Abstract 148: Genetically-Determined LDL Negatively Impacts Clinical Evolution Of Ischemic Stroke Survivors

Abstract

Introduction: Ischemic Stroke survivors are at high risk of stroke recurrence. Understanding the genetic risk factors for stroke recurrence will help guide future prevention strategies. Hypothesis: Genetically-elevated LDL-cholesterol (LDL-c) negatively impact clinical trajectories after stroke, leading to higher risk of post-stroke acute vascular events. Methods: We analyzed clinical and genetic data from the Vitamin Intervention Stroke Prevention (VISP) clinical trial, which examined high-dose vitamins in stroke survivors. Genetic susceptibility to increased LDL-c was modeled through a polygenic risk score built with genetic data on 38 known genetic risk variants for LDL-cholesterol (variants influencing other lipid traits were excluded). We divided the LDL-related polygenic risk score into 0-20, 20-80, and 80-100 percentile categories labeled as low, intermediate and high genetic predisposition to high LDL. We fitted multivariable (adjusting for age, sex, vascular risk factors, and statin treatment) Cox proportional hazards and logistic regression models to test whether higher polygenic risk for elevated LDL-c was associated with observed LDL-c, ischemic stroke recurrence, and composite risk of ischemic stroke and myocardial infarction. Results: Of the 2,164 stroke survivors enrolled in VISP, 1,567 (72%) had available LDL-c and genetic data. The mean LDL in the low, intermediate and high polygenic risk categories was 114.5 (SD 2.21), 123.2 (SD 1.23), and 128.8 (SD 2.35), respectively (unadjusted p<0.001). Compared to stroke survivors with low polygenic risk, those with intermediate (HR 1.52, 95% CI 0.91-2.54) and high (HR 2.03, 95% CI 1.14-3.61) polygenic risk had significantly higher risk of stroke recurrence (p test-for-trend 0.01). We observed similar associations when evaluating the composite risk of stroke and myocardial infarction (all p<0.05) and when conducting these analyses using logistic regression (all p<0.05). Conclusions: A higher polygenic risk for increased LDL-c is associated with worse clinical trajectories after stroke. Further research is needed to determine whether stroke survivors with an elevated genetic risk benefit from unique care pathways with additional monitoring and treatment.