Cognitive Functioning and Psychosocial Outcomes in Adults with Complex Congenital Heart Disease: A Cross-sectional Pilot Study.

Adults with complex congenital heart disease (CHD) are at risk for cognitive dysfunction. However, associations between cognitive dysfunction and psychosocial outcomes are poorly defined. Between June and November 2022, we prospectively recruited 39 adults with complex CHD who completed a computerized cognitive assessment (Cogstate) and validated psychosocial scales measuring psychological distress, health-related quality of life (HRQOL), and resilience. Participants had a mean age of 36.4 ± 11.2 years. Over half (62%) were women, most (79%) had complex biventricular CHD, and 21% had Fontan physiology. Prevalence of cognitive dysfunction was greatest in the domains of attention (29%), working memory (25%), and psychomotor speed (21%). Adjusting for age and sex, Pearson partial correlations between Cogstate z-scores and self-reported cognitive problems were small. Participants who lived in the most disadvantaged areas and those with a below-average annual household income had lower global cognitive z-scores (p = 0.02 and p = 0.03, respectively). Two-thirds (64%) reported elevated symptoms of depression, anxiety, and/or stress. Small correlations were observed between psychological distress and cognitive performance. Greater resilience was associated with lower psychological distress (r ≥ -0.5, p < 0.001) and higher HRQOL (r = 0.33, p = 0.02). Our findings demonstrate that adults with complex CHD have a high risk of cognitive dysfunction, though may not recognize or report their cognitive challenges. Lower socioeconomic status may be an indicator for those at risk of poorer cognitive functioning. Psychological distress is common though may not be a strong correlate of performance-based cognitive functioning. Formal cognitive evaluation in this patient population is essential. Optimizing resilience may be a protective strategy to minimize psychological distress and bolster HRQOL.

Biological and structural phenotypes associated with neurodevelopmental outcomes in congenital heart disease.

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.

A diffusion MRI study of brain white matter microstructure in adolescents and adults with a Fontan circulation: Investigating associations with resting and peak exercise oxygen saturations and cognition.

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 (SaO2), predicted maximal oxygen uptake during exercise (% pred VO2), 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 SaO2 and % pred VO2 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 SaO2 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 SaO2 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 SaO2 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 VO2 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.

Exercise Intolerance, Benefits, and Prescription for People Living With a Fontan Circulation: The Fontan Fitness Intervention Trial (F-FIT)-Rationale and Design.

Background: Despite developments in surgical techniques and medical care, people with a Fontan circulation still experience long-term complications; non-invasive therapies to optimize the circulation have not been established. Exercise intolerance affects the majority of the population and is associated with worse prognosis. Historically, people living with a Fontan circulation were advised to avoid physical activity, but a small number of heterogenous, predominantly uncontrolled studies have shown that exercise training is safe-and for unique reasons, may even be of heightened importance in the setting of Fontan physiology. The mechanisms underlying improvements in aerobic exercise capacity and the effects of exercise training on circulatory and end-organ function remain incompletely understood. Furthermore, the optimal methods of exercise prescription are poorly characterized. This highlights the need for large, well-designed, multi-center, randomized, controlled trials. Aims and Methods: The Fontan Fitness Intervention Trial (F-FIT)-a phase III clinical trial-aims to optimize exercise prescription and delivery in people with a Fontan circulation. In this multi-center, randomized, controlled study, eligible Fontan participants will be randomized to either a 4-month supervised aerobic and resistance exercise training program of moderate-to-vigorous intensity followed by an 8-month maintenance phase; or usual care (control group). Adolescent and adult (≥16 years) Fontan participants will be randomized to either traditional face-to-face exercise training, telehealth exercise training, or usual care in a three-arm trial with an allocation of 2:2:1 (traditional:telehealth:control). Children (<16 years) will be randomized to either a physical activity and exercise program of moderate-to-vigorous intensity or usual care in a two-arm trial with a 1:1 allocation. The primary outcome is a change in aerobic exercise capacity (peak oxygen uptake) at 4-months. Secondary outcomes include safety, and changes in cardiopulmonary exercise testing measures, peripheral venous pressure, respiratory muscle and lung function, body composition, liver stiffness, neuropsychological and neurocognitive function, physical activity levels, dietary and nutritional status, vascular function, neurohormonal activation, metabolites, cardiac function, quality of life, musculoskeletal fitness, and health care utilization. Outcome measures will be assessed at baseline, 4-months, and 12-months. This manuscript will describe the pathophysiology of exercise intolerance in the Fontan circulation and the rationale and protocol for the F-FIT.

Neurocognitive Dysfunction and Smaller Brain Volumes in Adolescents and Adults With a Fontan Circulation.

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.

Body Composition in Young Adults Living With a Fontan Circulation: The Myopenic Profile.

Background We sought to characterize body composition abnormalities in young patients living with a Fontan circulation and explore potential pathophysiologic associations. Methods and Results Twenty-eight patients with a Fontan circulation were prospectively recruited in this cross-sectional study. Participants underwent cardiopulmonary exercise testing, dual-energy X-ray absorptiometry, echocardiography, and biochemical assessment. Mean age was 26±7 years. Skeletal muscle mass, estimated by appendicular lean mass index Z score, was reduced compared with reference data (-1.49±1.10, P<0.001). Percentage body fat Z score overall was within normal range (0.23±1.26, P=0.35), although 46% had elevated adiposity. Those with reduced skeletal muscle mass (appendicular lean mass index Z score of -1 or lower) had lower percent predicted oxygen pulse (55±15 versus 76±16%, P=0.002). Overall agreement between body mass index and dual-energy X-ray absorptiometry to assess adiposity was fair only (weighted [linear] κ coefficient: 0.53; 95% CI, 0.34-0.73) and slight in the setting of muscle mass deficiency (weighted κ coefficient: 0.32; 95% CI, 0.13-0.50). Appendicular lean mass was independently associated with absolute peak VO2 (ß=70.6 mL/min, P=0.001). Appendicular lean mass index Z score was inversely associated with hemoglobin (r=-0.4, P=0.04), and the degree of muscle deficit was associated with ventricular systolic impairment. Conclusions Young patients with a Fontan circulation have a body composition characterized by reduced skeletal muscle mass, which is associated with peak exercise capacity. Increased adiposity is common despite a normal body mass index. Low skeletal muscle mass is associated with systolic dysfunction and compensatory erythrocytosis.

Long-term Out-of-Hospital Health Care Use for Fontan Survivors Across Childhood.

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.

"Why and how did this happen?": development and evaluation of an information resource for parents of children with CHD.

BACKGROUND: The causes of CHD are complex and often unknown, leading parents to ask how and why this has happened. Genetic counselling has been shown to benefit these parents by providing information and support; however, most parents currently do not receive this service. This study aimed to develop a brochure to determine whether an information resource could improve parents' knowledge about CHD causation and inheritance and increase psychosocial functioning. METHODS: In development, the resource was assessed against several readability scales and piloted. Parents of children attending preadmission clinic for surgery were included. Assessments occurred pre- and post-receiving the information resource using a purpose-designed knowledge measure and validated psychological measures. RESULTS: Participant's (n = 52) knowledge scores increased significantly from the pre-questionnaire ( ${\overline x}\, = \,5/10$ , sd = 2.086) to post-questionnaire ( $\overline x\, = \,7.88/10$ , sd = 2.094, p < 0.001), with all aware that CHD can be caused by genetic factors after reading the brochure. Perceived personal control also increased from pre- ( $\overline x\, = \,11.856/18$ , sd = 4.339) to post-brochure ( $\overline x\, = \,14.644/18$ , sd = 3.733, p < 0.001), and many reported reduced feelings of guilt. No negative emotional response to the brochure was reported. The information provided was considered relevant (88%), reassuring (86%), and 88% would recommend the brochure to other parents. However, some wanted more emotional support and assistance in what to tell their child. CONCLUSIONS: Use of the information resource significantly enhanced parents' knowledge of CHD causation and increased their psychosocial functioning. It is a valuable resource in the absence of genetic counselling; however, it should not replace formal genetic counselling when required.

Prevalence and risk factors for low bone density in adults with a Fontan circulation.

OBJECTIVE AND PATIENTS: This study aimed to characterize bone mineral density abnormalities and pathophysiological associations in young adults living with a Fontan circulation. DESIGN: Participants underwent bone mineral density measurement using dual-energy X-ray absorptiometry and serum biochemical analysis, cardiopulmonary exercise and strength testing and transthoracic echocardiography. RESULTS: In our cohort (n = 28), 29% had osteopenic-range bone mineral density and one patient was osteoporotic (average hip t score: -0.6 ± 1.1; spine t score: -0.6 ± 0.9). Four patients (14%) had z scores < -2.0. Parathyroid hormone levels were increased compared with laboratory median (6.1 ± 3.5 vs 4 pmol/L, P = .01) and 27% had 25-hydroxy-vitamin D < 50 nmol/L. 25-hydroxy-vitamin D negatively correlated with parathyroid hormone (ρ = -0.53, P = .01) suggesting secondary hyperparathyroidism. Atrioventricular valve systolic to diastolic duration ratio, an echocardiographic measure of diastolic dysfunction, inversely correlated with hip t and z scores (P < .01). Hip t scores were positively associated with oxygen saturations (ρ = 0.45, P = .05) and tended to be inversely associated with parathyroid hormone levels (ρ = -0.44, P = .07) and N-Terminal pro b-type natriuretic peptide (ρ = -0.42, P = .08). CONCLUSIONS: Many young adults with a Fontan circulation have abnormal bone mineral density. The underlying pathophysiology is likely multifactorial. Possible contributors include secondary hyperparathyroidism, hypoxemia, diastolic cardiac dysfunction and neurohormonal activation. As low bone mineral density is clinically relevant and potentially treatable, assessment of bone mineral density should be part of routine care in this cohort.

'Big issues' in neurodevelopment for children and adults with congenital heart disease.

It is established that neurodevelopmental disability (NDD) is common in neonates undergoing complex surgery for congenital heart disease (CHD); however, the trajectory of disability over the lifetime of individuals with CHD is unknown. Several 'big issues' remain undetermined and further research is needed in order to optimise patient care and service delivery, to assess the efficacy of intervention strategies and to promote best outcomes in individuals of all ages with CHD. This review article discusses 'gaps' in our knowledge of NDD in CHD and proposes future directions.

Two Ventricles Are Not Better Than One in the Fontan Circulation: Equivalent Late Outcomes.

BACKGROUND: A subset of patients who underwent Fontan operations has two adequate-sized ventricles, but an anatomic biventricular circulation cannot be achieved because of complex morphology or for technical reasons. This study sought to determine whether these patients with two-ventricle Fontan circulation had superior outcomes compared with those with a single ventricle. METHODS: A binational Fontan Registry of patients (n = 1,377) was analyzed to identify those patients with two adequate ventricles. This cohort was compared with patients with single-ventricle Fontan circulation. The primary end point was a composite end point called "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 79 Fontan patients with two adequate ventricles (2V) were compared with 1,291 single ventricle (1V) Fontan patients. Median follow-up for the entire cohort was 11.5 years (interquartile range, 5.1 to 18.8 years). There was no difference in unadjusted 15-year freedom from Fontan failure (2V: 81% [95% confidence interval (CI), 69% to 94%] vs 1V: 86% [95% CI, 83% to 88%], p = 0.4). Propensity-score matching for potential confounding factors yielded 75 two-ventricle Fontan patients matched with 604 single-ventricle Fontan patients, in which 15-year freedom from Fontan failure was also not different (2V: 79% [95% CI, 67% to 94%] vs 1V: 87% [95% CI, 84% to 91%], p = 0.3). CONCLUSIONS: The two-ventricle Fontan circulation does not have better outcomes compared with the single-ventricle Fontan circulation. Late outcomes may depend more on other characteristics of the Fontan circulation. This finding is relevant when the Fontan procedure is being considered as an alternative to anatomic repair in patients with complex two-ventricle morphologies.

Contemporary incidence of stroke (focal infarct and/or haemorrhage) determined by neuroimaging and neurodevelopmental disability at 12 months of age in neonates undergoing cardiac surgery utilizing cardiopulmonary bypass.

OBJECTIVES: When evaluated prospectively, acute brain injury is reported in up to 75% of neonates undergoing cardiopulmonary bypass (CPB), predominantly white matter injury rather than stroke. This study investigates the incidence of stroke (focal infarct and/or haemorrhage) detected by neuroimaging in contemporary clinical practice, whereby magnetic resonance imaging/computed tomography routinely occurs in response to clinical events, comparing those undergoing the Norwood procedure with those undergoing other neonatal procedures involving CPB, and defines the relationship between stroke and neurodevelopmental disability (NDD) at 12 months of age. METHODS: One hundred and twenty neonates underwent CPB between July 2011 and December 2014: 25 Norwood procedures and 95 non-Norwood procedures. Data were retrospectively collected including clinical data and 12-month neurodevelopmental assessment using the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III). RESULTS: Stroke was detected in 12% of neonates in current clinical practice: 24% of the Norwood group vs 8% of the non-Norwood group (P = 0.03). Significant predictors of stroke in the univariate analysis included the Norwood procedure, lowest operative temperature and use of extracorporeal membrane oxygenation (P < 0.05). The lowest operative temperature and use of extracorporeal membrane oxygenation remained significant in the multivariate analysis (P < 0.05). Fifty-seven percent were assessed using the BSID-III assessment, and 68% demonstrated NDD in at least 1 subscale. In neonates who suffered stroke, the incidence of NDD was significantly greater in 4/5 subscales compared with those with no injury (P < 0.05). The Norwood group had a significantly greater incidence of NDD in 2/5 subscales when compared with the non-Norwood group (P < 0.05). CONCLUSIONS: Stroke, established by neuroimaging in contemporary clinical practice, was detected in 12% of neonates having CPB, and those undergoing the Norwood procedure have a 3-fold risk of injury. Stroke was associated with NDD at 12 months of age.

Neonatal Ebstein Anomaly: A 30-year Institutional Review.

This study aimed to review our 30-year, single-center experience of neonates admitted with Ebstein anomaly. Between January 1985 and August 2015, 80 neonates with Ebstein anomaly were managed. The primary outcome measures were early and late survival, freedom from reoperation, and functional status. Pulmonary atresia or critical stenosis occurred in 18 neonates. Twenty-seven (34%) patients required intervention: 13 systemic-to-pulmonary shunts, 5 balloon pulmonary valvotomy, 3 relief of right ventricular outflow tract obstruction, 3 Starnes procedures, and 3 other procedures. Sixty-nine (86%) of the neonates survived to hospital discharge. Overall 15-year survival estimate was 67% (SE = 6.5), with a superior prognosis for those able to be managed medically (15-year survival of 79%, SE = 7.0) compared with those in whom surgical or catheter intervention was undertaken (15-year survival of 45%, SE = 11.2, P = 0.005). For early survivors of neonatal surgery, freedom from reoperation at 10 years was 16% (SE = 8.5). For long-term survivors, 96% were classified as New York Heart Association Class I or II. Neonates with Ebstein anomaly who can be managed without intervention have a good prognosis. Substantial mortality risk remains in those who require intervention, especially those complicated by pulmonary atresia.

Improved long-term outcomes in double-inlet left ventricle and tricuspid atresia with transposed great arteries: systemic outflow tract obstruction present at birth defines long-term outcome.

OBJECTIVES: In 2 subtypes of functional single ventricle, double inlet left ventricle (DILV) and tricuspid atresia with transposed great arteries (TA-TGA), systemic output passes through an outflow chamber before entering the aorta. Intracardiac obstruction to this pathway causing systemic outflow tract obstruction (SOTO) may be present at birth or develop over time. Long-term survival after Fontan has not been defined. We defined outcomes utilizing records from 2 centres that were cross-checked with data from a bi-national Fontan Registry for completeness and accuracy. METHODS: Two hundred and eleven patients were identified, 59 TA-TGA,152 DILV. Median follow-up was 17 years (range 4 days to 49.8 years). The Kaplan-Meier method was used for all of the time to event analyses and the log-rank test was used to compare the time-to-events. Cox proportional hazard models were used to test the association between potential predictors and time-to-event end-points. RESULTS: TA-TGA had reduced survival compared to DILV (cumulative risk of death 28.8% vs 11%, hazard ratio (HR) 3.1 (95% confidence interval (CI) 1.6-6.1), P = 0.001). In both groups, SOTO at birth carried a worse prognosis HR 3.54 (1.36-9.2, P = 0.01). SOTO was not more common in either morphology at birth ( P = 0.20). Periprocedural mortality accounted for 40% of deaths. Fontan was achieved in 82%, DILV were more likely to achieve Fontan than TA-TGA (91% vs 60%, P <0.001). After Fontan there were 9 deaths (4%) with no difference according to morphology. CONCLUSIONS: Patients with TA-TGA have poorer outcomes than those with DILV, affecting survival and likelihood of achieving Fontan. SOTO at birth carries a high risk of mortality suggesting that, when present, initial surgical management should address this.