Ventricular insertion site ablation of a Mahaim atriofascicular fibre in Ebstein anomaly.

Ebstein anomaly is frequently associated with accessory pathways, including Mahaim atriofascicular fibres. We herein illustrate successful Mahaim fibre ablation in Ebstein anomaly by targeting the ventricular insertion site below the tricuspid ridge.

Current diagnosis and treatment practice for pulmonary hypertension in bronchopulmonary dysplasia-A survey study in Germany (PUsH BPD).

Pulmonary hypertension (PH) is the most severe complication in preterm infants with bronchopulmonary dysplasia (BPD) and associated with significant mortality. Diagnostic and treatment strategies, however, still lack standardization. By the use of a survey study (PH in BPD), we assessed clinical practice (diagnosis, treatment, follow-up) in preterm infants with early postnatal persistent pulmonary hypertension of the newborn (PPHN) as well as at risk for or with established BPD-associated PH between 06/2018 and 10/2020 in two-thirds of all German perinatal centers with >70 very low birthweight infants/year including their cardiology departments and outpatient units. Data were analyzed descriptively by measures of locations and distributional shares. In routine postnatal care, clinical presentation and echocardiography were reported as the main diagnostic modalities to screen for PPHN in preterm infants, whereas biomarkers brain natriuretic peptide/N-terminal pro b-type natriuretic peptide were infrequently used. For PPHN treatment, inhaled nitric oxide was used in varying frequency. The majority of participants agreed to prescribe diuretics and steroids (systemic/inhaled) for infants at risk for or with established BPD-associated PH and strongly agreed on recommending respiratory syncytial virus immunization and the use of home monitoring upon discharge. Reported oxygen saturation targets, however, varied in these patients in in- and outpatient care. The survey reveals shared practices in diagnostic and therapeutic strategies for preterms with PPHN and BPD-associated PH in Germany. Future studies are needed to agree on detailed echo parameters and biomarkers to diagnose and monitor disease next to a much-needed agreement on the use of pulmonary vasodilators, steroids, and diuretics as well as target oxygen saturation levels.

Antiarrhythmic Drug Dosing in Children-Review of the Literature.

Antiarrhythmic drugs represent a mainstay of pediatric arrhythmia treatment. However, official guidelines and consensus documents on this topic remain scarce. There are rather uniform recommendations for some medications (including adenosine, amiodarone, and esmolol), while there are only very broad dosage recommendations for others (such as sotalol or digoxin). To prevent potential uncertainties and even mistakes with regard to dosing, we summarized the published dosage recommendations for antiarrhythmic drugs in children. Because of the wide variations in availability, regulatory approval, and experience, we encourage centers to develop their own specific protocols for pediatric antiarrhythmic drug therapy.

Platelets and ductus arteriosus closure in neonates.

Platelet plug formation is critically involved in murine ductus arteriosus closure and thrombocytopenia in preterm infants seems to negatively affect spontaneous and pharmacologically induced ductal closure. Furthermore, platelet dysfunction may contribute to ductal patency, especially in extremely immature infants. Neonatal platelets likely have multifaceted roles during ductal closure, such as secretion of several signaling molecules and facilitation of specific cell-cell interactions. The only available randomized-controlled trial on platelet transfusions in preterm infants with patent ductus arteriosus demonstrated that a liberal transfusion regimen did not promote ductal closure, but was associated with an increased rate of intraventricular hemorrhage. Herein, we discuss the available mechanistic evidence on the role of platelets in ductus arteriosus closure and their potential clinical implications in preterm infants. We further briefly outline future research directions aimed at a better understanding of platelet-endothelial interactions in neonatal health and disease.

Mild Acquired von Willebrand Syndrome and Cholestasis in Pediatric and Adult Patients with Fontan Circulation.

Background: Hemodynamic alterations in Fontan patients (FP) are associated with hemostatic dysbalance and Fontan-associated liver disease. Studies of other hepatopathologies indicate an interplay between cholestasis, tissue factor (TF), and von Willebrand factor (VWF). Hence, we hypothesized a relationship between the accumulation of bile acids (BA) and these hemostatic factors in FP. Methods: We included 34 FP (Phenprocoumon n = 15, acetylsalicylic acid (ASA) n = 16). BA were assessed by mass spectrometry. TF activity and VWF antigen (VWF:Ag) were determined by chromogenic assays. VWF collagen-binding activity (VWF:CB) was assessed via ELISA. Results: Cholestasis was observed in 6/34 FP (total BA ≥ 10 µM). BA levels and TF activity did not correlate (p = 0.724). Cholestatic FP had lower platelet counts (p = 0.013) from which 5/6 FP were not treated with ASA. VWF:Ag levels were increased in 9/34 FP and significantly lower in FP receiving ASA (p = 0.044). Acquired von Willebrand syndrome (AVWS) was observed in 10/34-FP, with a higher incidence in cholestatic FP (4/6) (p = 0.048). Conclusions: Cholestasis is unexpectedly infrequent in FP and seems to be less frequent under ASA therapy. Therefore, ASA may reduce the risk of advanced liver fibrosis. FP should be screened for AVWS to avoid bleeding events, especially in cholestatic states.

Accuracy of Algorithms Predicting Accessory Pathway Localization in Pediatric Patients with Wolff-Parkinson-White Syndrome.

We aimed to assess the accuracy of determining accessory pathway (AP) localization from 12 lead ECG tracings by applying 12 different algorithms in pediatric patients diagnosed with Wolff-Parkinson-White syndrome. We compared algorithm accuracy in electrophysiologic study ECG tracings with full preexcitation and resting ECG tracings. The assessing pediatric cardiologists were blinded regarding EP study results on AP localization. For exact AP location, the algorithms published by D'Avila et al. and Boersma et al. yielded the highest accuracy (58%). Distinguishing laterality, the median accuracy for predicting left or right-sided APs was 74%, while for septal APs it was 68%. We conclude that algorithms predicting AP location in pediatric patients with Wolff-Parkinson-White syndrome show low accuracy for exact AP localization. For laterality, however, accuracy was significantly higher.

Functional hepatic deterioration determined by 13C-methacetin breath test is associated with impaired hemodynamics and late Fontan failure in adults.

Background: Despite improved survival a substantial number of Fontan patients eventually develop late failure. Fontan-associated liver disease (FALD) is the most frequent end-organ dysfunction. Although impaired hemodynamics and Fontan failure correlate with FALD severity, no association between hepatic functional metabolic impairment and Fontan hemodynamics has been established. Hypothesis: Metabolic liver function measured by liver maximum function capacity test (LiMAx®) correlates with Fontan hemodynamics and Fontan failure. Methods: From 2020 to 2022, 58 adult Fontan patients [median age: 29.3 years, IQR (12.7), median follow-up time after Fontan operation: 23.2 years, IQR (8.7)] were analyzed in a cross-sectional study. Hemodynamic assessment included echocardiography, cardiopulmonary exercise testing and invasive hemodynamic evaluation. Fontan failure was defined based on commonly applied clinical criteria and our recently composed multimodal Fontan failure score. Results: LiMAx® test revealed normal maximum liver function capacity in 40 patients (>315 µg/h*kg). In 18 patients a mild to moderate impairment was detected (140-314 µg/h*kg), no patient suffered from severe hepatic deterioration (≤ 139 µg/kg*h). Fontan failure was present in 15 patients. Metabolic liver function was significantly reduced in patients with increased pulmonary artery pressure (p = 0.041. r = -0.269) and ventricular end-diastolic pressure (p = 0.033, r = -0.325), respectively. In addition, maximum liver function capacity was significantly impaired in patients with late Fontan failure (289.0 ± 99.6 µg/kg*h vs. 384.5 ± 128.6 µg/kg*h, p = 0.007). Conclusion: Maximum liver function capacity as determined by LiMAx® was significantly reduced in patients with late Fontan failure. In addition, elevated pulmonary artery pressure and end-diastolic ventricular pressure were associated with hepatic functional metabolic impairment.

An Update on Patent Ductus Arteriosus and What is Coming Next.

Patent ductus arteriosus is the most common cardiovascular condition in preterm infants. There is a significant uncertainty about when and how to close ductus arteriosus in preterm infants due to a high spontaneous closure rate even in very immature preterm infants. Diagnosis and management of patent ductus arteriosus remain a challenge for both neonatologists and pediatric cardiologists. Researchers have tried to define a balance between an expectant approach and active treatment in selected infants. This review aimed to focus on the pathophysiology and management of patent ductus arteriosus and to make suggestions about approaches that might eliminate the association of morbidities with patent ductus arteriosus.

Extremely premature infants born at 23-25 weeks gestation are at substantial risk for pulmonary hypertension.

OBJECTIVE: Extremely low gestational age newborns (ELGANs) represent an especially vulnerable population. Herein, we aimed to determine incidence and severity of pulmonary hypertension associated with bronchopulmonary dysplasia (BPD-PH) in extremely immature ELGANs (gestational age: 230/6-256/7 weeks). METHODS: In this prospective observational cohort study, we assessed BPD-PH by means of several echocardiography markers and serum N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels at 3 and 12 months of chronological age. In addition, we analyzed incidence and efficacy of pharmacologic treatment for BPD-PH. RESULTS: At 3 months 15/34 ELGANs had echocardiographic evidence of BPD-PH, while at 12 months of age 6/34 still had PH. PH-targeted therapy consisted of sildenafil monotherapy in 11 and dual oral combination therapy (sildenafil and macitentan) in four ELGANs at 3 and 12 months. CONCLUSION: 44% (15/34) of ELGANs developed BPD-PH. All received PH-targeted pharmacotherapy at 3 months, leading to hemodynamic improvements at 12 months in most infants.

Late Fontan failure in adult patients is predominantly associated with deteriorating ventricular function.

BACKGROUND: The Fontan operation is a palliative procedure and a substantial number of patients eventually experiences late Fontan circulation failure. Previous concepts of Fontan failure implicate increasing pulmonary vascular resistance (PVR) as a key contributor to late circulatory failure. However, data to support this assumption are sparse. We sought to characterize longitudinal hemodynamic and echocardiographic findings in adult failing Fontan patients. METHODS: We performed a retrospective cohort study in adult Fontan patients, identifying patients with Fontan failure. Hemodynamic, echocardiographic and clinical data were recorded. RESULTS: Of 173 adult patients (median follow-up after Fontan 20.2 years [IQR 15.7-24.3]), 48 (28%) showed signs of clinical Fontan failure. Thirty-seven patients (77.1%) exhibited ventricular dysfunction (systolic dysfunction defined by ejection fraction ≤45%, n = 22, or diastolic dysfunction defined by systemic ventricular end-diastolic pressure (SVEDP) ≥12 mmHg, n = 15). Elevated indexed PVR (≥2.5 WU*m2) was only observed in 9 (18.8%) patients. Ejection fraction declined from 60% [IQR 55-65] to 47% [IQR 35-55] during follow-up (p < 0.001). Mean pulmonary artery pressure and SVEDP increased from 11 mmHg [IQR 9-15] to 15 mmHg [IQR 12-18] and from 7 mmHg [IQR 4-10] to 11 mmHg [IQR 8-15] (both p < 0.001), respectively, while indexed PVR did not change significantly (2.1 [IQR 1.1-2.4] vs. 1.7 [IQR 1.1-2.5] WU*m2, p = 0.949). Fontan failure-associated mortality during follow-up was substantial (23/48; 48%). CONCLUSIONS: Systolic and diastolic ventricular dysfunction are frequent features in late Fontan failure in adults, while increases in PVR were rarely observed. The intricate interplay between hemodynamic compromises in Fontan failure deserves further research to optimize treatment strategies and outcome.

Soluble Receptor for Advanced Glycation End Products (sRAGE) Is a Sensitive Biomarker in Human Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) is a progressive condition with an unmet need for early diagnosis, better monitoring, and risk stratification. The receptor for advanced glycation end products (RAGE) is activated in response to hypoxia and vascular injury, and is associated with inflammation, cell proliferation and migration in PAH. For the adult cohort, we recruited 120 patients with PAH, 83 with idiopathic PAH (IPAH) and 37 with connective tissue disease-associated PAH (CTD-PAH), and 48 controls, and determined potential plasma biomarkers by enzyme-linked immunoassay. The established heart failure marker NTproBNP and IL-6 plasma levels were several-fold higher in both adult IPAH and CTD-PAH patients versus controls. Plasma soluble RAGE (sRAGE) was elevated in IPAH patients (3044 ± 215.2 pg/mL) and was even higher in CTD-PAH patients (3332 ± 321.6 pg/mL) versus controls (1766 ± 121.9 pg/mL; p < 0.01). All three markers were increased in WHO functional class II+III PAH versus controls (p < 0.001). Receiver-operating characteristic analysis revealed that sRAGE has diagnostic accuracy comparable to prognostic NTproBNP, and even outperforms NTproBNP in the distinction of PAH FC I from controls. Lung tissue RAGE expression was increased in IPAH versus controls (mRNA) and was located predominantly in the PA intima, media, and inflammatory cells in the perivascular space (immunohistochemistry). In the pediatric cohort, plasma sRAGE concentrations were higher than in adults, but were similar in PH (n = 10) and non-PH controls (n = 10). Taken together, in the largest adult sRAGE PAH study to date, we identify plasma sRAGE as a sensitive and accurate PAH biomarker with better performance than NTproBNP in the distinction of mild PAH from controls.

Immature Platelet Counts and Thrombopoietin Plasma Concentrations in Thrombocytopenic and Non-thrombocytopenic Preterm Infants.

Objective: Immature platelet counts (IPC) may prove useful in guiding platelet transfusion management in preterm neonates. However, the relationship between IPCs and thrombopoietin (Tpo) concentrations has not been evaluated in preterm neonates. Methods: Prospective cohort study in thrombocytopenic (n = 31) and non-thrombocytopenic very low birth weight (VLBW) infants (n = 38), and healthy term neonates (controls; n = 41). Absolute platelet counts (APCs), IPCs, and Tpo concentrations were assessed by a fully-automated hematological analyzer (IPC, APC) and by ELISA (Tpo concentrations) in parallel on day 1 of life (d1), d3, and d7. Results: In healthy term neonates, APCs remained stable between d1 and d3. In non-thrombocytopenic VLBW infants, APCs increased from d1 to d7, while in the thrombocytopenia group, APCs declined from d1 to d3, before they slightly increased again by d7. Median IPCs were similar in healthy term vs. non-thrombocytopenic VLBW infants and remained stable between d1 and d3 (p > 0.05). Notably, IPCs significantly increased between d3 and d7 in both non-thrombocytopenic and thrombocytopenic VLBW infants. However, in thrombocytopenic VLBW infants, IPC values were significantly lower at each time point as compared to non-thrombocytopenic VLBWs (p < 0.001). In each subgroup, Tpo concentrations increased from d1 to d3. The median Tpo concentrations were significantly higher in thrombocytopenic as compared to non-thrombocytopenic VLBW infants at d3 (p = 0.01) and d7 (p = 0.002). Discussion: Term infants, thrombocytopenic, and non-thrombocytopenic preterm infants display similar developmental changes in indices of megakaryopoietic activity. In thrombocytopenic preterm infants, however, the responsive increases in Tpo and immature platelets appear to be developmentally limited.

Current Controversy on Platelets and Patent Ductus Arteriosus Closure in Preterm Infants.

Platelets are critically involved in murine patent ductus arteriosus (PDA) closure. To date, the clinical significance of these findings in human preterm infants with PDA is still controversial. We discuss the available study data on the role of platelets for PDA closure in preterm infants: Several mostly retrospective studies have yielded conflicting results on whether thrombocytopenia contributes to failed spontaneous ductal closure. The same applies to investigations on the role of thrombocytopenia as a risk factor for unsuccessful ductus arteriosus closure by pharmacological treatment with cyclooxygenase inhibitors. Nonetheless, recent meta-analyses have concluded that thrombocytopenia constitutes an independent risk factor for both failed spontaneous and pharmacological PDA closure in preterm infants. However, the available investigations differ in regard to patient characteristics, diagnostic strategies, and treatment protocols. Several studies suggest that impaired platelet function rather than platelet number is critically involved in failure of ductus arteriosus closure in the preterm infant. A recent randomized-controlled trial on platelet transfusions in preterm infants with PDA failed to show any benefit for liberal vs. restrictive transfusion thresholds on PDA closure rates. Importantly, liberal transfusions were associated with an increased rate of intraventricular hemorrhage, and thus should be avoided. In conclusion, the available evidence suggests that thrombocytopenia and platelet dysfunction contribute to failure of spontaneous and pharmacological PDA closure in preterm infants. However, these platelet effects on PDA seem to be of only moderate clinical significance. Furthermore, platelet transfusions in thrombocytopenic preterm infants in order to facilitate PDA closure appear to cause more harm than good.