Macitentan in the Young-Mid-term Outcomes of Patients with Pulmonary Hypertensive Vascular Disease treated in a Pediatric Tertiary Care Center.

BACKGROUND: Pulmonary hypertension (PH) is a severe hemodynamic condition with high morbidity and mortality. Approved targeted therapies are limited for pediatric subjects, and treatments are widely adopted from adult algorithms. Macitentan is a safe and effective drug used for adult PH, but data on pediatric patients are limited. In this prospective single-center study, we investigated mid- and long-term effects of macitentan in children with advanced pulmonary hypertensive vascular disease. METHODS: Twenty-four patients were enrolled in the study for treatment with macitentan. Efficacy was determined by echo parameters and brain natriuretic peptide levels (BNP) at 3 months and 1 year. For detailed analysis, the entire cohort was subgrouped into patients with congenital heart disease-related PH (CHD-PH) and non-CHD-PH patients, respectively. RESULTS: Mean age of the patients was 10.7 ± 7.6 years; median observation period was 36 months. Twenty of 24 patients were on additional sildenafil and/or prostacyclins. Two of 24 patients discontinued because of peripheral edema. Within the entire cohort, BNP levels and all echo measures such as right ventricular systolic pressure (RVSP), right ventricular end-diastolic diameter (RVED), tricuspid annular plane systolic excursion (TAPSE), pulmonary velocity time integral (VTI), and pulmonary artery acceleration time (PAAT) improved significantly after 3 months (p ≤ 0.01), whereas in the long term significant improvement persisted for BNP levels (-16%), VTI (+14%) and PAAT (+11%) (p < 0.05). By subgroup analysis, non-CHD PH patients showed significant improvements in BNP levels (-57%) and all echo measures (TAPSE +21%, VTI +13%, PAAT +37%, RVSP -24%, RVED -12%) at 3 months (p ≤ 0.01), whereas at 12 months, improvements persisted (p < 0.05) except for RVSP and RVED (nonsignificant). In CHD-PH patients, none of the measures changed (nonsignificant). 6-MWD (distance walked in 6 minutes) slightly increased but was not statistically evaluated. CONCLUSION: Data presented herein account for the largest cohort of severely affected pediatric patients receiving macitentan. Overall, macitentan was safe and associated with significant beneficial effects and sustained positive signals after 1 year, albeit in the long term disease progression remains a major concern. Our data suggest limited efficacy in CHD-related PH, whereas favorable outcomes were mainly driven by improvements in patients with PH not related to CHD. Larger studies are needed to verify these preliminary results and to prove efficacy of this drug in different pediatric PH entities.

[Intergenerational care of patients with tachycardiac arrhythmias]. / Generationenübergreifende Betreuung von Patienten mit tachykarden Rhythmusstörungen.

Within the last decades the treatment options for patients with arrhythmias have developed from a purely conservative drug treatment to a really curative treatment with removal of the arrhythmogenic substrate by continuously more sophisticated possibilities in the sense of electrophysiological techniques and ablation. Parallel to this, special outpatient departments of cardiac rhythmology for the care of patients with ion channelopathies have also become established in pediatric cardiology centers. Their task is the intergenerational care of whole families, with the aim of primarily preventing malignant arrhythmias by appropriate counselling and guidance.

Focused Update on Pulmonary Hypertension in Children-Selected Topics of Interest for the Adult Cardiologist.

Pulmonary hypertensive vascular disease (PHVD), and pulmonary hypertension (PH), which is a broader term, are severe conditions associated with high morbidity and mortality at all ages. Treatment guidelines in childhood are widely adopted from adult data and experience, though big differences may exist regarding aetiology, concomitant conditions and presentation. Over the past few years, paediatric aspects have been incorporated into the common guidelines, which currently address both children and adults with pulmonary hypertension (PH). There are multiple facets of PH in the context of cardiac conditions in childhood. Apart from Eisenmenger syndrome (ES), the broad spectrum of congenital heart disease (CHD) comprises PH in failing Fontan physiology, as well as segmental PH. In this review we provide current data and novel aspects on the pathophysiological background and individual management concepts of these conditions. Moreover, we focus on paediatric left heart failure with PH and its challenging issues, including end stage treatment options, such as mechanical support and paediatric transplantation. PH in the context of rare congenital disorders, such as Scimitar Syndrome and sickle cell disease is discussed. Based on current data, we provide an overview on multiple underlying mechanisms of PH involved in these conditions, and different management strategies in children and adulthood. In addition, we summarize the paediatric aspects and the pros and cons of the recently updated definitions of PH. This review provides deeper insights into some challenging conditions of paediatric PH in order to improve current knowledge and care for children and young adults.

Radiofrequency catheter ablation can be performed with high success rates and very low complication rates in children and adolescents.

AIM: Radiofrequency catheter ablation is a standard treatment for tachyarrhythmia in children. Recently, several centres using cryoenergy for ablation have reported high success and low complication rates, but an increased risk of recurrence of arrhythmia. The aim of this study was to report success, complications and recurrence rates for radiofrequency catheter ablation in children under current conditions. METHODS: A retrospective cohort study of 333 consecutive children undergoing radiofrequency catheter ablation over the last two decades. RESULTS: Radiofrequency catheter ablation was performed successfully in 96.7% of patients, but was significantly less successful in patients with a right anterior or right anterolateral accessory pathway (81.8%). Overall mortality was 0%; there was only one (0.3%) major complication, a pericardial haemorrhage, and only 2.8% of the patients developed minor vascular complications at the puncture site. None of the patients developed a persistent atrioventricular block. Over a median observation time of 4.3 years (0.1; 17.8), recurrence of arrhythmia occurred in 9.3% of all patients, but 50% of children with right lateral accessory pathways. CONCLUSION: Radiofrequency catheter ablation can be performed with high success and very low complication rates in children. Recurrence rates are substantially lower than those reported for cryoablation in the literature.

Combined circular multielectrode catheter and point-by-point ablation is superior to point-by-point ablation alone in eliminating atrial fibrillation.

BACKGROUND: Besides conventional point-by-point ablation, novel multielectrode catheters emerge for ablation of atrial fibrillation (AF). We sought to evaluate the clinical utility of a pulmonary vein (PV) isolation approach combining the advantages of both technologies. METHODS: The study included 240 consecutive AF patients (60±11 years, 68% males, 62% paroxysmal). In the combined ablation group (n=120), PV isolation was performed with a circular multielectrode catheter (PVAC, Medtronic Ablation Frontiers) and completed by conventional point-by-point ablation (NaviStar ThermoCool Catheter, Lasso/CARTO technology, Biosense Webster). In the point-by-point ablation group (n=120), PV isolation was performed with point-by-point ablation alone. RESULTS: Complete 1-year ablation success (freedom from any atrial arrhythmia off antiarrhythmic drugs) was more frequently observed in the combined ablation group (58.0% versus 43.3%, hazard ratio 1.72, 95% confidence interval 1.19-2.48, p=0.004). Also clinical success (≥90% reduction of arrhythmia burden on/off antiarrhythmic drugs) was significantly associated with the combined ablation approach (p=0.001). These associations remained significant after multivariable adjustment (both p≤0.005) and were not dependent on the type of AF. The rate of major adverse events (3.3% versus 2.5%) and the procedure time did not differ between groups. The fluoroscopy time, however, was significantly shorter in the combined ablation group (p<0.001) reflecting the reduced need for radiation during multielectrode catheter ablation. CONCLUSIONS: A combined PV isolation approach based on multielectrode catheter ablation and complementary point-by-point ablation is superior to point-by-point ablation alone and reveals to be safe. A potential explanation for these findings is the improved durability of ablation lesion after the combined ablation approach.

Markers of oxidative stress after ablation of atrial fibrillation are associated with inflammation, delivered radiofrequency energy and early recurrence of atrial fibrillation.

BACKGROUND: The role of oxidative stress after radiofrequency ablation of atrial fibrillation (AF) has not yet been well characterized. We sought to evaluate the time course of biomarkers of oxidative stress and inflammation after AF ablation and their association with clinical variables. METHODS: Thirty consecutive patients (57.9 ± 1.7 years, 63% males) with paroxysmal AF underwent pulmonary vein isolation and ablation of complex fractionated atrial electrograms. Biomarkers were determined in blood samples before ablation and 6 h, 1, 2, 7, 30, 90 and 180 days post-ablation. RESULTS: The pro-oxidant enzyme myeloperoxidase and oxidized low-density lipoprotein reflecting oxidant damage of lipoproteins increased 2.9 ± 0.2-fold and 1.2 ± 0.1-fold, respectively, and were significantly up-regulated until day 2 post-ablation. The anti-oxidant enzyme copper/zinc superoxide dismutase did not change significantly. Inflammatory markers significantly increased (high-sensitivity C-reactive protein (hs-CRP): 41 ± 8-fold; interleukin-6: 4.4 ± 0.7-fold) for 7 and 2 days, respectively. The increase of myeloperoxidase and hs-CRP was interrelated and both predicted early recurrence of AF within the first post-ablation week (both p < 0.05). The increase of both markers was associated with the amount of delivered radiofrequency energy (p < 0.05). The up-regulation of hs-CRP correlated with troponin T (p = 0.008), while myeloperoxidase and troponin T were borderline associated (p = 0.054). However, the oxidative and inflammatory responses did not predict long-term ablation outcome (p > 0.05). CONCLUSIONS: Markers of oxidative stress showed a significant up-regulation during the first 2 days after AF ablation. Their up-regulation was linked to inflammation, delivered radiofrequency energy, and early recurrence of AF, but did not predict long-term ablation outcome.

Tachycardia-induced cardiomyopathy after functional closure of the foramen ovale in a fetus.

Although fetal tachyarrhythmias are relatively rare, they are an important causes of fetal morbidity and mortality. We report a 30-week pregnant woman with fetal tachycardia, fetal hydrops and ascites. Fetal heart rate was 230 bpm. Fetal heart rate was 230 bpm. M-mode echocardiography revealed a tachycardia with a 1:1 relationship between atrial and ventricular conduction and a short time interval between ventricular and atrial contraction. These findings suggested a diagnosis of atrioventricular re-entrant tachycardia. On the third day digoxin treatment, the fetal heart rate was still 225 bpm with a 1:1 relationship between atrial and ventricular conduction. At this time, no flow across the foramen ovale was detected. Functional closure of the foramen ovale was suspected.

Time course of markers of tissue repair after ablation of atrial fibrillation and their relation to left atrial structural changes and clinical ablation outcome.

BACKGROUND: Radiofrequency ablation of atrial fibrillation (AF) creates left atrial (LA) tissue damage with a subsequent healing process. We sought to prospectively assess the time course of biomarkers of tissue repair after ablation and to evaluate their association with clinical variables. METHODS: 30 consecutive patients (57.9 ± 1.7 yrs, 63% males) with paroxysmal AF underwent a CARTO-guided LA circumferential ablation, Lasso-guided segmental pulmonary vein isolation and ablation of complex fractionated atrial electrograms. Matrix metalloproteinase-9 (MMP-9) and transforming growth factor-ß1 (TGF-ß1), both key regulators of tissue repair, and the aminoterminal propeptide of type III procollagen (PIIINP), reflecting collagen synthesis, were determined in blood samples before and 6h, 1, 2, 7, 30, 90 and 180 days post-ablation. RESULTS: All markers showed a significant ablation-induced up-regulation (MMP-9: 1.8 ± 0.1-fold, TGF-ß1: 2.4 ± 0.4-fold, PIIINP: 1.3 ± 0.1-fold). MMP-9 was significantly up-regulated until day 90, TGF-ß1 only on day 2. PIIINP increased from day 2 to 7. The area under the curve (AUC) of MMP-9 and TGF-ß1 correlated with the ablation-induced reduction of LA volume (both p<0.05). The AUC of MMP-9 was additionally associated with the amount of radiofrequency energy delivered during ablation (p < 0.05). At 12 months of follow-up 57% of patients were free of AF off antiarrhythmic drugs. The AUC of PIIINP independently predicted recurrent AF (p < 0.05). CONCLUSIONS: Markers of healing showed a significant up-regulation after AF ablation detectable for up to 90 days. A more pronounced up-regulation of MMP-9 or TGF-ß1 is associated with a greater reduction of LA size. High PIIINP levels after ablation predict a poor ablation outcome.

Frequency of recurrence of atrial fibrillation within 48 hours after ablation and its impact on long-term outcome.

Because of delayed structural and electrophysiologic effects of radiofrequency ablation of atrial fibrillation (AF), early recurrence of AF after ablation does not necessarily indicate long-term ablation failure. This study was intended to assess the prognostic value of early recurrence of AF within 48 hours after ablation. The study included 234 patients (aged 23 to 80 years; 72% men) with symptomatic drug-resistant paroxysmal (n = 165) or persistent AF (n = 69) who underwent either Lasso-guided segmental pulmonary vein isolation (n = 83) or CARTO-guided left atrial circumferential ablation (n = 151). After a median follow-up of 12.7 months, 64% of patients with paroxysmal and 45% of patients with persistent AF were AF free. Early recurrence of AF occurred in 43% of patients and was more frequently observed in the persistent-AF group (paroxysmal vs persistent 39% vs 54%; p = 0.037). Early recurrence of AF was a significant predictor of long-term ablation failure in univariate (hazard ratio [HR] 2.29, p <0.001) and multivariate (HR 2.17. p <0.001) Cox regression analysis. Nevertheless, 46% of patients with early recurrence of AF were AF free during long-term follow-up compared with 68% of patients without early recurrence of AF. The prognostic value of early recurrence of AF was found in patients with paroxysmal (HR 2.05, p = 0.005) and persistent AF (HR 2.35, p = 0.013). In conclusion, early recurrence of AF within 48 hours after ablation was a significant predictor of a poor long-term ablation outcome. However, because nearly half the patients with early recurrence of AF remained AF free during long-term follow-up, early recurrence of AF should not automatically result in an early repeated procedure.

Tako-tsubo cardiomyopathy complicating left atrial radiofrequency ablation.

Two female patients undergoing left atrial radiofrequency catheter ablation developed Tako-tsubo cardiomyopathy. This reversible form of left ventricular dysfunction is known to occur under conditions associated with marked sympathetic nervous activation. Radiofrequency catheter ablation in the left atrium can damage autonomic ganglionated plexi, leading to vagal withdrawal, thus resulting in enhanced sympathetic tone. Tako-tsubo cardiomyopathy has not been previously described following radiofrequency catheter ablation.

Therapy with angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, and statins: no effect on ablation outcome after ablation of atrial fibrillation.

BACKGROUND: The renin-angiotensin-aldosterone system and inflammation are supposed to play a key role in the pathogenesis of atrial fibrillation (AF). This retrospective clinical study was intended to assess the influence of drugs with antiinflammatory and/or renin-angiotensin-aldosterone system-modulating properties, namely angiotensin-converting enzyme inhibitors (ACE-Is), angiotensin II receptor blockers (ARBs), and statins, on AF-free survival after AF ablation. METHODS: The study included 234 patients (23-80 years; 71.8% men) with drug-resistant paroxysmal (n = 165) or persistent AF (n = 69) who either underwent a Lasso-guided segmental pulmonary vein isolation (n = 83) or a CARTO-guided left atrial circumferential ablation (n = 151). Treatment with statins (n = 113), ACE-Is, or ARBs (n = 124), or a combination of a statin and an ACE-I or ARB (n = 75) was started >3 months before ablation and was continued during follow-up. RESULTS: After a median follow-up of 12.7 months, 64% of patients with paroxysmal and 45% of patients with persistent AF were free of AF. Statin use (hazard ratio [HR], 1.06; P = .79), ACE-I or ARB use (HR, 1.12; P = .59), and their combined use (statin + ACE-I/ARB; HR, 1.17; P = .54) did not significantly influence ablation outcome as assessed by Cox regression analysis. In addition, after multivariate adjustment for potential confounders, the examined drugs did not significantly affect ablation outcome. Ablation induced an acute up-regulation of C-reactive protein levels (preablation vs 48 hours postablation, 5.9 +/- 8.1 vs 33.7 +/- 30 mg/L; P < .001) and other inflammatory markers. The examined drugs did not significantly alter baseline levels or ablation-induced up-regulation of inflammatory markers. CONCLUSIONS: The routine use of statins, ACE-Is, or ARBs did not result in an improved outcome of AF ablation.

Is inducibility of atrial fibrillation after radio frequency ablation really a relevant prognostic factor?

AIMS: The study was intended to assess the prognostic value of inducibility of atrial fibrillation (AF) after radio frequency ablation. METHODS AND RESULTS: Two hundred and thirty four patients with drug-resistant paroxysmal (n=165) or persistent AF (n=69) underwent either Lasso-guided segmental pulmonary vein isolation (n=83) or CARTO-guided left atrial circumferential ablation (n=151). After ablation, two attempts to induce AF (>1 min) by decremental coronary sinus stimulation were performed. Patients were followed for at least 6 months (median: 12.7 months). At 6 months of follow-up, 67% of patients with paroxysmal and 48% of patients with persistent AF were AF-free. Inducibility of AF was a significant predictor of AF recurrence in univariate [hazard ratio (HR)=2.32, P<0.001] and multivariable (HR=2.19, P<0.001) Cox regression analyses. The prognostic value of inducibility was present in both patients with paroxysmal (HR=2.38, P=0.001) and persistent AF (HR=1.91, P=0.034) and did not significantly differ between both ablation techniques. The sensitivity, specificity, positive, and negative predictive values of the AF induction test to predict the 6-month ablation outcome were 46.7, 75, 53.8, and 69.2%, respectively. CONCLUSION: Inducibility of AF after ablation is a significant predictor of recurrent AF. However, owing to the low diagnostic accuracy of the AF induction test, non-inducibility does not qualify as reliable procedural endpoint.

Paediatric pulmonary vascular disease.

Pulmonary vascular disease comprises any congenital or acquired pathology of the intrinsic pulmonary vessels with the unique feature of pulmonary arteries carrying unsaturated blood and pulmonary veins carrying oxygenated blood. Pulmonary hypertension (PH) ensues when pulmonary vascular disease affects at least 50% of the capillary resistance vessels, i.e. pulmonary pre-acinar and intra-acinar arteries (so-called pre-capillary PH), or when pressure in the pulmonary venous system distal to the capillaries rises above a mean of 15 mmHg (so-called post-capillary PH). PH is defined by a mean pulmonary arterial pressure above 25 mmHg at rest. Vasoconstriction, remodelling and thrombosis of small pulmonary arteries lead to an increase in pulmonary vascular resistance. The consequence is failure of the afterload-intolerant right ventricle. In this review, pulmonary vascular disease in children will be addressed according to the 2003 World Health Organisation (Venice) classification of PH.

Dysarthria in a patient with probable acquired chloridorrhea.

The authors encountered a patient who had profound hypochloremic metabolic alkalosis after developing profuse diarrhea related to rejection of her small bowel transplant. Her ileostomy fluid showed massive electrolyte losses and was exceptionally high in chloride content. She improved with volume substitution and a proton pump inhibitor, although she subsequently required repeat small bowel transplant. The authors speculate that an impaired "downregulated in adenoma" gene (DRA) that enclodes an apical Cl(-)/HO(-)(HCO(3)) exchanger may have contributed to an acquired chloridorrhea in this patient.

Induction of cytokines and adhesion molecules in stable hemodialysis patients: is there an effect of membrane material?

BACKGROUND/AIMS: The aim of this study was to examine the effects of a biocompatible and a nonbiocompatible hemodialysis membrane on the secretion of cytokines and their specific antagonists as well as on the expression of adhesion molecules. METHODS: A crossover study using cuprophane (CU) and polysulfone (PS) dialyzers and measurements of serum tumor necrosis factor (TNF)-alpha, soluble TNF receptors, interleukin (IL)-6, IL-6 receptor, IL-2 receptor, IL-1 receptor antagonist and the adhesion molecules intercellular adhesion molecule 1, endothelial leukocyte adhesion molecule and vascular cell adhesion molecule was performed in 19 hemodialysis patients. 44 healthy volunteers served as controls. RESULTS: All of the measured cytokines and cytokine antagonists as well as all adhesion molecules were significantly elevated in hemodialysis patients compared to controls. There was a significant increase in TNF-alpha during a dialysis session with a CU dialyzer, but only a moderate increase using a PS dialyzer. None of the other cytokines and adhesion molecules were changed during a dialysis session. We were also able to show an upregulation of adhesion molecules in dialysis patients. CONCLUSION: Our study clearly demonstrates that levels of inflammatory cytokines as well as their antagonists and adhesion molecules are elevated in patients on hemodialysis therapy. Baseline values before the start of a dialysis session did not show any differences with regard to the usage of CU or PS dialysis membranes. However, CU dialyzers led to a significantly greater stimulation of TNF-alpha during the dialysis session in comparison to PS membranes, suggesting a higher degree of bioincompatibility.

Effect of cisapride on rate-corrected QT intervals in children on peritoneal dialysis.

The aim of this study was to investigate whether cisapride significantly increases corrected QT (QTc) intervals on resting 12-lead electrocardiograms (ECGs) in children on peritoneal dialysis. Medical records of children who were treated with chronic peritoneal dialysis and who had ECGs while off and on cisapride were obtained and reviewed. QTc on all 12-lead ECGs and past medical history were analyzed by two blinded pediatric cardiologists. A total of 79 ECGs (68 off/11 on cisapride) for 11 children on peritoneal dialysis were included. Of 11 children, 5 developed a prolongation of QTc, 2 of them beyond the normal range (453 and 478 ms). Mean data of QTc off versus on cisapride were 394+/-24 ms and 414+/-36 ms, respectively ( P=0.041). In 4 of the 5 children concomitant medications could be identified as factors to explain prolongation of the QT interval. No child had evidence of any arrhythmia or conduction defect on ECG. This retrospective study found mild but significant increases in QTc intervals with cisapride in children on chronic peritoneal dialysis, mostly due to concomitant medications.

Cold water submersion and cardiac arrest in treatment of severe hypothermia with cardiopulmonary bypass.

In the paediatric population, submersion injury with drowning or near-drowning represents a significant cause of morbidity and mortality. This study reviews retrospectively our own experiences and the literature on the use of cardiopulmonary bypass (CPB) to rewarm paediatric victims of cold water submersion who suffer severe hypothermia (<28 degrees C) and cardiac arrest (asystole or ventricular fibrillation). In addition to three children treated at our institution, nine other victims were found in the literature. In this cohort of 12 children aged between 2 and 12 years, there was a tendency to better outcome with lower core temperature at the beginning of extracorporeal circulation (mean temperature in nine survivors, 20 degrees C; in three non-survivors, 25.5 degrees C). The lowest temperature survived was 16 degrees C. Neither base excess, pH nor serum potassium levels were reliable prognostic factors. The lowest base excess in a survivor was -36.5 mmol/l, the lowest pH 6.29. We consider CPB as the method of choice for resuscitation and rewarming of children with severe accidental hypothermia and cardiac arrest (asystole or ventricular fibrillation). Compared with adults, children, especially smaller ones, require special consideration with regard to intravenous cannulation as drainage can be inadequate using femoral-femoral cannulation. In hypothermic children we advocate, therefore, emergency median sternotomy. Until more information regarding prognostic factors are available, children who are severely hypothermic and clinically dead after submersion in cold water--even if for an unknown length of time--should receive cardiopulmonary resuscitation (CPR) and be transported without delay to a facility with capabilities for CPB instituted via a median sternotomy.

Self-concept in male and female adolescents with congenital heart disease.

Cognitive achievement, behavioural problems, and various dimensions of personality were assessed in 48 male and female patients with congenital heart disease (CHD) aged from 12 to 16 years in comparison to a control group. The CHD group showed a lower speed of cognitive processing but seemed to have less state-anxiety and to possess a higher superego strength. Male adolescents with CHD presented with a reduced perceived capacity and self-esteem. This was not true for adolescent girls with CHD. The negative self-concept of boys with CHD may be partly explained by reduced physical ability interfering with peer relationships.