Causal role of endothelial dysfunction in ischemic stroke and its subtypes: A two-stage analysis

Area of Science:

• Cardiovascular Science
• Neurology
• Genetics

Background:

• Endothelial dysfunction is a known factor in ischemic stroke (IS) pathogenesis.
• The precise causal role of specific endothelial dysfunction proteins in IS remains to be fully elucidated.

Purpose of the Study:

• To systematically investigate the causal relationship between endothelial dysfunction proteins and IS, including its subtypes.
• To integrate observational and genetic evidence for a comprehensive understanding.

Main Methods:

• A two-stage approach combining systematic meta-analysis of 29 observational studies and Mendelian randomization (MR).
• Meta-analysis assessed associations between proteins (vWF, sE-selectin, sP-selectin, ICAM-1, VCAM-1, sLOX-1, VEGF, ET-1, SDF-1) and IS.
• MR analysis utilized genetically instrumental variants to infer causality.

Main Results:

• Meta-analysis confirmed significant correlations between IS and vWF, sE-selectin, ICAM-1, sP-selectin, sLOX-1, and VEGF.
• Mendelian randomization revealed that elevated vWF causally increases IS and cardioembolic stroke (CES) risk.
• E-selectin was found to be causally linked to large-artery atherosclerosis stroke (LAS).

Conclusions:

• Endothelial dysfunction, particularly via vWF's thrombotic activity and E-selectin's inflammatory function, causally contributes to IS subtypes.
• Findings provide mechanistic insights into IS pathogenesis and inform personalized stroke prevention strategies.