This is a single center, open-label trial designed to assess the safety and efficacy of ranolazine (Ranexa) in patients with pulmonary hypertension associated with left ventricular diastolic dysfunction. All patients will receive active drug. The study includes a screening period, 6 month treatment period and a follow up period. Eligible patients who provide informed consent and who meet all inclusion/exclusion criteria will be enrolled in this study.

There is neither proven therapy for patients with diastolic dysfunction-associated pulmonary hypertension nor for patients with diastolic dysfunction alone. Ranolazine, an inhibitor of cardiac repolarization (sodium channels), could represent a new and effective treatment of this entity.

This single center, prospective, open-label trial to assess the safety and efficacy of ranolazine in subjects with pulmonary hypertension associated with left ventricular diastolic dysfunction includes a screening period, 6 month treatment period and a follow up period. Eligible subjects who provide informed consent and who meet all inclusion/exclusion criteria will be enrolled in this study. All subjects will receive active study drug. There is no placebo group or use of control subjects. Treating will begin with 500mg twice daily and increased to 1000mg twice daily as tolerated after 2wks; the tolerated dose will be used for the remainder of the Treatment Period. Ranolazine will be limited to 500 mg BID in patients taking moderate inhibitors of CYP3A, including diltiazem, verapamil, aprepitant, erythromycin, fluconazole, grapefruit juice or grapefruit-containing products. During the Treatment Period subjects will be provided bottles of study medication to take home. Throughout the Treatment Period, subjects will return to the clinic for safety and/or efficacy assessments as well as resupply of Study Medication. Once the Treatment Period is complete, subjects will return to the clinic for a Follow-Up visit 14 days after the last dose of study medication, for a final safety assessment. Other therapies or possibly extension of the ranolazine treatment may be considered after completion of the Treatment Period at the discretion of the Investigator and will be recorded at the follow-up visit. Subjects who continue taking ranolazine (as part of there clinical care), will be asked to return for a 1 year follow up visit for safety and efficacy assessments.

As part of Amendment 2 (submitted November 2013), subjects who continue on ranolazine after the 6 month treatment period (as part of their clinical care) will be asked to return for further follow-up testing to better assess the safety and efficacy of the drug. The visit can be conducted once the patient has been on drug for a total of one year or greater (including the 6 month treatment period). This would replace the 1 Year follow-up visit for subjects who have not yet completed the visit and will be an additional visit for those subjects who have.

Subjects can opt to continue on ranolazine regardless of if they agree to complete the Post Treatment Follow up visit. They do not have to continue with the study after the treatment phase has been completed in order to stay on ranolazine. The PI and study personnel will complete the required forms for the Ranexa Connect application if patient wishes to stay on drug. The Ranexa Connect Program assists patients in obtaining insurance coverage of ranolazine and financial assistance if needed.

This is a 6 month, single center, prospective, open-label trial. All subjects will be receiving active treatment, ranolazine at doses approved by the FDA. Subjects will begin treatment at 500mg twice daily and increase to 1000mg twice daily as tolerated after 2 weeks. Subjects will take study drug twice daily with or without food. Ranolazine will be limited in subjects taking CYP3A including diltiazem, verapamil, arprepitant, erythromycin, fluconazole, grapefruit juice or grapefruit juice containing products. The study will consist of 3 periods: a screening period, a treatment period, and a follow-up period.

Subjects will be asked to come to the study center for 9-10 visits over the course of 6 months. Other therapies or possibly extension of the ranolazine treatment may be considered after completion of the treatment period at the discretion of the Investigator at the follow up visit. Subjects who continue on ranolazine after completion of the treatment period of the study will be asked to return for follow up testing.

Inclusion Criteria:

• Written consent prior to any study procedure
• Men or women, ages 18 to 75 years
• Suspicion of Pulmonary Hypertension by echo (RVSP ≥ 50mmHg) or diagnosis of Pulmonary Hypertension by cardiac cath (mPAP ≥25 mmHg at rest)
• LVEF ≥50%, (by ECHO, radionuclide imaging, or cardiac cath)
• 6MWT distance ≥150m and ≤450m at both time points within the Screening Period
• NYHA/WHO functional class II-III
• RHC measurements on Study Day 1: 1) mean pulmonary artery pressure (MPAP) ≥25 mmHg; 2) pulmonary artery occlusion pressure (PAOP) ≥18 mmHg and ≤30 mmHg; 3) pulmonary artery diastolic pressure (PADP) - PAOP ≤10 mmHg

Exclusion Criteria:

• Presence or history of any of the following cardiovascular co-morbidities or conditions: Hypotension at Screening (defined as a resting SBP≤90mmHg). Hypertension at Screening (defined as resting SBP ≥200mmHg), Unstable cardiovascular disease including paroxysmal atrial fibrillation or unstable angina, Amyloidosis, hypertrophic obstructive cardiomyopathy, restrictive cardiomyopathy, or constrictive pericarditis, History of myocardial infarction, coronary artery bypass graft surgery, or percutaneous cardiac intervention, Significant valvular heart disease, Cerebrovascular accident or transient ischemic attack
• Exercise tolerance limited by non-cardiac causes (exercise-induced asthma, malignancy, obesity, musculoskeletal disorder).
• Clinically significant psychiatric, addictive (DSM-IV criteria), neurologic disease or condition that would compromise his/her ability to give informed consent, participate fully in this study, or prevent adherence to the protocol
• Any other condition or co-morbidity that, in the opinion of the Investigator, would compromise his/her ability to give informed consent, participate fully in this study, or prevent adherence to the protocol
• Clinically significant laboratory abnormalities, including: Positive Hep B surface antigen or Hep C antibody, Positive HIV test within one year of Study Day 1, Serum alanine aminotransferase (ALT) ≥ 2.0 x ULN, Total bilirubin ≥ 1.2 x ULN (unless evidence of Gilbert's syndrome). Serum creatinine ≥ 2.5mg/dL (or calculated creatinine clearance less than or equal to 30mL/min). Hemoglobin less than or equal to 10g/dL (subject may qualify for the study following diagnosis and treatment of anemia, if the anemia is due to iron and/or vitamin deficiency).

Patients with moderate or severe hepatic impairment (Child-Pugh Classes B or C) or requiring hemidialysis.

• Subject has received any other investigational medication within the 30 days prior to Screening
• Prior treatment with ranolazine
• Pregnancy or lactation
• Women of childbearing potential and men without vasectomies who are not using barrier method of contraception
• Subject has the presence, or history, of malignancy that required significant medical intervention within the preceding 3 months and/or is likely to result in death within the next 2 years (exception of basal cell, non-metastatic squamous cell carcinoma of the skin, and carcinoma in-situ of the cervix)
• Treatment for pulmonary hypertension with epoprostenol (Flolan), treprostinil (Remodulin), iloprost (Ventavis), bosentan (Tracleer), ambrisentan (Letairis), sildenafil (Revatio), tadalafil (Adcirca). The use of sildenafil, tadalafil, or vardenafil is prohibited for any reason within 7 days of hemodynamic assessments on Days 1 and 180).
• Patients with QTc > 500 msec at baseline
• Treatment with potent CYP3A inhibitors, including ketoconazole, itraconazonle, clarithromycin, nefazodone, nelfinavir, indinavir, & saquinavir
• Treatment with CYP3A inducers, including rifampin, rifabutin, rifapentin, phenobarbital, phenytoin, carbamazepine, and St. John's wort.

180 Days

Small sample size; not all subjects completed Day 180 assessments