Original articleEndothelin Receptor Antagonists are an Effective Long Term Treatment Option in Pulmonary Arterial Hypertension Associated with Congenital Heart Disease With or Without Trisomy 21
Introduction
In patients with systemic to pulmonary shunts surgical correction is done early, frequently in the first year of life to avoid the development of irreversible pulmonary vascular disease. In adult congenital heart disease clinics however, there are patients who present late with pulmonary hypertension that has resulted from untreatable lesions, undiagnosed lesions, or progression of pulmonary vascular disease despite surgical correction.
Changes in the pulmonary vasculature resulting from systemic to pulmonary shunts have a propensity to progress, with the development of more severe histological changes in the pulmonary arterioles identical to the histology seen in idiopathic pulmonary arterial hypertension (IPAH) [1], [2]. Correspondingly, the pulmonary arterial and right ventricular pressures rise. Ultimately, shunt reversal occurs with the development of cyanosis – a situation known as Eisenmenger syndrome (ES) [2], [3], [4]. The natural history of this condition eventually, is one of a slow and gradual deterioration with worsening cyanosis and right heart failure [3].
The prevalence of pulmonary arterial hypertension (PAH) in adult patients with congenital heart disease (CHD) in the Dutch national registry was 4.2%. Of those with a septal defect, 6% developed pulmonary hypertension, half of whom had Eisenmenger's syndrome. Additionally, 3% of patients with previously closed septal defects developed pulmonary hypertension [5]. In the Euro Heart Survey of adult congenital heart disease, pulmonary hypertension was present in 28% of patients [5]. It was present in 34% with an open atrial septal defect, 28% with an open ventricular septal defect, and in 12% and 13% with closed defects respectively [5].
Traditionally, treatment options for PAH-CHD have been limited to supportive therapies, palliative surgical procedures or lung/heart–lung transplantation for highly selected patients. The availability of specific PAH specific treatment strategies, and further understanding of the pathophysiology associated with PAH-CHD have substantially improved in the last few years. The structural abnormalities of the pulmonary vasculature seen in PAH-CHD are histologically similar to those seen in IPAH including plexiform lesions [2], [4] and are associated with elevated tissue and plasma levels of endothelin (ET-1) [2].
Based on this knowledge, one randomised controlled study [6] and several small, uncontrolled and retrospective studies [1], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18] have suggested that endothelin receptor antagonists (ERAs) improve exercise capacity and haemodynamics in adult patients with ES. However, there is limited data available on the use of ERA therapy in patients with more complex congenital defects or Trisomy 21. This is particularly important as outcomes are reported to be considerably poorer in patients with these conditions [5], [19]. A retrospective study by Diller et al., showed that despite a relatively good short term prognosis, median survival is reduced by about 20 years in patients with simple underlying anatomy to their PAH-CHD, and a further 20 years in those with complex lesions [5]. The aims of our present study are firstly; to report the longer term outcomes and safety of ERA's in patients with PAH-CHD and secondly; to define the efficacy of ERA therapy in a significant cohort of patients with CHD and Trisomy 21.
Section snippets
Selection of Patients
Patients with PAH-CHD and/or ES (defined as an intracardiac or extracardiac systemic to pulmonary communication with reversal of the left-to-right shunt, resulting from severe pulmonary hypertension) were referred from the Adult CHD clinic. Patients who had undergone ASD/VSD closure with subsequent diagnosis of PAH were excluded from the study. At the time of enrolment, all patients were in a clinically stable condition and no patient had been previously exposed to specific PAH therapies.
Results
Between 2003 and July 2009, we recruited 53 patients with CHD-PAH. Patient demographics are presented in Table 1. Four paediatric and 49 adult patients were enrolled; two-thirds of patients were female and the mean age was 34 ± 12 years. The mean duration of ERA therapy was 14.7 ± 2.8 months (range 1–72 months). The majority of patients (70%) were in WHO functional class III (Table 1). ES was predominantly due to un-repaired VSD in 20 patients. Other cardiac lesions included 10 with
Discussion
In this study, we report that long term ERA therapy in patients with PAH-CHD and ES improves exercise capacity, WHO functional class and has no detrimental effects on SaO2. The incidence of adverse events was low with ERA therapy and well tolerated. Furthermore, our study extends the literature in PAH-CHD by offering a formal assessment of ERA therapy in a relatively large cohort of patients with Trisomy 21 and/or complex congenital lesions. These findings provide further support for ERA
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