Trackable, Targeted Anticoagulants for Atrial Fibrillation

心房纤颤（AF）是一种心律失常的疾病，在美国每年的治疗费用估计为60亿美元。 美国（CDC 2016）。AF的一个严重后果是卒中导致的死亡率增加， 血栓栓塞;房颤患者卒中风险增加2-17倍。不协调的收缩 心房导致血液流动不畅，在心脏中产生湍流或停滞区域，这些区域有发生心脏骤停的风险。 凝血因此，抗血栓治疗是患者管理中的关键考虑因素。战争已经在 使用多年，最近出现了新的药物，如利伐沙班（Xaralto®）;不幸的是， 这些全身循环的药物具有大出血的风险。颅内和腹腔内出血 是目前使用的抗凝剂的危险副作用之一。抗血栓治疗需要谨慎 在控制凝血同时不诱导离体出血之间保持平衡。因为据信90%的 房颤中的中风是由于起源于左心耳的凝块，我们考虑靶向输送是否 抗凝剂的心房可以减少凝血，减少出血的风险。炎症正在出现 因为在AF患者中，炎症标志物 免疫细胞在左心耳中高度升高。本项目建议验证硫酸化- 葡聚糖包被的氧化铁纳米颗粒（SDIO）成像剂，其还具有抗凝活性，用于 将抗凝活性靶向AF动物模型中心房的炎症部位。我们假设 SDIO将减少心房凝血，而不增加全身凝血时间。初步数据证实 SDIO可以促进炎症颈动脉中活化巨噬细胞的成像。此外，SDIO 在几个体外试验中显示抗凝活性。在目前的工作中，SDIO瞄准 将在心房的胸主动脉缩窄（TAC）小鼠模型中验证心房中的炎症。 纤维性颤动，其在反映人类疾病的心房中经历炎症和凝血。靶向 将通过磁共振成像（MRI）和正电子发射光谱（PET）确定SDIO对发炎心房的影响。 断层扫描（PET）。SDIO的稳定性将被量化，作为了解其潜力的垫脚石。 临床翻译。最后，降低体内凝血的能力和对全身凝血的影响将被评估。 在胸主动脉缩窄（TAC）模型中测定。SDIO代表一类可以 成像并且还具有抗凝血活性。该项目的成功将从根本上验证 与Warcantine和其他口服抗凝剂不同的抗凝治疗方法，通过定位 因此，我们可以将抗凝剂应用于炎症部位，而不是依赖于维持药物的循环剂量。

Atrial fibrillation (AF) is a condition of cardiac arrhythmia with an estimated treatment cost of $6 billion/yr in the United States (CDC 2016). A serious consequence of AF is increased mortality due to stroke and thromboembolism; patients with AF are at 2-17 fold increased risk of stroke. Uncoordinated contraction of the atria results in poor blood flow, creating regions of turbulence or stagnation in the heart that are at risk for clotting. Thus, antithrombotic therapy is a critical consideration in patient management. Warfarin has been in use for many years, and more recently new drugs such as rivaroxaban (Xaralto®) have emerged; unfortunately, these systemically circulating drugs carry risk of major bleeding. Intracranial and intra-abdominal bleeding are among the dangerous side effects of currently used anticoagulants. Antithrombotic treatment requires careful balance between managing clotting while not inducing off site bleeding. Because it is believed the 90% of strokes in AF are due to clots originating from the left atrial appendage, we consider whether targeted delivery of anticoagulants to the atrium could reduce clotting with less risk of bleeding off site. Inflammation is emerging as a potential target for delivery of drugs to the atrium in AF because, in AF patients, inflammatory markers and immune cells are highly elevated in the left atrial appendage. This project proposes to validate sulfated- dextran-coated, iron oxide nanoparticle (SDIO) imaging agents, which also possess anticoagulant activity, for targeting anticoagulant activity to sites of inflammation in the atria in AF animal models. We hypothesize that SDIO will reduce atrial clotting without increasing systemic blood coagulation time. Preliminary data confirmed that SDIO could facilitate imaging of activated macrophages in inflamed carotid arteries. In addition, SDIO show anticoagulant activity in several in vitro assays. In the current work, the ability of SDIO to target inflammation in the atria will be validated in the thoracic aortic constriction (TAC) mouse model of atrial fibrillation, which experiences inflammation and clotting in the atria that reflects the human disease. Targeting of SDIO to inflamed atria will be determined by Magnetic Resonance Imaging (MRI) and Positron Emission Tomography (PET). The stability of SDIO will be quantified, as a stepping stone to understanding the potential for clinical translation. Finally the ability to reduce clotting in vivo, and effect on systemic coagulation will be determined in the thoracic aortic constriction (TAC) model. SDIO represent a class of agents that can be imaged and also possesses anticoagulant activity. The success of this project would validate a fundamentally different approach to anticoagulant therapy from Warfarin and other oral anticoagulants, by localizing anticoagulant agents to sites of inflammation rather than relying on maintaining a circulating dose of drug.