Markers of extracellular matrix remodeling and systemic inflammation in patients with heritable thoracic aortic diseases

Bjørn Edvard Seim; Margrethe Flesvig Holt; Aleksandra Ratajska; Annika Michelsen; Monica Myklebust Ringseth; Bente Evy Halvorsen; Mona Skjelland; John-Peder Escobar Kvitting; Runar Lundblad; Kirsten Krohg-Sørensen; Liv T N Osnes; Pål Aukrust; Benedicte Paus; Thor Ueland

doi:10.3389/fcvm.2022.1073069

Markers of extracellular matrix remodeling and systemic inflammation in patients with heritable thoracic aortic diseases

Front Cardiovasc Med. 2022 Dec 20:9:1073069. doi: 10.3389/fcvm.2022.1073069. eCollection 2022.

Authors

Bjørn Edvard Seim^{1

2}, Margrethe Flesvig Holt^{2

3

4}, Aleksandra Ratajska⁵, Annika Michelsen^{2

4}, Monica Myklebust Ringseth¹, Bente Evy Halvorsen^{2

4}, Mona Skjelland^{2

6}, John-Peder Escobar Kvitting^{1

2}, Runar Lundblad¹, Kirsten Krohg-Sørensen¹, Liv T N Osnes⁷, Pål Aukrust^{2

4

8

9}, Benedicte Paus^{2

5}, Thor Ueland^{4

9}

Affiliations

¹ Department of Cardiothoracic Surgery, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
² Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
³ Department of Cardiology, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
⁴ Research Institute of Internal Medicine, Oslo University Hospital, Oslo, Norway.
⁵ Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
⁶ Department of Neurology, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
⁷ Department of Immunology, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
⁸ Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
⁹ Faculty of Health Sciences, K. G. Jebsen Thrombosis Research Center, University of Tromsø - The Arctic University of Norway, Tromsø, Norway.

Abstract

Background: In approximately 20% of patients with thoracic aortic aneurysms or dissections a heritable thoracic aortic disease (HTAD) is suspected. Several monogenic connective tissue diseases imply high risk of aortic disease, including both non-syndromic and syndromic forms. There are some studies assessing inflammation and extracellular matrix remodeling in patients with non-hereditary aortic disease, but such studies in patients with hereditary diseases are scarce.

Aims: To quantify markers of extracellular matrix (ECM) and inflammation in patients with vascular connective tissue diseases versus healthy controls.

Methods: Patients with Loeys-Dietz syndrome (LDS, n = 12), Marfan syndrome (MFS, n = 11), and familial thoracic aortic aneurysm 6 (FTAA6, n = 9), i.e., actin alpha 2 (ACTA2) pathogenic variants, were recruited. Exome or genome sequencing was performed for genetic diagnosis. Several markers of inflammation and ECM remodeling were measured in plasma by enzyme immunoassays. Flow cytometry of T-cell subpopulations was performed on a subgroup of patients. For comparison, blood samples were drawn from 14 healthy controls.

Results: (i) All groups of HTAD patients had increased levels matrix metalloproteinase-9 (MMP-9) as compared with healthy controls, also in adjusted analyses, reflecting altered ECM remodeling. (ii) LDS patients had increased levels of pentraxin 3 (PTX3), reflecting systemic inflammation. (iii) LDS patients have increased levels of soluble CD25, a marker of T-cell activation.

Conclusion: Our data suggest that upregulated MMP-9, a matrix degrading enzyme, is a common feature of several subgroups of HTAD. In addition, LDS patients have increased levels of PTX3 reflecting systemic and in particular vascular inflammation.

Keywords: Loeys-Dietz syndrome; Marfan syndrome; aorta; connective tissue disease (CTD)/collagen vascular disease (CVD); extracellular matrix (ECM); familial thoracic aortic aneurysm 6; heritable thoracic aortic disease; inflammation.