Rolf M.F. Berger

Bosentan Therapy in Patients With Eisenmenger Syndrome A Multicenter, Double-Blind, Randomized, Placebo-Controlled Study

Background— Eisenmenger syndrome is characterized by the development of pulmonary arterial hypertension with consequent intracardiac right-to-left shunt and hypoxemia in patients with preexisting congenital heart disease. Because Eisenmenger syndrome is associated with increased endothelin expression, patients may benefit from endothelin receptor antagonism. Theoretically, interventions that have some effect on the systemic vascular bed could worsen the shunt and increase hypoxemia. Methods and Results— The Bosentan Randomized Trial of Endothelin Antagonist Therapy-5 (BREATHE-5) was a 16-week, multicenter, randomized, double-blind, placebo-controlled study evaluating the effect of bosentan, a dual endothelin receptor antagonist, on systemic pulse oximetry (primary safety end point) and pulmonary vascular resistance (primary efficacy end point) in patients with World Health Organization functional class III Eisenmenger syndrome. Hemodynamics were assessed by right- and left-heart catheterization. Secondary end points included exercise capacity assessed by 6-minute walk distance, additional hemodynamic parameters, functional capacity, and safety. Fifty-four patients were randomized 2:1 to bosentan (n=37) or placebo (n=17) for 16 weeks. The placebo-corrected effect on systemic pulse oximetry was 1.0% (95% confidence interval, −0.7 to 2.8), demonstrating that bosentan did not worsen oxygen saturation. Compared with placebo, bosentan reduced pulmonary vascular resistance index (−472.0 dyne · s · cm−5; P=0.0383). The mean pulmonary arterial pressure decreased (−5.5 mm Hg; P=0.0363), and the exercise capacity increased (53.1 m; P=0.0079). Four patients discontinued as a result of adverse events, 2 (5%) in the bosentan group and 2 (12%) in the placebo group. Conclusions— In this first placebo-controlled trial in patients with Eisenmenger syndrome, bosentan was well tolerated and improved exercise capacity and hemodynamics without compromising peripheral oxygen saturation.

Pediatric pulmonary hypertension

Pulmonary hypertension (PH) is a rare disease in newborns, infants, and children that is associated with significant morbidity and mortality. In the majority of pediatric patients, PH is idiopathic or associated with congenital heart disease and rarely is associated with other conditions such as connective tissue or thromboembolic disease. Incidence data from the Netherlands has revealed an annual incidence and point prevalence of 0.7 and 4.4 for idiopathic pulmonary arterial hypertension and 2.2 and 15.6 for pulmonary arterial hypertension, respectively, associated with congenital heart disease (CHD) cases per million children. The updated Nice classification for PH has been enhanced to include a greater depth of CHD and emphasizes persistent PH of the newborn and developmental lung diseases, such as bronchopulmonary dysplasia and congenital diaphragmatic hernia. The management of pediatric PH remains challenging because treatment decisions continue to depend largely on results from evidence-based adult studies and the clinical experience of pediatric experts.

Transforming Growth Factor-β Receptor Mutations and Pulmonary Arterial Hypertension in Childhood

Background—Pulmonary arterial hypertension (PAH) is a potentially fatal vasculopathy that can develop at any age. Adult-onset disease has previously been associated with mutations in BMPR2 and ALK-1. Presentation in early life may be associated with congenital heart disease but frequently is idiopathic. Methods and Results—We performed mutation analysis in genes encoding receptor members of the transforming growth factor-&bgr; cell-signaling pathway in 18 children (age at presentation <6 years) with PAH. Sixteen children were initially diagnosed with idiopathic PAH and 2 with PAH in association with congenital heart defects. Germ-line mutations were observed in 4 patients (22%) (age at disease onset, 1 month to 6 years), all of whom presented with idiopathic PAH. The BMPR2 mutations (n=2, 11%) included a partial gene deletion and a nonsense mutation, both arising de novo in the proband. Importantly, a missense mutation of ALK-1 and a branch-site mutation of endoglin were also detected. Presenting clinical features or progression of pulmonary hypertension did not distinguish between patients with mutations in the different genes or between those without mutations. Conclusions—The cause of PAH presenting in childhood is heterogeneous in nature, with genetic defects of transforming growth factor-&bgr; receptors playing a critical role.

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. # 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.

Effects of sildenafil on invasive haemodynamics and exercise capacity in heart failure patients with preserved ejection fraction and pulmonary hypertension: a randomized controlled trial.

BACKGROUND Heart failure with preserved ejection fraction (HFpEF), with associated pulmonary hypertension is an increasingly large medical problem. Phosphodiesterase (PDE)-5 inhibition may be of value in this population, but data are scarce and inconclusive. METHODS AND RESULTS In this single centre, randomized double-blind, placebo-controlled trial, we included 52 patients with pulmonary hypertension [mean pulmonary artery pressure (PAP) >25 mmHg; pulmonary artery wedge pressure (PAWP) >15 mmHg] due to HFpEF [left ventricular ejection fraction (LVEF) ≥45%]. Patients were randomized to the PDE-5 inhibitor sildenafil, titrated to 60 mg three times a day, or placebo for 12 weeks. The primary endpoint was change in mean PAP after 12 weeks. Secondary endpoints were change in mean PAWP, cardiac output, and peak oxygen consumption (peak VO2). Mean age was 74 ± 10 years, 71% was female, LVEF was 58%, median NT-proBNP level was 1087 (535-1945) ng/L. After 12 weeks, change in mean PAP was -2.4 (95% CI -4.5 to -0.3) mmHg in patients who received sildenafil, vs. -4.7 (95% CI -7.1 to -2.3) mmHg in placebo patients (P = 0.14). Sildenafil did not have a favourable effect on PAWP, cardiac output, and peak VO2. Adverse events were overall comparable between groups. CONCLUSION Treatment with sildenafil did not reduce pulmonary artery pressures and did not improve other invasive haemodynamic or clinical parameters in our study population, characterized by HFpEF patients with predominantly isolated post-capillary pulmonary hypertension. (ClinicalTrials.gov, number NCT01726049).

Efficiency of oxidative work performance of skeletal muscle in patients with cystic fibrosis.

BACKGROUND--Exercise intolerance in patients with cystic fibrosis is commonly attributed to reduced pulmonary and nutritional status. The possible role of diminished efficiency of mitochondrial oxidative phosphorylation in relation to skeletal muscle performance was investigated in patients with cystic fibrosis. METHODS--In vivo synthesis of ATP in skeletal muscle during submaximal exercise was studied in eight patients with cystic fibrosis aged 12-17 years, and in 19 healthy control subjects aged 8-36 years. The intracellular pH and concentrations of phosphate compounds were calculated at four steady states from phosphorus-31 labelled nuclear magnetic resonance spectroscopy measurements in the forearm muscle during bulb squeezing in an exercise protocol. Normalised power output, expressed as percentage maximal voluntary contraction (Y, in %MVC), was related to the energy force of ATP hydrolysis (X = ln [ATP]/[ADP][Pi]). This relationship provides an in vivo measure of efficiency of oxidative work performance of skeletal muscle. RESULTS--During all workloads (but not at rest) intracellular pH was higher in the patients with cystic fibrosis than in the controls. The linear least square fit for Y = a-bX showed high correlations in both groups; the slope b was 19% lower in the patients than in the controls (11.8% v 14.5% MVC/ln M; 95% confidence interval for difference 0.3 to 5.0). CONCLUSIONS--In patients with cystic fibrosis oxidative work performance of skeletal muscle is reduced. This may be related to secondary pathophysiological changes in skeletal muscle in cystic fibrosis.

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.

Biological Serum Markers in the Management of Pediatric Pulmonary Arterial Hypertension

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.

Effect of bosentan on exercise capacity and quality of life in adults with pulmonary arterial hypertension associated with congenital heart disease with and without Down's syndrome

Pulmonary arterial hypertension associated with congenital heart disease caused by systemic-to-pulmonary shunting was associated with a high risk of morbidity and mortality. In this retrospective study, the longer term treatment effect of bosentan on exercise capacity and quality of life (QoL) were evaluated in 58 adult patients (>18 years) with pulmonary arterial hypertension associated with congenital heart disease, including patients with Downs syndrome. All patients were evaluated at baseline and during follow-up using laboratory tests, 6-minute walk test, QoL questionnaires, and Doppler echocardiography. Treatment efficacy was analyzed separately for patients without (n = 30) and with Downs syndrome (n = 28). Median follow-up of all patients treated with bosentan was 22 months (range 3 to 36). In patients without Downs syndrome, mean 6-minute walk distance increased from 427 +/- 97 to 461 +/- 104 m (p <0.01) after 6 months of treatment, followed by a gradual return to baseline and disease stabilization. QoL improved significantly during treatment and was maintained during 18 months of follow-up (p <0.05). In patients with Downs syndrome, 6-minute walk distance and QoL were stable during treatment. In conclusion, findings suggested that in patients without Downs syndrome, longer term bosentan treatment resulted in a persistent improvement in QoL and stabilization of exercise capacity.

Diagnostic evaluation of paediatric pulmonary hypertension in current clinical practice.

Current paediatric pulmonary hypertension (PH) diagnostic algorithms include some testing specifically for paediatrics, but it is unclear if this is used in clinical practice. We describe the current diagnostic workup of the TOPP (Tracking Outcomes and Practice in Paediatric Pulmonary hypertension) registry for suspected PH. We investigated 456 patients enrolled until February 2010. The majority had ECGs (94%), echocardiograms (96%) and/or chest radiographs (89%) performed and these were the noninvasive tests most frequently used for evaluation of suspected PH. No patient had all three tests considered normal, suggesting the potential for the combined use to rule out PH. For evaluation of complications associated with heart catheterisation (HC) we analysed a total of 908 HCs reported until February 2012. Of these, 554 were at diagnosis and 354 in follow-up. Complications were reported in 5.9% with five deaths considered related to HC, suggesting a higher rate of HC complications compared to adult studies. However, current recommendations support HC in paediatric PH. A proper application of the risk/benefit ratio for HC requires further data. Most children did not undergo the diagnostic workup currently recommended for adults, which highlights either incomplete awareness of current guidelines and/or challenges their appropriateness for children. Most PH children don’t undergo full diagnostic evaluations; despite complications, catheterisation is used for diagnosis http://ow.ly/mx4GW