Endothelial Cell Dysfunction in Pulmonary Hypertension

ELIGIBILITY CRITERIA: Pilot: The pilot study will enroll two groups of individuals: 1) patients who have either IPAH or a secondary form known to have similar histopathology (PAH), and 2) age, gender, and race matched control subjects for each patient. Main: The main study will enroll three groups of individuals: 1) patients who have either IPAH or a secondary form known to have similar histopathology (PAH), 2) patients with PH ascribed to a nonvascular injury process, and 3) age, gender, and race matched control subjects for each PAH patient. Subjects must be at least 18 years of age and must be able to provide informed, written consent for participation in this study. There is no exclusion based on race or gender. INCLUSION CRITERIA FOR PULMONARY ARTERIAL HYPERTENSION PATIENTS: The inclusion criteria for this study are as follows: Patients diagnosed with IPAH Patients diagnosed with secondary pulmonary hypertension known to have histopathology similar to the primary form or PAH. Clinical conditions causing pulmonary hypertension with histopathology similar to the primary form are listed below. i. Eisenmenger Syndrome ii. Collagen vascular disease iii. Liver disease with portal hypertension iv. Toxin induced injury (anorexic agents, rapeseed oil) v. HIV disease vi. Sickle cell disease EXCLUSION CRITERIA FOR PATIENTS WITH PULMONARY ARTERIAL HYPERTENSION: Pregnant women (all women of childbearing age will be required to have a screening urine or blood pregnancy test) Age less than 18 years Inability to provide informed written consent for participation in the study Mean PA less than or equal to 25mmHg or PVR less than 3 wood units PCW greater than 16 mmHg unless increase accounted for by increased transpulmonary gradient greater than or equal to 10 mmHg Patients receiving more than 1 year of oral therapy or more than 6 months of IV therapy. INCLUSION CRITERIA FOR PATIENTS WITH NONVASCULAR INJURY-INDUCED PULMONARY HYPERTENSION: The inclusion criteria are as follows: Patients diagnosed with pulmonary hypertension not known to have histopathology similar to the primary form. Etiologies are listed below. Congenital or acquired valvular or myocardial disease Pulmonary parasitic diseases Arterial hypoxemia with hypercapnea COPD with hypoxemia and forced expiratory volume/forced vital capacity (FEV1/FVC) greater than 2 standard deviations from normal Interstitial lung disease with reduced total lung capacity greater than 2 standard deviations from normal and infiltrates on chest x-ray Pulmonary thromboembolic disease as evidenced by lung perfusion scan or pulmonary angiogram, or intravenous drug abuse Pulmonary hypertension due to congenital abnormalities of the lungs, thorax and diaphragm EXCLUSION CRITERIA FOR PATIENTS WITH NONVASCULAR INJURY INDUCED PULMONARY HYPERTENSION: Pregnant women (all women of childbearing age will be required to have a screening urine or blood pregnancy test) Age less than 18 years Inability to provide informed written consent for participation in the study Mean PA less than or equal to 25mmHg or PVR less than 3 wood units EXCLUSION CRITERIA FOR MRI IN SUBJECTS WITH PULMONARY HYPERTENSION: 1) Implanted cardiac pacemaker or defibrillator 2) Central nervous system aneurysm clips 3) Cochlear implants 4) Neural stimulator 5) Ocular foreign body (e.g. metal shavings) 6) Insulin pump 7) Metal shrapnel or bullets 8) Claustrophobia. Furthermore, the following patient groups will be excluded from studies involving the administration of MRI contrast agents: 1) lactating women 2) renal disease (CrCl less than 20 ml/min) The creatinine clearance (CrCl) will be calculated using the Cockroft formula where age is in years, kg is weight in kilograms, and Cr is the serum creatinine. If there is no history of kidney disease from the patient or referring physician, additional testing will not be performed. If a patient has a history of renal insufficiency, a recent blood Cr will be used unless the physician performing the test believes the Cr may have changed since the last test. If the Cr may have changed, a blood sample will be obtained for Cr or the subject will be excluded from receiving gadolinium. CrCl = (140-age) (wt in kg)/72 X serum Cr (mg/dl) for men CrCl = (0.85) (140-age) (kg)/72 X serum Cr (mg/dl) for women INCLUSION CRITERIA FOR CONTROL SUBJECTS: Any healthy man or woman who is the appropriate age, race, and gender for matching to a PAH patient No history of HIV infection EKG and echocardiogram with no evidence of clinically relevant heart disease Spirometry with no evidence of clinically relevant lung disease No history of causes of pulmonary hypertension such as collagen vascular disease, chronic liver disease with ALT or AST greater than 2 times the upper limit of normal or cirrhosis of the liver, chronic thromboembolic disease, congenital heart defects, or pulmonary parenchymal disease with hypoxemia No history of diseases thought to be related to development of endothelial dysfunction including systemic hypertension or diabetes requiring drug therapy, hypercholesterolemia and obesity No history of anemia, thrombocytopenia or coagulopathy No history of renal insufficiency No medical conditions requiring chronic medication use with the exception of: a. Heartburn, GERD b. Environmental allergies, post nasal drip or non-allergic rhinitis c. Asthma with no history of oral steroid use, weekly inhaled steroids, or hospitalization for asthma exacerbation d. Dermatologic conditions that do not require the use of oral steroids or other immunosuppressants e. Treated and stable thyroid disease, depression, or anxiety. No more than 20 cigarettes per years for the previous 2 years and no cigarette use for 30 days prior to the screening evaluation until completion of the study EXCLUSION CRITERIA FOR CONTROL SUBJECTS: Current pregnancy, lactation or women not currently using medically acceptable birth control. (All women of childbearing age will be required to have a screening urine or blood pregnancy test) Contraindication to MRI scanning including individuals with the following devices: A) Implanted cardiac pacemaker or defibrillator B) Central nervous system aneurysm clips C) Cochlear implants D) Implanted Neural stimulator E) Ocular foreign body (e.g. metal shavings) F) Insulin pump G) Metal shrapnel or bullet H) Claustophobia Contraindications to MRI contrast agent administration Inability to provide informed written consent for participation in the study Chronic, medically refractory atrial tacharrhythmias Symptoms of heart failure. Mean PA greater than 25mmHG or PVR greater than 1.5 wood units, or PCWP greater than 15 mmHg History of recreational drug use with the exception of marijuana. No marijuana use within 3 months of protocol screening through completion of the study. Intravenous drug abuse. Volunteers may be excluded if in the opinion of the study investigators they have a condition that may adversely affect the outcome of the study or the safety of the volunteer.