Semilunar valves in pediatric orthotopic heart transplants grow at a slower rate than controls

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Nissen, Simon Chung, Andrew Brown, Emily Sanders-Chen, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6305563/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 12 May, 2025 Read the published version in Pediatric Cardiology → Version 1 posted 7 You are reading this latest preprint version Abstract Background: Partial heart transplantation is a novel approach to deliver a growing donor valve in pediatric recipients needing valve replacements. Objective data on the rate of growth of semilunar valves in patients following orthotopic heart transplantation (OHT) is necessary to set expectations for partial heart transplant semilunar valve growth. Methods: A retrospective cohort study was performed, which included twelve infants who underwent OHT and twelve controls with ventricular septal defects (VSD). Semilunar valve annulus absolute dimension over serial echocardiograms was recorded, Z-scores were calculated, and mixed-effects models were applied to the absolute dimension (mm) and scaled dimension (Boston Z-score). Results: Aortic and pulmonary valve annuli in OHT patients grow. There is a downward trend in aortic valve annulus Z-score over time for OHT patients compared to population norms and controls with VSDs (difference in slopes: -0.119 Z-score/y, 95% CI: [-0.209, -0.029], p = 0.011); there is a non-significant difference for the pulmonary valve annulus (difference in slopes: -0.067 Z-score/y, 95% CI: [-0.155 0.022], p = 0.140). Conclusions: Semilunar valves in pediatric OHT patients grow at a slower rate than controls. There was no semilunar valve obstruction in our cohort. While the described difference in valve growth may not be clinically significant for pediatric OHT recipients, these growth rates inform the anticipated growth trajectory for the partial heart transplant graft. Figures Figure 1 Figure 2 Figure 3 Background Since the first human-to-human heart transplant was performed in 1967, there have been remarkable strides in the field. 1 The most recent outcomes show significantly improved survival rates, with median survival of 22.3 y for patients aged < 1 year, 18.4 years for patients 1 to 5 years old, 14.4 years for patients 6 to 10 years old, and 13.1 years for adolescents. 2 Clinical studies suggest that transplanted heart valves grow at a rate comparable to non-transplants. In a recent series looking at the largest cohort of acute cellular and antibody mediated rejection in childhood orthotopic transplant (OHT) recipients, the semilunar valve function was not noted to be affected. 3 This has led to the recent interest in utilizing “growing” donor valves (not suitable for OHT) in patients who are in need for a valve replacement. Partial heart transplantation (PHT) is a novel approach wherein a living donor valve is transplanted, and the recipient is placed on an immunosuppressive regimen so that the transplanted valve can continue to grow in the recipient. Report of the first successful PHT was published in 2024, with transplantation of donor pulmonary and aortic valves into a neonate with truncus arteriosus and severe truncal valve dysfunction. 4 Early experience with PHT is promising, demonstrating valve growth throughout follow up through the first year of life. 4 However, objective data on the rate of growth of transplanted semilunar valves is limited. These data are important before widespread adoption of PHT to guide follow up in these recipients. Experience with pulmonary valve autografts placed in the aortic position (the Ross operation) has shown graft growth. 5 – 8 Further, evidence to date has reported growth of the cardiac chambers and semilunar valves (Rajab 2024) following OHT. 9 , 10 The objective of this study is to evaluate the growth of semilunar valves in OHT and to compare that growth to ventricular septal defect (VSD) controls and population norms by use of Z-scores. We hypothesized that the growth of semilunar valve annuli in OHT would be like that of non-transplanted controls and population norms. We anticipated that patients with hemodynamically significant VSDs requiring surgical repair would have slower aortic annulus growth after surgical repair of the VSD because left heart dilation, if present preoperatively, would resolve following closure of the left-to-right VSD shunt. Methods Study design A retrospective cohort study was performed. Twelve infants undergoing OHT at one year of age or younger and with available echocardiogram data spanning a period of at least five years were selected. The control group consisted of twelve infants with VSDs, also with five years of available serial echocardiogram data. The VSD control group was used in addition to population norms because a control group will be necessary for future work evaluating novel methods for which there are no population norms. Patients with VSDs were selected as a control group because of the availability of serial echocardiograms during the age range of interest. 11 When available, one echocardiogram every six months (+/- two months) was included for analysis. When more than one echocardiogram was available for a given six-month period, the echocardiogram with superior image quality was selected for inclusion by an investigator (TN). For OHT patients, the first echocardiogram eligible for analysis was the initial post-OHT transthoracic echocardiogram. For VSD controls, the first echocardiogram eligible for analysis was the patient’s initial available echocardiogram. All echocardiograms were de-identified and read by a blinded pediatric cardiologist (AQ). A subset of echocardiograms was also read by a second blinded pediatric cardiologist (ES or NP), and inter-rater reliability was assessed as detailed below. Relevant clinical and demographic data were obtained from electronic medical records retrospectively (Table 1 ). This study was approved by the University of Arkansas for Medical Sciences Institutional Review Board (IRB 276870, approved 02/29/2024). Table 1 Characteristics of included patients Group Orthotopic heart transplant N = 12 VSD Control N = 12 Race/Ethnicity Non-Hispanic White 7/12 (58.3%) 6/12 (50%) Non-Hispanic Black 0/12 (0%) 3/12 (25%) Hispanic or Latino/a/e 4/12 (33.3%) 2/12 (16.7%) Other 1/12 (8.3%) 1/12 (8.3%) Sex, n (%) Male 6/12 (50.0%) 5/12 (41.7%) Female 6/12 (50.0%) 7/12 (58.3%) Age at the First Echo (years) 0.355 (0.212) 0.153 (0.268) Age at the OHT/VSD Surgical Closure (years) 0.315 (0.198) 2.283 (2.189) OHT/VSD Surgical Closure, n(%) 12/12 (100%) 8/12 (67%) Follow-up Duration (years) 5.586 (0.486) 8.426 (1.792) Number of Echocardiograms 11.667 (1.155) 8.917 (1.084) Height at the First Echo (cm) 56.583 (6.477) 53.958 (6.426) Weight at the First Echo (kg) 5.058 (1.412) 4.392 (2.189) BSA at the First Echo (m 2 ) 0.267 (0.053) 0.240 (0.069) Genetic Diagnosis 0/12 (0%) 1/12 (8.3%) Initial VSD Size Small 2/12 (17%) Moderate 4/12 (33%) Large 6/12 (50%) VSD location, n (%) Perimembranous 9/12 (75%) Muscular 2/12 (17%) Conoseptal 1/12 (8%) Transplant indication, n (%) Cardiomyopathy or Myocarditis 2/12 (17%) Congenital Heart Disease 10/12 (83%) Rejection During Serial Follow-up, n (%) 0/12 (0%) n/N (%); Mean (SD); Echo: transthoracic echocardiogram; BSA: Body surface area; VSD: Ventricular septal defect; BSA: body surface area; OHT: Orthotopic heart transplantation Aortic valve annulus dimension was measured using standard electronic calipers on transthoracic echocardiograms (Syngo Dynamics VA41) by investigators (AQ, ES, NP). Aortic valve annulus measurement was made in mid-systole from the parasternal long axis view, measured between the aortic valve leaflet hinge points from inner edge to inner edge. 12 The pulmonary valve annulus measurement was made in mid-systole from the parasternal short axis view, measured between the pulmonary valve leaflet hinge points from inner edge to inner edge. For Table 1 , the reported VSD size and location were based on the original interpretation of the echocardiogram. Aortic and pulmonary valve annulus absolute dimension was converted to a Z-score, scaled to patient age and body surface area. Z-scores were calculated using the Boston Children’s Hospital (BCH) Z-score system, accessed via the BCH web platform ( https://zscore.chboston.org/ ; accessed 12/2024) and via a BCH Microsoft Excel calculator provided courtesy of BCH (accessed 12/2024). For the primary analysis, semilunar valve annulus measurements over time were recorded, and the corresponding Z-scores were computed. We fit a natural spline mixed-effects model to examine the growth in aortic and pulmonary valve annulus measurement for each group. We further fit a linear mixed-effect model to the Z-scores with age at the echocardiogram, surgery type, and their interaction as covariates. For the VSD controls, we conducted an interrupted time series analysis to compare preoperative versus postoperative semilunar valve annulus growth to understand the potential effect of expected perioperative annulus dimension changes (i.e., potential dilation preoperatively and potential resolution of dilation postoperatively) and whether these perioperative changes might lead to a bias towards the null hypothesis or towards the alternative hypothesis. To ensure the alignment across individuals, ages were centered on 0 at the operation date for patients who underwent surgical closure and at the last echocardiogram date for patients without surgical closure. Model-based marginal predictions and confidence bands were computed to visualize the growth over time from each analysis. Additionally, we conducted a leave-one-out sensitivity analysis for each model to assess the robustness of our findings. A p value < 0.05 was considered statistically significant. To assess echocardiogram measurement’s reliability, we obtained the Inter-rater Reliability with random effects model. All data were analyzed using R version 4.4.1. Results Twelve patients status-post OHT and twelve patients with VSDs were included for analysis. The mean age at first echocardiogram was 0.355 (SD 0.212) years for OHT and 0.153 (SD 0.268) years for VSD controls. OHT patients had a mean of 11.667 (SD 1.155) included echocardiograms spanning a mean of 5.586 (SD 0.486) years. VSD patients received less frequent echocardiograms, with a mean of 8.917 (SD 1.084) included echocardiograms spanning a mean of 8.426 (SD 1.792) years of available follow-up data. One VSD patient had a genetic diagnosis of 7q23.136.7 duplication, which can be associated with dilation of the aortic root and ascending aorta; this patient has mild ascending aorta dilation but no semilunar valve annulus dilation. Inter-rater reliability was good for aortic valve annulus measurements (intraclass correlation coefficient [ICC] 0.88) and moderate for pulmonary valve measurements (ICC 0.63). The natural spline mixed-effects model for absolute aortic and pulmonary valve annulus growth showed that valve annulus dimension increased over time for OHT patients and VSD controls for both semilunar valves (Fig. 1 ). While both semilunar valve annuli grew for OHT patients, when Z-scores were calculated and the linear mixed-effects model applied, there was a significant difference in Z-score change over time (i.e., growth rate) between the aortic valve annulus for OHT patients versus VSD controls. The slope of the growth in aortic valve annulus Z-score over time among OHT patients was − 0.130 Z-score/y, which significantly differed from the rate of growth of VSD controls (slope − 0.011 Z-score/y; difference in slopes: -0.119 Z-score/y, 95% CI: [-0.209, -0.029], p = 0.011) and what would be expected for population norms (no change in Z score over time). For the pulmonary valve annulus, the slope of the growth in Z-score over time was − 0.070 Z-score/y for OHT patients, which did not significantly differ from the VSD controls (slope: -0.003 Z-score/y; difference in slopes: -0.067 Z-score/y, 95% CI: [-0.155, 0.022], p = 0.140; Fig. 2 ). There was no clinical or echocardiographic evidence of valvar stenosis in any of the patients (peak velocity remained below 2 m/s in all patients; data not shown). A secondary analysis compared the trend in aortic and pulmonary valve annulus Z-scores preoperatively and postoperatively among patients undergoing surgical VSD closure. 8/12 VSD patients underwent surgical closure. For aortic valve annulus, VSD patients had a larger initial annulus size when compared to population norms (Fig. 3 ; Z-score 1.031, 95% CI: [0.138, 1.925], p = 0.037). The slope difference of Z-score change over time comparing pre-surgery and post-surgery (Fig. 3 ; -0.216 Z-score/y, 95% CI: [-0.353, -0.081], p = 0.003) suggests that surgery significantly impacted the trajectory of the aortic valve annulus. Because the aortic valve annulus dimension for VSD patients decreased postoperatively and because aortic annulus size in patients post OHT also decreased over time, the postoperative decrease in VSD patient annulus dimension biases results toward the null hypothesis. Initial pulmonary valve annulus size did not significantly differ from population norms, nor did pulmonary valve annulus size trend change significantly following surgery (Fig. 3 ). The sensitivity analysis with leave-one-out approach confirmed the robustness of our findings, as the results remained consistent with the analysis from the full dataset (supplemental data). Discussion The aortic valve annulus grows following OHT, though at a somewhat slower rate when compared to control patients with VSDs and to the general population as represented by the declining slope of Z-score over time in our data. Pulmonary valve annular dimension appears to have a similar trend, however the decrease in pulmonary valve annulus Z-score does not reach statistical significance. This is the first time semilunar valve growth in OHT patients has been objectively studied over time. Contrary to our original hypothesis, we found that growth rates in OHT significantly differed from VSD controls and population norms. The reasons for these observed differences are not entirely clear. One potential reason could be that transplanted valves follow the growth trajectory of the donor. Unfortunately, we did not have the data necessary from donors to accurately estimate donor growth trajectories. While the differences are statistically significant, since the valves continued to grow and did not have clinical evidence of stenosis, the differences are likely not clinically relevant for the OHT population. However, our data would be important in guiding what to expect for PHT grafts (i.e., decreasing Z-scores over time may not indicate PHT graft failure). The closest analogies to PHT in current medical practice are OHT and the Ross procedure. Prior investigation of semilunar valve growth in pediatric OHT patients has shown growth of aortic valve dimension with no significant change in Z-scores when comparing initial echocardiograms to 10-year echocardiograms (average − 0.4, range − 1.8 to 1.0, p = .26). However, this study did not include serial data points and their reported trend of Z-scores (from a mean Z-score of 1.67 postoperatively to 0.55 after ten years of follow up) appears to be consistent with the statistically significant declining trend described in our analysis. 10 In the pediatric population, the neoaortic valve annulus following a Ross procedure has been variably described as having stable growth or as having initial dilation followed by stabilization of Z-score. 6 – 8 , 10 For adults, pulmonary autografts after the Ross procedure have been described to have a small decrease in size of the neoaortic valve annulus, with a mean decrease of approximately 2.6 mm over the 44 months of follow-up. 13 Pediatric OHT trends appear to differ from trends following neonatal Ross because there is no aortic valve annular dilation following OHT and because there is a small decrease in Z-score following OHT which–perhaps due to initial dilation–is not seen following Ross; however, the aortic valve annulus following both procedures does demonstrate growth. The reason for selecting VSD patients as the control group was the availability of serial echocardiograms in this group. Including the VSD control group meant that the control group annuli were measured by the same cardiologists as the transplant annuli, which was a strength relative to using population norms as a control. One limitation of the VSD control group is the dilation of left-sided heart structures in patients with hemodynamically significant VSDs and the expected normalization of these structures following surgical VSD closure. As expected, we demonstrated a decrease in aortic valve annular Z-score trend following surgical VSD repair. Since the average age at VSD surgery was a mean of 833 days (median 604 days) and VSD controls were followed for a mean of 8.43 years, majority of the follow-up was following VSD repair and therefore we felt that was an informative control group. Further, the demonstrated decrease in aortic valve annulus Z-score following VSD closure (Fig. 3 ) would be expected to bias towards a null result because OHT patients are also seen to have a decrease in aortic valve annulus Z-score. Therefore, the limitations inherent to the VSD control group should not undermine the central difference between the OHT and VSD control groups, which was the difference in the growth rates between the two groups. The small, retrospective nature of our study with twelve patients in each arm is a limitation. However, each patient had multiple repeated measurements by two trained pediatric cardiologists with adequate reliability. The inclusion of a VSD control group in addition to comparison to population norms (via Z-score) improves robustness, but an ideal comparison group may have been age/size matched structurally normal hearts that are followed for the same duration as the VSD controls. Given the retrospective nature of this study, echocardiograms of structurally normal hearts are typically not available for comparison. Therefore, the VSD control group served as an appropriate alternative, and we further accounted for differences in VSD growth by investigating the interrupted time series analysis. VSD controls could also be used for future studies to develop novel echocardiographic measures of valve growth (such as leaflet length) that would be important for the surveillance of the PHT graft. 11 Conclusion Semilunar valves in OHT grow over time. When compared to VSD controls and population norms, the growth rate of the aortic valve annulus was significantly slower while that of the pulmonary valve annulus was slower but did not achieve statistical significance. The demonstration of growth over time, combined with the lack of a clinical gradient, indicate that these differences may not be clinically relevant for the OHT population. However, these growth rates provide vital information for the follow up growth trajectory of the PHT graft, which we would expect to be like that of OHT. Abbreviations OHT Orthotopic heart transplantation PHT Partial heart transplantation VSD Ventricular septal defect Declarations Disclosure Statement: The authors have nothing to disclose regarding commercial support or relationships to industry. Author Contribution Substantial contributions to the work were made by the following individuals: Tim Nissen, MD and Amna Qasim, MD: conception and design of the work, interpretation of data, literature review, manuscript drafting, and revisions. Nirbhay Parashar, MD and Emily Sanders-Chen, MD: data acquisition. Simon Chung and Andrew Brown performed the statistical analysis and helped with preparation of the figures. Kenneth Knecht, MD and Taufiek Konrad Rajab: manuscript review and revisions. Acknowledgements: None. Data Availability Data is provided within the manuscript or supplementary information files References Cooper DK (1984) Orthotopic and heterotopic transplantation of the heart: the Cape Town experience. Ann R Coll Surg Engl 66(4):228–234 Dipchand AI, Laks JA (2020) Pediatric heart transplantation: long-term outcomes. Indian J Thorac Cardiovasc Surg 36(Suppl 2):175–189 Everitt MD, Pahl E, Koehl DA, Cantor RS, Kirklin JK, Reed AC et al (2025) Clinical outcomes after a biopsy diagnosis of antibody-mediated rejection in pediatric heart transplant recipients. J Heart Lung Transpl 44(1):82–91 Turek JW, Kang L, Overbey DM, Carboni MP, Rajab TK (2024) Partial Heart Transplant in a Neonate With Irreparable Truncal Valve Dysfunction. JAMA 331(1):60–64 Fadel BM, Manlhiot C, Al-Halees Z, Di Salvo G, Al-Ahmadi M, McCrindle B et al (2013) The fate of the neoaortic valve and root after the modified Ross-Konno procedure. J Thorac Cardiovasc Surg . ;145(2):430–437.e1; discussion 436–437 Nguyen SN, Bouhout I, Singh S, Vinogradsky AV, Chung MM, Sevensky R et al (2024) Long-term autograft dilation and durability after the Ross procedure are similar in infants, children, and adolescents with primary aortic stenosis. J Thorac Cardiovasc Surg 168(4):1182–1191e3 Simon P, Aschauer C, Moidl R, Marx M, Keznickl FP, Eigenbauer E et al (2001) Growth of the pulmonary autograft after the Ross operation in childhood. Eur J Cardiothorac Surg 19(2):118–121 Williams IA, Quaegebeur JM, Hsu DT, Gersony WM, Bourlon F, Mosca RS et al (2005) Ross procedure in infants and toddlers followed into childhood. Circulation 112(9 Suppl):I390–I395 Bernstein D, Kolla S, Miner M, Pitlick P, Griffin M, Starnes V et al (1992) Cardiac growth after pediatric heart transplantation. Circulation 85(4):1433–1439 Rajab TK, Abdelrahman M, Schwartzenburg EJ, Aykut B, Turek JW, McVadon DH (2024) Semilunar valve growth and function 10 years after infant heart transplantation: Predicting long-term outcomes of partial heart transplants. Pediatr Transpl 28(3):e14746 Rajab TK, Nissen TE, Simionescu DT, Qasim A (2024) Leaflet Length as a Novel Echocardiography Parameter to Evaluate Partial Heart Transplant Growth. J Am Soc Echocardiogr 37(5):575–576 Lang RM, Badano LP, Mor-Avi V, Afilalo J, Armstrong A, Ernande L et al (2015) Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr 28(1):1–39e14 David TE, Omran A, Ivanov J, Armstrong S, de Sa MP, Sonnenberg B et al (2000) Dilation of the pulmonary autograft after the Ross procedure. J Thorac Cardiovasc Surg 119(2):210–220 Additional Declarations No competing interests reported. Supplementary Files Supplementaldata.docx Cite Share Download PDF Status: Published Journal Publication published 12 May, 2025 Read the published version in Pediatric Cardiology → Version 1 posted Editorial decision: Revision requested 17 Apr, 2025 Reviews received at journal 14 Apr, 2025 Reviewers agreed at journal 02 Apr, 2025 Reviewers invited by journal 02 Apr, 2025 Editor assigned by journal 25 Mar, 2025 Submission checks completed at journal 25 Mar, 2025 First submitted to journal 25 Mar, 2025 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-6305563","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":444489195,"identity":"5b7bf192-1fd6-46eb-ae50-dee981f57e11","order_by":0,"name":"Timothy E. 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16:07:22","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1050302,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6305563/v1/a86db224-cd7c-44df-9df3-586671e5689b.pdf"},{"id":81964469,"identity":"55eaad00-c4c9-4fbe-b231-714d990975f9","added_by":"auto","created_at":"2025-05-05 11:24:13","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":472441,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementaldata.docx","url":"https://assets-eu.researchsquare.com/files/rs-6305563/v1/a385f50c61006ba1cb0fcacd.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Semilunar valves in pediatric orthotopic heart transplants grow at a slower rate than controls","fulltext":[{"header":"Background","content":"\u003cp\u003eSince the first human-to-human heart transplant was performed in 1967, there have been remarkable strides in the field.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e The most recent outcomes show significantly improved survival rates, with median survival of 22.3 y for patients aged\u0026thinsp;\u0026lt;\u0026thinsp;1 year, 18.4 years for patients 1 to 5 years old, 14.4 years for patients 6 to 10 years old, and 13.1 years for adolescents.\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e Clinical studies suggest that transplanted heart valves grow at a rate comparable to non-transplants. In a recent series looking at the largest cohort of acute cellular and antibody mediated rejection in childhood orthotopic transplant (OHT) recipients, the semilunar valve function was not noted to be affected.\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e This has led to the recent interest in utilizing \u0026ldquo;growing\u0026rdquo; donor valves (not suitable for OHT) in patients who are in need for a valve replacement.\u003c/p\u003e \u003cp\u003ePartial heart transplantation (PHT) is a novel approach wherein a living donor valve is transplanted, and the recipient is placed on an immunosuppressive regimen so that the transplanted valve can continue to grow in the recipient. Report of the first successful PHT was published in 2024, with transplantation of donor pulmonary and aortic valves into a neonate with truncus arteriosus and severe truncal valve dysfunction.\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e Early experience with PHT is promising, demonstrating valve growth throughout follow up through the first year of life.\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e However, objective data on the rate of growth of transplanted semilunar valves is limited. These data are important before widespread adoption of PHT to guide follow up in these recipients. Experience with pulmonary valve autografts placed in the aortic position (the Ross operation) has shown graft growth.\u003csup\u003e\u003cspan additionalcitationids=\"CR6 CR7\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e Further, evidence to date has reported growth of the cardiac chambers and semilunar valves (Rajab 2024) following OHT.\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e,\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThe objective of this study is to evaluate the growth of semilunar valves in OHT and to compare that growth to ventricular septal defect (VSD) controls and population norms by use of Z-scores. We hypothesized that the growth of semilunar valve annuli in OHT would be like that of non-transplanted controls and population norms. We anticipated that patients with hemodynamically significant VSDs requiring surgical repair would have slower aortic annulus growth after surgical repair of the VSD because left heart dilation, if present preoperatively, would resolve following closure of the left-to-right VSD shunt.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design\u003c/h2\u003e \u003cp\u003eA retrospective cohort study was performed. Twelve infants undergoing OHT at one year of age or younger and with available echocardiogram data spanning a period of at least five years were selected. The control group consisted of twelve infants with VSDs, also with five years of available serial echocardiogram data. The VSD control group was used in addition to population norms because a control group will be necessary for future work evaluating novel methods for which there are no population norms. Patients with VSDs were selected as a control group because of the availability of serial echocardiograms during the age range of interest.\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e When available, one echocardiogram every six months (+/- two months) was included for analysis. When more than one echocardiogram was available for a given six-month period, the echocardiogram with superior image quality was selected for inclusion by an investigator (TN). For OHT patients, the first echocardiogram eligible for analysis was the initial post-OHT transthoracic echocardiogram. For VSD controls, the first echocardiogram eligible for analysis was the patient\u0026rsquo;s initial available echocardiogram. All echocardiograms were de-identified and read by a blinded pediatric cardiologist (AQ). A subset of echocardiograms was also read by a second blinded pediatric cardiologist (ES or NP), and inter-rater reliability was assessed as detailed below. Relevant clinical and demographic data were obtained from electronic medical records retrospectively (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). This study was approved by the University of Arkansas for Medical Sciences Institutional Review Board (IRB 276870, approved 02/29/2024).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCharacteristics of included patients\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGroup\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOrthotopic heart transplant \u003c/p\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;12\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eVSD Control\u003c/p\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;12\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eRace/Ethnicity\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNon-Hispanic White\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7/12 (58.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6/12 (50%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNon-Hispanic Black\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0/12 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3/12 (25%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHispanic or Latino/a/e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4/12 (33.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2/12 (16.7%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOther\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1/12 (8.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1/12 (8.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSex, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6/12 (50.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5/12 (41.7%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6/12 (50.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7/12 (58.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAge at the First Echo (years)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.355 (0.212)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.153 (0.268)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAge at the OHT/VSD Surgical Closure (years)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.315 (0.198)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.283 (2.189)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eOHT/VSD Surgical Closure, n(%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12/12 (100%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8/12 (67%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eFollow-up Duration (years)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5.586 (0.486)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8.426 (1.792)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNumber of Echocardiograms\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11.667 (1.155)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8.917 (1.084)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eHeight at the First Echo (cm)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e56.583 (6.477)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e53.958 (6.426)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eWeight at the First Echo (kg)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5.058 (1.412)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4.392 (2.189)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBSA at the First Echo (m\u003c/b\u003e\u003csup\u003e\u003cb\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/b\u003e\u003c/sup\u003e\u003cb\u003e)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.267 (0.053)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.240 (0.069)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eGenetic Diagnosis\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0/12 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1/12 (8.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eInitial VSD Size\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSmall\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2/12 (17%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eModerate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4/12 (33%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLarge\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6/12 (50%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eVSD location, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePerimembranous\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9/12 (75%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMuscular\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2/12 (17%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eConoseptal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1/12 (8%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTransplant indication, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCardiomyopathy or Myocarditis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2/12 (17%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCongenital Heart Disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10/12 (83%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eRejection During Serial Follow-up, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0/12 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003en/N (%); Mean (SD); Echo: transthoracic echocardiogram; BSA: Body surface area; VSD: Ventricular septal defect; BSA: body surface area; OHT: Orthotopic heart transplantation\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eAortic valve annulus dimension was measured using standard electronic calipers on transthoracic echocardiograms (Syngo Dynamics VA41) by investigators (AQ, ES, NP). Aortic valve annulus measurement was made in mid-systole from the parasternal long axis view, measured between the aortic valve leaflet hinge points from inner edge to inner edge.\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e The pulmonary valve annulus measurement was made in mid-systole from the parasternal short axis view, measured between the pulmonary valve leaflet hinge points from inner edge to inner edge. For Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, the reported VSD size and location were based on the original interpretation of the echocardiogram.\u003c/p\u003e \u003cp\u003eAortic and pulmonary valve annulus absolute dimension was converted to a Z-score, scaled to patient age and body surface area. Z-scores were calculated using the Boston Children\u0026rsquo;s Hospital (BCH) Z-score system, accessed via the BCH web platform (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://zscore.chboston.org/\u003c/span\u003e\u003cspan address=\"https://zscore.chboston.org/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e; accessed 12/2024) and via a BCH Microsoft Excel calculator provided courtesy of BCH (accessed 12/2024).\u003c/p\u003e \u003cp\u003eFor the primary analysis, semilunar valve annulus measurements over time were recorded, and the corresponding Z-scores were computed. We fit a natural spline mixed-effects model to examine the growth in aortic and pulmonary valve annulus measurement for each group. We further fit a linear mixed-effect model to the Z-scores with age at the echocardiogram, surgery type, and their interaction as covariates. For the VSD controls, we conducted an interrupted time series analysis to compare preoperative versus postoperative semilunar valve annulus growth to understand the potential effect of expected perioperative annulus dimension changes (i.e., potential dilation preoperatively and potential resolution of dilation postoperatively) and whether these perioperative changes might lead to a bias towards the null hypothesis or towards the alternative hypothesis. To ensure the alignment across individuals, ages were centered on 0 at the operation date for patients who underwent surgical closure and at the last echocardiogram date for patients without surgical closure. Model-based marginal predictions and confidence bands were computed to visualize the growth over time from each analysis. Additionally, we conducted a leave-one-out sensitivity analysis for each model to assess the robustness of our findings. A p value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant. To assess echocardiogram measurement\u0026rsquo;s reliability, we obtained the Inter-rater Reliability with random effects model. All data were analyzed using R version 4.4.1.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eTwelve patients status-post OHT and twelve patients with VSDs were included for analysis. The mean age at first echocardiogram was 0.355 (SD 0.212) years for OHT and 0.153 (SD 0.268) years for VSD controls. OHT patients had a mean of 11.667 (SD 1.155) included echocardiograms spanning a mean of 5.586 (SD 0.486) years. VSD patients received less frequent echocardiograms, with a mean of 8.917 (SD 1.084) included echocardiograms spanning a mean of 8.426 (SD 1.792) years of available follow-up data. One VSD patient had a genetic diagnosis of 7q23.136.7 duplication, which can be associated with dilation of the aortic root and ascending aorta; this patient has mild ascending aorta dilation but no semilunar valve annulus dilation. Inter-rater reliability was good for aortic valve annulus measurements (intraclass correlation coefficient [ICC] 0.88) and moderate for pulmonary valve measurements (ICC 0.63).\u003c/p\u003e \u003cp\u003eThe natural spline mixed-effects model for absolute aortic and pulmonary valve annulus growth showed that valve annulus dimension increased over time for OHT patients and VSD controls for both semilunar valves (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). While both semilunar valve annuli grew for OHT patients, when Z-scores were calculated and the linear mixed-effects model applied, there was a significant difference in Z-score change over time (i.e., growth rate) between the aortic valve annulus for OHT patients versus VSD controls. The slope of the growth in aortic valve annulus Z-score over time among OHT patients was \u0026minus;\u0026thinsp;0.130 Z-score/y, which significantly differed from the rate of growth of VSD controls (slope \u0026minus;\u0026thinsp;0.011 Z-score/y; difference in slopes: -0.119 Z-score/y, 95% CI: [-0.209, -0.029], \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.011) and what would be expected for population norms (no change in Z score over time). For the pulmonary valve annulus, the slope of the growth in Z-score over time was \u0026minus;\u0026thinsp;0.070 Z-score/y for OHT patients, which did not significantly differ from the VSD controls (slope: -0.003 Z-score/y; difference in slopes: -0.067 Z-score/y, 95% CI: [-0.155, 0.022], \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.140; Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). There was no clinical or echocardiographic evidence of valvar stenosis in any of the patients (peak velocity remained below 2 m/s in all patients; data not shown).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eA secondary analysis compared the trend in aortic and pulmonary valve annulus Z-scores preoperatively and postoperatively among patients undergoing surgical VSD closure. 8/12 VSD patients underwent surgical closure. For aortic valve annulus, VSD patients had a larger initial annulus size when compared to population norms (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e; Z-score 1.031, 95% CI: [0.138, 1.925], \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.037). The slope difference of Z-score change over time comparing pre-surgery and post-surgery (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e; -0.216 Z-score/y, 95% CI: [-0.353, -0.081], \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.003) suggests that surgery significantly impacted the trajectory of the aortic valve annulus. Because the aortic valve annulus dimension for VSD patients decreased postoperatively and because aortic annulus size in patients post OHT also decreased over time, the postoperative decrease in VSD patient annulus dimension biases results toward the null hypothesis. Initial pulmonary valve annulus size did not significantly differ from population norms, nor did pulmonary valve annulus size trend change significantly following surgery (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe sensitivity analysis with leave-one-out approach confirmed the robustness of our findings, as the results remained consistent with the analysis from the full dataset (supplemental data).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe aortic valve annulus grows following OHT, though at a somewhat slower rate when compared to control patients with VSDs and to the general population as represented by the declining slope of Z-score over time in our data. Pulmonary valve annular dimension appears to have a similar trend, however the decrease in pulmonary valve annulus Z-score does not reach statistical significance. This is the first time semilunar valve growth in OHT patients has been objectively studied over time. Contrary to our original hypothesis, we found that growth rates in OHT significantly differed from VSD controls and population norms. The reasons for these observed differences are not entirely clear. One potential reason could be that transplanted valves follow the growth trajectory of the donor. Unfortunately, we did not have the data necessary from donors to accurately estimate donor growth trajectories. While the differences are statistically significant, since the valves continued to grow and did not have clinical evidence of stenosis, the differences are likely not clinically relevant for the OHT population. However, our data would be important in guiding what to expect for PHT grafts (i.e., decreasing Z-scores over time may not indicate PHT graft failure).\u003c/p\u003e \u003cp\u003eThe closest analogies to PHT in current medical practice are OHT and the Ross procedure. Prior investigation of semilunar valve growth in pediatric OHT patients has shown growth of aortic valve dimension with no significant change in Z-scores when comparing initial echocardiograms to 10-year echocardiograms (average \u0026minus;\u0026thinsp;0.4, range \u0026minus;\u0026thinsp;1.8 to 1.0, p\u0026thinsp;=\u0026thinsp;.26). However, this study did not include serial data points and their reported trend of Z-scores (from a mean Z-score of 1.67 postoperatively to 0.55 after ten years of follow up) appears to be consistent with the statistically significant declining trend described in our analysis.\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eIn the pediatric population, the neoaortic valve annulus following a Ross procedure has been variably described as having stable growth or as having initial dilation followed by stabilization of Z-score.\u003csup\u003e\u003cspan additionalcitationids=\"CR7\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e,\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e For adults, pulmonary autografts after the Ross procedure have been described to have a small decrease in size of the neoaortic valve annulus, with a mean decrease of approximately 2.6 mm over the 44 months of follow-up.\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e Pediatric OHT trends appear to differ from trends following neonatal Ross because there is no aortic valve annular dilation following OHT and because there is a small decrease in Z-score following OHT which\u0026ndash;perhaps due to initial dilation\u0026ndash;is not seen following Ross; however, the aortic valve annulus following both procedures does demonstrate growth.\u003c/p\u003e \u003cp\u003eThe reason for selecting VSD patients as the control group was the availability of serial echocardiograms in this group. Including the VSD control group meant that the control group annuli were measured by the same cardiologists as the transplant annuli, which was a strength relative to using population norms as a control. One limitation of the VSD control group is the dilation of left-sided heart structures in patients with hemodynamically significant VSDs and the expected normalization of these structures following surgical VSD closure. As expected, we demonstrated a decrease in aortic valve annular Z-score trend following surgical VSD repair. Since the average age at VSD surgery was a mean of 833 days (median 604 days) and VSD controls were followed for a mean of 8.43 years, majority of the follow-up was following VSD repair and therefore we felt that was an informative control group. Further, the demonstrated decrease in aortic valve annulus Z-score following VSD closure (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e) would be expected to bias towards a null result because OHT patients are also seen to have a decrease in aortic valve annulus Z-score. Therefore, the limitations inherent to the VSD control group should not undermine the central difference between the OHT and VSD control groups, which was the difference in the growth rates between the two groups.\u003c/p\u003e \u003cp\u003eThe small, retrospective nature of our study with twelve patients in each arm is a limitation. However, each patient had multiple repeated measurements by two trained pediatric cardiologists with adequate reliability. The inclusion of a VSD control group in addition to comparison to population norms (via Z-score) improves robustness, but an ideal comparison group may have been age/size matched structurally normal hearts that are followed for the same duration as the VSD controls. Given the retrospective nature of this study, echocardiograms of structurally normal hearts are typically not available for comparison. Therefore, the VSD control group served as an appropriate alternative, and we further accounted for differences in VSD growth by investigating the interrupted time series analysis. VSD controls could also be used for future studies to develop novel echocardiographic measures of valve growth (such as leaflet length) that would be important for the surveillance of the PHT graft.\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eSemilunar valves in OHT grow over time. When compared to VSD controls and population norms, the growth rate of the aortic valve annulus was significantly slower while that of the pulmonary valve annulus was slower but did not achieve statistical significance. The demonstration of growth over time, combined with the lack of a clinical gradient, indicate that these differences may not be clinically relevant for the OHT population. However, these growth rates provide vital information for the follow up growth trajectory of the PHT graft, which we would expect to be like that of OHT.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eOHT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eOrthotopic heart transplantation\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePHT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ePartial heart transplantation\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eVSD\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eVentricular septal defect\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eDisclosure\u0026nbsp;Statement:\u003c/strong\u003e The authors have nothing to disclose regarding commercial support or relationships to industry.\u003c/p\u003e\n\u003cp\u003eAuthor Contribution\u003c/p\u003e\n\u003cp\u003eSubstantial contributions to the work were made by the following individuals: Tim Nissen, MD and Amna Qasim, MD: conception and design of the work, interpretation of data, literature review, manuscript drafting, and revisions. Nirbhay Parashar, MD and Emily Sanders-Chen, MD: data acquisition. Simon Chung and Andrew Brown performed the statistical analysis and helped with preparation of the figures. Kenneth Knecht, MD and Taufiek Konrad Rajab: manuscript review and revisions.\u003c/p\u003e\n\u003ch2\u003eAcknowledgements:\u003c/h2\u003e\n\u003cp\u003eNone.\u003c/p\u003e\n\u003ch2\u003eData Availability\u003c/h2\u003e\n\u003cp\u003eData is provided within the manuscript or supplementary information files\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eCooper DK (1984) Orthotopic and heterotopic transplantation of the heart: the Cape Town experience. Ann R Coll Surg Engl 66(4):228\u0026ndash;234\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDipchand AI, Laks JA (2020) Pediatric heart transplantation: long-term outcomes. Indian J Thorac Cardiovasc Surg 36(Suppl 2):175\u0026ndash;189\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEveritt MD, Pahl E, Koehl DA, Cantor RS, Kirklin JK, Reed AC et al (2025) Clinical outcomes after a biopsy diagnosis of antibody-mediated rejection in pediatric heart transplant recipients. J Heart Lung Transpl 44(1):82\u0026ndash;91\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTurek JW, Kang L, Overbey DM, Carboni MP, Rajab TK (2024) Partial Heart Transplant in a Neonate With Irreparable Truncal Valve Dysfunction. JAMA 331(1):60\u0026ndash;64\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFadel BM, Manlhiot C, Al-Halees Z, Di Salvo G, Al-Ahmadi M, McCrindle B et al (2013) The fate of the neoaortic valve and root after the modified Ross-Konno procedure. \u003cem\u003eJ Thorac Cardiovasc Surg\u003c/em\u003e. ;145(2):430\u0026ndash;437.e1; discussion 436\u0026ndash;437\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNguyen SN, Bouhout I, Singh S, Vinogradsky AV, Chung MM, Sevensky R et al (2024) Long-term autograft dilation and durability after the Ross procedure are similar in infants, children, and adolescents with primary aortic stenosis. J Thorac Cardiovasc Surg 168(4):1182\u0026ndash;1191e3\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSimon P, Aschauer C, Moidl R, Marx M, Keznickl FP, Eigenbauer E et al (2001) Growth of the pulmonary autograft after the Ross operation in childhood. Eur J Cardiothorac Surg 19(2):118\u0026ndash;121\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWilliams IA, Quaegebeur JM, Hsu DT, Gersony WM, Bourlon F, Mosca RS et al (2005) Ross procedure in infants and toddlers followed into childhood. Circulation 112(9 Suppl):I390\u0026ndash;I395\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBernstein D, Kolla S, Miner M, Pitlick P, Griffin M, Starnes V et al (1992) Cardiac growth after pediatric heart transplantation. Circulation 85(4):1433\u0026ndash;1439\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRajab TK, Abdelrahman M, Schwartzenburg EJ, Aykut B, Turek JW, McVadon DH (2024) Semilunar valve growth and function 10 years after infant heart transplantation: Predicting long-term outcomes of partial heart transplants. Pediatr Transpl 28(3):e14746\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRajab TK, Nissen TE, Simionescu DT, Qasim A (2024) Leaflet Length as a Novel Echocardiography Parameter to Evaluate Partial Heart Transplant Growth. J Am Soc Echocardiogr 37(5):575\u0026ndash;576\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLang RM, Badano LP, Mor-Avi V, Afilalo J, Armstrong A, Ernande L et al (2015) Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr 28(1):1\u0026ndash;39e14\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDavid TE, Omran A, Ivanov J, Armstrong S, de Sa MP, Sonnenberg B et al (2000) Dilation of the pulmonary autograft after the Ross procedure. J Thorac Cardiovasc Surg 119(2):210\u0026ndash;220\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"pediatric-cardiology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"pedc","sideBox":"Learn more about [Pediatric Cardiology](http://link.springer.com/journal/246)","snPcode":"246","submissionUrl":"https://submission.nature.com/new-submission/246/3","title":"Pediatric Cardiology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-6305563/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6305563/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003ePartial heart transplantation is a novel approach to deliver a growing donor valve in pediatric recipients needing valve replacements. Objective data on the rate of growth of semilunar valves in patients following orthotopic heart transplantation (OHT) is necessary to set expectations for partial heart transplant semilunar valve growth.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003eA retrospective cohort study was performed, which included twelve infants who underwent OHT and twelve controls with ventricular septal defects (VSD). Semilunar valve annulus absolute dimension over serial echocardiograms was recorded, Z-scores were calculated, and mixed-effects models were applied to the absolute dimension (mm) and scaled dimension (Boston Z-score).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eAortic and pulmonary valve annuli in OHT patients grow. There is a downward trend in aortic valve annulus Z-score over time for OHT patients compared to population norms and controls with VSDs (difference in slopes: -0.119 Z-score/y, 95% CI: [-0.209, -0.029], p = 0.011); there is a non-significant difference for the pulmonary valve annulus (difference in slopes: -0.067 Z-score/y, 95% CI: [-0.155 0.022], p = 0.140).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions: \u003c/strong\u003eSemilunar valves in pediatric OHT patients grow at a slower rate than controls. There was no semilunar valve obstruction in our cohort. While the described difference in valve growth may not be clinically significant for pediatric OHT recipients, these growth rates inform the anticipated growth trajectory for the partial heart transplant graft.\u003c/p\u003e","manuscriptTitle":"Semilunar valves in pediatric orthotopic heart transplants grow at a slower rate than controls","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-05-05 11:16:08","doi":"10.21203/rs.3.rs-6305563/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-04-17T15:23:39+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-04-14T18:51:29+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"145183164225302204903224499303003867743","date":"2025-04-02T21:03:37+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-04-02T17:49:51+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-03-26T03:27:38+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-03-26T03:26:32+00:00","index":"","fulltext":""},{"type":"submitted","content":"Pediatric Cardiology","date":"2025-03-25T16:00:12+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"pediatric-cardiology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"pedc","sideBox":"Learn more about [Pediatric Cardiology](http://link.springer.com/journal/246)","snPcode":"246","submissionUrl":"https://submission.nature.com/new-submission/246/3","title":"Pediatric Cardiology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"c5763ecf-5796-47ed-ae3f-acf2339f1389","owner":[],"postedDate":"May 5th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-05-19T16:02:43+00:00","versionOfRecord":{"articleIdentity":"rs-6305563","link":"https://doi.org/10.1007/s00246-025-03884-8","journal":{"identity":"pediatric-cardiology","isVorOnly":false,"title":"Pediatric Cardiology"},"publishedOn":"2025-05-12 15:58:07","publishedOnDateReadable":"May 12th, 2025"},"versionCreatedAt":"2025-05-05 11:16:08","video":"","vorDoi":"10.1007/s00246-025-03884-8","vorDoiUrl":"https://doi.org/10.1007/s00246-025-03884-8","workflowStages":[]},"version":"v1","identity":"rs-6305563","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6305563","identity":"rs-6305563","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}