mTor-inhibition within the first days after pediatric heart transplantation is a potentially safe option to prevent cardiac allograft vasculopathy.

BACKGROUND: Immunosuppression after heart transplantation (HTX) with mammalian target of rapamycin (mTOR) inhibitors serves as a prophylaxis against rejection and to treat coronary vascular injury. However, there is little data on the early, preventive use of everolimus after pediatric HTX. METHODS: Retrospective study of 61 pediatric HTX patients (48 cardiomyopathy and 13 congenital heart disease), 28 females, median age 10.1 (range 0.1-17.9) years transplanted between 2008 and 2020. We analyzed survival, rejection, renal function, occurrence of lymphoproliferative disorder, and allograft vasculopathy together with adverse effects of early everolimus therapy combined with low-dose calcineurin inhibitors. RESULTS: Everolimus therapy was started at a median 3.9 (1-14) days after HTX. Median follow-up was 4.3 (range 0.5-11.8) years, cumulative 184 patient years. The estimated 1- and 5-year survival probability was 89% (CI 82%:98%) and 87% (CI 78%:97%). Four patients developed rejection (6.6%) (maximum 2R ISHLT criteria). No patient suffered from chronic renal failure. Three patients (4.9%) developed post-transplant lymphoproliferative disorder. Five patients suffered relevant wound-healing disorders after transplantation, four of them carrying relevant risk factors before HTX (mechanical circulatory support (n = 3), delayed chest closure after HTX (n = 3)). No recipient developed cardiac allograft vasculopathy. CONCLUSION: Initiating everolimus within the first 14 days after HTX seems to be well tolerated, enabling a low incidence of rejection, post-transplant lymphoproliferative disorders, renal failure, and reveals no evidence of cardiac allograft vasculopathy as well as good overall survival in pediatric heart transplant recipients.

Disease severity, arrhythmogenesis, and fibrosis are related to longer action potentials in tetralogy of Fallot.

BACKGROUND: Arrhythmias may originate from surgically unaffected right ventricular (RV) regions in patients with tetralogy of Fallot (TOF). We aimed to investigate action potential (AP) remodelling and arrhythmia susceptibility in RV myocardium of patients with repaired and with unrepaired TOF, identify possible correlations with clinical phenotype and myocardial fibrosis, and compare findings with data from patients with atrial septal defect (ASD), a less severe congenital heart disease. METHODS: Intracellular AP were recorded ex vivo in RV outflow tract samples from 22 TOF and three ASD patients. Arrhythmias were provoked by superfusion with solutions containing reduced potassium and barium chloride, or isoprenaline. Myocardial fibrosis was quantified histologically and associations between clinical phenotype, AP shape, tissue arrhythmia propensity, and fibrosis were examined. RESULTS: Electrophysiological abnormalities (arrhythmias, AP duration [APD] alternans, impaired APD shortening at increased stimulation frequencies) were generally present in TOF tissue, even from infants, but rare or absent in ASD samples. More severely diseased and acyanotic patients, pronounced tissue susceptibility to arrhythmogenesis, and greater fibrosis extent were associated with longer APD. In contrast, APD was shorter in tissue from patients with pre-operative cyanosis. Increased fibrosis and repaired-TOF status were linked to tissue arrhythmia inducibility. CONCLUSIONS: Functional and structural tissue remodelling may explain arrhythmic activity in TOF patients, even at a very young age. Surprisingly, clinical acyanosis appears to be associated with more severe arrhythmogenic remodelling. Further research into the clinical drivers of structural and electrical myocardial alterations, and the relation between them, is needed to identify predictive factors for patients at risk.

Apixaban for Prevention of Thromboembolism in Pediatric Heart Disease.

BACKGROUND: Children with heart disease frequently require anticoagulation for thromboprophylaxis. Current standard of care (SOC), vitamin K antagonists or low-molecular-weight heparin, has significant disadvantages. OBJECTIVES: The authors sought to describe safety, pharmacokinetics (PK), pharmacodynamics, and efficacy of apixaban, an oral, direct factor Xa inhibitor, for prevention of thromboembolism in children with congenital or acquired heart disease. METHODS: Phase 2, open-label trial in children (ages, 28 days to <18 years) with heart disease requiring thromboprophylaxis. Randomization 2:1 apixaban or SOC for 1 year with intention-to-treat analysis. PRIMARY ENDPOINT: a composite of adjudicated major or clinically relevant nonmajor bleeding. Secondary endpoints: PK, pharmacodynamics, quality of life, and exploration of efficacy. RESULTS: From 2017 to 2021, 192 participants were randomized, 129 apixaban and 63 SOC. Diagnoses included single ventricle (74%), Kawasaki disease (14%), and other heart disease (12%). One apixaban participant (0.8%) and 3 with SOC (4.8%) had major or clinically relevant nonmajor bleeding (% difference -4.0 [95% CI: -12.8 to 0.8]). Apixaban incidence rate for all bleeding events was nearly twice the rate of SOC (100.0 vs 58.2 per 100 person-years), driven by 12 participants with ≥4 minor bleeding events. No thromboembolic events or deaths occurred in either arm. Apixaban pediatric PK steady-state exposures were consistent with adult levels. CONCLUSIONS: In this pediatric multinational, randomized trial, bleeding and thromboembolism were infrequent on apixaban and SOC. Apixaban PK data correlated well with adult trials that demonstrated efficacy. These results support the use of apixaban as an alternative to SOC for thromboprophylaxis in pediatric heart disease. (A Study of the Safety and Pharmacokinetics of Apixaban Versus Vitamin K Antagonist [VKA] or Low Molecular Weight Heparin [LMWH] in Pediatric Subjects With Congenital or Acquired Heart Disease Requiring Anticoagulation; NCT02981472).

Model-driven survival prediction after congenital heart surgery.

OBJECTIVES: The objective of the study was to improve postoperative risk assessment in congenital heart surgery by developing a machine-learning model based on readily available peri- and postoperative parameters. METHODS: Our bicentric retrospective data analysis from January 2014 to December 2019 of established risk parameters for dismal outcome was used to train and test a model to predict postoperative survival within the first 30 days. The Freiburg training data consisted of 780 procedures; the Heidelberg test data comprised 985 procedures. STAT mortality score, age, aortic cross-clamp time and postoperative lactate values over 24 h were considered. RESULTS: Our model showed an area under the curve (AUC) of 94.86%, specificity of 89.48% and sensitivity of 85.00%, resulting in 3 false negatives and 99 false positives.The STAT mortality score and the aortic cross-clamp time each showed a statistically highly significant impact on postoperative mortality. Interestingly, a child's age was barely statistically significant. Postoperative lactate values indicated an increased mortality risk if they were either constantly at a high level or low during the first 8 h postoperatively with an increase afterwards.When considering parameters available before, at the end of and 24 h after surgery, the predictive power of the complete model achieved the highest AUC. This, compared to the already high predictive power alone (AUC 88.9%) of the STAT mortality score, translates to an error reduction of 53.5%. CONCLUSIONS: Our model predicts postoperative survival after congenital heart surgery with great accuracy. Compared with preoperative risk assessments, our postoperative risk assessment reduces prediction error by half. Heightened awareness of high-risk patients should improve preventive measures and thus patient safety.

Benefit From a Humanitarian Pediatric Congenital Heart Surgery Program Over a 10-Year Period.

Background: The charity organization Kinderherzen retten e.V. (KHR) enables humanitarian congenital heart surgery for pediatric patients from low- and middle-income countries at the University Heart Center Freiburg, Germany. The aim of this study was to assess periprocedural and mid-term outcomes of these patients for evaluation of KHR sustainability. Methods: Part one of the study comprised retrospective medical chart analyses of the periprocedural course of all KHR-treated children from 2008 to 2017, and part two a prospective evaluation of their mid-term outcome, assessed by questionnaires concerning survival, medical history, mental and physical development, and socioeconomic situation. Results: Of the 100 consecutively presented children from 20 countries (median age 3.25 years), 3 patients were not invasively treatable, 89 underwent cardiovascular surgery, and 8 received a catheter intervention only. There were no periprocedural deaths. Median postoperative duration of mechanical ventilation, intensive care stay, and total hospital stay was 7 (interquartile range [IQR] 4-21) hours, 2 (IQR 1-3) days, and 12 (IQR 10-16) days, respectively. Mid-term postoperative follow-up demonstrated a 5-year survival probability of 94.4%. The majority of patients received continued medical care in their home country (86.2% of patients), were in good mental and physical condition (96.5% and 94.7% of patients, respectively), and able to engage in age-appropriate education/employment (98.3% of patients). Conclusions: Cardiac, neurodevelopmental, and socioeconomic outcomes of patients treated via KHR was satisfactory. Thorough pre-visit evaluation and close contact with local physicians are crucial when providing this high-quality, sustainable, and viable therapeutic option for these patients.

Adults With Congenital Heart Disease­a New, Expanding Group of Patients.

BACKGROUND: Congenital heart anomalies are the most common type of organ malformation, affecting approximately 1% of all newborn infants. More than 90% of these children now survive into adulthood. They need to be cared for by specialists for adults with congenital heart disease (ACHD), as well as by family physicians, internists, and cardiologists who are adequately versed in the basic management of persons with this lifelong condition. METHODS: This review is based on pertinent publications retrieved by a selective literature search, including guidelines and consensus statements from Germany and abroad. RESULTS: Cardiovascular malformations cover a very wide spectrum, and the evidence base for the treatment of older patients with these conditions is scant. Congestive heart failure, arrhythmias, and the sequelae of pulmonary arterial hypertension are the main contributors to cardiac morbidity and mortality. Preg - nancy counseling, endocarditis prophylaxis, vaccinations, and psychosocial aspects must be targeted to each individual patient. Neither the affected patients nor their family physicians are yet adequately acquainted with the recently created care structures for this patient group. CONCLUSION: The care of ACHD is a multidisciplinary task that requires basic care by primary care physicians as well as the involvement of specialized cardiologists in order to ensure optimal individualized treatment.

Successful Secondary Endovascular Intervention in Pediatric Patients with Venous Thromboembolic Events.

BACKGROUND: In the past, pediatric patients with venous thromboembolic events (VTE) were treated with low-molecular-weight heparin (LMWH) which was successful in around 70% of the cases. However, anticoagulation alone might not restore patency in all patients, and advanced therapeutic options to prevent postthrombotic syndrome are needed. During recent years, endovascular interventions have become a treatment option for pediatric patients with persistent thrombotic occlusion, not only in life- or limb-threatening VTE. METHODS: We evaluated 12 consecutive patients (11-17 years) with newly diagnosed VTE being treated at our department during the last 4 years (2017-2020). In case follow-up examination showed persistent venoocclusion under anticoagulation, patients received secondary interventional therapy like recanalization, percutaneous transluminal angioplasty with or without catheter-directed thrombolysis, and stenting. Patients with no clinical signs of venoocclusion or regredient thrombosis in imaging examination received anticoagulation alone. RESULTS: Six of 12 (50%) patients underwent catheter intervention. Median time from diagnosis to intervention was 4 months (0-12 months). Reintervention was necessary in one (8%) case and complete recanalization failed in one (8%) case. There were no major bleeding events or other major postinterventional complications, no acute or late local recurrence, and all patients reported clinical improvement after the procedure. CONCLUSION: If endovascular intervention is used in teenage patients with persistent symptomatic VTE, reduction of postthrombotic symptoms is possible, even if intervention is performed secondary to failure of anticoagulation. Multidisciplinary treatment decisions can be based on the clinical course and follow-up imaging.

Risk Assessment of Red Cell Transfusion in Congenital Heart Disease.

BACKGROUND: The storage time of packed red blood cells (pRBC) is an indicator of change in the product's pH, potassium, and lactate levels. Blood-gas analysis is a readily available bedside tool on every intensive care ward to measure these factors prior to application, thus facilitating a calculated decision on a transfusion's quantity and duration.Our first goal is to assess the impact of storage time on pH, potassium, and lactate levels in pRBC. The influence of those parameters in the transfused children will then be evaluated. METHODS: In this retrospective study, we conducted blood-gas analyses of pRBC units before they were administered over 4 hours to neonates, infants, and children in our pediatric cardiac intensive care ward. All patients underwent regular blood-gas analyses themselves, before and after transfusion. RESULTS: We observed a highly significant correlation between the storage time of pRBC units and a drop in pH, as well as an increase in potassium and lactate of stored red cells (p< 0.0001). Median age of recipients with a complete blood-gas dataset was 0.1 (interquartile range [IQR] = 0.0-0.7) years; median pRBC storage duration was 6 (IQR = 5-8) days. Further analyses showed no statistically significant effect on children's blood gases within 4 hours after transfusion, even after stratifying for pRBC storage time ≤7 days and >7 days. CONCLUSION: Stored red blood cells show a rapid decrease in pH and increase in potassium and lactate. Slow transfusion of these units had no adverse effects on the recipients' pH, potassium, and lactate levels.

Lessons Learned from Managing Antithrombotic Therapy in Children Supported with Pediatric Ventricular Assist Devices.

Stroke, thromboembolism, and bleeding are the most recognized complications associated with pediatric ventricular assist devices (VADs) and the leading cause of death and disability on VAD support. Recently, newer antithrombotic strategies like bivalirudin have emerged that appear to be associated with a reduction in the neurologic event rates, especially for smaller pediatric-specific VADs like the Berlin Heart and PediMag/CentriMag systems where the risk of stroke is the highest. While contemporary antithrombotic therapies have likely contributed to lowering adverse event rates, we speculate that clotting and bleeding adverse events may have dropped because of a variety of other seemingly small changes to antithrombotic management that are independent of the antithrombotic agents used. This view is supported by recent reports documenting low stroke rates with anticoagulants other than bivalirudin, a drug that may have a wider therapeutic window but is not available in all locations throughout the world. The primary purpose of this report is 1) to summarize contemporary antithrombotic regimens used for smaller pediatric VADs today associated with low event rates in the United States and abroad and () to review 10 practical lessons learned and pitfalls to avoid that we believe to be important to reducing bleeding and clotting events based on our collective experience managing pediatric VADs over the past 20 years irrespective of the antithrombotic agents used.

The European Registry for Patients with Mechanical Circulatory Support (EUROMACS): third Paediatric (Paedi-EUROMACS) report.

OBJECTIVES: A third paediatric report has been generated from the European Registry for Patients with Mechanical Circulatory Support (EUROMACS). The purpose of EUROMACS, which is operated by the European Association for Cardio-Thoracic Surgery, is to gather data related to durable mechanical circulatory support for scientific purposes and to publish reports with respect to the course of mechanical circulatory support therapy. Since the first report issued, efforts to increase compliance and participation have been extended. Additionally, the data provided the opportunity to analyse patients of younger age and lower weight. METHODS: Participating hospitals contributed pre-, peri- and long-term postoperative data on mechanical circulatory support implants to the registry. Data for all implants in paediatric patients (<19 years of age) performed from 1 January 2000 to 31 December 2020 were analysed. This report includes updates of patient characteristics, implant frequency, outcome (including mortality rates, transplants and recovery rates) as well as adverse events including neurological dysfunction, device malfunction, major infection and bleeding. RESULTS: Twenty-five hospitals contributed 537 registered implants in 480 patients. The most frequent aetiology of heart failure was any form of cardiomyopathy (59%), followed by congenital heart disease and myocarditis (15% and 14%, respectively). Competing outcomes analysis revealed that a total of 86% survived to transplant or recovery or are ongoing; at the 2-year follow-up examination, 21.9% died while on support. At 12 months, 45.1% received transplants, 7.5% were weaned from their device and 20.8% died. The 3-month adverse events rate was 1.59 per patient-year for device malfunction including pump exchange, 0.7 for major bleeding, 0.78 for major infection and 0.71 for neurological events. CONCLUSIONS: The overall survival rate was 79.2% at 12 months following ventricular assist device implant. The comparison of survival rates of the early and later eras shows no significant difference. A focus on specific subgroups showed that survival was less in patients of younger age (<1 year of age; P = 0.01) and lower weight (<20 kg; P = 0.015). Transplant rates at 6 months continue to be low (33.2%).

Prospective multicenter study of the breakable babystent for treatment of aortic coarctation in newborns and infants.

To assess the efficacy and safety of a breakable BabyStent to treat complex aortic coarctation (CoA) in early childhood. Although recommended in several guidelines, there is no approved aortic stent for young infants, because of the dilemma between two mandatory requirements: expandable up to adult size on the one hand, and small enough to fit through a baby's femoral artery on the other. Prospective interventional, multi-center clinical trial with the breakable Osypka BabyStent® (OBS). The OBS is a low-profile, 15-mm long cobalt-chromium stent, pre-mounted on a 6 mm balloon and inserted via a 4 Fr sheath. After implantation, its diameter is adjustable from 6 to 12 mm by balloon dilation. Further dilation opens predefined joints enabling unrestricted growth. Nineteen patients (9 male), median age 112 days (range: 7-539), median body weight 5.6 kg (range: 2.4-8.4) were deemed high risk and underwent stent implantation. Of those, 74% suffered from re-CoA following surgery, 53% had additional cardiac and 21% noncardiac malformations. Our primary combined endpoint was fulfilled: All stents were implanted in the desired region, and a >50% intrastenotic diameter-extension was achieved in 15 patients (78.9%, 80% confidence interval [62.2; 90.5], 95% confidence interval [54.4; 93.9]). Secondary endpoint confirmed that the OBS fits the baby's femoral vessel diameter. All children survived the procedure and 12-month follow-up. This stent enables percutaneous stenting of complex aortic coarctation to treat high-risk newborns and infants.

Transposition of great arteries with left outflow tract obstruction and non-committed VSD: surgical management and late results.

OBJECTIVES: Transposition of the great arteries with ventricular septal defect (VSD) and left ventricular outflow tract obstruction (LVOTO) is a rare malformation. Our objective was to report on management and results of the cohort with non-committed VSD from a national registry for congenital heart disease. METHODS: Multicentre data were screened in the German National Registry for Congenital Heart Defects (Berlin, Germany) for repairs of transposition of the great arteries-VSD-LVOTO. A subgroup of patients with a remote/non-committed VSD was identified. End points included survival, reoperation and a composite of reoperations for LVOTO-/VSD- or baffle-related problem. RESULTS: N = 47 patients were identified treated in 14 different national centres between 1984 and 2020. The mean age was 14 (standard deviation 9) months, ranging from 7 days to 9.5 years. Nine patients (19%) were treated as neonates, 21 (45%) as infants and 17 children (36%) beyond the age of 1 year. Survival was >90% (80-100%) at 20 years. Freedom from any reoperation was 30% (10-50%) at 20 years. Freedom from the composite end point was 72% (50-90%) at 20 years. Patients after Rastelli underwent more reoperations compared to those without intraventricular baffle (freedom from reoperation 14% vs 50%, P = 0.1). The rates of the composite end point were similar when comparing Rastelli to other techniques (63% vs 83%, P = 0.32). CONCLUSIONS: The Rastelli operation yields robust results in the setting of non-committed VSD. Late results after neonatal arterial switch operation are outstanding. If LVOTO is not resectable and neonatal arterial switch operation suboptimal, interim palliation does not negatively impact outcome, patients can be safely delayed to beyond 1 year of age.

Correction: Integrative analysis of genomic variants reveals new associations of candidate haploinsufficient genes with congenital heart disease.

[This corrects the article DOI: 10.1371/journal.pgen.1009679.].

Integrative analysis of genomic variants reveals new associations of candidate haploinsufficient genes with congenital heart disease.

Numerous genetic studies have established a role for rare genomic variants in Congenital Heart Disease (CHD) at the copy number variation (CNV) and de novo variant (DNV) level. To identify novel haploinsufficient CHD disease genes, we performed an integrative analysis of CNVs and DNVs identified in probands with CHD including cases with sporadic thoracic aortic aneurysm. We assembled CNV data from 7,958 cases and 14,082 controls and performed a gene-wise analysis of the burden of rare genomic deletions in cases versus controls. In addition, we performed variation rate testing for DNVs identified in 2,489 parent-offspring trios. Our analysis revealed 21 genes which were significantly affected by rare CNVs and/or DNVs in probands. Fourteen of these genes have previously been associated with CHD while the remaining genes (FEZ1, MYO16, ARID1B, NALCN, WAC, KDM5B and WHSC1) have only been associated in small cases series or show new associations with CHD. In addition, a systems level analysis revealed affected protein-protein interaction networks involved in Notch signaling pathway, heart morphogenesis, DNA repair and cilia/centrosome function. Taken together, this approach highlights the importance of re-analyzing existing datasets to strengthen disease association and identify novel disease genes and pathways.