Clinical trial NCT04489251: Assessment of the TGF-beta Pathway and Micro-RNA in Pediatric Pulmonary Arterial Hypertension
Official title: Assessment of the TGF-beta Pathway and Micro-RNA in Pediatric Pulmonary Arterial Hypertension
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: Pulmonary Arterial Hypertension
Keywords: pulmonary arterial hypertension
TGF-beta pathway
microRNA
Lead sponsor: Medical College of Wisconsin
Sponsor class: OTHER
First posted: 2020-07-28
Enrollment: 40
Sex: ALL
Minimum age (years): 2
Maximum age (years): 17
Standard ages: CHILD
Observational model: CASE_CONTROL
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Subjects with previously confirmed or suspected to have pulmonary arterial hypertension (PAH) that are undergoing a clinically indicated cardiac catheterization (for diagnostic evaluation) ages 2-17 years are eligible for participation.

Control subjects undergoing a catheterization as part of an intervention such as atrial septal defect closure or patent ductus arteriosus closure and have a routine right heart catheterization as a part of that procedure and meet inclusion criteria.

Brief summary: This is a prospective pilot study to assess the plasma levels of particular proteins involved in the transforming growth factor beta (TGF-β) pathway and its down stream regulators, CHIP, as well as micro RNA molecules in subjects with pulmonary arterial hypertension (PAH) and compare them to control subjects without PAH to see if they can be used as a diagnostic or prognostic marker of PAH and how this compares to other diagnostic biomarkers N-terminal pro-natriuretic peptide (NT Pro-BNP) and C-reactive protein (CRP).

Detailed description: Aim 1: This study will correlate proteins in the TGF- β signaling pathway and micro RNA levels with invasive (catheterization) and non-invasive (echocardiography) measurements of pulmonary artery pressures to assess for the presence and severity of PAH and compare these measurements to the established biomarkers of NT Pro BNP and CRP levels.

Hypothesis 1: Plasma levels of proteins of the TGF-β pathway; bone morphogenic protein (BMP) 2, 4, 6, 7, 9 and 10 along with activin A and TGF-β1 protein as well as CHIP (carboxyl-terminus of Hsp70-intracting protein), an enzyme that regulates the activations and exports of TGF- β to the nucleus will be significantly different in subjects with PH over control subjects.

Hypothesis 2: Plasma levels of proteins in the TGF- β pathway; BMP 2, 4, 6, 7, 9 and 10 along with activin A and TGF-β1 protein as well as CHIP will show better correlation with the presence of PAH and its severity than NT-Pro BNP and CRP levels.

Hypothesis 3: The micro-RNA profiles in plasma will be significantly different in subjects with PAHPH over control subjects.

Aim 2: To correlate protein/micro-RNA levels with clinical status in PAH subjects as assessed by functional status, exercise testing, and PAH drug regimen to determine if they can correlate with disease severity.

Hypothesis 1: Clinical findings in PAH patients will correlate with disease severity and study proteins and micro-RNA levels better than established biomarkers.

Aim 3: To correlate evidence of genetic abnormalities through whole exome sequencing especially in regions known or suspected to cause PAH (e.g. BMPR2, ENG, and ALK1 mutations), within the TGF-β pathway or lung development with the tested protein/micro-RNA levels.

Hypothesis 1: Genetic evaluation of patients with PAH will show abnormalities within the TGF-β pathway or lung development.

Eligibility criteria: Inclusion Criteria:

* Pediatric subjects ages 2-17 years
* Subjects undergoing a clinically indicated cardiac catheterization.
* Subjects with proven or being evaluated for pulmonary hypertension in WHO classification group 1 or 3†
* Subjects will be categorized as PAH subjects if they meet the hemodynamic criteria: pulmonary artery pressure \>20mmHg, pulmonary vascular resistance index \>3 Woods units\*m2, and wedge pressures \<15mmHg.
* Subjects can be categorized as control subjects if they do not have PH on catheterization and do not meet any exclusion criteria.

Exclusion Criteria:

-

Primary outcomes:
measure: Plasma levels of BMP proteins of the TGF-β pathway
timeFrame: One day
measure: Plasma Activin A and TGF-β1 level of the TGF-β pathway
timeFrame: One day
measure: Plasma CHIP levels assessment in PH patients and control subjects.
timeFrame: One day
Secondary outcomes:
measure: Plasma levels of proteins in the TGF- β pathway and PH disease severity
timeFrame: One day
measure: MicroRNA levels in PH vs control subjects
timeFrame: One day
measure: Clinical findings correlation with study proteins/microRNA
timeFrame: One day
measure: Whole exome sequence analysis in PH patients and protein/microRNA levels
timeFrame: One day
Other outcomes:
Locations:
city: Milwaukee
country: United States
facility: Children's Hospital of Wisconsin
state: Wisconsin
Study officials:
affiliation: Children's Hospital and Health System Foundation, Wisconsin
name: Edward C Kirkpatrick
role: PRINCIPAL_INVESTIGATOR
References: