Association of reduced Cu,Zn-superoxide dismutase with coronary microvascular dysfunction-An observational study of oxidative stress markers-

Background Coronary microvascular dysfunction (CMD) is increasingly recognized as a key contributor to angina and non-obstructive coronary arteries (ANOCA) and adverse cardiovascular outcomes. Despite its clinical importance, the molecular basis of CMD remains to be fully elucidated. CMD is known to be associated with systemic microvascular endothelial dysfunction. Methods We examined serum levels of molecules crucial for endothelium-dependent vasodilation, especially nitric oxide (NO)- mediated responses and endothelium-dependent hyperpolarizing responses. These included caveolin-1 (Cav1), endothelial NO synthase (eNOS), and Cu,Zn-superoxide dismutase (Cu,Zn-SOD) in patients with ANOCA enrolled in the nationwide registry by the Japanese Association of CMD. Results This multicenter study included 295 ANOCA patients (M/F 134/161, mean age 63.7 ± 13.9 years). All patients underwent coronary flow reserve (CFR) and index of microcirculatory resistance (IMR) measurements for CMD diagnosis. Serum Cav1, eNOS, and Cu,Zn-SOD levels were quantified by enzyme-linked immunosorbent assay. CMD was identified in 43% of patients who showed significantly lower Cu,Zn-SOD levels than non-CMD patients (P = 0.001). In patients with abnormal IMR, Cu,Zn-SOD was particularly reduced, while those with both abnormal CFR and IMR had reduced Cav1. In contrast, eNOS levels did not differ significantly between groups. Multivariable logistic regression analysis revealed that Cu,Zn-SOD levels below the cut-off value (97.2 ng/ml) independently predicted CMD [odds ratio (95% confidence interval) 2.71 (1.56–4.74), P < 0.001]. Conclusions Reduced Cu,Zn-SOD levels are associated with CMD, suggesting enhanced systemic oxidative stress. This reduction may impair the endothelium-derived hyperpolarizing factor pathway, thereby contributing to CMD pathophysiology.