DNA Methylation Dynamics Underlying Arterial Remodeling in PAH Patients: CLEOPAHTRA Clinical Trial (CLEOPAHTRA)

CLinical Epigenetic-sensitive trajectOries Underlying Pulmonary Arterial Hypertension and neTwoRk Analysis (CLEOPAHTRA)

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.

Study Overview

• Status: Completed
• Conditions: Pulmonary Arterial Hypertension; Pulmonary Arterial Remodeling

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.

• Study Type: Observational
• Enrollment (Actual): 30

Contacts and Locations

Study Locations

• Italy
  • Naples, Italy
    • Monaldi Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: N/A
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

30 PAH patients (familial and idiopathic) vs 30 sex and age-matched subjects.

Description

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.

Study Plan

How is the study designed?

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Identification of differentially methylated regions in CD04 and CD08 T cells	Reduced Representation Bisulfite Sequencing	3 Months
Identification of differentially expressed genes in lung tissue biopsies	Chip Microarray	5 Months
Bioinformatic analysis		8 Months

Collaborators and Investigators

• Sponsor: University of Campania "Luigi Vanvitelli"
• Investigators: Principal Investigator: Giuditta Benincasa, BiolD, MSc, University of Campania "L. Vanvitelli"

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): June 14, 2019
• Primary Completion (Actual): June 14, 2020
• Study Completion (Actual): October 14, 2020

Study Registration Dates

• First Submitted: February 21, 2020
• First Submitted That Met QC Criteria: February 21, 2020
• First Posted (Actual): February 24, 2020

Study Record Updates

• Last Update Posted (Actual): July 14, 2021
• Last Update Submitted That Met QC Criteria: July 13, 2021
• Last Verified: July 1, 2021

More Information

Terms related to this study

• Keywords: Adaptive immunity; RNA-sequencing; Network analysis; DNA methylome
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Lung Diseases; Pathological Conditions, Anatomical; Hypertension, Pulmonary; Hypertension; Pulmonary Arterial Hypertension; Familial Primary Pulmonary Hypertension; Vascular Remodeling
• Other Study ID Numbers: CLEOPAHTRA; PRIN2017F8ZB89 (Other Grant/Funding Number: Italian Ministry of University and Research (MIUR))

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No