Bosentan (Tracleer®) is an endothelin receptor antagonist prescribed for the treatment of pulmonary arterial hypertension (PAH). Its use is limited by drug-induced liver injury (DILI). To identify genetic markers of DILI, association analyses were performed on 56 Caucasian PAH patients receiving bosentan. Twelve functional polymorphisms in five genes (ABCB11, ABCC2, CYP2C9, SLCO1B1, SLCO1B3) implicated in bosentan pharmacokinetics were tested for associations with ALT, AST and DILI. After adjusting for BMI, CYP2C9*2 was the only polymorphism associated with ALT, AST and DILI (β = 2.16, P = 0.024; β = 1.92, P = 0.016; OR 95% CI = 2.29 - ∞, P = 0.003, respectively). Bosentan metabolism in vitro by CYP2C9*2 was significantly reduced compared to CYP2C9*1 and was comparable to CYP2C9*3. These results suggest that CYP2C9*2 is a potential genetic marker for prediction of bosentan-induced liver injury and warrants investigation for the optimization of bosentan treatment.

Studies systematically comparing the performance of health-related quality-of-life (HRQL) instruments in pulmonary arterial hypertension (PAH) are lacking. We sought to address this gap by comparing cardiac and respiratory-specific measures of HRQL in PAH. We prospectively assessed HRQL in 128 patients with catheterization-confirmed PAH at baseline and at 6, 12, and 24+ months. Cardiac-specific HRQL was assessed using the Minnesota Living with Heart Failure Questionnaire (LHFQ); respiratory-specific HRQL using the Airways Questionnaire 20 (AQ20); and general health status using the 36-item Short Form physical component summary (SF-36 PCS). The LHFQ and AQ20 were highly intercorrelated. Both demonstrated strong internal consistency and converged with the SF-36 PCS. Both discriminated among patients based on World Health Organization functional class (FC), 6-minute walk distance (6MWD), and Borg Dyspnea Index (BDI), except for a potential floor effect associated with low 6MWD. The LHFQ was more responsive than the AQ20 to changes over time in FC, 6MWD, and BDI. In multivariate analyses, the LHFQ and AQ20 were each longitudinal predictors of general health status, independent of FC, 6MWD and BDI. In conclusion, both cardiac-specific and respiratory-specific measures appropriately assess HRQL in most patients with PAH. Overall, the LHFQ demonstrates stronger performance characteristics than the AQ20.

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