Abstract WP329: Causal Association of Left Atrial Emptying Fraction With Ischemic Stroke: A Mendelian Randomization Analysis

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Introduction: Atrial cardiomyopathy (AC) is associated with ischemic stroke (IS) in the absence of known atrial fibrillation (AF), but it is not known if AC is causally linked to IS. We are using Mendelian randomization (MR) to study whether AC traits are causally linked to IS. Methods: We used genetic variants associated with atrial traits by GWAS as proxies for traits defined by cardiac MRI (left atrial (LA) minimum and maximum volumes and active, passive and total emptying fractions (LAAEF, LAPEF, LATEF)) and by EKG (PQ interval). Linkage of these variants with IS and with TOAST stroke subtypes was studied in IS cases and controls from the NINDS Stroke Genetics Network and Early Onset Stroke Consortium. Causal estimates were calculated using MR Inverse-Variance Weighted (IVW), MR-Egger, and median methods. Imaging-derived atrial traits were highly correlated with each other, but were minimally correlated with EKG-derived atrial traits (PQ Interval). Therefore, we set p value cutoff at 0.05/2=0.025 to claim statistical significance. Results: MR analysis using genetic variants passing genome-wide significance showed that decreased LATEF was causally associated with the risk of IS (IVW p=0.008), which appeared to be primarily driven by the risk of cardioembolic stroke (IVW p=0.028). Decreased LAAEF was causally associated with IS (MR-Egger p=0.003) and stroke of undetermined etiology (MR-Egger p=0.003). MR using variants with genome-wide significance did not find causal associations for the other traits with IS or its subtypes. Conclusion: The MR analysis suggests that left atrial dysfunction may be causally associated with an increased risk of ischemic stroke. Notably, reduced LATEF appears to primarily elevate the risk of cardioembolic stroke, while decreased LAAEF is associated particularly with strokes of undetermined etiology. Additional analysis will be conducted to examine whether atrial fibrillation mediates the causal connections between these atrial traits and stroke. These findings underscore the importance of atrial health as a potential target in stroke prevention.

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