Altered Serum Proteins Suggest Inflammation, Fibrogenesis and Angiogenesis in Adult Patients with a Fontan Circulation.

Previous omics research in patients with complex congenital heart disease and single-ventricle circulation (irrespective of the stage of palliative repair) revealed alterations in cardiac and systemic metabolism, inter alia abnormalities in energy metabolism, and inflammation, oxidative stress or endothelial dysfunction. We employed an affinity-proteomics approach focused on cell surface markers, cytokines, and chemokines in the serum of 20 adult Fontan patients with a good functioning systemic left ventricle, and we 20 matched controls to reveal any specific processes on a cellular level. Analysis of 349 proteins revealed 4 altered protein levels related to chronic inflammation, with elevated levels of syndecan-1 and glycophorin-A, as well as decreased levels of leukemia inhibitory factor and nerve growth factor-ß in Fontan patients compared to controls. All in all, this means that Fontan circulation carries specific physiological and metabolic instabilities, including chronic inflammation, oxidative stress imbalance, and consequently, possible damage to cell structure and alterations in translational pathways. A combination of proteomics-based biomarkers and the traditional biomarkers (uric acid, γGT, and cholesterol) performed best in classification (patient vs. control). A metabolism- and signaling-based approach may be helpful for a better understanding of Fontan (patho-)physiology. Syndecan-1, glycophorin-A, leukemia inhibitory factor, and nerve growth factor-ß, especially in combination with uric acid, γGT, and cholesterol, might be interesting candidate parameters to complement traditional diagnostic imaging tools and the determination of traditional biomarkers, yielding a better understanding of the development of comorbidities in Fontan patients, and they may play a future role in the identification of targets to mitigate inflammation and comorbidities in Fontan patients.

Serum tau protein and myelin basic protein in pediatric patients with congenital heart defects undergoing cardiac surgery: preliminary assessment as novel neuromarkers of brain injury.

INTRODUCTION: Neurological impairment is a big concern in the development of patients with congenital heart defects (CHD). A number of neuromarkers have been studied in search of a diagnostic or prognostic marker for brain injury during the vulnerable perioperative period. Our aim was to assess two novel neuromarkers, myelin basic protein (MBP) and protein Tau (pTau), as diagnostic markers for brain injury in perioperative period in children with CHD. METHODS: Forty patients were enrolled and dichotomized based on peripheric oxygen saturation in cyanotic and non-cyanotic group. Blood samples were collected preoperative, after the induction of anesthesia, and in postoperative day 1. Neuromarker concentrations were measured using commercially available ELISA kits. RESULTS: Neuromarkers' values were increased postoperative, with statistical significance reached only in non-cyanotic group (p < 0.0001). A significant positive correlation was observed between preoperatory MBP and albumin level, hemoglobin level, height, and weight of patients. Association with cerebral saturations were analyzed by a coefficient defined as ≥ 20% reduction in cerebral saturation measured by near-infrared spectroscopy during perioperative period. An acceptable predicting model was observed with pTau in cyanotic group (AUC = 0.7). CONCLUSION: We evaluated MBP and pTau as potential biomarkers of brain injury in children with CHD undergoing cardiac surgery. Elevated postoperative pTau and MBP concentrations were observed in both groups. Elevated pTau values were associated with perioperative hypoxemia.

CA125 como nuevo biomarcador en pacientes con circulación de Fontan / CA125: a new biomarker in patients with Fontan circulation

Introducción y objetivos Los pacientes con circulación de Fontan (CF) presentan una gran incidencia de complicaciones y ningún biomarcador estratifica el riesgo. El objetivo es analizar la asociación de biomarcadores con un perfil clínico de disfunción de la CF, incluyendo por primera vez el antígeno carbohidrato 125 (CA125), y proponer una estimación del riesgo basada en la combinación de biomarcadores. Métodos Estudio transversal de adultos con CF. Se consideró perfil clínico desfavorable el combinado de insuficiencia cardiaca, arritmias auriculares, fístulas venovenosas, enteropatía pierdeproteínas o bronquitis plástica. Se analizaron variables clínicas y analíticas, incluidos CA125, NT-proBNP, función renal y hepática y amplitud de distribución eritrocitaria (ADE). Se realizó un estudio univariado y multivariado de la relación de dichas complicaciones clínicas y curvas ROC para obtener puntos de corte. Resultados Se incluyó a 56 pacientes (media de edad, 27,4±7,8 años). El 34% tenía un perfil clínico desfavorable, con valores de CA125 significativamente mayores (30,1 frente a 12,6 UI/ml; p=0,001). LnCA125 (OR=5,1; IC95%, 1,2-22), ADE (OR=1,8; IC95%, 1,1-3.1) y FIB4 (OR=38; IC95%, 1,7-855) se asociaron con un perfil de disfunción clínica. Los puntos de corte fueron CA125 ≥ 20 U/ml, FIB4 ≥ 0,75 y ADE ≥ 14,5%, y la probabilidad de un perfil clínico desfavorable fue del 81% con 2 o más biomarcadores elevados. Conclusiones El aumento de CA125 se asocia con mayor prevalencia de complicaciones en pacientes con CF. Los valores de CA125 ≥ 20 U/ml, FIB4 ≥ 0,75 y ADE ≥ 14,5% identifican con alta probabilidad fracaso clínico de la CF. (AU)

Introduction and objectives Patients with Fontan circulation (FC) have a high incidence of clinical complications. However, no biomarker is able to accurately stratify risk. The aim of this study was to analyze the relationship between biomarkers and clinical complications, including carbohydrate antigen 125 (CA125) for the first time, and to propose a risk estimation based on a combination of biomarkers. Methods Cross-sectional study of patients with FC. The clinical endpoint was the combination of heart failure, atrial arrhythmias, veno-venous fistulae, protein-losing enteropathy, or plastic bronchitis. Demographic, clinical, and laboratory variables were analyzed, including CA125, NT-proBNP, renal and liver function, and red cell distribution width (RDW). We performed univariate and multivariate analyses of the relationship between these variables and the composite endpoint. Cutoff values were calculated by ROC curves. Results We included 56 patients (27.4±7.8 years). A total of 34% showed the composite endpoint, with significantly higher CA125 levels (30.1 IU/mL vs 12.6 IU/mL; P=.001). In the multivariate model, the biomarkers related to the endpoint were LnCA125 (OR, 5.1; 95%CI, 1.2-22), RDW (OR, 1.8; 95%CI, 1.1-3.1), and FIB4 (OR, 38, 95%CI, 1.7-855). The cutoff points were CA125 ≥ 20 U/mL, FIB4 ≥ 0.75, and RDW ≥ 14.5%, and the probability of the occurrence of the endpoint was 81% if ≥ 2 biomarkers were elevated. Conclusions CA125 elevation is associated with a higher prevalence of complications in patients with Fontan-type circulation. CA125 levels ≥ 20U/mL, FIB4 ≥ 0.75 and RDW ≥ 14.5% identify with a high probability the clinical failure of FC. (AU)

Hematologic Derangements among Children with Unoperated Cyanotic Congenital Heart Disease in Ethiopia.

Background: Surgical treatment has transformed the course and outcome of congenital heart defects in high-income countries, but children with congenital heart diseases in sub-Saharan Africa, where access to cardiac surgery is limited, often experience the natural course of untreated lesions and their complications. The objective of this study was to determine the prevalence of hematologic derangements among Ethiopian children with unoperated cyanoticcongenital heart diseases, to identify factors associated with coagulopathy in this population, and to describe how these complications are managed in this setting. Methods: In this single-center cross-sectional study, we prospectively collected clinical and demographic data from children (<18 years) with cyanotic congenital heart diseases. Blood samples were collected to measure hematologic parameters. Polycythemia was defined as hematocrit >50% and thrombocytopenia as <150,000 per microliter. Results: Among 70 children recruited, the overall prevalence of polycythemia and thrombocytopenia was 63% (n=44) and 26% (n=18), respectively. On multivariate logistic regression analysis, hematocrit ≥65% (p-value=.024), and oxygen saturation <85% (p-value=.018) were independently associated with moderate or severe thrombocytopenia. Thirty-one (44%) patients had undergone therapeutic phlebotomy, and 84% (26/31) of these patients received iron supplementation. Conclusion: We report a high prevalence of polycythemia and thrombocytopenia in Ethiopian children with untreated cyanotic congenital heart diseases. There was variable implementation of iron supplementation and therapeutic phlebotomy, highlighting the need to optimize supportive management strategies in this population to mitigate the risk of life-threatening complications.

Relationship Between Serum Brain-Type Natriuretic Peptide and Biomarkers of Growth in Infants With Shunt-Dependent Single Cardiac Ventricle.

For infants with shunt-dependent or ductal-dependent single ventricle heart disease, poor growth is common and associated with morbidity and impaired neurodevelopmental outcomes. Although attention has focused on nutrition to promote weight gain, little is known about the relation between heart failure and growth factors. A prospective observational pilot study was performed to assess the relation between heart failure, assessed by brain natriuretic peptide (BNP), and growth factors (insulin-like growth factor 1 [IGF-1] and insulin-like growth factor-binding protein 3) at 3 visits: (1) before discharge from neonatal intervention with the establishment of stable pulmonary blood flow, (2) immediately before superior cavopulmonary connection, and (3) before discharge after superior cavopulmonary connection operation. The relation between BNP and growth factors was analyzed using Spearman pairwise correlations at each visit and modeled over time with a linear mixed-effects model. Correlations were considered worthy of further exploration using a p <0.10, given the exploratory nature of the study. The study included 38 infants (66% male, 68% hypoplastic left heart syndrome). Median BNP was elevated at visit 1 and decreased over time (287 pg/dl [interquartile range 147 to 794], 85 pg/dl [52 to 183], and 90 pg/dl [70 to 138]). Median IGF-1 Z score was <0 at each visit but increased over time (-0.9 [interquartile range -1.1 to 0.1], -0.7 [-1.2 to 0.1], and -0.5 [-1.2 to 0]). Inverse correlations were found between BNP and IGF-1 at visit 1 (r = -0.40, p = 0.097), BNP and IGF-1 and insulin-like growth factor-binding protein 3 at visit 2 (r = -0.33, p = 0.080 and r = -0.33, p = 0.085, respectively) and BNP and IGF-1 Z score at visit 3 (r = -0.42, p = 0.049). Significant relations were likewise found between the change in BNP and the change in IGF-1 between visits 1 and 3 (p = 0.046) and between visits 2 and 3 (p = 0.048). In conclusion, this pilot study demonstrates an inverse correlation between BNP and growth factors, suggesting that the heart failure state associated with this physiology may play a mechanistic role in impaired growth.

Increased Circulating Endothelin 1 Is Associated With Postoperative Hypoxemia in Infants With Single-Ventricle Heart Disease Undergoing Superior Cavopulmonary Anastomosis.

Background Inadequate pulmonary vascular growth results in morbidity for many children with single-ventricle heart disease (SVHD). Endothelin 1 (ET1) is a potent vasoconstrictor and stimulator of pulmonary artery smooth muscle proliferation. Circulating ET1 levels and their association with outcomes have not been studied during early SVHD palliation. We aimed to define circulating levels of ET1 in patients with SVHD undergoing stage 2 palliation and evaluate their relationship to postoperative hypoxemia. We hypothesized that patients with SVHD with higher ET1 concentration would have a greater post-stage 2 hypoxemia. Methods and Results Prospective cohort study of 55 subjects with SVHD undergoing stage 2 palliation and 50 controls. Samples for ET1 analysis were collected at preoperation (systemic and pulmonary vein) and 2, 24, and 48 hours postoperation for cases and a single time point for controls. The primary outcome was percentage of first 48 postoperative hours with clinically significant hypoxemia (saturation, <70%). ET1 concentration was lower in preoperative cases than controls (2.2 versus 2.7 pg/mL; P=0.0015) and in the pulmonary vein than systemic vein (1.7 versus 2.2 pg/mL; P<0.001). ET1 level increased by 2 hours postoperation and trended back to baseline by 48 hours. Higher preoperative pulmonary vein ET1 and 2 hours postoperative ET1 were associated with larger hypoxemia burden (10.6% versus 2.7% [P=0.0081]; and 7.6% versus 3.2% [P=0.01], respectively). Multivariable testing demonstrated ET1 concentration and cardiopulmonary bypass time were associated with hypoxemia, whereas catheterization measurements and clinical variables were not. Conclusions Infants with SVHD with higher perioperative ET1 concentration experience more post-stage 2 hypoxemia. ET1 activity may be a modifiable risk factor of pulmonary vascular inadequacy for stage 2 palliation.

Determinants of soluble angiotensin-converting enzyme 2 concentrations in adult patients with complex congenital heart disease.

BACKGROUND: Angiotensin-converting enzyme (ACE) 2 is known to be a functional receptor for SARS-CoV-2 in the current pandemic. Soluble ACE2 (sACE2) concentrations are elevated in patients with various cardiovascular disorders including heart failure. METHODS: In a total of 182 consecutive adult patients with complex congenital heart disease (CHD) and 63 healthy controls, sACE2 concentrations were measured in serum using the Human ACE2® assay by Cloud-Clone Corporation and associated with clinical, laboratory and echocardiographic parameters. RESULTS: Median sACE2 levels were increased in patients with complex CHD as compared to healthy controls (761.9 pg/ml vs 365.2 pg/ml, p < 0.001). Moreover, sACE2 concentrations were significantly elevated in patients with a higher NYHA class ≥ III (1856.2 pg/ml vs 714.5 pg/ml in patients with NYHA class I/II, p < 0.001). Using linear regression analysis, higher sACE2 levels were associated with a higher NYHA class ≥ III, more severe CHD, a morphological left systemic ventricle, higher creatinine and the use of mineralocorticoid receptor antagonists (MRA) in the univariable model. The use of ACE inhibitors or angiotensin receptor blockers (ARB) was associated with lower sACE2 levels. In the multivariable model, higher sACE2 levels were independently associated with a higher NYHA class ≥ III (p = 0.002) and lower sACE2 levels with the use of ACE inhibitors or ARB (p = 0.001). CONCLUSION: Soluble ACE2 concentrations were significantly increased in all types of complex CHD with highest levels found in patients with NYHA class ≥ III. Moreover, a higher NYHA class ≥ III was the most significant determinant that was independently associated with elevated sACE2 concentrations.

Copeptin: Prognostic Relevance as a Perioperative Marker in Pediatric Cardiac Surgery.

BACKGROUND: Copeptin is a cleavage product of vasopressin. This study aimed to figure out if copeptin would be a suitable biomarker in patients with congenital heart disease in the postoperative course. METHODS: The primary outcome endpoint of this study was the change in copeptin concentration perioperatively in patients with congenital heart disease after surgery, with the use of a cardiopulmonary bypass. Three blood samples were taken from 81 patients up to 6 years of age in order to evaluate changes in copeptin concentration. RESULTS: Significant increase of copeptin concentration was shown between the first and second blood draws as well as between the first and third blood draws (Ps < .001). Additionally, positive and significant correlations (r ≥ .27) between the cardiopulmonary bypass times, The Society of Thoracic Surgeons and European Association for Cardio-Thoracic Surgery mortality category, the inotropic score, the duration of mechanical ventilation, the length of stay at the intensive care unit (ICU), the length of stay at the hospital, and the preoperative as well as the ICU copeptin levels were found. CONCLUSIONS: Copeptin showed a tendency to predict the clinical outcome of patients after congenital heart surgery. Patients with higher copeptin levels underwent more complex procedures, had longer cardiopulmonary bypass times, required more catecholamine support, needed longer time of invasive ventilation, and had longer overall stay and ICU stay.

Gamma-glutamyl transferase and cardiovascular events in patients with congenital heart disease.

INTRODUCTION: Serum gamma-glutamyl transferase activity (GGT) seems to predict cardiovascular events in different populations. However, no data exist on patients with congenital heart disease (CHD). METHODS: Observational, analytic, prospective cohort study design involving CHD patients and a control population to determine the effect of GGT levels on survival. RESULTS: A total of 589 CHD patients (58% males, 29 ± 14 years old) and 2745 matched control patients were followed up. A total of 69 (12%) CHD patients had a major acute cardiovascular event (MACE) during the follow-up time (6.1 [0.7-10.4] years). Patients with CHD and a GGT >60 U/L were significantly older, more hypertensive and dyslipidemic, had a worse NYHA functional class and a greater anatomical complexity than CHD patients with a GGT ≤60 U/L. The binary logistic regression analysis showed that age, a great CHD anatomical complexity, and having atrial fibrillation/flutter were the predictive factors of higher GGT levels (>60 U/L). The Kaplan-Meier analysis showed that patients with CHD and a GGT concentration above 60 UL showed the lowest probability of survival compared to that of CHD with GGT ≤60 U/L and controls irrespective of their GGT concentrations (p < .001). Similarly, the multivariable Cox regression analysis found an independent association between higher GGT levels (>60 U/L) and a worse prognosis (HR 2.44 [1.34-4.44], p = .003) among patients with CHD. CONCLUSION: Patients with CHD showed significant higher GGT levels than patients in the control group having those with higher GGT concentrations (>60 U/L) the worst survival.

Characterization of Circulating and Urinary Biomarkers in the Fontan Circulation and Their Correlation With Cardiac Imaging.

Several circulating biomarkers have been found to play a role in the surveillance and risk stratification of heart failure without congenital heart disease, but these have not been widely studied in patients with single ventricles palliated with a Fontan operation. Imaging predictors of worse outcomes in this population include ventricular dilation and dysfunction. Patients who weighed >30 kg with a Fontan circulation referred for cardiac magnetic resonance imaging were invited to participate in the study. Blood and urine samples were obtained at the time of imaging and multiple conventional and novel biomarkers were measured. A total of 82 patients with a median age of 18 years were enrolled. Among the novel biomarkers, N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity troponin T had the strongest correlation with ventricular dilation and dysfunction. NT-ProBNP >100 pg/ml has a sensitivity of 91% for the detection of significant ventricular dilation (end-diastolic volume >120 ml/body surface area1.3) and 82% for detection of ejection fraction <50%. The urinary neutrophil gelatinase-associated lipocalin-2 to creatinine ratio correlated with ejection fraction and estimated glomerular filteration rate. In conclusion, abnormalities in biomarkers of heart failure are common in ambulatory, largely asymptomatic patients with Fontan circulation. NT-ProBNP may serve as a sensitive marker for the identification of patients with significant ventricular dilation or dysfunction. Further work is needed to understand how these easily measured circulating biomarkers may be integrated into clinical care.

Predicting Major Adverse Cardiovascular Events in Children With Age-Adjusted NT-proBNP.

BACKGROUND: N-terminal pro-B-type natriuretic peptide (NT-proBNP) is frequently used as a valuable prognostic biomarker in cardiac diseases. In children, however, it has not been established because of its strong age dependency. To overcome this obstacle, we recently introduced the zlog value of N-terminal pro-B-type natriuretic peptide (zlog-proBNP) as an age-adjusted reference. OBJECTIVES: This study evaluates the prognostic power of zlog-proBNP for the occurrence of major adverse cardiovascular events (MACE) throughout childhood in patients with congenital heart diseases (CHD). METHODS: A total of 910 children with CHD (median age 5 months; range 0.0-18.0 years) were included. MACE was defined as death, resuscitation, mechanical circulatory support, or hospitalization caused by cardiac decompensation. Because the physiological NT-proBNP concentration decreases significantly during childhood, zlog values were applied for an age-independent evaluation. RESULTS: MACE occurred in 138 children during a median follow-up of 6 months (range 1 day to 7.6 years). High zlog-proBNP values (>+3.0) were most strongly associated with adverse events (n = 93; adjusted HR: 21.1; 95% CI: 2.9-154.2; P < 0.001). Among all evaluated indicators, zlog-proBNP was the best predictor for MACE (adjusted HR: 1.52; 95% CI: 1.31-1.76; P < 0.001) along with age and predictively superior to absolute NT-proBNP values. A cutoff value of +1.96 (age-independent upper limit of the physiological NT-proBNP concentration) achieved a negative predictive value of >96%. CONCLUSIONS: Zlog-proBNP overcomes the strong age dependency of NT-proBNP and is a powerful prognostic marker for age-independent exclusion and prediction of MACE in children with CHD. We therefore expect zlog-proBNP to play a pivotal role in the future management of children with heart diseases.

A prospective cohort study on association of first-trimester serum biomarkers and risk of isolated foetal congenital heart defects.

BACKGROUND: This study aims to assess the association between first-trimester biomarkers in foetuses with a non-chromosomal congenital heart defect (CHD) and compares it to the matched healthy foetuses. METHOD: Nuchal Translucency (NT), Pregnancy-Associated Plasma Protein-A (PAPP-A) and free beta-human Chorionic Gonadotropin (ß-hCG) were evaluated in 56 isolated foetal heart defects and 224 controls. The CHDs were further divided into Critical CHD (C-CHD) and Non-critical CHD (N-CHD) groups. RESULTS: The multiple of the median (MoM) values for PAPP-A were significantly lower (0.87 MoM vs. 0.92 MoM; p = 0.008) in the total CHD group than in controls. The median of foetal NT values was significantly higher in the total CHDs than in controls (1.16 MoM vs. 1.03 MoM; p < 0.001), especially for C-CHDs (1.28 MoM; P < 0.001). There were no significant differences in terms of PAPP-A (p = 0.779) and foetal NT values (p = 0.760) between the N-CHDs and control groups. There were no significant differences within the groups based on free ß-hCG, except for a lower ß-hCG in C-CHD group than in the control group (0.95 MoM vs. 1.11 MoM; p = 0.022). CONCLUSION: Lower PAPP-A levels and increased NT thickness were associated with an increased risk of CHDs, especially the critical type of CHDs.Clinical significanceMaternal serum PAPP-A, measured in the first trimester, is significantly lower in CHD.Foetal NT is significantly thicker in foetuses with CHD, especially those with critical CHD.Maternal serum ß-hCG was only decreased among critical CHD group.

MicroRNAs in Fetal Umbilical Cord Blood as a Prenatal Screening Tool for Congenital Heart Disease.

OBJECTIVE: MicroRNAs (miRNAs) have been used as molecular markers for various diseases. This study aimed to evaluate the predicted performance of miRNAs in fetal umbilical cord blood for detecting congenital heart disease (CHD). METHODS: In this retrospective cohort study, a total of 60 pregnant women (involving 30 fetuses with CHD and 30 normal fetuses requiring induction of labor) were included. Umbilical cord blood was collected for miRNA measurement. Expression levels of the miRNAs were detected by qRT-PCR. The predictive accuracy of miRNA was assessed by constructing a receiver operating characteristic (ROC) curve and evaluated by calculating the area under the curve (AUC). The point biserial correlation coefficient (PBCC) was analyzed to evaluate the correlation of miRNA with CHD. RESULTS: The CHD group and control group were well-balanced in age, gravidity, and parity. miRNA-133 was not detected in all subjects. Subjects with CHD fetuses had significantly lower levels of miRNA-1, miRNA-208, and miRNA-499. Different types of CHD showed different variation trends of miRNA expression. Correlation analysis showed that expression levels of miRNA-1, miRNA-208, and miRNA-499 were negatively correlated with the occurrence of CHD, with a PBCC of -0.65, -0.47, and -0.60, respectively. miRNA-1, miRNA-208, and miRNA-499 displayed an AUC of 0.86 (95% CI, 0.76-0.96; p<0.001), 0.75 (95% CI, 0.63-0.87; p=0.009), and 0.84 (95% CI, 0.74-0.95; p<0.001), respectively, for discriminating CHD from normal fetuses, with cut-off values of 0.795, 0.835, and 0.795, respectively. CONCLUSION: The expression levels of miRNA-1, miRNA-208, and miRNA-499 in umbilical cord blood may be useful for predicting fetal CHD. The findings indicated that miRNAs have the potential to be a prenatal screening tool in the early diagnosis of CHD.

Risk Factors Associated with an Increased Risk of Deep Sternal Wound Infections in Patients After Coronary Artery Bypass Grafting and Heart Defect Surgery.

BACKGROUND: Despite improvements over time with regard to morbidity, mortality, and long-term survival, deep sternal wound infection (DSWI) continues to be a major complication after open-heart surgery. This is why it is important to identify possible risk factors for postoperative development of DSWI in patients undergoing coronary artery bypass grafting and valve replacement. The aim of this study was to identify the risk factors for postoperative development of deep sternal wound infection in patients after coronary artery bypass grafting and heart defect surgery at the Department of Thoracic, Cardiac, and Vascular Surgery of the Hospital of Lithuanian University of Health Sciences. METHODS: This retrospective study analyzed 201 patients, who underwent coronary artery bypass grafting and heart defect surgery between January 2017 and December 2018. The case group contained 45 patients, who had to be reoperated because of deep sternal wound infection, and the control group consisted of 156 randomly selected patients. For descriptive statistics, we used means, median values, ranges, standard deviations, and 95% confidence intervals, where appropriate. Categorical data were analyzed using the chi-square or Fisher's exact test. Student T-test and Mann-Whitney used to compare numerical variables. Logistic regression model adjusting for age and gender was used to compare the risk of infection. A P-value of < 0.05 was considered to be statistically significant. SPSS 26.0 was used for calculations. RESULTS: Logistic regression analysis revealed that independent risk factors for sternal wound infection were high BMI (odds ratio [OR] 1.15, CI 1.06-1.24), preoperative CRP (OR 1.08, CI 1.01-1.16), long duration of cardiopulmonary bypass (OR 1.02, CI 1.01-1.03), intraoperative anemia (OR 0.97, CI 0.95-0.99), and postoperative CRP concentration (OR 1.10; CI 1.05-1.16). CONCLUSIONS: Preoperative assessment to identify obese individuals as being at risk and techniques to minimize the duration of surgery and intraoperative blood loss may help reduce postoperative deep sternal wound infections.

Impact of Protein-Losing Enteropathy on Inflammatory Biomarkers and Vascular Dysfunction in Fontan Circulation.

Fontan palliation has improved survival for single ventricle patients, but long-term complications persist including cardiovascular dysfunction, neurohormonal abnormalities, and protein-losing enteropathy (PLE). Although chronic inflammation contributes to morbidity, an association between inflammation and vascular dysfunction has not been studied. We assessed inflammation and vascular function in 31 Fontan-palliated patients (52% male, median age 14.3 years), including 10 PLE+. Fontan circulation was associated with altered inflammatory cytokines (TNF-α: mean 2.5 ± 1.4 vs. 0.7 ± 0.2 pg/ml, p < 0.0001; sTNFR2: 371 ± 108 vs. 2694 ± 884 pg/ml, p < 0.0001) and vascular dysfunction [log-transformed reactive hyperemia index (lnRHI) 0.28 ± 0.19 vs. 0.47 ± 0.26, p < 0.01; augmentation index (AI) -2.9 ± 13.8 vs. -16.3 ± 12.0, p = 0.001; circulating endothelial progenitor cells (cEPCs) 5.0 ± 8.1 vs. 22.8 ± 15.9, p = 0.0002)]. Furthermore, PLE+ patients showed greater inflammation (IFN-γ 6.3 ± 2.2 vs. 11.5 ± 7.9 pg/ml, p = 0.01; sTNFR1: 1181 ± 420 vs. 771 ± 350 pg/ml, p = 0.01) and decreased arterial compliance (AI: 5.4 ± 17.1 vs. -6.8 ± 10.2, p = 0.02) than PLE- patients. Circulating EPCs, but not inflammatory cytokines, were inversely associated with arterial stiffness in Fontan patients. In conclusion, chronic inflammation and vascular dysfunction are observed after Fontan operation, with greater inflammation and arterial stiffness in Fontan patients with active PLE. However, there is no clear association between inflammatory cytokines and vascular dysfunction, suggesting these pathophysiologic processes are not mechanistically linked.

Comparison of Del Nido and Blood Cardioplegia in Pediatric Patients Undergoing Surgical Repair for Congenital Heart Disease.

The aim of the study is to investigate the impact of two different cardioplegia solutions, the del Nido (dN) and blood cardioplegia (BC), on postoperative troponin concentrations, vasoactive-inotrope score, and length of hospital stay in pediatric patients undergoing cardiovascular surgery for CHD. 80 subjects aged between 1 and 120 months who were scheduled for surgical repair for a CHD were prospectively enrolled in this study. Study subjects were allocated to one of the study groups using simple randomization technique as follows: The del Nido cardioplegia group (n = 40, median age 8.5 [5.5-14] months) and conventional blood cardioplegia group (n = 40, median age 11 [5-36] months). Aortic cross-clamp time and cardiopulmonary bypass time were recorded in all subjects. Troponin I and vasoactive-inotropic score, which indicates the amount of cardiovascular support by various inotropes or vasopressors, were recorded following the repair. The difference in troponin I, vasoactive-inotropic score (VIS), length of ICU stay, and length of hospital stay between the two groups was the primary outcome measure of this study. The volume of cardioplegia was significantly lower in dN group than that of the BC group (p < 0.001). Cardiopulmonary bypass time and aortic cross-clamp time were significantly shorter in subjects receiving dN cardioplegia than those receiving BC (p = 0.006, and p = 0.001, respectively). Subjects assigned to BC had higher Troponin I concentrations at postoperative 24th hour compared to subjects receiving dN cardioplegia [1.60 (0.92-2.49) ng/mL vs. 1.03 (0.55-1.83) ng/mL, p = 0.045]. VIS was also significantly higher in BC group at 24th [10 (10-13) vs. 10 (5-10), p = 0.032] and 48th hours [10 (1.5-10) vs. 0 (0-10), p = 0.005] compared to that of the dN cardioplegia group. The median extubation time was 7.5 (3.5-20.5) hours in dN cardioplegia group and 5 (4-10) hours in the BC group (p = 0.384). There were no significant differences between the groups with respect to the length of ICU stay and length of hospital stay. No mortality and no significant arrhythmias requiring medical or electrical cardioversion were noted in any of the groups. In conclusion, dN cardioplegia provides shorter aortic cross-clamp time and cardiopulmonary bypass time, and lower postoperative troponin I concentration and vasoactive-inotrope scores compared to BC in pediatric subjects undergoing surgical repair for CHD. However, lengths of ICU and hospital stay are similar in dN cardioplegia and BC groups.

Cerebral oxygen saturation and cerebrovascular instability in newborn infants with congenital heart disease compared to healthy controls.

OBJECTIVE: Infants with Congenital Heart Disease (CHD) are at risk for developmental delays, though the mechanisms of brain injury that impair development are unknown. Potential causes could include cerebral hypoxia and cerebrovascular instability. We hypothesized that we would detect significantly reduced cerebral oxygen saturation and greater cerebrovascular instability in CHD infants compared to the healthy controls. METHODS: We performed a secondary analysis on a sample of 43 term infants (28 CHD, 15 healthy controls) that assessed prospectively in temporal cross-section before or at 12 days of age. CHD infants were assessed prior to open-heart surgery. Cerebral oxygen saturation levels were estimated using Near-Infrared Spectroscopy, and cerebrovascular stability was assessed with the response of cerebral oxygen saturation after a postural change (supine to sitting). RESULTS: Cerebral oxygen saturation was 9 points lower in CHD than control infants in both postures (ß = -9.3; 95%CI = -17.68, -1.00; p = 0.028), even after controlling for differences in peripheral oxygen saturation. Cerebrovascular stability was significantly impaired in CHD compared to healthy infants (ß = -2.4; 95%CI = -4.12, -.61; p = 0.008), and in CHD infants with single ventricle compared with biventricular defects (ß = -1.5; 95%CI = -2.95, -0.05; p = 0.04). CONCLUSION: CHD infants had cerebral hypoxia and decreased cerebral oxygen saturation values following a postural change, suggesting cerebrovascular instability. Future longitudinal studies should assess the associations of cerebral hypoxia and cerebrovascular instability with long-term neurodevelopmental outcomes in CHD infants.

Introduction of precordial Doppler ultrasound to confirm correct peripheral venous access during general anesthesia in children: A preliminary study.

BACKGROUND: Delayed identification of infiltration and dysfunction of peripheral intravenous (PIV) access can lead to serious consequences during general anesthesia in children. This preliminary study aimed to describe the application of precordial Doppler ultrasound during general anesthesia in children to detect and confirm the correct PIV access and to evaluate the accuracy of this method. METHODS: This was a single-center, preliminary study that was conducted in children (<18 years) who were scheduled for elective surgeries between October 2019 and March 2020. Rater anesthesiologists judged the change in precordial Doppler sound (S test) before and after injection of 0.5 mL/kg of normal saline (NS) via PIV. Blood flow velocity before and after NS injection was recorded, and multiple cutoff points were set to analyze the accuracy of detecting the infiltration and dysfunction of PIV catheter (V test). RESULTS: The total incidence of peripheral infiltration and dysfunction of PIV catheter was 7/512 (1.4%). In the S test, the sensitivity, specificity, positive and negative likelihood ratios, and area under the receiver-operating characteristic curves (AUCs) were 5/7 (71.4%; 95% confidence interval [CI], 29.0%-96.3%), 490/505 (97.0%; 95% CI, 95.1%-98.3%), 24.0, 0.29, and 0.84, respectively. The V test showed that the reasonable threshold of blood flow velocity change was 1.0 m/s, with sensitivity, specificity, positive and negative likelihood ratios, and AUC of 4/7 (57.1%; 95% CI, 18.4%-90.1%), 489/505 (96.8%; 95% CI, 94.9%-98.2%), 18.0 and 0.44, and 0.84, respectively. CONCLUSIONS: This preliminary study demonstrated that precordial Doppler ultrasound is a feasible, easy-to-use, and noninvasive technique with good accuracy to confirm the correct PIV access during general anesthesia in children. However, its accuracy requires further evaluation.

Fontan-Associated Dyslipidemia.

Background Hypocholesterolemia is a marker of liver disease, and patients with a Fontan circulation may have hypocholesterolemia secondary to Fontan-associated liver disease or inflammation. We investigated circulating lipids in adults with a Fontan circulation and assessed the associations with clinical characteristics and adverse events. Methods and Results We enrolled 164 outpatients with a Fontan circulation, aged ≥18 years, in the Boston Adult Congenital Heart Disease Biobank and compared them with 81 healthy controls. The outcome was a combined outcome of nonelective cardiovascular hospitalization or death. Participants with a Fontan (median age, 30.3 [interquartile range, 22.8-34.3 years], 42% women) had lower total cholesterol (149.0±30.1 mg/dL versus 190.8±41.4 mg/dL, P<0.0001), low-density lipoprotein cholesterol (82.5±25.4 mg/dL versus 102.0±34.7 mg/dL, P<0.0001), and high-density lipoprotein cholesterol (42.8±12.2 mg/dL versus 64.1±16.9 mg/dL, P<0.0001) than controls. In those with a Fontan, high-density lipoprotein cholesterol was inversely correlated with body mass index (r=-0.30, P<0.0001), high-sensitivity C-reactive protein (r=-0.27, P=0.0006), and alanine aminotransferase (r=-0.18, P=0.02) but not with other liver disease markers. Lower high-density lipoprotein cholesterol was independently associated with greater hazard for the combined outcome adjusting for age, sex, body mass index, and functional class (hazard ratio [HR] per decrease of 10 mg/dL, 1.37; 95% CI, 1.04-1.81 [P=0.03]). This relationship was attenuated when log high-sensitivity C-reactive protein was added to the model (HR, 1.26; 95% CI, 0.95-1.67 [P=0.10]). Total cholesterol, low-density lipoprotein cholesterol, and triglycerides were not associated with the combined outcome. Conclusions The Fontan circulation is associated with decreased cholesterol levels, and lower high-density lipoprotein cholesterol is associated with adverse outcomes. This association may be driven by inflammation. Further studies are needed to understand the relationship between the severity of Fontan-associated liver disease and lipid metabolism.

Noninvasive screening for congenital heart defects using a serum metabolomics approach.

OBJECTIVE: Heart anomalies represent nearly one-third of all congenital anomalies. They are currently diagnosed using ultrasound. However, there is a strong need for a more accurate and less operator-dependent screening method. Here we report a metabolomics characterization of maternal serum in order to describe a metabolomic fingerprint representative of heart congenital anomalies. METHODS: Metabolomic profiles were obtained from serum of 350 mothers (280 controls and 70 cases). Nine classification models were built and optimized. An ensemble model was built based on the results from the individual models. RESULTS: The ensemble machine learning model correctly classified all cases and controls. Malonic, 3-hydroxybutyric and methyl glutaric acid, urea, androstenedione, fructose, tocopherol, leucine, and putrescine were determined as the most relevant metabolites in class separation. CONCLUSION: The metabolomic signature of second trimester maternal serum from pregnancies affected by a fetal heart anomaly is quantifiably different from that of a normal pregnancy. Maternal serum metabolomics is a promising tool for the accurate and sensitive screening of such congenital defects. Moreover, the revelation of the associated metabolites and their respective biochemical pathways allows a better understanding of the overall pathophysiology of affected pregnancies.