Exercise Induced Pulmonary Hypertension in Systemic Sclerosis and Treatment With Ambrisentan

• Change in distance walked in six minutes from baseline to 24 week [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]
• SF-36, HAQ-DI, and St. George's respiratory questionnaire total score from baseline to 24 weeks of therapy [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]

The purpose of this study is to determine the clinical characteristics and hemodynamic profiles that predict exercise induced pulmonary hypertension in 15 patients with systemic sclerosis. The study also aims to determine the effectiveness of Ambrisentan for subjects with exercise induced Pulmonary Arterial Hypertension (PAH) with scleroderma

The current literature addresses therapies for patients with resting PAH only, diagnosed by right heart catheterization. However, the World Health Organization (WHO) also recognizes and defines exercise induced pulmonary arterial hypertension (ex-PAH), which may precede the development of resting PAH. The natural progression of PAH, especially during exercise, has not been well delineated. An exercise hemodynamic study previously showed that in normal healthy subjects the mean pulmonary pressure does not exceed 30mmHg even at maximal cardiac outputs. A prior study evaluated exercise Doppler echocardiography systemic sclerosis patients with normal resting echocardiograms, finding an abnormal response which was defined as an estimated right ventricular systolic pressure greater than 40 mmHg. In the same study, 6.6% of the patients progressed to resting PAH over the followup period of 12 months. Limited data is available regarding the prevalence of ex-PAH in systemic sclerosis using right heart catheterization.

• Systemic Sclerosis
• Shortness of Breath
• Pulmonary Hypertension

Inclusion Criteria:

1. Systemic Sclerosis diagnosed by the American College of Rheumatology consensus statement including any of the following:

   • Limited
   • Diffuse
   • Sine Scleroderma
2. Patients must be willing and able to undergo right heart catheterization with lower extremity cycle ergometry
3. Mean pulmonary artery pressure (mPAP) > 30mmHg with exercise; PCWP ≤ 15mmHg on RHC at rest
4. Men and women, ages 18 years of age or older
5. Standard adjunctive medications will be allowed concurrently in this study at the discretion of the treating pulmonologist and rheumatologist, including digoxin, diuretics, anticoagulants (e.g. warfarin), stable immunosuppression or other anti-fibrotic therapy for at least one month prior to enrollment

Exclusion Criteria:

1. Resting PAH (mPAP > 25mmHg) on right heart catheterization
2. Other known causes of PAH including prior venous thromboembolism, HIV infection, chronic liver disease with portal hypertension, left ventricular systolic dysfunction (e.g. LVEF < 40%), and congenital causes of PAH
3. Severe hepatic disease precluding the use of ambrisentan (AST/ALT ≥3x ULN).
4. Women who are pregnant or breastfeeding.
5. Concurrent therapy with a prostanoid or prostanoid analogue, PDE5 inhibitors, or enrolled in another active clinical study.
6. Use of any prostacyclin or endothelial receptor antagonist (ERA) within 30 days before study entry.
7. Bed or wheel chair bound or a baseline 6-Minute Walk distance (6MWD) less than 150 meters.
8. Childbearing capable women who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period.
9. New York Heart Association (NYHA) Classification: Class IV
10. Renal dysfunction (serum creatinine >2.5mg/dL).
11. Uncontrolled sleep apnea.