Sheila G. Haworth

Treatment and survival in children with pulmonary arterial hypertension: the UK Pulmonary Hypertension Service for Children 2001–2006

Objective: A retrospective study of the UK Pulmonary Hypertension Service for Children for the first 5-year period of its existence. Design and patients: Records of 216 children with idiopathic pulmonary arterial hypertension (IPAH) and associated pulmonary arterial hypertension (APAH) were reviewed. Kaplan-Meier survival curves were constructed for different diagnostic groups and for different therapies. Results: At cardiac catheterisation only 7.4% of those with IPAH and 6% of those with APAH responded positively to vasodilator testing and so were treated with nifedipine. Others needing treatment were given continuous intravenous epoprostenol, bosentan or sildenafil singly or in combination. For IPAH survival rates were 85.6%, 79.9% and 71.9% at 1, 3 and 5 years, respectively, compared with a survival time of less than a year in historical untreated controls. A combination of intravenous epoprostenol with either bosentan or sildenafil, or both, appeared to achieve the best outcome. Six children underwent lung transplantation. In APAH survival rates were 92.3%, 83.8% and 56.9% at 1, 3 and 5 years, respectively, postoperative congenital heart disease with severe pulmonary hypertension having the worst outcome. Conclusion: New pulmonary hypertension-specific medicines have improved survival in children as in adults. Outcome in this series compares favourably with international outcome data.

The 6-minute walk test: normal values for children of 4–11 years of age

Objective: The 6-minute walk test (6MWT) is an established measure of exercise capacity in adults and children with chronic cardiac or respiratory disease. Despite its widespread use, there are no normal values for healthy children under 12 years of age. We aimed to provide normal values for children between 4 and 11 years. Methods: Healthy children were recruited prospectively from two UK primary schools and also children visiting Great Ormond Street Hospital. 328 children (54% male) aged 4 to 11 years were included in the study. Main outcome measures were the distance walked in 6 minutes, and oxygen saturation and heart rate during the 6 minutes and during a 3-minute recovery period. Results: Mean oxygen saturation at baseline and during the 6MWT was 97–99%. Heart rate increased from 102±19 bpm at baseline to a maximum of 136±12 bpm. Overall, the mean distance walked in 6 minutes was 470±59 m. Distance walked correlated with age (r = 0.64, p<0.0001), weight (r = 0.51, p<0.0001) and height (r = 0.65, p<0.0001) with no significant difference between boys and girls. The distance walked increased significantly year on year from 4 to 7 years (4 years 383±41 m; 5 years 420±39 m, 6 years 463±40 m; 7 years 488±35 m; p<0.05 between each); further modest increases were observed beyond 7 years of age. Conclusions: Performing a 6MWT is feasible and practical in young children. This study provides data on normal children against which the performance of sick children and the response to therapeutic intervention can be judged.

Response to bosentan in children with pulmonary hypertension

Objective: To describe an early experience of treating 40 children with the dual endothelin receptor antagonist bosentan, which is known to be safe and effective in adults with pulmonary hypertension (PH). Design: In this retrospective, observational study the UK Service for Pulmonary Hypertension for children treated 40 children with bosentan, 20 with idiopathic pulmonary arterial hypertension (IPAH) (mean age 8.03 years, range 1.2–17) and 20 with PH associated with other conditions (congenital heart disease, parenchymal lung or connective tissue disease, or HIV). Their mean age was 8.3 years (range 0.6–16 years). Patients: 39 patients were in World Health Organization (WHO) class III and IV, and all had shown recent deterioration. In IPAH the mean pulmonary vascular resistance (PVR) was 21.7 units⋅m2 (range 5.6–42.8). In secondary PH the mean PVR was 18 units⋅m2 (range 4.9–49). No child had a positive response to vasodilator testing with nitric oxide. Interventions: Bosentan was given as first line treatment to 25. Nine were given intravenous epoprostenol. Children were treated for a mean of 12.7 months (range 2–24 months). Main outcome measures: Response to treatment was judged by WHO functional class, six minute walk test, weight, ECG and echocardiographic findings, and need to add additional treatment. Results: Bosentan was well tolerated. In the IPAH group 19 (95%) stabilised with bosentan treatment but 12 (60%) patients needed combined treatment with epoprostenol. In secondary PH, WHO class, six minute walk test, and weight gain improved significantly. Conclusion: Bosentan helped stabilise children with IPAH but intravenous epoprostenol was also needed by 60%. Children with secondary PH improved.

Developmental changes in endothelium‐dependent pulmonary vasodilatation in pigs

1 We compared in vitro endothelium‐dependent vasorelaxant responses to acetylcholine (ACh) and the endothelium‐independent vasodilator response to sodium nitroprusside (SNP) in prostaglandin F2α (PGF2α)‐precontracted muscular pulmonary arteries (PA) from pigs aged 5 min to 2 h (neonatal), 3–10 days, 3–8 weeks and adults. 2 In the pulmonary artery (PA) rings from neonatal animals, the vasodilator response to ACh was negligible. However, responses to ACh were present in all PA rings from older animals, being greatest at 3–10 days and then decreasing with age (P < 0.001, ANOVA). ACh (30 μm) induced a 1 ± 1%, 92 ± 9%, 62 ± 5% and 51 ± 6% reduction of the PGF2α‐generated tension in neonatal, 3–10 days, 3–8 weeks and adult groups, respectively. 3 The relaxant response to SNP was present in the PA rings from all age groups and increased with age (P < 0.001, ANOVA). SNP (1 μm)‐induced relaxation was 55 ± 9%, 73 ± 7%, 97 ± 5% and 93 ± 6% in neonatal, 3–10 days, 3–8 week and adult groups, respectively. 4 Removal of the vascular endothelium abolished the relaxant response to ACh but had no effect on the response to SNP in any groups. 5 NG‐monomethyl‐l‐arginine (30 μm), a nitric oxide synthesis inhibitor, inhibited the response to ACh but not to SNP. The lipoxygenase inhibitor, nordihydroguaiaretic acid, had no significant effect on responses to ACh or SNP in any group. 6 These findings suggest that the nitric oxide pathway may not play a part in dilating the pig pulmonary arteries at birth, but may be important during the transitional period of establishing a stable post‐natal pulmonary circulation. The increase in response to SNP with age parallels the increase in smooth muscle cell myofilaments to which it may be related.

Role of atrial septostomy in the treatment of children with pulmonary arterial hypertension

Objectives: To assess in retrospect the safety and effectiveness of atrial septostomy in children with severe pulmonary arterial hypertension without an intracardiac communication. Methods: 20 patients were reviewed retrospectively, 19 with idiopathic pulmonary arterial hypertension. The mean age at septostomy was 8.4 years (range 3 months to 17 years). Graded balloon septostomy alone was carried out in eight patients, a blade septostomy was done in two, a blade septostomy plus graded balloon septostomy was done in three, and a fenestrated device was inserted in seven. Results: There were no fatalities. Four children suffered complications during the procedure. None had further syncope and all improved symptomatically with a significant (p < 0.01) decrease in World Health Organization functional class (mean shift −0.6) and a significant improvement in the semiquantitative echocardiographic assessment of right ventricular function (p < 0.03). The mean oxygen saturation decreased by 7.8 percentage points. The atrial communication closed in two children, necessitating a repeat procedure. After a mean follow up of 2.1 years (range one month to 6.7 years), 18 of 20 children are still alive. Conclusion: Atrial septostomy improved symptoms and quality of life in a group of children deteriorating with severe pulmonary arterial hypertension. This procedure is to be recommended for severely symptomatic children, before they become critically ill. Fenestrated devices may help ensure indefinite patency of the atrial communication.

Epoprostenol treatment in children with severe pulmonary hypertension

Introduction: Severe, sustained pulmonary arterial hypertension leads to a progressive reduction in exercise capacity, right heart failure and death. Use of intravenous epoprostenol has improved survival in adults, but data are limited in children. Patients and methods: This study included all 39 children treated with continuous intravenous epoprostenol since November 1997 at Great Ormond Street Hospital for Children (London, UK). Patients were aged 4 months to 17 years (median 5.4 years) at the onset of therapy. The male:female ratio was 1:1.3. 25 patients had idiopathic pulmonary arterial hypertension and 14 had pulmonary arterial hypertension associated with congenital heart disease, connective tissue disease, chronic lung disease or HIV. All were in WHO functional class III and IV. Mean pulmonary arterial pressure (SD) was 59 (17) mmHg and mean pulmonary vascular resistance was 23.3 (11.6) units×m2. Patients were assessed regularly (2–3 monthly intervals) by physical examination, electrocardiography, transthoracic echocardiography and a 6-min walk test, when practicable. Results: The mean duration of follow-up was 27 (21) months. 7 patients died and 8 underwent transplantation. Cumulative survival at 1, 2 and 3 years was 94, 90 and 84%. The 6-min walking distance improved by a mean of 77 m (p<0.003). WHO functional class improved during the first year (p<0.001) and improvement was maintained for up to 3 years. Weight improved significantly from a baseline z score of −1.55 (1.74) to −1.16 (1.8) (p<0.03). 28 children had additional oral specific therapy. Hickman line changes were 0.33/patient year. Conclusions: Epoprostenol therapy improved survival, WHO functional class, exercise tolerance and ability to thrive in children with severe pulmonary arterial hypertension. Epoprostenol represents an effective and feasible therapy even in young children.

Pulmonary vascular development: Normal values of peripheral vascular structure

Uninjected postmortem normal lung from 49 children aged 1 hour to 14 years was studied using quantitative morphometric techniques to assess arterial size, number and muscularity, particularly in the respiratory region of lung. Arterial size increased most rapidly during the first 2 months of life, but growth rate remained high during the first 4 years. At all ages, the range of values for the mean external diameter of arteries accompanying peripheral airways was considerable, but marked differences from the normal range were usually associated with a marked difference in stature. Arterial number increased rapidly in the first 2 months, but subsequently arteries multiplied at the same rate as alveoli, and the alveolar:arterial ratio was relatively constant. Mean percentage arterial medial thickness fell quickly during the first 10 days and continued to decrease during the first 3 months of life, after which there was little change. The intra-acinar arteries became more muscular during childhood as they increased in size. Vein muscle wall thickness was low throughout childhood. The normal values given in this paper provide a basis for the evaluation of lung biopsies in childhood.

Smooth Muscle Proliferation and Role of the Prostacyclin (IP) Receptor in Idiopathic Pulmonary Arterial Hypertension

RATIONALE Prostacyclin analogs, used to treat idiopathic pulmonary arterial hypertension (IPAH), are assumed to work through prostacyclin (IP) receptors linked to cyclic AMP (cAMP) generation, although the potential to signal through peroxisome proliferator-activated receptor-γ (PPARγ) exists. OBJECTIVES IP receptor and PPARγ expression may be depressed in IPAH. We wished to determine if pathways remain functional and if analogs continue to inhibit smooth muscle proliferation. METHODS We used Western blotting to determine IP receptor expression in peripheral pulmonary arterial smooth muscle cells (PASMCs) from normal and IPAH lungs and immunohistochemistry to evaluate IP receptor and PPARγ expression in distal arteries. MEASUREMENTS AND MAIN RESULTS Cell proliferation and cAMP assays assessed analog responses in human and mouse PASMCs and HEK-293 cells. Proliferative rates of IPAH cells were greater than normal human PASMCs. IP receptor protein levels were lower in PASMCs from patients with IPAH, but treprostinil reduced replication and treprostinil-induced cAMP elevation appeared normal. Responses to prostacyclin analogs were largely dependent on the IP receptor and cAMP in normal PASMCs, although in IP(-/-) receptor cells analogs inhibited growth in a cAMP-independent, PPARγ-dependent manner. In IPAH cells, antiproliferative responses to analogs were insensitive to IP receptor or adenylyl cyclase antagonists but were potentiated by a PPARγ agonist and inhibited (∼ 60%) by the PPARγ antagonist GW9662. This coincided with increased PPARγ expression in the medial layer of acinar arteries. CONCLUSIONS The antiproliferative effects of prostacyclin analogs are preserved in IPAH despite IP receptor down-regulation and abnormal coupling. PPARγ may represent a previously unrecognized pathway by which these agents inhibit smooth muscle proliferation.

Development of the pulmonary circulation in ventricular septal defect: A quantitative structural study

The application of quantitative morphometric techniques to evaluation of the lungs of nine children who died with a ventricular septal defect between the ages of 3 months and 4 years showed that the presence of pulmonary hypertension interferes with the growth and development of the pulmonary circulation. In all cases the preacinar arteries were of normal size and not dilated, and arterial size and number within the acinus were reduced and similar to those seen in the normal child at birth. Arterial and venous muscularity was increased as judged by an increase in wall thickness and by the presence of muscle in smaller and more peripheral arteries than is normal. Elevation of resistance was associated with failure of the intraacinar pulmonary circulation to develop normally rather than to obliterative pulmonary vascular disease. In view of the rapidity with which impairment of growth and elevation of resistance can develop, closure of a large defect is recommended before age 2 years.

Pulmonary hypertension in scimitar syndrome in infancy.

Four infants with the scimitar syndrome presented with failure to thrive, cardiac failure, and pulmonary hypertension. In all cases systemic arteries arose from the upper abdominal aorta to perfuse the lower part of the right lung, and a large unobstructed anomalous pulmonary vein drained venous blood from almost the entire right lung to the inferior vena cava. An additional small pulmonary vein joined the inferior vena cava or right atrium and in three of the four cases angiography showed intrapulmonary connections between the two anomalous veins. At necropsy, in all four cases the right lung was hypoplastic. The bronchi were abnormal in size or number in three cases, but there was no sequestrated tissue. Microscopical examination showed normal peripheral airway and alveolar development. The pulmonary arterial branching pattern was deficient in three patients. Postmortem arteriography, dissection, and microscopical studies showed that in areas of lung not perfused by branches of the right pulmonary artery the systemic arteries anastomosed with intrapulmonary arteries to distribute blood to a dilated capillary bed. In all tissue examined arterial medial thickness was increased in both lungs while vein wall thickness was normal. For comparison a fifth patient, more typical of the syndrome, was included; this patient did not have pulmonary hypertension and died from septicaemia at 2 years of age. Symptomatic infants with pulmonary hypertension probably have the most severe form of the scimitar syndrome. It is recommended that sick infants should have a two stage correction, systemic arteries being ligated at the first procedure and the anomalous vein being reimplanted in the left atrium at a second and later procedure, with closure of an atrial septal defect if present.