Idiopathic degenerative thoracic aneurysms are associated with increased aortic medial amyloid

Abstract

Objective: To explore the relationship of aortic medial amyloid with biochemical and micromechanical properties of the aortic wall in aneurysm patients.Methods: Human aortic tissues removed during aneurysm surgery from tricuspid (idiopathic degenerative aneurysm, DA) and bicuspid valve (BAV) patients were subjected to oscillatory nanoindentation experiments to determine localised mechanical properties of the tissue (shear storage modulus, G´ and shear loss modulus, G˝). Collagen, elastin, matrix metalloproteinase 2 and glycosaminoglycans concentrations were determined, along with relative levels of aortic medial amyloid-related factors (medin, milk fat globule-EGF factor 8, oligomers and fibrils). Measurements were combined with clinical data and statistical analyses performed.Results: The DA cohort can be divided based on their phenotype. One group shared similar characteristics with BAV patients, termed bicuspid like phenotype-tricuspid valve. The second group had high amyloid oligomer species present with a significantly lower G´ (p = .01), indicative of reduced elastic response of the tissue, termed amyloid-rich.Conclusions: We identified a group of DA patients with high amyloid oligomers and altered micromechanical and structural properties of the vessel wall. We propose these findings as a cause for aneurysm formation in these patients. Amyloid is not found in BAV patients, suggesting at least two distinct mechanisms for pathogenesis.

Medin aggregation causes cerebrovascular dysfunction in aging wild-type mice

“…1A) or indicating an early stage of fibril formation and/or maturation. Interestingly, it has been reported that in human aortic tissue the amount of Medin in its amyloid state is significantly lower in patients with aortic aneurysm or dissection, while nonfibrillar Medin deposits are significantly higher in the diseased aorta (10) and correlate with reduced aortic elasticity (9). Thus, nonfibrillar forms of Medin could in fact be more pathogenic, and notably, we find that Medin deposits in the human brain vasculature do not stain with amyloid dyes.…”

“…Under which conditions and how Medin is cleaved from MFG-E8 remains unknown, but its exceedingly high prevalence in the aging population begs the question whether Medin-similar to other amyloids-is associated with tissue dysfunction (6). Of note, previous research suggests that ageassociated structural and functional alterations of the arteries contribute to cardiovascular diseases (7), and a role of Medin in promoting age-related vascular dysfunction has been hypothesized based on analyses of human autopsy and postmortem aorta samples (8)(9)(10). Most recently, evidence of increased Medin levels in patients with vascular dementia compared to cognitively unimpaired individuals was also reported (11).…”

Medin Oligomer Membrane Pore Formation: A Potential Mechanism of Vascular Dysfunction

“…The influence of agitation in aggregation may have implications in the formation of medin toxic species and deposition in atherosclerosis-prone vascular regions subjected to abnormal shear stress hemodynamics, a subject requiring further empiric study. Possibly related to this, we recently found that 89% (eight out of nine) of identified oligomer-rich thoracic aortic aneurysm patients had diagnosed hypertension, compared with 54% (seven out of 13) of patients with syndromic thoracic aortic aneurysm due to bicuspid valve disorder ( 28 ). We routinely observe medin aggregation into amyloid fibers when phosphate buffers are used for medin incubation ( 23 , 78 ); however, the protofibrillar structures formed by medin aggregates ( Figs.…”

“…Medin is the main constituent of AMA, the most common form of localized amyloid ( 20 ). Little is known about its exact in vivo pathological role; however, ex vivo evidence suggests medin is implicated in multiple cardiovascular disorders ( 28 , 29 , 30 , 31 ), including vascular contributions to neurodegeneration ( 33 , 34 ) and vascular dementia ( 32 ). An in vivo study found higher abundance of nonamyloidogenic medin species in aortas from patients with either thoracic aortic aneurysms or aortic dissection than in control individuals with normal aortas ( 29 ).…”

“…Despite its prevalence in the human vasculature, little is known about medin pathology when compared with other amyloid proteins. Medin may have a role in thoracic aortic aneurysm and dissection ( 28 , 29 ), a leading cause of rupture of the aorta ( 29 ). Furthermore, AMA deposits are found closely associated with elastic structures such as the vascular extracellular matrix ( 30 ), which can influence arterial stiffness and development of arterial hypertension ( 31 ).…”