The primary objectives of this exploratory study are to evaluate the effects of bosentan on hemodynamics (via cardiac catheterization) during exercise in patients with Pulmonary Arterial Hypertension (PAH) who have abnormal hemodynamics during exercise but normal hemodynamics at rest. The authors hypothesize that early treatment may change the course of disease progression by improving hemodynamics during exercise, thus delaying disease progression.

Inclusion Criteria:

• Men or women ≥ 18 years of age

• For female patients, only non-pregnant women who are surgically sterile, postmenopausal or have documented infertility (over 50 years of age and amenorrheic for at least 1 year), or those of childbearing potential using one of the following methods of contraception:

  • Barrier-type devices (e.g., condom, diaphragm) used ONLY in combination with a spermicide. A double-barrier method is recommended.
  • Intrauterine devices (IUDs)
  • Oral contraceptives, if used in combination with a barrier method

• Body weight of 40 kg or higher

• Patients diagnosed with connective tissue disease

• Hemodynamics at rest, based on cardiac catheterization, should be as follows:

  • Mean pulmonary arterial pressure (mPAP) : 18 - 25 mmHg
  • PCWP ≤ 15 mmHg

• Hemodynamics during exercise, based on cardiac catheterization, should be as follows: mPAP > 30 mmHg

• Provide written informed consent

Exclusion Criteria:

• PAH associated with any other condition
• Severe obstructive lung disease : FEV1∕ FVC <0.5
• Total lung capacity <60% of normal predicted value
• Unable or unwilling have a cardiac catheterization procedure
• Acute or chronic impairment (other than dyspnea), limiting the ability to comply with study requirements (6-MWT)
• Psychotic, addictive or other disorder limiting the ability to provide informed consent or to comply with study requirements
• Moderate to severe hepatic impairment, i.e., Child-Pugh Class B or C
• AST and ∕or ALT > 3 times uln
• Hemoglobin concentration > 25% below the lower limit of normal
• Systolic blood pressure < 85 mm Hg
• Pregnancy or breast-feeding
• Treatment or planned treatment with another investigational drug
• Treatment with an endothelin receptor antagonist, phosphodiesterase type 5 inhibitor, or with prostanoids (excluding acute administration during a catheterization procedure to test vascular reactivity) within 2 months of inclusion
• Treatment with calcineurin-inhibitors (i.e., cyclosporine A and tacrolimus), fluconazole, glibenclamide (glyburide) within 1 week of study start;
• Known hypersensitivity to bosentan or any of the excipients