Evidence that acetylsalicylic acid attenuates inflammation in the walls of human cerebral aneurysms: preliminary results

David M Hasan, Nohra Chalouhi, Pascal Jabbour, Aaron S Dumont, David K Kung, Vincent A Magnotta, William L Young, Tomoki Hashimoto, H Richard Winn, Donald Heistad, David M Hasan, Nohra Chalouhi, Pascal Jabbour, Aaron S Dumont, David K Kung, Vincent A Magnotta, William L Young, Tomoki Hashimoto, H Richard Winn, Donald Heistad

Abstract

Background: Inflammatory cells and molecules may play a critical role in formation and rupture of cerebral aneurysms. Recently, an epidemiologic study reported that acetylsalicylic acid (ASA) decreases the risk of aneurysm rupture. The goal of this study was to determine the effects of ASA on inflammatory cells and molecules in the walls of human cerebral aneurysms, using radiographic and histological techniques.

Methods and results: Eleven prospectively enrolled patients harboring unruptured intracranial aneurysms were randomized into an ASA-treated (81 mg daily) group (n=6) and an untreated (control) group (n=5). Aneurysms were imaged at baseline using ferumoxytol-enhanced MRI to estimate uptake by macrophages. After 3 months, patients were reimaged before undergoing microsurgical clipping. Aneurysm tissues were collected for immunostaining with monoclonal antibodies for cyclooxygenase-1 (COX-1), cyclooxygenase-2 (COX-2), microsomal prostaglandin E2 synthase-1 (mPGES-1), and macrophages. A decrease in signal intensity on ferumoxytol-enhanced MRI was observed after 3 months of ASA treatment. Expression of COX-2 (but not COX-1), mPGES-1, and macrophages was lower in the ASA group than in the control group.

Conclusions: This study provides preliminary radiographical and histological evidence that ASA may attenuate the inflammatory process in the walls of human cerebral aneurysms.

Clinical trial registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01710072.

Figures

Figure 1.
Figure 1.
Right posterior carotid wall aneurysm from a 69‐year‐old female patient. (a) T1 spin‐echo sequence. Images A1 to A5 are baseline images (ie, before aspirin treatment). A1, Before ferumoxytol infusion. A2, Immediately after ferumoxytol infusion. A3, Seventy‐two hours after ferumoxytol infusion. A4, A2 minus A1. A5, A3 minus A1. Images B1 to B5 were obtained after 3 months of aspirin treatment. B1, Before ferumoxytol infusion. B2, Immediately after ferumoxytol infusion. B3, Seventy‐two hours after ferumoxytol infusion. B4, B2 minus B1. B5, B3 minus B1. (b) T2* sequence. Images A1 to A5 are baseline images (ie, before aspirin treatment). A1, Before ferumoxytol infusion. A2, Immediately after ferumoxytol infusion. A3, Seventy‐two hours after ferumoxytol infusion. A4, A2 minus A1. A5, A3 minus A1. Images B1 to B5 were obtained after 3 months of aspirin treatment. B1, Before ferumoxytol infusion. B2, Immediately after ferumoxytol infusion. B3, 72 hours after ferumoxytol infusion. B4, B2 minus B1. B5, B3 minus B1. (c) T1 spin‐echo sequence. Left, baseline image (ie, before aspirin treatment) 72 hours after ferumoxytol infusion; middle, 3‐month follow‐up images (after aspirin treatment) obtained 72 hours following ferumoxytol infusion; right, A2 minus A1. Note the decrease in signal intensity on various magnetic resonance imaging (MRI) sequences after aspirin treatment.
Figure 2.
Figure 2.
A and B, Immunostaining for 2 aneurysms, 1 from the ASA group and the other from the control group. A, Immunostaining for COX‐1 is similar between the 2 aneurysms. Immunostaining shows downregulation of COX‐2 and mPGES‐1 in the ASA group compared with the control group. B, Immunostaining shows downregulation of macrophages in the ASA group compared with the control group. ASA indicates acetylsalicylic acid; COX‐1, oxygenase‐1; COX‐2, cyclooxygenase‐2; mPGES‐1, microsomal prostaglandin E2 synthase‐1.
Figure 3.
Figure 3.
Semiquantitative grading for aneurysm tissues collected from 5 aneurysms in the ASA group and 5 aneurysms in the control group. Immunostaining for COX‐1 is similar in both groups. Immunostaining shows downregulation of COX‐2, mPGES‐1 and macrophages in the ASA group. ASA indicates acetylsalicylic acid; COX‐1, cyclooxygenase‐1; COX‐2, cyclooxygenase‐2; mPGES‐1, microsomal prostaglandin E2 synthase‐1.

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