Natural History Study of Biomarkers in Pulmonary Arterial Hypertension

  • End date
    Dec 31, 2030
  • participants needed
  • sponsor
    National Institutes of Health Clinical Center (CC)
Updated on 18 September 2023
pulmonary function test
walk tests
pulmonary arterial hypertension
left ventricular end-diastolic pressure
Accepts healthy volunteers


  • High blood pressure in the lungs, known as pulmonary arterial hypertension (PAH), is a rare disorder. Some people have disease-associated PAH and some have PAH from an unknown cause. Researchers want to follow the natural history of all PAH patients to understand how PAH progresses in order to discover targets for future research into new treatments. To further identify treatment targets, they will compare healthy volunteers to patients with PAH.
  • To study the natural history of PAH.
  • Individuals at least 18 years of age who have PAH.
  • Healthy volunteers at least 18 years of age.
  • Participants with PAH will have periodic visits to the National Institutes of Health Clinical Center. After the first visit, they will return in 6 months and then yearly or every other year for as long as the study continues.
  • The first visit will take up to 3 days. It will involve the following tests:
  • Physical exam and medical history
  • Blood and urine samples
  • Heart and lung function tests and imaging studies
  • Six-minute walk test
  • Questions about exercise and physical activity
  • Healthy volunteers will have only one visit to the Clinical Center, during which they will undergo screening tests, and complete many of the same tests as patients with PAH



Pulmonary arterial hypertension (PAH) is a rare disorder associated with poor survival. Endothelial dysfunction resulting from 1) genetic susceptibility, and 2) a triggering stimulus that initiates pulmonary vascular injury, the two-hit hypothesis, appears to play a central role both in the pathogenesis and progression of PAH. Inflammation appears to drive this dysfunctional endothelial phenotype, propagating cycles of injury and repair in genetically susceptible patients with idiopathic PAH (IPAH) and patients with disease-associated PAH. However, despite mounting evidence of vascular inflammation in patients with PAH, detailed phenotypic studies are lacking on the temporal evolution of this process and its contribution to right ventricular (RV) and pulmonary vascular remodeling. We hypothesize that a detailed characterization of the temporal evolution of vascular inflammation in PAH and its impact on RV and pulmonary vascular function will add prognostic value to traditional measures of disease severity and suggest novel therapeutic targets for future research.


Patients with IPAH and disease-associated PAH will be recruited to the NIH and enrolled in this natural history study investigating the ability of circulating markers of vascular inflammation as well as high-resolution cardiac magnetic resonance imaging (MRI) to accurately stage severity of disease and/or predict clinically relevant outcomes.


The total population for the study will be 150 PAH subjects and approximately 55 age and gender matched controls (i.e. each healthy volunteer is matched to less than or equal to 3 PAH subjects).

PAH subjects will undergo 1) standard clinical examinations including 6-minute walk distance and echocardiography; 2) cardiopulmonary exercise testing; 3) markers of coagulation and fibrotic disease; 4) plasma profiling of inflammatory

markers; 5) gene expression profiling of peripheral blood mononuclear cells PBMCs); 6) high-resolution MRI-based determination of pulmonary vascularand RV structure and function and 7) Cardiac CT scan.

Plasma markers of endothelial inflammation, PBMC expression profiles, and high-resolution cardiac MRI will also be studied in age and gender matched controls to define normal ranges and variability for each of these novel assessments. Comparison of these results to PAH subjects at baseline will be used to determine the degree to which these investigative tests distinguish PAH patients from healthy subjects. Likewise, baseline clinical evaluations of PAH subjects will be used to examine whether any novel test (inflammatory markers, or cardiac MRI), accurately classifies patients according to their disease severity. In addition, these tests will be investigated prospectively for their ability to predict PAH disease progression. Disease progression will be defined prospectively as a decrease in the 6-minute walk distance of greater than or equal to10% from baseline or clinical worsening requiring an escalation in therapy, hospitalization due to right heart failure, transplantation or death.

Additional plasma will be collected from PAH subjects and age/gender matched control subjects. This material will be used to probe for new biomarkers and inflammatory factors using discovery based approaches (i.e. Proteomics and pulmonary artery endothelial cell bioassay).

Condition Pulmonary Disease, Pulmonary Hypertension
Clinical Study IdentifierNCT01730092
SponsorNational Institutes of Health Clinical Center (CC)
Last Modified on18 September 2023


Yes No Not Sure

Inclusion Criteria

The following parameters on RHC are required to meet the hemodynamic definition of PAH
mean pulmonary artery pressure of greater than 25 mmHg at rest
pulmonary capillary wedge pressure of less than or equal to 15 mmHg (or a left
pulmonary vascular resistance of greater than 3 Wood units (240 dyn s cm(5))
ventricular end-diastolic pressure of less than or equal to 12mmHg) and
For patients with suspected PAH (Group I PH) who have not undergone a RHC and/or additional
testing to confirm the diagnosis, this testing will be completed as clinically indicated
under a procedural consent. If clinically indicated (diagnostic) testing indicates that the
subject with suspected PAH does not in fact meet standard criteria for PAH (Group I PH)
then the subject will be removed from the study

Exclusion Criteria

Pregnant or breastfeeding women (all women of childbearing potential will be required
Age less than 18 years
to have a screening urine or blood pregnancy test)
Inability to provide informed written consent for participation in the study
Inclusion Criteria for Control Subjects
Any healthy man or woman who is the appropriate age and gender for matching to a PAH
Must be eligible for MRI and Gadolinium Based MRI studies
Must be eligible for CT and Iodine Based Contrast CT studies
Exclusion Criteria for Healthy Control Subjects
Electrocardiographic evidence of clinically relevant heart disease
Current pregnancy or breastfeeding (All women of childbearing potential will be
Symptoms of coronary or cardiac insufficiency
required to have a screening urine or blood pregnancy test)
More than one major risk factor for coronary artery disease (excluding age and gender)
Obesity (defined as a body mass index > 30 kg/m(2))
Anemia, thrombocytopenia or coagulopathy
History of underlying conditions/risk factors associated with pulmonary hypertension
such as collagen vascular disease, HIV infection, use of appetite suppressants
chronic liver disease or cirrhosis of the liver, chronic thromboembolic disease
Inability to provide informed written consent for participation in the study
congenital heart defects, hypoxemia and/or significant pulmonary parenchymal disease
Systemic hypertension that is not well controlled (i.e. blood pressure at the time of
Exclusion Criteria for MRI in Healthy Control Subjects and Subjects with PAH
screening greater than or equal to140/90 mmHg) in adults < 60 years old or greater
than or equal to 150/90 mmHg in adults 60 years or older) on medications. Subjects
taking > 2 anti-hypertensive medications will be excluded irrespective of their
Implanted cardiac pacemaker or defibrillator
current blood pressure at time of screening
Cochlear Implants
Ocular foreign body (e.g. metal shavings)
Renal insufficiency (defined as an estimated glomerular filtration rate of < 60
Embedded shrapnel fragments
mL/min/1.73m(2) of body surface area)
Central nervous system aneurysm clips
Active tobacco use (> 6 months) in the past ten years, any tobacco use within 3 months
Implanted neural stimulator
prior to the screening evaluation or any tobacco use prior to completion of the study
Any implanted device that is incompatible with MRI
History of recreational drug use with the exception of marijuana (as long as marijuana
Subjects requiring monitored sedation for MRI studies
use was > 3 months from the time of study screening)
These contraindications include but are not limited to the following devices or conditions
Exclusion Criteria for Gadolinium Based MRI Studies Only
obesity, claustrophobia, etc.)
Exclusion Criteria for Iodine Based Contrast CTA Studies Only
Unsatisfactory performance status as judged by the referring physician such that the
Serum creatinine > 1.4 mg/dL
subject could not tolerate an MRI scan. Examples of medical conditions that would not
History of multiple myeloma
be accepted would include unstable angina and severe dyspnea at rest
Subjects with a condition precluding entry into the scanner (e.g. morbid obesity
claustrophobia, etc.)
Subjects with severe back-pain or motion disorders who will be unable to tolerate
supine positioning within the MRI scanner and hold still for the duration of the
History of severe allergic reaction to gadolinium contrast agents despite pre-
medication with diphenhydramine and prednisone
Chronic kidney disease (an estimated glomerular filtration rate of < 60
mL/min/1.73m(2) of body surface area)
Exclusion Criteria for Cardiac Computed Tomography in Healthy Control Subjects and Subjects
with PAH
) Subjects with a condition precluding entry into the scanner (e.g. morbid
Use of metformin-containing products less than 24 hours prior to contrast
History of significant allergic reaction to CTA contrast agents despite premedication
with diphenhydramine and prednisone
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