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Background: Congenital heart disease (CHD) is the most common congenital anomaly. Almost 90% of isolated cases have an unexplained genetic etiology after clinical testing. Non-canonical splice variants that disrupt mRNA splicing through the loss or creation of exon boundaries are not routinely captured and/or evaluated by standard clinical genetic tests. Recent computational algorithms such as SpliceAI have shown an ability to predict such variants, but are not specific to cardiac-expressed genes and transcriptional isoforms., Methods: We used genome sequencing (GS) (n = 1101 CHD probands) and myocardial RNA-Sequencing (RNA-Seq) (n = 154 CHD and n = 43 cardiomyopathy probands) to identify and validate splice disrupting variants, and to develop a heart-specific model for canonical and non-canonical splice variants that can be applied to patients with CHD and cardiomyopathy. Two thousand five hundred seventy GS samples from the Medical Genome Reference Bank were analyzed as healthy controls., Results: Of 8583 rare DNA splice-disrupting variants initially identified using SpliceAI, 100 were associated with altered splice junctions in the corresponding patient myocardium affecting 95 genes. Using strength of myocardial gene expression and genome-wide DNA variant features that were confirmed to affect splicing in myocardial RNA, we trained a machine learning model for predicting cardiac-specific splice-disrupting variants (AUC 0.86 on internal validation). In a validation set of 48 CHD probands, the cardiac-specific model outperformed a SpliceAI model alone (AUC 0.94 vs 0.67 respectively). Application of this model to an additional 947 CHD probands with only GS data identified 1% patients with canonical and 11% patients with non-canonical splice-disrupting variants in CHD genes. Forty-nine percent of predicted splice-disrupting variants were intronic and > 10 bp from existing splice junctions. The burden of high-confidence splice-disrupting variants in CHD genes was 1.28-fold higher in CHD cases compared with healthy controls., Conclusions: A new cardiac-specific in silico model was developed using complementary GS and RNA-Seq data that improved genetic yield by identifying a significant burden of non-canonical splice variants associated with CHD that would not be detectable through panel or exome sequencing., (© 2024. The Author(s).)

Background: To characterize global and health-related quality of life (QOL) among adults with Fontan physiology enrolled in the Australian and New Zealand Fontan Registry (ANZFR), and identify sociodemographic, clinical, psychological, and relational factors associated with outcomes., Methods and Results: Using a cross-sectional survey design, 66 adults with Fontan physiology (58% women; mean age, 29.6±7.7 years; range, 18-50 years) completed validated self-report measures. Health-related QOL was assessed using the Pediatric Quality of Life Inventory, and global QOL was assessed using a visual analog scale (0-10). Participants reported lower total health-related QOL ( P <0.001), as well as lower physical ( P <0.001) and social ( P =0.002) functioning compared with normative data. Median global QOL was 7.0 (interquartile range: 5.0-8.0) and most participants (71%) rated their QOL ≥6. For health-related QOL, age, sex, university education, and length of hospital stay in the past 12 months explained 27% of the variance in scores, while general psychological stress, medical traumatic stress, communication problems, and access to emotional support explained a further 44% of variance (final model: 71% of variance explained). For global QOL, sociodemographic and clinical factors explained 20% of the variance in scores, while psychological stress and sense of coherence explained a further 24% (final model: 44% of variance explained)., Conclusions: Adults with Fontan physiology reported lower overall health-related QOL compared with community-based norms. Variance in QOL outcomes were predominantly attributable to psychological and relational factors. Tailored screening and assessment to identify Fontan patients at greatest risk of lower QOL, and a proactive approach to supportive care, are needed.

Introduction: Contemporary care of congenital heart disease (CHD) is largely standardised, however there is heterogeneity in post-surgical outcomes that may be explained by genetic variation. Data linkage between a CHD biobank and routinely collected administrative datasets is a novel method to identify outcomes to explore the impact of genetic variation., Objective: Use data linkage to identify and validate patient outcomes following surgical treatment for CHD., Methods: Data linkage between clinical and biobank data of children born from 2001-2014 that had a procedure for CHD in New South Wales, Australia, with hospital discharge data, education and death data. The children were grouped according to CHD lesion type and age at first cardiac surgery. Children in each 'lesion/age at surgery group' were classified into 'favourable' and 'unfavourable' cardiovascular outcome groups based on variables identified in linked administrative data including; total time in intensive care, total length of stay in hospital, and mechanical ventilation time up to 5 years following the date of the first cardiac surgery. A blind medical record audit of 200 randomly chosen children from 'favourable' and 'unfavourable' outcome groups was performed to validate the outcome groups., Results: Of the 1872 children in the dataset that linked to hospital or death data, 483 were identified with a 'favourable' cardiovascular outcome and 484 were identified as having a 'unfavourable' cardiovascular outcome. The medical record audit found concordant outcome groups for 182/192 records (95%) compared to the outcome groups categorized using the linked data., Conclusions: The linkage of a curated biobank dataset with routinely collected administrative data is a reliable method to identify outcomes to facilitate a large-scale study to examine genetic variance. These genetic hallmarks could be used to identify patients who are at risk of unfavourable cardiovascular outcomes, to inform strategies for prevention and changes in clinical care., Competing Interests: Statement of conflicts of interest: All authors have no conflicts of interest.

Background: Polymeric heart valves (PHVs) may address the limitations of mechanical and tissue valves in the treatment of valvular heart disease. In this study, a bioinspired valve was designed, assessed in silico, and validated by an in vitro model to develop a valve with optimum function for pediatric applications., Methods: A bioinspired heart valve was created computationally with leaflet curvature derived from native valve anatomies. A valve diameter of 18 mm was chosen to approach sizes suitable for younger patients. Valves of different thicknesses were fabricated via dip-coating with siloxane-based polyurethane and tested in a pulse duplicator for their hydrodynamic function. The same valves were tested computationally using an arbitrary Lagrangian-Eulerian plus immersed solid approach, in which the fluid-structure interaction between the valves and fluid passing through them was studied and compared with experimental data., Results: Computational analysis showed that valves of 110 to 200 μm thickness had effective orifice areas (EOAs) of 1.20 to 1.30 cm 2 , with thinner valves exhibiting larger openings. In vitro tests demonstrated that PHVs of similar thickness had EOAs of 1.05 to 1.35 cm 2 and regurgitant fractions (RFs) <7%. Valves with thinner leaflets exhibited optimal systolic performance, whereas thicker valves had lower RFs., Conclusions: Bioinspired PHVs demonstrated good hydrodynamic performance that exceeded ISO 5840-2 standards. Both methods of analysis showed similar correlations between leaflet thickness and valve systolic function. Further development of this PHV may lead to enhanced durability and thus a more reliable heart valve replacement than contemporary options., (© 2023 The Author(s).)

Neurodevelopmental disability (NDD) is recognised as one of the most common comorbidities in children with congenital heart disease (CHD) and is associated with altered brain structure and growth throughout the life course. Causes and contributors underpinning the CHD and NDD paradigm are not fully understood, and likely include innate patient factors, such as genetic and epigenetic factors, prenatal haemodynamic consequences as a result of the heart defect, and factors affecting the fetal-placental-maternal environment, such as placental pathology, maternal diet, psychological stress and autoimmune disease. Additional postnatal factors, including the type and complexity of disease and other clinical factors such as prematurity, peri-operative factors and socioeconomic factors are also expected to play a role in determining the final presentation of the NDD. Despite significant advances in knowledge and strategies to optimise outcomes, the extent to which adverse neurodevelopment can be modified remains unknown. Understanding biological and structural phenotypes associated with NDD in CHD are vital for understanding disease mechanisms, which in turn will advance the development of effective intervention strategies for those at risk. This review article summarises our current knowledge surrounding biological, structural, and genetic contributors to NDD in CHD and describes avenues for future research; highlighting the need for translational studies that bridge the gap between basic science and clinical practice., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-22-687/coif). The column “Pediatric Heart” was commissioned by the editorial office without any funding or sponsorship. JT was supported by the Office of the Assistant Secretary of Defense for Health Affairs through the Autism Research Program (Award No. W81XWH-21-ARP-CDA). NAK receives funding from the National Heart Foundation of Australia, Additional Ventures and the National Health and Medical Research Council of Australia (research grant only, payment made to the institution). The authors have no other conflicts of interest to declare., (2023 Translational Pediatrics. All rights reserved.)

Congenital heart diseases (CHDs) frequently impact the right ventricular outflow tract, resulting in a significant incidence of pulmonary valve replacement in the pediatric population. While contemporary pediatric pulmonary valve replacements (PPVRs) allow satisfactory patient survival, their biocompatibility and durability remain suboptimal and repeat operations are commonplace, especially for very young patients. This places enormous physical, financial, and psychological burdens on patients and their parents, highlighting an urgent clinical need for better PPVRs. An important reason for the clinical failure of PPVRs is biofouling, which instigates various adverse biological responses such as thrombosis and infection, promoting research into various antifouling chemistries that may find utility in PPVR materials. Another significant contributor is the inevitability of somatic growth in pediatric patients, causing structural discrepancies between the patient and PPVR, stimulating the development of various growth-accommodating heart valve prototypes. This review offers an interdisciplinary perspective on these challenges by exploring clinical experiences, physiological understandings, and bioengineering technologies that may contribute to device development. It thus aims to provide an insight into the design requirements of next-generation PPVRs to advance clinical outcomes and promote patient quality of life., (© 2023 The Authors. Bioengineering & Translational Medicine published by Wiley Periodicals LLC on behalf of The American Institute of Chemical Engineers.)

Background: A wide range of tools are available for the detection of copy number variants (CNVs) from whole-genome sequencing (WGS) data. However, none of them focus on clinically-relevant CNVs, such as those that are associated with known genetic syndromes. Such variants are often large in size, typically 1-5 Mb, but currently available CNV callers have been developed and benchmarked for the discovery of smaller variants. Thus, the ability of these programs to detect tens of real syndromic CNVs remains largely unknown., Results: Here we present ConanVarvar, a tool which implements a complete workflow for the targeted analysis of large germline CNVs from WGS data. ConanVarvar comes with an intuitive R Shiny graphical user interface and annotates identified variants with information about 56 associated syndromic conditions. We benchmarked ConanVarvar and four other programs on a dataset containing real and simulated syndromic CNVs larger than 1 Mb. In comparison to other tools, ConanVarvar reports 10-30 times less false-positive variants without compromising sensitivity and is quicker to run, especially on large batches of samples., Conclusions: ConanVarvar is a useful instrument for primary analysis in disease sequencing studies, where large CNVs could be the cause of disease., (© 2023. The Author(s).)

People with a Fontan circulation are at risk of neurodevelopmental delay and disability, and cognitive dysfunction, that has significant implications for academic and occupational attainment, psychosocial functioning, and overall quality of life. Interventions for improving these outcomes are lacking. This review article discusses current intervention practices and explores the evidence supporting exercise as a potential intervention for improving cognitive functioning in people living with a Fontan circulation. Proposed pathophysiological mechanisms underpinning these associations are discussed in the context of Fontan physiology and avenues for future research are recommended., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer AP declared a shared affiliation with the author DW to the handling editor at the time of review., (© 2023 Verrall, Tran, Yang, Lubans, Winlaw, Ayer, Celermajer and Cordina.)

Introduction: Advances in the care of patients with single-ventricle congenital heart disease have led to a new generation of individuals living with a Fontan circulation. For people with Fontan physiology, physical, psychological and neurodevelopmental challenges are common. The objective of this study is to describe and develop a deeper understanding of the factors that contribute to quality of life (QOL) among children, adolescents and adults living with a Fontan circulation across Australia and New Zealand, their parents and siblings., Methods and Analysis: This article presents the protocol for the Australian and New Zealand Fontan Registry (ANZFR) QOL Study, a cross-sectional, population-based study designed to examine QOL among people of all ages with a Fontan circulation, their parents and siblings. Study eligibility criteria includes (1) individuals with a Fontan circulation aged ≥6 years, at least 12 months post-Fontan procedure and enrolled in the ANZFR; (2) parents of individuals enrolled in the ANZFR; and (3) siblings aged ≥6 years of an individual enrolled in the ANZFR. A novel, online research platform is used to distribute personalised assessments tailored to participant age and developmental stage. A suite of validated psychometric self-report and parent-proxy report instruments capture potential correlates and predictors of QOL, including symptoms of psychological distress, personality attributes, coping and cognitive appraisals, family functioning, healthcare experiences and costs, access to emotional support and socioeconomic factors. Clinical characteristics are captured via self-report and parent-proxy report, as well as the ANZFR. Descriptive analyses and multilevel models will be used to examine QOL across groups and to investigate potential explanatory variables., Ethics and Dissemination: Approval has been obtained from all relevant Human Research Ethics Committees (HRECs), including the Sydney Children's Hospitals Network and the Royal Children's Hospital Melbourne HRECs. Study findings will be published in peer-reviewed journals and presented at national and international meetings and seminars., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Competing Interests: Conflict of interest: none declared.

Mitochondrial DNA (mtDNA) mutations contribute to human disease across a range of severity, from rare, highly penetrant mutations causal for monogenic disorders to mutations with milder contributions to phenotypes. mtDNA variation can exist in all copies of mtDNA or in a percentage of mtDNA copies and can be detected with levels as low as 1%. The large number of copies of mtDNA and the possibility of multiple alternative alleles at the same DNA nucleotide position make the task of identifying allelic variation in mtDNA very challenging. In recent years, specialized variant calling algorithms have been developed that are tailored to identify mtDNA variation from whole-genome sequencing (WGS) data. However, very few studies have systematically evaluated and compared these methods for the detection of both homoplasmy and heteroplasmy. A publicly available synthetic gold standard dataset was used to assess four mtDNA variant callers (Mutserve, mitoCaller, MitoSeek, and MToolBox), and the commonly used Genome Analysis Toolkit "best practices" pipeline, which is included in most current WGS pipelines. We also used WGS data from 126 trios and calculated the percentage of maternally inherited variants as a metric of calling accuracy, especially for homoplasmic variants. We additionally compared multiple pathogenicity prediction resources for mtDNA variants. Although the accuracy of homoplasmic variant detection was high for the majority of the callers with high concordance across callers, we found a very low concordance rate between mtDNA variant callers for heteroplasmic variants ranging from 2.8% to 3.6%, for heteroplasmy thresholds of 5% and 1%. Overall, Mutserve showed the best performance using the synthetic benchmark dataset. The analysis of mtDNA pathogenicity resources also showed low concordance in prediction results. We have shown that while homoplasmic variant calling is consistent between callers, there remains a significant discrepancy in heteroplasmic variant calling. We found that resources like population frequency databases and pathogenicity predictors are now available for variant annotation but still need refinement and improvement. With its peculiarities, the mitochondria require special considerations, and we advocate that caution needs to be taken when analyzing mtDNA data from WGS data., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Ip, Troup, Xu, Winlaw, Dunwoodie and Giannoulatou.)

Objectives: There are limited data available on the height of the ventricular component of the septal deficiency (VSD) in patients undergoing complete atrioventricular septal defect (CAVSD) repair. VSD height may influence optimal choice of repair strategy with potential consequences for long-term outcomes. We aimed to measure VSD height using 2-dimensional echocardiography and review its association with postoperative outcomes., Methods: We retrospectively reviewed the preoperative echocardiograms of 45 consecutive patients who underwent CAVSD repair between May 2010 and December 2015 at a single centre. VSD height and left ventricular length on the four-chamber view were measured. Demographic details and early and late outcomes including reoperation and long-term survival were studied., Results: Twenty patients underwent modified single-patch repair and 25 patients underwent double-patch repair of CAVSD. VSD height in the modified single-patch group ranged from 4.2 to 11.7 mm and in the double-patch group ranged from 5.1 to 14.9 mm. Nine patients had a deep 'scoop' with a VSD height of >10 mm, (7 double patch, 2 modified single patch). VSD height did not correlate with a specific Rastelli classification. There was no significant difference in the VSD height (P = 0.51) or the VSD height-to-left ventricular length ratio (P = 0.43) between the 2 repair groups. There was no 30-day mortality. Eight patients required reoperation; however, VSD height was not a significant predictor of reoperation (hazard ratio 0.95, 95% confidence interval 0.69-1.33; P = 0.08)., Conclusions: There was no correlation between VSD height and risk of reoperation after CAVSD repair. A deep ventricular scoop is uncommon in CAVSD patients., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery.)

Objectives: The age at which the Fontan operation is performed varies globally. Over the last decade, the median age of patients having the Fontan in Australia and New Zealand has been 4.6 years, including 6% of patients younger than 3 years. Long-term outcomes of an early Fontan operation are unclear and are described in this study., Methods: Patients from the Australian and New Zealand Fontan Registry were grouped by age at Fontan. A Fontan before 3 years (early Fontan) was compared to the combined second and third quartiles by age at surgery in the Registry (3.6-6.1 years; control). Outcomes included Fontan failure (death, transplant, New York Heart Association functional group III/IV heart failure, Fontan takedown or conversion, protein losing enteropathy and plastic bronchitis), arrhythmias, thromboembolism and reinterventions., Results: A total of 191 patients who had early Fontan operations were compared to 781 controls. Profound or progressive cyanosis was noted more frequently in the early than in the control group (63% vs 23%; P < 0.001). The early group was followed up for a median 22.1 years. The incidence of long-term failure was similar between the 2 groups (early, 1.08 failures per 100 patient-years of follow-up vs control, 0.99; log-rank P = 0.79). Adjusted for risk factors, early age at Fontan was not a risk factor for long-term failure [hazard ratio (HR) 1.16, 95% confidence interval (CI) 0.77-1.76; P = 0.48], new-onset arrhythmia (HR 0.93, 95% CI 0.63-1.39; P = 0.73), thromboembolism (HR 0.50, 95% CI 0.28-0.91; P = 0.024) or reintervention (HR 1.08, 95% CI 0.80-1.45; P = 0.62)., Conclusions: Having the Fontan operation at an early age was not a risk factor for short- or long-term adverse outcomes in our cohort., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Objective: The objective of this study was to characterize early and midterm outcomes after the Ross/Ross-Konno procedure performed in infancy for severe aortic valve disease., Methods: Between January 1995 and December 2018, 35 infants younger than 1 year (13 neonates) underwent a Ross/Ross-Konno procedure. Patients were followed up to a median of 4.1 years (interquartile range [IQR], 2.6-9.5). Primary outcome measures were survival, early morbidity, freedom from reintervention and long-term functional and echocardiographic status., Results: Median age at operation was 49 days (IQR, 17-135) and weight was 4 kg (IQR, 3.4-5.2). Thirty-one (89%) had undergone a previous procedure, including balloon valvuloplasty in 26 (74%). Thirty (86%) required annular enlargement (Konno incision). Five required concomitant aortic arch surgery (2 neonates, 3 infants). There were no early deaths, and 1 late death at 18 months. Freedom from reoperation was 85% (95% confidence interval [CI], 68%-93%) at 1 year, 76% (95% CI, 54%-88%) at 5 years, and 62% (95% CI, 36%-79%) at 10 years. One modified Konno was performed at 5 years after a Ross in infancy. Ten right ventricle to pulmonary artery conduits have required reintervention (2 percutaneous pulmonary valve implantations). One child required a permanent pacemaker for complete heart block. At latest follow-up, 32 (94%) of 34 survivors were asymptomatic. There was no significant change in neoaortic Z-scores between 6 weeks and latest follow-up., Conclusions: The neonatal and infant Ross/Ross-Konno procedure can be performed with low mortality and achieves a stable left ventricular outflow tract. Significant early morbidity reflects the preoperative condition of the patients but definitive surgery of this type can be considered as a primary approach., (Crown Copyright © 2021. Published by Elsevier Inc. All rights reserved.)

Introduction: Adolescents and adults with a Fontan circulation are at risk of cognitive dysfunction; Attention and processing speed are notable areas of concern. Underlying mechanisms and brain alterations associated with worse long-term cognitive outcomes are not well determined. This study investigated brain white matter microstructure in adolescents and adults with a Fontan circulation and associations with resting and peak exercise oxygen saturations (SaO 2 ), predicted maximal oxygen uptake during exercise (% pred VO 2 ), and attention and processing speed., Methods: Ninety-two participants with a Fontan circulation (aged 13-49 years, ≥5 years post-Fontan completion) had diffusion MRI. Averaged tract-wise diffusion tensor imaging (DTI) metrics were generated for 34 white matter tracts of interest. Resting and peak exercise SaO 2 and % pred VO 2 were measured during cardiopulmonary exercise testing (CPET; N = 81). Attention and processing speed were assessed using Cogstate (N = 67 and 70, respectively). Linear regression analyses adjusted for age, sex, and intracranial volume were performed to investigate associations between i) tract-specific DTI metrics and CPET variables, and ii) tract-specific DTI metrics and attention and processing speed z-scores., Results: Forty-nine participants were male (53%), mean age was 23.1 years (standard deviation (SD) = 7.8 years). Mean resting and peak exercise SaO 2 were 93.1% (SD = 3.6) and 90.1% (SD = 4.7), respectively. Mean attention and processing speed z-scores were -0.63 (SD = 1.07) and -0.72 (SD = 1.44), respectively. Resting SaO 2 were positively associated with mean fractional anisotropy (FA) of the left corticospinal tract (CST) and right superior longitudinal fasciculus I (SLF-I) and negatively associated with mean diffusivity (MD) and radial diffusivity (RD) of the right SLF-I (p ≤ 0.01). Peak exercise SaO 2 were positively associated with mean FA of the left CST and were negatively associated with mean RD of the left CST, MD of the left frontopontine tract, MD, RD and axial diffusivity (AD) of the right SLF-I, RD of the left SLF-II, MD, RD and AD of the right SLF-II, and MD and RD of the right SLF-III (p ≤ 0.01). Percent predicted VO 2 was positively associated with FA of the left uncinate fasciculus (p < 0.01). Negative associations were identified between mean FA of the right arcuate fasciculus, right SLF-II and right SLF-III and processing speed (p ≤ 0.01). No significant associations were identified between DTI-based metrics and attention., Conclusion: Chronic hypoxemia may have long-term detrimental impact on white matter microstructure in people living with a Fontan circulation. Paradoxical associations between processing speed and tract-specific DTI metrics could be suggestive of compensatory white matter remodeling. Longitudinal investigations focused on the mechanisms and trajectory of altered white matter microstructure and associated cognitive dysfunction in people with a Fontan circulation are required to better understand causal associations., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: Previous studies investigating risk factors associated with reoperation or mortality after repair of complete atrioventricular septal defect (CAVSD) often have not included sizeable cohorts undergoing modified single-patch repair. Both double patch and modified single-patch techniques have been widely used in Australia since the 1990s. Using a large multi-institutional cohort, we aimed to identify risk factors associated with reoperation or mortality following CAVSD repair., Methods: Between January 1990 and December 2015, a total of 829 patients underwent biventricular surgical repair of CAVSD in Australia at 4 centres. Patients with associated tetralogy of Fallot and other conotruncal abnormalities were excluded. Demographic details, postoperative outcomes including reoperation and survival, and associated risk factors were analysed., Results: Fifty-six patients (6.8%) required early reoperation (≤30 days) for significant left atrioventricular valve regurgitation or residual septal defects. Freedom from reoperation at 10, 15 and 20 years was 82.7%, 81.1% and 77%, respectively. Patients without Down syndrome and moderate left atrioventricular valve regurgitation on postoperative echocardiogram were found to be independent risk factors for reoperation. Operative mortality was 3.3%. Overall survival at 10, 15 and 20 years was 91.7%, 90.7% and 88.7%, respectively. Prior pulmonary artery banding was a predictor for mortality, while later surgical era (2010-2015) was associated with a reduction in mortality risk., Conclusions: Improved survival in the contemporary era is in keeping with improvements in surgical management and higher rates of primary CAVSD repair over time. The presence of residual moderate left atrioventricular valve regurgitation on postoperative echocardiography is an important factor associated with reoperation and close surveillance is essential to allow timely reintervention. Primary CAVSD repair at age <3 months should be preferenced to palliation with pulmonary artery banding due to the association of pulmonary artery banding with mortality in the long-term., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Objective: To study the outcomes of a novel modified pulmonary artery banding (mPAB) technique used for staged repair of a subset of patients with complex transposition physiology., Methods: A total of 13 patients who underwent mPAB during their staged repair (biventricular repair [BVR], n = 6) or palliation (1-1/2 repair, n = 1; univentricular repair [UVR], n = 6) from 2004 to 2020 were studied retrospectively. A restrictive interposition graft was used to reconstruct the main PA between the pulmonary root and the distal pulmonary confluence, functioning as a mPAB. Twelve of the 13 patients (92.3%) underwent a concurrent arterial switch operation (ASO), of which 6 were palliative ASOs for 1-1/2 repair (n = 1) or UVR (n = 5). Patient weight and cardiac anatomy determined the size of interposition graft., Results: The disease spectrum included dextro transposition of the great arteries (d-TGA) with multiple ventricular septal defects (VSDs) (n = 4), Taussig-Bing anomaly (n = 3), d-TGA with VSD and hypoplastic right ventricle (RV) (n = 3), double-inlet left ventricle with l-TGA (n = 2), and congenitally corrected TGA with double-outlet RV (n = 1). The Lecompte procedure was performed in 10 patients. Predischarge echocardiography revealed a band gradient of 61 mm Hg (interquartile range [IQR], 40-90 mm Hg) for BVR/1-1/2 ventricular repair (n = 7) and 49 mm Hg (IQR, 37-61 mm Hg) for UVR (n = 6). Survival was 100% at a median follow-up of 3.7 years (IQR, 2.6-4.0 years)., Conclusions: The mPAB technique is effective and reproducible for staged BVR or UVR for patients with TGA. It effectively regulates pulmonary blood flow, may reduce neopulmonary root distortion, and eliminates complications associated with band migration in standard PAB., (© 2021 The Author(s).)

Background: Neurocognitive outcomes beyond childhood in people with a Fontan circulation are not well defined. This study aimed to investigate neurocognitive functioning in adolescents and adults with a Fontan circulation and associations with structural brain injury, brain volumetry, and postnatal clinical factors., Methods: In a binational study, participants with a Fontan circulation without a preexisting major neurological disability were prospectively recruited from the Australia and New Zealand Fontan Registry. Neurocognitive function was assessed by using Cogstate software in 107 participants with a Fontan circulation and compared with control groups with transposition of the great arteries (n=50) and a normal circulation (n=41). Brain MRI with volumetric analysis was performed in the participants with a Fontan circulation and compared with healthy control data from the ABIDE I and II (Autism Brain Imaging Data Exchange) and PING (Pediatric Imaging, Neurocognition, and Genetics) data repositories. Clinical data were retrospectively collected., Results: Of the participants with a Fontan circulation who had a neurocognitive assessment, 55% were male and the mean age was 22.6 years (SD 7.8). Participants with a Fontan circulation performed worse in several areas of neurocognitive function compared with those with transposition of the great arteries and healthy controls ( P <0.05). Clinical factors associated with worse neurocognitive outcomes included more inpatient days during childhood, younger age at Fontan surgery, and longer time since Fontan procedure ( P <0.05). Adults with a Fontan circulation had more marked neurocognitive dysfunction than adolescents with a Fontan circulation in 2 domains (psychomotor function, P =0.01 and working memory, P =0.02). Structural brain injury was present in the entire Fontan cohort; the presence of white matter injury was associated with worse paired associate learning ( P <0.001), but neither the presence nor severity of infarct, subcortical gray matter injury, and microhemorrhage was associated with neurocognitive outcomes. Compared with healthy controls, people with a Fontan circulation had smaller global brain volumes ( P <0.001 in all regions) and smaller regional brain volumes in most cerebral cortical regions ( P <0.05). Smaller global brain volumes were associated with worse neurocognitive functioning in several domains ( P <0.05). A significant positive association was also identified between global brain volumes and resting oxygen saturations ( P ≤0.04)., Conclusions: Neurocognitive impairment is common in adolescents and adults with a Fontan circulation and is associated with smaller gray and white matter brain volume. Understanding modifiable factors that contribute to brain injury to optimize neurocognitive function is paramount.

Objective: Fontan takedown remains an option for the management of Fontan failure. We sought to evaluate early and late outcomes after Fontan takedown., Methods: The Australia and New Zealand Fontan Registry was interrogated to identify all patients who had a Fontan takedown., Results: Over a 43-year study period (1975-2018), 36 of 1540 (2.3%) had a Fontan takedown. The median age at takedown was 5.1 years (interquartile range [IQR], 3.7, 7.0). Nine (25%) patients had a takedown within 48 hours, 6 (16%) between 2 days and 3 weeks, 14 (39%) between 3 weeks and 6 months, whereas 7 (19%) had a late takedown (>6 months). Median interval to takedown was 26 days (IQR, 1.5, 127.5). Sixteen (44%) patients died at a median of 57.5 days (IQR, 21.8, 76.8). The greatest mortality occurred between 3 weeks and 6 months (<2 days: 1/9, 11%; 2 days to 3 weeks: 2/6, 33%; 3 weeks to 6 months: 11/14, 79%; >6 months: 2/7, 28%; P = .007). At median follow-up of 9.4 years (IQR, 4.5, 15.3), 11 (31%) patients were alive with an intermediate circulation (10 in New York Heart Association class I/II). Five (14%) patients underwent a successful second Fontan. Freedom from death/transplant after Fontan takedown was 59%, 56%, and 52% at 1, 5, and 10 years, respectively., Conclusions: The incidence of Fontan takedown is low, but mortality is high. The majority of takedowns occurred within 6 months. Mortality was lowest when takedown occurred <2 days and highest between 3 weeks and 6 months. A second Fontan is possible in a small proportion of survivors., (Crown Copyright © 2020. Published by Elsevier Inc. All rights reserved.)

Background: Surgery is the cornerstone of treatment for single-ventricle patients, but life just begins for most when the staged procedures are completed. A package of care, including primary care, out-of-hospital specialist visits, and medication, is required for patients living with Fontan. This study quantified the current state of out-of-hospital health care use across childhood for Fontan patients using evidence from Australia., Methods: Patients recruited from the Fontan Registry were linked with the administrative Medicare (universal health insurance) data. Frequency of medical and pharmaceutical care and costs were estimated., Results: Data for 115 patients with 12,726 medical and 8,336 pharmaceutical claims were obtained. From age 0 to 20 years, patients on average visited a general practitioner an estimated 6.4 times per year (95% confidence interval [CI], 5.9-7.0 times per year), and specialists, including cardiologists, 2.8 times per year (95% CI, 2.5-3.0 times per year). Average use of allied health professional care peaked at age 6 to 9 years (1.0 visits per year; 95% CI, 0.7-1.4 visits per year) with psychologic services being most prominent. For pharmaceuticals, an average of 13.3 prescriptions filled per patient per year throughout childhood was observed (95% CI, 12.4-14.2 prescriptions per year). Overall, out-of-hospital doctor visits of all types averaged 11 visits per year from birth to 20 years. A decline in care was observed when patients reached 18 years across services., Conclusions: Patterns of out-of-hospital health care use were observed; however, current guidelines are silent about whether this is optimal. Further research is needed to better understand the comprehensive needs of this population., (Copyright © 2020 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Heterotaxy is considered a risk factor for poor outcomes after the Fontan operation. However, long-term data to support this notion are lacking. The aims of this study were to ascertain the long-term outcomes of patients with heterotaxy after hospital discharge after Fontan completion and to compare these outcomes with those of a contemporary nonheterotaxy cohort., Methods: A binational Fontan registry (n = 1540) was analyzed to identify patients with heterotaxy and compare them with patients without heterotaxy. The primary composite end point was Fontan failure, encompassing death, heart transplantation, Fontan takedown or conversion, protein-losing enteropathy, plastic bronchitis, or New York Heart Association functional class III or IV., Results: A total of 109 patients with heterotaxy were identified and they were compared with 1431 nonheterotaxy patients after Fontan completion. There was no difference in unadjusted 15-year freedom from Fontan failure (heterotaxy, 78% vs nonheterotaxy, 85%; P = .2). Patients in the heterotaxy group had a significantly higher cumulative incidence of post-Fontan arrhythmias (P < .001). Propensity-score matching for confounders yielded 73 patients with heterotaxy matched with 439 patients without heterotaxy, in whom 15-year freedom from Fontan failure was also not different (heterotaxy, 76% vs nonheterotaxy, 81%; P = .2). There was no difference in 15-year freedom from Fontan failure in patients with right vs left isomerism (right isomerism, 80% vs left isomerism, 76%; P = .7)., Conclusions: Although heterotaxy may complicate the pre-Fontan course, once the Fontan procedure is successfully completed, heterotaxy does not appear to be an important risk factor for Fontan failure. Patients with heterotaxy are at a higher risk of post-Fontan arrhythmias compared with patients without heterotaxy., (Copyright © 2020 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Heterotaxy is considered a risk factor for adverse events at all stages in the pre-Fontan pathway, and Fontan outcomes are expected to be worse in patients with heterotaxy. The aim of this study was to review existing literature reporting outcomes of the Fontan operation systematically in patients with heterotaxy., Methods: A systematic review and meta-analysis was performed to identify and synthesize early mortality and medium- and long-term survival in heterotaxy patients after the Fontan procedure. Subsequent outcome analyses were stratified by study period era, cohort size, and proportion of right versus left atrial isomerism to explore predictors of outcome., Results: A total of 21 studies were included for analysis, which were composed of 848 post-Fontan heterotaxy patients. Early mortality varied between 1% and 30% with a weighted event rate of 14% (95% confidence interval [CI], 10%-19%). Survival at 1, 5, and 10 years was 86% (95% CI, 79%-91%), 80% (95% CI, 71%-87%), and 74% (95% CI, 59%-85%), respectively. Stratification by study period highlighted that studies with a median study period year of 1995 or later had similar early mortality and 1- and 5-year survival, but superior 10-year survival (P = .02) compared with earlier studies. Stratification by cohort size and right versus left atrial isomerism did not reveal subgroup differences., Conclusions: Compared with existing literature, in patients with heterotaxy, early mortality after Fontan is higher than for the overall Fontan population. Long-term survival is comparable to the overall Fontan cohort. When heterotaxy patients are successfully transitioned to Fontan, subsequent survival is acceptable and predictable. Long-term follow-up is lacking., (Copyright © 2020 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Objectives: Atrioventricular valve regurgitation is known to adversely impact outcomes of single-ventricle palliation, and valve repair rarely provides long-lasting results. Closure of a atrioventricular valve can sometimes be performed, but the long-term outcomes of this manoeuvre are unknown., Methods: This retrospective study was conducted using patient data extracted from an existing bi-national, population-based registry of survivors of the Fontan procedure., Results: Between January 1975 and June 2018, 1574 patients survived to hospital discharge with an intact Fontan circulation. Of these patients, 128 with a common atrioventricular valve were excluded. Thirty-eight patients underwent closure of an atrioventricular valve, and complete follow-up data were available for 36 patients. Twenty-nine patients underwent closure of the tricuspid valve and 7 patients underwent closure of the mitral valve. Seventeen patients underwent valve closure prior to Fontan, 13 patients underwent valve closure concomitant with Fontan and 6 patients underwent valve closure post-Fontan. Valve closure was performed using a patch technique in 29 cases and with direct suture in 7 cases. At the most recent echocardiography, 33 patients had no regurgitation, 2 patients had recurrent mild regurgitation and 1 patient had no echocardiographic follow-up. Six patients required reintervention post-valve closure and 7 patients required permanent pacemaker insertion post-valve closure. Freedom from reintervention at 1, 5 and 18 years post-valve closure was 86% [95% confidence interval (CI) 76-98%], 83% (95% CI 72-96%) and 83% (95% CI 72-96%), respectively., Conclusion: Atrioventricular valve closure is an effective surgical technique in selected patients with a single ventricle providing long-lasting competency in the majority of cases., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Background People with a Fontan circulation experience a range of physical, psychosocial and neurodevelopmental challenges alongside, or caused by, their cardiac condition, with significant consequences for health-related quality of life (HRQOL). We meta-analyzed HRQOL outcomes reported by people with a Fontan circulation or their proxies and evaluated predictors of poorer HRQOL. Methods and Results Six electronic databases were searched for peer-reviewed, English-language articles published before March 2019. Standardized mean differences (SMD) were calculated using fixed and random-effects models. Fifty articles reporting on 29 unique studies capturing HRQOL outcomes for 2793 people with a Fontan circulation and 1437 parent-proxies were analyzed. HRQOL was lower in individuals with a Fontan circulation compared with healthy referents or normative samples (SMD, -0.92; 95% CI, -1.36 to -0.48; P <0.001). Lower scores were reported across all HRQOL domains, with the largest differences found for physical (SMD, -0.90; 95% CI, -1.13 to -0.67; P <0.001) and school/work functioning (SMD, -0.71; 95% CI, -0.90 to -0.52; P <0.001). Meta-regression analyses found no significant predictors of self-reported physical functioning, but older age at Fontan operation was associated with poorer emotional functioning (β=-0.124; P =0.004), and diagnosis of hypoplastic left heart was associated with poorer social functioning (β=-0.007; P =0.048). Sensitivity analyses showed use of the PedsQL Core Module was associated with lower HRQOL scores compared with the Short-Form Health Survey-36. Conclusions HRQOL outcomes for people with a Fontan circulation are lower than the general population. Optimal care acknowledges the lifelong impact of the Fontan circulation on HRQOL and offers targeted strategies to improve outcomes for this growing population.

Objectives: Right ventricle to pulmonary artery (RV-PA) conduits are required for the surgical management of pulmonary atresia with ventricular septal defect and truncus arteriosus. Bioengineered RV-PA connections may address some of the shortcomings of homografts and xenografts, such as lack of growth potential and structural deterioration and may be manufactured to accommodate patient-specific anatomy. The aim of this study was to develop a methodology for in silico patient-specific design and analysis of RV-PA conduits., Methods: Cross-sectional imaging was obtained from patients with truncus arteriosus (n = 5) and pulmonary atresia with ventricular septal defect (n = 5) who underwent complete repair with a RV-PA conduit. Three-dimensional models of the heart were constructed by segmentation of the right ventricle, existing conduit, branch pulmonary arteries, and surrounding structures. A customized conduit design for each patient was proposed. Computational fluid dynamics analysis was performed and outputs, including wall shear stress and energy loss, were used to compare the performance of the existing conduits and the customized geometries., Results: In this study, a methodology for patient-specific analysis of RV-PA conduit in silico was developed. The results of simulations for 10 patients showed between 23% and 56% decrease in the average wall shear stress and between 24% and 87% reduction in average power requirements in customized designs compared with the stenosed conduits, translating into better hemodynamic performance., Conclusions: Creation of an optimal conduit for an individual patient can be achieved using surgeon-guided design and computational fluid dynamics analysis. Manufacture of personalized RV-PA conduits may obviate the need for surgical customization to accommodate existing materials and provide superior long-term outcomes., (© 2020 by The Authors. Published by Elsevier Inc. on behalf of The American Association for Thoracic Surgery.)

Congenital heart disease (CHD) is the most common birth defect and brings with it significant mortality and morbidity. The application of exome and genome sequencing has greatly improved the rate of genetic diagnosis for CHD but the cause in the majority of cases remains uncertain. It is clear that genetics, as well as environmental influences, play roles in the aetiology of CHD. Here we address both these aspects of causation with respect to the Notch signalling pathway. In our CHD cohort, variants in core Notch pathway genes account for 20% of those that cause disease, a rate that did not increase with the inclusion of genes of the broader Notch pathway and its regulators. This is reinforced by case-control burden analysis where variants in Notch pathway genes are enriched in CHD patients. This enrichment is due to variation in NOTCH1. Functional analysis of some novel missense NOTCH1 and DLL4 variants in cultured cells demonstrate reduced signalling activity, allowing variant reclassification. Although loss-of-function variants in DLL4 are known to cause Adams-Oliver syndrome, this is the first report of a hypomorphic DLL4 allele as a cause of isolated CHD. Finally, we demonstrate a gene-environment interaction in mouse embryos between Notch1 heterozygosity and low oxygen- or anti-arrhythmic drug-induced gestational hypoxia, resulting in an increased incidence of heart defects. This implies that exposure to environmental insults such as hypoxia could explain variable expressivity and penetrance of observed CHD in families carrying Notch pathway variants., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Objectives: To evaluate whether the long-term outcomes of modified-single-patch (MSP) repair of complete atrioventricular septal defect are equivalent to double-patch (DP) repair with respect to survival and risk of reoperation for left atrioventricular valve regurgitation or left ventricular outflow tract obstruction., Methods: All patients who underwent biventricular repair of complete atrioventricular septal defect in Australia from 1990 to 2015 using either a MSP or DP technique were identified. Demographic characteristic details, operative data, and outcomes were analyzed. A propensity score analysis was performed to balance the 2 treatment groups according to several baseline covariates. Survival and freedom from reintervention between the 2 groups were compared using Kaplan-Meier curves and log-rank tests., Results: A total of 819 patients underwent repair of complete atrioventricular septal defect (252 MSP and 567 DP) during the study period. There was no significant difference in unmatched survival (P = .85) and event-free survival (P = .49) between MSP and DP repair. Propensity score matching resulted in a total of 223 matched pairs. Matched analysis found no difference in overall survival (P = .59) or event-free survival (P = .90) between repair techniques, with an estimated event-free survival at 5, 10, and 15 years of 83%, 83%, and 74% for DP and 83%, 80%, and 77% for the MSP group, respectively. There was no significant difference between repair techniques in reoperation for left atrioventricular valve regurgitation or left ventricular outflow tract obstruction or need for permanent pacemaker., Conclusions: Overall and event free survival are similar following either MSP or DP repair of complete atrioventricular septal defect. There is no increased risk of reoperation for left ventricular outflow tract obstruction with the MSP technique., (Crown Copyright © 2019. Published by Elsevier Inc. All rights reserved.)

Valvular heart diseases (VHD) are a major health burden, affecting millions of people worldwide. The treatments for such diseases rely on medicine, valve repair, and artificial heart valves including mechanical and bioprosthetic valves. Yet, there are countless reports on possible alternatives noting long-term stability and biocompatibility issues and highlighting the need for fabrication of more durable and effective replacements. This review discusses the current and potential materials that can be used for developing such valves along with existing and developing fabrication methods. With this perspective, we quantitatively compare mechanical properties of various materials that are currently used or proposed for heart valves along with their fabrication processes to identify challenges we face in creating new materials and manufacturing techniques to better mimick ​the performance of native heart valves., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this article., (© 2019 The Authors.)

Objectives: Patients with hypoplastic left heart syndrome are at high risk of late adverse events after Fontan completion, but it is unclear whether their morphological characteristics influence these outcomes., Methods: Retrospective review of the data from the Australian and New Zealand Fontan Registry identified 185 patients with hypoplastic left heart syndrome who survived to hospital discharge after Fontan completion. Their outcomes were reviewed to identify predictors of adverse events with a particular focus on the impact of morphological characteristics. All available echocardiographic parameters were collected, and the hypoplasia of the left ventricle was subjectively considered to be mild, moderate or severe., Results: The mean follow-up after the Fontan procedure was 6.4 ± 4.7 years. The median age at Fontan procedure was 4.41 years, 95% (176/185) of patients underwent an extracardiac conduit Fontan procedure and 71% (132/185) of those were fenestrated. At 15 years after Fontan, freedom from death and cardiac transplantation was 90% [95% confidence interval (CI) 85-97], freedom from Fontan failure was 78% (95% CI 70-87) and freedom from adverse events was 32% (95% CI 22-46). Morphological parameters did not influence transplant-free survival or Fontan failure. Independent risk factors predicting higher incidence of adverse events included aortic atresia (P = 0.003)., Conclusions: The long-term survival of Fontan survivors with hypoplastic left heart syndrome is excellent and appears comparable to that of the general Fontan population. However, intrinsic morphological characteristics may continue to burden patients with late morbidity., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)