[Pulmonary hypertension in grown-ups with congenital heart disease: Recommendations of the Cologne Consensus Conference 2016]. / Pulmonale Hypertonie bei Erwachsenen mit angeborenen Herzfehlern: Empfehlungen der Kölner Konsensus-Konferenz 2016.

The 2015 European Guidelines on Diagnosis and Treatment of Pulmonary Hypertension are also valid for Germany. The guidelines contain detailed recommendations for different forms of PH, and specifically address PH associated with congenital heart disease (CHD). However, the practical implementation of the European Guidelines in Germany requires the consideration of several country-specific issues and already existing novel data. This requires a detailed commentary to the guidelines, and in some aspects an update already appears necessary. In June 2016, a Consensus Conference organized by the PH working groups of the German Society of Cardiology (DGK), the German Society of Respiratory Medicine (DGP) and the German Society of Pediatric Cardiology (DGPK) was held in Cologne, Germany. This conference aimed to solve practical and controversial issues surrounding the implementation of the European Guidelines in Germany. To this end, a number of working groups was initiated, one of which was specifically dedicated to PH in grown-ups with congenital heart disease (GUCH). This article summarizes the results and recommendations of this working group.

Outpatient management of intra-corporeal left ventricular assist device system in children: a multi-center experience.

Little is known about the outcomes of children supported on intracorporeal left ventricular assist device (HVAD), and the feasibility of outpatient management. All centers with pediatric patients discharged from the hospital on the device were identified using company database. A total of 14 centers were contacted, with 9 centers, contributing data retrospectively. From 2011 to 2013, 12 pediatric patients (7 females), mean aged 11.9 ± 2.3 years (range 8-15), mean weight 43 ± 19 kg (range 18-81), mean body surface area 1.3 ± 0.3 m(2) (range 0.76-1.96) were identified. Diagnosis included: dilated cardiomyopathy (CMP) (n = 5), noncompaction CMP (n = 4), toxic CMP (n = 2) and viral CMP (n = 1). Indications for support were permanent support (n = 1), bridge to recovery (n = 1) and bridge to transplantation (n = 10). Prior to HVAD implantation, all patients received intravenous inotropes and two patients were on temporary mechanical support. Overall mortality was 0%. Mean duration of inpatient and outpatient support were 56 (range: 19-95 days) and 290 days (range: 42-790), respectively. Mean readmission rate was 0.02 per patient month (2.1 per patient). No adverse events involving emergency department occurred. Eight children resumed local schooling. Home discharge of children supported on HVAD is feasible and safe. School integration can be achieved. There is wide center variability to discharge practice for children.

Caval flow reflects Fontan hemodynamics: quantification by magnetic resonance imaging.

INTRODUCTION: Failing Fontan circulation is a multifactorial problem without clear predictors and with uncertain onset. We sought to investigate the correlations between systemic venous flow return and the clinical condition of Fontan patients. METHODS: Flow measurements using phase contrast magnetic resonance imaging (MRI) were performed in the superior and inferior vena cava (SVC, IVC) in 61 Fontan patients. Median postoperative follow-up time was 6.7 (0.6-14.1) years; median age at MRI was 11.6 (4.0-44.6) years. Eight patients were identified clinically as a subgroup with suboptimal hemodynamics. The effective forward flow of combined SVC and IVC flow volume was defined as the venous cardiac index (vCI, l/min/m(2)). SVC flow ratio was defined as SVC flow in relation to vCI. The vCI and flow distribution between the SVC and IVC were investigated in relation to the hemodynamics and patients' age at MRI. RESULTS: Venous flow return through the SVC was 1.1 (0.6-3.4) l/min/m(2) and through the IVC 1.8 (0.6-3.2) l/min/m(2); total vCI was 3 l/min/m(2) (1.2-5.1). Patients with suboptimal Fontan hemodynamics showed significantly lower IVC flow return (median of 1.5 vs. 1.9 l/min/m(2), p = 0.027) and increased SVC flow ratio (0.56 vs. 0.35, p = 0.005) in comparison to those with good clinical condition. The total vCI decrease was correlated with older patient age (r = 0.575, p < 0.001). CONCLUSIONS: Altered systemic venous flow return is associated with suboptimal Fontan hemodynamics and seems to progress with patients' age and long-term follow-up after Fontan operation. Thus, MRI flow volume measurements might help in monitoring Fontan patients before the onset of clinical signs of suboptimal hemodynamics.

Onset of pulmonary stenosis after arterial switch operation for transposition of great arteries with intact ventricular septum.

INTRODUCTION: Pulmonary stenosis remains the most frequent complication and cause of reintervention after the arterial switch operation for transposition of the great arteries We investigated the onset, incidence, and outcome of pulmonary stenosis after arterial switch operation in neonates with transposition of the great arteries and intact ventricular septum. METHODS: Arterial switch operation using Lecompte maneuver was performed in 222 neonates with transposition of great arteries and intact ventricular septum. Complete medical records with serial echocardiograms were available for 174 (73%) patients and were reviewed for incidence of postoperative pulmonary stenosis defined as a thickened and doming pulmonary valve and/or a pressure gradient of >25 mmHg. RESULTS: During a mean follow-up of 14.4 ± 0.54 years, 31 children developed pulmonary stenosis. Onset of significant stenosis occurred as early as 30 days and as late as 10 years after arterial switch operation. Uncomplicated interventional balloon/stent angioplasty was performed in 11 patients with supravalvular stenosis (mean pressure gradients of 65 mmHg). Severe restenosis occurred in these patients post-angioplasty (range 2-7 years). In other 10 patientseither patch enlargement of the area involved or angioplasty were performed. Freedom from intervention was 68.6±8.7% at 1 year and 42.8.1±9.5% at 15 years and onwards. CONCLUSION: Over time, pulmonary stenosis developed after arterial switch operation. Balloon angioplasty for supravalvular pulmonary stenosis could be the initial treatment of choice owing to the high success rate. Surgical intervention is offered to those with pulmonary valve stenosis having pressure gradients of >50 mmHg, and for re-stenosis after intervention/stent implantation.

[Treatment of pulmonary arterial hypertension (PAH): recommendations of the Cologne Consensus Conference 2010]. / Therapie der pulmonal arteriellen Hypertonie (PAH): Empfehlungen der Kölner Konsensus-Konferenz 2010.

The 2009 European Guidelines on Diagnosis and Treatment of Pulmonary Hypertension have been adopted for Germany. The guidelines contain detailed recommendations for the treatment of pulmonary arterial hypertension (PAH). However, the practical implementation of the European Guidelines in Germany requires the consideration of several country-specific issues and already existing novel data. This requires a detailed commentary to the guidelines, and in some aspects an update already appears necessary. In June 2010, a Consensus Conference organized by the PH working groups of the German Society of Cardiology (DGK), the German Society of Respiratory Medicine (DGP) and the German Society of Pediatric Cardiology (DGPK) was held in Cologne, Germany. This conference aimed to solve practical and controversial issues surrounding the implementation of the European Guidelines in Germany. To this end, a number of working groups was initiated, one of which was specifically dedicated to the treatment of PAH. This commentary summarizes the results and recommendations of the working group on treatment of PAH.

[Pharmacological treatment of pulmonary hypertension in patients with congenital heart disease]. / Medikamentöse Therapie des Lungenhochdrucks bei Patienten mit angeborenen Herzfehlern.

The development of drugs for lowering pressures in pulmonary arterial hypertension (PHT) has provided possible therapeutic application in patients with pulmonary hypertension associated with congenital heart disease (CHD). Prostanoids, both nonselective and selective endothelin-receptor antagonists and phosphodiesterase-V inhibitors have been used for this purpose. The efficacy of these drugs - from different classes of bioactivity - in this context have been shown in several studies. However, the long-term effects of drug treatment on prognosis and course of PHT have not yet been adequately investigated. The current status of drug treatment of PHT in patients with CHD is reviewed in this article.

First experience with an oral combination therapy using bosentan and sildenafil for pulmonary arterial hypertension.

BACKGROUND: New oral substances such as beraprost, bosentan and sildenafil have proven effective in different forms of pulmonary arterial hypertension (PAH), both alone and in combination with standard treatment such as intravenous and inhaled prostacyclins. However, there are few reports so far on the effect of a combination of exclusively oral substances. In this paper, we present our initial findings of treatment using a combination of these oral substances in a heterogeneous group of patients with different forms of PAH. MATERIALS AND METHODS: Eleven patients with a median age of 12.9 years (5.5-54.7 years) with both idiopathic PAH and forms associated with congenital cardiac defects (PAH-CHD) with a mean pulmonary arterial pressure > 25 mmHg were enrolled in an observational, open-label, prospective, single-centre study. Either combination treatment with bosentan and sildenafil was started initially, or an existing bosentan treatment was complemented with sildenafil given as an add-on therapy. Mean doses given were 2.3 +/- 0.6 mg kg(-1) for bosentan and 2.1 +/- 0.9 mg kg(-1) for sildenafil. Clinical status, exercise capacity, and haemodynamics were assessed at baseline and at the end of the observation period after a mean follow-up time of 1.1 years (0.5-2.5 years). RESULTS: No major side effects regarding liver function and blood pressure regulation were noted. One patient died of sudden death elsewhere. Most patients were in New York Heart Association (NYHA) functional class III. Clinical improvement was about one NYHA class (mean 2.8 +/- 0.4-1.6 +/- 0.8, P = 0.001), which was associated with an increase of transcutaneous oxygen saturation (89.9 +/- 9.9-92.3 +/- 7.1%; P = 0.037), maximum oxygen uptake (18.1 +/- 6.8-22.8 +/- 10.4 mL kg(-1) x min; P = 0.043), and 6-minute walking distance (351 +/- 58-451 +/- 119 m; P = 0.039). Mean pulmonary arterial pressure measured invasively decreased (62 +/- 12-46 +/- 18 mmHg; P = 0.041). CONCLUSIONS: In our patient group, a combination of oral bosentan and sildenafil proved to be safe and effective. Clearly, randomized, double-blind, placebo-controlled studies are warranted to define the role and type of combination therapies in PAH.

Advantages of C2 monitoring to avoid acute rejection in pediatric heart transplant recipients.

BACKGROUND: Inadequate cyclosporine (CsA) blood levels are a major risk factor for acute rejection in transplant recipients. The CsA trough level (C0 level) measured just before the next dose is commonly used to adjust the oral dosage. However, the 2-hour post-CsA dose concentration (C2 level) is favored as the best single-point correlate of CsA area-under-the-curve concentration and may better reflect the immunosuppressive effect of CsA. Because an adequate C2 level has not yet been defined, this study was performed to assess the value of C2 monitoring for the prevention of acute rejection and to define target levels in pediatric heart transplant recipients. METHODS: C2 levels were assessed in 50 pediatric heart transplant patients with oral CsA therapy and compared with trough C0 levels using full blood sampling, mass spectrometry and a blinded analysis. Acute graft rejection was detected using intramyocardial electrocardiogram (IMEG) and serial conventional and tissue Doppler echocardiography (TDE). Rejection was confirmed or excluded by endomyocardial biopsy. RESULTS: C2 and not C0 levels were significantly reduced in patients with acute graft rejection (ISHLT Grade > or =2). Patients with a C2 level <600 ng/ml had a significantly higher risk of developing acute rejection (100% sensitivity and 82% specificity). Patients with impaired CsA absorption were identified with C2 monitoring and switched to another calcineurin inhibitor. CONCLUSIONS: Monitoring of the C2 rather than the C0 level better reflects immunosuppressive efficiency and identifies patients at increased risk of acute rejection. A C2 level of >600 ng/ml should be the target to prevent acute rejection.

Initial experience with bosentan (Tracleer) as treatment for pulmonary arterial hypertension (PAH) due to congenital heart disease in infants and young children.

INTRODUCTION: Bosentan, a dual endothelin-receptor antagonist, has been shown to be an effective treatment option in patients with the idiopathic form of pulmonary arterial hypertension (PAH). We used bosentan as compassionate treatment in infants and young children with congenital heart disease (CHD) who had a) PAH preoperatively representing a contraindication to corrective surgery or b) persisting PAH after corrective surgery causing right heart failure and reduced exercise tolerance. METHODS: Seven children with PAH due to CHD (median age 3.8 years; range 1.5 to 6.4 years) received 3 mg/kg/d bosentan (Tracleer) orally. Clinical, echocardiographic and hemodynamic parameters were measured and laboratory tests performed before treatment and during steady state while on treatment. Routine liver function parameters were monitored monthly. RESULTS: Mean bosentan treatment time was 8.6+/-5 months. During bosentan therapy there were no significant adverse events. The clinical status remained stable or improved in all patients: NYHA class decreased from 2.6+/-0.6 to 1.7+/-0.6 (p<0.05). This was associated with a mean reduction of the right ventricular systolic pressure (RVSP) from 96+/-11 mmHg to 71+/-26 mmHg (p<0.05). CONCLUSIONS: Treatment with bosentan in infants and young children with PAH due to congenital heart disease was tolerated without significant side effects and resulted in stabilization of clinical status. A significant reduction in right ventricular systolic pressure (RVSP) could be demonstrated. These results suggest that the dose regimen used is appropriate and safe for the treatment of infants and children with PAH, resulting in a reduction of pathologically increased pulmonary vascular resistance.

[Neonatal chylothorax with trisomy 21]. / Neonataler Chylothorax bei Trisomie 21.

Neonatal chylothorax is an uncommon cause of respiratory distress in the newborn. It may result from anomalous lymph drainage with or without association with aneuploidy syndromes (trisomy, Turner's syndrome, Noonan's syndrome), from injury to the thoracic duct, and from obstruction of the superior vena cava. We report a term newborn and a premature infant with neonatal chylothorax, both associated with trisomy 21. In the case of the term infant, bilateral pleural effusions were diagnosed immediately before birth. The baby suffered from respiratory distress. The physical findings were characteristic of trisomy 21. In the premature infant (gestational age 24 weeks, 735 g) the ductus arteriosus was ligated on day nine after birth. Four days after surgery a central venous line was inserted via the left vena mediana cubiti into the left vena subclavia. Nine days after surgery a left-sided chylothorax occurred. The infant had subtle signs of a trisomy 21 (slightly enlarged tongue, brachycephalic head. questionable simian crease). In both children, cytogenetic studies were done and confirmed the diagnosis of trisomy 21. Infants with neonatal chylothorax should be carefully evaluated for dysmorphic signs of a trisomy or monosomy. Premature infants may present with only subtle clinical signs requiring cytogenetic studies to confirm an aneuploidy syndrome.

Chemosensitivity of B cell chronic lymphocytic leukemia and correlated expression of proteins regulating apoptosis, cell cycle and DNA repair.

B cell chronic lymphocytic leukemia (B-CLL) cannot be cured with conventional chemotherapy. This clinical enigma appears to be at least partially due to the fact that B-CLL cells are resistant to programmed cell death (apoptosis) and that they are arrested in G0/G1 phase of the cell cycle. The reasons for the dysregulation of these two key cellular events in B-CLL are unclear. The present study aimed at determining correlations between the expression levels of proteins regulating apoptosis, cell cycle and DNA repair in B-CLL cells and normal B cells. In addition, the differential sensitivity of B-CLL cells to drug-induced apoptosis was quantified. We show that in B-CLL cells levels of the death-suppressor Bcl-2 correlated positively with those of the pro-apoptotic protein Bax and of the cyclin-dependent kinase (cdk) inhibitor p27Kip1. In B-CLL cells levels of the anti-apoptotic Bcl-xL showed a positive correlation with levels of the 80 kDa regulatory component (Ku80) of the DNA-dependent protein kinase that is involved in DNA double-stranded break repair. These correlations were not detected in normal B cells. The sensitivity of leukemic cells to FLUD but not to ADM, CPM or to DEX was reduced in pre-treated patients. These data support the hypothesis that in B-CLL cells death-modulators and molecules modulating cell cycle and DNA repair are regulated in a coordinated manner. Leukemia (2000) 14, 40-46.

[Comparison of gastric emptying, blood glucose, and oro-cecal transit times after a conventional morning meal and a Kollath breakfast]. / Vergleichende Messungen von Magenentleerung, Blutglukose und orozökaler Transitzeit nach einer konventionellen Morgenmahlzeit und einem Kollath-Frühstück.

Blood glucose kinetics and intestinal transit times were investigated in 12 adult volunteers aged 28 to 52 years after ingestion of a conventional morning meal made up of white flour rolls, butter, marmalade, and coffee with sugar as compared with an isocaloric Kollath-breakfast consisting of whole wheat flakes as a basis. For estimation of gastric emptying time the sodium-[13C]acetate breath test technique was used. Oro-coecal transit time and gastric emptying were determined by simultaneous administration of lactose-[13C]ureide and consecutive drawings of breath samples in intervals of 15, 30, and 60 min through 12 h. The 13CO2-excess of the breath test samples was measured by continuous flow isotope ratio mass spectrometry. The postprandial rise in blood glucose following the ingestion of the Kollath-breakfast was lower as compared with the conventional morning meal, showing significant differences between the 90 min values and the area below the blood glucose curve. The half time of gastric emptying was not different between the two breakfast versions (1.7 vs. 1.6 h). The oro-coecal transit time averaged out at 4.2 h after the Kollath-breakfast and 5.3 h following the conventional morning meal. Likewise, there were no significant differences in the coecal retention time nor in the cumulative percentage of 13CO2-exhalation between the two breakfast versions. Concerning the blood glucose kinetics the differences in the nutritional physiology between the breakfast based on whole wheat flakes and the conventional breakfast as claimed by Kollath were only detectable in outlines in our study. Gastric emptying time showed no differences between the two breakfast versions.