Individualized Interactomes from Pulmonary Arterial Hypertension Cell Biopsies Predict Therapeutic Response

Area of Science:

• Cardiovascular Research
• Genomics and Bioinformatics
• Translational Medicine

Background:

• Pulmonary arterial hypertension (PAH) exhibits molecular diversity, leading to varied responses to therapies.
• Current treatment strategies for PAH often lack personalization due to this heterogeneity.

Purpose of the Study:

• To investigate the utility of transcriptomic data for constructing individualized protein-protein interactomes in PAH patients.
• To determine if these patient-specific interactomes can inform and predict pharmacotherapeutic response in PAH.

Main Methods:

• Utilized an in silico clinical trial design incorporating transcriptomic data from pulmonary artery endothelial cell biopsies.
• Generated individualized protein-protein interactomes for 25 PAH participants.
• Analyzed the enrichment of PAH endophenotype genes within patient-specific interactomes.
• Correlated interactome topology with clinical response to PAH pharmacotherapies.

Main Results:

• Individualized PAH interactomes showed significant enrichment with key PAH-related genes (hypoxia, oxidant stress, apoptosis).
• Concordance between drug targets and interactome topology was linked to improved PAH metrics.
• Observed significant reductions in brain natriuretic peptide levels and REVEAL 2.0 Risk scores at 6 and 12 months.

Conclusions:

• Integrating point-of-care transcriptomics with network medicine offers a pathway to personalize PAH treatment selection.
• This approach holds potential for improving clinically relevant endpoints in pulmonary arterial hypertension.