Abstract 524: Fibrinogen Depletion Attenuates Angiotensin II-induced Abdominal Aortic Aneurysm

Background: Fibrinogen and fibrin provide physical and biochemical support to a developing clot and is defined as one of the most crucial independent risk factors for cardiovascular diseases (CVDs). In addition to clot formation, fibrinogen promotes wound healing and powerful inflammatory and immune responses by engagement of leukocytes. Increased circulating fibrinogen and fibrin degradation products are correlated with increased diameter and progression of abdominal aortic aneurysm (AAA). However, a causal link between fibrinogen and AAA has not yet been established. The objective of this study was to determine the role of fibrinogen depletion in a mouse model of AAA. Methods and results: To determine whether aneurysm resulted in a procoagulant environment, we examined plasma levels of thrombin generation by calibrated automated thrombography (CAT), thrombin anti-thrombin (TAT), and fibrinogen in control and AAA plasma from mice and humans. Patients and mice with AAA had significant elevations in thrombin generation, TAT, and fibrinogen versus saline controls (mice) and control patients (human). To determine the effect of fibrinogen, in vivo, low density lipoprotein receptor deficient ( Ldlr -/- ) mice were injected with scrambled anti-sense oligonucleotide (ASO) or β-fibrinogen ASO (30 mg/kg) 3 weeks prior to experimentation and throughout the study. Fibrinogen ASO treatment achieved > 90% depletion of fibrinogen. After 3 weeks, mice were fed a fat and cholesterol enriched diet (42% milk fat; 0.2% cholesterol) 1 week prior to and throughout infusion with angiotensin II (AngII; 1,000 ng/kg/day) for 28 days. Fibrinogen ASO attenuated abdominal diameter (33% decrease; P = 0.001), and inflammatory cytokines (>75% decreased IL-1 and IL-6; P = 0.001) versus scrambled ASO control. Further, fibrinogen depletion significantly attenuated aneurysm incidence and rupture-induced death (P < 0.05). Conclusions: Our results demonstrate that AAAs augment procoagulant markers in both humans and mice. Importantly, fibrinogen depletion attenuates AAA incidence, diameter, rupture-induced death, and inflammation. Therefore, reduction of plasma fibrinogen may be a novel treatment strategy in patients with AAA.