Biventricular Congenital Heart Disease Research Articles

Factors Associated with Growth in a Cohort of Children with Complex Biventricular Congenital Heart Disease

ObjectivesTo evaluate patterns and determinants of longitudinal growth among children requiring complex biventricular repair for congenital heart disease, and to assess for associations of growth with early feeding modality, comorbidities, postoperative complications, and socioeconomic characteristics. Study DesignA single-institution retrospective cohort study was performed in children born 2/1999-3/2009 with complex congenital heart disease who underwent biventricular repair before age 4, defined by Risk Adjustment in Congenital Heart Surgery-1 (RACHS-1) category 3-5. Clinical characteristics, height, weight, and body mass index (BMI) from ages 2-12 were collected by chart review. Neighborhood-level socioeconomic data were identified using a geographic information system approach. The adjusted association of covariates with growth outcomes was estimated using multivariable linear regression models using generalized estimating equations. ResultsCompared with population growth curves, the cohort (n = 150) trended toward early decrease in age-adjusted weight and height. Early tube feeding was significantly associated with decreased BMI prior to adolescence (-0.539; 95% CI -1.02, -0.054; p = 0.029). Additionally, other clinical and perioperative characteristics had significant associations with growth, including low birthweight, preoperative tube feeds, need for multiple bypass runs, and diagnosis of feeding disorder. ConclusionsEarly childhood growth in children with complex biventricular repair may be impaired. Early tube feeding was associated with decreased BMI over the course of early childhood, which may indicate a need for continued close nutrition follow-up and support even beyond the duration of tube feeds.

Long-term outcomes after heart transplantation in adult patients with univentricular versus biventricular congenital heart disease.

Heart transplantation (HT) is the only life-extending therapy in adults with congenital heart disease (CHD) and end-stage heart failure. HT is considered at high risk in complex CHD given the anatomical complexity and past medical history. Little is known about long-term outcomes after HT in these patients. We aimed to evaluate early and long-term outcomes after HT in adult patients with univentricular versus biventricular CHD. This multicentre retrospective cohort study included all adult CHD patients who underwent HT between 1988 and 2021 in 3 tertiary centres. Factors associated with early (<30 days) and conditional long-term survival were assessed in the entire cohort. Over a mean follow-up of 10.1 ± 7.8 years, 149 patients were included, of whom 55 (36.9%) had univentricular CHD. Sixty-four patients died during follow-up including 47 deaths before discharge from hospital. In multivariable analysis, univentricular physiology and female recipient gender were independently associated with a higher risk of early mortality (odds ratio 2.99; 95% confidence interval [1.33-6.74] and odds ratio 2.76; 95% confidence interval [1.23-6.20], respectively). For patients who survived the early period, conditional long-term survival was excellent for both groups and was not different between 2 groups (P = 0.764). Adult CHD patients have a high incidence of overall mortality due to a high rate of early mortality. Univentricular physiology was associated with a significant increased risk of early death compared to biventricular physiology. However, late mortality was excellent and no longer different between the 2 physiologies.

Mid-term results following pulmonary artery patch augmentation in congenital heart disease.

Treatment of pulmonary artery (PA) stenosis in congenital heart disease is associated with adverse outcomes. The aim of this retrospective cohort study was to compare outcomes after surgical patch augmentation of PA stenosis in patients with biventricular congenital heart disease using different patch materials. We identified all patients from our institutional congenital heart disease database who underwent patch augmentation for PA stenosis on the main pulmonary artery (MPA) or PA branches between 2012 and 2018. Patch materials used were glutaraldehyde fixated autologous pericardium (AP), expanded polytetrafluoroethylene (ePTFE), equine pericardium (EP), and bovine pericardium (BP). The primary study endpoint was the composite of catheter-based re-intervention or re-operation to relieve recurrent stenosis at the site of prior implanted patch material. A total of 156 patients (median age, 5 months, range, 0-85 months; median weight, 6.2 kg, range, 2.8-15.0 kg) underwent patch augmentation using 163 patches (ePTFE =99, 61%; EP =34, 21%; AP =25, 15%; BP =5, 3%). Overall, 131 (84%) patients underwent patch augmentation at the MPA, and 25 (16%) patients underwent patch augmentation at one or both PA branches. Over a mean follow-up period of 4±2 years, 30 patients (19%) reached the study endpoint. Freedom from primary endpoint was 92%±3% for the MPA and 25%±9% for PA branches at 5 years, respectively (P<0.001). Comparison of patch materials revealed similar re-intervention rates between ePTFE, AP, and EP. In contrast, outcomes were significantly decreased following the usage of BP when compared to other materials (ePTFE vs. BP, P=0.01; EP vs. BP, P=0.005). In the multivariable analysis, lower weight at index operation, patch augmentation of PA branches, and usage of BP were independently associated with re-intervention. Patch augmentation of the MPA was associated with acceptable outcomes, while patch augmentation of PA branch stenosis remained independently associated with re-intervention. None of the used patch materials demonstrated superiority; however, BP had a higher rate of re-interventions.

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.

Survival After Cardiac Transplantation in Adults With Single-Ventricle Congenital Heart Disease

BackgroundWithout large-scale analyses of adults with single-ventricle congenital heart disease (CHD) undergoing heart transplantation, little evidence exists to guide listing practices and patient counseling. ObjectivesThis study aims to evaluate survival after heart transplantation in adults with single and biventricular CHD and compare it to that of non-CHD transplant recipients. MethodsIn this 15-year (2005-2020) retrospective analysis, outcome-blinded investigators used probability-linkage to merge the National (Nationwide) Inpatient Sample and Organ Procurement and Transplantation Network data sets. ResultsOf 382 adult (≥18 years of age) heart transplant recipients with CHD, 185 (48%) had single-ventricle physiology. Compared to biventricular CHD, single-ventricle patients showed significantly reduced survival at 1 (80% vs 91%; HR: 2.50; 95% CI: 1.40-4.49; P = 0.002) and 10 years (54% vs 71%; HR: 2.10; 95% CI: 1.38-3.18; P < 0.001). Among patients who survived the first post-transplantation year, biventricular CHD patients exhibited similar 10-year survival as single-ventricle patients, except for those with hypoplastic left heart syndrome (79% vs 71%; HR: 1.58; 95% CI: 0.85-2.92; P = 0.15). Additionally, biventricular CHD transplant recipients showed significantly better 10-year conditional survival compared to their non-CHD counterparts (79% vs 68%; HR: 0.73; 95% CI: 0.59-0.90; P = 0.003). ConclusionsAmong adult CHD transplant recipients, single-ventricle physiology correlated with higher short-term mortality. However, 10-year conditional survival was similar for biventricular and most single-ventricle CHD patients, and notably better for biventricular CHD patients compared to non-CHD heart transplant recipients. These findings have significant implications towards patient selection and listing strategies, easing concerns related to heart transplantation in adults with CHD and destigmatizing most subtypes of single-ventricle CHD.

Association of albuminuria with kidney function and hemodynamic disturbance in pre-school children who undergo congenital heart disease surgery.

We validated the prevalence of albuminuria and its association with kidney function and hemodynamics in pre-school children who underwent surgery for congenital heart disease (CHD). From 403 patients who had undergone surgery for CHD at least 6months before pre-school and were admitted to our hospital between 2011 and 2015, 75 who underwent blood and urine tests and cardiac catheterization were included in this study. The urinary albumin-to-creatinine ratio (ACR) was quantified, and the relationship of ACR with physical and laboratory findings and hemodynamics assessed using cardiac catheterization was analyzed. The study cohort was divided into three groups: Fontan group (n = 25), tetralogy of Fallot (TOF) group (n = 18), and control group (other biventricular CHDs; n = 32). The median age of patients was 5.9years. ACR was higher in the Fontan group than in the TOF and control groups (median: 15.0 vs. 5.0 and 0.0mg/g, p < 0.001). Moreover, albuminuria (ACR > 30mg/g) was observed in 20.0% of Fontan patients, while ACR was associated with potential complicating factors of Fontan circulation: high central venous pressure, high mean pulmonary artery pressure, and worse than moderate atrioventricular regurgitation. ACR showed a moderate correlation with the cystatin C-based estimated glomerular filtration rate (r = - 0.725, p < 0.001). Measurement of albuminuria in Fontan patients before they join elementary school is useful because it reflects kidney function and hemodynamic factors that can worsen their condition. Identification and management of patients with albuminuria may facilitate early therapeutic intervention for worsening Fontan factors, eventually delaying the deterioration of kidney function. A higher resolution version of the Graphical abstract is available as Supplementary information.

Flow evaluation software for four-dimensional flow MRI: a reliability and validation study

PurposeFour-dimensional time-resolved phase-contrast cardiovascular magnetic resonance imaging (4D flow MRI) enables blood flow quantification in multiple vessels, which is crucial for patients with congenital heart disease (CHD). We investigated net flow volumes in the ascending aorta and pulmonary arteries by four different postprocessing software packages for 4D flow MRI in comparison with 2D cine phase-contrast measurements (2D PC).Material and methods4D flow and 2D PC datasets of 47 patients with biventricular CHD (median age 16, range 0.6–52 years) were acquired at 1.5 T. Net flow volumes in the ascending aorta, the main, right, and left pulmonary arteries were measured using four different postprocessing software applications and compared to offset-corrected 2D PC data. Reliability of 4D flow postprocessing software was assessed by Bland–Altman analysis and intraclass correlation coefficient (ICC). Linear regression of internal flow controls was calculated. Interobserver reproducibility was evaluated in 25 patients.ResultsCorrelation and agreement of flow volumes were very good for all software compared to 2D PC (ICC ≥ 0.94; bias ≤ 5%). Internal controls were excellent for 2D PC (r ≥ 0.95, p < 0.001) and 4D flow (r ≥ 0.94, p < 0.001) without significant difference of correlation coefficients between methods. Interobserver reliability was good for all vendors (ICC ≥ 0.94, agreement bias < 8%).ConclusionHaemodynamic information from 4D flow in the large thoracic arteries assessed by four commercially available postprocessing applications matches routinely performed 2D PC values. Therefore, we consider 4D flow MRI-derived data ready for clinical use in patients with CHD.

Effect of preoperative pulmonary hemodynamic and cardiopulmonary bypass on lung function in children with congenital heart disease

In children with congenital heart disease (CHD), pulmonary blood flow (Qp) contributes to alterations of pulmonary mechanics and gas exchange, while cardiopulmonary bypass (CPB) induces lung edema. We aimed to determine the effect of hemodynamics on lung function and lung epithelial lining fluid (ELF) biomarkers in biventricular CHD children undergoing CPB. CHD children were classified as high Qp (n = 43) and low Qp (n = 17), according to preoperative cardiac morphology and arterial oxygen saturation. We measured ELF surfactant protein B (SP-B) and myeloperoxidase activity (MPO) as indexes of lung inflammation and ELF albumin as index of alveolar capillary leak in tracheal aspirate (TA) samples collected before surgery and in 6 hourly intervals within 24 h after surgery. At the same time points, we recorded dynamic compliance and oxygenation index (OI). The same biomarkers were measured in TA samples collected from 16 infants with no cardiorespiratory diseases at the time of endotracheal intubation for elective surgery. Preoperative ELF biomarkers in CHD children were significantly increased than those found in controls. In the high Qp, ELF MPO and SP-B peaked 6 h after surgery and tended to decrease afterward, while they tended to increase within the first 24 h in the low Qp. ELF albumin peaked 6 h after surgery and decreased afterwards in both CHD groups. Dynamic compliance/kg and OI significantly improved after surgery only in the High Qp. Conclusion: In CHD children, lung mechanics, OI, and ELF biomarkers were significantly affected by CPB, according to the preoperative pulmonary hemodynamics.What is Known:• Congenital heart disease children, before cardiopulmonary run, exhibit changes in respiratory mechanics, gas exchange, and lung inflammatory biomarkers that are related to the preoperative pulmonary hemodynamics.• Cardiopulmonary bypass induces alteration of lung function and epithelial lining fluid biomarkers according to preoperative hemodynamics.What is New:• Our findings can help to identify children with congenital heart disease at high risk of postoperative lung injury who may benefit of tailored intensive care strategies, such as non-invasive ventilation techniques, fluid management, and anti-inflammatory drugs that can improve cardiopulmonary interaction in the perioperative period.

Compressed Sensing Cardiac Cine Imaging Compared with Standard Balanced Steady-State Free Precession Cine Imaging in a Pediatric Population.

To compare real-time compressed sensing (CS) and standard balanced steady-state free precession (bSSFP) cardiac cine imaging in children. Twenty children (mean age, 15 years ± 5 [SD], range, 7-21 years; 10 male participants) with biventricular congenital heart disease (n = 11) or cardiomyopathy (n = 9) were prospectively included. Examinations were performed with 1.5-T imagers by using both bSSFP and CS sequences in all participants. Quantification of ventricular volumes and function was performed for all images by two readers blinded to patient diagnosis and type of sequence. Values were correlated with phase-contrast flow measurements by one reader. Intra- and interreader agreement were analyzed. There were no significant differences between ventricular parameters measured on CS compared with those of bSSFP (P > .05) for reader 1. Only ejection fraction showed a significant difference (P = .02) for reader 2. Intrareader agreement was considerable for both sequences (bSSFP: mean difference range, +1 to -2.6; maximum CI, +7.9, -13; bias range, 0.1%-4.1%; intraclass correlation coefficient [ICC] range, 0.931-0.997. CS: mean difference range, +7.4 to -5.6; maximum CI, +37.2, -48.8; bias range, 0.5%-7.5%; ICC range, 0.717-0.997). Interreader agreement was acceptable but less robust, especially for CS (bSSFP: mean difference range, +2.6 to -5.6; maximum CI, +60.7, -65.3; bias range, 1.6%-6.2%; ICC range, 0.726-0.951. CS: mean difference range, +10.7 to -9.1; maximum CI, +87.5, -84.6; bias range, 1.1%-17.3%; ICC range, 0.509-0.849). The mean acquisition time was shorter for CS (20 seconds; range, 17-25 seconds) compared with that for bSSFP (160 seconds; range, 130-190 seconds) (P < .001). CS cardiac cine imaging provided equivalent ventricular volume and function measurements with shorter acquisition times compared with those of bSSFP and may prove suitable for the pediatric population.Keywords: Compressed Sensing, Balanced Steady-State Free Precession, Cine Imaging, Cardiovascular MRI, Pediatrics, Cardiac, Heart, Cardiomyopathies, Congenital, Segmentation© RSNA, 2022.

Inter-Rater Reliability of Total Cardiac Volume Measurement for Heart Transplantation: An ACTION Collaborative Study

<h3>Purpose</h3> There is increasing evidence that size-matching pediatric donor hearts by direct measurement of total cardiac volume (TCV) is superior to traditional methods based on body size. Currently, there are no standardized protocols for assessing TCV or studies evaluating the inter-rater reliability of such measurements, both critical requirements to support a national TCV-based size-matching system. We sought to evaluate the inter-rater reliability of a standardized TCV measurement protocol across multiple pediatric transplant centers. <h3>Methods</h3> A total of nine pediatric transplant centers within the Advanced Cardiac Therapies Improving Outcomes Network (ACTION) performed TCV assessments in 12 test subjects. TCV was assessed from computed tomography (CT) or magnetic resonance imaging (MRI) files using a standard TCV measurement protocol that was reviewed with each center. Interclass correlation coefficients (ICC) were calculated between all centers and each center in relation to the primary center. <h3>Results</h3> Of the 12 test subjects, the median age was 9.5 years (range 18 days to 30 years), the median weight was 28 (2.5 to 89) kg; 3 had no heart disease (donors), 3 had cardiomyopathy (CMP); 6 had congenital heart disease (CHD) including 4 single-ventricle CHD (1 shunted newborn, 2 Glenns, and 2 Fontans) and 2 biventricular CHD (aortic stenosis, tetralogy of Fallot/pulmonary atresia). Imaging modalities included 7 contrast CTs (CCT), 3 non-contrast CT (NCT), and 2 MRI. TCV was performed by 7 cardiologists, 1 radiologists, and 1 biomedical engineer. Overall compared to the primary center, the ICC across all 8 centers for all 12 scans was 0.99 (95% CI 0.98-0.99), including in normal hearts 0.98 (0.95-1.0), in CMP 0.99 (0.96-1.0), in CHD 0.99 (95% CI 0.99-0.99) and single ventricle CHD 0.99 (95% CI 0.97-0.99). By imaging modality, ICC for NCT was 0.98 (0.94-1.0), CCT 0.99 (0.99-0.99), and MRI 0.79 (0.32-1.0). By age, infants ICC was 0.99 (0.95-1.0), children 0.99 (0.98-0.99), and adults 0.97 (0.81-1.0). <h3>Conclusion</h3> The inter-rater reliability for total cardiac volume assessment in healthy and diseased hearts appears excellent across a variety of age groups and diagnoses. ICC for MRI was modest compared to CT imaging albeit the small sample size. Further validation of a standardized TCV measurement protocol among ACTION transplant centers is warranted.

Risk Factors Associated With Bleeding in Children With Cardiac Disease Receiving Extracorporeal Membrane Oxygenation: A Multi-Center Data Linkage Analysis.

Background: Bleeding is a common complication of extracorporeal membrane oxygenation (ECMO) for pediatric cardiac patients. We aimed to identify anticoagulation practices, cardiac diagnoses, and surgical variables associated with bleeding during pediatric cardiac ECMO by combining two established databases, the Collaborative Pediatric Critical Care Research Network (CPCCRN) Bleeding and Thrombosis in ECMO (BATE) and the Extracorporeal Life Support Organization (ELSO) Registry.Methods: All children (<19 years) with a primary cardiac diagnosis managed on ECMO included in BATE from six centers were analyzed. ELSO Registry criteria for bleeding events included pulmonary or intracranial bleeding, or red blood cell transfusion >80 ml/kg on any ECMO day. Bleeding odds were assessed on ECMO Day 1 and from ECMO Day 2 onwards with multivariable logistic regression.Results: There were 187 children with 114 (61%) bleeding events in the study cohort. Biventricular congenital heart disease (94/187, 50%) and cardiac medical diagnoses (75/187, 40%) were most common, and 48 (26%) patients were cannulated directly from cardiopulmonary bypass (CPB). Bleeding events were not associated with achieving pre-specified therapeutic ranges of activated clotting time (ACT) or platelet levels. In multivariable analysis, elevated INR and fibrinogen were associated with bleeding events (OR 1.1, CI 1.0–1.3, p = 0.02; OR 0.77, CI 0.6–0.9, p = 0.004). Bleeding events were also associated with clinical site (OR 4.8, CI 2.0–11.1, p < 0.001) and central cannulation (OR 1.75, CI 1.0–3.1, p = 0.05) but not with cardiac diagnosis, surgical complexity, or cannulation from CPB. Bleeding odds on ECMO day 1 were increased in patients with central cannulation (OR 2.82, 95% CI 1.15–7.08, p = 0.023) and those cannulated directly from CPB (OR 3.32, 95% CI 1.02–11.61, p = 0.047).Conclusions: Bleeding events in children with cardiac diagnoses supported on ECMO were associated with central cannulation strategy and coagulopathy, but were not modulated by achieving pre-specified therapeutic ranges of monitoring assays.

Adverse Events Associated with Cardiac Catheterization in Children Supported with Ventricular Assist Devices.

Children on ventricular assist device (VAD) support can present several unique challenges, including small patient size, univentricular or biventricular congenital heart disease (1V- or 2V-CHD) and need for biventricular VAD (BiVAD) support. While cardiac catheterization can provide valuable information, it is an invasive procedure with inherent risks. We sought to evaluate the safety of catheterization in pediatric patients on VAD support. We performed a retrospective review of patients on VAD support who underwent catheterization at Lucile Packard Children's Hospital between January 1, 2014 and September 1, 2019. Using definitions adapted from Pedimacs, adverse events (AEs) after catheterization were identified, including arrhythmia; major bleeding or acute kidney injury within 24 hours; respiratory failure persisting at 24 hours; and stroke, pericardial effusion, device malfunction, bacteremia or death within 7 days. AEs were categorized as related or unrelated to catheterization. Sixty procedures were performed on 39 patients. Underlying diagnoses were dilated cardiomyopathy (48%), 1V-CHD (35%), 2V-CHD (8%), and other (8%). Devices were implantable continuous flow (72%), paracorporeal pulsatile (18%) and paracorporeal continuous flow (10%). Catheterizations were performed on patients in the ICU (60%), on inotropic support (42%), with deteriorating clinical status (37%) and on BiVAD support (12%). There were 9 AEs possibly related to catheterization including 6 episodes of respiratory failure, 2 major bleeding events, and 1 procedural arrhythmia. AE occurrence was associated with ICU status ( P = 0.01), BiVAD support ( P = 0.04) and procedural indication to evaluate worsening clinical status ( P = 0.04). Despite high medical acuity, catheterization can be performed with an acceptable AE profile in children on VAD support.

A NOVEL LIVER T1 MAPPING SEQUENCE (PROFIT1): TOWARDS EARLY DETECTION OF FONTAN ASSOCIATED LIVER DISEASE

<h3>BACKGROUND</h3> The Fontan procedure is the final surgical stage for congenital heart disease (CHD) patients with single ventricles. Systemic venous return is routed directly to the lungs while the ventricle pumps arterial blood to the body. One long-term complication is known as Fontan-associated liver disease (FALD). Liver damage is due to a combination of chronic congestion from increased venous pressures and ischemic damage during the multiple surgeries a single ventricle patient undergoes. Fibrotic myocardial remodeling may further increase backup and contribute to liver pathology. Liver biopsy is the gold standard for diagnosis of FALD but is invasive and may not detect heterogenous disease. MRI T1 mapping (longitudinal relaxation time) of the liver provides quantitative assessment of fluid overload and diffuse fibrosis that may overcome these limitations. Our hypothesis is that liver T1 will be elevated in Fontan patients compared to corrected biventricular CHD and normal controls. <h3>METHODS AND RESULTS</h3> Cross-sectional cohort study of 33 patients within three cohorts: 11 Fontans, 12 biventricular CHD, and 10 controls with structurally normal hearts. Liver T1 was measured with a new water-specific T1 mapping method (PROFIT1 – Proton Density Fat Fraction Imaging with Water-Specific T1) from three axial slices at the widest dimension of the liver (free-breathing acquisition). Whole-liver average values were calculated, excluding blood vessels. Ventricular volumes and ejection fraction (EF) were calculated from the systemic ventricle. Myocardial native T1 mapping (MOLLI) at a mid-ventricular short axis were quantified in both the septum and free wall of the systemic or dominant ventricle. Cohort means were compared with Kruskal Wallis test and Dunn's posthoc test and association was determined with Spearman correlation coefficient. The Fontan cohort had higher liver T1 (795±59 ms) compared to control (668±62 ms; p=0.002) and CHD (672±54 ms; p=0.0007); control and CHD did not differ (Figure 1A). Fontans also had a significantly lower mean EF compared to CHD and controls (p=0.001); there were no significant differences in myocardial T1 between the 3 groups (Table 1). Liver T1 did, however, correlate with septal myocardial T1 within the whole dataset (Figure 1B; r=0.810; p=0.02); liver T1 did not correlate with EF. <h3>CONCLUSION</h3> T1 mapping with PROFIT1 appears feasible and discriminates Fontan patients from CHD and control. Furthermore, increased liver T1 also was associated with negative cardiac indicators suggesting an association between liver fibrosis and myocardial fibrosis. PROFIT1 is a fast, patient-friendly approach that may provide an early, non-invasive means to detect FALD.

Mitochondrial Respiration Defects in Single-Ventricle Congenital Heart Disease.

Background: Congenital heart disease (CHD) with single-ventricle (SV) physiology is now survivable with a three-stage surgical course ending with Fontan palliation. However, 10-year transplant-free survival remains at 39–50%, with ventricular dysfunction progressing to heart failure (HF) being a common sequela. For SV-CHD patients who develop HF, undergoing the surgical course would not be helpful and could even be detrimental. As HF risk cannot be predicted and metabolic defects have been observed in Ohia SV-CHD mice, we hypothesized that respiratory defects in peripheral blood mononuclear cells (PBMCs) may allow HF risk stratification in SV-CHD.Methods: SV-CHD (n = 20), biventricular CHD (BV-CHD; n = 16), or healthy control subjects (n = 22) were recruited, and PBMC oxygen consumption rate (OCR) was measured using the Seahorse Analyzer. Respiration was similarly measured in Ohia mouse heart tissue.Results: Post-Fontan SV-CHD patients with HF showed higher maximal respiratory capacity (p = 0.004) and respiratory reserve (p < 0.0001), parameters important for cell stress adaptation, while the opposite was found for those without HF (reserve p = 0.037; maximal p = 0.05). This was observed in comparison to BV-CHD or healthy controls. However, respiration did not differ between SV patients pre- and post-Fontan or between pre- or post-Fontan SV-CHD patients and BV-CHD. Reminiscent of these findings, heart tissue from Ohia mice with SV-CHD also showed higher OCR, while those without CHD showed lower OCR.Conclusion: Elevated mitochondrial respiration in PBMCs is correlated with HF in post-Fontan SV-CHD, suggesting that PBMC respiration may have utility for prognosticating HF risk in SV-CHD. Whether elevated respiration may reflect maladaptation to altered hemodynamics in SV-CHD warrants further investigation.

SVEGFR1 Is Enriched in Hepatic Vein Blood-Evidence for a Provisional Hepatic Factor Candidate?

Background: Pulmonary arteriovenous malformations (PAVMs) are common sequelae of palliated univentricular congenital heart disease, yet their pathogenesis remain poorly defined. In this preliminary study, we used paired patient blood samples to identify potential hepatic factor candidates enriched in hepatic vein blood.Methods: Paired venous blood samples were collected from the hepatic vein (HV) and superior vena cava (SVC) from children 0 to 10 years with univentricular and biventricular congenital heart disease (n = 40). We used three independent protein analyses to identify proteomic differences between HV and SVC blood. Subsequently, we investigated the relevance of our quantified protein differences with human lung microvascular endothelial assays.Results: Two independent protein arrays (semi-quantitative immunoblot and quantitative array) identified that soluble vascular endothelial growth factor receptor 1 (sVEGFR1) is significantly elevated in HV serum compared to SVC serum. Using ELISA, we confirmed the previous findings that sVEGFR1 is enriched in HV serum (n = 24, p < 0.0001). Finally, we studied the quantified HV and SVC serum levels of sVEGFR1 in vitro. HV levels of sVEGFR1 decreased tip cell selection (p = 0.0482) and tube formation (fewer tubes [p = 0.0246], shorter tube length [p = 0.0300]) in vitro compared to SVC levels of sVEGFR1.Conclusions: Based on a small heterogenous cohort, sVEGFR1 is elevated in HV serum compared to paired SVC samples, and the mean sVEGFR1 concentrations in these two systemic veins cause pulmonary endothelial phenotypic differences in vitro. Further research is needed to determine whether sVEGFR1 has a direct role in pulmonary microvascular remodeling and PAVMs in patients with palliated univentricular congenital heart disease.

Computational Analysis of the Pulmonary Arteries in Congenital Heart Disease: A Review of the Methods and Results.

With the help of computational fluid dynamics (CFD), hemodynamics of the pulmonary arteries (PA's) can be studied in detail and varying physiological circumstances and treatment options can be simulated. This offers the opportunity to improve the diagnostics and treatment of PA stenosis in biventricular congenital heart disease (CHD). The aim of this review was to evaluate the methods of computational studies for PA's in biventricular CHD and the level of validation of the numerical outcomes. A total of 34 original research papers were selected. The literature showed a great variety in the used methods for (re) construction of the geometry as well as definition of the boundary conditions and numerical setup. There were 10 different methods identified to define inlet boundary conditions and 17 for outlet boundary conditions. A total of nine papers verified their CFD outcomes by comparing results to clinical data or by an experimental mock loop. The diversity in used methods and the low level of validation of the outcomes result in uncertainties regarding the reliability of numerical studies. This limits the current clinical utility of CFD for the study of PA flow in CHD. Standardization and validation of the methods are therefore recommended.

Randomized Controlled Trial of Working Memory Intervention in Congenital Heart Disease

To evaluate the efficacy of Cogmed Working Memory Training compared with the standard of care to improve executive function and social outcomes in adolescents with congenital heart disease (CHD) who underwent open-heart surgery in infancy and to identify factors associated with changes in outcomes following the intervention. In a single-center, randomized controlled trial, adolescents (13-16years) with CHD were randomly assigned to either Cogmed (home-based 45-minutes sessions for 5-8weeks) or to a control group. The primary outcome was working memory. Secondary outcomes included inhibitory control and cognitive flexibility as well as parent-reported executive function, symptoms of attention deficit hyperactivity disorder, and social outcomes. All measures were assessed at baseline, post-treatment (1-3weeks post-training) and at 3-month follow-up. Data were analyzed using an intention-to-treat approach. Sixty adolescents with CHD participated (28 assigned to Cogmed). No improvement at the post-treatment or 3-month follow-up assessments was found for the primary outcome measure of working memory. Compared with the control group, participants assigned to the intervention demonstrated benefits in inhibitory control and attention at the 3-month follow-up (P=.02) and in parent-reported cognitive regulatory skills at post-treatment and 3-month follow-up (P=.02 and P=.04, respectively). Preterm birth, biventricular CHD, and history of attention deficit hyperactivity disorder diagnosis were associated with improved response to the intervention. Cogmed intervention produced improvements in the self-regulatory control abilities of adolescents with CHD. The training did not enhance other areas of executive function or behavioral outcomes. Further studies are needed to evaluate the longer-term potential benefits to other domains. Clinicaltrials.gov: NCT02759263.

Safety and Feasibility of Home INR Monitoring for Outpatient Ventricular Assist Device Support in Children

The use of intracorporeal continuous flow (CF) ventricular assist devices- namely the Heartware™ HVAD™- has expanded dramatically in the children, with many being discharged home. We sought to evaluate the feasibility and outcomes of children discharged home with point of care (POC) INR monitors for their warfarin anticoagulation management. This is a retrospective single center review of all pediatric patients, aged ≤19 years at time of implantation, who were discharged home for longer than 1 week. Efficacy of warfarin anticoagulation and outcomes were evaluated in those with home POC monitors as compared to children who went to laboratory. Between November 11, 2012 and January 1, 2018, a total of 12 patients, 33% female, aged median 14.5 years (range 10-18 years), weighing median 65.8kg (range 18.0-89.5 kg) were discharged home or to rehab with HeartWare as a bridge to transplantation. Underlying diagnosis included dilated cardiomyopathy in 67% (n=8), arrhythmogenic right ventricular dysplasia (ARVD) in 8% (n=1), and biventricular congenital heart disease (CHD) in 25% (n=3).Two patients were discharged to rehab before returning home. All patients were discharged with Coagucheck XS™ POC INR machines, with goal INR of 2-3 in first 3 patients (23%) and goal INR of 2.5-3.5 in later 10 patients. There were a median number of INR tests of 27 (range 1-99) at home, over the course of a median 185 days (25-625) outpatient VAD support days. Overall median time in the therapeutic range(TTR) was 62.1%(range 20.0-70.7%). There was 100% adherence to clinician recommended INR testing at home. There was 4 bridging events with low molecular weight heparin for sub-therapeutic INR. There were no pump thrombosis or other thrombotic events. There were no major bleeding or clinically relevant non major bleeding events. Epistaxis was the most common minor bleeding event that was mitigated by dose reductions and preventative strategies. All patients were bridged to transplantation with no mortality. Use if home POC INR machines in children with intracorporeal VADs, in the outpatient setting was associated with 100% adherence to recommended testing regime. Despite low TTR, there was no major bleeding or thrombotic events.

Adverse Events Following Cardiac Catheterization among Infants, Children, and Young Adults on Ventricular Assist Device Support

Children on ventricular assist device (VAD) support often present unique challenges, such as small size, univentricular or biventricular congenital heart disease (1V- or 2V-CHD), and need for biventricular (BiVAD) support. While cardiac catheterization (cath) can provide valuable information in the management of pediatric patients on VAD support, it is an invasive procedure with inherent risks. We sought to evaluate the safety of cath in this population. We performed a retrospective review of patients on VAD support who underwent cath at a single pediatric VAD center between 2014 and 2019. Using definitions based on Pedimacs, adverse events (AEs) following cath were identified, including respiratory failure (persistent need for intubation ≥ 48 hours post-cath), acute kidney injury (AKI), or arrhythmia within 24 hours, and stroke, pericardial effusion, device malfunction, infection, and death within 7 days. AEs were reviewed by two cardiologists, blinded to each other's assessments, and categorized as directly related or unrelated to cath. Strokes were unrelated to cath if there was documentation of baseline neurologic status after cath but prior to stroke. Descriptive statistics were employed. There were 60 caths on 39 patients. Median age was 11 years (range 2 months - 22 years) and median weight was 36 kg (3.8 - 99.2). Underlying diagnoses included dilated cardiomyopathy (DCM) (54%), 1V-CHD (31%), 2V-CHD (10%), hypertrophic cardiomyopathy (2.5%) and re-transplant (2.5%); 10% were on BiVAD support. Devices were paracorporeal pulsatile (20%), durable continuous flow (72%), and temporary continuous flow (8%). Caths were performed at a median 50 days (6 - 311) from VAD implant; 60% (36/60) were performed on patients in the intensive care unit. Of the 60 caths, there were 7 AEs following cath believed to be directly or possibly related to cath (12%, 7/60), occurring in 6 patients (2 DCM, 3 1V-CHD, 1 other): 1 major bleeding event, 1 AKI, 2 moderate pericardial effusions, and 3 episodes of respiratory failure. There were no strokes, arrhythmia, infections, or mortality attributable to cath. Despite medical complexity such as small size, complex CHD and intensive care needs, cardiac catheterization can be performed with an acceptable adverse event profile in infants, children and young adults on VAD support.

Ventricular-Arterial Coupling in Children and Infants With Congenital Heart Disease After Cardiopulmonary Bypass Surgery: Observational Study.

Ventricular-arterial coupling represents the interaction between the left ventricle and the arterial system. Ventricular-arterial coupling is measured as the ratio between arterial elastance and ventricular end-systolic elastance. Scant information is available in critically ill children about these variables. The aim of this study was to prospectively assess ventricular-arterial coupling after pediatric cardiac surgery and evaluate its association with other commonly recorded hemodynamic parameters. Single-center retrospective observational study. Pediatric cardiac surgery operating room. Children undergoing corrective cardiac surgery. Hemodynamic monitoring with transesophageal echocardiography. Twenty-seven patients with biventricular congenital heart disease, who underwent elective cardiac surgery with cardiopulmonary bypass, were enrolled before operating room discharge. Chen single-beat modified method was applied to calculate ventricular-arterial coupling. The median arterial elastance and end-systolic elastance values were 5.9 mm Hg/mL (2.2-9.3 mm Hg/mL) and 4.3 mm Hg/mL (1.9-8.3 mm Hg/mL), respectively. The median ventricular- arterial coupling was 1.2 (1.1-1.6). End-systolic elastance differences between patients with a ventricular-arterial coupling below (low ventricular-arterial coupling) and above (high ventricular-arterial coupling) the median value were -5.2 (95% CI, -6.28 to -0.7; p = 0.008). Differently, arterial elastance differences were -2.1 (95% CI, -5.7 to 1.6; p = 0.19). Ventricular-arterial coupling showed a significant association with pre-ejection time (r, 0.44; p = 0.02), total ejection time (r, -0.41; p = 0.003), cardiac cycle efficiency (r, -0.46; p = 0.02), maximal delta pressure over delta time (r, -0.44; p = 0.02), ejection fraction (r, -0.57; p = 0.01), and systemic vascular resistances indexed (0.56; p = 0.003). After adjustment, total ejection time (p = 0.001), pre-ejection time (p = 0.02), and ejection fraction (p = 0.001) remained independently associated with ventricular-arterial coupling. Median ventricular-arterial coupling values in children after cardiac surgery appear high (above 1). Uncoupling was particularly evident in high ventricular-arterial coupling patients who showed the lowest end-systolic elastance values (but not significantly different arterial elastance values) compared with low ventricular-arterial coupling. Ventricular-arterial coupling appears to be inversely proportional to pre-ejection time, total ejection time, and ejection fraction.