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 contractions 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) anticoagulation agents, which can also be imaged, 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 possesses anticoagulant activity and also can be imaged. 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.
Atrial fibrillation is a serious condition of arrhythmia that puts sufferers at high risk of stroke due to blood clotting. Unfortunately the standard of care for prevention of thrombosis is to maintain a circulating dose of anticoagulants, which carries a high risk of intracranial and and abdominal bleeding. This project will develop novel, image-able anticoagulants that work in a fundamentally different way from oral anticoagulants by directly targeting inflamed atria, and offer safer therapy with reduced off-target bleeding.
