Search

Tuberous sclerosis complex is associated with the occurrence of cardiac rhabdomyomas that may result in life‐threatening arrhythmia unresponsive to standard antiarrhythmic therapy. We report the case of an infant with multiple cardiac rhabdomyomas who developed severe refractory supraventricular tachycardia (SVT) that was successfully treated with everolimus. Pharmacological mTOR inhibition rapidly improved arrhythmia within few weeks after treatment initiation and correlated with a reduction in tumor size. Intermediate attempts to discontinue everolimus resulted in rhabdomyoma size rebound and recurrence of arrhythmic episodes, which resolved on resumption of therapy. While everolimus treatment led to successful control of arrhythmia in the first years of life, episodes of SVT reoccurred at the age of 6 years. Electrophysiologic testing confirmed an accessory pathway that was successfully ablated, resulting in freedom of arrhythmic events. In summary we present an in‐depth evaluation of the long‐term use of everolimus in a child with TSC‐associated SVT, including the correlation between drug use and arrhythmia outcome. This case report provides important information on the safety and efficacy of an mTOR inhibitor for the treatment of a potentially life‐threatening cardiac disease manifestation in TSC for which the optimal treatment strategy is still not well established. [ABSTRACT FROM AUTHOR]

Background and Aims Childhood-onset cardiomyopathies are rare and poorly characterized. This study examined the baseline characteristics and 1-year follow-up of children with cardiomyopathy in the first European Cardiomyopathy Registry. Methods Prospective data were collected on individuals aged 1–<18 years enrolled in the European Society of Cardiology EURObservational Research Programme Cardiomyopathy and Myocarditis long-term registry (June 2014–December 2016). Results A total of 633 individuals aged ≤18 years with hypertrophic [HCM; n = 388 (61.3%)], dilated [DCM; n = 206 (32.5%)], restrictive [RCM; n = 28 (4.4%)], and arrhythmogenic right ventricular cardiomyopathy [ARVC; n = 11 (1.7%)] were enrolled by 23 referral centres in 14 countries. Median age at diagnosis was 4.0 [interquartile range (IQR) 0–10] years, and there was a male predominance [ n = 372 (58.8%)] across all subtypes, with the exception of DCM diagnosed <10 years of age; 621 (98.1%) patients were receiving cardiac medication and 80 (12.6%) had an implantable cardioverter-defibrillator. A total of 253 patients (253/535, 47.3%) had familial disease. Genetic testing was performed in 414 (67.8%) patients with a pathogenic or likely pathogenic variant reported in 250 (60.4%). Rare disease phenocopies were reported in 177 patients (28.0%) and were most frequent in patients under 10 years [142 (30.9%) vs. 35 (19.6%); P =.003]. Over a median follow-up of 12.5 months (IQR 11.3–15.3 months), 18 patients (3.3%) died [HCM n = 9 (2.6%), DCM n = 5 (3.0%), RCM n = 4 (16.0%)]. Heart failure events were most frequent in RCM patients (36.0%). Conclusions The findings confirm the heterogeneous aetiology of childhood cardiomyopathies and show a high frequency of familial disease. Outcomes differed by cardiomyopathy subtype, highlighting a need for disease-specific evaluation and treatment. [ABSTRACT FROM AUTHOR]

(1) Background: In propionic acidemia (PA), myocardial involvement often leads to progressive cardiac dysfunction of the left ventricle (LV). Cardiomyopathy (CM) is an important contributor to mortality. Although known to be of prognostic value in CM, there are no published data on right ventricular (RV) function in PA patients. (2) Methods: In this cross-sectional single-center study, systolic and diastolic RV function of PA patients was assessed by echocardiography, including frequency, onset, and combinations of echocardiographic parameters, as well as correlations to LV size and function. (3) Results: N = 18 patients were enrolled. Tricuspid annulus S' was abnormal in 16.7%, RV-longitudinal strain in 11.1%, tricuspid annular plane systolic excursion (TAPSE) in 11.1%, Tricuspid valve (TV) E/e' in 33.3%, and TV E/A in 16.7%. The most prevalent combinations of pathological parameters were TV E/A + TV E/e' and TAPSE + TV S'. With age, the probability of developing abnormal RV function increases according to age-dependent normative data. There is a significant correlation between TAPSE and mitral annular plane systolic excursion (MAPSE), and RV/LV-longitudinal strain (p ≤ 0.05). N = 5 individuals died 1.94 years (mean) after cardiac evaluation for this study, and all had abnormal RV functional parameters. (4) Conclusions: Signs of diastolic RV dysfunction can be found in up to one third of individuals, and systolic RV dysfunction in 16.7% of individuals in our cohort. RV function is impaired in PA patients with a poor outcome. RV functional parameters should be used to complement clinical and left ventricular echocardiographic findings. [ABSTRACT FROM AUTHOR]

Riociguat, a soluble guanylate cyclase stimulator, is approved for treatment of adults with pulmonary arterial hypertension (PAH). The safety, tolerability, and pharmacokinetics (PK) of oral riociguat in a pediatric population with PAH was assessed in PATENT–CHILD (NCT02562235), a multicenter, single‐arm, 24‐week, open‐label, Phase 3 study. Patients aged 6–17 years in World Health Organization functional class (WHO‐FC) I–III treated with stable endothelin receptor antagonists and/or prostacyclin analogs received riociguat equivalent to 0.5–2.5 mg three times daily in adults, as either oral pediatric suspension or tablets, based on bodyweight. Primary outcomes were safety, tolerability, and PK of riociguat. Twenty‐four patients (mean age 12.8 years), 18 of whom were in WHO‐FC II, were enrolled. Adverse events (AEs), mostly mild or moderate, were reported in 20 patients (83%). Four patients (17%) experienced a serious AE; all resolved by study end and two (8%) were considered study‐drug related. Hypotension was reported in three patients and hemoptysis in one (all mild/moderate intensity). Riociguat plasma concentrations in pediatric patients were consistent with those published in adult patients. From baseline to Week 24, mean ± standard deviation increase in 6‐minute walking distance was 23 ± 69 m (n = 19), and mean decrease in NT‐proBNP was –66 ± 585 pg/ml (n = 14). There was no change in WHO‐FC. Two patients experienced clinical worsening events of hospitalization for right heart failure. PK results confirmed a suitable riociguat dosing strategy for pediatric patients with PAH. The data suggest an acceptable safety profile with potential efficacy signals. [ABSTRACT FROM AUTHOR]

Background Dextrocardia is a congenital anomaly in which the apex of the heart is abnormally located on the right side of the chest. Situs solitus describes viscera that are in the normal position, with the stomach on the left side. In these patients, implantation of transvenous implantable cardioverter-defibrillator (ICD) can be limited by anatomical abnormalities commonly associated with this condition. Case summary We present the case of a young female patient with absent right atrioventricular connection, morphologically left systemic ventricle, muscular restrictive ventricular septal defect, and dextrocardia with situs solitus who was indicated for secondary prophylactic ICD implantation after resuscitation for polymorphic ventricular tachycardia. Due to a bilateral bidirectional Glenn anastomosis, transvenous access via the vena cava superior to the right ventricle could not be achieved. For this reason, we successfully implanted a subcutaneous ICD (S-ICD) with an individually optimized right parasternal electrode position. Potential complications of epimyocardial implantation via re-thoracotomy could thus be circumvented. Discussion In patients with complex congenital heart disease, the S-ICD is an effective method of preventing sudden cardiac death. Our case report demonstrates the feasibility of left S-ICD implantation even in the presence of dextrocardia with situs solitus. [ABSTRACT FROM AUTHOR]

Heart failure is a significant burden among the multiple complications that adults with congenital heart disease (CHD) may encounter. There is an increasing need to address the long-term implications of heart failure in affected patients, as the diagnosis and treatment of heart failure in CHD are particularly challenging due to the complexity of the various underlying congenital cardiac anomalies and the residual cardiac defects. Moreover, management strategies for CHD often differ from those for acquired heart disease. Therefore, the development of a comprehensive database is crucial to enhance the understanding and improve the care of adults with heart failure due to CHD. The prospective Pathfinder-CHD Registry is tailored to capturing and analyzing data on heart failure in ACHD, encompassing all key aspects of heart failure management, including demographic details, medical history, laboratory results, electrocardiographic and other cardiac imaging findings, as well as information on medical, surgical or interventional treatment, and clinical outcomes. As data privacy and security are paramount considerations in this endeavor, robust measures are implemented to ensure that patient confidentiality is upheld, with adherence to relevant ethical guidelines and data protection regulations. In conclusion, the Pathfinder-CHD Registry is designed to improve the care, management, and outcomes of these complex diseases, and to enable longitudinal studies to examine prevalence, disease progression, risk factors, and the effectiveness of various treatment strategies. By identifying patterns and trends within the ACHD population, this database can support the development of evidence-based strategies, tailored therapeutic approaches, and prognostic models to improve the care and outcomes of adults with CHD and heart failure. The ultimate goal of this registry is to serve as a platform for collaborative research, fostering multidisciplinary efforts and facilitating the evaluation of new, targeted therapies, interventions, and guidelines specifically designed for managing this growing population of adults with heart failure due to CHD. [ABSTRACT FROM AUTHOR]

Abstract Background Aim of this prospective study was to compare clinical and genetic findings in children with idiopathic or heritable pulmonary arterial hypertension (I/HPAH) with children affected with congenital heart defects associated PAH (CHD-APAH). Methods Prospectively included were 40 consecutive children with invasively diagnosed I/HPAH or CHD-APAH and 117 relatives. Assessment of family members, pedigree analysis and systematic screening for mutations in TGFß genes were performed. Results Five mutations in the bone morphogenetic protein type II receptor (BMPR2) gene, 2 Activin A receptor type II-like kinase-1 (ACVRL1) mutations and one Endoglin (ENG) mutation were found in the 29 I/HPAH children. Two mutations in BMPR2 and one mutation in ACVRL1 and ENG, respectively, are described for the first time. In the 11 children with CHD-APAH one BMPR2 gene mutation and one Endoglin gene mutation were found. Clinical assessment of relatives revealed familial aggregation of the disease in 6 children with PAH (HPAH) and one CHD-APAH patient. Patients with mutations had a significantly lower PVR. Conclusion Mutations in different TGFß genes occurred in 8/29 (27.6%) I/HPAH patients and in 2/11 (18.2%) CHD-APAH patients and may influence the clinical status of the disease. Therefore, genetic analysis in children with PAH, especially in those with I/HPAH, may be of clinical relevance and shows the complexity of the genetic background.

We aimed at identifying the developmental stage at which leukemic cells of pediatric T‐ALLs are arrested and at defining leukemogenic mechanisms based on ATAC‐Seq. Chromatin accessibility maps of seven developmental stages of human healthy T cells revealed progressive chromatin condensation during T‐cell maturation. Developmental stages were distinguished by 2,823 signature chromatin regions with 95% accuracy. Open chromatin surrounding SAE1 was identified to best distinguish thymic developmental stages suggesting a potential role of SUMOylation in T‐cell development. Deconvolution using signature regions revealed that T‐ALLs, including those with mature immunophenotypes, resemble the most immature populations, which was confirmed by TF‐binding motif profiles. We integrated ATAC‐Seq and RNA‐Seq and found DAB1, a gene not related to leukemia previously, to be overexpressed, abnormally spliced and hyper‐accessible in T‐ALLs. DAB1‐negative patients formed a distinct subgroup with particularly immature chromatin profiles and hyper‐accessible binding sites for SPI1 (PU.1), a TF crucial for normal T‐cell maturation. In conclusion, our analyses of chromatin accessibility and TF‐binding motifs showed that pediatric T‐ALL cells are most similar to immature thymic precursors, indicating an early developmental arrest. Synopsis: Analysis of chromatin accessibility of human T‐cell precursors revealed progressive chromatin condensation during maturation. Pediatric T‐ALLs resemble the most immature populations indicating that the epigenetic landscape of this type of leukemia is most similar to the earliest thymic precursors. The chromatin of differentiating human thymocytes becomes gradually condensed during maturation.Human T‐cell differentiation leaves a detectable signature in genome‐wide chromatin accessibility, which can be used to predict thymocyte maturation stage.The chromatin architecture and TF binding motif accessibility of pediatric T‐ALLs exhibit the highest resemblance to the most immature thymic precursors.Integration of ATAC‐Seq and RNA‐Seq identifies differentially accessible and expressed genes in T‐cell leukemias in comparison to healthy T‐cell precursors.Pediatric T‐ALLs either exhibit hyper‐accessibility of DAB1 overexpressing an atypical isoform, or hyper‐accessibility of SPI1(PU.1) binding motifs as well as SPI1 overexpression. [ABSTRACT FROM AUTHOR]

Background: Depth of anesthesia may be insufficient in pediatric cardiac anesthesia if a total intravenous anesthetic regimen with opioids and midazolam is used during cardiopulmonary bypass. The advantages of sevoflurane-based balanced anesthesia may be (1) a more graduated regulation of the depth of anesthesia during cardiopulmonary bypass and (2) a reduction in postoperative ventilation time for children in comparison with total intravenous anesthesia. Aim: To evaluate a possibly positive effect of sevoflurane-based balanced anesthesia in children undergoing cardiac surgery we analyzed whether this anesthetic regimen had a significant effect related to (1) depth of anesthesia, (2) the need for opioids during cardiopulmonary bypass as well as on postoperative characteristics such as (3) time of postoperative ventilation, and (4) duration of stay in the intensive care unit in comparison with total intravenous anesthesia. Methods: In a retrospective analysis, data from heart-lung machine protocols from 2013 to 2016 were compared according to anesthetic regimen (sevoflurane-balanced anesthesia, n = 70 vs. total intravenous anesthesia, n = 65). Children (age: 8 weeks to 14 years) undergoing cardiac surgery with cardiopulmonary bypass were included. As a primary outcome measure, we compared Narcotrend® system–extracted data to detect insufficient phases of anesthetic depth during extracorporeal circulation under moderate hypothermia. Postoperatively, we measured the postoperative ventilation time and the number of days in the intensive care unit. Furthermore, we analyzed patients' specific characteristics such as opioid consumption during cardiopulmonary bypass. Regression analysis relating primary objectives was done using the following variables: anesthetic regimen, age, severity of illness/surgery, and cumulative dosage of opiates during cardiopulmonary bypass. Results: No significant differences were observed in descriptive patient characteristics (age, body weight, height, and body temperature) between the two groups. Further, no significant differences were found in depth of anesthesia by analyzing phases of superficial B1-C2-electroencephalography Narcotrend® data. No marked difference between the groups was observed for the duration of postoperative intensive care unit stay. However, the postoperative ventilation time (median (95% CI, hours)) was significantly lower in the sevoflurane-based balanced anesthesia group (6.0 (2.0-15.0)) than in the total intravenous anesthesia group (13.5 (7.0-25)). A higher dosage of opioids and midazolam was required in the total intravenous anesthesia group to maintain adequate anesthesia during cardiopulmonary bypass. Regression analysis showed an additional, significant impact of the following factors: severity of illness and severity grade of cardiac surgery (according to Aristotle) on the primary endpoint. Conclusion: In children undergoing cardiac surgery in our department, the use of sevoflurane-balanced anesthesia during cardiopulmonary bypass showed no superiority of inhalational agents over total intravenous anesthesia with opioids and benzodiazepines preventing phases of superficial anesthesia, but a marked advantage for the postoperative ventilation time compared with total intravenous anesthesia. [ABSTRACT FROM AUTHOR]

Background: In this study, we investigated the impact of the new haemodynamic definition of pulmonary arterial hypertension (PAH) as proposed by the 6th PH World Symposium on phenotypes and survival in patients with systemic sclerosis (SSc).Methods: In SSc patients who were prospectively and consecutively screened for PAH including right heart catheterisation in Heidelberg or Zurich, haemodynamic and clinical variables have been reassessed according to the new PAH definition. Patients have been followed for 3.7±3.7 (median 3.4) years; Kaplan-Meier survival analysis was performed. Patients with significant lung or left heart disease were excluded from comparative analyses.Results: The final dataset included 284 SSc patients, 146 patients (49.2%) had mean pulmonary arterial pressure (mPAP) ≤20 mm Hg, 19.3% had mPAP 21-24 mm Hg and 29.4% had mPAP ≥25 mm Hg. In the group of mildly elevated mPAP, only four patients (1.4% of the whole SSc cohort) had pulmonary vascular resistance (PVR) values ≥3 Wood Units (WU) and could be reclassified as manifest SSc-APAH. Twenty-eight (9.8%) patients with mPAP of 21-24 mm Hg and PVR ≥2 WU already presented with early pulmonary vascular disease with decreased 6 min walking distance (6MWD) (p<0.001), TAPSE (p=0.004) and pulmonary arterial compliance (p<0.001). A PVR ≥2 WU was associated with reduced long-term survival (p=0.002). PVR and 6MWD were independent prognostic predictors in multivariate analysis.Conclusion: The data of this study show that a PVR threshold ≥3 WU is too high to enable an early diagnosis of PAH. A PVR threshold ≥2 WU was already associated with pulmonary vascular disease, significantly reduced survival and would be more appropriate in SSc patients with mild PAH. [ABSTRACT FROM AUTHOR]

While Wilms tumors (WT) typically present solely with an abdominally palpable mass, rare cases exhibiting vascular tumor growth can also present with circulatory problems. Here, we report the case of a 2.5-year-old girl presenting with upper venous congestion and arterial hypertension as the primary symptoms of intraventricular tumor growth exhibiting remarkable tubular and perfused morphology. Clinical situation stabilized after initiation of neoadjuvant chemotherapy (NAC) with actinomycin D and vincristine, followed by surgical resection via laparotomy and sternotomy supported by cardiopulmonary bypass and deep hypothermia. Our results highlight the previously reported feasibility of this approach, even in primarily unstable patients. [ABSTRACT FROM AUTHOR]