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2017 Cardiovascular Research Day Abstract Book

71 Fibrinogen Depletion

71 Fibrinogen Depletion Attenuates Angiotensin II-induced Abdominal Aortic Aneurysm Hannah Russell 1 • Keith Saum 1 • Alexandra Sundermann 2 • Shannon Jones 1 • Anders Wanhainen, MD, PhD 3 • Todd Edwards, PhD 2 • Lori Holle 4 • Alisa Wolberg, PhD 4 • A. Phillip Owens III, PhD 1 1Internal Medicine, University of Cincinnati • 2 Medicine and Public Health, Vanderbilt University Medical Center • 3 Surgery, Uppsala University • 4 Pathology, UNC Chapel Hill Graduate Student Background: Fibrinogen and fibrin [collectively fibrin(ogen)] provides physical and biochemical support to a developing clot and is one of the most crucial independent risk factors for cardiovascular diseases (CVDs). In addition to clot formation, fibrin(ogen) also promotes wound healing and powerful inflammatory and immune responses via engagement of leukocytes. Increased levels of circulating fibrin(ogen) degradation products are correlated with increased diameter and progression of the inflammatory disease 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: We first determine whether AAA resulted in elevated procoagulant activity by quantifying plasma levels of thrombin anti-thrombin (TAT) and thrombin generation via calibrated automated thrombography (CAT). Compared to controls, both mice and humans with AAA had significantly elevated TAT as well as CAT parameters velocity index, peak height, and endogenous thrombin potential. To identify a role of fibrinogen in AAA, low density lipoprotein receptor deficient (Ldlr-/-) mice were injected intraperitoneally with scrambled anti-sense oligonucleotide (ASO) or β-fibrinogen ASO (30 mg/kg) 3 weeks prior to experimentation and throughout the study. Administration of fibrinogen ASO successfully achieved > 90% depletion of fibrinogen. After 3 weeks of ASO, mice were fed a high fat/cholesterol ‘Western’ diet for 1 week prior to and throughout infusion with angiotensin II (AngII; 1,000 ng/kg/day) for 28 days. Compared to controls, fibrinogen depletion decreased abdominal diameter (33% decrease; P = 0.001), atherosclerotic lesion area (~63% decrease; P = 0.001), and inflammatory cytokines (>75% decreased IL-1 and IL-6; P = 0.001). Fibrinogen depletion also decreased aneurysm incidence (P < 0.05) and rupture-induced death (P = 0.078). Conclusions: Our results show that AAAs are associated with elevated TAT and thrombin generation in both patients and mice, and that fibrinogen depletion attenuates AAA incidence, diameter, rupture-induced death, atherosclerosis, and inflammation. We propose that increased procoagulant activity accelerates the rate of fibrinogen to fibrin conversion, which promotes inflammation and increases cardiovascular disease. Further studies will define whether reducing plasma fibrinogen may be a novel treatment strategy. 87

72 Increased Circulating Trimethylamine N-oxide (TMAO) Augments the Incidence of Abdominal Aortic Aneurysm in Low Penetrant C57BL/6J Mice Kelsey Conrad, MS 1 • Shannon Jones 1 • Robert Helsley, PhD 2 • Rebecca Schugar, PhD 2 • Zeneng Wang, PhD 2 • Stanley Hazen, MD, PhD 2 • J. Mark Brown, PhD 2 • A. Phillip Owens III, PhD 1 1Internal Medicine, University of Cincinnati • 2 Cellular and Molecular Medicine, Cleveland Clinic Graduate Student Background: The gut microbiota is a metabolically active endocrine organ critical to the maintenance of cardiovascular health. Nutrients common in high fat foods (phosphatidylcholine, choline, L-carnitine) are metabolized by microbial enzymes to form the gut microbial metabolite trimethylamine (TMA). Metabolism by the host enzyme flavin-containing monooxygenase 3 (FMO3) converts TMA to the pro-inflammatory molecule trimethylamine N-oxide (TMAO). Human clinical trials have correlated high levels of circulating TMAO to an increased risk of cardiovascular diseases. However, this meta-organismal pathway has not been evaluated in the context of abdominal aortic aneurysm (AAA). The objective of this study was to determine the effects of a high choline diet on the development of AAA. Methods: C57BL/6J male (n=20) and female (n=20) mice were fed either a standard chow control diet (n = 10 each sex) or a choline-rich diet (1%; n = 10 each sex) for 5 weeks. After 1 week of diet, basal abdominal ultrasounds were performed and angiotensin II (AngII; 1,000 ng/kg/min) was infused for 28 days via implantation of osmotic minipumps. Termination ultrasounds were performed on day 27 and mice were sacrificed on day 28. Aortas were harvested for evaluation of aneurysm progression and plasma was analyzed for the metabolites TMA, TMAO, and choline. To determine whether TMAO was elevated in human patients with AAA, plasma samples from participants with fast growing AAAs (n = 85), slow growing AAAs (n = 84), and normal (nonaneurysmal) aortas (n = 115) were analyzed for plasma TMAO levels via liquid chromatography tandem mass spectrometry (LC-MS/MS). Results: Administration of a choline-rich diet augmented the incidence (P < 0.02) and aortic diameter (P < 0.001) of AAAs in both male and female mice versus placebo-fed mice. Plasma levels of TMA, TMAO, and choline were significantly elevated in choline-fed mice versus normal chow (P < 0.05). Importantly, circulating levels of plasma TMAO were significantly elevated in a step-wise fashion with the rate of aneurysm growth versus non-aneurysmal control patients (fast growing > slow growing > normal patients; P < 0.001). Conclusions: Our results indicate increases in circulating TMAO augments the growth status of aneurysms in human patients and the incidence of AAA in a low penetrant C57BL/6J mouse model. 88

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