Congenital heart diseases (CHDs) are among the most common congenital malformations at birth, with an incidence of 8/1,000 live births. These defects are characterised by a heterogeneous group of abnormal communications and connections between the cardiac chambers and vessels with different haemodynamic consequences and, hence, varying need for follow-up and interventions. The most common forms are congenital cardiac shunts (i.e. ventricular septal defects, atrial septal defects, atrioventricular septal defects or patent ductus arteriosus), which account for almost 60% of the malformations. Pulmonary arterial hypertension (PAH) remains a major complicating factor of many types of congenital heart disease characterised by a systemic to pulmonary shunt, causing increased morbidity and mortality during or immediately after surgical repair or even preventing complete repair for those with advanced pulmonary vascular disease (PVD).1
If uncorrected, left-to-right shunting can lead to pulmonary vascular injury due to elevated pulmonary blood flow and shear stress.2,3 Vascular remodelling ensues, leading to increased pulmonary vascular resistance (PVR) and PVD: 15% of the CHD population is thought to develop PVD.4 This includes patients whose PVR may exceed systemic vascular resistance, resulting in reversed shunting (Eisenmenger physiology, EP), with consequent chronic hypoxaemia.5 Cardiac surgery performed at an early age is the treatment of choice for CHD, but the timing of surgery is crucial.6,7 Early intervention and protection of the pulmonary circulation is therefore a major determinant of prognosis for patients with PAH associated with CHD (PAH-CHD) and screening of patients with CHD and systemic-to-pulmonary shunts for the presence of pulmonary vascular disease is essential.
Based on the haemodynamic findings, three groups of patients may present with PAH associated with congenital cardiac shunts:
- patients with increased pulmonary blood flow and low PVR allowing for surgical repair, which, as already mentioned, is curative;
- patients who present later in life with borderline PVR and PVD at high risk for surgical repair, in whom pulmonary vascular lesions may not reverse despite surgical repair and thus potential early improvement in quality of life may lead to decreased survival; and
- patients with EP and advanced PVD considered inoperable, in whom, until now, treatment was largely empirical.
Patients with closed cardiac shunts and persistent PAH despite surgical repair should be considered as having a disease that behaves like idiopathic PAH (IPAH), as they present the same haemodynamic profile and potential for right ventricular failure. They should be treated following the usual recommendations.8
The EP group is characterised haemodynamically by decreased pulmonary blood flow and high PVR, impeding surgery. The progression of the pulmonary vascular lesions has led to an increase in PVR higher than the systemic vascular resistance, which means that the shunt reverses (right to left) and, as a result, the patient is cyanosed. It is well known that surgery (closure of the shunt) will lead to right ventricular failure and death, with the shunt acting as a decompressing valve for a right ventricle facing a very high afterload. These patients are cyanosed and most of their problems are related to the resulting secondary polyglobulia. As they show a clearly longer survival compared with IPAH patients, their therapy has been largely empirical.5 Pregnancy and unnecessary surgery should be avoided. The empirical approach may associate domiciliary oxygen that has not shown a definite effect; anticoagulation that is still controversial; venosection, which may reveal a dangerously increased risk of thrombosis and emboli if the patient becomes iron-deprived; and diuretics. For more detailed descriptions, a recent review by Diller et al. describes these approaches extensively.5 None of these therapies is clearly directed to the pulmonary vascular lesions. Most of the so-called vasodilators can cause systemic hypotension and aggravate cyanosis (i.e. calcium channel blockers are not used). Recent data have shown that their exercise capacity and quality of life is not good. Finally, there is a certain attrition, calling for more directed therapy.9
Histopathological changes in the pulmonary vasculature of patients having PVD associated with CHD usually closely resemble those in IPAH.10 For these reasons, PAH-CHD (congenital cardiac shunts) is classified in the same group as IPAH in the revised clinical classification of pulmonary hypertension (Venice, 2003).11 As a result, treatment strategies applied in IPAH may also carry therapeutic potential for PAH-CHD patients. The dual endothelin receptor antagonist bosentan has emerged as a beneficial therapy in the treatment of patients with IPAH and PAH associated with systemic sclerosis. Increasing evidence suggests that endothelial dysfunction, as characterised by elevated endothelin (ET) expression,12 contributes to the development and maintenance of pulmonary hypertension in CHD patients,13 who may therefore benefit from bosentan therapy. Animal studies confirm this hypothesis.14 Bosentan therapy has indeed been shown to have beneficial effects in patients with PAH-CHD, with demonstrated improvements in World Health Organization (WHO) functional class, exercise capacity and haemodynamics. Promising results on the use of bosentan in patients with EP have also been obtained in a series of open-label studies.15–18
In the open-label study BREATHE-3, the pharmacokinetic, safety and tolerability profiles of bosentan were evaluated in 19 paediatric patients with IPAH or PAH-CHD.19 The results showed that the single- and multiple-dose pharmacokinetics of bosentan were comparable to those observed in healthy adults. Although the BREATHE-3 study was designed primarily to assess the pharmacokinetic and safety profile, improvements in mean pulmonary artery pressure and PVR were evident after 12 weeks of bosentan therapy. These data therefore suggest that bosentan both is well tolerated and may be an effective therapeutic option in the treatment of paediatric patients with IPAH or PAH-CHD.
Consistently, in another prospective, open-label, multicentre study, 33 adult patients with PAH-CHD treated with bosentan for a mean of 2.1±0.5 years showed significant improvements in 6-MWD, WHO class and right ventricular systolic pressure.20 In an uncontrolled study with 27 PAH-CHD patients (children and adults), six-minute walk distance (6-MWD), PVR and WHO class showed significant improvements after 15 months of bosentan therapy.21 A recent retrospective, observational study with 40 paediatric PAH patients treated for a mean of 12.7 months showed that children with IPAH were stabilised after treatment with bosentan or a combination of bosentan and epoprostenol.22 Children with PAH associated with other conditions significantly improved in WHO class with bosentan monotherapy.22 Gibert et al. showed in a small uncontrolled study that bosentan therapy was well tolerated and of benefit to paediatric patients with PAH-CHD.23 Rosenzweig et al. recently presented that the PAH-CHD subgroup of a large cohort of paediatric patients treated with bosentan showed clinical and haemodynamic benefit.24
Building upon this experience, the BREATHE-5 trial was initiated as the first randomised, controlled trial in patients with EP.25 At 16 weeks, significant improvements were observed in PVR and 6-MWD with no shunt aggravation, as evidenced by measures of oxygen saturation. These results showed that bosentan is an effective and well-tolerated treatment option in EP. A subgroup analysis of BREATHE-5 patients, the ASD (pre-tricuspid shunts) and the VSD-VSD/ASD (post-tricuspid shunts) was performed and showed that a favourable effect on exercise capacity was observed similarly in the two groups.26
However, caution should apply when evaluating such small groups of patients. An open-label extension to BREATHE-5 has recently shown that exercise capacity was maintained for at least six months, an important achievement given that exercise capacity is a predictor of hospitalisation and/or death in adult CHD patients and that patients with EP have the worst exercise capacity among these patients.9 However, long-term data are required to better define the role of bosentan in this difficult group of patients. Recently, d’Alto et al. presented their experience with 22 patients after one year of bosentan therapy and showed an improvement in clinical status exercise tolerance and pulmonary haemodynamics.16 However, Apolostopoulou showed that after two years, 6-MWD returned to baseline in a majority of patients, and thus questioned the potential long-term effect.28 Other medium- to long-term-effect studies should be published this year and will provide more information on this particular aspect. With respect to the safety of bosentan in clinical practice and in agreement with the European Agency for the Evaluation of Medicinal Product,29 a post-marketing surveillance programme (Tracleer PMS) was established in 2002. A total of 579 patients with PAH-CHD were included. Elevated liver aminotransferase values after bosentan initiation were recorded in 2.8% (IPAH: 8.4%). These data provide additional evidence of the safety of bosentan in PAH-CHD and confirm an excellent safety profile under daily practice conditions, but emphasise the need for careful monthly evaluation of liver enzymes.
In conclusion, bosentan seems promising for the Eisenmenger group of patients. These patients are at the extreme end of the spectrum of PAH-CHD (congenital cardiac shunts). The frequency is declining in developed countries as surgery is performed early in life, but remains a major problem for developing countries, where access to surgery is not so simple. Notwithstanding, 12,000 patients with Eisenmenger syndrome are thought to be alive in Europe. Patients with mildly increased PVR contraindicating surgery or patients with complex CHD (single-ventricle physiology, cavopulmonary anastomosis) may also benefit from therapies aiming at the de-remodelling of the pulmonary circulation. So far, no data are available in this group of patients, but studies are currently being performed that should bring additional knowledge and hope for these particular patients.