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Background- Incidence and prevalence rates for pediatric pulmonary hypertension (PH) and pulmonary arterial hypertension (PAH) are unknown. This study describes the nationwide epidemiological features of pediatric PH in the Netherlands during a 15-year period and the clinical course of pediatric PAH. Methods and Results- Two registries were used to retrospectively identify children (0-17 years) with PH. Overall, 3263 pediatric patients were identified with PH due to left heart disease (n=160; 5%), lung disease/hypoxemia (n=253; 8%), thromboembolic disease (n=5; <1%), and transient (n=2691; 82%) and progressive (n=154; 5%) PAH. Transient PAH included persistent PH of the newborn and children with congenital heart defects (CHD) and systemic-to-pulmonary shunt, in whom PAH resolved after successful shunt correction. Progressive PAH mainly included idiopathic PAH (n=36; iPAH) and PAH associated with CHD (n=111; PAH-CHD). Pulmonary arterial hypertension associated with CHD represented highly heterogeneous subgroups. Syndromes were frequently present, especially in progressive PAH (n=60; 39%). Survival for PAH-CHD varied depending on the subgroups, some showing better and others showing worse survival than for iPAH. Survival of children with Eisenmenger syndrome appeared worse than reported in adults. For iPAH and PAH-CHD, annual incidence and point prevalence averaged, respectively, 0.7 and 4.4 (iPAH) and 2.2 and 15.6 (PAH-CHD) cases per million children. Compared to studies in adults, iPAH occurred less whereas PAH-CHD occurred more frequently. Conclusions- Pediatric PH is characterized by various age-specific diagnoses, the majority of which comprise transient forms of PAH. Incidence of pediatric iPAH is lower whereas incidence of pediatric PAH-CHD is higher than reported in adults. Pediatric PAH-CHD represents a heterogeneous group with highly variable clinical courses. [ABSTRACT FROM AUTHOR]

Background: Evidence suggests that hypoxic-ischemic brain injury in infants with congenital heart disease already occurs during early life. The aim of our study was, therefore, to assess the course of regional cerebral oxygen saturation (r c SO 2 ) and fractional tissue oxygen extraction (FTOE) during the first 72h after birth in infants with prenatally diagnosed duct-dependent congenital heart disease. In addition, we identified clinical parameters that were associated with r c SO 2 ., Materials and Methods: We included 56 infants with duct-dependent congenital heart disease. We measured arterial oxygen saturation (SpO 2 ) and r c SO 2 during the first 72h after birth. Simultaneously, we calculated FTOE., Results: We observed median r c SO 2 values of approximately 60%, a decreasing FTOE from 0.34 on day 1 to 0.28 on day 3 and stable preductal SpO 2 values around 90%. Several clinical variables were associated with r c SO 2 . In a multiple linear regression model only type of CHD and preductal SpO 2 were significant predictors of r c SO 2 during the first three days after birth. Infants with a duct-dependent pulmonary circulation had up to 12% lower r c SO 2 values than infants with a duct-dependent systemic circulation., Conclusion: We demonstrated that, during the first three days after birth, cerebral oxygen saturation is low in infants with duct-dependent congenital heart disease. Furthermore, this study provides preoperative reference values of r c SO 2 and FTOE in infants with duct-dependent CHD., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Congenital heart disease (CHD) is a frequent cause of pediatric pulmonary arterial hypertension (PAH), with diverse etiology and outcome. We aimed to describe phenotypic heterogeneity in pediatric PAH associated with CHD (PAH-CHD), assess the applicability of the Nice CHD classification, and explore whether this classification accurately reflects patient/disease characteristics and survival. All children with CHD from a contemporary cohort of consecutive pediatric PAH patients followed in three major referral centers (Denver, New York, the Netherlands) were characterized and classified on the basis of the latest proposed clinical classification for PAH-CHD (World Symposium on Pulmonary Hypertension, Nice, 2013). According to this classification, 24% of 134 children were classified into group 1, 14% into group 2, 19% into group 3, and 30% into group 4; 11% could not be classified. Types of CHD and hemodynamic profile differed between groups, with the highest right atrial pressure in group 4 (P < 0.040). Group 3 children had Down syndrome less frequently (P = 0.011) but other (un)defined syndromes most frequently (P = 0.063) and received most intense PAH-targeted therapy (P = 0.003). With 15 deaths and one lung transplant (12%; median follow-up: 4.3 years), survival differences could not be demonstrated between the groups in the Nice CHD classification. Pediatric PAH-CHD is a heterogeneous condition frequently associated with extracardiac, developmental factors that are believed to affect disease development. The Nice CHD classification identifies groups with specific patient/disease characteristics. However, a substantial proportion of children could not be classified. Group 3 forms a distinct disease entity. Its prognostic value could not be determined because of the low number of events. The Nice CHD classification supports clinical characterization of PAH-CHD; however, further refinement is needed to classify all children with PAH-CHD.

Objectives: Cardiac output may be compromised in preterm infants with sepsis. Whether low cardiac output is associated with low tissue oxygen supply in these patients is unclear. The aim of the current study was to assess the association between cardiac output, assessed by echocardiography, and tissue oxygenation, measured with multisite near-infrared spectroscopy, in a cohort of preterm infants with clinical sepsis., Design: Prospective observational cohort study., Setting: Level III neonatal ICU., Patients: Twenty-four preterm infants (gestational age < 32 wk) with clinical sepsis., Interventions: None., Measurements and Main Results: Clinical and echocardiographic assessment of hemodynamics was performed within 48 hours of sepsis workup and repeated at least 24 hours later. We measured cerebral, renal, and intestinal tissue oxygen saturation using near-infrared spectroscopy during an hour of stable measurements directly preceding or following echocardiography and calculated fractional tissue oxygen extraction in each tissue. We determined Spearman correlation coefficients between fractional tissue oxygen extraction and right ventricular output corrected for patent foramen ovale flow, left ventricular output corrected for ductus arteriosus flow, and superior vena cava flow. Right ventricular output corrected for patent foramen ovale and left ventricular output corrected for ductus arteriosus flow both correlated significantly with intestinal fractional tissue oxygen extraction (ρ, -0.700; p = 0.036 and ρ, -0.604; p = 0.029, respectively). In contrast, no significant correlations were found between cardiac output measurements and cerebral and renal fractional tissue oxygen extraction, respectively. Changes in cardiac output measurements were not associated with observed changes in fractional tissue oxygen extraction values., Conclusions: Right ventricular output corrected for patent foramen ovale and left ventricular output corrected for ductus arteriosus flow, indicators of systemic blood flow in preterm infants with shunts, were negatively associated with intestinal fractional tissue oxygen extraction, but not with renal and cerebral fractional tissue oxygen extraction. These findings suggest that during low output states due to clinical sepsis intestinal perfusion is most at risk.

Background: Patent ductus arteriosus (PDA) is common in preterm infants and is associated with significant morbidity. To determine whether the PDA is hemodynamically significant (HSDA), several echocardiographic parameters have been suggested, including retrograde diastolic blood flow in the descending aorta (Dao)., Objective: To assess the impact of an HSDA, including retrograde diastolic flow in the Dao, on regional tissue oxygen saturation (rSO2) and extraction measured by near-infrared spectroscopy (NIRS)., Methods: This is a prospective observational cohort study in which we included preterm infants (GA <32 weeks) who underwent echocardiographic screening because of clinical signs of an HSDA within 2 weeks after birth. We measured cerebral and renal rSO2 on the day of echocardiography. HSDA was diagnosed if left-to-right shunting through the PDA was accompanied by left atrial-to-aortic root ratio >1.4 and/or left pulmonary artery end-diastolic flow velocity >0.2 m/s and/or retrograde diastolic blood flow in the Dao., Results: Forty-nine infants were included, with a median GA of 27.6 weeks (IQR: 26.1-29.0), birth weight of 980 g (IQR: 800-1,200), and postnatal age of 77 h (IQR: 70-107). Infants with a closed duct (n = 11), a non-HSDA (n = 18), and an HSDA (n = 20) had similar cerebral and renal NIRS measurements. Retrograde diastolic blood flow in the Dao, present in 11 infants with PDA, also did not affect cerebral and renal NIRS measurements., Conclusion: In preterm infants with clinical signs of an HSDA within 2 weeks after birth, cerebral and renal oxygen saturation and extraction are not affected by an HSDA or by retrograde diastolic blood flow in the Dao., (© 2016 S. Karger AG, Basel.)

Objective: To investigate the prognostic value of the 6-minute walking distance (6-MWD), transcutaneous saturation (tcSO2) and heart rate (HR) obtained during the 6-minute walk test (6-MWT) in pediatric pulmonary arterial hypertension (PAH)., Methods: This was an observational study with forty-seven pediatric PAH patients, aged ≥7 years, and diagnosed and followed at the national referral center for pediatric PAH in the Netherlands. All patients performed a comprehensive 6-minute walk test (6-MWT), which measures 6-MWD and tcSO2 and HR before ("baseline"), during ("exercise") and 5 min after ("recovery") the walk test., Results: The 6-MWD expressed either in meters or in sex- and age-corrected z-scores, was associated with transplant-free survival, independently from sex, age, and the presence of a shunt-defect. Shorter 6-MWD correlated with higher WHO-FC and increased NT-pro-BNP. Absolute tcSO2 at exercise and tcSO2-decrease during 6-MWT were associated with transplant-free survival, independent from 6-MWD. Combining tcSO2-decrease with 6-MWD provided the strongest prognostic model. Patients with 6-MWD>352 m (the median 6-MWD) had a better outcome than those with smaller 6-MWD. A large tcSO2-decrease during 6-MWT (>19% for patients with and >5% for patients without a shunt defect) identified patients with worse transplant-free survival both in patients with a 6-MWD above and below the median 6-MWD., Conclusions: The 6-MWD is an independent predictor of prognosis in pediatric PAH, that reflects disease severity and clinically relevant exercise-tolerance and therefore qualifies as a treatment goal. The magnitude of tcSO2-decrease during 6-MWT, adjusted for the presence of a shunt, indicates an additional risk factor for prognosis in children with PAH., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Background: The value of echocardiography in assessing disease severity and predicting outcome in pediatric pulmonary arterial hypertension (PAH) is insufficiently defined. The aim of this study was to describe correlations between echocardiography and disease severity and outcome in pediatric PAH., Methods and Results: Forty-three consecutive children (median age, 8.0 years; range, 0.4-21.5) with idiopathic/hereditary PAH (n=25) or PAH associated with congenital heart disease (n=18) were enrolled in a prospective single-center observational study. Anatomic and right ventricular-functional variables were obtained by two-dimensional echocardiography and Doppler-echocardiography at presentation and at standardized follow-up and were correlated with measures of disease severity (World Health Organization functional class [WHO-FC], N-terminal-pro-B-type natriuretic peptide, hemodynamics) and lung-transplantation-free survival. Right atrial and right ventricular dimensions correlated with WHO-FC and hemodynamics (P<0.05), whereas left ventricular dimensions correlated with hemodynamics and survival (P<0.05). Right-to-left ventricular dimension ratiocorrelated with WHO-FC, hemodynamics and survival (P<0.05). Right ventricular ejection time correlated with hemodynamics and survival (P<0.05) and tended to correlate with WHO-FC (P=0.071). Tricuspid annular plane systolic excursion correlated with WHO-FC, mean right atrial pressure and survival (P<0.05)., Conclusions: This early descriptive study shows that echocardiographic chararacteristics of both the right and the left heart correlate with disease severity and outcome in pediatric PAH, both at presentation and during the course of the disease. The preliminary data from this study support the potential value of echocardiography as a tool in guiding management in children with PAH., (© 2014 American Heart Association, Inc.)

To be able to design goal-oriented treatment strategies in paediatric pulmonary arterial hypertension (PAH), we aimed to identify treatment goals by investigating the prognostic value of treatment-induced changes in noninvasive predictors of transplant-free survival. 66 consecutive, treatment-naïve paediatric PAH patients in the Dutch National Network for Paediatric Pulmonary Hypertension who started taking PAH-targeted drugs between January 2000 and April 2013 underwent prospective, standardised follow-up. Clinical, biochemical and echocardiographic measures were longitudinally collected at treatment initiation and follow-up, and their respective predictive values for transplant-free survival were assessed. Furthermore, the predictive values of treatment-induced changes were assessed. From the identified set of baseline predictors, the variables World Health Organization functional class (WHO-FC), N-terminal pro-brain natriuretic peptide (NT-proBNP) and tricuspid annular plane systolic excursion (TAPSE) were identified as follow-up predictors in which treatment-induced changes were associated with survival. Patients in whom these variables improved after treatment showed better survival (p<0.002). Therefore, WHO-FC, NT-proBNP and TAPSE are not only predictors of transplant-free survival in paediatric PAH but can also be used as treatment goals, as treatment-induced improvements in these variables are associated with improved survival. The identification of these variables allows for the introduction of goal-oriented treatment strategies in paediatric PAH., (©ERS 2014.)

Objective: In paediatric pulmonary arterial hypertension (PAH), the effectiveness of add-on combination PAH-therapy has not yet been systematically studied. The purpose of this study was to determine the effect of sildenafil add-on therapy in paediatric PAH patients treated with bosentan., Methods: In this observational study within a national paediatric patient cohort, follow-up data of 24 consecutive paediatric PAH patients initially treated with bosentan monotherapy and prospectively followed at the Dutch national referral centre for paediatric PAH in 2007-2013, were reviewed. Patients received add-on sildenafil therapy in case of clinical worsening., Results: Fifteen children received add-on sildenafil therapy; nine remained on bosentan monotherapy. Patient characteristics, 6-minute walk distance (6MWD), WHO functional class (WHO-FC), N-terminal pro-Brain Natriuretic Peptide (NT-proBNP), and haemodynamic measurements at bosentan start were similar in both patient groups. In children with clinical worsening, sildenafil add-on therapy improved 6MWD at 5, 10, 15 and 21 months of follow-up, improved WHO-FC at 10, 15 and 21 months and stabilised NT-proBNP. Patients who received add-on sildenafil therapy had more advanced disease progression during bosentan monotherapy. Despite that, they had better or, at least, no worse survival compared to patients who remained on bosentan monotherapy., Conclusions: In children with PAH, sildenafil add-on therapy indicated by clinical deterioration on bosentan monotherapy, was associated with a significant improvement of WHO-functional class and 6MWD. Despite clinical deterioration on bosentan monotherapy, patients receiving sildenafil add-on therapy, had either better or, at least, no worse survival than patients remaining on bosentan monotherapy.

Data concerning the prevalence, risk factors, and prognostic significance of hemoptysis in pediatric pulmonary arterial hypertension (PAH) are scarce. A Dutch national cohort of 74 children with either idiopathic or heritable PAH (IPAH/HPAH, n = 43) or PAH associated with congenital heart disease (PAH-CHD, n = 31) were followed from 1993 to 2012. During a median follow-up of 3.5 years (range 0.1 to 19.2), hemoptysis occurred in 13 children (17.6%). The hemoptysis event rate was 9.9 per 100 patient-years, equally divided between IPAH/HPAH and PAH-CHD (p = 0.824). The median age at first hemoptysis was 12.5 years, and the median time since PAH diagnosis to first hemoptysis was 6.1 years. Patients with hemoptysis had longer time since PAH diagnosis (p = 0.001) and more frequently used anticoagulant therapy (p = 0.006). Univariate Cox regression analysis indicated that older age (hazard ratio [HR] 1.15, 95% confidence interval [CI] 1.01 to 1.30, p = 0.031), World Health Organization functional class IV (HR 0.28, 95% CI 0.08 to 0.95, p = 0.042), higher mean pulmonary arterial pressure (HR 1.04, 95% CI 1.00 to 1.07, p = 0.028), and higher indexed pulmonary vascular resistance (HR 1.08, 95% CI 1.02 to 1.15, p = 0.009), all at the time of PAH diagnosis, were associated with increased risk of hemoptysis during follow-up. Ten of 13 patients with hemoptysis died or underwent (heart-) lung transplantation; in 6 patients, this was directly related to hemoptysis. In conclusion, the occurrence of hemoptysis in pediatric IPAH/HPAH and PAH-CHD increases with time since diagnosis, is a serious condition, and is, in case of life-threatening hemoptysis, associated with poor outcome., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: There is a need for reliable prognostic parameters in pulmonary arterial hypertension (PAH), especially in children. Pulsatile components of the right ventricular afterload, represented by pulmonary arterial compliance (PACi) and pulmonary stroke volume (PSVi), may provide important additional prognostic information to conventional static haemodynamic parameters. The aim of this study was to determine the prognostic value of PACi and PSVi in paediatric PAH., Methods: Right heart catheterization data of 52 consecutive paediatric idiopathic/hereditary PAH and PAH associated with congenital heart disease patients with full haemodynamic evaluation seen at the Dutch national referral centre for paediatric pulmonary hypertension between 1993 and 2010 were reviewed. A control group was composed of patients with normal pulmonary vascular resistance. PSVi and PACi were calculated and tested for predictive value for transplant-free survival., Results: PAH patients had significantly lower PSVi and PACi compared to control patients. PSVi and PACi were lower in patients with higher WHO-functional class compared to those with lower functional classes. Higher PSVi, PACi and mSAP and lower mPAP/mSAP and heart rate were associated with improved survival, independent from WHO-functional class and PAH-targeted therapy. In multivariate analyses PSVi, heart rate and mSAP emerged as the strongest haemodynamic predictors of survival. The effect of vasodilator challenge on the haemodynamic variables did not provide additional prognostic information., Conclusions: The parameters of both the pulsatile and static pulmonary circulations are strong independent predictors for transplant-free survival, and therefore can be of complementary value in assessing disease severity, predicting survival and guiding treatment in paediatric PAH., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Pulmonary arterial hypertension (PAH) and renal thrombotic microangiopathy (rTMA) are rare diseases in childhood, frequently leading to death and end-stage renal disease, respectively. Their combined occurrence has been reported anecdotally. We investigated the clinical, biochemical, and genetic aspects of 5 children with the rare combination of PAH and rTMA. Onset of disease ranged from 1.5 to 14 years of age. The 2 youngest patients presented with concomitant pulmonary and renal disease; in the older patients, PAH was preceded by rTMA from age 2.5 to 7 years. Three patients presenting at ≤ 3 years of age died of right ventricular failure secondary to progressive PAH. In 2 patients, cobalamin C (cblC) deficiency was diagnosed postmortem. Three patients were treated with hydroxocobalamin; 1 died 2 weeks after diagnosis, 1 patient exhibited progressive pulmonary vasculopathy, and 1 patient is currently in stable condition. cblC deficiency was diagnosed biochemically 2 days to 18 years after initial presentation. Genetic analysis confirmed mutations in MMACHC in all patients; 4 patients were compound heterozygous, with all having base-pair substitutions (G>A or G>T) at nucleotide 276 in addition to frame-shift mutations. One patient had homozygous nonsense mutations of MMACHC. We established cblC deficiency as the denominator in the rare combination of PAH and rTMA in these children. Early recognition of cblC deficiency and vigorous treatment with hydroxocobalamin may beneficially affect the course of this devastating disease.

Background: Childhood-onset pulmonary arterial hypertension (PAH) is rare and differs from adult-onset disease in clinical presentation, with often unexplained mental retardation and dysmorphic features (MR/DF). Mutations in the major PAH gene, BMPR2, were reported to cause PAH in only 10-16% of childhood-onset patients. We aimed to identify more genes associated with childhood-onset PAH., Methods: We studied 20 consecutive cases with idiopathic or heritable PAH. In patients with accompanying MR/DF (n=6) array-comparative genomic hybridisation analysis was performed, with the aim of finding common deletion regions containing candidate genes for PAH. Three patients had overlapping deletions of 17q23.2. TBX2 and TBX4 were selected from this area as candidate genes and sequenced in all 20 children. After identifying TBX4 mutations in these children, we subsequently sequenced TBX4 in a cohort of 49 adults with PAH. Because TBX4 mutations are known to cause small patella syndrome (SPS), all patients with newly detected TBX4 mutations were screened for features of SPS. We also screened a third cohort of 23 patients with SPS for PAH., Results: TBX4 mutations (n=3) or TBX4-containing deletions (n=3) were detected in 6 out of 20 children with PAH (30%). All living patients and two parents with TBX4 mutations appeared to have previously unrecognised SPS. In the adult PAH-cohort, one TBX4 mutation (2%) was detected. Screening in the cohort of (predominantly adult) SPS patients revealed no PAH., Conclusions: These data indicate that TBX4 mutations are associated with childhood-onset PAH, but that the prevalence of PAH in adult TBX4 mutation carriers is low.

Aims: To assess the occurrence and prognostic value of acute vasodilator response (AVR) in paediatric vs. adult pulmonary arterial hypertension, and idiopathic/hereditary pulmonary arterial hypertension (iPAH/HPAH) vs. pulmonary arterial hypertension associated with congenital heart disease (PAH-CHD) using three different response criteria., Methods and Results: Ninety-nine PAH patients underwent AVR testing (37 children, 62 adults; 70 iPAH/HPAH, 29 PAH-CHD). Three response criteria from clinical practice were used to define AVR. The number of responders was evaluated separately in subgroups based on age, diagnosis, and presence of a non-restrictive post-tricuspid shunt. Numbers of responders varied importantly using the different criteria but were always higher in iPAH/HPAH, compared with PAH-CHD. The number of responders did not differ between paediatric and adult iPAH/HPAH. No responders were identified in patients with a post-tricuspid shunt. Acute vasodilator response was associated with improved survival using all three criteria. Low baseline mean right atrial pressure (mRAP) was associated with improved survival in adults (P< 0.001). High baseline mean pulmonary arterial pressure (mPAP)/mean systemic arterial pressure (mSAP) and pulmonary vascular resistance (PVR)/systemic vascular resistance (SVR) were associated with worse survival, statistically independent from age, diagnosis, and the presence of a post-tricuspid shunt., Conclusion: The proportion of patients with AVR highly depends on the used criteria, but did not differ between paediatric and adult iPAH/HPAH. Current response criteria are not suitable for patients with a post-tricuspid shunt. In both children and adults without post-tricuspid shunts, AVR was associated with improved survival independent of the used criteria. Nevertheless, prognostic value in the individual patient was limited. Baseline mRAP showed a good correlation with survival for adult PAH patients, but not for children. High baseline mPAP/mSAP and PVR/SVR was associated with worse prognosis independent from age, diagnosis, or the presence of a post-tricuspid shunt.

We present the case of an 11-year-old boy presenting with haemoptysis, dyspnoea and weight loss as a manifestation of isolated pulmonary vasculitis, leading to pulmonary hypertension. He also appeared to have a longstanding dural venous sinus thrombosis. This rare presentation, especially in childhood, might represent a case of the seldomly reported Hughes-Stovin syndrome. The patient achieved remission after therapy with cyclophosphamide pulses and high-dose steroids. Based on the presented case and review of the literature, we propose that this syndrome might be a variant of polyarteritis nodosa. This report highlights diagnostic issues and describes a successful treatment regimen.

Objective. To assess the impact of PPHN on mortality, morbidity, and behavioural skills. Methods. A retrospective observational study of 143 newborns with PPHN, over an 11-year period, using objective health-status data from medical records and family doctors, and subjective health status data from a standardized Child Behaviour Checklist. Results. The majority of patients were males, treated with inhaled nitric oxide had maladaptation/maldevelopment as pathophysiological mechanism and a gestational age >37 weeks. In term newborns, types of pathophysiological mechanism (P < .001) and Oxygen Index (P = .02) were independent predicting risk factors for PPHN-related mortality. Analysis of preexisting disease and outcome categories in term newborns showed only a significant correlation between the use of iNO and respiratory complaints (P = .03), not confirmed by multivariate analysis and regression analysis. Conclusions. PPHN is a serious, often fatal condition. The incidence of PPHN in preterm newborns is high. In term survivors, PPHN had no additional role in morbidity/outcome.

Background: Infants with congenital heart disease (CHD) are at risk for brain injury. An accurate tool to monitor brain function is amplitude integrated EEG (aEEG). It records both background patterns and electrographic seizure activity (EA)., Aims: Our aim was to determine aEEG patterns in infants with CHD and to determine the differences between infants with a cyanotic or an acyanotic CHD., Study Design and Subjects: Sixty-two full term newborns had either a cyanotic CHD (transposition of the great arteries (n=24)) or an acyanotic CHD (hypoplastic left heart syndrome (n=26), critical aortic valve stenosis (n=1) or aortic coarctation (n=11)). The background patterns, sleep-wake cycling (SWC), and EA were assessed. The first 72h after starting prostaglandin E(1)-therapy were used for analysis., Results: The background patterns were mildly abnormal in 45% of the infants and severely abnormal at some point during the recording in 14% of the infants. We found no differences in background patterns between the two groups. EA was present in 12 (19%) infants. EA was more frequent in infants with acyanotic CHD (OR 9.4, 95% CI 1.1-78, p=0.039). SWC was equally frequent in infants with cyanotic and infants with acyanotic CHD. A severely abnormal aEEG and EA were associated with more profound acidosis., Conclusions: Before surgery the majority of infants with a CHD had an abnormal aEEG. aEEG helped to identify EA and it was a useful tool to evaluate brain function prior to surgery in CHD., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

In this review we discuss the new anti- Pulmonary Arterial Hypertension [PAH] drugs and the available data on their use in paediatric PAH. Treatment of patients with PAH, children and adults, is aimed at a reduction of symptoms, survival and improvement of haemodynamics as well as exercise capacity. PAH may reflect significant different disease conditions in infants and children when compared to PAH in adults. In contrast to adult PAH, characterized mainly by idiopathic PAH and PAH associated with connective tissue disease, more than half of the cases of PAH in children are associated with congenital heart disease. Therefore, efficacy of PAH drugs in these diseases can not be extrapolated from that in adults with PAH., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Background. About 30% of dilated cardiomyopathy (DCM) cases are familial. Mutations are mostly found in the genes encoding lamin A/C, beta-myosin heavy chain and the sarcomeric protein cardiac troponin-T (TNNT2). Mutations in TNNT2 are reported in approximately 3% of DCM patients. The overall phenotype caused by TNNT2 mutations is thought to be a fully penetrant, severe disease. This also seems to be true for a recurrent deletion in the TNNT2 gene; p.K217del (also known as p.K210del). Methods. We compared the phenotype of all Dutch patients identified as carrying the TNNT2 p.K217del mutation with those described in the literature. All index patients underwent cardiological evaluation. Family screening was done in all described families. Results. Six DCM patients carrying the TNNT2 p.K217del mutation were identified from four Dutch families. Mean age of disease manifestation was 33 years. Heart transplantation was required in three of them at ages 12, 18 and 19 years. These outcomes are comparable with those described in the literature. Conclusion. Carriers of the TNNT2 p.K217del mutation in our Dutch families, as well as in families described in the literature before, generally show a severe, early-onset form of DCM. (Neth Heart J 2010;18:478-85.).

Little is known about the effects of "second-generation drugs" (prostanoids, endothelin receptor antagonists, 5-phosphodiesterase inhibitors) in children with pulmonary arterial hypertension (PAH). This study describes the outcome of a national cohort of children with PAH in an era when these drugs became available. From 1993 to 2008, 52 consecutive children with idiopathic PAH (n = 29) or systemic-to-pulmonary shunt-associated PAH (n = 23) underwent baseline and follow-up assessments. Treatment was initiated depending on functional class, acute pulmonary vasoreactivity response, and drug availability. Observed survival was evaluated depending on time of diagnosis in relation to second-generation drug availability and subsequently compared to calculated predicted survival. Children for whom second-generation drugs were available had improved survival compared to their predicted survival (1-, 3-, and 5-year survival rates 93%, 83%, and 66% vs 79%, 61%, and 50%, respectively). However, this improved survival was observed only in patients for whom second-generation drugs became available during their disease course. No improved survival was observed in patients for whom drugs were available already at diagnosis. Baseline variables associated with decreased survival included higher functional class, higher pulmonary-to-systemic arterial pressure ratio, lower cardiac index, and higher serum levels of N-terminal pro-brain natriuretic peptide and uric acid. After start of second-generation drugs, functional class, 6-minute walking distance, and N-terminal pro-brain natriuretic peptide improved but gradually decreased after longer follow-up. In conclusion, survival of pediatric PAH seemed improved since the introduction of second-generation drugs only in selected patients for whom these drugs became available during their disease course. Start of second-generation drugs initially induced clinical improvements, but these effects decreased after longer follow-up., (Copyright (c) 2010 Elsevier Inc. All rights reserved.)

Objectives: To describe the clinical presentation of pediatric pulmonary arterial hypertension (PAH) and the intricacies of how to classify pediatric PAH according to the Venice classification., Study Design: Children (n = 63) seen at a national referral center for pediatric PAH underwent a diagnostic work-up for diagnosis of pulmonary hypertension (PH) and associated conditions and for assessment of the explanatory role of associated conditions for the PH. Subsequently, PH was classified., Results: In 18 patients (29%), no associated conditions were identified; they were classified as having idiopathic PAH. In 45 patients (71%), > or = 1 associated conditions were detected: congenital heart defects (CHD, n = 40), connective tissue disease (CTD, n = 2), disorders of respiratory system and/or hypoxemia (RSH, n = 17), and chronic thromboembolic disease (CTE, n = 1). Patients were classified according to the condition judged to be primarily explanatory for the PH. In 11 of 45 patients with associated conditions, the PH was not sufficiently explained by these conditions; these patients were classified as having idiopathic-like PAH. In 17 of 40 cases of CHD and 9 of 17 cases of RSH, these conditions were not sufficiently explanatory for the PH. Syndromal abnormalities were frequent (43%). Ultimately, classification revealed idiopathic (-like) PAH (n = 29; 46%), PAH-CHD (n = 23; 37%), PAH-CTD (n = 2; 3%), PH-RSH (n = 8; 12%), and CTE-PH (n = 1; 2%)., Conclusion: Pediatric PH frequently presents with associated conditions and syndromal abnormalities. However, detailed evaluation of this complex presentation reveals that associated conditions are not always explanatory for the PH.

Down syndrome (DS) may be associated with various organ system disorders. Feeding problems are frequent in children with DS and may be caused by associated defects, including congenital heart defects, gastrointestinal defects, or endocrine disorders. In the absence of these associated conditions, feeding problems are often attributed to general hypotonia. However, an aberrant right subclavian artery (ARSA), a rare vascular anomaly and an unusual cause of problems with the passage of solid food through the esophagus, has recently been suggested to occur more frequently in patients with DS. This knowledge is of importance when evaluating feeding difficulties in patients with DS. Additional investigation for identifying an ARSA may be indicated in selected patients. Diagnostic techniques, such as transthoracic echocardiography, barium contrast esophagram, angiography, or computed tomography-angiography (CT) can be used in a diagnostic flow chart. The presence of ARSA is not synonymous to the cause of feeding problems in patients with DS and corrective surgery of this vascular anomaly should be restricted to selected cases.

We present a neonate with a large saccular aneurysm of the thoracoabdominal aorta, extending from the intrathoracic aorta to the left common iliac artery. No underlying cause could be identified. Despite an early diagnosis, the aneurysm was deemed inoperable because of the lengthy involvement and the frail aspect of all visceral arteries. A review of the literature on congenital abdominal aortic aneurysm in infants was conducted. Eleven cases of live-born infants with a congenital abdominal aortic aneurysm have previously been published. None of them involved as large a part of the thoracic and abdominal aorta as the case presented here.

Appropriate parameters are needed for the monitoring of children with pulmonary arterial hypertension (PAH). Various biologic markers seem to be of use in adults with PAH. No data are available on their value in children with PAH. In this study, the relation between serum markers, functional parameters, and hemodynamic variables in pediatric PAH and their ability to predict survival is determined. Serum N-terminal pro brain natriuretic peptide (NT-proBNP), uric acid, norepinephrine, and epinephrine were measured and correlated with invasive hemodynamics, functional parameters, and outcome in 29 pediatric patients with PAH who visited a tertiary reference center for pediatric PAH between 1997 and 2005. NT-proBNP correlated with functional class (R = 0.36; p = 0.03) and 6-min walking distance (6MWD) (R = -0.53; p < 0.001). Uric acid correlated with mean pulmonary arterial pressure, pulmonary vascular resistance, and cardiac index (R = 0.63, p = 0.01; R = 0.71, p = 0.03, and R = -0.65, p = 0.007, respectively). After initiation of treatment, NT-proBNP decreased. This decrease correlated with an increased 6MWD. Finally, norepinephrine and NT-proBNP levels were highly predictive for mortality. In this series of children with PAH, biologic markers were correlated with hemodynamics and functional capacity, as parameters of disease severity. The data indicate that these markers can be used to monitor treatment effects and predict mortality in pediatric PAH.

Background: Persistent pulmonary hypertension of the newborn (PPHN) in patients with transposition of the great arteries (TGA) is reported to be a high-risk and often therapy-resistant condition, associated with a high mortality. However, data on its incidence and prognosis are scarce and originate mostly from the era before introduction of inhaled nitric oxide (iNO) therapy for PPHN., Methods: This is a retrospective study of consecutive newborns with TGA, admitted to a tertiary cardiac and neonatal intensive unit over a 10-year period. In this period, iNO therapy was available., Results: Fourteen out of 112 patients with TGA (12.5%) presented with associated PPHN. The PPHN occurred more frequently in patients with TGA and intact ventricular septum (IVS) compared with those with TGA and ventricular septal defect (13 out of 83 patients versus one out of 29 patients, respectively; p = 0.06, Fisher exact test). Of those newborns, six presented with severe PPHN, whereas eight presented with mild-to-moderate PPHN. Despite currently available treatment modalities, including iNO, four out of 14 patients died before corrective surgical procedures were considered to be an option (TGA/PPHN preoperative mortality 28.6%). These included three out of six patients (50%) with severe PPHN and one out of eight (12.5%) with mild-to-moderate PPHN., Conclusions: The combination of TGA with PPHN is a serious and often fatal condition. It may jeopardize the usually favorable outcome of newborns with TGA. Despite the introduction of iNO therapy, the combination of TGA and PPHN remains a condition with unacceptable high mortality (in our series). Additional treatment strategies need to be investigated.

This report describes the mid-term beneficial hemodynamic effect of biventricular pacing in an infant with congestive heart failure after congenital heart surgery, due to resynchronization of the left and right ventricle, optimization of the AV delay, and (partial) correction of the LV dyssynchrony.