Background: and Purpose We performed a two-sample Mendelian randomization (MR) analysis to evaluate the causal effect of genetically proxied AMP-activated protein kinase (AMPK) activation, which is the target of metformin, on functional outcome following ischemic stroke onset. Methods: A total of 44 AMPK-related variants associated with HbA1c (%) were used as instruments for AMPK activation. The primary outcome was the modified Rankin Scale (mRS) score at 3 months following the onset of ischemic stroke, evaluated as a dichotomous variable (3–6 vs. 0–2) and subsequently as an ordinal variable. Summary-level data for the 3-month mRS were obtained from the Genetics of Ischemic Stroke Functional Outcome network, including 6,165 patients with ischemic stroke. The inverse-variance weighted method was used to obtain causal estimates. The alternative MR methods were used for sensitivity analysis. Results: Genetically predicted AMPK activation was significantly associated with lower odds of poor functional outcome (mRS 3–6 vs. 0–2, odds ratio [OR]: 0.06, 95% confidence interval [CI]: 0.01–0.49, P=0.009). This association was maintained when 3-month mRS was analyzed as an ordinal variable. Similar results were observed in the sensitivity analyses, and there was no evidence of pleiotropy. Conclusion This MR study provided evidence that AMPK activation by metformin may exert beneficial effects on functional outcome following ischemic stroke.

Background: and Purpose Left ventricular hypertrophy (LVH) is associated with the risk of stroke and dementia independently of other vascular risk factors, but its association with cerebral small vessel disease (CSVD) remains unknown. Here, we employed a systematic review and meta-analysis to address this gap.
Methods: Following the MOOSE guidelines (PROSPERO protocol: CRD42018110305), we systematically searched the literature for studies exploring the association between LVH or left ventricular (LV) mass, with neuroimaging markers of CSVD (lacunes, white matter hyperintensities [WMHs], cerebral microbleeds [CMBs]). We evaluated risk of bias and pooled association estimates with random-effects meta-analyses.
Results: We identified 31 studies (n=25,562) meeting our eligibility criteria. In meta-analysis, LVH was associated with lacunes and extensive WMHs in studies of the general population (odds ratio [OR]lacunes, 1.49; 95% confidence interval [CI], 1.12 to 2.00) (ORWMH, 1.73; 95% CI, 1.38 to 2.17) and studies in highrisk populations (ORlacunes: 2.39; 95% CI, 1.32 to 4.32) (ORWMH, 2.01; 95% CI, 1.45 to 2.80). The results remained stable in general population studies adjusting for hypertension and other vascular risk factors, as well as in sub-analyses by LVH assessment method (echocardiography/electrocardiogram), study design (cross-sectional/cohort), and study quality. Across LV morphology patterns, we found gradually increasing ORs for concentric remodelling, eccentric hypertrophy, and concentric hypertrophy, as compared to normal LV geometry. LVH was further associated with CMBs in high-risk population studies.
Conclusions LVH is associated with neuroimaging markers of CSVD independently of hypertension and other vascular risk factors. Our findings suggest LVH as a novel risk factor for CSVD and highlight the link between subclinical heart and brain damage.