Dose-dependent association between elevated resting IL-6 levels and severity of mental stress-induced myocardial perfusion defects

BACKGROUND: Mental stress-induced myocardial ischemia (MSIMI) is common in women with angina with no obstructive coronary artery disease (ANOCA) and is associated with adverse cardiovascular outcomes. Interleukin-6 (IL-6), a central mediator of chronic inflammation, predicts future cardiovascular risk, but its relationship with MSIMI remains unclear. METHODS: N-ammonia positron emission tomography/computed tomography to assess myocardial perfusion and myocardial blood flow (MBF) at rest, during mental stress, and during adenosine-induced stress. Resting inflammatory biomarkers were measured, and multivariable logistic and linear regression models were used to evaluate associations with mental stress-induced perfusion defects. Proteomic profiling was performed in a selected subset to explore potential underlying mechanisms. RESULTS: = 0.024). Although baseline CRP, hsCRP, and complement C3 levels were also higher in MSIMI+ patients, only resting IL-6 remained independently associated with both the presence of MSIMI and the severity of mental stress-induced myocardial perfusion defects after adjustment for demographic, clinical, and psychosocial factors, and resting MBF. Proteomic analyses demonstrated enrichment of innate immune-hemostatic pathways and mitochondrial oxidative phosphorylation in MSIMI+ patients with high IL-6 levels. CONCLUSIONS: Elevated resting IL-6 is independently associated with the presence and severity of MSIMI in women with ANOCA. These findings suggest that IL-6 may serve as a biomarker of MSIMI and support IL-6-related inflammation as a key pathophysiological pathway underlying MSIMI, with potential implications for targeted therapeutic strategies.