Introduction: Vasoconstrictive endothelin signaling is not limited to idiopathic pulmonary arterial hypertension, but has also been implicated in pulmonary hypertension due to valvular heart disease. The efficacy and safety of endothelin receptor antagonists in these patients is unknown. We investigated the effects of bosentan in patients with transthoracic echocardiographic (TTE) evidence of pulmonary hypertension due to mitral stenosis associated with rheumatic fever.
Methods: This was a prospective, single-center, open-label, uncontrolled study of bosentan in outpatients with uncorrected mitral stenosis due to rheumatic fever. The primary endpoint was exercise capacity at six months, as determined by six-minute walking distance (6MWD) and maximal oxygen uptake (VO₂max). Secondary endpoints were the BORG dyspnea index (BDI), echocardiographic left ventricular ejection fraction (LVEF) and pulmonary arterial pressure (PAP), serum pro-brain natriuretic peptide (proBNP), and adverse events at six months.
Results: Ten patients (eight females; mean age 75 years) were enrolled. Bosentan was well tolerated by nine, whereas one withdrew from treatment. By intention-to-treat analysis, bosentan resulted in a marked increase in 6MWD (+32 m, p=0.015), but a significant reduction in VO₂max (-0.45 mL/min/kg, p=0.011). Peak PAP did not change significantly, but mean PAP dropped by 16% (p=0.03) and LVEF increased by 6.5% (p=0.003). Profound reductions were observed in BDI and serum proBNP (-67% and -37%, p=0.002 and p=0.011, respectively). Adverse events included minor reductions in body mass and hematocrit.
Conclusion: The results of this pilot study suggest that endothelin receptor antagonism improves the functional status of patients with TTE evidence of pulmonary hypertension due to valvular heart disease. Randomized controlled trials are needed to confirm the results.