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Lymphangiogenic factors are associated with pulmonary arterial hypertension in systemic sclerosis


Didriksen, Henriette; Molberg, Øyvind; Fretheim, Håvard; Gude, Einar; Jordan, Suzana; Brunborg, Cathrine; Palchevskiy, Vyacheslav; Garen, Torhild; Midtvedt, Øyvind; Andreassen, Arne K; Distler, Oliver; Belperio, John; Hoffmann-Vold, Anna-Maria (2021). Lymphangiogenic factors are associated with pulmonary arterial hypertension in systemic sclerosis. Arthritis and Rheumatology:Epub ahead of print.

Abstract

OBJECTIVES

Pulmonary arterial hypertension (PAH) is a major complication in systemic sclerosis (SSc), a disease marked by vascular and lymphatic vessel abnormalities. In this study, we aimed to assess lymphangiogenic factors Vascular Endothelial Growth Factor-C (VEGFC) and Angiopoietin 2 (Ang2) and soluble forms of their cognate receptors; VEGFR3 and Tie-2 in SSc; and evaluate their predictive ability of PAH development.

METHODS

In this cohort study, we used multiplex bead assays to assess serum levels of lymphangiogenic factors in sera samples from two well-characterized SSc cohorts; an unselected identification cohort from Oslo and a PAH enriched validation cohort from Zurich and Oslo, all assessed by right heart catheterizations (RHC). We defined PAH according to ESC/ERS 2015 Guidelines. Statistics included logistic- and Cox-regression analyses.

RESULTS

We found in the identification cohort (n=371) lower mean serum levels of VEGF-C and higher Ang-2 levels in SSc patients compared to healthy controls, and the same trend in SSc cases with PAH compared to those without PH. We confirmed VEGF-C associations to SSc and PAH in the PAH enriched RHC validation cohort (n=149). For prediction analysis, we assembled all 251 cases assessed by RHC from the identification and validation cohorts. In multivariable Cox analysis we found, after adjusting for age and gender, that VEGF-C (HR 0.53 95% CI 0.29-0.97, p=0.040) and sVEGFR3 (HR 1.21 95% CI 1.01-1.45, p=0.042) predicted PAH development.

CONCLUSION

This study supports the notion of deregulated lymphangiogenesis during PAH development in SSc, and indicates VEGF-C as a promising marker for early PAH detection.

Abstract

OBJECTIVES

Pulmonary arterial hypertension (PAH) is a major complication in systemic sclerosis (SSc), a disease marked by vascular and lymphatic vessel abnormalities. In this study, we aimed to assess lymphangiogenic factors Vascular Endothelial Growth Factor-C (VEGFC) and Angiopoietin 2 (Ang2) and soluble forms of their cognate receptors; VEGFR3 and Tie-2 in SSc; and evaluate their predictive ability of PAH development.

METHODS

In this cohort study, we used multiplex bead assays to assess serum levels of lymphangiogenic factors in sera samples from two well-characterized SSc cohorts; an unselected identification cohort from Oslo and a PAH enriched validation cohort from Zurich and Oslo, all assessed by right heart catheterizations (RHC). We defined PAH according to ESC/ERS 2015 Guidelines. Statistics included logistic- and Cox-regression analyses.

RESULTS

We found in the identification cohort (n=371) lower mean serum levels of VEGF-C and higher Ang-2 levels in SSc patients compared to healthy controls, and the same trend in SSc cases with PAH compared to those without PH. We confirmed VEGF-C associations to SSc and PAH in the PAH enriched RHC validation cohort (n=149). For prediction analysis, we assembled all 251 cases assessed by RHC from the identification and validation cohorts. In multivariable Cox analysis we found, after adjusting for age and gender, that VEGF-C (HR 0.53 95% CI 0.29-0.97, p=0.040) and sVEGFR3 (HR 1.21 95% CI 1.01-1.45, p=0.042) predicted PAH development.

CONCLUSION

This study supports the notion of deregulated lymphangiogenesis during PAH development in SSc, and indicates VEGF-C as a promising marker for early PAH detection.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Rheumatology Clinic and Institute of Physical Medicine
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:26 January 2021
Deposited On:02 Feb 2021 14:46
Last Modified:02 Feb 2021 14:46
Publisher:Wiley-Blackwell Publishing, Inc.
ISSN:2326-5191
OA Status:Closed
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1002/art.41665
PubMed ID:33497027

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Embargo till: 2022-01-26