Therapy for pulmonary arterial hypertension due to congenital heart disease and 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.
References (38)
- et al.
Ethnicity, sex, and the incidence of congenital heart defects: a report from the National Down Syndrome Project
Genet Med
(2008) - et al.
Pulmonary vascular disease in Down's syndrome with complete atrioventricular septal defect
Am J Cardiol
(2000) - et al.
Cardiac malformation in mongolism: a prospective study of 184 mongoloid children
Am J Med
(1961) - et al.
The pulmonary vascular bed in children with Down syndrome
J Pediatr
(1975) - et al.
Endothelial cell function in patients with Down's syndrome
Am J Cardiol
(2004) - et al.
Longer-term bosentan therapy improves functional capacity in Eisenmenger syndrome: results of the BREATHE-5 open-label extension study
Int J Cardiol
(2008) - et al.
Efficacy of bosentan in a small cohort of adult patients with pulmonary arterial hypertension related to congenital heart disease
Chest
(2006) - et al.
Down patients with Eisenmenger syndrome: is bosentan treatment an option?
Int J Cardiol
(2009) - et al.
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
Am J Cardiol
(2009) - et al.
Down's syndrome, complete atrioventricular canal, and pulmonary vascular obstructive disease
J Thorac Cardiovasc Surg
(1990)
Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: a randomised placebo-controlled study
Lancet
Trends in Down's syndrome live births and antenatal diagnoses in England and Wales from 1989 to 2008: analysis of data from the National Down Syndrome Cytogenetic Register
BMJ
Distribution of symptomatic congenital heart disease in Hong Kong
Pediatr Cardiol
Cardiovascular malformations in Omani Arab children with Down's syndrome
Cardiol Young
Anomalies in Down syndrome individuals in a large population-based registry
Am J Med Genet
The pattern of Down syndrome among children in Qatar: a population-based study
Birth Defects Res A Clin Mol Teratol
Prevalence of congenital heart defects and persistent pulmonary hypertension of the neonate with Down syndrome
Eur J Pediatr
Precocity of pulmonary vascular obstruction of Down's syndrome
Eur J Cardiol
Plasma endothelin-1 and nitrate levels in Down's syndrome with complete atrioventricular septal defect-associated pulmonary hypertension: a comparison with non-Down's syndrome children
Eur J Pediatr
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