Peripheral blood signature of vasodilator-responsive pulmonary arterial hypertension.

Hemnes AR, Trammell AW, Archer SL, Rich S, Yu C, Nian H, Penner N, Funke M, Wheeler L, Robbins IM, Austin ED, Newman JH, West J
Circulation. 2015 131 (4): 401-9; discussion 409

PMID: 25361553 · PMCID: PMC4308423 · DOI:10.1161/CIRCULATIONAHA.114.013317

BACKGROUND - Heterogeneity in response to treatment of pulmonary arterial hypertension (PAH) is a major challenge to improving outcome in this disease. Although vasodilator-responsive PAH (VR-PAH) accounts for a minority of cases, VR-PAH has a pronounced response to calcium channel blockers and better survival than vasodilator-nonresponsive PAH (VN-PAH). We hypothesized that VR-PAH has a different molecular cause from VN-PAH that can be detected in the peripheral blood.

METHODS AND RESULTS - Microarrays of cultured lymphocytes from VR-PAH and VN-PAH patients followed at Vanderbilt University were performed with quantitative polymerase chain reaction performed on peripheral blood for the 25 most different genes. We developed a decision tree to identify VR-PAH patients on the basis of the results with validation in a second VR-PAH cohort from the University of Chicago. We found broad differences in gene expression patterns on microarray analysis including cell-cell adhesion factors and cytoskeletal and rho-GTPase genes. Thirteen of 25 genes tested in whole blood were significantly different: EPDR1, DSG2, SCD5, P2RY5, MGAT5, RHOQ, UCHL1, ZNF652, RALGPS2, TPD52, MKNL1, RAPGEF2, and PIAS1. Seven decision trees were built with the use of expression levels of 2 genes as the primary genes: DSG2, a desmosomal cadherin involved in Wnt/β-catenin signaling, and RHOQ, which encodes a cytoskeletal protein involved in insulin-mediated signaling. These trees correctly identified 5 of 5 VR-PAH patients in the validation cohort.

CONCLUSIONS - VR-PAH and VN-PAH can be differentiated with the use of RNA expression patterns in peripheral blood. These differences may reflect different molecular causes of the 2 PAH phenotypes. This biomarker methodology may identify PAH patients who have a favorable treatment response.

© 2014 American Heart Association, Inc.

MeSH Terms (13)

Adolescent Adult Cells, Cultured Cohort Studies Female Humans Hypertension, Pulmonary Lymphocytes Male Microarray Analysis Middle Aged Vasodilation Young Adult

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