Early Change in Ferumoxytol-Enhanced Magnetic Resonance Imaging Signal Suggests Unstable Human Cerebral Aneurysm

Abstract

Background and Purpose The clinical significance of early (i.e. within the first 24 hours) uptake of ferumoxytol by macrophages in the wall of human cerebral aneurysms is not clear. The purpose of this study was to determine whether early uptake of ferumoxytol suggests unstable cerebral aneurysm. Methods Thirty unruptured aneurysms in 22 patients were imaged with MRI 24 hours after infusion of ferumoxytol. Eighteen aneurysms were also imaged 72 hours after infusion of ferumoxytol. Aneurysm dome tissue was collected from four patients with early MRI signal changes, five patients with late signal changes, and five other patients with ruptured aneurysms. The tissue was immunostained for expression of cyclooxygenase-1 (COX-1), cyclooxygenase-2 (COX-2), microsomal-prostaglandin-E2 synthase-1 (mPGES-1) and macrophages. Results In 23% (7/30) of aneurysms, there was pronounced early uptake of ferumoxytol. Four aneurysms were clipped. The remaining three aneurysms were managed conservatively; all three ruptured within six months. In 53% (16/30) of aneurysms, there was pronounced uptake of ferumoxytol at 72 hours. Eight aneurysms were surgically clipped and eight were managed conservatively; none ruptured or increased in size after six months. Expression of COX-2, mPGES-1, and macrophages was similar in unruptured aneurysms with early uptake of ferumoxytol and ruptured aneurysms. Expression of these inflammatory molecules was significantly higher in aneurysms with early uptake of ferumoxytol versus aneurysms with late uptake. Conclusions Uptake of ferumoxytol in aneurysm walls within the first 24 hours strongly suggests aneurysm instability and probability of rupture within six months, and may warrant urgent intervention.

Estrogen Deficiency Promotes Cerebral Aneurysm Rupture by Upregulation of Th17 Cells and Interleukin‐17A Which Downregulates E‐Cadherin

“…E‐cadherin's role in the pathobiology of aneurysms and ruptures is compatible with findings of inflammatory cell infiltration of the vascular wall of human aneurysms 11, 12, 13. We demonstrate that E‐cadherin blockade causes significant infiltration of macrophages in cell migration assays and in vivo at the murine COW.…”

“…Experimental and human studies have demonstrated that aneurysms are the result of a vascular inflammatory process initiated by hemodynamic injury at bifurcations. Inflammatory cells, notably macrophages, infiltrate the vessel wall and contribute to matrix metalloproteinase–mediated degeneration of the extracellular matrix 11, 12, 13. This process leads to an eventual weakening of vascular structural integrity, leading to aneurysm formation and rupture 9, 10…”

Inflammation in human cerebral aneurysms: pathogenesis, diagnostic imaging, genetics, and therapeutics

“…Those exhibiting early uptake (24 h postinjection) ruptured within 6 months. [51] Furthermore, immunostaining of surgically resected aneurysm dome tissue revealed increased expression of COX-2, mPGES, and the number of M1 variety macrophages in aneurysms with early uptake. It should be noted that this suggests imaging beyond 24 h may prove unnecessary with respect to rupture risk stratification; however, 72 h remains the optimal timing for imaging macrophages in the walls of IA's.…”

“…[48] Given the role of macrophages in IA pathogenesis, several studies conducted by Hasan et al [49][50][51][52] investigated the possibility of in vivo aneurysm wall macrophage quantification through infusion of a carbohydrate coated superparamagnetic iron oxide nanoparticle, ferumoxytol (AMAG Pharmaceuticals, Lexington, Massachusetts, USA). Ferumoxytol is cleared by macrophages in either the arterial lumen or subendothelium of IAs, thus allowing for delayed visualization of macrophage activity as a surrogate biomarker for inflammatory status of a particular lesion.…”

“…This time interval may still be used to access the efficacy of anti-inflammatory therapeutics. [51] Additionally, previous studies that provided evidence of inflammatory changes in ruptured aneurysms had fallen short of providing evidence of its involvement prior to rupture, rather than as a response to rupture. [5] These data, therefore, provide the first direct evidence that inflammation is a causal factor in IA rupture progression.…”