U-Shaped Relationship of High-Density Lipoprotein Cholesterol and Incidence of Total, Ischemic and Hemorrhagic Stroke: A Prospective Cohort Study

Background: We aimed to investigate the association between serially measured HDL-C (high-density lipoprotein cholesterol) levels and stroke risk in a prospective cohort study. Methods: We included 96 258 individuals (79.6% men, mean age 51.5 years) without a history of stroke, myocardial infarction, or cancer at baseline from the Kailuan Study, with repeated measurements of HDL-C in 2006, 2008, 2010, 2012, 2014, and 2016. Cumulatively, averaged HDL-C concentrations were calculated using all available HDL-C measurements before incidence stroke or end of follow-up (December 31, 2017). Incident stroke cases were confirmed by review of medical records and further subclassified into ischemic or hemorrhagic stroke. Cox proportional hazards regression and restricted cubic splines were used to examine these associations. Results: During a median follow-up of 10.7 years, 5012 incident stroke cases occurred. Restricted cubic splines analysis suggested a U-shaped association between concentrations of cumulatively averaged HDL-C and risk of stroke (P-nonlinearity <0.001), with the nadir of risk at 1.29 mmol/L. After adjustment for cardiovascular risk factors, individuals with cumulatively averaged HDL-C <= 1.06 mmol/L or >= 2.05 mmol/L had hazard ratios for total stroke of 1.31 (95% CI, 1.15-1.49) and 1.85 (1.63-2.09) compared with those with HDL-C of 1.26 to 1.39 mmol/L. Corresponding hazard ratios were 1.29 (1.11-1.48) and 1.84 (1.60-2.11) for ischemic stroke and 1.54 (1.12-2.12) and 2.29 (1.73-3.04) for hemorrhagic stroke, respectively. Conclusions: Both low and high cumulatively averaged HDL-C were associated with an increased risk of ischemic and hemorrhagic strokes.