Arend D.J. ten Harkel

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.nnMethods 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.nnConclusions— 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.nn# Clinical Perspective {#article-title-25}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.

Mechanism of right precordial ST-segment elevation in structural heart disease: Excitation failure by current-to-load mismatch

BACKGROUNDnThe Brugada sign has been associated with mutations in SCN5A and with right ventricular structural abnormalities. Their role in the Brugada sign and the associated ventricular arrhythmias is unknown.nnnOBJECTIVEnThe purpose of this study was to delineate the role of structural abnormalities and sodium channel dysfunction in the Brugada sign.nnnMETHODSnActivation and repolarization characteristics of the explanted heart of a patient with a loss-of-function mutation in SCN5A (G752R) and dilated cardiomyopathy were determined after induction of right-sided ST-segment elevation by ajmaline. In addition, right ventricular structural discontinuities and sodium channel dysfunction were simulated in a computer model encompassing the heart and thorax.nnnRESULTSnIn the explanted heart, disappearance of local activation in unipolar electrograms at the basal right ventricular epicardium was followed by monophasic ST-segment elevation. The local origin of this phenomenon was confirmed by coaxial electrograms. Neither early repolarization nor late activation correlated with ST-segment elevation. At sites of local ST-segment elevation, the subepicardium was interspersed with adipose tissue and contained more fibrous tissue than either the left ventricle or control hearts. In computer simulations entailing right ventricular structural discontinuities, reduction of sodium channel conductance or size of the gaps between introduced barriers resulted in subepicardial excitation failure or delayed activation by current-to-load mismatch and in the Brugada sign on the ECG.nnnCONCLUSIONnRight ventricular excitation failure and activation delay by current-to-load mismatch in the subepicardium can cause the Brugada sign. Therefore, current-to-load mismatch may underlie the ventricular arrhythmias in patients with the Brugada sign.

Diastolic dysfunction in paediatric patients on peritoneal dialysis and after renal transplantation.

BACKGROUNDnCardiovascular disease is the leading cause of death in children with end-stage renal disease. We investigated the presence of cardiac systolic and diastolic dysfunction in patients on peritoneal dialysis or after renal transplantation. Methods and results. Fourteen patients on peritoneal dialysis for a mean of 1.4 years (range 0.1-5.3) and 39 patients with a functioning kidney transplant for a median time of 3.3 years (range 1.2-14.5) were studied. These patients were compared to 153 age-matched healthy controls. As assessed by echocardiography, both dialysis and transplant patients showed left ventricular dysfunction. Systolic tissue Doppler values were lower as compared to controls. Mitral E/A ratios were significantly lower as well, indicating diastolic dysfunction (transplant 1.82 +/- 0.58 versus 2.15 +/- 0.63, P < 0.01; dialysis patients 1.57 +/- 0.73 versus 2.31 +/- 0.52, P < 0.01). Also, tissue Doppler values were different, showing an increased E/E ratio in the patients, indicating diastolic dysfunction (transplant 9.49 +/- 1.71 versus 7.50 +/- 1.60, P < 0.01; dialysis patients 11.90 +/- 2.11 versus 8.10 +/- 1.24, P < 0.01). The left ventricular mass index was increased in the transplant patients (controls 25 +/- 7 g/m(2.7); transplant 59 +/- 64 g/m(2.7); P < 0.01), as well as in the dialysis patients (controls 28 +/- 7 g/m(2.7); dialysis 43 +/- 11 g/m(2.7); P < 0.01) and was associated with systolic hypertension (R = 0.46, P < 0.05). High parathyroid hormone (PTH) levels, more prevalent in dialysis patients, were associated with abnormal E/A and E/E ratios.nnnCONCLUSIONSnAbnormalities in diastolic function are present in both peritoneal dialysis and renal transplanted patients. In the dialysis group, abnormalities in calcium-phosphate metabolism are associated with diastolic dysfunction. Cardiac hypertrophy was noted in both patient groups and was associated with systolic hypertension.

Exercise capacity in children after total cavopulmonary connection: Lateral tunnel versus extracardiac conduit technique

OBJECTIVESnIn patients with univentricular heart disease, the total cavopulmonary connection (TCPC) is the preferred treatment. TCPC can be performed using the intra-atrial lateral tunnel (ILT) or extracardiac conduit (ECC) technique. The purpose of the present study was to evaluate exercise capacity in contemporary TCPC patients and compare the results between the 2 techniques.nnnMETHODSnA total of 101 TCPC patients (ILT, n=42; ECC, n=59; age, 12.2±2.6 years; age at TCPC completion, 3.2±1.1 years) underwent cardiopulmonary exercise testing. The patients were recruited prospectively from 5 tertiary referral centers.nnnRESULTSnFor the entire group, the mean peak oxygen uptake was 74%±14%, peak heart rate was 90%±8%, peak workload was 62%±13%, and slope of ventilation versus carbon dioxide elimination (VE/VCO2 slope) was 127%±30% of the predicted value. For the ILT and ECC groups, patient age, age at TCPC completion, body surface area, peak workload, and peak heart rate were comparable. The percentage of predicted peak oxygen uptake was lower in the ILT group (70%±12% vs 77%±15%; P=.040), and the percentage of predicted VE/VCO2 slope was greater in the ILT group (123%±36% vs 108%±14%; P=.015). In a subgroup analysis that excluded ILT patients with baffle leak, these differences were not statistically significant.nnnCONCLUSIONSnCommon exercise parameters were impaired in contemporary Fontan patients. Chronotropic incompetence was uncommon. The peak oxygen uptake and VE/VCO2 slope were less favorable in ILT patients, likely related to baffle leaks in some ILT patients. These results have shown that a reduced exercise capacity in Fontan patients remains an important issue in contemporary cohorts. The ECC had a more favorable exercise outcome at medium-term follow-up.

Congenital valvular aortic stenosis: limited progression during childhood.

Objective: Congenital valvular aortic stenosis is a common congenital heart malformation. The rate of progression in childhood, however, remains to be established. We assessed the progression of peak aortic velocity before intervention as well as the frequency of intervention in paediatric patients with isolated congenital valvular aortic stenosis. Methods: A retrospective cohort study was performed in 245 consecutive patients with aortic stenosis. Both clinical and echocardiographic data were obtained. Results: Over a period of 9.0 (SD 5.2) years (range 0.1–19.4), the mean annual increase in peak systolic velocity was 0.04 m/s/year (95% CI 0.028 to 0.056 m/s/year; p<0.001) as shown by ANOVA. 40 patients underwent a cardiac intervention shortly after their first echocardiogram. Another 33 patients underwent intervention during follow-up. Interventions were performed significantly more often in patients diagnosed at a younger age and/or with a higher peak velocity at diagnosis (p<0.001). Mortality was considerable in those diagnosed in infancy (5-year survival rate of 73% (SD 9%), whereas it was nearly absent in patients diagnosed after infancy. Most patients who died during infancy had progressive left ventricular dysfunction despite adequate relief of left ventricular outflow obstruction. Conclusions: Valvular aortic stenosis in the paediatric age group usually has a good prognosis beyond the neonatal period. Progression over time is usually limited, although a considerable proportion of patients need intervention shortly after initial diagnosis. Mortality, except for the neonatal age group, is nearly absent.

Does functional health status predict health-related quality of life in children after Fontan operation?

PURPOSEnIt is important to identify those children with a Fontan circulation who are at risk for impaired health-related quality of life. We aimed to determine the predictive value of functional health status - medical history and present medical status - on both physical and psychosocial domains of health-related quality of life, as reported by patients themselves and their parents.nnnMETHODSnWe carried out a prospective cross-sectional multi-centre study in Fontan patients aged between 8 and 15, who had undergone staged completion of total cavopulmonary connection according to a current technique before the age of 7 years. Functional health status was assessed as medical history - that is, age at Fontan, type of Fontan, ventricular dominance, and number of cardiac surgical procedures - and present medical status - assessed with magnetic resonance imaging, exercise testing, and rhythm assessment. Health-related quality of life was assessed with The TNO/AZL Child Questionnaire Child Form and Parent Form.nnnRESULTSnIn multivariate prediction models, several medical history variables, such as more operations post-Fontan completion, lower age at Fontan completion, and dominant right ventricle, and present medical status variables, such as smaller end-diastolic volume, a higher score for ventilatory efficiency, and the presence of sinus node dysfunction, predicted worse outcomes on several parent-reported and self-reported physical as well as psychosocial health-related quality of life domains.nnnCONCLUSIONSnMedical history and worse present medical status not only predicted worse physical parent-reported and self-reported health-related quality of life but also worse psychosocial health-related quality of life and subjective cognitive functioning. These findings will help in identifying patients who are at risk for developing impaired health-related quality of life.

Longitudinal Strain as Risk Factor for Outcome in Pediatric Dilated Cardiomyopathy.

In adults with dilated cardiomyopathy (DCM), it has been demonstrated that global longitudinal and circumferential strain have value in addition to left ventricular ejection fraction (LVEF) in predicting the risk of mortality, heart transplantation, and hospitalization for worsening heart failure [(

Response profiles of oxygen uptake efficiency during exercise in healthy children

Background Oxygen uptake efficiency (OUE), the relation between oxygen uptake (VO2) and minute ventilation (VE), differs between healthy children and children with heart disease. This study aimed to investigate the normal response profiles of OUE during a progressive cardiopulmonary exercise test. Design: Cross-sectional. Methods Healthy children between eight and 19 years of age (114 boys and 100 girls, meanu2009±u2009SD age 12.7u2009±u20092.8 years) performed a maximal cardiopulmonary exercise test. Peak VO2 (VO2peak), ventilatory threshold and peak VE were determined. OUE was determined by the OUE plateau (OUEP), OUE at the ventilatory threshold (OUE@VT) and OUE slope (OUES). Results OUEP (42.4u2009±u20094.6) and OUE@VT (41.9u2009±u20094.7) were similar and less variable than OUES (2138u2009±u2009703). OUEP correlated strongly with OUE@VT (ru2009=u20090.974); however, OUEP was weak-to-moderately correlated with VO2peak (ru2009=u20090.646), the ventilatory threshold (ru2009=u20090.548) and OUES (ru2009=u20090.589). OUES correlated strongly with VO2peak (ru2009=u20090.948) and the ventilatory threshold (ru2009=u20090.856). Reference centiles for OUEP show an almost linear increase from about 37 in eight-year olds to about 47 in 18-year olds, with no sex-difference. OUES increased from about 1400 in eight-year-old boys to approximately 3500 in 18-year-old boys. OUES increased from roughly 1250 in eight-year-old girls to about 2650 in 18-year-old girls. Conclusions This study provides sex- and age-related normative values for both OUEP and OUES, which facilitates the interpretation of OUE in children. OUEP and OUES are objective and non-invasive cardiopulmonary exercise test parameters which do not require a maximal effort and might be indicative of cardiorespiratory function during exercise.

Parent reports of health-related quality of life and heart failure severity score independently predict outcome in children with dilated cardiomyopathy

BACKGROUNDnDilated cardiomyopathy in children causes heart failure and has a poor prognosis. Health-related quality of life in this patient group is unknown. Moreover, results may provide detailed information of parents sense of their childs functioning. We hypothesised that health-related quality of life, as rated by parents, and the paediatric heart failure score, as assessed by physicians, have both predictive value on outcome. Methods and results In this prospective study, health-related quality of life was assessed by parent reports: the Infant Toddler Quality of Life questionnaire (0-4 years) or Child Health Questionnaire-Parent Form 50 (4-18 years) at 3-6-month intervals. We included 90 children (median age 3.8 years, interquartile range (IQR) 0.9-12.3) whose parents completed 515 questionnaires. At the same visit, physicians completed the New York University Pediatric Heart Failure Index. Compared with Dutch normative data, quality of life was severely impaired at diagnosis (0-4 years: 7/10 subscales and 4-18 years: 8/11 subscales) and ⩾1 year after diagnosis (3/10 and 6/11 subscales). Older children were more impaired (p<0.05). After a median follow-up of 3 years (IQR 2-4), 15 patients underwent transplantation. Using multivariable time-dependent Cox regression, physical functioning subscale and the Heart Failure Index were independently predictive of the risk of death and heart transplantation (hazard ratio 1.24 per 10% decrease of predicted, 95% confidence interval (CI) 1.06-1.47 and hazard ratio 1.38 per unit, 95% CI 1.19-1.61, respectively).nnnCONCLUSIONnPhysical impairment rated by parents and heart failure severity assessed by physicians independently predicted the risk of death or heart transplantation in children with dilated cardiomyopathy.