Cardiovascular health, genetic susceptibility, and the risk of ischemic stroke: A large prospective cohort study

Ischemic stroke (IS) remains a major cause of death and disability. We assessed the association between cardiovascular health (CVH), quantified by Life's Essential 8 (LE8), and incident IS, and examined whether polygenic risk score (PRS) modifies this association.

We studied 234,991 UK Biobank participants with no history of ischemic stroke at baseline (median age 58 years [IQR, 50-64]; range, 37-73), evaluating CVH with the LE8 score, categorized as low (< 50), intermediate (50-79), or high (≥80). Genetic risk was assessed using a GWAS-derived PRS, classified into low (Q1), intermediate (Q2-Q4), or high (Q5). Cox models were used to estimate IS hazard ratios, with analyses performed for subgroups, joint effects, and interactions.

During a median follow-up of 13.6 years, 4220 IS cases were identified. Each 10-point increase in LE8 was associated with an 18% lower risk of IS (HR = 0.82, 95% CI: 0.80-0.84). Compared with low CVH, intermediate and high CVH were linked to 37% and 51% lower IS risks, respectively. Stronger protective effects were observed among women and younger adults. Joint analyses indicated that high CVH substantially reduced the excess IS risk in participants with high PRS.

Better CVH is linearly and inversely associated with ischemic stroke risk, with greater benefits in women and younger adults. Optimal CVH can lower the additional risk in people with a high genetic predisposition, endorsing the joint application of CVH evaluation and PRS for IS risk assessment and targeted prevention.