Inflammatory profiling in ANOCA: IL-6 predicts cardiovascular events independent of coronary microvascular dysfunction

Background Women with angina and no obstructive coronary artery disease (ANOCA) remain at increased cardiovascular risk, likely in part driven by systemic inflammation and coronary microvascular dysfunction (CMD). Interleukin-6 (IL-6) is a key inflammatory mediator associated with cardiovascular events in the general population and with CMD in women with ANOCA. We aimed to investigate whether IL-6 identifies a cardiometabolic high-risk phenotype and whether IL-6 predicts long-term cardiovascular prognosis in women with ANOCA, more on whether its prognostic value is influenced by CMD. Methods We studied 1,636 women with stable angina and <50% coronary stenosis from the iPOWER (Improving Diagnosis and Treatment of Women with Angina Pectoris and Microvascular Disease) cohort. Key exclusion criteria in the iPOWER cohort were suspected non-ischemic chest pain, reduced left ventricular ejection fraction (<45%), prior myocardial infarction or coronary revascularization and severe comorbidity. Plasma IL-6 was measured at baseline. The primary outcomes was a composite of cardiovascular death, myocardial infarction, revascularization, ischemic stroke, and heart failure. Associations with outcome were assessed using Fine-Gray sub distribution hazard model including non-cardiovascular death as a competing risk adjusted for age and cardiovascular risk factors. Prespecified subgroup analyses included assessment of potential effect modification by CMD defined as coronary flow velocity reserve (CFVR) <2.0. Results Higher IL-6 was associated with a cardiometabolically shifted phenotype characterized by adiposity, diabetes, a high triglyceride–low HDL-C lipid profile and reduced CFVR. During a median follow-up of 10.8 years, 250 women (15.3%) experienced major adverse cardiovascular events (MACE). Doubling in IL-6 was associated with increased risk of MACE (subdistribution hazard ratio (SHR) 1.19, 95% confidence interval (CI): 1.03-1.37). The association was independent of CMD (unadjusted SHR: 1.30 vs 1.27). Conclusion IL-6 identified an inflammation-driven cardiometabolic high-risk phenotype in women with ANOCA and independently predicted major adverse cardiovascular events. Its prognostic value was not explained by CMD, underscoring IL-6 as a clinically relevant marker of long-term cardiovascular risk.