Therapy for pulmonary arterial hypertension due to congenital heart disease and Down's syndrome

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Abstract

Background

Oral bosentan is effective in pulmonary arterial hypertension (PAH) related to congenital heart disease (CHD). In patients with Down's syndrome, the effect of bosentan is largely unknown. Aim of the study was to evaluate the long-term effects of bosentan in adult patients with CHD-related PAH with and without Down's syndrome.

Methods

WHO functional class, resting oxygen saturation, 6-minute walk test (6MWT) and hemodynamics were assessed at baseline and after 12 months of bosentan therapy in patients with CHD-related PAH with and without Down's syndrome.

Results

Seventy-four consecutive patients were enrolled: 18 with and 56 without Down's syndrome. After 12 months of bosentan therapy, both with and without Down's syndrome patients showed an improvement in WHO functional class (Down: 2.5 ± 0.5 vs 2.9 ± 0.6, p = 0.005; controls: 2.5 ± 0.5 vs 2.9 ± 0.5, p = 0.000002), 6-minute walk distance (Down: 288 ± 71 vs 239 ± 74 m, p = 0.0007; controls: 389 ± 80 vs 343 ± 86 m, p = 0.00003), and hemodynamics (pulmonary flow, Down: 4.0 ± 1.6 vs 3.5 ± 1.4 l/m/m2, p = 0.006; controls: 3.5 ± 1.4 vs 2.8 ± 1.0 l/m/m2, p = 0.0005; pulmonary to systemic flow ratio, Down: 1.4 ± 0.7 vs 1.0 ± 0.4, p = 0.003; controls: 1.1 ± 0.7 vs 0.9 ± 0.3, p = 0.012; pulmonary vascular resistance index, Down: 15 ± 9 vs 20 ± 13 WU m2, p = 0.007; controls: 20 ± 10 vs 26 ± 15 WU m2, p = 0.002). No differences in the efficacy of therapy were observed between the two groups.

Conclusions

Bosentan was safe and well tolerated in adult patients with CHD-related PAH with and without Down's syndrome during 12 months of treatment. Clinical status, exercise tolerance, and pulmonary hemodynamics improved, regardless of the presence of Down's syndrome.

Introduction

Down's syndrome is the most common autosomal chromosome abnormality with an estimated incidence of approximately 1.1 per 1000 births [1]. The prevalence of congenital heart disease (CHD) in the Down's population is 40–60%, and atrioventricular septal defect is the most commonly occurring CHD (~ 30–50%) [2], [3], [4], [5], [6], [7], [8], [9].

It is known that children with Down's syndrome may develop progressive pulmonary changes earlier than non-Down's counterparts with similar congenital heart defects [10], [11]. Nevertheless, it is unclear whether intrinsic molecular factors in the pulmonary endothelium can accelerate pulmonary arterial hypertension (PAH) in patients with Down's syndrome [12], [13], [14], [15], [16], [17], [18].

In recent years, new treatment strategies targeting pulmonary endothelial pathways have largely improved the clinical status of patients with CHD-related PAH. A large randomized controlled trial [19], [20] and several single-center, open-label studies [21], [22], [23], [24] have shown that bosentan, an oral dual endothelin receptor antagonist, is effective at mid- and long-term follow-up in patients with CHD-related PAH and Eisenmenger syndrome. However, in Down patients, the treatment effect of bosentan is largely unknown. Two recent papers from the same group [25], [26] suggested that oral bosentan therapy is safe and well tolerated in adult patients with CHD-related PAH and Down's syndrome, with no change in quality of life during treatment. Notwithstanding this, the results of the 6-minute walk test (6MWT) were conflicting. In addition, no invasive measurements of pulmonary hemodynamics are available so far in Down's patients with CHD-related PAH.

The aim of our study was to evaluate the safety and long-term effects of oral bosentan in adult patients with CHD-related PAH with and without Down's syndrome by assessing functional class, exercise capacity, and hemodynamics.

Section snippets

Patient selection

From January 2005 to June 2010, all consecutive patients referred to two Italian Cardiology Units (Monaldi Hospital, Second University of Naples, and University La Sapienza of Rome) for PAH due to an unoperated, non-restrictive intra- or extracardiac communication with a bidirectional or right-to-left shunt were considered. Concomitant causes of pulmonary hypertension, such as lung or liver disease, were excluded using mandatory chest X-ray, respiratory function tests, perfusion lung scan,

Results

Seventy-seven consecutive adult patients with CHD-related PAH were enrolled. After 2–4 weeks of treatment, 3 patients (5%, 1 with and 2 without Down's syndrome) withdrew because of severe leg edema despite an increased diuretic dose, and were not considered in the analysis. Of the 74 CHD-related PAH participating patients, 18 had Down's syndrome and 56 had not. Concomitant background therapy was continued during the study without significant changes. Demographics and diagnosis are reported in

Discussion

The main finding of our study is that oral bosentan is safe and well tolerated at 12-month follow-up, resulting in an improvement in clinical status, effort SpO2 and hemodynamics in adult patients with CHD-related PAH with and without Down's syndrome.

The mechanisms that contribute to the development of pulmonary hypertension in Down patients are multifactorial and likely due to both anatomical and physiological alterations in the pulmonary circulation. Recurrent pulmonary infection, pulmonary

Conclusions

Our study suggests that long-term bosentan therapy is safe, well tolerated and effective in patients with CHD-related PAH with and without Down's syndrome, showing a significant improvement in clinical status, effort SpO2 and hemodynamics. In particular, the presence of Down's syndrome does not affect the response to oral bosentan therapy.

Acknowledgments

Authors express their gratitude to all the nurses of the Division of Adult Cardiology and GUCH and PH Units of Monaldi Hospital, for their important technical support, particularly: Mrs Antonella Nannolo, Mrs Deborah De Santis, Mrs Luisa Romano, Mrs Assunta Carandente, and Mrs Gabriella Lettieri.

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