Single Ventricle Heart Disease Research Articles

Neurodevelopment in patients with repaired tetralogy of Fallot.

Neurodevelopmental sequelae are prevalent and debilitating for patients with congenital heart defects. Patients born with tetralogy of Fallot (TOF) are susceptible for abnormal neurodevelopment as they have several risk factors surrounding the perinatal and perioperative period. Some risk factors have been well described in other forms of congenital heart defects, including transposition of the great arteries and single ventricle heart disease, but they have been less studied in the growing population of survivors of TOF surgery, particularly in infancy and childhood. Adolescents with TOF, even without a genetic syndrome, exhibit neuro-cognitive deficits in executive function, visual-spatial skills, memory, attention, academic achievement, social cognition, and problem-solving, to mention a few. They also have greater prevalence of anxiety disorder, disruptive behavior and attention-deficit hyperactivity disorder. These deficits impact their academic performance, social adjustment, and quality of life, thus resulting in significant stress for patients and their families. Further, they can impact their social adjustment, employment and career development as an adult. Infants and younger children can also have significant deficits in gross and fine motor skills, cognitive deficits and abnormal receptive language. Many of the risk factors associated with abnormal neurodevelopment in these patients are not readily modifiable. Therefore, patients should be referred for evaluation and early intervention to help maximize their neurodevelopment and improve overall outcomes. More study is needed to identify potentially modifiable risk factors and/or mediators of neurodevelopment, such as environmental and socio-economic factors.

The Incidence and Relevance of Hematochezia in the Interstage Congenital Heart Population.

Necrotizing enterocolitis (NEC) increases morbidity and mortality for infants with single ventricle heart disease (SVHD). While hematochezia often proceeds NEC not all hematochezia progresses to NEC. We aimed to examine the incidence, risk-factors, and outcomes associated with hematochezia and NEC for infants with SVHD. A single-center cohort study including SVHD patients requiring Stage I palliation from 12/2010 to 12/2015 was performed. Demographic, clinical, and outcome measures during the interstage period were abstracted from medical records. We defined hematochezia as blood in the stool without alternative etiology and NEC as systemic or intestinal signs concurrent with hematochezia and/or the presence of radiographic pneumatosis. Clinical characteristics and outcome measures were compared between patients with/without hematochezia and with/without NEC. Of 135 patients, 59(44%) had hematochezia and 20(15%) developed NEC. Demographic and operative factors were similar between patients with and without hematochezia. Patients with NEC were more often premature (15% vs 0%, p = 0.04), have lower birth weight (3.0 ± 0.6 vs 3.3 ± 0.5kg, p = 0.03), longer cardiopulmonary bypass time (median 131 vs. 90min, p = 0.02) and more often underwent unplanned cardiac catheterization (20% vs 3%, p = 0.04). Patients with hematochezia had more line days (p < 0.0001) and longer post-Stage-I length of stay (p < 0.0001) than those without hematochezia, and those with NEC had more line days than those without NEC (p = 0.02). Hematochezia is frequent following Stage-I palliation, however only one third of these patients develop NEC. Non-NEC Hematochezia is associated with a similar increase in line and hospital days. Further research is needed to identify methods to avoid over treatment.

Risk Factors for Death or Transplant After Stage 2 Palliation for Single Ventricle Heart Disease

BackgroundFor infants with single ventricle heart disease, the time after stage 2 procedure (S2P) is believed to be a lower risk period compared with the interstage period; however, significant morbidity and mortality still occur. ObjectivesThis study aimed to identify risk factors for mortality or transplantation referral between S2P surgery and the first birthday. MethodsRetrospective cohort analysis of infants in the National Pediatric Cardiology Quality Improvement Collaborative who underwent staged single ventricle palliation from 2016 to 2022 and survived to S2P. Multivariable logistic regression and classification and regression trees were performed to identify risk factors for mortality and transplantation referral after S2P. ResultsOf the 1,455 patients in the cohort who survived to S2P, 5.2% died and 2.3% were referred for transplant. Overall event rates at 30 and 100 days after S2P were 2% and 5%, respectively. Independent risk factors for mortality and transplantation referral included the presence of a known genetic syndrome, shunt type at stage 1 procedure (S1P), tricuspid valve repair at S1P, longer time to extubation and reintubation after S1P, ≥ moderate tricuspid regurgitation prior to S2P, younger age at S2P, and the risk groups identified in the classification and regression tree analysis (extracorporeal membrane oxygenation after S1P and longer S2P cardiopulmonary bypass time without extracorporeal membrane oxygenation). ConclusionsMortality and transplantation referral rates after S2P to 1 year of age remain high ∼7%. Many of the identified risk factors after S2P are similar to those established for interstage factors around the S1P, whereas others may be unique to the period after S2P.

Arginine-NO metabolites are associated with morbidity in single ventricle infants undergoing stage 2 palliation.

Infants with single ventricle heart disease (SVHD) suffer morbidity from insufficient pulmonary blood flow, which may be related to impaired arginine metabolism. No prior study has reported quantitative mapping of arginine metabolites to evaluate the relationship between circulating metabolite levels and outcomes. Prospective cohort study of 75 SVHD cases peri-Stage 2 and 50 healthy controls. We targeted pre- and post-op absolute serum quantification of 9 key members of the arginine metabolism pathway by tandem mass spectrometry. Primary outcomes were length of stay (LOS) and post-Stage 2 hypoxemia. Pre-op cases showed alteration in 6 metabolites including decreased arginine and increased asymmetric dimethyl arginine (ADMA) levels compared to controls. Post-op cases demonstrated decreased arginine and citrulline levels persisting through 48 h. Adjusting for clinical variables, lower pre-op and 2 h post-op concentrations of multiple metabolites, including arginine and citrulline, were associated with longer post-op LOS (p < 0.01). Increased ADMA at 24 h was associated with greater post-op hypoxemia burden (p < 0.05). Arginine metabolism is impaired in interstage SVHD infants and is further deranged following Stage 2 palliation. Patients with greater metabolite alterations experience greater post-op morbidity. Decreased arginine metabolism may be an important driver of pathology in SVHD. Interstage infants with SVHD have significantly altered arginine-nitric oxide metabolism compared to healthy children with deficiency of multiple pathway intermediates persisting through 48 h post-Stage 2 palliation. After controlling for clinical covariates and classic catheterization-derived predictors of Stage 2 readiness, both lower pre-operation and lower post-operation circulating metabolite levels were associated with longer post-Stage 2 LOS while increased post-Stage 2 ADMA concentration was associated with greater post-op hypoxemia. Arginine metabolism mapping offers potential for development using personalized medicine strategies as a biomarker of Stage 2 readiness and therapeutic target to improve pulmonary vascular health in infants with SVHD.

Impact of Age-Related Change in Caval Flow Ratio on Hepatic Flow Distribution in the Fontan Circulation.

The Fontan operation is a palliative technique for patients born with single ventricle heart disease. The superior vena cava (SVC), inferior vena cava (IVC), and hepatic veins are connected to the pulmonary arteries in a total cavopulmonary connection by an extracardiac conduit or a lateral tunnel connection. A balanced hepatic flow distribution (HFD) to both lungs is essential to prevent pulmonary arteriovenous malformations and cyanosis. HFD is highly dependent on the local hemodynamics. The effect of age-related changes in caval inflows on HFD was evaluated using cardiac magnetic resonance data and patient-specific computational fluid dynamics modeling. SVC and IVC flow from 414 patients with Fontan were collected to establish a relationship between SVC:IVC flow ratio and age. Computational fluid dynamics modeling was performed in 60 (30 extracardiac and 30 lateral tunnel) patient models to quantify the HFD that corresponded to patient ages of 3, 8, and 15 years, respectively. SVC:IVC flow ratio inverted at ≈8 years of age, indicating a clear shift to lower body flow predominance. Our data showed that variation of HFD in response to age-related changes in caval inflows (SVC:IVC, 2, 1, and 0.5 corresponded to ages, 3, 8, and 15+, respectively) was not significant for extracardiac but statistically significant for lateral tunnel cohorts. For all 3 caval inflow ratios, a positive correlation existed between the IVC flow distribution to both the lungs and the HFD. However, as the SVC:IVC ratio changed from 2 to 0.5 (age, 3-15+) years, the correlation's strength decreased from 0.87 to 0.64, due to potential flow perturbation as IVC flow momentum increased. Our analysis provided quantitative insights into the impact of the changing caval inflows on Fontan's long-term HFD, highlighting the importance of SVC:IVC variations over time on Fontan's long-term hemodynamics. These findings broaden our understanding of Fontan hemodynamics and patient outcomes.

Epidemiology of Fontan-associated liver disease in Japan: Results from a nationwide survey in 2021.

Although the Fontan procedure has improved the survival of patients with single-ventricle heart disease, the long-term consequences of the procedure have been a concern. This study aimed to explore the patients' postoperative clinical characteristics, including a diagnosis of Fontan-associated liver disease (FALD). A nationwide Japanese epidemiological survey of post-Fontan patients was undertaken in 2021. The survey targets were selected from all departments of pediatrics, pediatric surgery, cardiology, cardiovascular surgery, and gastroenterology using stratified random sampling by the number of beds. Each department was asked to complete a mail-back questionnaire on the numbers of patients and their clinical characteristics. The diagnosis of FALD was made by each attending physician. The estimated number of post-Fontan patients was 7810 (95% confidence interval, 5430-10200) in 2020, with a period prevalence of 61.9 per million. During the follow-up of 13.8years after the Fontan procedure, 40% of patients were diagnosed with FALD. An elevated γ-glutamyl transpeptidase level was the most common finding leading to the FALD diagnosis (41%), and 45% of the patients also showed liver fibrosis. Compared with non-FALD patients, FALD patients were older, had longer duration since the Fontan procedure, and had more severe cardiac or liver conditions. However, more than half of the non-FALD patients had elevated liver enzyme levels, suggesting underestimation of the number of FALD patients. In 2020, approximately 40% of post-Fontan patients underwent follow-up with a diagnosis of FALD, although the lack of established diagnostic criteria for FALD could affect the reported prevalence of FALD.

Days alive and out of hospital for children born with single-ventricle heart disease.

This study describes the illness burden in the first year of life for children with single-ventricle heart disease, using the metric of days alive and out of hospital to characterize morbidity and mortality. This is a retrospective single-centre study of single-ventricle patients born between 2005 and 2021 who had their initial operation performed at our institution. Patient demographics, anatomical details, and hospitalizations were extracted from our institutional single-ventricle database. Days alive and out of hospital were calculated by subtracting the number of days hospitalized from number of days alive during the first year of life. A multivariable linear regression with stepwise variable selection was used to determine independent risk factors associated with fewer days alive and out of hospital. In total, 437 patients were included. Overall median number of days alive and out of hospital in the first year of life for single-ventricle patients was 278 days (interquartile range 157-319 days). In a multivariable analysis, low birth weight (<2.5kg) (b = -37.55, p = 0.01), presence of a dominant right ventricle (b = -31.05, p = 0.01), moderate-severe dominant atrioventricular valve regurgitation at birth (b = -37.65, p <0.05), index hybrid Norwood operation (b = -138.73, p < 0.01), or index heart transplant (b = -158.41, p < 0.01) were all independently associated with fewer days alive and out of hospital. Children with single-ventricle heart defects have significant illness burden in the first year of life. Identifying risk factors associated with fewer days alive and out of hospital may aid in counselling families regarding expectations and patient prognosis.

Effect of patient factors, center, and era on Fontan timing: An observational study using the Pediatric Health Information Systems Database

BackgroundThere are no consensus guidelines defining optimal timing for the Fontan operation, the last planned surgery in staged palliation for single-ventricle heart disease. ObjectivesIdentify patient-level characteristics, center-level variation, and secular trends driving Fontan timing. MethodsA retrospective observational study of subjects who underwent Fontan from 2007-2021 at centers in the Pediatric Health Information Systems database was performed using linear mixed-effects modeling in which age at Fontan was regressed on patient characteristics and date of operation with center as random effect. ResultsWe included 10,305 subjects (40.4% female, 44% non-white) at 47 centers. Median age at Fontan was 3.4 years (IQR 2.6-4.4). Hypoplastic left heart syndrome (-4.4 months, 95% CI -5.5 to -3.3) and concomitant conditions (-2.6 months, 95% CI -4.1 to -1.1) were associated with younger age at Fontan. Subjects with technology-dependence (+4.6 months, 95% CI 3.1 to 6.1) were older at Fontan. Black (+4.1 months, 95% CI 2.5 to 5.7) and Asian (+8.3 months, 95% CI 5.4 to 11.2) race were associated with older age at Fontan. There was significant variation in Fontan timing between centers. Center accounted for 10% of variation (ICC 0.10, 95% CI 0.07 to 0.14). Center surgical volume was not associated with Fontan timing (p=0.21). Operation year was associated with age at Fontan, with a 3.1 month increase in age for every 5 years (+0.61 months, 95% CI 0.48 to 0.75). ConclusionsAfter adjusting for patient-level characteristics there remains significant inter-center variation in Fontan timing. Age at Fontan has increased. Future studies addressing optimal Fontan timing are warranted.

Decreased erythrocyte aggregation in Glenn and Fontan: univentricular circulation as a rheologic disease model.

In the Fontan palliation for single ventricle heart disease (SVHD), pulmonary blood flow is non-pulsatile/passive, low velocity, and low shear, making viscous power loss a critical determinant of cardiac output. The rheologic properties of blood in SVHD patients are essential for understanding and modulating their limited cardiac output and they have not been systematically studied. We hypothesize that viscosity is decreased in single ventricle circulation. We evaluated whole blood viscosity, red blood cell (RBC) aggregation, and RBC deformability to evaluate changes in healthy children and SVHD patients. We altered suspending media to understand cellular and plasma differences contributing to rheologic differences. Whole blood viscosity was similar between SVHD and healthy at their native hematocrits, while viscosity was lower at equivalent hematocrits for SVHD patients. RBC deformability is increased, and RBC aggregation is decreased in SVHD patients. Suspending SVHD RBCs in healthy plasma resulted in increased RBC aggregation and suspending healthy RBCs in SVHD plasma resulted in lower RBC aggregation. Hematocrit corrected blood viscosity is lower in SVHD vs. healthy due to decreased RBC aggregation and higher RBC deformability, a viscous adaptation of blood in patients whose cardiac output is dependent on minimizing viscous power loss. Patients with single ventricle circulation have decreased red blood cell aggregation and increased red blood cell deformability, both of which result in a decrease in blood viscosity across a large shear rate range. Since the unique Fontan circulation has very low-shear and low velocity flow in the pulmonary arteries, blood viscosity plays an increased role in vascular resistance, therefore this work is the first to describe a novel mechanism to target pulmonary vascular resistance as a modifiable risk factor. This is a novel, modifiable risk factor in this patient population.

The proteomic fingerprint in infants with single ventricle heart disease in the interstage period: evidence of chronic inflammation and widespread activation of biological networks.

Children with single ventricle heart disease (SVHD) experience significant morbidity across systems and time, with 70% of patients experiencing acute kidney injury, 33% neurodevelopmental impairment, 14% growth failure, and 5.5% of patients suffering necrotizing enterocolitis. Proteomics is a method to identify new biomarkers and mechanisms of injury in complex physiologic states. Infants with SVHD in the interstage period were compared to similar-age healthy controls. Serum samples were collected, stored at -80°C, and run on a panel of 1,500 proteins in single batch analysis (Somalogic Inc., CO). Partial Least Squares-Discriminant Analysis (PLS-DA) was used to compare the proteomic profile of cases and controls and t-tests to detect differences in individual proteins (FDR <0.05). Protein network analysis with functional enrichment was performed in STRING and Cytoscape. PLS-DA readily discriminated between SVHD cases (n = 33) and controls (n = 24) based on their proteomic pattern alone (Accuracy = 0.96, R2 = 0.97, Q2 = 0.80). 568 proteins differed between groups (FDR <0.05). We identified 25 up-regulated functional clusters and 13 down-regulated. Active biological systems fell into six key groups: angiogenesis and cell proliferation/turnover, immune system activation and inflammation, altered metabolism, neural development, gastrointestinal system, and cardiac physiology and development. We report a clear differentiation in the circulating proteome of patients with SVHD and healthy controls with >500 circulating proteins distinguishing the groups. These proteomic data identify widespread protein dysregulation across multiple biologic systems with promising biological plausibility as drivers of SVHD morbidity.

Association of genetic and sulcal traits with executive function in congenital heart disease.

Persons with congenital heart disease (CHD) are at increased risk of neurodevelopmental disabilities, including impairments to executive function. Sulcal pattern features correlate with executive function in adolescents with single-ventricle heart disease and tetralogy of Fallot. However, the interaction of sulcal pattern features with genetic and participant factors in predicting executive dysfunction is unknown. We studied sulcal pattern features, participant factors, and genetic risk for executive function impairment in a cohort with multiple CHD types using stepwise linear regression and machine learning. Genetic factors, including predicted damaging de novo or rare inherited variants in neurodevelopmental disabilitiesrisk genes, apolipoprotein E genotype, and principal components of sulcal pattern features were associated with executive function measures after adjusting for age at testing, sex, mother's education, and biventricular versus single-ventricle CHD in a linear regression model. Using regression trees and bootstrap validation, younger participant age and larger alterations in sulcal pattern features were consistently identified as important predictors of decreased cognitive flexibility with left hemisphere graph topology often selected as the most important predictor. Inclusion of both sulcal pattern and genetic factors improved model fit compared to either alone. We conclude that sulcal measures remain important predictors of cognitive flexibility, and the model predicting executive outcomes is improved by inclusion of potential genetic sources of neurodevelopmental risk. If confirmed, measures of sulcal patterning may serve as early imaging biomarkers to identify those at heightened risk for future neurodevelopmental disabilities.

Population Pharmacokinetics of Caffeine in Neonates with Congenital Heart Disease and Associations with Acute Kidney Injury.

Cardiac surgery-associated acute kidney injury (CS-AKI) occurs in approximately 65% of neonates undergoing cardiac surgery on cardiopulmonary bypass and contributes to morbidity and mortality. Caffeine may reduce CS-AKI by counteracting adenosine receptor upregulation after bypass, but pharmacokinetics (PK) in this population are unknown. The goal of our analysis is to address knowledge gaps in age-, disease-, and bypass-related effects on caffeine disposition and explore preliminary associations between caffeine exposure and CS-AKI using population PK modeling techniques and an opportunistic, electronic health record-integrated trial design. We prospectively enrolled neonates receiving preoperative caffeine per standard of care and collected PK samples. We retrospectively identified neonates without caffeine exposure undergoing surgery on bypass as a control cohort. We followed US Food and Drug Administration guidance for population PK model development using NONMEM. Effects of clinical covariates on PK parameters were evaluated. We simulated perioperative exposures and used multivariable logistic regression to evaluate the association between caffeine exposure and CS-AKI. Twenty-seven neonates were included in model development. A 1-compartment model with bypass time as a covariate on clearance and volume of distribution best fit the data. Twenty-three neonates with caffeine exposure and 109 controls were included in the exposure-response analysis. Over half of neonates developed CS-AKI. On multivariable analysis, there were no significant differences between CS-AKI with and without caffeine exposure. Neonates with single-ventricle heart disease without CS-AKI had consistently higher simulated caffeine exposures. Our results highlight areas for further study to better understand disease- and bypass-specific effects on drug disposition and identify populations where caffeine may be beneficial.

Abstract 17103: The Proteomic Fingerprint in Patients With Single Ventricle Disease in the Interstage Period: Evidence of Chronic Inflammation and Widespread Activation of Biological Networks

Introduction: Children with single ventricle heart disease (SVHD) experience significant morbidity across systems and time: (AKI 70%, neurodevelopmental impairment 33%, growth failure 14%, NEC 5.5%). Proteomics is a novel method to identify new biomarkers and mechanisms of injury in complex physiologic states. Hypothesis: Does the proteome of patients with SVHD differ from healthy children, and which biological systems are activated or repressed? Methods: Infants with SVHD in the interstage period were compared to similar-age healthy controls. Serum samples were collected, stored at -80C, and run on a panel of 1500 proteins in single batch analysis (Somalogic Inc., CO). Partial Least Squares-Discriminant Analysis (PLS-DA) was used to compare the proteomic profile of cases and controls and t-tests to detect differences in individual proteins (FDR &lt; 0.05). Protein network analysis with functional enrichment was performed in STRING and Cytoscape. Results: PLS-DA readily discriminated between cases (n=33) and controls (n=24) based on their proteomic pattern alone (Accuracy=0.96, R2=0.97, Q2=0.80) (Fig 1a). 568 proteins differed between groups (FDR &lt; 0.05). The 15 proteins with the greatest effect on the proteomic phenotype between the groups are shown (Fig 1b). We identified 25 up-regulated functional clusters and 13 down-regulated (5 clusters highlighted in Fig 1c). Active biological systems fell into six key groups: angiogenesis and cell proliferation/turnover, immune system activation and inflammation, altered metabolism, neuronal development, gastrointestinal system, and cardiac development. Conclusions: We report a clear differentiation in the circulating proteome of patients with SVHD and healthy controls with &gt;500 circulating proteins distinguishing the groups. This proteomic data identifies various dysregulated protein networks across multiple organ systems with promising biological plausibility as drivers of SVHD morbidity.

Abstract 17256: Perturbations of Tryptophan Catabolism Through the Kynurenine Pathway Are Associated With Prolonged Mechanical Ventilation and Length of Stay After Stage 2 Palliation for Single Ventricle Heart Disease

Background: Infants with single ventricle heart disease (SVHD) have perturbed kynurenine pathway (KP) function prior to stage 2 palliation. Buildup of kynurenic acid—a byproduct of this pathway—is linked to worse outcomes post stage 2. To date, perturbations along the entire KP have not been delineated in SVHD infants at the time of stage 2 operation. Methods: This is a single center prospective cohort study of 75 infants with SVHD undergoing stage 2 palliation and 50 controls. Targeted analysis of KP metabolites was performed on serum samples via tandem mass spectroscopy prior to stage 2 (baseline) and post-operatively at 2, 24, and 48 hours. Results: Of the 9 KP metabolites, 7 were different between controls and SVHD at baseline (Figure 1A). SVHD infants had lower tryptophan and serotonin; and higher kynurenic acid, 3-hydroxykynurenine, anthranilic acid, picolinic acid, and 3-hydroxyanthranilic acid. After stage 2, there were time related changes in all KP metabolites except tryptophan (Figure 1B). Metabolite concentrations at baseline and 2 hours post-op were poorly correlated with outcomes. At 24 hours, decreases in tryptophan and serotonin along with elevations in kynurenine, kynurenic acid, 3-hydroxykynurine, and quinolinic acid concentrations correlated with outcomes (Figure 1C). At 48 hours, kynurenic acid remained positively correlated with all 3 outcomes (length of stay, hypoxia burden, and intubation length). Conclusions: We demonstrated numerous perturbations in the KP pathway at baseline in SVHD infants compared to controls. We also profiled the trajectory of each metabolite over the 48 hours post stage 2. The link between KP intermediates and poor outcomes post-operatively—but not at baseline—demonstrates that the acute, peri-operative changes in tryptophan catabolism in response to cardiopulmonary bypass are more important to tolerating new stage 2 physiology than chronic changes during the interstage period.

Abstract 15192: The Impact of Fontan Circulatory Failure on Heart Transplant Survival: A 20 Center Study

Introduction: Fontan circulatory failure (FCF) is a chronic state in palliated single ventricle heart disease with high morbidity and mortality including heart failure, multisystem end-organ disease, and need for heart transplant (HT). Specific FCF morbidities have not been rigorously defined limiting study of how FCF morbidities impact pre- and post-HT outcomes. Hypothesis: FCF-specific morbidities affect survival from HT waitlisting (WL) through 1-year post-HT. Methods: This 20-center, retrospective cohort study collected demographic, medical/surgical history, WL data, and peri- and post-HT data in Fontan patients WL since 2008. Using Delphi methodology, investigators defined FCF-specific morbidities and collected data. Appropriate univariate 2-group statistics compared surviving individuals with those who 1) died anytime from WL to 1-year post-HT, 2) died on the WL, 3) died within 1-year post-HT. Multivariable logistic regression determined independent risk factors for mortality between WL and 1-year post-HT. Results: Of 409 WL patients, 24 (5.9%) died on the WL. Of the 316 (77%) who underwent HT, 27 (8.5%) did not survive to 1-year. Univariate risk factors for WL death included higher aortopulmonary collateral burden, &gt; 1 hospitalizations in prior year, younger age, sleep apnea, higher NYHA class, non-enrollment in school or work, and single-parent home. Risk factors for 1-year post-HT mortality included HLHS diagnosis, patent fenestration, anatomic Fontan obstruction, clinical cyanosis (pulse oximetry &lt; 90%), polycythemia, portal variceal disease, psychiatric disease requiring treatment, and higher HLA class II PRA. For the 15% of patients not surviving from WL to 1-year post-HT, independent risk factors for mortality included &gt;1 hospitalization in the year prior to WL (aOR 2.0, p=0.05) and clinical cyanosis (aOR 5.0, p=0.002). Notably, some FCF morbidities did not impact post-WL survival including protein-losing enteropathy, plastic bronchitis, and kidney disease. Conclusions: Fontan-palliated patients continue to have high mortality from WL through HT. Among FCF specific morbidities, cyanosis is associated with worsened survival and needs further study. Continued study of FCF phenotype is possible via this dataset.

Hybrid stage 1 palliation with simultaneous off-pump ventricular assist device placement in neonates with high-risk single ventricle anatomy: Initial experience

BackgroundInfants with single ventricle heart disease and severe atrioventricular valve regurgitation have poor outcomes following conventional staged palliation. As such, ventricular assist device (VAD) placement along with hybrid stage 1 palliation has been proposed as a bridge to heart transplant. We present a novel surgical technique for VAD implantation concurrent with hybrid stage 1 that avoids cardiopulmonary bypass. MethodsWe performed a retrospective review of our institutional experience with this novel surgical technique. ResultsThree patients (weight, 2.7-3.5 kg; age, 3 to 5 days) underwent hybrid stage 1 with VAD placement, consisting of bilateral 3.5-mm expandable polytetrafluoroethylene (PTFE) pulmonary artery bands, a ductal stent, a 6-mm Berlin Heart outflow cannula onto the main pulmonary trunk with a 10-mm graft, a 6-mm Berlin Heart outflow cannula onto the right atrium, and a 10-mL Berlin Heart pump. In patients with severe aortic arch hypoplasia or coarctation, a 4-mm PTFE graft was sewn from the VAD outflow graft to the innominate artery to protect coronary and cerebral perfusion. Procedures were performed off bypass with minimal blood product use. Patients were extubated on postoperative days 2, 2, and 5. There were no procedural complications. All patients were transferred out of the intensive care unit and demonstrated appropriate weight gain. Anticoagulation strategy was bivalirudin and antiplatelet therapy. The patients underwent transplantation after 149 days, 157 days, and 288 days of support. ConclusionsOff-pump single ventricle VAD placement is technically feasible and can be done at the time of hybrid stage 1 palliation with minimal operative morbidity as a bridge to transplant.

Hereditary haemorrhagic telangiectasia and SMAD4 mutation in a patient with complex single ventricle heart disease.

We report a case of hypoplastic left heart syndrome and with subsequent aortopathy and then found to have hereditary haemorrhagic telangiectasia/juvenile polyposis syndrome due to a germline SMAD4 pathologic variant. The patient's staged palliation was complicated by the development of neoaortic aneurysms, arteriovenous malformations, and gastrointestinal bleeding thought to be secondary to Fontan circulation, but workup revealed a SMAD4 variant consistent with hereditary haemorrhagic telangiectasia/juvenile polyposis syndrome. This case underscores the importance of genetic modifiers in CHD, especially those with Fontan physiology.

Circulating biomarkers of extracellular matrix dysregulation are associated with adverse post-stage 2 outcomes in infants with single ventricle heart disease

Children with single ventricle heart disease (SVHD) experience morbidity due to inadequate pulmonary blood flow. Using proteomic screening, our group previously identified members of the matrix metalloproteinase (MMP), tissue inhibitor of metalloproteinase (TIMP), and fibroblast growth factor (FGF) families as potentially dysregulated in SVHD. No prior study has taken a targeted approach to mapping circulating levels of these protein families or their relationship to pulmonary vascular outcomes in SVHD. We performed a prospective cohort study of 70 SVHD infants pre-Stage 2 palliation and 24 healthy controls. We report targeted serum quantification of 39 proteins in the MMP, TIMP, and FGF families using the SomaScan platform. Clinical variables were extracted from the medical record. Twenty of 39 tested proteins (7/14 MMPs, 2/4 TIMPs, and 11/21 FGFs) differed between cases and controls. On single variable testing, 6 proteins and no clinical covariates were associated with both post-Stage 2 hypoxemia and length of stay. Multiple-protein modeling identified increased circulating MMP 7 and MMP 17, and decreased circulating MMP 8 and FGFR2 as most associated with post-Stage 2 hypoxemia; increased MMP 7 and TIMP 4 and decreased circulating MMP 1 and MMP 8 were most associated with post-operation length of stay. The MMP, TIMP, and FGF families are altered in SVHD. Pre-Stage 2 imbalance of extracellular matrix (ECM) proteins—increased MMP 7 and decreased MMP 8—was associated with multiple adverse post-operation outcomes. Maintenance of the ECM may be an important pathophysiologic driver of Stage 2 readiness in SVHD.

Genetic and clinical variables act synergistically to impact neurodevelopmental outcomes in children with single ventricle heart disease

BackgroundRecent large-scale sequencing efforts have shed light on the genetic contribution to the etiology of congenital heart defects (CHD); however, the relative impact of genetics on clinical outcomes remains less understood. Outcomes analyses using genetics are complicated by the intrinsic severity of the CHD lesion and interactions with conditionally dependent clinical variables.MethodsBayesian Networks were applied to describe the intertwined relationships between clinical variables, demography, and genetics in a cohort of children with single ventricle CHD.ResultsAs isolated variables, a damaging genetic variant in a gene related to abnormal heart morphology and prolonged ventilator support following stage I palliative surgery increase the probability of having a low Mental Developmental Index (MDI) score at 14 months of age by 1.9- and 5.8-fold, respectively. However, in combination, these variables act synergistically to further increase the probability of a low MDI score by 10-fold. The absence of a damaging variant in a known syndromic CHD gene and a shorter post-operative ventilator support increase the probability of a normal MDI score 1.7- and 2.4-fold, respectively, but in combination increase the probability of a good outcome by 59-fold.ConclusionsOur analyses suggest a modest genetic contribution to neurodevelopmental outcomes as isolated variables, similar to known clinical predictors. By contrast, genetic, demographic, and clinical variables interact synergistically to markedly impact clinical outcomes. These findings underscore the importance of capturing and quantifying the impact of damaging genomic variants in the context of multiple, conditionally dependent variables, such as pre- and post-operative factors, and demography.

Mental Health Conditions Among Children and Adolescents With Congenital Heart Disease: A Danish Population-Based Cohort Study.

Despite the known mental health burden among children with congenital heart disease (CHD), the literature is constrained by a lack of comparison cohorts and population-based follow-up data. We examined the incidence of mental health conditions among children with CHD, relative to 3 comparison cohorts. This population-based cohort study identified all children with CHD (<18 years of age; n=16 473) in Denmark from 1996 to 2017, through linkage of individual-level data across national registries. This allowed for complete follow-up of the population. Comparison cohorts included children from the general population (n=162 204), siblings of children with CHD (n=20 079), and children with non-CHD major congenital anomalies (n=47 799). Mental health conditions were identified using inpatient and outpatient hospital discharge codes, prescription data, and data on use of community-based psychology, psychiatry, and psychotherapy services. We computed cumulative incidence by 18 years of age, incidence rates, and adjusted hazard ratios (aHRs) using Cox regression. aHRs accounted for sex, year of CHD diagnosis, parental mental health, and socioeconomic status. All estimates were stratified by age, sex, and CHD complexity. The cumulative incidence of mental health conditions by 18 years of age in the CHD cohort was 35.1% (95% CI, 34.0%-36.1%), corresponding to aHRs of 1.64 (95% CI, 1.58-1.71), 1.41 (95% CI, 1.30-1.52), and 1.02 (95% CI, 0.98-1.07) compared with the general population, sibling, and major congenital anomaly cohorts, respectively. Mental health incidence rates showed prominent peaks in early childhood and adolescence. Males and children with severe or single-ventricle CHD demonstrated higher incidence rates of mental health conditions relative to females and children with mild or moderate CHD, respectively. Compared with the general population and sibling cohorts, incidence rates and aHRs in the CHD cohort were highest for severe stress reactions, attention deficit/hyperactivity disorder, intellectual disability, and autism spectrum disorder. Compared with children in the major congenital anomaly cohort, the aHRs were close to 1. More than one-third of children with CHD were diagnosed or treated for a mental health condition by 18 years of age. Mental health conditions began early in life and were most prominent among males and children with severe or single-ventricle heart disease.