Cardiac Valve Annulus Diameters in Extremely Preterm Infants: A Cross-Sectional Echocardiographic Study.

BACKGROUND: With the increasing incidence of births of very preterm very-low-birth-weight infants, there is a demand for echocardiographic reference values of cardiac dimensions. OBJECTIVES: The aim of this study was to provide reference values of cardiac valve annulus diameters in a cohort of extremely preterm very-low-birth-weight neonates and to correlate these with patient characteristics. METHODS: Valve diameters of 376 infants of < 32 weeks' gestation and with a birth weight of ≤2,000 g were measured using 2-dimensional echocardiography. Correlations between valve diameters and patient characteristics (birth length/weight, body surface area, gestational age, and sex) were assessed. Birth weight was used to establish linear regression models. Inter- and intraobserver agreement was assessed through intraclass correlation coefficient (ICC) analysis. RESULTS: Substantial variability was found (aortic valve mean [standard deviation; range]: 5.0 mm [0.6; 3.7-6.5]; pulmonic valve: 5.8 mm [0.8; 3.4-7.9]; mitral valve: 8.0 mm [1.0; 5.5-10.5]; tricuspid valve: 7.6 mm [1.2; 4.9-10.6]). There was a moderate correlation between birth weight and valve diameter (R2 aortic valve: 0.36; pulmonic valve: 0.20; mitral valve: 0.24; tricuspid valve: 0.24). Adequate intraobserver (ICC range 0.74-0.91) and interobserver agreement (ICC range 0.77-0.89) was found. CONCLUSIONS: Our study provides ready-to-use reference values for cardiac valve annulus diameters for extremely preterm infants.

Long-term results of balloon angioplasty for native coarctation of the aorta in childhood in comparison with surgery.

OBJECTIVES: Coarctation of the aorta (CoA) can be treated either surgically or with balloon angioplasty (BA). Long-term follow-up for either treatment has been limited. Our objective was to compare long-term results of BA and surgery for treatment of native CoA in childhood. METHODS: Retrospective cohort study of patients with native CoA treated with BA or surgery between 3 months and 16 years of age. Forty-eight patients filled out questionnaires and approved review of their medical records. Twenty-four patients underwent additional testing, including 24-h ambulatory blood pressure measurement, cardiopulmonary exercise testing and cardiac magnetic resonance imaging. Results were analysed cross-sectionally and longitudinally. RESULTS: Nineteen and 29 patients received BA and surgery, respectively. Prevalence of hypertension and aneurysms was similar in both groups. Fifty percent of patients were hypertensive. Two-thirds of patients demonstrating hypertension were not receiving antihypertensive medication. Aneurysm formation occurred in 1 BA (5%) and 1 surgery (3%) patient. The BA group had a significantly higher risk of recoarctation (47% vs 24%) and reintervention (hazard ratio 2.95, 95% confidence interval 1.04-8.32). Exercise capacity and global left ventricular function were preserved in both groups and not significantly different after correction for age. Quality of life was good to excellent in the majority of the patients. CONCLUSIONS: After CoA repair in childhood, most patients perform well in daily life. However, on the long term, more than half of the patients develop hypertension and many develop re-CoA, especially in those who underwent BA. Therefore, we do not recommend BA for the treatment of native CoA in children.

Computational fluid dynamics in Fontan patients to evaluate power loss during simulated exercise.

OBJECTIVE: Exercise intolerance is common in total cavopulmonary connection (TCPC) patients. It has been suggested that power loss (Ploss) inside the TCPC plays a role in reduced exercise performance. Our objective is to establish the role of Ploss inside the TCPC during increased flow, simulating exercise in a patient-specific way. METHODS: Cardiac MRI (CMR) was used to obtain flow rates from the caval veins during rest and increased flow, simulating exercise with dobutamine. A 3D reconstruction of the TCPC was created using CMR data. Computational fluid dynamics (CFD) simulations were performed to calculate Ploss inside the TCPC structure for rest and stress conditions. To reflect the flow distribution during exercise, a condition where inferior caval vein (IVC) flow was increased twofold compared with rest was added. 29 TCPC patients (15 intra-atrial lateral tunnel (ILT) and 14 extracardiac conduit (ECC)) were included. RESULTS: Mean Ploss at rest was 1.36 ± 0.94 (ILT) and 3.20 ± 1.26 (ECC) mW/m(2) (p<0.001), 2.84 ±1.95 (ILT) and 8.41 ± 3.77 (ECC) mW/m(2) (p<0.001) during dobutamine and 5.21 ± 3.50 (ILT) and 15.28 ± 8.30 (ECC) mW/m(2) (p=0.001) with twofold IVC flow. The correlation between cardiac index and Ploss was exponential (ILT: R(2)=0.811, p<0.001; ECC: R(2)=0.690, p<0.001). CONCLUSIONS: Ploss inside the TCPC structure is limited but increases with simulated exercise. This relates to the anatomy of TCPC and the surgical technique used. In all flow conditions, ILT patients have lower Ploss than ECC patients. We did not find a relationship between Ploss and exercise capacity.

Ventricular response to dobutamine stress relates to the change in peak oxygen uptake during the 5-year follow-up in young patients with repaired tetralogy of Fallot.

AIMS: To evaluate the additional value of dobutamine stress testing in patients with repaired tetralogy of Fallot (TOF) by relating stress imaging parameters at baseline to relevant parameters of clinical condition and right ventricular (RV) size during a serial follow-up. METHODS AND RESULTS: We prospectively included 27 patients (14 ± 4 years at baseline), who were studied twice with a 5-year interval. Patients underwent cardiovascular magnetic resonance imaging to assess RV systolic and diastolic function at rest and during dobutamine stress. Normal response to dobutamine was defined as a decrease in RV end-systolic volume, and a increase in RV ejection fraction (EF) during stress. Exercise testing and electrocardiography were performed to determine peak oxygen uptake (peak VO2), QRS duration, and QT interval corrected for heart rate (QTc) interval. RV volumes, QRS duration, and QTc interval increased significantly from baseline to follow-up; peak VO2 tended to decrease (95 ± 20-89 ± 14%, P = 0.086). Response to dobutamine was normal in 26 of 27 patients and remained stable during the follow-up [relative increase in RVEF during stress: +25 ± 9% (baseline) vs. +27 ± 10% (follow-up)]. A smaller relative increase in RVEF during stress at baseline related to a larger relative decrease in peak VO2 during the follow-up (r = 0.59, P = 0.004). No significant associations were found with the relative increase in QRS duration, QTc interval, or RV end-diastolic volume during a 5-year follow-up. CONCLUSION: In a young TOF population, response to dobutamine stress was normal and remained stable during the 5-year follow-up. A smaller increase in RVEF during stress at baseline was predictive for a larger decrease in peak VO2 during the 5-year follow-up.

Pediatric pulmonary hypertension in the Netherlands: epidemiology and characterization during the period 1991 to 2005.

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.

Outcome of pediatric patients with pulmonary arterial hypertension in the era of new medical therapies.

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.

Clinical outcome 5 to 18 years after the Fontan operation performed on children younger than 5 years.

OBJECTIVE: This study assessed clinical condition at midterm follow-up after total cavopulmonary connection for a functionally univentricular heart performed on children younger than 5 years. METHODS: Thirty-four Fontan patients (median age 10.4 years, range 6.8-20.7 years, 22 boys, median follow-up 7.8 years, 5.0-17.8 years) underwent electrocardiography, Holter monitoring, bicycle exercise testing, cardiac magnetic resonance imaging, and N-terminal prohormone brain natriuretic peptide (NT-pro-BNP) analysis. RESULTS: Twenty-three patients (68%) were in sinus rhythm. Holter monitoring demonstrated normal mean heart rate, low maximal heart rate, and no clinically significant arrhythmias or sinus node dysfunction. With maximal bicycle ergometry (n = 19), maximum workload (60% of normal), maximum heart rate (90% of normal), and maximal oxygen uptake (69% of normal) were all significantly lower in the Fontan group than in a control group (P < .001). Variables of submaximal exercise indicated less efficient oxygen uptake during exercise in all Fontan patients. Ejection fraction was lower than in control subjects (59% +/- 13% vs 69% +/- 5%, P < .001). Mean end-diastolic and end-systolic volumes and ventricular mass were higher than in control subjects (P < .001). Mean NT-pro-BNP levels were increased relative to reference values, but only 8 patients had levels above the upper reference limit. CONCLUSION: At midterm follow-up, Fontan patients were in acceptable clinical condition, with preserved global ventricular function, moderately decreased exercise capacity, and NT-pro-BNP levels within reference range. Systemic ventricular mass was elevated, however, suggesting contractility-afterload mismatch. Long-term consequences for ventricular function merit further investigation.

Clinical characterization of pediatric pulmonary hypertension: complex presentation and diagnosis.

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.

Assessment of biventricular functional reserve and NT-proBNP levels in patients with RV volume overload after repair of tetralogy of Fallot at young age.

PURPOSE: To assess biventricular functional reserve (FR), NT-proBNP levels and exercise performance, in relation to right ventricular volume in patients with pulmonary regurgitation (PR) after repair of tetralogy of Fallot (TOF) at young age. METHODS: In 53 TOF patients (maximum age at repair 2.0 years, interval since repair 15 (5) years) without residual lesions except PR, biventricular FR (derived from magnetic resonance imaging with dobutamine stress), NT-proBNP levels, maximal workload, and peak oxygen uptake were assessed. RESULTS: Mean right ventricular end-diastolic volume was 140(38) ml/m(2). Median pulmonary regurgitant fraction was 37% (range 0-57%). Biventricular systolic stress response was normal: mean (SD) ESV decreased (DeltaRVESV -17(8) ml/m(2), DeltaLVESV -11(5)), SV increased (DeltaRVSV +12(9) ml/m(2), DeltaLVSV +9(6)), FR was positive in all (RV-FR +11(5)%, LV-FR +13(6)). No serious adverse effects to dobutamine were encountered. NT-proBNP was increased in 2 patients. Median level was 10 pmol/L (range 2-42). NT-proBNP correlated with PR-percentage but not with right ventricular size. High-risk levels of NT-proBNP indicated a smaller RV-FR and a smaller decrease of biventricular ESV. Mean (SEM) VO2(max) was 96(3)%, mean Workload(max) 89(2)% of predicted. CONCLUSION: At mid to long term follow-up overall NT-proBNP levels are normal and biventricular functional reserve and exercise tolerance are well preserved in TOF repaired at young age, irrespective of RV volume. This questions the validity of isolated PR or RV volume criteria for pulmonary valve replacement in this group. Low-dose dobutamine stress testing is well tolerated and may be a useful additional tool for clinical decision making.

Cardiovascular follow-up at school age after perinatal glucocorticoid exposure in prematurely born children: perinatal glucocorticoid therapy and cardiovascular follow-up.

OBJECTIVE: To study whether antenatal or neonatal glucocorticoid therapy to reduce the incidence and severity of chronic lung disease in preterm infants is associated with long-term adverse cardiac effects and hypertension. DESIGN: Retrospective matched-cohort study. SETTING: Outpatient clinic of a tertiary care hospital. PARTICIPANTS: One hundred ninety-three children aged 7 to 10 years who had been born prematurely between December 2, 1993, and September 15, 1997. Main Exposure Neonatal treatment with dexamethasone disodium phosphate(n = 48) or the clinically equally effective glucocorticoid hydrocortisone (n = 51), or only antenatal treatment with betamethasone disodium phosphate and betamethasone acetate (n = 51). These 3 groups were compared with a reference group of prematurely born children who had not been exposed to perinatal glucocorticoid therapy (n = 43). MAIN OUTCOME MEASURES: General hemodynamic data (heart rate and blood pressure), cardiovascular function as assessed at echocardiography, intima-media thickness of the carotid arteries, and cardiac biochemical features as early markers of expansion and volume overload of the cardiac left ventricle (B-type natriuretic peptide and N-terminal pro-B-type natriuretic peptide). RESULTS: No significant group differences were found for heart rate, blood pressure, biochemical features, intima-media thickness, or systolic or diastolic left ventricular function. CONCLUSIONS: Although no differences were found in blood pressure and cardiovascular function at school age in children antenatally or neonatally treated with glucocorticoids, further cardiovascular follow-up may be advisable because cardiovascular dysfunction may become apparent only later in life.

Down syndrome: a novel risk factor for respiratory syncytial virus bronchiolitis--a prospective birth-cohort study.

OBJECTIVES: Respiratory syncytial virus is the single-most important cause of lower respiratory tract infections in children. Preterm birth and congenital heart disease are known risk factors for severe respiratory syncytial virus infections. Although Down syndrome is associated with a high risk of respiratory tract infections, little is known about the incidence of respiratory syncytial virus infections in this group. The aim of our study was to determine the incidence of respiratory syncytial virus lower respiratory tract infection-associated hospitalization among children with Down syndrome. PATIENTS AND METHODS: We performed a retrospective observational study and a prospective nationwide birth-cohort study of children with Down syndrome. The retrospective cohort comprised 176 children with Down syndrome. A birth cohort of 219 children with Down syndrome was prospectively followed until 2 years of age. All 276 siblings of the birth cohort were used as controls. RESULTS: Of the 395 patients with Down syndrome, 180 (45.6%) had a known risk factor for severe respiratory syncytial virus infections; 39 (9.9%) of these were hospitalized for respiratory syncytial virus lower respiratory tract infections. Two control children (0.7%) versus 9 term children with Down syndrome without congenital heart disease (7.6%) were hospitalized for respiratory syncytial virus lower respiratory tract infections. The median duration of hospitalization was 10 days; mechanical ventilation was required for 5 children (12.8%). CONCLUSIONS: This is the first study, to our knowledge, to demonstrate that Down syndrome is a novel independent risk factor for severe respiratory syncytial virus lower respiratory tract infections. These findings should prompt studies to investigate possible mechanisms that underlie severe respiratory syncytial virus lower respiratory tract infections in children with Down syndrome. The effect of respiratory syncytial virus prophylaxis in this specific population needs to be established.

Exercise limitation in patients with Fontan circulation: a review.

The aim of the current literature study was to perform a literature review of the factors contributing to exercise limitation and physiological response to exercise in patients with Fontan circulation. In patients with Fontan circulation, peak oxygen uptake ranged from about 14.4 to 32.3 ml/min/kg, and showed a slowed acceleration in the kinetics of oxygen uptake at the onset of exercise. Peak heart rate during exercise was decreased to an average of 153 +/- 10 bpm and arterial oxygen saturation was also decreased at peak exercise, with an average of 89.5 +/- 1.94%. Cardiac output was subnormal, owing to reduced stroke volume, heart rate response and affected pulmonary venous return. Ventilatory anaerobic threshold was below normal values. Moreover, the ventilatory equivalent for carbon dioxide was found to be higher. Patients with Fontan circulation possess a unique physiological response to exercise. Although there is a wide range in exercise capacity among patients, all patients have reduced tolerance to exercise. Cardiac, pulmonary, and muscular factors might play a role in reduced exercise capacity and this distinct response to exercise.

Clinical condition at mid-to-late follow-up after transatrial-transpulmonary repair of tetralogy of Fallot.

OBJECTIVES: To assess the clinical condition at mid-to-late follow-up in tetralogy of Fallot corrected by a transatrial-transpulmonary approach at a young age and to identify risk factors associated with right ventricular dilation/dysfunction and with decreased exercise tolerance. METHODS: Patients with tetralogy of Fallot underwent cardiac magnetic resonance imaging, maximal bicycle ergometry, electrocardiography, Holter monitoring, and spirometry. Multivariate linear regression analyses were used to determine independent predictors for selected clinical parameters. RESULTS: Fifty-nine patients (mean +/- SD), age at repair 0.9 +/- 0.5 years, interval since repair 14 +/- 5 years, were included. The median pulmonary regurgitant fraction was 32% (0%-57%). Compared with published data on healthy controls, Fallot patients had significantly larger right ventricular end-diastolic and end-systolic volumes and smaller right ventricular and left ventricular ejection fractions. Maximum oxygen consumption was 97% +/- 17% and maximum workload 89% +/- 13% of predicted. Median QRS duration was 110 ms (82-161 ms). No important ventricular arrhythmias were found. Compared with patients without a transannular patch, patients with a patch had more pulmonary regurgitation, a larger right ventricle, worse right ventricular and left ventricular ejection fractions, but comparable exercise capacity. Multivariate regression analysis identified the following independent determinants for larger right ventricular volumes: longer interval since repair, longer QRS duration, and higher pulmonary regurgitation percentage. The following were independent determinants for smaller right ventricular ejection fraction: abnormal right ventricular outflow tract wall motion, longer interval since repair, and longer QRS duration. For smaller maximum oxygen consumption, the independent determinants were smaller right ventricular ejection fraction and longer QRS duration. CONCLUSIONS: At mid-to-late follow-up, clinical condition in tetralogy of Fallot corrected according to contemporary surgical approaches appears well preserved. However, even these patients show right ventricular dilation and dysfunction associated with impaired functional capacity. Abnormalities relate to right ventricular outflow tract motion abnormalities, longer interval since repair, longer QRS duration, and more severe pulmonary regurgitation.