Clinical trial NCT04282434: DNA Methylation Dynamics Underlying Arterial Remodeling in PAH Patients: CLEOPAHTRA Clinical Trial
Official title: CLinical Epigenetic-sensitive trajectOries Underlying Pulmonary Arterial Hypertension and neTwoRk Analysis (CLEOPAHTRA)
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Pulmonary Arterial Hypertension
Pulmonary Arterial Remodeling
Keywords: Adaptive immunity
DNA methylome
RNA-sequencing
Network analysis
Lead sponsor: University of Campania Luigi Vanvitelli
Sponsor class: OTHER
First posted: 2020-02-24
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Observational model: CASE_CONTROL
Time perspective: CROSS_SECTIONAL
Sampling method: PROBABILITY_SAMPLE
Study population: 30 PAH patients (familial and idiopathic) vs 30 sex and age-matched subjects.

Brief summary: To identify epigenetic-sensitive modifications and novel biomarkers linked to pathogenesis of pulmonary arterial hypertension (PAH), we will perform the first study analyzing differentially-methylated regions (DMRs) in circulating T cells (CD04+ and CD08+) isolated from peripheral blood of patients undergoing right heart catheterization. Moreover, we will perform RNA deep sequencing on lung tissue biopsies to validate if DNA methylation signatures in circulating T cells could reflect perturbations of gene expression in lung tissues.

Detailed description: Pulmonary arterial hypertension (PAH) is characterized by remodeling of pulmonary arteries caused by an inbalance of proliferation/apoptosis rate within the vascular wall. This pathological phenotype seems to be triggered by different environmental stress and injury events such as increased inflammation, DNA damage, and epigenetic deregulation. Many immune cells are increased in PAH, such as T and B lymphocytes. Remarkably, T cells are essential players of adaptive immunity and may be relevant initiators ("initial hit") of vascular remodelling. We will perform the first multi-omics study to: 1) investigate DNA methylome of circulating T cells isolated from peripheral blood of PAH patients, 2) detect transcriptomic profiles of lung tissues, 3) to assess if DNA methylation of distinct genomic regions in circulating T cells could reflect modifications of lung gene expression programs.

Eligibility criteria: Inclusion Criteria:

* Newly diagnosed patients with World Health Organization (WHO) Group I PAH.
* ≥ 18 years
* Documentation of the following hemodynamic parameters by right heart catheterization, performed at time of study enrolment:
* Mean pulmonary arterial pressure (mPAP) \> 25 mmHg at rest or mPAP \> 30 mm Hg with exercise.
* Pulmonary arterial wedge pressure (PAWP) ≤ 15 mm Hg.
* Pulmonary vascular resistance (PVR) ≥ 240 dynes.sec.cm-5 (e.g., ≥ 3.0 Wood units)

Exclusion Criteria:

* Patients who meet the criteria for inclusion into WHO Groups II, III, IV or V.
* Do not meet the required hemodynamic criteria for entry into the study.
* Patients with known history of cancer, malignancy disorders, active infections, and chronic or immune-mediated diseases.

Primary outcomes:
measure: Identification of differentially methylated regions in CD04 and CD08 T cells
timeFrame: 3 Months
measure: Identification of differentially expressed genes in lung tissue biopsies
timeFrame: 5 Months
measure: Bioinformatic analysis
timeFrame: 8 Months
Secondary outcomes:
Other outcomes:
Locations:
city: Naples
country: Italy
facility: Monaldi Hospital
Study officials:
affiliation: University of Campania "L. Vanvitelli"
name: Giuditta Benincasa, BiolD, MSc
role: PRINCIPAL_INVESTIGATOR
References:
citation: Napoli C, Benincasa G, Loscalzo J. Epigenetic Inheritance Underlying Pulmonary Arterial Hypertension. Arterioscler Thromb Vasc Biol. 2019 Apr;39(4):653-664. doi: 10.1161/ATVBAHA.118.312262.