Endothelial Cell Dysfunction in Pulmonary Hypertension
|ClinicalTrials.gov Identifier: NCT00098072|
Recruitment Status : Completed
First Posted : December 3, 2004
Last Update Posted : March 29, 2018
|First Submitted Date ICMJE||December 2, 2004|
|First Posted Date ICMJE||December 3, 2004|
|Last Update Posted Date||March 29, 2018|
|Study Start Date ICMJE||December 1, 2004|
|Actual Primary Completion Date||July 8, 2009 (Final data collection date for primary outcome measure)|
|Current Primary Outcome Measures ICMJE
|Original Primary Outcome Measures ICMJE||Not Provided|
|Change History||Complete list of historical versions of study NCT00098072 on ClinicalTrials.gov Archive Site|
|Current Secondary Outcome Measures ICMJE||Not Provided|
|Original Secondary Outcome Measures ICMJE||Not Provided|
|Current Other Outcome Measures ICMJE||Not Provided|
|Original Other Outcome Measures ICMJE||Not Provided|
|Brief Title ICMJE||Endothelial Cell Dysfunction in Pulmonary Hypertension|
|Official Title ICMJE||Endothelial Cell Dysfunction in Pulmonary Arterial Hypertension: Biomarkers, Mechanisms of Disease and Novel Therapeutic Targets|
This study will examine and test healthy volunteers and patients with pulmonary hypertension to try to learn more about the disease and find better ways to detect, treat, and, if possible, slow progression. Pulmonary hypertension is a rare blood vessel disorder of the lung in which the pressure in the pulmonary artery (the blood vessel that leads from the heart to the lungs) rises above normal levels and may become life-threatening.
Normal volunteers and patients with pulmonary hypertension 18 years of age and older may be eligible for this study. All candidates are screened with a review of their medical records. Normal volunteers also have a medical history, electrocardiogram, echocardiogram (heart ultrasound), and pulmonary function test, in which the subject breathes in and out of a tube that measures lung volume, mechanics and function.
All participants undergo the following tests and procedures:
In addition to the above, patients whose pulmonary hypertension was caused by a blood vessel injury undergo the tests described below. The right heart catheter inserted for the catheterization procedure remains in place to obtain measurements of the effects of nitric oxide and nitrite in the following procedures:
In patients whose pulmonary hypertension was caused by a blood vessel injury, we also plan to follow response to standard therapy. After the initiation of standard therapy, we will restudy the same parameters (excluding NO and sodium nitrite studies) in these patients at approximately 4 months, and yearly for 5 years
Introduction: Primary pulmonary hypertension, now known as idiopathic pulmonary arterial hypertension (IPAH), a subgroup of pulmonary arterial hypertension (PAH), is a rare disorder characterized by severe morbidity and high mortality rates. There are no routine screening tests or validated markers of disease activity in IPAH, or the broader group of PAH. Therefore, patients usually present at advanced stages of disease. The pathogenesis of IPAH and other forms of PAH remain unclear. Prior theories stressed a "one-hit" hypothesis. Current thinking focuses on a "two-hit" hypothesis: 1) genetic susceptibility, and 2) a triggering stimulus that initiates pulmonary vascular injury, resulting in endothelial cell (EC) dysfunction and the mobilization of endothelial progenitor cells (EPC). Loss of function mutations in the bone morphogenetic protein receptor 2 (BMPR2) gene, has been implicated in the pathogenesis of IPAH. EC dysfunction in IPAH has been associated with decreases in both endothelial nitric oxide synthase (eNOS) expression and nitric oxide (NO) production. Peripheral blood mononuclear cells (PBMCs) interact with an altered endothelial cell surface, which may also be important in the disease process.
Objectives: We plan to define a subset of differentially regulated biomarkers in IPAH and PAH that may lead to earlier diagnosis and better methods for measuring responses to therapy. Specifically, we hope to identify biomarkers of IPAH and other forms of PAH that is suggestive of NO therapeutic response and which may be useful in titrating NO therapy. We also hope to identify novel targets for the development of new therapeutic strategies.
Methods: This study will consist of a pilot study and a primary study. The pilot study will enroll up to 30 patients and 30 controls in order to obtain completed studies on 10 normal subjects and 10 patients with PAH. The goal of the pilot study is to determine the best technique for circulating endothelial cell (CEC) and PBMC identification, quantification, and isolation and EPC identification and quantification. The subjects in the pilot phase undergo right heart catheterization to obtain hemodynamics and pulmonary artery blood. Pulmonary artery and peripheral blood will be used for EPC quantification and CEC and PBMC isolation. CECs and PBMCs will be studied in depth using high density oligonucleotide microarrays. In addition, plasma obtained from PAH patients and healthy volunteers will be applied in vitro to various cell populations suspected to be central to disease pathogenesis including but not limited to ECs, circulating mononuclear cells, cardiac myocytes and/or vascular smooth muscle cells. Phenotypic alterations induced by plasma exposure will be assessed using in vitro assays.
The primary study will recruit the following subject groups: 1) patients with IPAH and other forms of PAH (vascular injury-induced pulmonary hypertension) who currently are on no therapy, less than or equal to 6 months of IV therapy, or less than or equal to one year of oral therapy, 2) patients with pulmonary hypertension (PH) ascribed to a nonvascular injury process and 3) normal individuals. The following baseline studies will be performed in all groups: 1) noninvasive assessment of right ventricular (RV) function by echocardiogram and magnetic resonance imaging (MRI), 2) determination of exercise capacity by cardiopulmonary stress test and six minute walk, 3) measurement of hemodynamic parameters by right heart catheterization and 4) characterization of disease phenotype by cell surface markers, oligonucleotide microarrays, and proteomics using peripheral and pulmonary arterial blood. EPCs will be quantitated and CECs and PBMCs will be isolated and analyzed by flow cytometry for expression of cell surface markers involved in coagulation, adhesion, and angiogenesis, as these are important processes in IPAH and PAH. Furthermore, ECs (identified by positive and negative selection and isolated by cell sorting) and PBMCs will be studied in depth using high density oligonucleotide microarrays to more fully characterize their transcriptome.
A major impediment to the widespread use of chronic home based inhaled NO are related to its delivery system and duration of effects. In PAH patients we plan to study a novel NO delivery system (INO pulse delivery device). Patients with PAH will be given inhaled NO (20 and 40 ppm) and then placed on inhaled NO using the INO pulse delivery device for 24 hours. Hemodynamics will be obtained serially with each dose and upon completion of 24 hours of therapy, pulmonary artery and peripheral blood will be drawn and reexamined by flow cytometry, microarrays, and proteomics.
We also plan to follow response to standard therapy (as determined by the referring physician). After the initial day 0 studies, we will restudy the same parameters (excluding NO studies) in patients with PAH at approximately 4 months, and yearly for 5 years after therapeutic intervention.
|Study Type ICMJE||Interventional|
|Study Phase||Phase 1|
|Study Design ICMJE||Primary Purpose: Treatment|
|Condition ICMJE||Hypertension, Pulmonary|
|Study Arms||Not Provided|
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Completed|
|Actual Enrollment ICMJE
|Original Enrollment ICMJE
|Actual Study Completion Date||July 8, 2009|
|Actual Primary Completion Date||July 8, 2009 (Final data collection date for primary outcome measure)|
|Eligibility Criteria ICMJE||
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:
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.
EXCLUSION CRITERIA FOR PATIENTS WITH NONVASCULAR INJURY INDUCED PULMONARY HYPERTENSION:
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
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:
EXCLUSION CRITERIA FOR CONTROL SUBJECTS:
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.
|Ages||18 Years and older (Adult, Older Adult)|
|Accepts Healthy Volunteers||No|
|Contacts ICMJE||Contact information is only displayed when the study is recruiting subjects|
|Listed Location Countries ICMJE||United States|
|Removed Location Countries|
|NCT Number ICMJE||NCT00098072|
|Other Study ID Numbers ICMJE||050041
|Has Data Monitoring Committee||Not Provided|
|U.S. FDA-regulated Product||Not Provided|
|IPD Sharing Statement||Not Provided|
|Responsible Party||Not Provided|
|Study Sponsor ICMJE||National Institutes of Health Clinical Center (CC)|
|Collaborators ICMJE||Not Provided|
|PRS Account||National Institutes of Health Clinical Center (CC)|
|Verification Date||November 27, 2017|
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP