Peripheral blood signature of vasodilator-responsive pulmonary arterial hypertension

Anna R. Hemnes*, Aaron W. Trammell, Stephen L. Archer, Stuart Rich, Chang Yu, Hui Nian, Niki Penner, Mitchell Funke, Lisa Wheeler, Ivan M. Robbins, Eric D. Austin, John H. Newman, James West

*Corresponding author for this work

Research output: Contribution to journalArticle

50 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)401-409
Number of pages9
JournalCirculation
Volume131
Issue number4
DOIs
StatePublished - Jan 27 2015

Keywords

  • biomarkers
  • pulmonary hypertension
  • treatment

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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  • Cite this

    Hemnes, A. R., Trammell, A. W., Archer, S. L., Rich, S., Yu, C., Nian, H., Penner, N., Funke, M., Wheeler, L., Robbins, I. M., Austin, E. D., Newman, J. H., & West, J. (2015). Peripheral blood signature of vasodilator-responsive pulmonary arterial hypertension. Circulation, 131(4), 401-409. https://doi.org/10.1161/CIRCULATIONAHA.114.013317