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.

Neurological Impact of Slower Rewarming during Bypass Surgery in Infants.

BACKGROUND: Hypothermia is a neuroprotective strategy during cardiopulmonary bypass. Rewarming entailing a rapid rise in cerebral metabolism might lead to secondary neurological sequelae. In this pilot study, we aimed to validate the hypothesis that a slower rewarming rate would lower the risk of cerebral hypoxia and seizures in infants. METHODS: This is a prospective, clinical, single-center study. Infants undergoing cardiac surgery in hypothermia were rewarmed either according to the standard (+1°C in < 5 minutes) or a slow (+1°C in > 5-8 minutes) rewarming strategy. We monitored electrocortical activity via amplitude-integrated electroencephalography (aEEG) and cerebral oxygenation by near-infrared spectroscopy during and after surgery. RESULTS: Fifteen children in the standard rewarming group (age: 13 days [5-251]) were cooled down to 26.6°C (17.2-29.8) and compared with 17 children in the slow-rewarming group (age: 9 days [4-365]) with a minimal temperature of 25.7°C (20.1-31.4). All neonates in both groups (n = 19) exhibited suppressed patterns compared with 28% of the infants > 28 days (p < 0.05). During rewarming, only 26% of the children in the slow-rewarming group revealed suppressed aEEG traces (vs. 41%; p = 0.28). Cerebral oxygenation increased by a median of 3.5% in the slow-rewarming group versus 1.5% in the standard group (p = 0.9). Our slow-rewarming group revealed no aEEG evidence of any postoperative seizures (0 vs. 20%). CONCLUSION: These results might indicate that a slower rewarming rate after hypothermia causes less suppression of electrocortical activity and higher cerebral oxygenation during rewarming, which may imply a reduced risk of postoperative seizures.

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.

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.

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.

Quantitative collagen assessment in right ventricular myectomies from patients with tetralogy of Fallot.

AIMS: Patients with tetralogy of Fallot (TOF) are often affected by right ventricular fibrosis, which has been associated with arrhythmias. This study aimed to assess fibrosis distribution in right ventricular outflow tract (RVOT) myocardium of TOF patients to evaluate the utility of single histology-section analyses, and to explore the possibility of fibrosis quantification in unlabelled tissue by second harmonic generation imaging (SHGI) as an alternative to conventional histology-based assays. METHODS AND RESULTS: We quantified fibrosis in 11 TOF RVOT samples, using a tailor-made automated image analysis method on Picrosirius red-stained sections. In a subset of samples, histology- and SHGI-based fibrosis quantification approaches were compared. Fibrosis distribution was highly heterogeneous, with significant and comparable variability between and within samples. We found that, on average, 67.8 mm2 of 10 µm thick, histologically processed tissue per patient had to be analysed for accurate fibrosis quantification. SHGI provided data faster and on live tissue, additionally enabling quantification of collagen anisotropy. CONCLUSION: Given the high intra-individual heterogeneity, fibrosis quantification should not be conducted on single sections of TOF RVOT myectomies. We provide an analysis algorithm for fibrosis quantification in histological images, which enables the required extended volume analyses in these patients.

Surgically placed radiopaque markers: Proof-of-concept of a novel technique to facilitate percutaneous interventions in neonates and infants.

OBJECTIVES: Aim of this study was to evaluate feasibility and benefit of self-designed, radiopaque markers as a novel technique in neonates and infants with shunt- or duct-dependent lesions. BACKGROUND: Surgically placed radiopaque markers have the potential to facilitate postoperative percutaneous interventions. METHODS: All consecutive children with surgically placed radiopaque markers involving systemic-to-pulmonary artery connections or arterial ducts in the context of hybrid palliation and subsequent cardiac catheterization between January 2013 and March 2019 were included in this analysis. Our primary endpoint was our concept's feasibility, which we defined as a combination of surgical feasibility and the percutaneous intervention's success. Secondary endpoint was the rate of complications resulting from the surgical procedure or during catheterization. RESULTS: Radiopaque markers that reveal the proximal entry of a surgical shunt or the arterial duct proved to be a feasible and beneficial approach in 25 postoperative catheterizations. The markers' high accuracy enabled easy probing and proper stent positioning in 13 neonates with a median age and weight of 121 days (range 9-356) and 4.7 kg (1.6-9.4) at the intervention. No procedural complications or unanticipated events associated with the radiopaque marker occurred. The markers were never lost, never migrated, and caused no local obstructive lesion. Surgical removal was straightforward in all patients. CONCLUSIONS: Radiopaque markers are a promising and refined technique to substantially facilitate target vessel access and enabling the accurate positioning of stents during postoperative percutaneous procedures.

The Transcription Factor ETV1 Induces Atrial Remodeling and Arrhythmia.

RATIONALE: Structural and electrophysiological remodeling of the atria are recognized consequences of sustained atrial arrhythmias, such as atrial fibrillation. The identification of underlying key molecules and signaling pathways has been challenging because of the changing cell type composition during structural remodeling of the atria. OBJECTIVE: Thus, the aims of our study were (1) to search for transcription factors and downstream target genes, which are involved in atrial structural remodeling, (2) to characterize the significance of the transcription factor ETV1 (E twenty-six variant 1) in atrial remodeling and arrhythmia, and (3) to identify ETV1-dependent gene regulatory networks in atrial cardiac myocytes. METHODS AND RESULTS: The transcription factor ETV1 was significantly upregulated in atrial tissue from patients with permanent atrial fibrillation. Mice with cardiac myocyte-specific overexpression of ETV1 under control of the myosin heavy chain promoter developed atrial dilatation, fibrosis, thrombosis, and arrhythmia. Cardiac myocyte-specific ablation of ETV1 in mice did not alter cardiac structure and function at baseline. Treatment with Ang II (angiotensin II) for 2 weeks elicited atrial remodeling and fibrosis in control, but not in ETV1-deficient mice. To identify ETV1-regulated genes, cardiac myocytes were isolated and purified from mouse atrial tissue. Active cis-regulatory elements in mouse atrial cardiac myocytes were identified by chromatin accessibility (assay for transposase-accessible chromatin sequencing) and the active chromatin modification H3K27ac (chromatin immunoprecipitation sequencing). One hundred seventy-eight genes regulated by Ang II in an ETV1-dependent manner were associated with active cis-regulatory elements containing ETV1-binding sites. Various genes involved in Ca2+ handling or gap junction formation ( Ryr2, Jph2, Gja5), potassium channels ( Kcnh2, Kcnk3), and genes implicated in atrial fibrillation ( Tbx5) were part of this ETV1-driven gene regulatory network. The atrial ETV1-dependent transcriptome in mice showed a significant overlap with the human atrial proteome of patients with permanent atrial fibrillation. CONCLUSIONS: This study identifies ETV1 as an important component in the pathophysiology of atrial remodeling associated with atrial arrhythmias.

Von Willebrand factor parameters as potential biomarkers for disease activity and coronary artery lesion in patients with Kawasaki disease.

Elevated von Willebrand factor (vWF):Antigen plasma levels have been observed in conjunction with cardiovascular diseases or vasculitis. The association of Kawasaki disease, a vascular inflammatory disease and vWF:Antigen, vWF:Collagen binding activity, and vWF multimers is unknown. We therefore investigated vWF parameters in 28 patients with acute Kawasaki disease in association with disease activity and coronary artery lesions. VWF:Antigen and vWF:Collagen binding activity were assessed via enzyme-linked immunoassay. The ratio of both (vWF:Collagen binding activity and VWF:Antigen) was calculated and vWF multimeric structure analysis performed. We analyzed the association between vWF parameters and our clinical data focusing on coronary artery outcome. VWF:Antigen and vWF:Collagen binding activity levels were significantly higher in the acute than in the disease's convalescence phase, and correlated positively with CRP levels. Neither variable was associated with coronary artery lesions. The vWF:Collagen binding activity/vWF:Antigen ratio, however, was significantly decreased in patients with a coronary artery lesion (z-score > 2; N = 10; mean ratio 0.96 vs. 0.64; p = 0.031) and even more so in those with a coronary artery aneurysm (z-score > 2.5; N = 8; mean ratio 0.94 vs. 0.55; p = 0.02). In a sub-analysis, those patients with a very low ratio in the acute phase presented a persistent coronary artery aneurysm at their 1-year follow-up.Conclusion: This study suggests that comprehensive analysis of vWF parameters may help to both monitor KD inflammation and facilitate the identification of those patients carrying an increased risk for coronary artery lesion.What is Known:• Von Willebrand factor (VWF)-parameters represent surrogate markers for vascular inflammation.• Kawasaki disease is a generalized vasculitis in children, which can be complicated by coronary artery lesions.What is New:• In those Kawasaki disease patients with coronary artery lesions, the vWF:CB/vWF:Ag ratio was significantly decreased.• VWF parameters may help to identify patients at risk for coronary artery lesions.

Cannabidiol Interacts Significantly with Everolimus-Report of a Patient with Tuberous Sclerosis Complex.

A 6.5-year-old female patient with a TSC2 mutation had been given everolimus (EVE) for 3 years for pharmacoresistant focal epilepsy and for life-threatening, severe ventricular dysrhythmia. EVE had been started with daily dose of 0.15 mg/kg/day and was increased up to 0.6 mg/kg/day. Target blood trough levels of around 9 µg/L had been documented. Although EVE therapy revealed no effect on seizure activity, cardiac rhythm normalized completely. Thus, EVE was reduced to a dose of 0.3 mg/kg/day leading to stable blood trough levels of 4 to 5 µg/L. Due to refractory tonic seizures with a frequency of 1 to 4 per day, we initiated cannabidiol (CBD) treatment, raising it to a daily dose of 200 mg. After 6 weeks, the EVE blood trough levels rose to 12.0 µg/L. Although we halved the EVE dose, her EVE blood trough level continued increasing up to 16.0 µg/L.The CBD dose was increased to 500 mg/day (20.4 g/kg/day), but EEG parameters and seizures failed to respond. Serum concentrations of EVE were unstable under the co-medication with CBD. Depending on the CBD dose, they varied between 1.7 and 12.3 µg/L, while EVE was always administered at the same dose.Although never before reported, CBD and EVE appear to interact, due to the metabolic pathway through CYP 450 3A4. Although we detected no side effects in our patient, we strongly recommend drug monitoring using the combination of CBD with EVE to prevent harmful overdosing.

Long-term safety and tolerability of valsartan in children aged 6 to 17 years with hypertension.

OBJECTIVE: The present study aimed to assess the long-term safety and tolerability of valsartan in hypertensive children aged 6-17 years, with or without chronic kidney disease (CKD). METHODS: This was an 18-month, open-label, multicentre, prospective study conducted in 150 patients with history of hypertension with or without CKD. The primary endpoint was long-term safety and tolerability of valsartan and valsartan-based treatments, assessed in terms of adverse events (AEs), serious AEs, laboratory measurements, estimated glomerular filtration rate (eGFR), urinalysis and electrocardiogram. RESULTS: Of 150 enrolled patients, 117 (78%) completed the study. At week 78, a clinically and statistically significant reduction in mean sitting systolic and diastolic blood pressures was observed in all patients (- 14.9 mmHg and - 10.6 mmHg, respectively). Within the first 3 months of treatment, mean urine albumin creatinine ratio decreased in CKD population, which was sustained. A higher percentage of CKD patients had at least one AE compared to non-CKD patients (85.3% vs. 73.3%, respectively). The majority of AEs were mild (50.7%) or moderate (18.7%) in severity. As expected, in patients with underlying CKD, increases in serum potassium, creatinine and blood urea nitrogen were more commonly reported compared to non-CKD patients. A > 25% decrease in Schwartz eGFR was observed in 28.4% of CKD patients and 13.5% of non-CKD patients. CONCLUSIONS: Valsartan was generally well tolerated, with an AE profile consistent with angiotensin receptor blockers in the overall population and in patients with underlying CKD. Long-term efficacy was maintained and a beneficial effect on proteinuria was observed.

Collateral closure in congenital heart defects with Amplatzer vascular plugs: single-center experience and a simplified delivery technique for exceptional cases.

The study describes our experience with Amplatzer Vascular Plugs (AVP2 and 4) and highlights a more refindes telescopic technique for AVP2 delivery. AVPs are well-established occlusion devices for vascular anomalies in congenital heart disease (CHD). The AVP2 is sometimes preferred to the AVP4 due to its shorter length, flat-profiled retention disks, and the availability of larger diameters, but its profile requires a larger inner lumen for safe delivery. The latter may actually hamper access to target lesions. This is a retrospective analysis of all CHD patients treated with the AVP2 and AVP4 between 12/2012 and 12/2015. Target vessels were characterized, measured, and the device-to-vessel diameter ratio calculated. A modified pigtail technique for AVP2 delivery was frequently used: a floppy wire was simply reinforced by the curved tip of a pigtail catheter (instead of the long sheath's dilator) to guide the required delivery sheath towards the desired landing zone. 59 patients with a median age and bodyweight of 3.0 years (range 0.1-75) and 13.8 kg (range 2.5-80) underwent the implantation of 106 plug-devices (30 AVP2, 76 AVP4) in 91 target vessels. Indications for their use were ductus arteriosus (19%), aortopulmonary (43%) as well as venovenous collaterals (34%) and other miscellaneous lesions (4%). The pigtail-supported AVP2 delivery in six patients proved very convenient. No complications occurred. AVPs are excellent devices for embolizing shunt vessels in CHD patients. Here, we describe a simplified telescoping technique for AVP2 delivery to enter curvy target lesions gently and efficiently.

Management of a dissection of matrix P right ventricular-to-pulmonary artery conduit by implanting two pre-stents and a melody valve.

Reconstructing the right ventricular outflow tract and pulmonary valve via a bovine-derived valve conduit such as Matrix-P-Xenograft is a common surgical repair technique for pulmonary atresia and ventricular septal defect. After conduit degeneration due to calcification or aneurysmal dilatation, percutaneous transvenous stenting of the right ventricular outflow tract followed by pulmonary valve implantation has become the standard interventional treatment. Applied to stenotic conduits, the method is considered safe and effective. An important but seldom-reported problem is graft failure related to the formation of a Matrix membrane due to inflammation and fibrosis inside the xenograft, which can cause serious problems when dissection and rupture occur during transcatheter intervention. The torn pseudomembrane may cause the complete obstruction of both pulmonary arteries, resulting in a life-threatening situation requiring rapid intervention, as in this case presentation. © 2016 Wiley Periodicals, Inc.

Everolimus-associated perianal ulcers in an eight-month-old heart transplant recipient.

mTOR inhibitors have a wide spectrum of therapeutic applications in adults and children. Little is known, however, about serious adverse effects in children undergoing mTOR inhibitor therapy. Oral ulcers are common and sometimes severe, but no other gastrointestinal involvement has been reported so far. Here we present a case of everolimus-associated perianal ulcers in an eight-month-old infant, 3 months after heart transplantation, which necessitated the drug's discontinuation. In a thorough series of diagnostic tests, we identified no other cause for the progressive perianal ulceration. The recognition and appropriate management of mTOR inhibitors' adverse effects in pediatric patients are essential and remain challenging.

Multicenter Experience With Mechanical Circulatory Support Using a New Diagonal Pump in 233 Children.

Technological innovations in pediatric extracorporeal life support circuits can reduce system-related complications and may improve patients' outcome. The Deltastream DP3 (Medos Medizintechnik AG, Stolberg, Germany) is a novel rotational pump with a diagonally streamed impeller that can be used over a broad range of flows. We collected patient data from seven pediatric centers to conduct a retrospective cohort study. We examined 233 patients whose median age was 1.9 (0-201) months. The DP3 system was used for cardiopulmonary support as veno-arterial extracorporeal membrane oxygenation (ECMO) in 162 patients. Respiratory support via veno-venous ECMO was provided in 63 patients. The pump was used as a ventricular assist device in eight patients. Median supporting time was 5.5 (0.2-69) days and the weaning rate was 72.5%. The discharge home rate was 62% in the pulmonary group versus 55% in the cardiac group. Extracorporeal cardiopulmonary resuscitation was carried out in 24 patients (10%) with a survival to discharge of rate of 37.5%. About 106 (47%) children experienced no complications, while 33% suffered bleeding requiring blood transfusion or surgical intervention. Three patients suffered a fatal cerebral event. Renal replacement therapy was performed in 28% and pump or oxygenator exchange in 26%. Multivariable analysis identified system exchange (OR 1.94), kidney failure (OR 3.43), and complications on support (OR 2.56) as risk factors for dismal outcome. This novel diagonal pump has demonstrated its efficacy in all kinds of mechanical circulatory and respiratory support, revealing good survival rates.

Implementing and Assessing a Standardized Protocol for Weaning Children Successfully From Extracorporeal Life Support.

Extracorporeal life support (ECLS) weaning is a complex interdisciplinary process with no clear guidelines. To assess ventricular and pulmonary function as well as hemodynamics including end-organ recovery during ECLS weaning, we developed a standardized weaning protocol. We reviewed our experience 2 years later to assess its feasibility and efficacy. In 2015 we established an inter-professional, standardized, stepwise protocol for weaning from ECLS. If the patient did not require further surgery, weaning was conducted bedside in the intensive care unit (ICU). Most of the weaning procedures are guided via echocardiography. Data acquisition began at baseline level, followed by four-step course (each step lasting 10 min), entailing flow-reduction and ending 30 min after decannulation. Moreover, data from the preprotocol era are presented. Between May 2015 and 2017, 26 consecutive patients (18 male), median age 177 days (2 days-20 years) required ECLS with median support of 4 (2-11) days. Excluding eight not weanable patients, 21 standardized weaning procedures were protocolled in the remaining 18 children. Our generally successful protocol-guided weaning rate (with at least 24-h survival) was 89%, with a discharge home rate of 58%. Practical application of the novel standard protocol seems to facilitate ECLS weaning and to improve its success rate. The protocol can be administered as part of standard bedside ICU assessment.

Echocardiographic characteristics in Fontan patients before the onset of protein-losing enteropathy or plastic bronchitis.

BACKGROUND: It was this study's objective to evaluate the echocardiographic characteristics and flow patterns in abdominal arteries of Fontan patients before the onset of protein-losing enteropathy (PLE) or plastic bronchitis (PB). DESIGN: In this retrospective cohort investigation, we examined 170 Fontan patients from 32 different centers who had undergone echocardiographic and Doppler ultrasound examinations between June 2006 and May 2013. Follow-up questionnaires were completed by 105 patients a median of 5.3 (1.5-8.5) years later to evaluate whether one of the complications had occurred since the examinations. RESULTS: A total of 91 patients never developed PLE or PB ("non-PLE/PB"); they were compared to 14 affected patients. Eight of the 14 patients had already been diagnosed with "present PLE/PB" when examined. Six "future PLE/PB" patients developed those complications later on and were identified on follow-up. The "future PLE/PB" patients presented significantly slower diastolic flow velocities in the celiac artery (0.1 (0.1-0.5) m/s vs 0.3 (0.1-1.0) m/s (P = .04) and in the superior mesenteric artery (0.0 (0.0-0.2) m/s vs 0.2 (0.0-0.6) m/s, P = .02) than the "non-PLE/PB" group. Median resistance indices in the celiac artery were significantly higher (0.9 (0.8-0.9) m/s vs 0.8 (0.6-0.9) m/s, (P = .01)) even before the onset of PLE or PB. CONCLUSION: An elevated flow resistance in the celiac artery may prevail in Fontan patients before the clinical manifestation of PLE or PB.

Multicenter midterm follow-up results using the gore septal occluder for atrial septal defect closure in pediatric patients.

OBJECTIVES: To assess the safety and efficacy of the Gore Septal Occluder (GSO) used for device-closure of significant secundum-type atrial septal defects (ASD II) focusing on pediatric patients. BACKGROUND: The GSO is a patch-like double disc device. Due to its design, it is assumed to be safe, even when implanted in ASDs with deficient retro-aortic rims. METHODS: Multicenter retrospective analysis of consecutive children and adolescents with a GSO in situ for at least 12 months according to a 1- to 4-year midterm follow-up. RESULTS: Hundred and seventy three pediatric patients were enrolled. At implantation, median age was 6 years (range 0.7-17.9), median body weight and length were 21 kg (6.4-95) and 119 cm (65-193). Median follow-up period was 20 months (range 12-51). ASD anatomy was comprised of single defects in 131 patients (76%), multi-fenestrated defects in 42 (24%), and deficient retro-aortic rims in 33 (19%). Follow-up confirmed an overall closure-rate of 95.4%. Small residual shunts were reported in eight patients (4.6%) without need for any re-intervention. Complications were classified as minor events both during the initial procedure (9 patients, 5.2%) and on follow-up (another 9 patients), including transient AV block II in three patients (1.8%) and four snare-retrievals (2.4%) during the initial procedure. CONCLUSIONS: Periprocedural and midterm follow-up data have shown the GSO to be effective and safe for ASD device closure in children and adolescents. GSO may be considered the first-choice device in deficient retro-aortic rims and multi-fenestrated defects, when covering most of the atrial septum is necessary. © 2016 Wiley Periodicals, Inc.

Adrenergic Repression of the Epigenetic Reader MeCP2 Facilitates Cardiac Adaptation in Chronic Heart Failure.

RATIONALE: In chronic heart failure, increased adrenergic activation contributes to structural remodeling and altered gene expression. Although adrenergic signaling alters histone modifications, it is unknown, whether it also affects other epigenetic processes, including DNA methylation and its recognition. OBJECTIVE: The aim of this study was to identify the mechanism of regulation of the methyl-CpG-binding protein 2 (MeCP2) and its functional significance during cardiac pressure overload and unloading. METHODS AND RESULTS: MeCP2 was identified as a reversibly repressed gene in mouse hearts after transverse aortic constriction and was normalized after removal of the constriction. Similarly, MeCP2 repression in human failing hearts resolved after unloading by a left ventricular assist device. The cluster miR-212/132 was upregulated after transverse aortic constriction or on activation of α1- and ß1-adrenoceptors and miR-212/132 led to repression of MeCP2. Prevention of MeCP2 repression by a cardiomyocyte-specific, doxycycline-regulatable transgenic mouse model aggravated cardiac hypertrophy, fibrosis, and contractile dysfunction after transverse aortic constriction. Ablation of MeCP2 in cardiomyocytes facilitated recovery of failing hearts after reversible transverse aortic constriction. Genome-wide expression analysis, chromatin immunoprecipitation experiments, and DNA methylation analysis identified mitochondrial genes and their transcriptional regulators as MeCP2 target genes. Coincident with its repression, MeCP2 was removed from its target genes, whereas DNA methylation of MeCP2 target genes remained stable during pressure overload. CONCLUSIONS: These data connect adrenergic activation with a microRNA-MeCP2 epigenetic pathway that is important for cardiac adaptation during the development and recovery from heart failure.