Blood Levels of Angiotensinogen and Risk of Ischemic Stroke: The Multi‐Ethnic Study of Atherosclerosis

Background We investigated whether circulating angiotensinogen levels are associated with the risk of ischemic stroke and examined sex‐specific differences. Methods We included 5622 participants (mean age, 62.7 years; 52% women) free of cardiovascular disease at baseline (2000–2002) and followed them through 2020. Cox models assessed the association between angiotensinogen and ischemic stroke, including sex‐stratified hazard ratios (HRs) with 95% CIs. Mediation analyses estimated the contribution of risk factors to observed associations. Subgroup analyses with multiplicative interaction testing were conducted. Results During follow‐up, 283 ischemic stroke events occurred. Each 1‐SD increase in log‐transformed angiotensinogen was associated with a 16% higher stroke risk (HR, 1.16 95% CI, 1.00–1.34). Significant interaction with sex was observed ( P interaction20 μg/mL) tertiles, respectively ( P trend=0.004). Diabetes marginally mediated the association in men (proportion mediated, 0.04 95% CI, 0.00–0.15). Significant evidence of an association between angiotensinogen and ischemic stroke in women was not observed (HR, 1.07 95% CI, 0.88–1.29 per SD). No significant multiplicative interactions were observed across subgroups defined by age, race, smoking status, diabetes, obesity, angiotensin‐converting enzyme inhibitor/angiotensin II receptor blocker use, hypertension, chronic kidney disease, and high‐sensitivity C‐reactive protein levels in either sex after Bonferroni correction (all P interaction>0.002). Conclusions Higher circulating angiotensinogen levels are associated with an increased risk of ischemic stroke in men, independent of blood pressure.