Exercise Induced Pulmonary Hypertension in Systemic Sclerosis and Treatment With Ambrisentan

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.

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.