Mendelian Randomization Study of Heart Failure and Stroke Subtypes

BACKGROUND: Whether heart failure (HF) is an independent risk factor of ischemic stroke (IS) and hemorrhagic stroke remains controversial. We employed a multivariable Mendelian randomization (MR) to further investigate the causal effects of HF on the risk of stroke and stroke subtypes. METHODS: Genetically predicted HF was selected as an instrumental variable (IV) from published genome-wide association studies (GWAS) meta-analyses. Stroke data with different etiologies were extracted as outcome variables from another two GWAS meta-analyses. The random-effects inverse variance-weighted (IVW) model was applied as the main method, along with sensitivity analysis. Atrial fibrillation (AF), coronary heart disease (CHD), and systolic blood pressure (SBP) were controlled for mediating effects in multivariable MR. RESULTS: Genetically predicted HF was significantly associated with any IS [odds ratio (OR), 1.39; 95% CI, 1.12–1.74; p = 0.03], large artery stroke (LAS; OR, 1.84; 95% CI, 1.27–2.65; p = 0.001), and cardioembolic stroke (CES; OR, 1.73; 95% CI, 1.21–2.47; p = 0.003), but without small vessel stroke (SVS; OR, 1.1; 95% CI, 0.80–1.52; p = 0.56) and intracerebral hemorrhage (ICH; OR, 0.86; 95% CI, 0.41–1.83; p = 0.699) in univariable MR. However, these significant associations were attenuated to the null after adjusting for confounding factor in multivariable MR. CONCLUSION: There was no direct causal association between HF and stroke in our study. The association between HF and IS can be driven by AF, CHD, and SBP.