Ranolazine and Pulmonary Hypertension

This study is looking to enroll patients with pulmonary hypertension (PH). PH is abnormally
high blood pressure in the arteries of the lungs. It makes the right side of the heart need
to work harder than normal and is usually caused by a narrowing of the small arteries of the
lung. This narrowing makes it harder for the right side of the heart to circulate the blood
to the lungs. Over time, the right side of the heart may become enlarged and symptoms (such
as angina [chest pain] shortness of breath, fatigue, edema) begin to appear.

Ranolazine is a safe, well-tolerated, and FDA-approved medication for the treatment of
chronic stable angina. Ranolazine may potentially improve blood flow to the right ventricle
(RV), thereby relieving angina while simultaneously improving RV performance and
contractility. This latter effect may increase stroke volume and cardiac output which could
translate into benefits in exercise capacity and improved quality of life.

The purpose of this single center, non-randomized, prospective pilot study is to investigate
the effects of 3 months treatment with ranolazine on pulmonary artery hemodynamics, exercise
capacity and quality of life in patients with PAH and symptoms of angina or angina
equivalent.

Inclusion criteria:

1. World Health Organization (WHO) Group 1 PAH, defined as a pulmonary hypertension with
mean pulmonary artery pressure > 25 mmHg, pulmonary capillary wedge pressure < 15
mmHg, and pulmonary vascular resistance > 3 Wood units.

2. Right ventricular dysfunction, defined as RV fractional area change < 32% or RV
tricuspid annular plane systolic excursion (TAPSE) < 15 mm.

3. Symptoms of angina or angina equivalent (exertional dyspnea, exertional epigastric
pain, exertional nausea).

4. New York Heart Association functional class II or III symptoms.

5. Stable doses of pulmonary vasodilators (prostacyclins, endothelin receptor
antagonists, phosphodiesterase inhibitors), with no new therapy initiation or dose
escalation > 50% in the 4 weeks prior to randomization.

6. Age 18-80 years.

Exclusion criteria:

1. Acute coronary syndrome or coronary revascularization within the prior 3 months.

2. Patients with unstable angina.

3. Patients with Class IV congestive heart failure.

4. Planned revascularization, pacemaker or defibrillator placement during the study
period.

5. Changes in antianginal medical therapy likely to occur during the study period.

6. Corrected QT interval measurement >500 ms.

7. Patients with pre-existing QT prolongation (including congenital long QT syndrome) or
receiving other QT prolonging drugs (including Class Ia—e.g., quinidine, Class
III—e.g., dofetilide, sotalol, antiarrhythmics; antipsychotics (e.g., thioridazine,
ziprasidone), or known history of complex ventricular arrhythmias requiring
antiarrhythmic medications or ICD implantation.

8. Patients with known history of hepatic dysfunction.

9. Current use of strong CYP3A inhibitors, including ketoconazole, itraconazole,
clarithromycin, nefazodone, nelfinavir, ritonavir, indinavir, saquinavir and
diltizaem.

10. Patients with pacemakers, cochlear implants, aneurysm clips, who have worked with
metal.

11. Patients with metallic hardware, implants, or prostheses will consult with the
radiologist/cardiologist prior to the study.

12. Patients with severe or end stage renal disease (an estimated GFR < 30 mL/min/1.73 m).

13. Women who are pregnant or lactating

14. Any contraindications for the use of a right heart catheter including, but not limited
to:

- Pulmonic or tricuspid valve stenosis

- Prosthetic pulmonic or tricuspid valve

- Right atrial or ventricular masses

- Previous pneumonectomy

- Risk of severe arrhythmias, including left bundle branch block (LBBB)

15. Subjects unable to perform cardiopulmonary exercise testing will be excluded (i.e.
extensive musculoskeletal disease)