involves pulmonary valvotomy/RVOT opening, patch or RV-to-PA conduit when needed, and withdrawal of ductal support ‎16‎-17 .1.5-ventricle repair combines a superior cavopulmonary connection (bidirectional Glenn) with antegrade RV-to-PA flow; the RV supports part—but not all—of the systemic venous return, reducing RV volume load while preserving pulsatile pulmonary flow. This pathway suits “borderline” RVs in which full BV physiology would be high-risk. Univentricular repair (single-ventricle palliation) is chosen when the RV is too small/noncompliant or when RV-dependent coronaries make RV decompression hazardous. It usually begins with a source of pulmonary blood flow (BT shunt or ductal stent), followed by staged cavopulmonary connections (bidirectional Glenn then Fontan) later in childhood. Contemporary imaging—high-resolution echocardiography and fetal/infant cardiac MRI—facilitates early recognition of RV morphology and thus early routing to the BV/1.5-ventricle versus univentricular repair. As summarized in Figure 2, classification of RV partition with targeted assessment of valve size, RV adequacy, and coronary sinusoids routes patients toward biventricular, 1.5-ventricle, or univentricular strategies. Conclusion Understanding right ventricular morphogenesis through updated embryology is critical for interpreting the heterogeneity of pulmonary atresia. The distinction between bipartite and tripartite RVs provides a practical framework for surgical planning. Future integration of molecular and genetic data with modern embryology will further refine risk stratification and therapeutic strategies ‎ 22 . Data Availability Statement No new data were created or analyzed in this study; data sharing is not applicable to this article. Conflict of Interest The authors declare no conflicts of interest related to this work. Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. References 1. Human Developmental Biology Resource (HDBR) Atlas. Available at: www.hdbratlas.org. → Primary human embryology datasets anchoring the Carnegie stage timing for RV inlet/outlet formation and supporting the bipartite vs tripartite framework. Google Scholar 2. Hikspoors, J. P. J. M., Kruepunga, N., Mommen, G. M. C., Kohler, S. E. A pictorial account of the human embryonic heart between 3.5 and 8 weeks of development. Communications Biology. 2022; 5:226. → Modern, image-rich human embryology clarifying morphologic transitions across CS15–CS17 referenced in the developmental timeline. Google Scholar 3. Restivo, A., Piacentini, G., Placidi, S., Saffirio, C., Marino, B. Cardiac outflow tract: a review of embryogenetic aspects of the conotruncal region. Anat Rec A. 2006;288(9):936–943. → Synthesizes outflow-tract morphogenesis and supports statements linking RVOT continuity to later PA phenotypes. Google Scholar 4. Hutson, M. R., Kirby, M. L. Neural crest and cardiovascular development: a 20-year perspective. Developmental Biology. 2007;306(1):1–12. → Establishes neural-crest roles in outflow septation and coronary development, informing discussion of RV–coronary sinusoids. Google Scholar 5. Alnaami, G. Right Ventricular Morphology in PA/IVS: Integrating Developmental Pathology with Echocardiographic Prognostication. Echocardiography. 2025;42(5): e70190. → Links RV partition phenotype on imaging with prognostic pathways (BV vs 1.5-ventricle vs univentricular), supporting the management schema. Google Scholar 6. Moorman, A. F., Christoffels, V. M. Cardiac chamber formation: Development, genes, and evolution. Physiological Reviews. 2003;83(4):1223–1267. → Foundational account of chamber ballooning and inlet/outlet allocation grounding the tripartite RV concept. Google Scholar 7. Sadler, T. W. Langman’s Medical Embryology. 15th ed. Wolters Kluwer; 2023. → Standard reference for CS timing and terminology, confirming normal milestones contrasted with PA deviations. Google Scholar 8. Moore, K. L., Persaud, T. V. N., Torchia, M. G. The Developing Human: Clinically Oriented Embryology. 11th ed. Elsevier; 2022. → Corroborates human CS staging and provides clinically oriented context for early imaging statements. Google Scholar 9. Kirby, M. L., Hutson, M. R. The neural crest and congenital heart defects. Current Topics in Developmental Biology. 2010; 90:275–317. → Mechanistic link between crest perturbation and cardiac malformations, supporting outflow anomalies relevant to PA. Google Scholar 10. 21. Moras, P., Pasquini, L., Campanale, C. M., Masci, M., Ventrella, S., Di Chiara, L., Butera, G., Toscano, A. Echocardiographic phenotype predicts complications after pulmonary valve balloon dilation in neonates with PA/critical PS/IVS. Echocardiography. 2025;42(5): e70182. → Emerging evidence that echocardiographic phenotype predicts early post-PVBD complications, supporting imaging-based triage. Google Scholar 11. Crucean, A., Spicer, D. E., Tretter, J. T., Mohun, T. J., Anderson, R. H. Revisiting the anatomy of the right ventricle in the light of knowledge of its development. Journal of Anatomy. 2024;244(2):297–311. → Contemporary reinterpretation of RV anatomy through a developmental lens, reinforcing the partition-based morphological framework. Google Scholar 12. Webb, S., Qayyum, S. R., Anderson, R. H., Lamers, W. H., Richardson, M. K. Septation and separation within the outflow tract of the developing heart. Journal of Anatomy. 2003;202(4):327–342. → Primary developmental anatomy of outflow septation cited to justify the clinical importance of RVOT continuity. Google Scholar 13. Human Developmental Biology Resource (HDBR) Atlas. Interactive 3D model of the human heart at Carnegie Stage 17. https://hdbratlas.org/hikspoors-pdf/JH_CS17.html → Specific CS17 3D resource illustrating atrioventricular and outflow relationships used in the figure and timeline. Google Scholar 14. The Virtual Human Embryo (EHD). Carnegie Stage 15 overview (≈36 days). https://www.ehd.org/virtual-human-embryo/stage.php?stage=15 → Independent CS15 benchmark supporting early milestones in the developmental sequence. Google Scholar 15. García-Molina, E., Manso, M. E., Zunzunegui, J. L., de la Calzada, C. S. Pulmonary atresia with intact ventricular septum: Clinical and surgical considerations. Revista Española de Cardiología (English Edition). 2005;58(12):1439–1451. → Classic clinical review grounding statements on natural history, initial palliation, and risks related to RV decompression. Google Scholar 16. Perry, C. D., Ziegler, K. M., Holzer, R. J. Pulmonary atresia with intact ventricular septum. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020. → Practical, up-to-date clinical summary cited for definitions, stabilization, and management options. Google Scholar 17. Cleuziou, J., Schreiber, C., Eicken, A., Hörer, J., Busch, R., Holper, K., Lange, R. Predictors for biventricular repair in pulmonary atresia with intact ventricular septum. Thoracic and Cardiovascular Surgeon. 2010;58(6):339–344. → Outcome data supporting thresholds (e.g., tricuspid annulus z-score, RV size) for choosing BV vs staged/1.5-ventricle pathways. Google Scholar 18. Kirby, M. L. Pulmonary atresia or persistent truncus arteriosus: Is it important to make the distinction and how do we do it? Circulation Research. 2007;100(6):736–738. → Perspective clarifying nosology and diagnostic distinctions referenced in the background. Google Scholar 19. Sana, M. K., Alahmadi, M. Pulmonary atresia with ventricular septal defect. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024. → PA/VSD contrasts and contemporary imaging guidance that broaden the management section’s scope. Google Scholar 20. Anderson, R. H., Becker, A. E. Cardiac Anatomy: An Integrated Text and Colour Atlas. Gower Medical Publishing; 1983. → Gold-standard anatomic reference underpinning precise RV component terminology used throughout. Google Scholar 21. Hoffman, J. I. E. The Natural and Unnatural History of Congenital Heart Disease. Wiley-Blackwell; 2009. → Historical/mechanistic context for fetal cardiovascular remodeling and clinical course in PA/IVS. Google Scholar 22. Fahed, A. C., Gelb, B. D., Seidman, J. G., Seidman, C. E. Genetics of congenital heart disease: The glass half empty. Circulation Research. 2013;112(4):707–720. → Genetics overview framing the limits of genotype–phenotype prediction and supporting the “limitations” statement. Google Scholar Information & Authors Information Version history V1 Version 1 10 October 2025 Copyright This work is licensed under a Non Exclusive No Reuse License. Keywords fetal mri pulmonary atresia right ventricle morphology right ventricular partition rv-dependent coronary sinusoids tricuspid valve z-score Authors Affiliations Ghassan Al-Naami 0009-0003-0636-3478 [email protected] University of Alberta View all articles by this author Metrics & Citations Metrics Article Usage 187 views 135 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Ghassan Al-Naami. Embryological Determinants of Right Ventricular Morphogenesis in Pulmonary Atresia: The Role of Bipartite and Tripartite Configurations. Authorea . 10 October 2025. DOI: https://doi.org/10.22541/au.176009604.43965635/v1 If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download. For more information or tips please see 'Downloading to a citation manager' in the Help menu . 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