Use of subcutaneous treprostinil in pediatric pulmonary arterial hypertension-Bridge-to-transplant or long-term treatment?

PAH is a progressive life-threatening disease in children. While parenteral prostacyclin therapy improves survival in patients with severe PAH, central line-related complications are common. Our aim was to assess the efficacy, safety, and tolerability of subcutaneous treprostinil treatment in pediatric PAH patients. Eight patients were treated with subcutaneous treprostinil at the Pediatric Heart Center Budapest. Indications for subcutaneous treprostinil therapy were clinical worsening and/or echocardiographic progression or switch from intravenous to subcutaneous therapy. Following treprostinil initiation, clinical status improved or did not change in four of eight patients. Two patients were lost early during treprostinil therapy, parenteral treprostinil as a rescue therapy being insufficient in these cases. The final dose in long-term treated patients was between 60 and 100 ng/kg/min. Aside from thrombocytopenia, other severe side effects were not observed. Potts shunt was performed as palliative treatment in two cases. Three patients had successful lung transplantation, and one died while on the waiting list. Long-term subcutaneous treprostinil could be a safe and well-tolerated therapy in children with severe PAH even at higher doses. It may serve as an alternative to intravenous prostacyclin treatment allowing to avoid the potential complications of permanent central line placement.

Frequency of Miscarriage/Stillbirth and Terminations of Pregnancy Among Women With Congenital Heart Disease in Germany, Hungary and Japan.

BACKGROUND: The 2011 guidelines of the European Society of Cardiology (ESC) on the management of cardiovascular diseases during pregnancy define the maternal predictors for neonatal complications. The aim of this study was to determine whether these are associated with an increased number of miscarriages/stillbirths and terminations of pregnancy (TOPs) also in patients with congenital heart defects (CHD). METHODS AND RESULTS: The 634 women from Germany, Hungary and Japan were surveyed concerning the issues of sexuality and reproductive health, as well as their general life situation and medical care. 25% of the recorded pregnancies in women with CHD resulted in miscarriage, stillbirth or TOP. Affecting 16.8% of all recorded pregnancies, miscarriages or stillbirths occurred more frequently than in the general population and more than previously recorded for patients with CHD. TOP occurred in 8% of the surveyed pregnancies. Underlying maternal predictors for neonatal events had an influence on the number of TOP; among those with underlying predictors, TOP was recorded 3-fold more than in those without such predictors (15.6% vs. 5.5%). Remarkably, a significant deficit regarding the level of information on potential pregnancy-associated risks was observed in all 3 participating countries. CONCLUSIONS: Pregnant women with CHD should always be treated and counseled individually by cardiologists, gynecologists, obstetricians and anesthetists with appropriate expert knowledge. (Circ J 2016; 80: 1846-1851).

Fluid Overload Is Associated With Higher Mortality and Morbidity in Pediatric Patients Undergoing Cardiac Surgery.

OBJECTIVES: Fluid overload after pediatric cardiac surgery is common and has been shown to increase both mortality and morbidity. This study explores the risk factors of early postoperative fluid overload and its relationship with adverse outcomes. DESIGN: Secondary analysis of the prospectively collected data of children undergoing open-heart surgery between 2004 and 2008. SETTING: Tertiary national cardiac center. PATIENTS: One thousand five hundred twenty consecutive pediatric patients (<18 years old) were included in the analyses. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: In the first 72 hours of the postoperative period, the daily fluid balance was calculated as milliliter per kilogram and the daily fluid overload was calculated as fluid balance (L)/weight (kg) × 100. The primary endpoint was in-hospital mortality; the secondary outcomes were low cardiac output syndrome and prolonged mechanical ventilation. One thousand three hundred and sixty-seven patients (89.9%) had a cumulative fluid overload below 5%; 120 patients (7.8%), between 5% and 10%; and 33 patients (2.1%), above 10%. After multivariable analysis, higher fluid overload on the day of the surgery was independently associated with mortality (adjusted odds ratio, 1.14; 95% CI, 1.008-1.303; p = 0.041) and low cardiac output syndrome (adjusted odds ratio, 1.21; 95% CI, 1.12-1.30; p = 0.001). Higher maximum serum creatinine levels (adjusted odds ratio, 1.01; 95% CI, 1.003-1.021; p = 0.009), maximum vasoactive-inotropic scores (adjusted odds ratio, 1.01; 95% CI, 1.005-1.029; p = 0.042), and higher blood loss on the day of the surgery (adjusted odds ratio, 1.01; 95% CI, 1.004-1.025; p = 0.015) were associated with a higher risk of fluid overload that was greater than 5%. CONCLUSIONS: Fluid overload in the early postoperative period was associated with higher mortality and morbidity. Risk factors for fluid overload include underlying kidney dysfunction, hemodynamic instability, and higher blood loss on the day of the surgery.

Impact of V9302, a Competitive Antagonist of Transmembrane Glutamine Flux on Reversal of Resistance in Breast Cancer Cell Lines.

Chemotherapy is a known treatment modality that improves the long-term survival of breast cancer patients. However, due to the resistance to numerous anticancer drugs, alternative chemotherapeutic strategies are required. Regarding antimetabolic drugs, several compounds have proven anticancer properties, such as statins. The present study aimed to investigate the in vitro effects of V9302, a competitive antagonist of glutamine flux, on different subtypes of breast cancers (estrogen, progesterone, and HER2 receptor-positive or negative, and Pgp-negative and Pgp-overexpressing). The interactions of V9302 with standard chemotherapeutic drugs (doxorubicin and cisplatin) were also determined by MTT staining on breast cancer cell lines. Furthermore, the influence of V9302 on the cell cycle of MCF-7 and its Pgp-overexpressing counterpart KCR was monitored by flow cytometry. It was shown that V9302 exerted synergistic interactions with doxorubicin in all breast cancer cell lines. In cell cycle analysis, the KCR cell line was more sensitive to V9302. After 48 h, cell proliferation was completely blocked, and elevated G1, suppressed S, and decreased G2/M could be detected. Inhibition of glutamate transport can be assumed to block resistance related to Pgp.

A randomized, double-blind, placebo-controlled, dose-ranging study of oral sildenafil citrate in treatment-naive children with pulmonary arterial hypertension.

BACKGROUND: Safe, effective therapy is needed for pediatric pulmonary arterial hypertension. METHODS AND RESULTS: Children (n=235; weight ≥8 kg) were randomized to low-, medium-, or high-dose sildenafil or placebo orally 3 times daily for 16 weeks in the Sildenafil in Treatment-Naive Children, Aged 1-17 Years, With Pulmonary Arterial Hypertension (STARTS-1) study. The primary comparison was percent change from baseline in peak oxygen consumption (PV(O(2))) for the 3 sildenafil doses combined versus placebo. Exercise testing was performed in 115 children able to exercise reliably; the study was powered for this population. Secondary end points (assessed in all patients) included hemodynamics and functional class. The estimated mean±SE percent change in PV(O(2)) for the 3 doses combined versus placebo was 7.7±4.0% (95% confidence interval, -0.2% to 15.6%; P=0.056). PV(O(2)), functional class, and hemodynamics improved with medium and high doses versus placebo; low-dose sildenafil was ineffective. Most adverse events were mild to moderate in severity. STARTS-1 completers could enter the STARTS-2 extension study; patients who received sildenafil in STARTS-1 continued the same dose, whereas placebo-treated patients were randomized to low-, medium-, or high-dose sildenafil. In STARTS-2 (ongoing), increased mortality was observed with higher doses. CONCLUSIONS: Sixteen-week sildenafil monotherapy is well tolerated in pediatric pulmonary arterial hypertension. Percent change in PV(O(2)) for the 3 sildenafil doses combined was only marginally significant; however, PV(O(2)), functional class, and hemodynamic improvements with medium and high doses suggest efficacy with these doses. Combined with STARTS-2 data, the overall profile favors the medium dose. Further investigation is warranted to determine optimal dosing based on age and weight. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov. Unique identifier: NCT00159913.

[Percutaneous left atrial appendage closure after resolution of left atrial appendage thrombi with dabigatran]. / Percutan bal pitvari fülcsezárás dabigatrannal való fülcsethrombus feloldását követoen.

The "gold standard" of the prevention of atrial fibrillation related thromboembolic events is anticoagulation therapy with oral vitamin K antagonists. A certain proportion of high-risk patients with atrial fibrillation are not receiving effective antithrombotic therapy because of problems associated with its use. Resolution of subsequent left atrial appendage thrombi is quite a great challenge in patients who are not tolerating "standard" antithrombotic drugs. According to the knowledge of the authors, this is the first report of a patient with non-valvular persistent atrial fibrillation and high stroke risk, who was intolerant to "standard" anticoagulant therapy and had persistent left atrial appendage thrombi following the use of a wide variety of "standard" anticoagulants. Successful resolution of left atrial appendage thrombi with dabigatran and successful percutaneous left atrial appendage closure were performed in this case.

Ventricular septal rupture caused by myocardial bridge, solved by interventional closure device.

Myocardial bridging is a common coronary anomaly, which is generally described as a benign phenomenon. However, a growing number of studies consider this anomaly a relevant pathophysiological phenomenon with serious pathological consequences. Here we report on the case of an 88-year-old woman suffering from myocardial infarction and ventricular septal rupture, lacking any recognizable coronary disease except for a myocardial bridge causing the systolic compression of the left anterior descending coronary artery. A wide range of diagnostic procedures, including coronarography, echocardiography, and magnetic resonance imaging were used. The septal rupture was finally closed by using a percutaneous closure device. This event indicates that myocardial bridges - at least in some cases - may have notable clinical relevance.

[Right ventricular outflow tract reconstruction in adolescents and adults after previous repair of congenital heart defects]. / A jobbkamra-kifolyási pálya rekonstrukciója elozoleg korrigált veleszületett szívhibák esetén fiatal- és felnottkorban.

UNLABELLED: Due to successful surgical treatment of congenital heart defects in infants and children, the number of patients who reach the adolescent/adult age is continuously increasing. AIMS: The authors sought to identify the short- and medium-term outcomes of reconstruction of right ventricular outflow tract in adolescents and adults who underwent surgical intervention for congenital heart defect in infancy or early childhood. METHODS: Between 2001 and 2012, 48 patients (age: 15-39, mean 21 years) (30 tetralogy of Fallot, 11 pulmonary atresia + ventricular septal defect, 6 transposition of great arteries + ventricular septal defect + left ventricular outflow tract obstruction, and 1 truncus arteriosus) had repeat operation because of right ventricular dysfunction. All patients previously underwent right ventricular outflow tract procedures in early childhood. RESULTS: In 31 patients, the small homograft, and in 9 patients the transannular-paths were replaced for "adult-size" homograft. Bioprosthetic pulmonary valve replacement was performed in pulmonary (6 patients) and homograft annuli (2 patients). In 14 patients, resection of the right ventricular outflow tract aneurism was also necessary to be performed. There was no early and mid-time (10 years) mortality. In 97.5% of patients with homograft-re-implantation, there was no need for repeat intervention for 5 years. CONCLUSIONS: The right ventricular outflow tract restoration in adolescents and adults is an effective procedure. The reconstruction should be performed in early adolescent period to prevent right ventricular dysfunction. The authors prefer using bioprosthetic pulmonary valve replacement in patients with adult-size pulmonary or homograft annulus.

Transpulmonary thermodilution in neonates undergoing arterial switch surgery.

Measurement of the global end-diastolic volume index (GEDI) by transpulmonary thermodilution (TPTD) has become a useful technique for measuring preload in adults. This study aimed to investigate the hemodynamic changes in neonates during the postoperative period after arterial switch surgery. Over a 13-month period, the postoperative data of 12 neonates with transposition of the great arteries were retrospectively investigated. Arterial and central venous blood pressures were monitored, Cardiac index (CI), stroke volume index (SVI), systemic vascular resistance index (SVRI), GEDI, and extravascular lung water index (ELWI) were measured by thermodilution. The CI was significantly correlated with the SVRI only in the closed chest condition (r = -0.92; P < 0.001). The CI and SVI values were significantly lower and the ELWI and SVRI values significantly higher in both the open and closed chest conditions than the postextubation values. The relationship between change in GEDI and change in CI was stronger in the open chest condition (r = 0.93; P < 0.006) than in the closed chest condition (r = 0.75; P = 0.055). However, the latter just missed statistical significance. According to the findings, TPTD seems to be a useful tool for assessing cardiac function after neonatal arterial switch surgery. Establishment of normal values will be essential for proper guidance of therapy for this population using volumetric parameters.

[Heart transplantation after corrective surgery of a congenital heart disease. Surgical technical problems]. / Sikeres szívátültetés veleszületett szívhiba korrekciós szívmutéte után. Sebésztechnikai problémák.

Heart transplantation was performed in a 17-year old boy with severe left ventricular failure. Previously a congenital heart disease, tetralogy of Fallot was reconstructed in one and half years old of age. Authors present the different surgical problems complicated this procedure. In Hungary this is the first heart transplantation after a corrective surgical procedure of a complex congenital heart disease.

[Percutaneous closure of left atrial appendage in non-valvular atrial fibrillation--international and Hungarian experiences]. / A bal pitvari fülcse perkután zárása nonvalvularis pitvarfibrillációban--nemzetközi és hazai tapasztalatok.

In patients with non-valvular atrial fibrillation, efficacy of stroke prevention with oral anticoagulant therapy has been proved. Despite their high risk for thromboembolic events, there are substantial numbers of patients who are not candidates for long-term oral anticoagulant therapy, therefore the interest in alternative treatment strategies are in focus these days. The most common place within the heart for thrombus formation in patients with non-valvular atrial fibrillation is the left atrial appendage. Two devices specifically designed for percutaneous left atrial appendage closure are currently available in Europe: the WATCHMAN LAA system (Atritech, Inc) and the AMPLATZER Cardiac Plug (AGA Medical Corporation). Although present trial results (PLAATO, PROTECT AF) suggest that LAA closure may be performed at acceptable safety and it may reduce the long-term stroke risk, available data are still very limited. At present these procedures may be an acceptable alternative in selected high-risk patients with non-valvular atrial fibrillation who are not or suboptimal candidates for oral anticoagulant therapy. On 28. January, 2010 we performed the first three successful percutaneous left atrial appendage closure procedures in Gottsegen György Hungarian Institute of Cardiology in Hungary.

[Redo procedures for correction of aortic valve diseases in infants and children. The Bentall-Konno procedure]. / Csecsemô- és gyermekkori REDO mûtéteket igénylô aortabillentyû-betegség. Az elsô magyarországi Bentall-Konno-mûtét gyermekkorban.

On an infant with critical valvular aortic stenosis balloon-valvoplasty, and 3 years later because of the aortic valve regurgitation Ross operation was performed. In the early postoperative period an aortic-root abscess occurred due to an infective endocarditis; the aortic root was corrected by homograft implantation. Due to a relatively small, calcified aortic valve, with aortic valve regurgitation grade III at the age of 12 years, a Bentall-Konno procedure was performed successfully. This is the first case when this complex surgical procedure was performed successfully on a child in Hungary.

[Infective endocarditis appearing with meningeal signs]. / Meningealis izgalmi tünetekkel jelentkezo infektív endocarditis.

The authors present the case of a 12-year old girl with infective endocarditis. Following an initial three-day period of malaise, she was admitted to the hospital with meningeal signs. The clinical symptoms and the results of the laboratory examinations, lumbar puncture and hemoculture supported the diagnosis of Staphylococcus sepsis and meningitis. The initiation of antimicrobial therapy resulted in temporary improvement while a systolic cardiac murmur appeared. Transthoracal echocardiogram raised the diagnosis of mitral valve endocarditis. Due to the subsequent deterioration in her condition, the patient was referred to the Pediatric Heart Center of the Gottsegen György National Institute of Cardiology where transoesophageal echocardiogram confirmed the diagnosis. The vegetations were removed by extracorporeal cardiac surgery including mitral valve plasty. Retrospectively, septic embolisation caused multiplex brain infarcts were identified by cranial MRI scan as the underlying cause of the initial clinical symptoms and liquor results. Following her recovery, patient remained well with some mild residual mitral regurgitation and without any residual neurological symptoms.

[Surgical management of congenital heart defects in adolescent and adult patients, between years 2001-2008]. / Tapasztalataink a fiatal- és felnottkori veleszületett szívhibák sebészi kezelésében 2001-2008.

UNLABELLED: The leading interventions due to congenital heart defects performed in adults are: (I) reconstructive operations, including: (a) newly diagnosed malformations, (b) previously adjudged to be inoperable defects, (c) so called "tardive" interventions due to pulmonary hypertension or right ventricle insufficiency. There is a growing number of (II) REDO operations, including: (a) correction of residual defects, (b) replacement of damaged or outgrown homografts, (c) recoarctation (aneurysm, dissection) of the aorta after surgical or catheter interventions, (d) Ross procedure, valve replacements due to previously performed aortic valvulotomy/valvuloplasty or corrections of different malformations (e.g. TGA). PATIENTS AND RESULTS: 166 of all 4496 operations were performed in adolescents and adults (age: 16-52 years, mean: 28 years) between years 2001-2008. The distribution of these interventions: Ia: 77, Ib: 15, Ic: 4, IIa: 11, IIb: 22, IIc: 9, IId: 28. Mortality rates were the following: 0 intraoperative, 4 early postoperative, 1 pulmonary hypertensive crisis, 1 malignant rhythm disturbances, 2 multi-organ failure. CONCLUSIONS: The main risk factors are pulmonary hypertension and right ventricle failure. Complex surgical solutions do not mean extreme problems for a congenital cardiac surgeon, but earlier diagnosis and the use of ECMO during therapy may improve the results.

Pharmacotherapeutic management of paediatric heart failure and ACE-I use patterns: a European survey.

OBJECTIVE: To characterise heart failure (HF) maintenance pharmacotherapy for children across Europe and investigate how angiotensin-converting enzyme inhibitors (ACE-I) are used in this setting. METHODS: A Europe-wide web-based survey was conducted between January and May 2015 among European paediatricians dedicated to cardiology. RESULTS: Out of 200-eligible, 100 physicians representing 100 hospitals in 27 European countries participated. All participants reported prescribing ACE-I to treat dilated cardiomyopathy-related HF and 97% in the context of congenital heart defects; 87% for single ventricle physiology. Twenty-six per cent avoid ACE-I in newborns. Captopril was most frequently selected as first-choice for newborns (73%) and infants and toddlers (66%) and enalapril for children (56%) and adolescents (58%). Reported starting and maintenance doses varied widely. Up to 72% of participants follow formal creatinine increase limits for decision-making when up-titrating; however, heterogeneity in the cut-off points selected existed. ACE-I formulations prescribed by 47% of participants are obtained from more than a single source. Regarding symptomatic HF maintenance therapy, 25 different initial drug combinations were reported, although 79% select a regimen that includes ACE-I and diuretic (thiazide and/or loop), 61% ACE-I and aldosterone antagonist; 44% start with beta-blocker, 52% use beta-blockers as an add-on drug. Of the 89 participants that prescribe pharmacotherapy to asymptomatic patients, 40% do not use ACE-I monotherapy or ACE-I-beta-blocker two-drug only combination. CONCLUSIONS: Despite some reluctance to use them in newborns, ACE-I seem key in paediatric HF treatment strategies. Use in single ventricle patients seems frequent, in apparent contradiction with current paediatric evidence. Disparate dosage criteria and potential formulation-induced variability suggest significant differences may exist in the risk-benefit profile children are exposed to. No uniformity seems to exist in the drug regimens in use. The information collected provides relevant insight into real-life clinical practice and may facilitate research to identify the best therapeutic options for HF children.

Orodispersible minitablets of enalapril for use in children with heart failure (LENA): Rationale and protocol for a multicentre pharmacokinetic bridging study and follow-up safety study.

INTRODUCTION: Treatment of paediatric heart failure is based on paradigms extensively tested in the adult population assuming similar underlying pathophysiological mechanisms. Angiotensin converting enzyme inhibitors (ACEI) like enalapril are one of the cornerstones of treatment and commonly used off-label in children. Dose recommendations have been extrapolated from adult experience, but the relationship between dose and pharmacokinetics (PK) in (young) children is insufficiently studied. Furthermore, appropriate paediatric formulations are lacking. Within the European collaborative project LENA, a novel formulation of enalapril orodispersible minitablets (ODMT), suitable for paediatric administration, will be tested in (young) children with heart failure due to either dilated cardiomyopathy or congenital heart disease in two pharmacokinetic bridging studies. Paediatric PK data of enalapril and its active metabolite enalaprilat will be obtained. In a follow-up study, the safety of enalapril ODMTs will be demonstrated in patients on long-term treatment of up to 10 months. Furthermore, additional information about pharmacodynamics (PD) and ODMT acceptability will be collected in all three studies. METHODS AND ANALYSIS: Phase II/III, open-label, multicentre study. Children with dilated cardiomyopathy (DCM) (n = 25; 1 month to less than 12 years) or congenital heart disease (CHD) (n = 60; 0 to less than 6 years) requiring or already on ACEI will be included. Exclusion criteria include severe heart failure precluding ACEI use, hypotension, renal impairment, hypersensitivity to ACEI. For those naïve to ACEI up-titration to an optimal dose will be performed, those already on ACEI will be switched to an expected equivalent dose of enalapril ODMT and optimised. In the first 8 weeks of treatment, a PK profile will be obtained at the first dose (ACEI naïve patients) or when an optimal dose is reached. Furthermore, population PK will be done with concentrations detected over the whole treatment period. PD and safety data will be obtained at least at 2-weeks intervals. Subsequently, an intended number of 85 patients will be followed-up up to 10 months to demonstrate long-term safety, based on the occurrence of (severe) adverse events and monitoring of vital signs and renal function. ETHICS AND DISSEMINATION: Clinical Trial Authorisation and a favourable ethics committee opinion were obtained in all five participating countries. Results of the studies will be submitted for publication in a peer-reviewed journal. TRIAL REGISTRATION NUMBERS: EudraCT 2015-002335-17, EudraCT 2015-002396-18, EudraCT 2015-002397-21.

[Treatment of arrhythmias associated with congenital heart disease using transcatheter ablation]. / Veleszületett szívbetegséghez társuló ritmuszavarok katéterablatiós kezelése.

UNLABELLED: Rhythm disturbances are common long after surgical repair of congenital heart disease. These arrhythmias caused by the progression of the disease itself, however, a significant proportion is a result of the presence of surgical scar. Although interventional electrophysiology procedures are complex and encounter difficulties, pharmacological therapy is often very disappointing. AIM AND METHODS: In the present study we aimed to describe our experience obtained between 2004 and 2006 in patients undergoing transcatheter ablation long after surgery for congenital heart disease. RESULTS: During this period 26 patients underwent catheter ablation. The procedure was successful in 24 out of the 26 patients (92%). Three patients required redo ablations due to arrhythmia recurrences (11%). There were no major complications related to the intervention. In four patients minor complications occurred (small hematomas). CONCLUSIONS: Our descriptive data indicate that transcatheter ablation for arrhythmias after surgery for congenital heart disease is a effective safe and more importantly curative procedure. It is associated with reasonable success rate, low complication rate, but slightly higher recurrence rate as compared to the classical electrophysiological interventions.

[Role of heart transplantation in pediatric heart surgery. The first successful pediatric heart transplantation in Hungary]. / A szívtranszplantáció helye a gyermekszívsebészetben. Az elsô sikeres gyermekszív-átültetés Magyarországon.

7-year-old boy, who underwent aortic valve replacement two years previously, suffered from idiopathic dilated cardiomyopathy. Because of poor condition (NYHA-IV), heart transplantation was performed on 18th October 2007. It was the first pediatric heart transplantation in Hungary. It was an uneventful early postoperative period, 6 months after the operation he is doing well, no biopsy-proven and tissue Doppler echocardiography (TDI-derived velocities measurement) rejection was detected. The immunosuppression was based on triple-drug therapy (tacrolimus+mycophenolate mofetil+corticosteroid) with use of induction therapy with interleukin-2 receptor blocker (basiliximab).