The main goals of this project are to identify mechanisms underlying thrombogenesis in patients with left atrial (LA) fibrosis and to validate this new knowledge via a prospective proof-of-concept clinical study. Atrial fibrillation (AFib) affects millions of Americans and carries a five-fold increased risk of stroke, a leading cause of mortality and morbidity. Around 30% of all ischemic strokes are caused by thromboembolism in AFib patients. In patients without AFib, embolic strokes of undetermined source (ESUS) account for an additional 30% of ischemic strokes. Current stroke risk stratification tools in AFib and ESUS (e.g., CHA2DS2-VASc) are deficient in predictive accuracy, leaving many patients either under-treated for stroke prevention or over- treated and subjected to unnecessary bleeding risk. The growing evidence that LA fibrosis serves as a mechanistic nexus between AFib and ESUS is a very promising advance that could open new avenues for stroke prevention. However, taking advantage of this opportunity requires detailed knowledge of the mechanism(s) by which fibrotic atria are prone to thrombosis, with or without AFib. Fibrosis has complex structural, electrical, and contractile effects in the LA. These phenomena may independently or synergistically influence thrombosis risk by altering LA hemodynamics, but prior work has not systematically assessed inter-dependencies or clarified each factor’s relative importance. This is due to difficulties associated with experimental manipulation and acquisition of clinical measurements. Advances in computational modeling offer an unprecedented opportunity to address this critical knowledge gap. Specifically, the stage is set to create a multi-scale, multi- physics framework that can comprehensively simulate the pro-thrombotic potential of each unique patient-specific LA fibrosis pattern. Our central hypothesis is that LA fibrosis is a key mechanistic factor in determining each individual’s risk of thromboembolic stroke due to structural, electrical, and contractile factors. Our approach consists of three specific aims. Aim 1 will develop and calibrate a computational framework that integrates electrophysiological, biomechanical, and mechano- fluidic modeling in patient-specific LA models, paying special attention to resolving the effects of fibrosis. We will parameterize the framework using multi-modality magnetic resonance imaging acquisitions in AFib patients with prior stroke and non-AFib, non-stroke controls. Aim 2 will use the new computational framework to systematically characterize mechanistic connections between LA fibrosis and thrombogenesis. We will examine how each individual’s mix of fibrosis extent/pattern, LA anatomy, and susceptibility to emergent electromechanical phenomena combine (with or without simulated AFib) to create a thrombogenic milieu that can be characterized by computational modeling. Aim 3 will validate the mechanistic connections between fibrosis and risk of recurrent stroke/brain microinfarction in a proof-of-concept prospective clinical study. We will examine a high-risk cohort of ESUS patients, but notably without a current indication for oral anticoagulation. We will test if model-predicted thrombogenic combinations of LA shape, fibrosis pattern, deranged electromechanics, and disrupted blood flow exist in patients who experience more adverse outcomes. Our validated multi-physics modeling framework will, for the first time, yield new insight on fibrosis-mediated stroke mechanisms, and pave the way for new treatments for millions of patients who are borderline candidates for anticoagulation (e.g., individuals with ESUS or AFib with intermediate risk scores).

PROJECT NARRATIVE In this project our goal is to use computer modeling and medical imaging to better understand why some people experience stroke. We will create a new infrastructure that reads in a patient’s MRI scans then outputs an accurate and custom-tailored measurement of stroke risk based on simulations of structure, electrical activity, contraction, and blood flow in their heart. Through this work we hope to better understand links between disease- related changes to the heart (i.e., fibrosis), abnormal heart rhythms, and clotting events that lead to stroke.