Publications by authors named "Brigitte Stiller"

127 Publications

Arrhythmic risk during pregnancy in patients with congenital heart disease.

Herzschrittmacherther Elektrophysiol 2021 Apr 1. Epub 2021 Apr 1.

Department of Congenital Heart Disease and Pediatric Cardiology, University Heart Center Freiburg-Bad Krozingen, Medical Center-University of Freiburg, Faculty of Medicine, Freiburg, Germany.

Arrhythmias play a significant role in the morbidity and mortality of patients with adult congenital heart disease (CHD). Pregnancy-associated physiological changes in hormonal status, hemodynamics, and myocardial structure further enhance arrhythmic risk in CHD patients, leading to increased adverse maternal and foetal events and making arrhythmias one of the most common complications during pregnancy. Nearly all CHD patients are affected by asymptomatic rhythm disturbances during the ante-, peri-, or post-partum periods, and almost one tenth of patients develop sustained, symptomatic arrhythmias requiring treatment. The majority of arrhythmias originate from the atrium, mostly in the form of supraventricular tachycardia or atrial fibrillation. Patients with CHD often tolerate these even more poorly during pregnancy than before pregnancy. Sustained ventricular tachycardia or ventricular fibrillation are rare, but potentially life-threatening for mother and foetus. Risk stratification models developed specifically for arrhythmias during pregnancy in CHD patients are lacking, but direct or indirect signs of heart failure, previous history of arrhythmia, and complex CHD may be associated with higher arrhythmic risk in these patients. Rigorous individual assessment before, and careful monitoring during pregnancy in a multidisciplinary team is crucial to ensure the best possible pregnancy outcome for patients with CHD.
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http://dx.doi.org/10.1007/s00399-021-00754-7DOI Listing
April 2021

A Rare Case of Severe Dilated Cardiomyopathy in Early Infancy.

Thorac Cardiovasc Surg Rep 2021 Jan 20;10(1):e12-e14. Epub 2021 Jan 20.

Department of Congenital Heart Disease and Paediatric Cardiology, Freiburg University Hospital, Freiburg, Baden-Württemberg, Germany.

We report the case of a 3-month-old girl presenting with end-stage dilated cardiomyopathy and therapy-resistant cardiogenic shock. A left ventricular assist device (LVAD) Berlin Heart EXCOR was implanted, her organs recovered, and she was listed for heart transplantation. Two months later, while still on the LVAD, she was diagnosed with the rare genetic Alström syndrome. Weaning was no option, and she underwent successful heart transplantation at the age of 9 months. The follow-up 15 months later revealed an uneventful transplant course in a child with Alström syndrome.
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http://dx.doi.org/10.1055/s-0040-1721038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7817335PMC
January 2021

Ex-vivo allograft perfusion for complex pediatric heart transplant recipients.

Ann Thorac Surg 2021 Jan 6. Epub 2021 Jan 6.

Department of Congenital Heart Disease and Pediatric Cardiology, University Heart Center Freiburg - Bad Krozingen, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Germany.

Background: Pediatric heart transplant (HTx) recipients with congenital heart defects require complex concomitant surgical procedures with the risk of prolonging the allograft's ischemic time. Ex- vivo allograft perfusion with the Organ Care System (OCS) may improve survival of these challenging patients.

Methods: Retrospective, single center study. A consecutive series of 8 children with allografts preserved using the OCS was compared to 13 children after HTx with cold storage of the donor heart from 3/2018 to 3/2020.

Results: Median recipients age in the control group was 18 (range 1- 189) months vs. 155 (83- 214) months in the OCS group, the baseline differences between the two groups were not significant. 50% of the children in the OCS group had complex congenital heart defects (vs. 15% of the controls). Median operation time during HTx in the OCS group was 616 (270- 809) min vs. 329 (283- 617) min. Due to the time of ex- vivo allograft perfusion (265 (202- 372) minutes) median total ischemia time was significantly shorter in the OCS group 78 (52- 111) vs. 222 (74-326) minutes. The incidence of primary graft failure, renal or hepatic failure did not differ between the groups. Graft function and the occurrence of any treated rejection at follow up revealed no significant difference between the two groups. One-year survival was 88% in the OCS group (vs. 85%).

Conclusions: Ex-vivo allograft perfusion enabled complex pediatric heart transplantations, yielding outcomes as positive as those of children whose donor hearts were stored in ice-cold solution.
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http://dx.doi.org/10.1016/j.athoracsur.2020.12.025DOI Listing
January 2021

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

Europace 2021 Mar;23(Supplement_1):i38-i47

Institute for Experimental Cardiovascular Medicine, University Heart Center Freiburg-Bad Krozingen, Medical Center- University of Freiburg, Faculty of Medicine, Elsässer Straße 2Q, 79110 Freiburg, Germany.

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.
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http://dx.doi.org/10.1093/europace/euaa389DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7943371PMC
March 2021

Frequency of thyroid dysfunction in pediatric patients with congenital heart disease exposed to iodinated contrast media - a long-term observational study.

J Pediatr Endocrinol Metab 2020 Nov;33(11):1409-1415

Department of Pediatrics and Adolescent Medicine, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

Background The thyroid gland of patients with congenital heart disease may be exposed to large doses of iodine from various sources. We assessed the thyroid response after iodine exposure during conventional angiography in cardiac catheterization and angiographic computer tomography in childhood. Methods Retrospective mid- to long-term follow-up of 104 individuals (24% neonates, 51% infants, 25% children) with a median age and body weight of 104 days [0-8 years] and 5.3 kg [1.6-20]. Serum levels of thyroid-stimulating hormone, free triiodthyronine and free thyroxine were evaluated at baseline and after excess iodine. We also assessed risk factors that may affect thyroid dysfunction. Results Baseline thyroidal levels were within normal range in all patients. The mean cumulative iodinate contrast load was 6.6 ± 1.6 mL/kg. In fact, 75% had experienced more than one event involving iodine exposure, whose median frequency was three times per patient [1-12]. During the median three years follow-up period [0.5-10], the incidence of thyroid dysfunction was 15.4% (n=16). Those patients developed acquired hypothyroidism (transient n=14, long-lasting n=2 [both died]) with 10 of them requiring temporary replacement therapy for transient thyroid dysfunction, while four patients recovered spontaneously. 88 individuals (84.6%) remained euthyroid. Repeated cardiac interventions, use of drugs that interfere with the thyroid and treatment in the intensive care unit at the index date were strong predictors for acquired thyroid dysfunction. Conclusions The incidence of acquired hypothyroidism after iodine excess was 15.4%. However, most patients developed only transient hypothyroidism. Systemic iodine exposure seems to be clinically and metabolically well tolerated during long-term follow-up.
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http://dx.doi.org/10.1515/jpem-2020-0032DOI Listing
November 2020

Catheter strategy to ease the procedure and reduce radiation exposure when requiring neck access.

Open Heart 2020 06;7(1)

Department of Congenital Heart Disease and Paediatric Cardiology, University Heart Center Freiburg - Bad Krozingen, Medical Centre - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany, Freiburg, Germany.

Objectives: To assess the potential occupational radiation reduction and technical feasibility in patients rotated 180° (upside-down) when requiring neck access for transcervical or trans-subclavian catheterisation.

Methods: Upside-down positioning is defined as rotating patients in supine position by 180°, so that the feet come to rest where the head would otherwise be. We retrospectively evaluated all these procedures performed between March 2016 and May 2019. Furthermore, two different phantoms (paediatric and adult) were used prospectively to quantify the occupational dose between conventional or upside-down positioning. In this context, ambient dose equivalents were measured using real-time dosimeters. Three different projection angles were applied.

Results: 44 patients with median age and body weight of 1.0 year (range 0-56) and 9.5 kg (range 1.3-74.3) underwent 63 procedures positioned upside-down. This position proved advantageous for practical reasons, since the length of the examination table could be optimally used. Additionally, it resulted in a significantly lower overall ambient dose equivalent for the primary operator (PO) of 94.8% (mean: 2569±807 vs 135±23 nSv; p<0.01) in the adult, and of 65.5% (mean: 351±104 vs 121±56 nSv; p<0.01) in the paediatric phantom, respectively.

Conclusion: Upside-down positioning facilitates handling in a straightforward manner when access from the neck is required. Moreover, it significantly reduces local radiation exposure for the PO in the paediatric and, most impressively, in the adult phantom.
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http://dx.doi.org/10.1136/openhrt-2020-001267DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7322512PMC
June 2020

Pulmonary Hypertension in Adults with Congenital Heart Disease: Real-World Data from the International COMPERA-CHD Registry.

J Clin Med 2020 05 13;9(5). Epub 2020 May 13.

Missionsärztliche Klinik gGmbH, Abteilung für Innere Medizin, 97074 Würzburg, Germany.

Introduction: Pulmonary hypertension (PH) is a common complication in patients with congenital heart disease (CHD), aggravating the natural, post-operative, or post-interventional course of the underlying anomaly. The various CHDs differ substantially in characteristics, functionality, and clinical outcomes among each other and compared with other diseases with pulmonary hypertension.

Objective: To describe current management strategies and outcomes for adults with PH in relation to different types of CHD based on real-world data.

Methods And Results: COMPERA (Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension) is a prospective, international PH registry comprising, at the time of data analysis, >8200 patients with various forms of PH. Here, we analyzed a subgroup of 680 patients with PH due to CHD, who were included between 2007 and 2018 in 49 specialized centers for PH and/or CHD located in 11 European countries. At enrollment, the patients´ median age was 44 years (67% female), and patients had either pre-tricuspid shunts, post-tricuspid shunts, complex CHD, congenital left heart or aortic disease, or miscellaneous other types of CHD. Upon inclusion, targeted therapies for pulmonary arterial hypertension (PAH) included endothelin receptor antagonists, PDE-5 inhibitors, prostacyclin analogues, and soluble guanylate cyclase stimulators. Eighty patients with Eisenmenger syndrome were treatment-naïve. While at inclusion the primary PAH treatment for the cohort was monotherapy (70% of patients), with 30% of the patients on combination therapy, after a median observation time of 45.3 months, the number of patients on combination therapy had increased significantly, to 50%. The use of oral anticoagulants or antiplatelets was dependent on the underlying diagnosis or comorbidities. In the entire COMPERA-CHD cohort, after follow-up and receiving targeted PAH therapy ( = 511), 91 patients died over the course of a 5-year follow up. The 5-year Kaplan-Meier survival estimate for CHD associated PH was significantly better than that for idiopathic PAH (76% vs. 54%; < 0.001). Within the CHD associated PH group, survival estimates differed particularly depending on the underlying diagnosis and treatment status.

Conclusions: In COMPERA-CHD, the overall survival of patients with CHD associated PH was dependent on the underlying diagnosis and treatment status, but was significantly better as than that for idiopathic PAH. Nevertheless, overall survival of patients with PAH due to CHD was still markedly reduced compared with survival of patients with other types of CHD, despite an increasing number of patients on PAH-targeted combination therapy.
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http://dx.doi.org/10.3390/jcm9051456DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7290703PMC
May 2020

Primary carnitine deficiency - diagnosis after heart transplantation: better late than never!

Orphanet J Rare Dis 2020 04 10;15(1):87. Epub 2020 Apr 10.

Department of General Paediatrics, Adolescent Medicine and Neonatology, Medical Centre-University of Freiburg, Faculty of Medicine, Mathildenstraße 1, 79106, Freiburg, Germany.

Background: Primary carnitine deficiency due to mutations in the SLC22A5 gene is a rare but well-treatable metabolic disorder that puts patients at risk for metabolic decompensations, skeletal and cardiac myopathy and sudden cardiac death.

Results: We report on a 7-year-old boy diagnosed with primary carnitine deficiency 2 years after successful heart transplantation thanks his younger sister's having been identified via expanded newborn screening during a pilot study evaluating an extension of the German newborn screening panel.

Conclusion: As L-carnitine supplementation can prevent and mostly reverse clinical symptoms of primary carnitine deficiency, all patients with cardiomyopathy should be investigated for primary carnitine deficiency even if newborn screening results were unremarkable.
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http://dx.doi.org/10.1186/s13023-020-01371-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7146900PMC
April 2020

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

Catheter Cardiovasc Interv 2020 09 8;96(3):E303-E309. Epub 2020 Apr 8.

Department of Congenital Heart Disease and Pediatric Cardiology, University Heart Center Freiburg-Bad Krozingen, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

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.
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http://dx.doi.org/10.1002/ccd.28891DOI Listing
September 2020

Evaluation of a biocompatible sealant for on-demand repair of vascular defects-a chronic study in a large animal model.

Interact Cardiovasc Thorac Surg 2020 05;30(5):715-723

Department of Congenital Heart Defects and Pediatric Cardiology, University Heart Center Freiburg-Bad Krozingen, University of Freiburg, Freiburg, Germany.

Objectives: Existing surgical sealants fail to combine design requirements, such as sealing performance, on-demand activation and biocompatibility. The aim of this study was to compare the effectiveness and safety of the SETALIUM™ Vascular Sealant (SVS), a novel, on-demand activatable sealant, with the commercial sealant, BioGlue®, for the repair of vascular defects.

Methods: In an in vivo porcine model, the use of SVS was compared with BioGlue, for sealing 2-mm defects of the carotid artery and jugular vein. Animals were followed for 7 days and 5 weeks (each time point and per experimental group, n = 4), respectively. The degree of stenosis and flow velocity was determined, and the local tissue response was evaluated.

Results: In vivo incision closure succeeded in all cases, and SVS was superior in clinical usability, enabled by its on-demand activation. Unlike BioGlue, SVS use did not induce stenosis and was associated with physiological blood flow in all cases. Moreover, closure with SVS was associated with a low inflammatory reaction and no thrombus formation or intima proliferation, in contrast to BioGlue.

Conclusions: SVS demonstrated effective and rapid sealing of 2-mm vascular defects, with favourable biocompatibility compared to BioGlue. Thus, SVS seems to be an effective and safe vascular sealant.
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http://dx.doi.org/10.1093/icvts/ivaa012DOI Listing
May 2020

Left recurrent laryngeal nerve palsy following aortic arch stenting: A case report.

World J Cardiol 2019 Dec;11(12):316-321

Department of Congenital Heart Disease and Pediatric Cardiology, University Heart Centre Freiburg - Bad Krozingen, Medical Centre - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg 79106, Germany.

Background: Aortic arch stenting is continuously emerging as a safe and effective option to alleviate aortic arch stenosis and arterial hypertension.

Case Summary: We present a 15-year-old girl with aortic arch hypoplasia who had undergone implantation of an uncovered 22 mm Cheatham-Platinum stent due to severe (native) aortic arch stenosis. On follow-up seven months later, she presented a significant re-stenosis of the aortic arch. A second stent (LD Max 26 mm) was implanted and both stents were dilated up to 16 mm. After an initially unremarkable post-interventional course, the patient presented with hoarseness five days after the intervention. MRI and CT scans ruled out an intracranial pathology, as well as thoracic hematoma, arterial dissection, and aneurysm around the intervention site. Laryngoscopy confirmed left vocal fold paresis attributable to an injury to the left recurrent laryngeal nerve (LRLN) during aortic arch stenting, as the nerve loops around the aortic arch in close proximity to the area of the implanted stents. Following a non-invasive therapeutic approach entailing regular speech therapy, the patient recovered and demonstrated no residual clinical symptoms of LRLN palsy after six months.

Conclusion: Left recurrent laryngeal nerve palsy is a rare complication of aortic arch stenting not previously reported.
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http://dx.doi.org/10.4330/wjc.v11.i12.316DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6937415PMC
December 2019

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

Eur J Pediatr 2020 Mar 23;179(3):377-384. Epub 2019 Nov 23.

Department of Pediatrics and Adolescent Medicine, Division of Pediatric Hematology and Oncology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

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.
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http://dx.doi.org/10.1007/s00431-019-03513-6DOI Listing
March 2020

Transplant challenges in adults with congenital heart disease.

Int J Cardiol 2020 02 31;300:145-146. Epub 2019 Oct 31.

University Heart Center Freiburg - Bad Krozingen, Department of Congenital Heart Disease and Pediatric Cardiology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Germany.

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http://dx.doi.org/10.1016/j.ijcard.2019.10.038DOI Listing
February 2020

Repair of Complex Transposition of Great Arteries: Up to 30 Years of Follow-up.

Ann Thorac Surg 2020 02 9;109(2):555-565. Epub 2019 Nov 9.

Competence Network for Congenital Heart Defects, German Registry for Congenital Heart Defects, Berlin, Germany.

Background: To characterize treatment of transposition of great arteries with ventricular septal defect and left ventricular outflow tract obstruction (LVOTO) in Germany and to analyze late outcomes.

Methods: German Registry for Congenital Heart Defects data were searched for transposition of great arteries with ventricular septal defect and LVOTO. One hundred thirty-nine patients were treated at 15 institutions between 1968 and 2016. Risk factor analyses were performed for the primary endpoints of death and reoperation/reintervention.

Results: Follow-up was 88% complete, with a mean follow-up of 16 ± 7 years (median, 15 years [range, 1-48]) and a cumulative follow-up comprising 1739 patient-years. Atrial switches were performed in 15%, Rastelli procedure in 48%, Nikaidoh procedure in 9%, réparation a l'étage ventriculair (REV) in 8%, and arterial switch in 20%. Actuarial survival at 30 years was 86% (range, 83%-90%), with no difference between repairs. Freedom from primary reoperation was 17% (range, 12%-21%) at 30 years. Freedom from reoperation for LVOTO at 30 years was 74% (range, 70%-78%). Recurrent LVOTO was found in 9%, with risk factor diffuse subvalvular LVOTO (odds ratio, 9.8; P = .04). Late freedom from first reoperations other than right ventricle-to-pulmonary artery conduit was 60% (range, 59%-61%), with predictors multiple ventricular septal defect (hazard ratio, 6; P = .03) and Rastelli procedure (hazard ratio, 12; P = .03). Absolute reoperation rates were lowest for REV procedure (16% at a mean of 12 years).

Conclusions: Long-term survival is good without detectable differences between operations. Since the early 2000s increasing use of Nikaidoh and REV procedures was obvious, with REV performing particularly well. Surgery-specific and -unspecific reoperations are most common after the Rastelli technique.
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http://dx.doi.org/10.1016/j.athoracsur.2019.09.059DOI Listing
February 2020

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

Neuropediatrics 2019 12 20;50(6):400-403. Epub 2019 Sep 20.

Clinic for Children and Adolescents, Epilepsy Center Kork, Tuberous Sclerosis Center, Kehl-Kork, Germany.

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.
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http://dx.doi.org/10.1055/s-0039-1695786DOI Listing
December 2019

Retrograde transcatheter aortic valve closure in an infant with failing Norwood stage I palliation: a case report.

J Med Case Rep 2019 Jul 17;13(1):217. Epub 2019 Jul 17.

Department of Congenital Heart Disease and Pediatric Cardiology, University Heart Center Freiburg - Bad Krozingen, Medical Center - University of Freiburg, Faculty of Medicine, Mathildenstrasse 1, 79106, Freiburg, Germany.

Background: Aortic valve regurgitation leading to coronary steal phenomenon can severely impair cardiac function in hypoplastic left heart syndrome, thus worsening long-term outcome.

Case Presentation: A German infant with borderline aortic and mitral valve, hypoplastic left ventricle, ventricular septal defect, and hypoplastic aortic arch with critical coarctation initially underwent aortic arch reconstruction and aortic valve dilation with the aim of biventricular correction later on. Unfortunately, severe cardiac dysfunction necessitated a change in strategy entailing modified stage I Norwood palliation. Increasing aortic regurgitation with coronary steal was revealed postoperatively, which required redo surgery to oversew the valve. However, pronounced aortic regurgitation recurred, causing severe cardiac decompensation with repeated resuscitation. As a bailout strategy, we performed aortic valve closure via transfemoral retrograde implantation of an Amplatzer Duct Occluder II device. This led to the patient's rapid stabilization while circumventing highly risky renewed surgery in such a critically ill infant.

Conclusions: Retrograde transcatheter aortic valve closure may be considered a feasible alternative in infants with a failing single ventricle due to aortic regurgitation, with critical device evaluation being crucial for successful device implantation in this young age group.
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http://dx.doi.org/10.1186/s13256-019-2141-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6635989PMC
July 2019

Effect and safety of treatment with ACE-inhibitor Enalapril and β-blocker metoprolol on the onset of left ventricular dysfunction in Duchenne muscular dystrophy - a randomized, double-blind, placebo-controlled trial.

Orphanet J Rare Dis 2019 05 10;14(1):105. Epub 2019 May 10.

Institute of Neuropathology, Erlangen University Hospital, Erlangen, Germany.

Background: X-linked Duchenne muscular dystrophy (DMD), the most frequent human hereditary skeletal muscle myopathy, inevitably leads to progressive dilated cardiomyopathy. We assessed the effect and safety of a combined treatment with the ACE-inhibitor enalapril and the β-blocker metoprolol in a German cohort of infantile and juvenile DMD patients with preserved left ventricular function.

Methods Trial Design: Sixteen weeks single-arm open run-in therapy with enalapril and metoprolol followed by a two-arm 1:1 randomized double-blind placebo-controlled treatment in a multicenter setting.

Inclusion Criteria: DMD boys aged 10-14 years with left ventricular fractional shortening [LV-FS] ≥ 30% in echocardiography. Primary endpoint: time from randomization to first occurrence of LV-FS < 28%. Secondary: changes of a) LV-FS from baseline, b) blood pressure, c), heart rate and autonomic function in ECG and Holter-ECG, e) cardiac biomarkers and neurohumeral serum parameters, f) quality of life, and g) adverse events.

Results: From 3/2010 to 12/2013, 38 patients from 10 sites were centrally randomized after run-in, with 21 patients continuing enalapril and metoprolol medication and 17 patients receiving placebo. Until end of study 12/2015, LV-FS < 28% was reached in 6/21 versus 7/17 patients. Cox regression adjusted for LV-FS after run-in showed a statistically non-significant benefit for medication over placebo (hazard ratio: 0.38; 95% confidence interval: 0.12 to 1.22; p = 0.10). Analysis of secondary outcome measures revealed a time-dependent deterioration of LV-FS with no statistically significant differences between the two study arms. Blood pressure, maximal heart rate and mean-NN values were significantly lower at the end of open run-in treatment compared to baseline. Outcome analysis 19 months after randomization displayed significantly lower maximum heart rate and higher noradrenalin and renin values in the intervention group. No difference between treatments was seen for quality of life. As a single, yet important adverse event, the reversible deterioration of walking abilities of one DMD patient during the run-in period was observed.

Conclusions: Our analysis of enalapril and metoprolol treatment in DMD patients with preserved left ventricular function is suggestive to delay the progression of the intrinsic cardiomyopathy to left ventricular failure, but did not reach statistical significance, probably due to insufficient sample size.

Clinical Trial Registration: DRKS-number 00000115, EudraCT-number 2009-009871-36.
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http://dx.doi.org/10.1186/s13023-019-1066-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6509833PMC
May 2019

Fascicular parasystole and recurrent syncope - a case report.

Eur Heart J Case Rep 2018 Mar 5;2(1):yty020. Epub 2018 Mar 5.

Department of Cardiology and Angiology I, Heart Center Freiburg University, Hugstetter Str. 55, 79106 Freiburg, Germany.

Introduction: Parasystole refers to an ectopic pacemaker that discharges with a constant rate competing with the primary pacemaker of the heart the sinus node. Parasystolic pacemakers have been described in the atrium, atrioventricular node, His bundle, and in the ventricle. Ventricular parasystole usually carries a benign prognosis, but there are a few reports of ventricular tachyarrhythmia initiated by parasystolic beats.

Case Presentation: We present a case of a 15-year-old otherwise healthy teenager with recurrent most likely arrhythmic syncope who was diagnosed with ventricular parasystole from the left posterior fascicle. After exclusion of structural and primary electrical heart disease, the patient was deemed at increased risk of parasystole-induced tachyarrhythmia, and thus catheter ablation of the ectopic focus was performed. Since catheter ablation the patient continues to be free of any symptoms.

Discussion: This report highlights the potential risks of parasystole in context of recurrent syncope and reviews the available literature on parasystole and ventricular tachyarrhythmia.
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http://dx.doi.org/10.1093/ehjcr/yty020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6426017PMC
March 2018

Acquired von Willebrand syndrome in paediatric patients during mechanical circulatory support.

Eur J Cardiothorac Surg 2019 Jun;55(6):1194-1201

Department of Pediatrics and Adolescent Medicine, Division of Pediatric Hematology and Oncology, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

Objectives: Bleeding signs can become life-threatening complications in patients on mechanical circulatory support (MCS). Clinical phenotyping and comprehensive analyses of the cause of bleeding are, therefore, essential, especially when risk-stratifying patients during MCS workup. We conducted coagulation analyses and determined von Willebrand factor (VWF) parameters in a paediatric cohort on temporary extracorporeal life support, extracorporeal membrane oxygenation or long-term ventricular assist device support.

Methods: We carried out an observational single-centre study including 30 children with MCS (extracorporeal life support, n = 13; extracorporeal membrane oxygenation, n = 5; and ventricular assist device, n = 12). We also assessed the acquired von Willebrand parameters of each study participant: collagen binding capacity (VWF:CB), the ratio of collagen-binding capacity to VWF antigen (VWF:CB/VWF:Ag) and high-molecular-weight VWF multimers. We also documented bleeding events, transfusion requirement, haemolysis parameters and surgical interventions.

Results: All children developed AVWS (acquired von Willebrand syndrome) during MCS, usually during the early postoperative course. They presented no AVWS after device explantation. We detected a loss of high-molecular-weight VWF multimers, decreased VWF:CB/VWF:Ag ratios and reduced VWF:CB levels. Twenty of the 30 patients experienced bleeding complications; approximately 53% of them required surgical revision. There were no deaths due to bleeding during support.

Conclusions: The AVWS prevalence in paediatric patients on MCS is 100% regardless of the types of devices tested in this study. The bleeding propensity of AVWS patients widely varies.
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http://dx.doi.org/10.1093/ejcts/ezy408DOI Listing
June 2019

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

Pediatr Nephrol 2019 03 5;34(3):495-506. Epub 2018 Nov 5.

Shanghai Novartis Trading Ltd, Shanghai, China.

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.
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http://dx.doi.org/10.1007/s00467-018-4114-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6349801PMC
March 2019

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

Heart Vessels 2019 Jan 24;34(1):134-140. Epub 2018 Jul 24.

Department of Congenital Heart Disease and Pediatric Cardiology, Faculty of Medicine, Medical Center, University Heart Center Freiburg, Bad Krozingen, University of Freiburg, Mathildenstraße 1, 79106, Freiburg, Germany.

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.
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http://dx.doi.org/10.1007/s00380-018-1232-3DOI Listing
January 2019

The Transcription Factor ETV1 Induces Atrial Remodeling and Arrhythmia.

Circ Res 2018 08;123(5):550-563

From the Institute of Experimental and Clinical Pharmacology and Toxicology, Faculty of Medicine (C.R., S.R., A.L., M.B., M.S., R.G., T.B., T.S., S.M., L.H.).

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 Ca 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.
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http://dx.doi.org/10.1161/CIRCRESAHA.118.313036DOI Listing
August 2018

Antithrombotic therapy in pediatric ventricular assist devices: Multicenter survey of the European EXCOR Pediatric Investigator Group.

Int J Artif Organs 2018 Jul 11;41(7):385-392. Epub 2018 May 11.

18 Department of Pediatric Cardiology and Cardiac Surgery, Bambino Gesù Children's Hospital, Rome, Italy.

Objectives: Mechanical circulatory support for pediatric heart failure patients with the Berlin Heart EXCOR ventricular assist system is the only approved and established bridging strategy for recovery or heart transplantation. In recent years, the burden of thromboembolic events has led to modifications of the recommended antithrombotic therapy. Therefore, we aimed to assess modifications of antithrombotic practice among the European EXCOR Pediatric Investigator Group members.

Methods: We sent a questionnaire assessing seven aspects of antithrombotic therapy to 18 European hospitals using the EXCOR device for children. Returned questionnaires were analyzed and identified antithrombotic strategies were descriptively compared to "Edmonton protocol" recommendations developed for the US EXCOR pediatric approval study.

Results: Analysis of 18 received surveys revealed substantial deviations from the Edmonton protocol, including earlier start of heparin therapy at 6-12 h postoperatively and in 50% of surveyed centers, monitoring of heparin effectiveness with aPTT assay, administering vitamin K antagonists before 12 months of age. About 39% of centers use higher international normalized ratio targets, and platelet inhibition is changed in 56% including the use of clopidogrel instead of dipyridamole. Significant inter-center variability with multiple deviations from the Edmonton protocol was discovered with only one center following the Edmonton protocol completely.

Conclusion: Current antithrombotic practice among European EXCOR users representing the treatment of more than 600 pediatric patients has changed over time with a trend toward a more aggressive therapy. There is a need for systematic evidence-based evaluation and harmonization of developmentally adjusted antithrombotic management practices in prospective studies toward revised recommendations.
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http://dx.doi.org/10.1177/0391398818773040DOI Listing
July 2018

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

Artif Organs 2018 Apr 8;42(4):394-400. Epub 2018 Feb 8.

Department of Congenital Heart Disease and Pediatric Cardiology, University Heart Center Freiburg - Bad Krozingen, Freiburg, Germany.

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.
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http://dx.doi.org/10.1111/aor.13069DOI Listing
April 2018

Failure to Predict High-risk Kawasaki Disease Patients in a Population-based Study Cohort in Germany.

Pediatr Infect Dis J 2018 09;37(9):850-855

Department of Epidemiology, Institute of Social Pediatrics and Adolescent Medicine, Ludwig-Maximilians-University of Munich, Munich, Germany.

Background: Diverse scores on high-risk Kawasaki disease (KD) patients have proven a good prognostic validity in the Japanese population. However, data on non-Japanese have been inconclusive. Do the Kobayashi, Egami and Sano scores or application of up-to-date statistical methods (Random Forest) predict response to standard intravenous immunoglobulin (IVIG) therapy and the risk of persistent coronary artery aneurysm (CAA) in patients with KD in a mainly Caucasian population in Germany?

Methods: Data on 442 children (German population-based survey, 2013 and 2014) were used to assess the prognostic validity of the Kobayashi, Egami and Sano scores for being refractory to IVIG treatment and for predicting the risk of persistent CAA. Additionally, an up-to-date statistical approach (Random Forest) was applied to identify a potentially more valid score.

Results: A total of 301 children were eligible for assessment of their response to IVIG treatment. Among those, 177 children were followed-up for 1 year to identify persistent CAA. Although all scores were significantly associated with being refractory to IVIG (relative risk range between 2.32 and 3.73), the prognostic properties were low (likelihood ratio positive: 1.83-4.57; sensitivity in the range of 0.28-0.53). None of the scores was a significant predictor of CAA 1 year after acute illness. Application of statistical analysis such as Random Forest did not yield a more valid score.

Conclusions: None of the available scores appears to be appropriate for identifying high-risk Caucasian children with KD who might need intensified therapy.
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http://dx.doi.org/10.1097/INF.0000000000001923DOI Listing
September 2018

Bilateral Arterial Ducts Causing Airway Compression by a Vascular Ring.

Ann Thorac Surg 2018 Feb;105(2):e89

Department of Congenital Heart Defects/Pediatric Cardiology, Heart Center, University of Freiburg, Freiburg, Germany. Electronic address:

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http://dx.doi.org/10.1016/j.athoracsur.2017.09.014DOI Listing
February 2018

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

Artif Organs 2018 Apr 29;42(4):377-385. Epub 2017 Nov 29.

Department of Congenital Heart Disease and Pediatric Cardiology, Faculty of Medicine, University Heart Center Freiburg - Bad Krozingen, Medical Center - University of Freiburg, Germany.

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.
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http://dx.doi.org/10.1111/aor.13016DOI Listing
April 2018

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

Echocardiography 2018 01 29;35(1):79-84. Epub 2017 Oct 29.

University Heart Center Freiburg-Bad Krozingen, Department of Congenital Heart Disease and Pediatric Cardiology, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

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.
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http://dx.doi.org/10.1111/echo.13737DOI Listing
January 2018

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

Pediatr Transplant 2018 02 24;22(1). Epub 2017 Oct 24.

Department of Congenital Heart Defects and Pediatric Cardiology, Heart Center, University of Freiburg, Freiburg, Germany.

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.
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http://dx.doi.org/10.1111/petr.13072DOI Listing
February 2018

Prophylactic levosimendan for the prevention of low cardiac output syndrome and mortality in paediatric patients undergoing surgery for congenital heart disease.

Cochrane Database Syst Rev 2017 08 2;8:CD011312. Epub 2017 Aug 2.

Department of Congenital Heart Defects and Pediatric Cardiology, Heart Center, University of Freiburg, Mathildenstr. 1, Freiburg, Germany, 79106.

Background: Low cardiac output syndrome remains a serious complication, and accounts for substantial morbidity and mortality in the postoperative course of paediatric patients undergoing surgery for congenital heart disease. Standard prophylactic and therapeutic strategies for low cardiac output syndrome are based mainly on catecholamines, which are effective drugs, but have considerable side effects. Levosimendan, a calcium sensitiser, enhances the myocardial function by generating more energy-efficient myocardial contractility than achieved via adrenergic stimulation with catecholamines. Thus potentially, levosimendan is a beneficial alternative to standard medication for the prevention of low cardiac output syndrome in paediatric patients after open heart surgery.

Objectives: To review the efficacy and safety of the postoperative prophylactic use of levosimendan for the prevention of low cardiac output syndrome and mortality in paediatric patients undergoing surgery for congenital heart disease.

Search Methods: We identified trials via systematic searches of CENTRAL, MEDLINE, Embase, and Web of Science, as well as clinical trial registries, in June 2016. Reference lists from primary studies and review articles were checked for additional references.

Selection Criteria: We only included randomised controlled trials (RCT) in our analysis that compared prophylactic levosimendan with standard medication or placebo, in infants and children up to 18 years of age, who were undergoing surgery for congenital heart disease.

Data Collection And Analysis: Two review authors independently extracted data and assessed risk of bias according to a pre-defined protocol. We obtained additional information from all but one of the study authors of the included studies. We used the five GRADE considerations (study limitations, consistency of effect, imprecision, indirectness, and publication bias) to assess the quality of evidence from the studies that contributed data to the meta-analyses for the prespecified outcomes. We created a 'Summary of findings' table to summarise the results and the quality of evidence for each outcome.

Main Results: We included five randomised controlled trials with a total of 212 participants in the analyses. All included participants were under five years of age. Using GRADE, we assessed there was low-quality evidence for all analysed outcomes. We assessed high risk of performance and detection bias for two studies due to their unblinded setting. Levosimendan showed no clear effect on risk of mortality (risk ratio (RR) 0.47, 95% confidence interval (CI) 0.12 to 1.82; participants = 123; studies = 3) and no clear effect on low cardiac output syndrome (RR 0.64, 95% CI 0.39 to 1.04; participants = 83; studies = 2) compared to standard treatments. Data on time-to-death were not available from any of the included studies.There was no conclusive evidence on the effect of levosimendan on the secondary outcomes. The length of intensive care unit stays (mean difference (MD) 0.33 days, 95% CI -1.16 to 1.82; participants = 188; studies = 4), length of hospital stays (MD 0.26 days, 95% CI -3.50 to 4.03; participants = 75; studies = 2), duration of mechanical ventilation (MD -0.04 days, 95% CI -0.08 to 0.00; participants = 208; studies = 5), and the risk of mechanical circulatory support or cardiac transplantation (RR 1.49, 95% CI 0.19 to 11.37; participants = 60; studies = 2) did not clearly differ between the groups. Published data about adverse effects of levosimendan were limited. A meta-analysis of hypotension, one of the most feared side effects of levosimendan, was not feasible because of the heterogeneous expression of blood pressure values.

Authors' Conclusions: The current level of evidence is insufficient to judge whether prophylactic levosimendan prevents low cardiac output syndrome and mortality in paediatric patients undergoing surgery for congenital heart disease. So far, no significant differences have been detected between levosimendan and standard inotrope treatments in this setting.The authors evaluated the quality of evidence as low, using the GRADE approach. Reasons for downgrading were serious risk of bias (performance and detection bias due to unblinded setting of two RCTs), serious risk of inconsistency, and serious to very serious risk of imprecision (small number of included patients, low event rates).
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http://dx.doi.org/10.1002/14651858.CD011312.pub3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6483297PMC
August 2017