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.

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.

Evaluation of bone mineral density and bone turnover in children on anticoagulation.

Background: Childhood and adolescence are critical periods of bone mineral acquisition. Children on anticoagulation (AC) might have an increased risk for reduced bone mineral density (BMD). Risk factors for impaired bone accumulation include chronic diseases, immobility, and medication. Vitamin K (VK) deficiency reflected by undercarboxylated osteocalcin levels (ucOC) has been identified as a predictor of osteoporosis and fractures. Data on bone health in children under AC are sparse. Aims: To evaluate BMD in children on AC and characterize the risk factors of low BMD, including VK and Vitamin D (VD) status. Methods: Single-center cross-sectional study of clinical, biochemical, and densitometric parameters. Assessment of VK surrogate parameters included ucOC and matrix gla protein (MGP). Results: A total of 39 children (4-18 years; 12 females) receiving AC were included, 31 (79%) on VK antagonists and 8 (21%) on direct oral anticoagulants. Overall, BMD was decreased for both the lumbar spine (LS; -0.7SDS) and total body less head (TBLH; -1.32SDS) compared with pediatric reference data. Significant associations were found between early pubertal development and TBLH-BMD, and between BMI and LS-BMD. VK surrogate parameters were highly related to patients' age and pubertal development. Neither serum parameters nor AC-related factors predicted BMD. VD was detected in 10/39 patients with lower values during puberty. Conclusion: Our data indicate BMD reduction in pediatric patients on AC. Although AC-related factors did not predict reduced BMD, low BMI and pubertal stages represented important risk factors. Awareness of risk factors for low BMD and high prevalence of VD deficiency during puberty could contribute to the improvement of bone health in this vulnerable patient group.

Macitentan in infants and children with pulmonary hypertensive vascular disease. Feasibility, tolerability and practical issues - a single-centre experience.

Macitentan is a safe and effective substance for treatment of adults with pulmonary arterial hypertension. Data on its use in paediatric patients are limited. In this single-centre prospective study, we report on our experience with macitentan in children focusing on applicability and practical aspects. Between December 2014 and July 2018, macitentan was introduced to paediatric patients according to a dosing protocol adjusted to body weight. Blood pressure, heart rate, saturation and clinical symptoms were recorded daily during introduction. Liver function parameters and haemoglobin levels were measured at baseline, four weeks and three months after initiation and after one year of treatment. Twenty-four patients (14 male, 10 female) were enrolled for treatment with macitentan. The mean age was 10.7 ± 7.6 years (range: 0.1 year-23 years). Fifteen out of 24 patients were World Health Organization functional class (FC) II, 7 patients in FC III and 2 patients in FC IV. Twenty out of 24 patients (83%) received additional advanced therapy with sildenafil and/or prostacyclines. We had two early discontinuations because of clinical relevant oedema. In the remaining 22 patients, macitentan was well tolerated. Liver function parameters and blood count levels remained stable during the observational time. The introduction of macitentan was feasible and mostly well tolerated in paediatric patients. Special attention should be paid to oedema during introduction of the drug. To the best of our knowledge, this is the first study to report on its applicability in infants and children. However, larger prospective trials are warranted to verify these preliminary findings.

Special schooling in children with congenital heart disease: a risk factor for being disadvantaged in the world of employment.

The objective of this study was to evaluate type of schooling in children with congenital heart disease (CHD) who were inpatients at a tertiary pediatric cardiology center. This retrospective cohort study included 227 consecutive children with CHD (male, 125; female, 102) who had been inpatients from 1996 to 2005. Data on type of schooling had been documented by the in-hospital teacher at the time of admission. Medical data were obtained by reviewing medical charts. The primary endpoint was the percentage of children requiring special schooling, which was related to the respective percentage in the Austrian pediatric background population. Furthermore, the influence of clinical and demographic covariables was assessed. Fifteen percent (vs. 3.6% in the background population) of the study cohort required special schooling; 86% of them had a history of cardiac surgery. Cardiopulmonary bypass surgery in the first year of life showed a trend for an association with an increased frequency of special schooling. There were no significant associations with the Aristotle Basic Score (a measure for procedure complexity in CHD), gender, or first language. In conclusion, the need for special schooling is increased in children with CHD.

Vasoactive intestinal peptide gene alterations in patients with idiopathic pulmonary arterial hypertension.

Pulmonary arterial hypertension is a progressive disease, characterised by increased proliferation of pulmonary artery smooth muscle cells, vasoconstriction and remodelling of the vascular wall leading to right heart failure and death. The idiopathic form is rare (idiopathic arterial primary hypertension (IPAH); formerly PPH, MIM# 178600). Our group correlated a deficiency in vasoactive intestinal peptide (VIP; MIM# 192320) levels in serum and lung tissue with the pathogenesis of IPAH. The aim of this study was to investigate the relevance of genetic alterations in VIP to the development of IPAH. We screened 10 patients (age 4-66 years) for alterations in the coding, the noncoding regions and the enhancer region of the VIP gene by direct sequencing. In eight of 10 patients, we found alterations compared to the wild-type sequence. We detected nine alterations. In the noncoding regions, eight alterations were in the introns 1, 2, 3 and 4 (g.448G>A g.501C>T g.764T>C g.2267A>T g.2390C>T g.3144T>C g.3912A>G g.4857A>G). In the coding regions, a single alteration in the 3' untranslated region in exon 7 (g.8129T>C) was observed in five patients. It appeared in 46% of the control group. The frequency of this alteration in the coding region of the VIP gene could therefore not be correlated with the appearance of IPAH. Apart from the importance of VIP signalling, genetic and/or environmental modifiers might therefore contribute to the development and perpetuation of the disease.

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.

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.