Individualized Interactomes from Pulmonary Arterial Hypertension Cell Biopsies Predict Therapeutic Response

Pulmonary arterial hypertension (PAH) is characterized by molecular heterogeneity and variable pharmacotherapeutic responses. We used an in silico clinical trial design to test whether transcriptomic data from pulmonary artery endothelial cell biopsies collected during right heart catheterization could be used to build individualized protein-protein interactomes and inform treatment response. Twenty-five PAH participants (56 [range: 30-84] yr; 91% female; 81%, white) and three controls contributed 32 and three cell biopsy specimens, respectively. Patient-specific interactomes varied widely in topology and complexity. All 32 individualized PAH interactomes were enriched significantly with key PAH endophenotypes genes such as hypoxia, oxidant stress, and apoptosis. Concordance between the molecular targets of a prescribed PAH pharmacotherapy class and the corresponding individualized interactome topology was associated with improvement in multiple PAH metrics, including a reduction in brain natriuretic peptide levels at 6 months (β -627.6 pg/mL, [95% CI -986.4, -268.8]; p = 0.003) and a decrease from high to intermediate REVEAL 2.0 Risk scores at 6 months (β -1.3 units, [95% CI -2.6, -0.04]; p=0.043) that persisted at 12 months (β -1.7, [95% CI -3.4, -0.1]; p=0.059). Integration of transcriptomics acquired at point-of-care with network medicine may individualize treatment selection and improve clinically relevant endpoints in PAH.