Introduction
Chronic thromboembolic pulmonary hypertension (CTEPH) is an underdiagnosed disease
of uncertain etiology. Altered endothelial homeostasis, defective angiogenesis and
inflammation are implicated. Angiopoietin 2 (Ang2) impairs acute thrombus resolution
and is associated with vasculopathy in idiopathic pulmonary arterial hypertension.
Methods
We assessed circulating proteins associated with these processes in serum from patients
with CTEPH (n = 71) before and after pulmonary endarterectomy (PEA), chronic thromboembolic
pulmonary disease without pulmonary hypertension (CTEPD, n = 9) and healthy controls
(n = 20) using Luminex multiplex arrays. Comparisons between groups were made using
multivariable rank regression models. Ang2 and high-sensitivity C-reactive protein
(hsCRP) were measured in a larger validation dataset (CTEPH = 277, CTEPD = 26). Cox
proportional hazards models were used to identify markers predictive of survival.
Results
In CTEPH patients, Ang2, interleukin (IL) 8, tumor necrosis factor α, and hsCRP were
elevated compared to controls, while vascular endothelial growth factor (VEGF) c was
lower (p < 0.05). Ang2 fell post-PEA (p < 0.05) and was associated with both pre- and post-PEA pulmonary hemodynamic variables
and functional assessments (p < 0.05). In the validation dataset, Ang2 was significantly higher in CTEPH compared
to CTEPD. Pre-operative hsCRP was an independent predictor of mortality.
Conclusions
We hypothesize that CTEPH patients have significant distal micro-vasculopathy and
consequently high circulating Ang2. Patients with CTEPD without pulmonary hypertension
have no discernible distal micro-vasculopathy and therefore have low circulating Ang2.
This suggests Ang2 may be critical to CTEPH disease pathogenesis (impaired thrombus
organization and disease severity).
KEYWORDS
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Article info
Publication history
Published online: September 07, 2022
Identification
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Related Podcast
This month’s JHLT: The Podcast is hosted by Digital Media Editor David Schibilsky, MD, who leads a discussion of two studies from the March issue of The Journal of Heart and Lung Transplantation—and the first authors who presented them.
First, the editors explore a study entitled “Angiopoietin 2 and hsCRP are associated with pulmonary hemodynamics and long-term mortality respectively in CTEPH—Results from a prospective discovery and validation biomarker study,” which comes from Hadinnapola and colleagues at the Papworth group in Cambridge, UK.
The editors welcome Charaka Hadinnapola, MA, MB, BChir, first author on the CTEPH study, to share the rationale in performing the research, its main findings, the changing understanding of the pathobiology of pulmonary arterial hypertension, and how Ang2 and hsCRP fit into the bigger cytokine picture in CTEPD and CTEPH patients.
Next, the editors welcome author J.K. Peel, MD, MSc, from the University of Toronto to discuss the paper her first authored, “Determining the impact of ex-vivo lung perfusion on hospital costs for lung transplantation: a retrospective cohort study.”
