Imperial College London
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DrChristopherRhodes

Faculty of Medicine, National Heart & Lung Institute

Reader in Pulmonary Vascular Disease
 
 
 
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Contact

 

+44 (0)20 7594 7638c.rhodes07

 
 
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Location

 

535ICTEM buildingHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{Sweatt:2021:10.1016/j.chest.2021.06.028,
author = {Sweatt, AJ and Miyagawa, K and Rhodes, CJ and Taylor, S and Del, Rosario PA and Hsi, A and Haddad, F and Spiekerkoetter, E and Bental-Roof, M and Bland, RD and Swietlik, EM and Gräf, S and Wilkins, MR and Morrell, NW and Nicolls, MR and Rabinovitch, M and Zamanian, RT},
doi = {10.1016/j.chest.2021.06.028},
journal = {Chest},
pages = {1442--1458},
title = {Severe pulmonary arterial hypertension is characterized by increased neutrophil elastase and relative elafin deficiency},
url = {http://dx.doi.org/10.1016/j.chest.2021.06.028},
volume = {160},
year = {2021}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - BACKGROUND: Preclinical evidence implicates neutrophil elastase (NE) in PAH pathogenesis, and the NE inhibitor elafin is under early therapeutic investigation. RESEARCH QUESTION: Are circulating NE and elafin levels abnormal in PAH and associated with clinical severity? STUDY DESIGN/METHODS: . In an observational Stanford University PAH cohort (N=249), plasma NE and elafin were measured in comparison to healthy controls (N=106) then related to clinical features and relevant ancillary biomarkers. Cox regression models were fitted with cubic spline functions to associate NE and elafin with survival. To validate prognostic relationships, we analyzed two United Kingdom cohorts (N=75, N=357). Mixed effects models evaluated NE and elafin changes during disease progression. Finally, we studied effects of NE/elafin balance on pulmonary artery endothelial cells (PAECs) from PAH patients. RESULTS: Relative to controls, patients had increased NE (205.1 [123.6-387.3] vs. 97.6 [74.4-126.6] ng/mL, P<0.0001) and decreased elafin (32.0 [15.3-59.1] vs. 45.5 [28.1-92.8] ng/mL, P<0.0001) independent of PAH subtype, illness duration, and therapies. Higher NE associated with worse symptom severity, shorter six-minute walk distance, higher NT-proBNP, greater right ventricular dysfunction, worse hemodynamics, increased circulating neutrophils, elevated cytokine levels, and lower blood BMPR2 expression. In Stanford patients, NE>168.5 ng/mL portended increased mortality risk after adjustment for known clinical predictors (HR 2.52, CI 1.36-4.65, P=0.003) or prognostic cytokines (HR 2.63, CI 1.42-4.87, P=0.001), and NE added incremental value to established PAH risk scores. Similar prognostic thresholds were identified in validation cohorts. Longitudinal NE changes tracked with clinical trends and outcomes. PAH-PAECs exhibited increased apoptosis and attenuated angiogenesis when exposed to NE at the level observed in patients' blood. Elafin rescued PAEC homeostasis, yet the required
AU  - Sweatt,AJ
AU  - Miyagawa,K
AU  - Rhodes,CJ
AU  - Taylor,S
AU  - Del,Rosario PA
AU  - Hsi,A
AU  - Haddad,F
AU  - Spiekerkoetter,E
AU  - Bental-Roof,M
AU  - Bland,RD
AU  - Swietlik,EM
AU  - Gräf,S
AU  - Wilkins,MR
AU  - Morrell,NW
AU  - Nicolls,MR
AU  - Rabinovitch,M
AU  - Zamanian,RT
DO  - 10.1016/j.chest.2021.06.028
EP  - 1458
PY  - 2021///
SN  - 0012-3692
SP  - 1442
TI  - Severe pulmonary arterial hypertension is characterized by increased neutrophil elastase and relative elafin deficiency
T2  - Chest
UR  - http://dx.doi.org/10.1016/j.chest.2021.06.028
UR  - https://www.ncbi.nlm.nih.gov/pubmed/34181952
UR  - http://hdl.handle.net/10044/1/90261
VL  - 160
ER  -
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