Although there has been a great interest in identifying the underlying mechanisms of CSFP, the etiology and pathogenesis remain uncertain. Coronary microcirculation dysfunction and impaired endothelial functions seem to play an important role in the etiopathogenesis of CSFP [26-27]. Zengin et al. found a significant positive correlation between Urotensin-II and CSFP, and demonstrated that Urotensin-II may be one of the underlying factors in the pathogenesis of CSFP. When vascular endothelium dependent relaxation function is impaired, various stimulators, such as endothelin, homocysteine, prostaglandin H2 and peroxyanion phase equilibrium, do not produce vasodilation and instead, induce vasoconstriction. This causes abnormal vascular endothelial metabolism, injury of coronary microvascular endothelial function and endothelial dysfunction, eventually leading to CSFP [29-31]. One study found that the abnormalities in nail fold capillaries suggesting the presence of inflammation and anatomical changes were significantly higher in patients with CSFP .
Moreover, Soylu et al. encountered significant elevations in the hematocrit level, and erythrocyte, eosinophil and basophil counts in the CSFP patients compared to those with normal coronary blood flow, despite the causative mechanisms are unclear, the results presented to the increases in hematocrit levels and in the eosinophil and basophil counts may have direct or indirect effects on the rate of coronary blood flow. Aksan et al.  found that the elevated neutrophil gelatinase-associated lipocalin levels might be a useful tool in predicting slow coronary flow phenomenon in patients. CSFP can leads to significant alterations in the myocardial deformation parameters of the left ventricle, specifically, circumferential deformation parameters are affected in CSFP patients .
One study showed that the level of serum inflammatory factors in patients with chronic coronary flow was significantly high, suggesting that an inflammatory mechanism may be involved in the occurrence and development of CSFP . However, the exact mechanisms underlying CSFP caused by early atherosclerosis as well as the role of CXCL9 chemokines are still unclear. Our previous studies have shown that CXCL9 is an important risk factor for the occurrence and severity of coronary heart disease . In this work, we found that there was no significant difference between the CSFP group and the no-CSFP group in gender, age, BMI, WHR, blood pressure and LVEF. However, there was a significant difference with smoking habits and the prevalence of diabetes between the two groups (p<0.05), which is consistent with previous clinical studies. This also confirms that such factors may be critical risk factors for atherosclerosis and may also be involved in the occurrence of CSFP. Further analysis indicated that the serum levels of hsCRP, Hcy, IL-1, IL-6, IL-10, and CD40L and IFN-γ in the CSFP group were significantly higher than those in the no-CSFP group, suggesting that these factors may play an important role in the occurrence and development of CSFP.
In order to find new molecular targets for CSFP, we compared the serum levels of CXCL9 between the two groups. Remarkably, we found that serum CXCL9 levels in CSFP patients were significantly higher than those in the no-CSFP group (p<0.01). Furthermore, the statistically significant positive association was observed between the serum levels of IL-1, IL-6, IL-10 and the mean TIMI frame count and the serum CXCL9 level. So we speculate that CXCL9 may play an important role in the occurrence and development of CSFP through IL-1, IL-6 and IL-10. The multivariate logistic regression analysis revealed that serum CXCL9 levels may be an important risk factor for CSFP. To further explore the applicability of serum CXCL9 levels as a potential diagnostic biomarker of CSFP, ROC curve analyses were performed. The results indicated that the serum CXCL9 levels has high diagnostic value to CSFP (AUC=0.758), and the ROC curve revealed that the serum CXCL9 level of 131.915 mg/L was a predictor of CSFP, with a sensitivity of 54.3% and a specificity of 96.0%.
Although the role of CXCL9 in CSFP has not been reported previously, some scholars have pointed out that CXCL8 may be an important factor in CSFP. The expression of CXCL8 in CSFP patients is significant [23, 29]. This study offers perspective on the role of chemokines in CSFP. We found that CXCL9 is positively correlated with CSFP, hence providing a new molecular target for the pathogenesis of CSFP. Based on our results, we speculate that the up-regulation of inflammatory cytokines (such as IL-1, IL-6 and IL-10) in CSFP patients may be regulated by CXCL9. Our analysis suggests that the role of CXCL9 in CSFP, which supports the existing literature that inflammation promotes slow coronary flow, is a complex interaction between CXCL9 and the interleukin family. For example, previous studies have shown that IL-18 can promote the expression of CXCL9, while the latter affects vascular endothelial function through vascular factors such as vascular endothelial growth factor [37-38]. In addition, CXCL9 can activate more interleukins and exacerbate the prognosis of cardiovascular diseases. CXCL9 may also be involved in more complex inflammation signaling pathways in the progress of coronary CSFP, such as inflammation corpuscles. In particular, CXCL9 may further induce interleukin production and obstruct coronary blood flow via recruitment or activation of NLRP1 and NLRP3 inflammatory corpuscles. However, such hypotheses must be explored in animal and basic histology studies.
In brief, we explored the association between the CXCL9 and CSFP in patients with CAD in the study. It indicates that CXCL9 may play an important role in the occurrence and development of CSFP. Although our research has unveiled a potential correlation between CXCL9 and the occurrence of CSFP, there should be a larger sample coherents to clarify the role and mechanism of CXCL9 in CSFP.