OBJECTIVES:Patients with pulmonary atresia/critical pulmonary stenosis with intact ventricular septum (PA/cPS-IVS) show fibrous subendocardial tissue of unclear origin accompanied by right ventricular (RV) hypoplasia. While in hypoplastic left heart syndrome, it is known that flow-induced endothelial-to-mesenchymal transition (EndMT) of endocardial endothelial cells (EECs) is the source of this fibrous tissue, it remains unclear whether similar mechanisms exist in PA/cPS-IVS. METHODS:We analysed 13 PA/cPS-IVS patients who underwent staged ventricular rehabilitation surgery aimed at preserving RV function between March 2021 and July 2025 at Boston Children's Hospital. Resected tissue was examined for the degree of fibrosis and elastin and the presence of active EndMT by histology, immunohistochemistry, and flow cytometry. To mimic human disease conditions, isolated EECs were exposed to pathological flow and compared with physiological flow conditions. RESULTS:Flow disturbances across the pulmonary and/or tricuspid valves were present in all patients. Resected RV tissue revealed an active subendocardial fibroelastic remodelling process, infiltrating into the underlying myocardium. Patients showed RV diastolic dysfunction, as evidenced by elevated filling pressures, suggesting a pathophysiological role of fibroelastic remodelling of the endocardium. Mimicking the human disease, exposure of isolated EECs to pathological flow conditions induced loss of endothelial characteristics and transition towards a mesenchymal phenotype through EndMT. CONCLUSIONS:In PA/cPS-IVS patients, restrictive RV physiology and diastolic dysfunction are likely driven by infiltrative fibroelastic remodelling caused by localized fibrogenic activation of EECs through EndMT in response to flow disturbances from valvular defects. Fibrogenic pathway activation may represent a promising therapeutic target in PA/cPS-IVS.

Standard assessments of decellularization protocols used to prepare leaflets for tissue-engineered heart valve (TEHV) applications have demonstrated variable histologic, biochemical, and biomechanical properties between protocols. However, the relationship of these differences to in situ recellularization and in vivo leaflet performance remains unclear. We hypothesized that ultrastructural and proteomic analysis would identify differences between chemical decellularization protocols to guide TEHV applications. Porcine semilunar valves were decellularized using seven protocols compared to native controls. To establish suitability for recellularization, SDS/SDC decellularized leaflets were recellularized in vitro with ovine endothelial colony forming cells (ECFCs), bone marrow mesenchymal stem cells (BM-MSCs), or both cell types under either static or dynamic flow. Proteomics revealed that native and decellularized samples cluster separately, with different decellularization protocols forming distinct clusters. Relative abundances of extracellular matrix (ECM) proteins and damage-associated molecular patterns (DAMPs) differed by decellularization protocol. Scanning electron micrographs detected residual cellularization more accurately than standard histology, revealed that ECM structure varies by decellularization agent, and demonstrated optimal preservation of basement membrane structures using SDS/SDC decellularization. We concluded that proteomic analysis and scanning electron microscopy augmented traditional evaluations of TEHVs. In addition, we established an SDS/SDC decellularization protocol to prepare leaflets for in vitro recellularization and determined that in vitro recellularization is most effective under flow conditions with both ECFCs and BM-MSCs as seeding cells. This work demonstrates the utility of proteomic analysis and scanning electron microscopy for studying TEHVs and serves as a foundation for future studies to determine how recellularization may alter the TEHV proteome.

This chapter contains sections titled: Definition Historical background Incidence Etiology Morphology Pathophysiology Treatment Imaging References

Background:Growth is the Holy Grail of tissue implants in pediatrics, yet the outcomes from a small but increasing number of studies have not been assessed using metrics of growth. Methods:A systematic review was conducted to identify preclinical and pediatric clinical trials of implanted vascular grafts and heart valves, indicating growth of the implant based on a proposed definition of functional regenerative growth: increases in critical physical dimension(s) by increases in tissue mass with maintenance of required function. Results:Five distinct approaches, distinguished by scaffold type and use of preseeded cells, were identified among studies reported for tissue-engineered vascular grafts (TEVGs) and heart valves (TEHVs), with 2 of these approaches being used for both indications. A total of 11 publications were selected for data tabulation. For TEVGs, increases in length are reported across all studies (14%-130%), whereas diameter change (-38% to +89%) varied with anatomical location. For TEHVs, increases of diameter consistent with somatic growth have been reported for 4 different biologic valves (12%-78%) across preclinical studies. Commensurate leaflet growth has not been clearly established. Conclusions:Growth capacity of TEVGs has been established in preclinical studies for multiple approaches, including some proceeding to clinical trials. For TEHVs, increases in the diameter are reported for several approaches in preclinical studies, but limited evidence exists to date for leaflet growth. TEVGs and TEHVs have both demonstrated potential for growth and, thus, improved clinical outcomes compared with current implants that have no growth capacity.

While exome and whole genome sequencing have transformed medicine by elucidating the genetic underpinnings of both rare and common complex disorders, its utility to predict clinical outcomes remains understudied. Here, we use artificial intelligence (AI) technologies to explore the predictive value of whole exome sequencing in forecasting clinical outcomes following surgery for congenital heart defects (CHD). We report results for a prospective observational cohort study of 2,253 CHD patients from the Pediatric Cardiac Genomics Consortium with a broad range of complex heart defects, pre- and post-operative clinical variables and exome sequencing. Damaging genotypes in chromatin-modifying and cilia-related genes are associated with an elevated risk of adverse post-operative outcomes, including mortality, cardiac arrest and prolonged mechanical ventilation. The impact of damaging genotypes is further amplified in the context of specific CHD phenotypes, surgical complexity and extra-cardiac anomalies. The absence of a damaging genotype in chromatin-modifying and cilia-related genes is also informative, reducing the risk for some adverse postoperative outcomes. Thus, genome sequencing enriches the ability to forecast outcomes following congenital cardiac surgery.

Individuals with lower extremity amputation (LLA) have high rates of low back pain (LBP) and related disability. The purpose of this technical note is to discuss considerations and provide initial recommendations about what exercises may be appropriate for management of LBP in persons with LLA. Five commonly prescribed motor control and strengthening exercises (cat-camel, curl-up, bird dog, side bridge, and Roman chair extensor exercise) were examined for use in the LLA population. Each exercise seemed to be safe and appropriate for use in persons with LLA yet required additional considerations for use in this population. For example, some of the exercises, such as the bird dog, pose challenges to balance. Thus, more detailed up-front instruction, closer monitoring, and adequate support are recommended to facilitate usefulness and success. This technical note provides initial guidance for clinical decision-making about implementation of commonly prescribed exercises in the general non-amputee patient population with the LLA population. While future research is needed, implementation of appropriate exercise interventions has the potential to decrease disability, hasten recovery, and improve resiliency in persons with LLA suffering from LBP.

Objectives:Accurate characterization of patients with congenital heart disease is fundamental to research, outcomes reporting, quality improvement, and clinical decision-making. Here we present an approach to computing the anatomy of patients with congenital heart disease based on the whole of their diagnostic and surgical codes. Materials and Methods:All diagnostic and procedure codes for patients cared for between 1981 and 2020 at Boston Children's Hospital were extracted from a database containing diagnostic codes from echocardiograms, and procedural codes from surgical and catheterization procedures. The pipeline sequentially (1) mapped each of the 7500 native codes to algorithm codes; (2) computed the parent anatomy for each study using a pre-defined hierarchy; (3) computed the parent anatomy for the patient, based on highest ranking parent anatomy; and (4) computed the subcategories and mandatory co-variate findings for each patient. Thereafter, diagnostic accuracy of 500 unseen patients was adjudicated against clinical documentation by clinical experts. Results:A total of 514 541 echocardiograms on 161 735 patients were available for this study. Phenotypes of congenital cardiac diseases were assigned in 84 285 patients (52%), and the remainder were computed to have normal anatomy. Clinicians agreed with algorithm assignments in 96.4% (482 of 500 patients), with disagreements most often representing definitional differences. An interactive dashboard enabled by the output of this algorithm is presented. Conclusions:The computation of detailed congenital heart defect phenotypes from raw diagnostic and procedure codes is possible with a high degree of accuracy and efficiency. This framework may enable tools to support interactive outcomes reporting and clinical decision support.

OBJECTIVE:To systematically analyze the macroscopic and microscopic anatomic characteristics of the common atrioventricular valve in patients with Down syndrome (DS) and those without DS. Such findings could explain the difference in outcomes between these 2 groups. METHODS:We reviewed the clinical records and examined archived heart specimens with unrepaired common atrioventricular canal (AVC) defect. The common atrioventricular valve (CAVV) annulus and leaflets were measured for dimensions and area. The histology of leaflets at age <1 month, 3 months, and 6 months were reviewed. Leaflet nuclear density was calculated and used as an objective marker of maturation. Histologic findings were compared with normal controls. RESULTS:A total of 129 hearts with an AVC defect, including 47 DS hearts and 82 non-DS hearts, were studied. The DS hearts had a greater proportion of complete AVC (CAVC), particularly Rastelli type C, and fewer unbalanced AVC. The CAVV leaflet area-to-annulus area ratio (LA/AA) was significantly larger in the DS group than in the non-DS group overall and in patients age <12 months with CAVC. Leaflets in DS hearts showed a near-normal stratification by age 6 to 7 months; however, leaflets in the non-DS hearts remained quite amorphous at the same age. Leaflet interstitial nuclear density decreased more rapidly in the DS hearts, such that the nuclear density was similar to normal by 6 to 7 months; however, it remained significantly higher in non-DS hearts. CONCLUSIONS:The AVC defect in DS hearts compared with non-DS hearts was characterized by more CAVCs, fewer unbalanced defects, more Rastelli type C defects, larger LA/AA ratio, and histologically more organized and mature leaflets by 6 months. These characteristics might explain the better outcomes in DS patients. Our findings offer potential opportunities for optimizing surgical management.

Aims Replacement heart valves that grow with children remain an unmet need. We previously reported valves fabricated from tubes of fibroblast-derived collagenous matrix increased in size while functioning with low systolic gradients and less than moderate regurgitation over 52 weeks in most cases, when implanted as interpositional grafts in the pulmonary artery of lambs. Here, we evaluated valved conduits fabricated by including an inflow segment to the tri-tube valve allowing for myocardial anastomosis as done in a typical right ventricular outflow tract (RVOT) surgical repair, in the same growing lamb model.Methods and results In this pilot study, 19 mm valved conduits fabricated from resorbable suture were implanted into Dorset lambs (n = 3), sutured to the pulmonary annulus and distal pulmonary artery with resorbable suture after dissection of the pulmonary valve leaflets and resection of an arterial segment. Valve function and dimensions were measured with longitudinal transthoracic echocardiography. All animals exhibited an increase in valve diameter (18.2 +/- 1.8 mm at 1 week to 25.1 +/- 2.4 mm at 52 weeks) and leaflet free-edge length (21.1 +/- 2.4 mm at 1 week to 26.2 +/- 3.9 mm at 52 weeks) while functioning with at most mild regurgitation over 52 weeks. The inflow segment of the conduit grew somatically based on its unchanged thickness and increased diameter (38%) and collagen content (128%). In all three explanted conduits, the leaflets contained interstitial cells, new collagen and elastin primarily around the base, a developing endothelium on the surfaces, and they remained thin and pliable without macroscopic calcification. There was interdigitating integration of the conduit with the myocardium at the pulmonary annulus. Further, a stent was successfully placed in a valved conduit at term to evaluate feasibility of a prospective clinical intervention.Conclusion This valved conduit grows in lambs based on this pilot study and thus has clinical potential for RVOT reconstruction and long-term valve growth in children.

Congenital heart defects (CHD) are the most prevalent birth defects in the United States and surgical outcomes vary considerably across the country. The outcomes of treatment for CHD differ for specific patient subgroups, with non-Hispanic Black and Hispanic populations experiencing higher rates of mortality and morbidity. A valid comparison of outcomes within racial/ethnic subgroups is difficult given large differences in case-mix and small subgroup sizes. We propose a causal inference framework for outcome assessment and leverage advances in transfer learning to incorporate data from both target and source populations to help estimate causal effects while accounting for different sources of risk factor and outcome differences across populations. Using the Society of Thoracic Surgeons' Congenital Heart Surgery Database (STS-CHSD), we focus on a national cohort of patients undergoing the Norwood operation from 2016-2022 to assess operative mortality and morbidity outcomes across U.S. geographic regions by race/ethnicity. We find racial and ethnic outcome differences after controlling for potential confounding factors. While geography does not have a causal effect on outcomes for non-Hispanic Caucasian patients, non-Hispanic Black patients experience wide variability in outcomes with estimated 30-day mortality ranging from 5.9 21.6

BACKGROUND:Mortality after congenital heart surgery is an important metric across benchmarking, quality, and reporting initiatives. All rely on estimates from prior years, and how well these reflect current outcomes is unclear. METHODS:Index operations from The Society of Thoracic Surgeons Congenital Database (2014-2019) were included. Adjusted operative mortality in "past" 4-year and 1-year intervals vs the most recent year ("present") was evaluated using Bayesian hierarchical logistic regression with results presented as odds ratios and 95% credible intervals (CrI). RESULTS:Among 115,699 operations (106 hospitals), overall present observed mortality was 2.5%. Regression to the mean was evident, and individual hospital's present vs past adjusted mortality were only weakly correlated (-0.11 vs past 1-year data, 0.22 vs past 4-year data). A significant relationship was found between past and present mortality only for the group of hospitals in the highest mortality quartile, most prominent for past 4-year data (adjusted odds ratio vs lowest mortality quartile, 2.04; 95% CrI, 1.44-2.80). The proportion of present hospital mortality variation explained by past mortality quartile was 52% (95% CrI, 20%-90%) using past 4-year data and only 27% (95% CrI, 92%-83%) using past 1-year data. Overall 66% of hospitals changed mortality quartiles from past to present (30% by ≥2 quartiles). CONCLUSIONS:Past mortality relates to present primarily for groups of hospitals at the extremes, with past 4-year data more informative than past 1-year data. For individual hospitals, past may differ from present, regression to the mean is common, and many change quartiles. Past mortality should be used thoughtfully and not as the sole factor informing present decision making.

BACKGROUND Neo-aortic root dilatation can lead to significant late morbidity after the arterial switch operation (ASO) for dextro-transposition of the great arteries (d-TGA). OBJECTIVES We sought to examine the growth of the neo-aortic root in d-TGA. METHODS A single -center, retrospective cohort study of patients who underwent the ASO between July 1, 1981 and September 30, 2022 was performed. Morphology was categorized as dextro-transposition of the great arteries with intact ventricular septum (d-TGA-IVS), dextro-transposition of the great arteries with ventricular septal defect (d-TGAVSD), and double-outlet right ventricle-transposition of the great arteries type (DORV-TGA). Echocardiographically determined diameters and derived z scores were measured at the annulus, sinus of Valsalva, and sinotubular junction immediately before the ASO and throughout follow-up. Trends in root dimensions over time were assessed using linear mixed-effects models. The association between intrinsic morphology and the composite of moderate-severe aortic regurgitation (AR) and neo-aortic valve or root intervention was evaluated with univariable and multivariable Cox proportional hazards models. RESULTS Of 1,359 patients who underwent the ASO, 593 (44%), 666 (49%), and 100 (7%) patients had d-TGA-IVS, d-TGA-VSD, and DORV-TGA, respectively. Each patient underwent a median of 5 echocardiograms (Q1 -Q3: 3-10 echocardiograms) over a median follow-up of 8.6 years (range: 0.1-39.3 years). At 30 years, patients with DORV-TGA demonstrated greater annular (P < 0.001), sinus of Valsalva (P = 0.039), and sinotubular junction (P = 0.041) dilatation relative to patients with d-TGA-IVS. On multivariable analysis, intrinsic anatomy, older age at ASO, at least mild AR at baseline, and high -risk root dilatation were associated with moderate-severe AR and neo-aortic valve or root intervention at late follow-up (all P < 0.05). CONCLUSIONS Longitudinal surveillance of the neo-aortic root is warranted long after the ASO. (J Am Coll Cardiol 2024;83:516-527) (c) 2024 by the American College of Cardiology Foundation.

BACKGROUND:As more pediatric patients become candidates for heart transplantation (HT), understanding pathological predictors of outcome and the accuracy of the pretransplantation evaluation are important to optimize utilization of scarce donor organs and improve outcomes. The authors aimed to investigate explanted heart specimens to identify pathologic predictors that may affect cardiac allograft survival after HT. METHODS:Explanted pediatric hearts obtained over an 11-year period were analyzed to understand the patient demographics, indications for transplant, and the clinical-pathological factors. RESULTS:In this study, 149 explanted hearts, 46% congenital heart defects (CHD), were studied. CHD patients were younger and mean pulmonary artery pressure and resistance were significantly lower than in cardiomyopathy patients. Twenty-one died or underwent retransplantation (14.1%). Survival was significantly higher in the cardiomyopathy group at all follow-up intervals. There were more deaths and the 1-, 5- and 7-year survival was lower in patients ≤10 years of age at HT. Early rejection was significantly higher in CHD patients exposed to homograft tissue, but not late rejection. Mortality/retransplantation rate was significantly higher and allograft survival lower in CHD hearts with excessive fibrosis of one or both ventricles. Anatomic diagnosis at pathologic examination differed from the clinical diagnosis in eight cases. CONCLUSIONS:Survival was better for the cardiomyopathy group and patients >10 years at HT. Prior homograft use was associated with a higher prevalence of early rejection. Ventricular fibrosis (of explant) was a strong predictor of outcome in the CHD group. We presented several pathologic findings in explanted pediatric hearts.

Prior authorization is a process that health insurance companies use to determine if a patient's health insurance will cover certain medical treatments, procedures, or medications. Prior authorization requests are common in adult congenital and pediatric cardiology (ACPC) due to need for advanced diagnostics, complex procedures, disease-specific medications, and the heterogeneity of the ACPC population. Prior authorizations in ACPC are rarely denied, but nonetheless, they are often accompanied by significant administrative burden on clinical care teams and delays in patient care. Prior authorizations have been implicated in worsening care inequities. The prior authorization process is insurer specific with differences between commercial and public insurers. Prior authorization rejections were previously found to be more common for women, racial minorities, those with low education, and in low-income groups. Prior authorization unduly burdens routine diagnostics, routine interventional and surgical procedures, and routine cardiac specific medication use in the ACPC population. This manuscript highlights the burdens of prior authorization and advocates for the elimination of prior authorization for ACPC patients.