Peripheral Blood Signature of Vasodilator-Responsive Pulmonary Arterial Hypertension

• Published in: Circulation (New York, N.Y.) N.Y.), 2015-01, Vol.131 (4), p.401-409
• Main Authors: Hemnes, Anna R, Trammell, Aaron W, Archer, Stephen L, Rich, Stuart, Yu, Chang, Nian, Hui, Penner, Niki, Funke, Mitchell, Wheeler, Lisa, Robbins, Ivan M, Austin, Eric D, Newman, John H, West, James
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Cells, Cultured; Cohort Studies; Female; Humans; Hypertension, Pulmonary - diagnosis; Hypertension, Pulmonary - genetics; Lymphocytes - pathology; Lymphocytes - physiology; Male; Microarray Analysis - methods; Middle Aged; Vasodilation - physiology; Young Adult
• ISSN: 0009-7322; 1524-4539
• 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 differentEPDR1, 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 genesDSG2, 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.