A Mendelian randomization analysis of the relationship between cardioembolic risk factors and ischemic stroke

Observational studies have shown that several risk factors are associated with cardioembolic stroke. However, whether such associations reflect causality remains unknown. We aimed to determine whether established and provisional cardioembolic risk factors are causally associated with cardioembolic stroke. Genetic instruments for atrial fibrillation (AF), myocardial infarction (MI), electrocardiogram (ECG) indices and N-terminal pro-brain natriuretic peptide (NT-pro BNP) were obtained from large genetic consortiums. Summarized data of ischemic stroke and its subtypes were extracted from the MEGASTROKE consortium. Causal estimates were calculated by applying inverse-variance weighted analysis, weighted median analysis, simple median analysis and Mendelian randomization (MR)-Egger regression. Genetically predicted AF was significantly associated with higher odds of ischemic stroke (odds ratio (OR): 1.20, 95% confidence intervals (CI): 1.16-1.24, P=6.53x10(-30)) and cardioembolic stroke (OR: 1.95, 95% CI: 1.85-2.06, P=8.81x10(-125)). Suggestive associations were found between genetically determined resting heart rate and higher odds of ischemic stroke (OR: 1.01, 95% CI: 1.00-1.02, P=0.005), large-artery atherosclerotic stroke (OR: 1.02, 95% CI: 1.00-1.04, P=0.026) and cardioembolic stroke (OR: 1.02, 95% CI: 1.00-1.04, P=0.028). There was no causal association of P-wave terminal force in the precordial lead V1 (PTFVI), P-wave duration (PWD), NT-pro BNP or PR interval with ischemic stroke or any subtype.