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Clinical, Hemodynamic, and Genetic Associations with Parenteral Prostacyclin Response in Pulmonary Arterial Hypertension

Stephen Halliday

Eric Farber-Eger

Quanhu Sheng

M Xu

F Ye

Meredith Pugh

Ivan Robbins

Tufik Assad

Jonathan Mosley

James West


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Conference: 2018 PHA International PH Conference & Scientific Sessions

Release Date: 06.28.2018

Presentation Type: Abstracts

File Download: Conference 2018_1021

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2018 International PH Conference and Scientific SeAbstract presented at the 2018 International PH Conference and Scientific Sessions in Orlando, Fla., June 28-July 1, 2018.

Authors (Continued) 

Brittain E, Hemnes A


Pulmonary arterial hypertension (PAH) is a highly morbid disease, and despite recent advances in therapeutic options, parenteral prostacyclin therapy remains the most efficacious pharmacologic treatment. However, there is significant heterogeneity of response to parenteral prostacyclins in PAH, with some patients having tremendous improvements in functional class and survival, while others continue to deteriorate despite aggressive treatment. We sought to better characterize prostacyclin "responders" and "non-responders", and identify clinical, hemodynamic, and genetic associations with response to therapy.


Patients were found in Vanderbilt's de-identified electronic medical record and the associated DNA biobank by exporting right heart catheterization (RHC) reports, cross-referencing these with references to epoprostenol and treprostinil, and manual chart review. Patients with confirmed PAH and a RHC in the 6 months prior to initiation of a parenteral prostacyclin were included. Responders were defined by attainment of World Health Organization (WHO) function class (FC) 2 or better at the time of repeat RHC within 2 years of initiation of parenteral prostacyclin. Non-responders were defined by WHO FC >2 at repeat RHC, or death within 2 years of drug initiation if there was no repeat RHC. Genotyping was performed on the Illumina MEGAEX chip. Single nucleotide variants (SNVs) with p < 0.01 were matched to the nearest gene by expression quantitative trait loci mapping.


Of 129 patients identified, 54 met our criteria for "responders". These patients were younger, more likely to be male, and were less likely to have connective tissue disease related PAH (Table 1). At follow-up, responders had more favorable hemodynamics and 6-minute walk distance than non-responders (Table 1) and significantly improved long-term survival (Figure 1). In Cox proportional hazards models, the variables most associated with survival at baseline were younger age and higher pulmonary artery oxygen saturation (Figure 2). At follow-up, WHO FC was the variable most associated with survival (Figure 3). Among the 32 patients of white European ancestry with genotyping data, 1275 genes were different between the responders and non-responders. Gene ontology analysis using WebGestalt revealed highly statistically significant enrichment in genes related to cell development, cell adhesion, and circulatory system development. Significant pathways included aldosterone synthesis and secretion, calcium signaling, insulin secretion, cAMP signaling, and vascular smooth muscle contraction.


Our study suggests that age at treatment initiation, WHO FC at short-term follow up, and PA O2% are associated with survival in this population. Exploratory genetic comparison between these groups yielded associations in biologically plausible pathways in the pathogenesis of PAH.

Figure 1: Survival in Prostacyclin Responders vs. Non-responders
Unadjusted survival between parenteral prostacyclin responders and non-responders (p < 0.0001 by log-rank test)

Figure 2: Variables Measured at RHC Prior to Starting Prostanoid
IPAH = idiopathic pulmonary arterial hypertension, HPAH = Heritable PAH, APAH = associated PAH, BPM = beats per minute, mRAP = mean right atrial pressure, PA O2 sat % = pulmonary artery oxygen % saturation.

Figure 3: Variables Measured at RHC After Starting Prostanoid
See Table 1 and Figure 2 for acronym definitions.