Background Pulmonary arterial hypertension (PAH) is a major complication of congenital heart disease (CHD), causing increase morbidity and mortality with age. Sustained increase in the pulmonary arterial pressure (PAP) may result in progressive pulmonary vascular remodelling and eventually lead to irreversible changes including extensive intimal injury, obliteration, adventitial fibrosis and smooth muscle cell proliferation. In recent years, insight into the pathogenesis of PAH has resulted in the development of therapeutic strategies for PAH including endothelin receptor antagonists, prostacyclin analogues and phosphodiesterase-5 inhibitors. Endothelin has a key role in the pathobiology of PAH, exerting vasoconstrictor and mitogenic effects by binding to two distinct receptor isoforms in the pulmonary vascular smooth musc-le cells. Bosentan, an orally active dual endothelin receptor antagonist, has been shown to improve exercise capacity, hemodynamics in patients with idiopathic, chronic thromboembolic, and connective tissue disease-associated PAH. However the data of efficacy and safety of bosentan in patients with CHD and PAH is limited.

Objective The present study aimed to investigate the efficiency and safety of dual endothelin receptor antagonist bosentan in patients with CHD and severe PAH.

Methods Between May 2008 and January 2011, a total of 18 patients with severe PAH secondary to left-to-right shunt CHD were treated with bosentan. All patients underwent cardiac evaluation, including reviewing medical history, physical examination, electrocardiogram and echocardiogram, and cardiac catheterization. The patients with IPAH or PAH secondary to valvular heart diseases, complex CHDs, heart failure (≥NYHA Class III) and other system diseases, and those who had a positive response during acute vasodilator test were excluded from this study. All the patients were treated with bosentan as well as digoxin, diuretics and warfarin for 6 months. Oral bosentan was initiated at 62.5 mg twice daily, increasing after 4 weeks to 125 mg twice daily thereafter in patients weighing > 40 kg and initiated at 31.25 mg twice daily, increasing after 4 weeks to 62.5 mg twice daily in patients weighing ≤40kg. Patients were assessed at 1-month intervals using physical examination, 6-minute walk test, complete blood count and blood biochemistry. Electrocardiogram, X-ray, echocardiogram and right heart catheterization were repeated 6 months after treatment with bosentan.

Results There were 6 males and 12 females with age ranging from 9 to 55 (28.7 ± 11.3) years in this series. The basic defects included atrial septal defect (ASD; n = 6), ventricular septal defect (VSD; n = 4) and patent ductus arteriosus (PDA; n = 8). The echocardiogram showed right ventricular diameter (RVD) of 26 ± 8 mm, tricuspid regurgitation speed (VP) of 5.0 ± 0.7 m/s, transtricuspid pressure gradient (PGTV) of 100 ± 26 mmHg, left ventricular end-diastolic diameter (LVEDD) of 37 ± 5mm, left ventricular end-diastolic volume (LVEDV) of 51 ± 21 ml and left ventricular ejection fraction (LVEF) of 0.71 ± 0.06. Right heart catheterization showed oxygen saturation (SaO2) of femoral artery blood of 88.7 ± 5.9%, systolic pulmonary artirial pressure (sPAP) of 115 ± 19 mmHg (1mmHg = 0.133kp), diastolic pulmonary arterial pressure (dPAP) of 63 ± 13 mmHg, mean pulmonary artery pressure (mPAP) of 81 ± 15 mmHg, pulmonary-to-systemic flow (Qp/Qs) ratio of 0.76 ± 0.24 and pulmonary vascular resistance (PVR) of 19.6 ± 7.7 Woods. Six months after treatment with bosentan, echocardiogram showed no significant changes in right ventricular diameter (24 ± 8 mm, P > 0.05), VP (4.7 ± 0.4 m/s, P > 0.05), PGTV (93.3 ± 13.7 mmHg, P > 0.05), LVEDD (39 ± 4 mm, P > 0.05), LVEDV (60 ± 20 ml, P > 0.05), and LVEF (0.72 ± 0.07, P > 0.05). However, 6-minute walk distance (6-MWD) increased from 353 ± 101 to 480 ± 81 m (P < 0.05). Although no significant changes were observed in sPAP (113 ± 15 mmHg, P > 0.05), dPAP (59 ± 14 mmHg, P > 0.05) and mPAP (78 ± 10 mmHg, P > 0.05), the SaO2 of femoral artery blood and Qp/Qs ratio were increased to 91.0 ± 3.2% (P < 0.05) and 1.02 ± 0.35 (P < 0.05), and PVR was decreased to 15.3 ± 3.6 Woods (P < 0.05), respectively at 6 months after treatment. There was no marked change in white blood cells, red blood cells, haemoglobin and platelet, urea nitrogen and creatinine, and transaminases in all but 2 who had a transient increase in transaminases at one month after being treated with bosentan.

Conclusions Bosentan was well tolerated and effective for improving exercise capacity and hemodynamics in patients with PAH secondary to CHD. Different to IPAH and PAH secondary to other diseases, bosentan therapy did not cause decrease in pulmonary arterial pressure but PVR and increase in Qp/Qs ratio.