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Assessment of the right ventricular outflow tract and pulmonary arteries (RVOT) for percutaneous pulmonary valve implantation (PPVI) uses discrete measurements (diameters and lengths) from medical images. This multi-centre study identified the 3D RVOT shape features prevalent in patients late after surgical repair of congenital heart disease (CHD). A 3D RVOT statistical shape model (SSM) was computed from 81 retrospectively selected CHD patients (14.7 ± 6.8 years) who required pulmonary valve replacement late after surgical repair. A principal component analysis identified prevalent shape features (modes) within the population which were compared with standard geometric measurements (diameter, length and surface area) and between sub-groups of diagnosis, RVOT type and dysfunction. Shape mode 1 and 2 represented RVOT size and curvature and tapering and length, respectively. Shape modes 3-5 related to branch pulmonary artery calibre, conical vs. bulbous RVOTs and RVOT curvature, respectively. Tetralogy of Fallot, transannular patch type and regurgitant RVOTs were larger and straighter while conduit and stenotic types were longer and more cylindrical than other subgroups. This SSM analysed the main 3D shape features present in a population of RVOTs, exploiting the wide 3D anatomical information provided by routine imaging. This morphological information may have implications for PPVI patient selection and device design.

Background: The Melody valve (Medtronic, Minneapolis, MN) for mitral valve replacement (MVR) (MelodyMVR) has been an effective strategy to treat unrepairable mitral valve disease in small children. This study analyzed survival, durability, and complications of the MelodyMVR strategy., Methods: Patients who underwent MelodyMVR between 2014 and 2023 were included. Transplant-free survival was analyzed with Kaplan-Meier analysis. The Fine and Gray subdistribution method was applied to quantify the cumulative incidence., Results: Twenty-five patients underwent MelodyMVR. Median age and weight were 6.3 months (interquartile range, 4.4-15.2 months) and 6.36 kg (interquartile range, 4.41-7.57 kg). Fifteen patients (60%) had congenital mitral valve disease and 13 (52%) had dominant mitral regurgitation. The median diameter of the implanted Melody was 16 mm (interquartile range, 14-18 mm). Mortality at 6 months, 1 year, and 5 years was 8.3% (95% CI, 2.2%-29.4%), 12.5% (95% CI, 4.2%-33.9%), and 17.6% (95% CI, 7.0%-40.7%), respectively. Two hospital survivors (8%) required early Melody replacement. Competing risk analysis showed that ∼50% of patients underwent mechanical MVR by 3.5 years after MelodyMVR. Freedom from bleeding and thrombosis at 4 years was 87.5% (95% CI, 74.2%-100%). Eleven patients underwent subsequent mechanical MVR with no deaths. One (9%) required pacemaker implantation after mechanical MVR., Conclusions: MelodyMVR provides reasonable early and medium-term survival in small children and a high rate of successful bridge to mechanical MVR. MelodyMVR is associated with minimal pacemaker requirement, bleeding, and thrombosis. Early Melody functional deterioration necessitates early repeat MVR, which can be achieved with minimal morbidity and mortality., Competing Interests: Disclosures Lee Benson reports a relationship with Medtronic that includes: consulting. All other authors declare that they have no conflicts of interest., (Copyright © 2024 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Pathogenic variants in NOTCH1 are associated with non-syndromic congenital heart disease (CHD) and Adams-Oliver syndrome (AOS). The clinical presentation of individuals with damaging NOTCH1 variants is characterized by variable expressivity and incomplete penetrance; however, data on systematic phenotypic characterization are limited. We report the genotype and phenotype of a cohort of 33 individuals (20 females, 13 males; median age 23.4 years, range 2.5-68.3 years) from 11 families with causative NOTCH1 variants (9 inherited, 2 de novo; 9 novel), ascertained from a proband with CHD. We describe the cardiac and extracardiac anomalies identified in these 33 individuals, only four of whom met criteria for AOS. The most common CHD identified was tetralogy of Fallot, though various left- and right-sided lesions and septal defects were also present. Extracardiac anomalies identified include cutis aplasia (5/33), cutaneous vascular anomalies (7/33), vascular anomalies of the central nervous system (2/10), Poland anomaly (1/33), pulmonary hypertension (2/33), and structural brain anomalies (3/14). Identification of these findings in a cardiac proband cohort supports NOTCH1-associated CHD and NOTCH1-associated AOS lying on a phenotypic continuum. Our findings also support (1) Broad indications for NOTCH1 molecular testing (any familial CHD, simplex tetralogy of Fallot or hypoplastic left heart); (2) Cascade testing in all at-risk relatives; and (3) A thorough physical exam, in addition to cardiac, brain (structural and vascular), abdominal, and ophthalmologic imaging, in all gene-positive individuals. This information is important for guiding the medical management of these individuals, particularly given the high prevalence of NOTCH1 variants in the CHD population., (© 2024. The Author(s).)

Low blood flow through the fetal left heart is often conjectured as an etiology for hypoplastic left heart syndrome (HLHS). To investigate if a decrease in left heart flow results in growth failure, we generate left ventricular inflow obstruction (LVIO) in mid-gestation fetal lambs by implanting coils in their left atrium using an ultrasound-guided percutaneous technique. Significant LVIO recapitulates important clinical features of HLHS: decreased antegrade aortic valve flow, compensatory retrograde perfusion of the brain and ascending aorta (AAo) from the arterial duct, severe left heart hypoplasia, a non-apex forming LV, and a thickened endocardial layer. The hypoplastic AAo have miRNA-gene pairs annotating to cell proliferation that are inversely differentially expressed by bulk RNA-seq. Single-nucleus RNA-seq of the hypoplastic LV myocardium shows an increase in fibroblasts with a reciprocal decrease in cardiomyocyte nuclei proportions. Fibroblasts, cardiomyocytes and endothelial cells from hypoplastic myocardium have increased expression of extracellular matrix component or fibrosis genes with dysregulated fibroblast growth factor signaling. Hence, a severe sustained ( ~ 1/3 gestation) reduction in fetal left heart flow is sufficient to cause left heart hypoplasia. This is accompanied by changes in cellular composition and gene expression consistent with a pro-fibrotic environment and aberrant induction of mesenchymal programs., (© 2023. The Author(s).)

Purpose: The purpose of this study was to compare outcomes of Melody mitral valve to mechanical mitral valve replacement (MVR) for young children., Description: Children who underwent Melody MVR from 2014 to 2020 were case-matched to mechanical MVR patients. Transplant-free survival and cumulative incidence of reintervention were compared. A subanalysis was performed for infants aged < 1 year (9 Melody MVRs and their matches)., Evaluation: Twelve children underwent Melody MVR. Two children (17%) salvaged from mechanical support died. Five of 10 survivors (50%) had subsequent MVR. At 1 and 3 years, transplant-free survival (Melody: 83%, 83%; mechanical: 83%, 67%; P = .180) and reintervention (Melody: 9%, 39%; mechanical: 0%, 18%; P = .18) were equivalent between groups. For children < 1 year of age, Melody MVR had a modest survival benefit (Melody: 89%, 89%; mechanical: 80%, 60%; P = .046), while rate of reintervention remained equivalent (Melody: 13%, 32%; mechanical: 0%, 22%; P = .32)., Conclusions: For patients < 1 year old, Melody MVR offers a promising alternative and is a reasonable bridge to mechanical MVR, which can be performed safely at an older age. Further studies are necessary to corroborate these findings., (Copyright © 2023 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Cardiac magnetic resonance imaging (CMR) may augment 2-dimensional (2D) echocardiography in decision-making for biventricular repair in borderline hypoplastic left hearts., Objectives: This study evaluates: 1) the relationship between 2D echocardiography and CMR; 2) imaging variables affecting assignment to biventricular vs non-biventricular management; and 3) variables affecting transplant-free biventricular survival., Methods: We reviewed clinical, echocardiographic, and CMR data in 67 infants, including CMR-determined ascending aortic (AAo) flow and comparable left ventricular end-diastolic volume indexed (LVEDVi) by 2D-echocardiography and CMR., Results: Treatment assignment to biventricular repair was either direct (BV, n = 45) or with a bridging hybrid procedure (H1-BV, n = 12). Echocardiographic LVEDVi was <20 mL/m 2 in 83% of biventricular repair infants and underestimated CMR-LVEDVi by 16.8 mL/m 2 . AAo flows had no/weak correlation with aortic and mitral valve z -scores or LVEDVi. AAo flows differed between BV, H1-BV, and single-ventricle groups (median): 2.1, 1.7, and 0.7 L/min/m 2 , respectively. Important variables for treatment assignment were presence of endocardial fibroelastosis, AAo flow, and mitral valve z -score. Biventricular repair was achieved in 54. The median follow-up was 8.0 (0.1-16.4) years. Transplant-free biventricular survival was 96%, 82%, and 77% at 1, 5, and 10 years, respectively. Patients without aortic coarctation repair were at higher risk of death, transplantation, or single-ventricle conversion (HR: 54.3; 95% CI: 6.3-47.1; P  < 0.001) during follow-up. AAo flow had a smaller nonlinear effect with hazard ratio increasing at lower flows., Conclusions: Historical 2D echocardiographic criteria would have precluded many patients from successful biventricular repair. AAo flow, an integrative index of left heart performance, was important in assigning patients to a biventricular circulation and affected survival. Biventricular survival was strongly associated with the need for aortic coarctation repair., Competing Interests: Dr Chaturvedi is supported by the Ted Rogers Centre for Heart Research, Toronto. The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2022 The Authors.)

Hypoplastic left heart syndrome (HLHS) is a life-threatening congenital heart disease that is characterized by severe underdevelopment of left heart structures. Currently, there is no cure, and affected individuals require surgical palliation or cardiac transplantation to survive. Despite these resource-intensive measures, only about half of individuals reach adulthood, often with significant comorbidities such as liver disease and neurodevelopmental disorders. A major barrier in developing effective treatments is that the etiology of HLHS is largely unknown. Here, we discuss how intracardiac blood flow disturbances are an important causal factor in the pathogenesis of impaired left heart growth. Specifically, we highlight results from a recently developed mouse model in which surgically reducing blood flow through the mitral valve after cardiogenesis led to the development of HLHS. In addition, we discuss the role of interventional procedures that are based on improving blood flow through the left heart, such as fetal aortic valvuloplasty. Lastly, using the surgically-induced mouse model, we suggest investigations that can be undertaken to identify the currently unknown biological pathways in left heart growth failure and their associated therapeutic targets.

Purpose: To assess regional blood flow in fasting pediatric patients with Fontan circulation by using MRI and to explore associations with clinical parameters., Materials and Methods: In this retrospective study, pediatric patients who had undergone the Fontan procedure (<18 years of age) and had undergone clinical cardiac MRI, performed after at least 4 hours of fasting, between 2018 and 2021 were included. Regional blood flow was compared with published healthy volunteer data ( n = 19) and assessed in relation to hemodynamic parameters and clinical status. Data are presented as medians, with first to third quartiles in parentheses. Mann-Whitney U , Kruskal-Wallis, χ 2 , and Spearman rank correlation tests were used., Results: Fifty-five patients (38 boys) with median age at MRI of 14 years (IQR, 11-16 years) and median time from Fontan procedure to MRI of 10 years (IQR, 8-12 years) were included. Patients after Fontan procedure had lower ascending aortic, inferior vena cava, and total systemic blood flow compared with healthy volunteers (3.00 L/min/m 2 [IQR, 2.75-3.30 L/min/m 2 ] vs 3.61 L/min/m 2 [IQR, 3.29-4.07 L/min/m 2 ]; 1.73 L/min/m 2 [IQR, 1.40-1.94 L/min/m 2 ] vs 2.24 L/min/m 2 [IQR, 2.06-2.75 L/min/m 2 ]; 2.78 L/min/m 2 [IQR, 2.45-3.10 L/min/m 2 ] vs 3.95 L/min/m 2 [IQR, 3.20-4.30 L/min/m 2 ], respectively; P < .001). Portal vein flow was greater than hepatic vein flow in 25% of patients. Fontan blood flow was inversely correlated with pre-Fontan mean pulmonary artery pressure (Spearman rank correlation coefficient [ r s ]= -0.42, P = .005) and ventricular end diastolic pressure ( r s = -0.33, P = .04) and positively correlated with post-Fontan percent predicted oxygen consumption at peak workload ( r s = 0.34, P = .02)., Conclusion: Reference ranges are provided for regional systemic blood flow derived by using MRI in fasting pediatric patients with Fontan circulation, who had lower systemic blood flow compared with healthy volunteers. Lower fasting Fontan blood flow correlated with lower exercise capacity. Keywords : Pediatrics, Heart, Congenital, MR Imaging, Hemodynamics/Flow Dynamics, Cardiac Supplemental material is available for this article. © RSNA, 2022., Competing Interests: Disclosures of conflicts of interest: C.Z.L. Grant-funded reimbursement from Additional Ventures as the site primary investigator at the Hospital for Sick Children for participation in the Fontan Outcomes Registry using CMR Extractions (FORCE); member of the executive leadership team for FORCE. D.D. No relevant relationships. L.A.I. No relevant relationships. P.P. No relevant relationships. A.I.D. No relevant relationships. E.J.S.M. No relevant relationships. R.R.C. No relevant relationships. S.C.L. No relevant relationships. R.M.W. No relevant relationships. G.B.C. Service on the Society for Pediatric Radiology Board. M.S. No relevant relationships. S.J.Y. No relevant relationships., (© 2022 by the Radiological Society of North America, Inc.)

Background: The optimal initial treatment pathway for aortic valve stenosis remains debated., Objectives: The objective of this study was to review current outcomes of balloon aortic valvotomy (BAV) in neonates and infants., Methods: Neonates and infants with a biventricular circulation treated with BAV between 2004 and 2019 were reviewed., Results: One hundred thirty-nine infants (48% neonates) with median (Q1, Q3) age of 33(7, 84) days and weight 4.0 (3.4, 5.1) kg were followed up for 7.1 (3.3, 11.0) years. BAV reduced peak-to-peak gradient from mean (SD) 52 (16) mmHg to 18 (12) mmHg; P  < 0.001. Aortic regurgitation (AI) increased with time after BAV. Three children died during follow-up. Fifty-one reinterventions (26 BAV, 19 aortic valve replacements [AVRs], and 6 surgical valvotomies) were performed on 40 children. Freedom from AVR (95% CI) was 96% (93%-99%) at 1, 91% (86%-96%) at 5, and 86% (79%-93%) at 10 years. The predictors of AVR were a unicommissural valve (hazard ratio [HR] [95% CI]: 3.7 [1.4-9.6]; P  = 0.007) and moderate to severe AI after index BAV (HR [95% CI]: 3.3 [1.1-9.7]; P  = 0.029). Freedom from reintervention was 84% (78%-90%) at 1, 76% (69%-83%) at 5, and 69% (60-78%) at 10 years. Main predictors of reintervention were age below 1 month (HR [95% CI]: 2.1 [1.1-4.1]; P  = 0.032) and postdilation peak-to-peak gradient (per 10-mmHg increase; HR [95% CI]: 1.36 [1.02-1.79]; P  = 0.032)., Conclusions: BAV is a safe and effective treatment for aortic valve stenosis in neonates and infants. Outcomes are competitive with contemporary published data on aortic valve repair in relation to mortality, gradient relief, long-term AVR, and reintervention rates. In the absence of significant AI, surgery can be reserved for those with gradients resistant to valve dilation., Competing Interests: The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2022 The Authors.)

Background: The optimal management pathway for the dysfunctional right ventricular outflow tract (RVOT) is uncertain. We evaluated the long-term outcomes and clinical impact of stent implantation for obstructed RVOTs in an era of rapidly progressing transcatheter pulmonary valve technology., Methods: Retrospective review of 151 children with a biventricular repair who underwent stenting of obstructed RVOT between 1991 and 2017., Results: RVOT stenting resulted in significant changes in peak right ventricle (RV)-to-pulmonary artery (PA) gradient (39.4 ± 17.1-14.9 ± 8.3; p < 0.001) and RV-to-aortic pressure ratio (0.78 ± 0.22-0.49 ± 0.13; p < 0.001). Subsequent percutaneous reinterventions in 51 children to palliate recurrent stenosis were similarly effective. Ninety-nine (66%) children reached the primary outcome of subsequent pulmonary valve replacement (PVR). Freedom from PVR from the time of stent implantation was 91%, 51%, and 23% at 1, 5, and 10 years, respectively. Small balloon diameters for stent deployment were associated with shorter freedom from PVR. When additional children without stent palliation (with RV-to-PA conduits) were added to the stent cohort (total 506 children), the multistate analysis showed the longest freedom from PVR in those with stent palliation and subsequent catheter reintervention. Pulmonary regurgitation was well-tolerated clinically. Indexed RV dimensions and function estimated by echocardiography remained stable at last follow up or before primary outcome., Conclusion: Prolongation of conduit longevity with stent implant remains an important strategy to allow for somatic growth to optimize the risk-benefit profile for subsequent surgical or transcatheter pulmonary valve replacement performed at an older age., (© 2021 Wiley Periodicals LLC.)

In hypoplastic left heart syndrome (HLHS), the mechanisms leading to left heart hypoplasia and their associated fetal abnormalities are largely unknown. Current animal models have limited utility in resolving these questions as they either do not fully reproduce the cardiac phenotype, do not survive to term and/or have very low disease penetrance. Here, we report the development of a surgically induced mouse model of HLHS that overcomes these limitations. Briefly, we microinjected the fetal left atrium of embryonic day (E)14.5 mice with an embolizing agent under high-frequency ultrasound guidance, which partially blocks blood flow into the left heart and induces hypoplasia. At term (E18.5), all positively embolized mice exhibit retrograde aortic arch flow, non-apex-forming left ventricles and hypoplastic ascending aortas. We thus report the development of the first mouse model of isolated HLHS with a fully penetrant cardiac phenotype and survival to term. Our method allows for the interrogation of previously intractable questions, such as determining the mechanisms of cardiac hypoplasia and fetal abnormalities observed in HLHS, as well as testing of mechanism-based therapies, which are urgently lacking., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2021. Published by The Company of Biologists Ltd.)

Background: Tetralogy of Fallot (TOF)-the most common cyanotic heart defect in newborns-has evidence of multiple genetic contributing factors. Identifying variants that are clinically relevant is essential to understand patient-specific disease susceptibility and outcomes and could contribute to delineating pathomechanisms., Methods: Using a clinically driven strategy, we reanalyzed exome sequencing data from 811 probands with TOF, to identify rare loss-of-function and other likely pathogenic variants in genes associated with congenital heart disease., Results: We confirmed a major contribution of likely pathogenic variants in FLT4 (VEGFR3 [vascular endothelial growth factor receptor 3]; n=14) and NOTCH1 (n=10) and identified 1 to 3 variants in each of 21 other genes, including ATRX , DLL4 , EP300 , GATA6 , JAG1 , NF1 , PIK3CA , RAF1 , RASA1 , SMAD2 , and TBX1 . In addition, multiple loss-of-function variants provided support for 3 emerging congenital heart disease/TOF candidate genes: KDR (n=4), IQGAP1 (n=3), and GDF1 (n=8). In total, these variants were identified in 63 probands (7.8%). Using the 26 composite genes in a STRING protein interaction enrichment analysis revealed a biologically relevant network ( P =3.3×10 -16 ), with VEGFR2 (vascular endothelial growth factor receptor 2; KDR ) and NOTCH1 (neurogenic locus notch homolog protein 1) representing central nodes. Variants associated with arrhythmias/sudden death and heart failure indicated factors that could influence long-term outcomes., Conclusions: The results are relevant to precision medicine for TOF. They suggest considerable clinical yield from genome-wide sequencing, with further evidence for KDR (VEGFR2) as a congenital heart disease/TOF gene and for VEGF (vascular endothelial growth factor) and Notch signaling as mechanisms in human disease. Harnessing the genetic heterogeneity of single gene defects could inform etiopathogenesis and help prioritize novel candidate genes for TOF.

Background: Creation of a Potts shunt, a connection between the left pulmonary artery (LPA) and descending aorta (DAo), improves functional status and survival in drug-refractory suprasystemic pulmonary arterial hypertension. We investigated a new approach to transcatheter Potts shunt creation in pigs., Methods and Results: In six pigs, a steerable SureFlex sheath was used to optimize the trajectory of perforation from the DAo into LPA using a 0.035″ radiofrequency wire. The combination of a larger perforation, stiffer radiofrequency wire and smooth dilator-to-sheath transition allowed sheath entry into the LPA without requiring an arterio-venous wire circuit. The Occlutech Atrial Flow Regulator (AFR), a double-disc device with a central fenestration, was deployed through this sheath with apposition of the distal disc to the posterior LPA wall and the proximal disc to the anterior DAo wall. The AFR is compliant and crumpling of the central fenestration was resolved by balloon dilation. It was feasible to implant a stent within the fenestration (n = 3). Aortography confirmed a left-to-right shunt through the AFR without contrast extravasation. Autopsy demonstrated anchoring of both discs against the vessel walls, patency of the fenestration and secure placement of the stent with no intra-thoracic bleeding., Conclusions: In an acute pig model, we have demonstrated the feasibility of creating a transcatheter Potts shunt with a simplified technique using a steerable sheath, a double-disc device with a central fenestration that acts as the shunt channel and optional stenting of the fenestration., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objective: The aim of this systematic review and meta-analysis is to evaluate whether duct stenting is associated with better survival and other clinical outcomes compared with the modified Blalock-Taussig shunt in infants with duct-dependent pulmonary flow., Methods: A systematic search of the Medline, Embase, and Cochrane databases was performed by 4 independent reviewers from inception to March 2019. Meta-analysis was performed using the DerSimonian and Laird method with inverse-variance weighting. The quality of evidence was summarized using the Grading of Recommendations, Assessment, Development, and Evaluation framework., Results: Six comparative observational studies were included, of which 3 were rated low risk of bias. There was no difference in 30-day mortality between the Blalock-Taussig shunt and duct stenting groups (risk ratio, 1.02; 95% confidence interval, 0.46-2.27; P = .96; I 2  = 0%). However, there was benefit in favor of duct stenting for medium-term mortality (risk ratio, 0.63; 95% confidence interval, 0.40-0.99; P = .05; I 2  = 0%). Duct stenting demonstrated a reduced risk for procedural complications compared with the Blalock-Taussig shunt (risk ratio, 0.50; 95% confidence interval, 0.31-0.81; P = .005; I 2  = 0%). However, there was an increased risk for unplanned reintervention for duct stenting (risk ratio, 1.77; 95% confidence interval, 1.39-2.26; P < .00001; I 2  = 10%). Duct stenting demonstrated shorter mean intensive care unit length of stay (mean difference, -4.69 days; 95% confidence interval, -7.30 to -2.07; P = .0004; I 2  = 80%), as well as shorter hospital length of stay (mean difference, -5.78 days; 95% confidence interval, -9.27 to -2.28; P = .0009, I 2  = 75%). The overall quality of evidence was rated low using the Grading of Recommendations, Assessment, Development, and Evaluation framework., Conclusions: Duct stenting demonstrated comparable early mortality, lower medium-term mortality, lower risk of procedural complications, and higher risk of reintervention compared with the Blalock-Taussig shunt., (Crown Copyright © 2020. Published by Elsevier Inc. All rights reserved.)

Background: Balloon angioplasty for native coarctation of the aorta (CoA) is successful in children and adults but in neonates results in frequent restenosis. The efficacy of balloon angioplasty for native CoA during infancy beyond the neonatal period was examined in infants aged 3 to 12 months of age., Methods: A retrospective review of 68 infants who underwent balloon angioplasty for native CoA. 95% CI are in parentheses., Results: Procedural age was (mean±SD) 6±3.4 months and weight was 7±1.8 kg. Balloon angioplasty produced a large decrease in both the noninvasive arm-to-leg blood pressure gradient (41.2±18.7 to 5.6±9.6 mm Hg) and the invasive peak systolic pressure gradient (34±12 to 11±9 mm Hg). Balloon angioplasty increased the CoA diameter from 2.7±1 mm to 4.6±1.2 mm. One patient was lost to follow-up. A catheter reintervention was required in 11.8% and surgery in 10.3%. The hazard of reintervention was highest early. Median freedom from reintervention was 89% (95% CI, 80%-96%) at 1 year, 83% (95% CI, 73%-92%) at 5 years, and 81% (95% CI, 69%-90%) at 10 years. Femoral artery thrombosis was documented in 6 (9%) infants without any long-term consequence. One patient developed a small aortic aneurysm late and has not required treatment. A robust estimate of the frequency of aortic aneurysms remains to be determined as the majority of subjects have not had cross-sectional imaging., Conclusions: Balloon angioplasty of native CoA is effective and safe in infants aged 3 to 12 months with outcomes comparable to those in older children and adults. Catheter reinterventions can avoid the need for surgery in most patients.

Digital reality is an emerging platform for three-dimensional representation of medical imaging data. In this technical innovation paper, the authors evaluated the accuracy and utility of mixed-reality technology in the morphological evaluation of complex congenital heart disease. The authors converted CT datasets of 12 heart specimens with different subtypes of double-outlet right ventricle to stereoscopic images and interrogated them using a mixed-reality system. The morphological features identified on the stereoscopic models were compared with findings at macroscopic examination of the actual heart specimens. The results showed that the mixed-reality system provided highly accurate stereoscopic display of spatially complex congenital cardiac lesions, with interactive features that might enhance 3-D understanding of morphology. Additionally, the authors found that high-resolution digital reproduction of cardiac specimens using clinical CT scanners is feasible for preservation and educational purposes.

Purpose: This study investigated the diagnostic utility of nontargeted genomic testing in patients with pediatric heart disease., Methods: We analyzed genome sequencing data of 111 families with cardiac lesions for rare, disease-associated variation., Results: In 14 families (12.6%), we identified causative variants: seven were de novo (ANKRD11, KMT2D, NR2F2, POGZ, PTPN11, PURA, SALL1) and six were inherited from parents with no or subclinical heart phenotypes (FLT4, DNAH9, MYH11, NEXMIF, NIPBL, PTPN11). Outcome of the testing was associated with the presence of extracardiac features (p = 0.02), but not a positive family history for cardiac lesions (p = 0.67). We also report novel plausible gene-disease associations for tetralogy of Fallot/pulmonary stenosis (CDC42BPA, FGD5), hypoplastic left or right heart (SMARCC1, TLN2, TRPM4, VASP), congenitally corrected transposition of the great arteries (UBXN10), and early-onset cardiomyopathy (TPCN1). The identified candidate genes have critical functions in heart development, such as angiogenesis, mechanotransduction, regulation of heart size, chromatin remodeling, or ciliogenesis., Conclusion: This data set demonstrates the diagnostic and scientific value of genome sequencing in pediatric heart disease, anticipating its role as a first-tier diagnostic test. The genetic heterogeneity will necessitate large-scale genomic initiatives for delineating novel gene-disease associations.

Fetal cardiac interventions (FCI) offer the opportunity to rescue a fetus at risk of intrauterine death, or more ambitiously to alter disease progression. Most of these fetuses require multiple additional postnatal procedures, and it is difficult to disentangle the effect of the fetal procedure from that of the postnatal management sequence. The true clinical impact of FCI may only be discernible in large-volume institutions that can commit to a standardized postnatal approach and have sufficient case volume to overcome their FCI learning curve.

Background: Although adoption of "smart" infusion pumps has improved intravenous medication administration safety, pump integration with electronic health records (EHRs) remains rare. Early-adopter hospitals have recently implemented intravenous clinical integration (IVCI) to allow bidirectional communication between their EHRs and infusion pumps. However, the challenges and strategies involved in IVCI implementation have not been described., Methods: A qualitative description of one hospital's IVCI implementation was conducted. The research team interviewed 33 pharmacists, technologists, clinicians, nurse managers, educators, and organizational leaders; observed nurses on five units using EHR-integrated pumps; and attended nurse training. Interview notes and transcripts were analyzed to describe IVCI implementation, highlighting its effects on clinicians and the organization., Results: Motivations for implementation included a culture of innovation, simultaneous pump and EHR upgrades, and belief that IVCI would improve patient safety. Proactive planning included a simultaneous go-live across selected units, financial investment, multidisciplinary planning teams, and clinical training. Challenges included lack of direct communication between EHR and pump vendors, nonstandardized unit-specific drug libraries, and unit- and nurse-specific variation in workflows for administering infusions. Mitigation strategies included serving as messenger between vendors, conducting hospitalwide efforts to standardize drug libraries and workflows, and standardizing organizational policies. Lessons learned included that IVCI adoption was as much a nursing workflow and organizational policy intervention as a technological implementation., Conclusion: Integrating infusion pumps and EHRs involves much more than installing new technologies. Hospitals considering IVCI should prepare to undertake significant simultaneous changes to organizational policies and clinician workflows., (Copyright © 2019 The Joint Commission. Published by Elsevier Inc. All rights reserved.)

Objective: The relationship between right ventricular (RV) fibrosis and right heart reverse remodelling following pulmonary valve replacement (PVR) has not been well studied in adults with repaired tetralogy of Fallot (rTOF). Our aims were to histologically quantify RV fibrosis and to explore the relationship between fibrosis severity and cardiac remodelling post-PVR., Methods: Adults with rTOF and pre-PVR cardiovascular (CMR) imaging were consented to procurement of RV muscle during PVR. Samples were stained with picrosirius red to quantify collagen volume fraction. Clinical data at baseline and at last follow-up were reviewed. Adverse cardiovascular outcomes included death, sustained arrhythmia and heart failure., Results: Fifty-three patients (male 58%, 38±11 years) were studied. Those with severe fibrosis (collagen volume fraction >11.0%, n=13) had longer aortic cross-clamp times at initial repair compared with the remainder of the population (50 vs 33 min, p=0.018) and increased RV mass:volume ratio pre-PVR (0.20 vs 0.18 g/mL, p=0.028). Post-PVR, the severe fibrosis group had increased indexed RV end-systolic volume index (RVESVi) (74 vs 66 mL/m 2 , p=0.044), decreased RVESVi change (Δ29 vs Δ45 mL/m 2 , p=0.005), increased RV mass (34 vs 25 g/m 2 , p=0.023) and larger right atrial (RA) area (21 vs 17 cm 2 , p=0.021). A trend towards increased heart failure events was observed in the severe fibrosis group (15% vs 0%, p=0.057)., Conclusions: Severe RV fibrosis was associated with increased RVESVi, RV mass and RA area post-PVR in rTOF. Further study is required to define the impact of fibrosis and persistent right heart enlargement on clinical outcomes., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: To determine disease-associated single-gene variants in conotruncal defects, particularly tetralogy of Fallot (TOF)., Methods: We analyzed for rare loss-of-function and deleterious variants in FLT4 (VEGFR3) and other genes in the vascular endothelial growth factor (VEGF) pathway, as part of a genome sequencing study involving 175 adults with TOF from a single site., Results: We identified nine (5.1%) probands with novel FLT4 variants: seven loss-of-function, including an 8-kb deletion, and two predicted damaging. In ten other probands we found likely disruptive variants in VEGF-related genes: KDR (VEGFR2; two stopgain and two nonsynonymous variants), VEGFA, FGD5, BCAR1, IQGAP1, FOXO1, and PRDM1. Detection of VEGF-related variants (19/175, 10.9%) was associated with an increased prevalence of absent pulmonary valve (26.3% vs. 3.4%, p < 0.0001) and right aortic arch (52.6% vs. 29.1%, p = 0.029). Extracardiac anomalies were rare. In an attempt to replicate findings, we identified three loss-of-function or damaging variants in FLT4, KDR, and IQGAP1 in ten independent families with TOF., Conclusion: Loss-of-function variants in FLT4 and KDR contribute substantially to the genetic basis of TOF. The findings support dysregulated VEGF signaling as a novel mechanism contributing to the pathogenesis of TOF.

We report the first ultrasonographically guided percutaneous balloon atrial septoplasty (BAS), to our knowledge, in a fetus with transposition of the great arteries and an intact ventricular and atrial septum (37 + 2 weeks). After vaginal delivery at 38 weeks, the infant had an elective septostomy (day 1) and an arterial switch procedure (day 7), with an uneventful postoperative course. For centres with experience in fetal cardiac interventions, fetal BAS is a superior management option compared with the alternatives for this high-risk physiology., (Copyright © 2017 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Acute cellular rejection (ACR) compromises graft function after heart transplantation (HTX). The purpose of this study was to describe systolic myocardial deformation in pediatric HTX and to determine whether it is impaired during ACR. Eighteen combined cardiac magnetic resonance imaging (CMR)/endomyocardial biopsy (EMBx) examinations were performed in 14 HTX patients (11 male, age 13.9 ± 4.7 years; 1.2 ± 1.3 years after HTX). Biventricular function and left ventricular (LV) circumferential strain, rotation, and torsion by myocardial tagging CMR were compared to 11 controls as well as between patients with and without clinically significant ACR. HTX patients showed mildly reduced biventricular systolic function when compared to controls [LV ejection fraction (EF): 55 ± 8% vs. 61 ± 3, p = 0.02; right ventricular (RV) EF: 48 ± 7% vs. 53 ± 6, p = 0.04]. Indexed LV mass was mildly increased in HTX patients (67 ± 14 g/m 2 vs. 55 ± 13, p = 0.03). LV myocardial deformation indices were all significantly reduced, expressed by global circumferential strain (-13.5 ± 2.3% vs. -19.1 ± 1.1%, p < 0.01), basal strain (-13.7 ± 3.0% vs. -17.5 ± 2.4%, p < 0.01), mid-ventricular strain (-13.4 ± 2.7% vs. -19.3 ± 2.2%, p < 0.01), apical strain (-13.5 ± 2.8% vs. -19.9 ± 2.0%, p < 0.01), basal rotation (-2.0 ± 2.1° vs. -5.0 ± 2.0°, p < 0.01), and torsion (6.1 ± 1.7° vs. 7.8 ± 1.1°, p < 0.01). EMBx demonstrated ACR grade 0 R in 3 HTX cases, ACR grade 1 R in 11 HTX cases and ACR grade 2 R in 4 HTX cases. When comparing clinically non-significant ACR (grades 0-1 R vs. ACR 2 R), basal rotation, and apical rotation were worse in ACR 2 R patients (-1.4 ± 1.8° vs. -4.2 ± 1.4°, p = 0.01 and 10.2 ± 2.9° vs. 2.8 ± 1.9°, p < 0.01, respectively). Pediatric HTX recipients demonstrate reduced biventricular systolic function and decreased myocardial contractility. Myocardial deformation indices by CMR may serve as non-invasive markers of graft function and, perhaps, rejection in pediatric HTX patients.

Control of both tissue architecture and scale is a fundamental translational roadblock in tissue engineering. An experimental framework that enables investigation into how architecture and scaling may be coupled is needed. We fabricated a structurally organized engineered tissue unit that expanded in response to regenerative cues after implantation into mice with liver injury. Specifically, we found that tissues containing patterned human primary hepatocytes, endothelial cells, and stromal cells in a degradable hydrogel expanded more than 50-fold over the course of 11 weeks in mice with injured livers. There was a concomitant increase in graft function as indicated by the production of multiple human liver proteins. Histologically, we observed the emergence of characteristic liver stereotypical microstructures mediated by coordinated growth of hepatocytes in close juxtaposition with a perfused vasculature. We demonstrated the utility of this system for probing the impact of multicellular geometric architecture on tissue expansion in response to liver injury. This approach is a hybrid strategy that harnesses both biology and engineering to more efficiently deploy a limited cell mass after implantation., (Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Background: Adverse fibrotic remodeling is detrimental to myocardial health and a reliable method for monitoring the development of fibrotic remodeling may be desirable during the follow-up of patients after heart transplantation (HTx). Quantification of diffuse myocardial fibrosis with cardiovascular magnetic resonance (CMR) has been increasingly applied and validated histologically in adult patients with heart disease. However, comparisons of CMR findings with histological fibrosis burden in children are lacking. This study aimed to compare native T1 times and extracellular volume fraction (ECV) derived from CMR with the degree of collagen on endomyocardial biopsy (EmBx), and to investigate the association between myocardial fibrosis and clinical as well as functional markers in children after HTx., Methods: EmBx and CMR were performed on the same day. All specimens were stained with picrosirius red. The collagen volume fraction (CVF) was calculated as ratio of stained collagen area to total myocardial area on EmBx. Native T1 values and ECV were measured by CMR on a mid-ventricular short axis slice, using a modified look-locker inversion recovery approach., Results: Twenty patients (9.9 ± 6.2 years of age; 9 girls) after HTx were prospectively enrolled, at a median of 1.3 years (0.02-12.6 years) post HTx, and compared to 24 controls (13.9 ± 2.6 years of age; 12 girls). The mean histological CVF was 10.0 ± 3.4%. Septal native T1 times and ECV were higher in HTx patients compared to controls (1008 ± 32 ms vs 979 ± 24 ms, p < 0.005 and 0.30 ± 0.03 vs 0.22 ± 0.03, p < 0.0001, respectively). CVF showed a moderate correlation with native T1 (r = 0.53, p < 0.05) as well as ECV (r = 0.46, p < 0.05). Native T1 time, but not ECV and CVF, correlated with ischemia time (r = 0.46, p < 0.05)., Conclusions: CMR-derived fibrosis markers correlate with histological degree of fibrosis on EmBx in children after HTx. Further, native T1 times are associated with longer ischemia times.

Aim: To evaluate cardiac magnetic resonance imaging (CMR) as a non-invasive tool to detect acute cellular rejection (ACR) in children after heart transplant (HT)., Methods: Thirty pediatric HT recipients underwent CMR at the time of surveillance endomyocardial biopsy (EMB) and results were compared to 14 non-transplant controls. Biventricular volumes, ejection fractions (EFs), T2-weighted signal intensities, native T1 times, extracellular volumes (ECVs) and presence of late gadolinium enhancement (LGE) were compared between patients and controls and between patients with International Society of Heart and Lung Transplantation (ISHLT) grade ≥ 2R rejection and those with grade 0/1R. Heart rate (HR) and brain natriuretic peptide (BNP) were assessed as potential biomarkers., Results: Significant ACR (ISHLT grade ≥ 2R) was an infrequent event in our population (5/30, 17%). Ventricular volumes, EFs, LGE prevalence, ECVs, native T1 times, T2 signal intensity ratios, HR and BNP were not associated with the presence of ≥ 2R ACR., Conclusion: In this pilot study CMR did not reliably identify ACR-related changes in pediatric HT patients., Competing Interests: Conflict-of-interest statement: The authors of this manuscript have no conflicts of interest to disclose.

Background: Tetralogy of Fallot with cyanosis requiring surgical repair in early infancy reflects poor anatomy and is associated with more clinical instability and longer hospitalization than those who can be electively repaired later. We bridged symptomatic infants with risk factors for early primary repair by right ventricular outflow tract stenting (stent)., Methods and Results: Four groups of tetralogy of Fallot with confluent central pulmonary arteries were studied: stent group (n=42), primary repair (aged <3 months) with pulmonary stenosis (early-PS group; n=44), primary repair (aged <3 months) with pulmonary atresia (early-PA group; n=49), and primary repair between 3 and 11 months of age (surg>3mo group; n=45). Stent patients had the smallest pulmonary arteries with a median (95% credible intervals) Nakata index (mm 2 /m 2 ) of 79 (66-85) compared with the early-PA 139 (129-154), early-PS 136 (121-153), and surg>3mo 167 (153-200) groups. Only stent infants required unifocalization of aortopulmonary collaterals (17%). Stent and early-PA infants had younger age and lower weight than early-PS infants. Stent infants had the most multiple comorbidities. Stenting allowed deferral of complete surgical repair to an age (6 months), weight (6.3 [5.8-7.0] kg), and Nakata index (147 [132-165]) similar to the low-risk surg>3mo group. The 3 early treatment groups had similar intensive care unit/hospital stays and high reintervention rates in the first 12 months after repair, compared with the surg>3mo group., Conclusions: Right ventricular outflow tract stenting of symptomatic tetralogy of Fallot with poor anatomy (small pulmonary arteries) and adverse factors (multiple comorbidities, low weight) relieves cyanosis and defers surgical repair. This allowed pulmonary arterial and somatic growth with clinical results comparable to early surgical repair in more favorable patients., (© 2016 American Heart Association, Inc.)

A 33-day-old infant with obstructed cor triatriatum sinister and partial anomalous pulmonary venous drainage presented with respiratory distress and fever. Her suprasystemic pulmonary hypertension was relieved by opening the connection to the right atrium using balloon atrial septoplasty and septostomy, and to the inferior chamber using balloon dilation of a fenestration in the dividing membrane. This enabled extubation and discharge, with elective surgical repair at 2 months. To our knowledge, this is the youngest patient to receive a catheter intervention for obstructed cor triatriatum sinister, providing relief of pulmonary hypertension and postponement of surgical repair., (Copyright © 2016 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Background: It is unclear whether the myocardium undergoes accelerated fibrotic remodeling in children after heart transplantation (HTx)., Methods: In this prospective study, cardiac magnetic resonance (CMR) studies in 17 patients 1.3 years (median, range 0.03-12.6 years) after HTx (mean age, 9.8 ± 6.2 years; 8 girls) were compared to CMR studies in 9 healthy controls (mean age, 12.4 ± 2.4 years; 4 girls). T1 measurements were performed at a midventricular short axis slice before (ie, native T1 times) and after the application of 0.2 mmol/kg gadopentetate dimeglumine in the interventricular septum, left ventricular (LV) free wall and encompassing the entire LV myocardium. The tissue-blood partition coefficient (TBPC), reflecting the degree of diffuse myocardial fibrosis, was calculated as a function of the ratio of T1 change of myocardium compared to blood. Native T1 times and TBPC were correlated with echocardiographic parameters of diastolic function., Results: Native T1 times were significantly higher in HTx patients compared to controls in all regions assessed (LV free wall 973 ± 42 vs 923 ± 12 ms; P < 0.005; interventricular septum 1003 ± 31 vs 974 ± 21 ms, P < 0.05; entire LV myocardium 987 ± 33 vs 951 ± 16 ms; P < 0.005) and correlated with LV E/e' as an echocardiographic marker of diastolic dysfunction (r = 0.54, P < 0.05). The TBPC was elevated in the LV free wall (0.45 ± 0.06 vs 0.40 ± 0.03, P < 0.005) and the entire LV myocardium (0.47 ± 0.06 vs 0.43 ± 0.03, P < 0.05)., Conclusions: Evidence of diffuse myocardial fibrosis and is already present in children after HTx. It appears to be associated with diastolic dysfunction.

Background: Sirolimus-eluting stents may have clinical advantages over bare-metal stents in the extremely proliferative environment of the neonatal arterial duct. However, sirolimus has immunosuppressive actions and little is known regarding sirolimus pharmacokinetics in the newborn., Methods and Results: This is a retrospective review of sirolimus pharmacokinetics in neonates who underwent sirolimus-eluting stent implantation in the arterial duct for pulmonary blood flow augmentation. Pharmacokinetic parameters were obtained by noncompartmental analysis and by a Bayesian one-compartment nonlinear mixed model. Nine neonates received a single sirolimus-eluting stent with a total sirolimus dose of 245 μg (n = 1), 194 μg (n = 5), or 143 μg (n = 3). Peak sirolimus concentrations were 13.6 ± 4.5 μg/L (24.8 μg/L highest) and clearance was 0.042 ± 0.03 L/hour (noncompartmental analysis) and 0.051 L/hour (95% credible intervals 0.037-0.069, nonlinear mixed model). Sirolimus remained > 5 μg/L, the trough level used in oral immunosuppressive therapy, for (95% credible interval) 15.9 (11.4, 22.8), 12.9 (7.6, 19.0), and 8.4 (2.3, 14.5) days for the 245, 194, and 143 μg sirolimus dose stents, respectively. Estimates of the duration of systemic immunosuppression are provided for combinations of 2 stents., Conclusions: In neonates after sirolimus-eluting stent implantation, peak sirolimus levels were 20 × higher and clearance 30 × lower than previously reported in older children and adults. Sirolimus levels were within the immunosuppressive range for a prolonged period, but with no observable clinically significant adverse outcomes., (© 2015 American Heart Association, Inc.)

The ultimate design of functionally therapeutic engineered tissues and organs will rely on our ability to engineer vasculature that can meet tissue-specific metabolic needs. We recently introduced an approach for patterning the formation of functional spatially organized vascular architectures within engineered tissues in vivo. Here, we now explore the design parameters of this approach and how they impact the vascularization of an engineered tissue construct after implantation. We used micropatterning techniques to organize endothelial cells (ECs) into geometrically defined "cords," which in turn acted as a template after implantation for the guided formation of patterned capillaries integrated with the host tissue. We demonstrated that the diameter of the cords before implantation impacts the location and density of the resultant capillary network. Inclusion of mural cells to the vascularization response appears primarily to impact the dynamics of vascularization. We established that clinically relevant endothelial sources such as induced pluripotent stem cell-derived ECs and human microvascular endothelial cells can drive vascularization within this system. Finally, we demonstrated the ability to control the juxtaposition of parenchyma with perfused vasculature by implanting cords containing a mixture of both a parenchymal cell type (hepatocytes) and ECs. These findings define important characteristics that will ultimately impact the design of vasculature structures that meet tissue-specific needs.

Objective: Pulmonary artery growth is an important determinant of outcome in single-ventricle strategies. Higher rates of pulmonary artery intervention have been reported with hybrid-based palliation when compared with Norwood palliation., Methods: We performed a retrospective review of pulmonary artery growth and clinical outcomes in patients undergoing hybrid-based single-ventricle palliation., Results: The stage I hybrid procedure was performed in 72 patients between 2004 and 2012, of whom 54 were on a Fontan palliative pathway. Thirty-four infants completed stage II, and 20 infants underwent the Fontan operation. The mean diameters of the right pulmonary artery (5.6 ± 1.9 mm) and left pulmonary artery (5.6 ± 2.1 mm) were similar before stage II. After stage II, the right and left pulmonary artery diameters were 8.5 ± 2.1 mm and 5.8 ± 1.3 mm, respectively (P < .001), and after the Fontan operation, these were 8.8 ± 2.0 mm and 6.4 ± 1.1 mm, respectively (P = .002). The mean right pulmonary artery z score was normal throughout, but the left pulmonary artery did not maintain a normal size. The cumulative pulmonary artery intervention rate was 50% at any time after stage II. Fifteen interventions (88%) were performed after stage II (35% during the same hospitalization, 71% <60 days). The most intervened site was the midsection of the left pulmonary artery (41%). Initial pulmonary artery intervention was balloon dilation in 59% of patients and stent implantation in 41% of patients. Half of patients with initial balloon dilation required reintervention., Conclusions: There is significant risk of left pulmonary artery compromise after the second stage of hybrid palliation associated with a high intervention rate., (Copyright © 2015 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Background: Hypoplastic left heart syndrome with a highly restrictive or intact atrial septum (HLHS-RAS) has a very high mortality. Fetal left atrial (LA) hypertension results in abnormal lung development with lymphangiectasia and pulmonary vein muscularization. We report our initial experience with percutaneous ultrasound-guided stenting of the fetal atrial septum to decompress the LA., Methods: Retrospective review of fetuses with HLHS-RAS or a variant that underwent active perinatal management from 2000 to 2012., Results: Ten fetuses were identified. Two died in utero (33, 29 weeks). Four required the urgent creation of an atrial communication immediately after birth but died subsequently (5-54 days). Four fetuses (28-36 weeks) underwent percutaneous stenting of the atrial septum, with ultrasound guidance and intravenous maternal sedation. Elevated LA pressure, pulmonary vein dilation and MRI estimated pulmonary perfusion all improved after stenting. Three of four stented fetuses were delivered vaginally. Atrial septectomy was performed within 48 h of delivery to ensure complete LA decompression, rather than for hypoxemia. Intraoperative lung biopsy demonstrated muscularized pulmonary veins and lymphangiectasia in all four. Two fetuses developed stent stenosis in utero and died after birth, from pulmonary hypertension and sepsis respectively. Two are alive, representing an improved outcome over our previous experience (p=0.03)., Conclusion: Fetal atrial septal stenting is feasible without maternal complications and allows vaginal delivery of a more stable neonate. Fetal LA decompression ameliorates rather than reverses lung injury, and is one component of an approach that may improve survival in HLHS-RAS., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Objective: To report three different antenatal therapeutic approaches for fetal lung masses associated with hydrops., Methods: Three prospectively followed cases are described, and all 30 previously published minimally invasive cases of fetal therapy for hydropic lung masses are reviewed., Results: Three hydropic fetuses with large intrathoracic lung masses presented at 17, 25 and 21 weeks of gestation, respectively. An aortic feeding vessel was identified in each case and thus a bronchopulmonary sequestration (BPS) was suspected. Under ultrasound guidance, the feeding vessel was successfully occluded with interstitial laser (Case 1), radiofrequency ablation (RFA) (Case 2) and thrombogenic coil embolization (Case 3). Complete (Cases 1 and 2) or partial (Case 3) resolution of the lung mass and hydrops was observed. A healthy infant was born at term after laser therapy (Case 1), and the involved lung lobe was resected on day 2 of postnatal life. In Case 2, hydrops resolved completely following RFA, but an iatrogenic congenital diaphragmatic hernia and abdominal wall defect became apparent 4 weeks later. The neonate died from sepsis following spontaneous preterm labor at 33 weeks. In Case 3, despite technical success in complete vascular occlusion with coils, a stillbirth ensued 2 days after embolization., Conclusions: The prognosis of large microcystic or echogenic fetal chest masses associated with hydrops is dismal. This has prompted attempts at treatment by open fetal surgery, with mixed results, high risk of premature labor and consequences for future pregnancies. We have demonstrated the possibility of improved outcome following ultrasound-guided laser ablation of the systemic arterial supply. Despite technical success, RFA and coil embolization led to procedure-related complications and need further evaluation., (Copyright © 2013 ISUOG. Published by John Wiley & Sons Ltd.)

Background: All 3 palliation strategies, Norwood, Sano, and Hybrid, currently used for hypoplastic left heart syndrome pose a risk of myocardial injury at different times and through different mechanisms. We sought to compare these strategies to understand longitudinal differences in interstage ventricular dysfunction and their subsequent impact on transplant-free survival and atrioventricular valve regurgitation (AVVR) as well as the relationship between adverse events and ventricular function., Methods and Results: Serial echocardiographic reports and clinical data were reviewed for 138 children with hypoplastic left heart syndrome who underwent stage I surgical palliation (Sano: 11; Norwood: 73; Hybrid: 54) between 2004 and 2011. Stage II palliation was achieved in 92 (67%) patients (Sano: 7; Norwood: 51; Hybrid: 34). Interstage transplant-free survival, ventricular dysfunction, and AVVR were equivalent among palliation strategies. Patients with preserved ventricular function had a higher rate of transplant-free survival and freedom from AVVR, regardless of palliation strategy. Patients who had cardiac arrest, cardiopulmonary resuscitation, or extracorporeal membrane oxygenation (adverse events) experienced more transient and persistent ventricular dysfunction compared to those without adverse events. Surgical palliation strategies were not identified as risk factors for ventricular dysfunction or AVVR., Conclusions: Surgical palliation strategy does not affect mortality, interstage ventricular function, or interstage AVVR in children with hypoplastic left heart syndrome. Therefore, the different timing and mechanisms of myocardial injury among palliation strategies do not affect outcomes. Ventricular dysfunction adversely affects transplant-free survival and atrioventricular valve function. Adverse events are associated with the development of ventricular dysfunction. To improve outcomes, interstage treatment should focus on the preservation of ventricular function.

Tissue vascularization and integration with host circulation remains a key barrier to the translation of engineered tissues into clinically relevant therapies. Here, we used a microtissue molding approach to demonstrate that constructs containing highly aligned "cords" of endothelial cells triggered the formation of new capillaries along the length of the patterned cords. These vessels became perfused with host blood as early as 3 d post implantation and became progressively more mature through 28 d. Immunohistochemical analysis showed that the neovessels were composed of human and mouse endothelial cells and exhibited a mature phenotype, as indicated by the presence of alpha-smooth muscle actin-positive pericytes. Implantation of cords with a prescribed geometry demonstrated that they provided a template that defined the neovascular architecture in vivo. To explore the utility of this geometric control, we implanted primary rat and human hepatocyte constructs containing randomly organized endothelial networks vs. ordered cords. We found substantially enhanced hepatic survival and function in the constructs containing ordered cords following transplantation in mice. These findings demonstrate the importance of multicellular architecture in tissue integration and function, and our approach provides a unique strategy to engineer vascular architecture.

Complex tissues contain multiple cell types that are hierarchically organized within morphologically and functionally distinct compartments. Construction of engineered tissues with optimized tissue architecture has been limited by tissue fabrication techniques, which do not enable versatile microscale organization of multiple cell types in tissues of size adequate for physiological studies and tissue therapies. Here we present an 'Intaglio-Void/Embed-Relief Topographic molding' method for microscale organization of many cell types, including induced pluripotent stem cell-derived progeny, within a variety of synthetic and natural extracellular matrices and across tissues of sizes appropriate for in vitro, pre-clinical, and clinical studies. We demonstrate that compartmental placement of non-parenchymal cells relative to primary or induced pluripotent stem cell-derived hepatocytes, compartment microstructure, and cellular composition modulate hepatic functions. Configurations found to sustain physiological function in vitro also result in survival and function in mice for at least 4 weeks, demonstrating the importance of architectural optimization before implantation.

A novel method to control three-dimensional cell cluster size and geometry using two-dimensional patterning techniques is described. Cells were first cultured on two-dimensional micropatterned collagen using conventional soft lithography techniques. Collagenase was used to degrade the micropatterned collagen and release cells from the micropatterns, forming clusters of cells which were then resuspended in a three-dimensional collagen matrix. This method facilitated the formation of uniformly sized clusters within a single sample. By systematically varying the geometry of the two-dimensional micropatterned islands, final cluster size and cell number in three dimensions could be controlled. Using this technique, we showed that proliferation of cells within collagen gels depended on the size of clusters, suggesting an important role for multicellular structure on biological function. Furthermore, by utilizing more complex two-dimensional patterns, non-spherical structures could be produced. This technique demonstrates a simple way to exploit two-dimensional micro-patterning in order to create complex and structured multicellular clusters in a three-dimensional environment.

Background: The bidirectional cavopulmonary connection (BCPC) is used in the staged palliation of univentricular hearts and places the cerebral and pulmonary vascular beds in series. Angiotensin-converting enzyme inhibitors (ACEI) are often used in this complex circulation, but the effects of their vasodilation are unclear., Objective: Assessment of the acute response of perfusion pressure, flow and resistance across the systemic, cerebral and pulmonary vascular beds to ACEI in patients with a BCPC., Design: Prospective interventional study., Setting: Single tertiary care centre., Patients: 12 patients with a BCPC (median age 28 months, weight 11.8 kg) undergoing a pre-Fontan catheterisation with MRI measurement of flows., Intervention: Intravenous enalaprilat 0.005 or 0.01 mg/kg., Results: Enalaprilat increased descending aorta flow (median 21.6%, p=0.0005), decreased total pulmonary vein flow (median 10.6%, p=0.025), and both superior caval vein flow (median 8.6%, p=0.065) and aortopulmonary collateral flow (median 15.5%, p=0.077) tended to decrease. Total cardiac output was unchanged (p=0.57). Systemic vascular resistance (median 41.9%, p=0.0005) and cerebral vascular resistance (median 23.4%, p=0.0005) decreased, but pulmonary vascular resistance (p=0.73) showed little change. There was evidence of autoregulation of cerebral blood flow. The proportion of descending aortic flow to total cardiac output increased (median 27 to 35%, p=0.001). Systemic oxygen saturation decreased from 87% to 83% (p=0.02)., Conclusion: Enalaprilat did not increase total cardiac output but redistributed flow to the lower body, with a concomitant decrease in arterial oxygen saturation. It is difficult to increase cardiac output in patients with a BCPC and ACEI should be used with caution in those with borderline aortic saturations.