Abstract 394: Differential Effects of Platelet Inhibition on Angiotensin II-Induced Abdominal Aortic Aneurysm Rupture in Mice

Abstract

Objective: Currently, there is no proven medical approach to attenuate the expansion or rupture of abdominal aortic aneurysms (AAAs). It is estimated that >90% of AAA patients are on anti-platelet regiments without documented benefit or clinical evaluation. Therefore, we examined the effects of pharmaceutical blockade of platelet activation in either early or late-stage angiotensin II (AngII)-induced AAA formation. Methods and Results: Male Ldlr -/- mice (8 weeks) fed a saturated fat and cholesterol-enriched diet were infused with AngII (1,000 ng/kg/min) via mini-osmotic pumps for 28 days. In one experiment, groups of mice received either aspirin (30 mg/L via drinking water [ASA]) or diet supplemented with the P2Y 12 inhibitor clopidogrel (50 mg/kg/day [Plavix]) 1 week prior to and throughout infusion (n > 15 all groups). All treatments were associated with a significant increase in aortic rupture-induced death versus placebo groups (P < 0.05; Plavix [58% vs. 0%]; and ASA [64% vs. 10%]). In a second experiment, Ldlr -/- mice were similarly fed and infused for 28 days and then stratified, based on aortic lumen diameters, utilizing noninvasive ultrasonography into 4 different groups: ASA (30 mg/L via drinking water), ASA placebo control, Plavix (50 mg/kg/day via food), and Plavix placebo control. Mice were continuously infused with AngII for an additional 42 days. Ex vivo platelet reactivity to adenosine diphosphate and arachidonic acid was conducted throughout the experiment to confirm systemic drug delivery. All treatments were associated with a significant decrease in aortic rupture-induced death versus placebo groups (P < 0.05; [66% placebo vs. 8% ASA] and [58% placebo vs. 0% Plavix]. None of the treatments affected plasma cholesterol, lipoprotein distributions, or increases in systolic blood pressure in either study. In vivo imaging and histopathology demonstrated these anti-platelet agents reduced abdominal macrophage infiltration and matrix metalloproteinase activity in the intervention study. Conclusion: This study demonstrates different roles of platelets in the initiation and progression of AAA and warrants further investigation.