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Plasma extracellular matrix and inflammatory proteins as biomarkers for diagnosis, differentiation, and risk assessment in pulmonary arterial hypertension - utilizing Lund Cardio Pulmonary Registry

Arvidsson, Mattias LU orcid (2024) In Lund University, Faculty of Medicine Doctoral Dissertation Series
Abstract
Pulmonary arterial hypertension (PAH) is a rare disease that affects the pulmonary vasculature. Characterized by increased pulmonary arterial pressures and vascular resistance, it causes right heart failure (HF), and premature death. The main symptom, exertional dyspnoea, is non-specific where patient’s and doctor’s delay often lead to diagnosis in advanced stages. Despite development of PAH specific drugs and new treatment strategies, prognosis remains poor. This dissertation aimed to
screen for bloodborne biomarkers with potential to facilitate differentiation between various causes of dyspnoea for earlier diagnosis, and more accurate risk assessment in PAH.

Patients with PAH, chronic thromboembolic pulmonary hypertension,... (More)
Pulmonary arterial hypertension (PAH) is a rare disease that affects the pulmonary vasculature. Characterized by increased pulmonary arterial pressures and vascular resistance, it causes right heart failure (HF), and premature death. The main symptom, exertional dyspnoea, is non-specific where patient’s and doctor’s delay often lead to diagnosis in advanced stages. Despite development of PAH specific drugs and new treatment strategies, prognosis remains poor. This dissertation aimed to
screen for bloodborne biomarkers with potential to facilitate differentiation between various causes of dyspnoea for earlier diagnosis, and more accurate risk assessment in PAH.

Patients with PAH, chronic thromboembolic pulmonary hypertension, pulmonary hypertension (PH) associated with HF with preserved or reduced ejection fraction, and patients with HF without PH who underwent right heart catheterisation as part of investigation for dyspnoea, and healthy controls enrolled in the Lund Cardio Pulmonary Registry were included. Venous blood samples were analysed with proximity extension assays and quantitative PCR. Statistical analyses were used to compare proteins’
levels in the different groups and evaluate proteins as discriminators of PAH.

In paper I-II, plasma matrix metalloproteinase (MMP)-7 and prolargin were identified as candidates that
could discriminate PAH from controls and among the other patient groups with dyspnea.

In paper III, increased plasma levels of MMP-2, perlecan, and tissue inhibitor of metalloproteinases 4
(TIMP-4) were negative predictors of survival. MMP-2 levels at diagnosis correlated with the European
3-strata risk assessment score.

In paper IV, plasma tumor necrosis factor related apoptosis-inducing ligand (TRAIL) could identify PAH
among the other dyspnea patients and controls. Additionally, annexin A1 was a prognostic marker in
PAH.

The present thesis provides evidence for several new biomarkers, related to extracellular matrix or
inflammation, with a diagnostic and prognostic potential in PAH. Combining multiple proteins in a
biomarker panel may further improve the discriminative and/or prognostic ability. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • Professor, MD Lang, Irene, Department of Cardiology AKH-Vienna, Medical University of Vienna, Austria
organization
publishing date
type
Thesis
publication status
published
subject
keywords
pulmonary arterial hypertension, plasma biomarkers, diagnosis, differentiation, risk assessment, MMP-7, prolargin, MMP-2, TRAIL, ANXA1
in
Lund University, Faculty of Medicine Doctoral Dissertation Series
issue
2024:130
pages
80 pages
publisher
Lund University, Faculty of Medicine
defense location
Föreläsningssal 5, Centralblocket, Entrégatan 7, Skånes Universitetssjukhus, Lund
defense date
2024-11-15 09:00:00
ISSN
1652-8220
ISBN
978-91-8021-628-9
language
English
LU publication?
yes
id
bd5062c7-a28d-445e-9ac3-b28cb452e2e8
date added to LUP
2024-10-17 17:26:06
date last changed
2025-04-04 14:03:05
@phdthesis{bd5062c7-a28d-445e-9ac3-b28cb452e2e8,
  abstract     = {{Pulmonary arterial hypertension (PAH) is a rare disease that affects the pulmonary vasculature. Characterized by increased pulmonary arterial pressures and vascular resistance, it causes right heart failure (HF), and premature death. The main symptom, exertional dyspnoea, is non-specific where patient’s and doctor’s delay often lead to diagnosis in advanced stages. Despite development of PAH specific drugs and new treatment strategies, prognosis remains poor. This dissertation aimed to<br/>screen for bloodborne biomarkers with potential to facilitate differentiation between various causes of dyspnoea for earlier diagnosis, and more accurate risk assessment in PAH.<br/><br/>Patients with PAH, chronic thromboembolic pulmonary hypertension, pulmonary hypertension (PH) associated with HF with preserved or reduced ejection fraction, and patients with HF without PH who underwent right heart catheterisation as part of investigation for dyspnoea, and healthy controls enrolled in the Lund Cardio Pulmonary Registry were included. Venous blood samples were analysed with proximity extension assays and quantitative PCR. Statistical analyses were used to compare proteins’<br/>levels in the different groups and evaluate proteins as discriminators of PAH.<br/><br/>In paper I-II, plasma matrix metalloproteinase (MMP)-7 and prolargin were identified as candidates that<br/>could discriminate PAH from controls and among the other patient groups with dyspnea.<br/><br/>In paper III, increased plasma levels of MMP-2, perlecan, and tissue inhibitor of metalloproteinases 4<br/>(TIMP-4) were negative predictors of survival. MMP-2 levels at diagnosis correlated with the European<br/>3-strata risk assessment score.<br/><br/>In paper IV, plasma tumor necrosis factor related apoptosis-inducing ligand (TRAIL) could identify PAH<br/>among the other dyspnea patients and controls. Additionally, annexin A1 was a prognostic marker in<br/>PAH.<br/><br/>The present thesis provides evidence for several new biomarkers, related to extracellular matrix or<br/>inflammation, with a diagnostic and prognostic potential in PAH. Combining multiple proteins in a<br/>biomarker panel may further improve the discriminative and/or prognostic ability.}},
  author       = {{Arvidsson, Mattias}},
  isbn         = {{978-91-8021-628-9}},
  issn         = {{1652-8220}},
  keywords     = {{pulmonary arterial hypertension; plasma biomarkers; diagnosis; differentiation; risk assessment; MMP-7; prolargin; MMP-2; TRAIL; ANXA1}},
  language     = {{eng}},
  number       = {{2024:130}},
  publisher    = {{Lund University, Faculty of Medicine}},
  school       = {{Lund University}},
  series       = {{Lund University, Faculty of Medicine Doctoral Dissertation Series}},
  title        = {{Plasma extracellular matrix and inflammatory proteins as biomarkers for diagnosis, differentiation, and risk assessment in pulmonary arterial hypertension - utilizing Lund Cardio Pulmonary Registry}},
  url          = {{https://lup.lub.lu.se/search/files/197771503/e-nailing_ex_Mattias.pdf}},
  year         = {{2024}},
}