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

Abstract

BackgroundIn 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.AimsTo quantify markers of extracellular matrix (ECM) and inflammation in patients with vascular connective tissue diseases versus healthy controls.MethodsPatients 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.ConclusionOur 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.

Navigating toward gene therapy in Marfan syndrome: A hope for halting aortic aneurysm

“… 3 The authors rationalize that this endoribonuclease might be involved in Marfan syndrome aortopathy because (1) its expression is regulated by TGF-β, a crucial aggravating driver of aortopathy, 4 (2) it is a negative regulator of oxidative stress, another known actor in TAAD progression, 5 and (3) its intrinsic anti-inflammatory properties, where the role of inflammation is becoming increasingly more evident in the progression of the aortopathy. 6 …”

Molecular Mechanisms Underlying Vascular Remodeling in Hypertension

“…In another study, Seim et al . [ 30 ] conducted research on plasma extracellular matrix (ECM) remodeling markers in patients with heritable thoracic aortic disease (HTAD) by employing an enzyme-linked immunosorbent assay. They found that all subgroups of HTAD patients have elevated levels of MMP-9, indicating its role as a mediator of inflammation and ECM remodeling.…”