Introduction: We previously found that aspirin decreases the risk of cerebral aneurysm (CA) rupture in humans. We aim to assess whether a gender differential exists in the response of human CAs to aspirin and confirm these observations in a mouse model of CA.
Methods: A nested case-control analysis from the International Study of Unruptured Intracranial Aneurysms (ISUIA) was performed to assess whether a gender differential exists in the response of human CAs to aspirin. A series of experiments were subsequently performed in a mouse model of CAs. Aneurysms were induced with hypertension and elastase injection into mice basal cisterns.
Results: Aspirin decreased the risk of aneurysm rupture in men significantly more than women in ISUIA. There was a significant decreasing OR for hemorrhage with the increasing use of aspirin in men (OR, 0.05; p=0.0024) but not in women (OR, 0.46; p=0.23). In mice, aspirin and cyclooxygenase-2 (COX-2) inhibitor did not affect CA formation but significantly decreased the incidence of rupture. The incidence of CA rupture was significantly lower in male vs. female mice on aspirin. Gene expression analysis from cerebral arteries showed higher 15-PGDH levels in male mice. The rate of CA rupture was similar in male mice receiving aspirin and 15-PGDH inhibitor compared to females receiving aspirin and 15-PGDH agonist signaling a reversal of the gender-differential response to aspirin. As compared to superficial temporal arteries, female human CAs showed higher Cox-2 levels and lower 15-PGDH levels.
Conclusions: Aspirin decreases aneurysm rupture in human and mice, in part through cyclooxygenase-2 pathways. Evidence from animal and human studies suggests a consistent differential effect by gender. 15-PGDH activation in females reduces the incidence of rupture and eliminates the gender-differential response to aspirin.
Patient Care: The data in this manuscript was used to get approval from the NINDS council to proceed with a multi-center randomized double blinded (placebo vs. aspirin) phase 3 clinical trial. The trial is designed to recruit 70 centers to enroll 1716 patients to validate the role of aspirin in decreasing the risk of aneurysm rupture and decrease aneurysm growth. The budget is 34 million dollars for 7 years. After thorough scrutiny from the council, the trial team was given the green light to proceed with the application.
Learning Objectives: By the conclusion of this session, participants should be able to: 1) Describe the effect of aspirin in decreasing CA rupture, 2) understand the gender differential response, and 3) familiarize with the ARREST trial that assesses whether aspirin decreases the risk of CA rupture