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

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.

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.

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.