A Risk Score for Thromboembolism in Heart Failure Without Atrial Fibrillation

About This Grant

PROJECT SUMMARY/ABSTRACT Heart failure (HF) affects 6.7 million Americans and creates a hypercoagulable state that substantially increases the risk of left ventricular thrombus and related systemic embolic complications, including ischemic stroke and extracranial embolism. These thromboembolic events cause major disability and death, yet no validated risk stratification tool exists to identify the 4-5 million HF patients without atrial fibrillation (AF) who would benefit most from anticoagulation. Randomized trials demonstrate that universal anticoagulation in HF without AF reduces stroke but causes net harm due to increased major bleeding, highlighting the critical need for precision risk stratification analogous to the CHA2DS2-VASc score used in AF. This R21 project will develop and validate the first comprehensive risk prediction tool for thromboembolism in HF patients without AF by integrating clinical variables with cardiovascular magnetic resonance (CMR) biomarkers of the thrombogenic substrate. The broad objective is to enable targeted anticoagulation strategies that prevent stroke in high-risk HF patients while avoiding unnecessary bleeding in lower-risk individuals. The project will use secondary analysis of existing multicenter CMR datasets to develop and internally validate a risk score for incident ischemic stroke and extracranial embolism in HF patients with reduced ejection fraction and no AF, followed by external validation in an independent patient cohort. The risk score will integrate clinical predictors with CMR biomarkers corresponding to Virchow's triad: systolic dysfunction, myocardial scar, and left ventricular hypertrabeculation. The project will further demonstrate that left ventricular thrombus serves as the mechanistic mediator linking risk factors to thromboembolic events through formal causal mediation analysis, providing biological validation for the risk score and establishing left ventricular thrombus prevention as a therapeutic target. This work directly addresses Strategic Objective 5 in the NHLBI Strategic Vision by developing a novel diagnostic strategy to prevent cardiovascular disease. If validated, the risk score will provide essential data to enable targeted anticoagulation trials in high-risk subgroups and to create a reproducible framework for integrating advanced imaging biomarkers into cardiovascular risk assessment, potentially preventing thousands of annual strokes among Americans with HF without AF.