A Study of Ranolazine Acute Administration and Short Term Administration in Pulmonary Arterial Hypertension

Pulmonary arterial hypertension is a medical disorder in which pressure in the blood vessels
going from the right side of the heart to the lungs is higher than normal. The increased
blood pressure in the lungs places a strain on the heart. This strain causes the heart to
pump less blood into the lungs, causing physical symptoms of shortness of breath and
tiredness. The added strain to the heart can cause physical symptoms of swelling in the feet
and abdomen. These symptoms can get worse over time due to the decreased pumping ability of
the heart.

This study will use a drug called ranolazine. This drug has been approved by the Food and
Drug Administration (FDA) to treat chronic angina (chest pain). However, since it has not
been approved for use in PAH its use in this study is considered experimental.

Inclusion Criteria:

- All subjects age 18-72 yrs will have a diagnosis of PAH. PAH as defined as idiopathic
PAH, heritable PAH or PAH associated with collagen vascular disease, congenital heart
disease (repaired), or anorexigen use. A history of PAH as defined by hemodynamics at
diagnosis by right heart catheterization defined as: mean PAP >25 mmHg with a normal
PCWP < 15 mm Hg at rest and a PVR >3 Wood units.

- Baseline 6MW >150 meters

- Patients will be receiving FDA approved PAH monotherapy or dual therapy medications:
including, ambrisentan (5,10mg), sildenafil (60-240mg), tadalafil (40mg),
epoprostenol, treprostinil, or iloprost at stable doses for >90days.

- Receiving conventional therapy as clinically indicated (oxygen, calcium channel
blockers, digoxin) with dose that is unchanged in the preceding 30 days prior to
enrollment. This is excluding anticoagulants (warfarin) as the patient's dose may not
be stable if the patient is having a cardiac catheterization at baseline within 30
days of enrollment and warfarin is being held.

Exclusion Criteria:

- PAH Category II-IV and Category I associated with all other etiologies: HIV,
portopulmonary disease

- All subjects on monotherapy calcium blockers as "calcium blocker responders"
irrespective of therapy

- All subjects receiving CY3P4 inducer (i.e. bosentan)

- Subjects with pulmonary hypertension due to significant interstitial lung disease,
chronic obstructive pulmonary disease, congestive heart failure, valvular heart
disease

- Subjects with (World Health Organization (WHO) functional Class I or Class IV

- Subjects with total lung capacity (TLC) < 60% of predicted

- Subjects with significant obstructive lung disease with FEV1/FVC ratio < 70% of
predicted

- Subjects with hypotension defined as systolic arterial pressure < 90 mmHg at baseline

- Subjects with hypertension defined as systolic arterial pressure >140 mmHg at
baseline and a diastolic arterial pressure > 90 mmHg despite adequate medical
therapy.

- Subjects with impaired renal function as defined as estimated glomerular filtration
rate (eGFR) less than 45 mL/min/BSA (where BSA=1.73m2) as calculated by the
Modification of Diet in Renal Disease (MDRD) equation:

Patients with eGFR 45-50 mL/min/BSA may be enrolled only after discussion with data safety
monitoring board. Patients with eGFR ≥ 50 mL/min/BSA may be enrolled without such a
discussion.

- Subjects with liver function tests (transaminases (AST/ALT), total bilirubin, and
alkaline phosphatase) >2X normal values

- Subjects with acutely decompensated heart failure requiring hospitalization or
medication adjustment or hospitalization for any cause within the previous 30 days
prior to screening

- Subjects may not be receiving any other investigational agents

- Subjects with left ventricular ejection fraction <45% or left ventricular shortening
fraction <0.2

- Subjects with acute myocardial infarction within 90 days prior to screening

- Subjects taking nitrates for any medical problem

- Subjects with a recent (<180 days) history of pulmonary embolism verified by
ventilation/perfusion scan, angiogram or spiral CT scan

- Pregnant or lactating women

- Subjects with a history of current drug abuse including alcohol

- History of gastric bypass surgery

- History of sinus or atrioventricular nodal disease ie. sick sinus syndrome, or second
or third degree heart block.