Women with angina and no obstructive coronary artery disease: IL-6 identifies a cardiometabolic high-risk phenotype and predicts cardiovascular events

AIMS: Interleukin-6 (IL-6) has been linked to major adverse cardiovascular events (MACE) in the general population. Among women with angina and no obstructive coronary artery disease (ANOCA), IL-6 has been associated with coronary microvascular dysfunction (CMD), a known driver of risk in this population. We aimed to investigate whether IL-6 identifies a cardiometabolic high-risk phenotype and predicts long-term cardiovascular outcomes in women with ANOCA, and whether its prognostic value is modified by CMD. METHODS AND RESULTS: The iPOWER cohort included 1853 women with stable angina and <50% coronary stenosis at coronary angiography. Of these, 1636 had measures of plasma IL-6 at baseline. The primary outcome was a composite of cardiovascular death, myocardial infarction, revascularization, ischaemic stroke, and heart failure. Associations with outcomes were assessed using Cox proportional hazards models adjusted for age and cardiovascular risk factors, with prespecified subgroup analyses, including assessment of potential effect modification by CMD assessed by TTE-derived coronary flow velocity reserve (CFVR). Higher IL-6 was associated with a cardiometabolically shifted phenotype characterized by adiposity, diabetes, a high triglyceride-high-density lipoprotein-cholesterol lipid profile, and reduced CFVR. During a median follow-up of 10.8 years, 250 women (15.3%) experienced MACE. IL-6 predicted MACE [hazard ratios (HR) 1.23, 95% confidence interval 1.07-1.41]. The association did not vary by CMD status (HR 1.25 vs. 1.16). CONCLUSION: IL-6 identifies an inflammation-driven cardiometabolic high-risk phenotype in women with ANOCA and independently predicts MACE. The prognostic value of IL-6 does not depend on CMD, underscoring IL-6 as a clinically relevant marker of long-term cardiovascular risk.