Circulating microRNAs in pulmonary arterial hypertension: biomarkers for diagnosis, prognostic stratification, and treatment.

Pulmonary arterial hypertension (PAH) is a rare and progressive and life-threatening clinical condition characterized by elevated mean pulmonary arterial pressure (mPAP ≥ 20 mmHg at rest), increased pulmonary vascular resistance (PVR ≥ 2 Wood units), and normal pulmonary arterial wedge pressure. PAH group 1 comprises idiopathic, heritable, and drug- or toxin-induced forms, as well as cases associated with connective tissue diseases, HIV infection, portal hypertension, congenital heart disease, schistosomiasis, persistent pulmonary hypertension of the newborn, and pulmonary veno-occlusive disease (PVOD)/pulmonary capillary hemangiomatosis. The diagnosis of PAH is frequently delayed, and clinical outcomes remain poor in a significant proportion of patients, although several targeted therapies, acting on the endothelin (ET-1), nitric oxide (NO), and prostacyclin pathways, have been developed, and novel agents (i.e., sotatercept) are showing promising results in clinical trials. Circulating microRNAs (miRNAs) have emerged as promising biomarker candidates for risk stratification and prediction of therapeutic response in PAH group 1. These small non-coding RNAs that regulate gene expression at the post-transcriptional level are released into the circulation either actively, via extracellular vesicles such as exosomes and microvesicles, or passively as a result of cell damage. These features confer remarkable stability in biological fluids, making circulating miRNAs particularly attractive not only as innocent bystanders but also as factors actively involved in the pathogenesis of the disease. The aim of this review is to provide an overview of the role of circulating miRNAs in PAH group 1, with a focus on their diagnostic, prognostic, and therapeutic potential.