In this study, we found that higher SII before coronary angiography was significantly and independently associated with the presence of CSFP. The SII level in patients with CSFP was significantly elevated and increased with the number of vessels involved and was also positively correlated with mTFC. Multivariate regression analysis indicated that SII/10 was an independent predictor of CSFP. To the best of our knowledge, this is the first study in the literature reporting the relationship between SII and CSFP.
CSFP is an angiographic phenomenon with specific pathogenesis and diagnostic criteria [2], which usually occurs in young men, smokers and those with comorbid metabolic syndrome [16]. Similarly, in our study, CSFP was more common in men, smokers, and patients with diabetes mellitus and hypertension. The main clinical symptom of CSFP is unstable angina pectoris, although CSFP is usually a benign phenomenon, it has also been reported to be associated with life-threatening adverse cardiovascular events such as acute coronary syndrome, ventricular fibrillation, and sudden cardiac death [17]. The exact pathophysiological mechanisms of CSFP are still unclear, but inflammation [4, 18], diffuse atherosclerosis [8, 19], microvascular [20] and endothelial dysfunction [7], and oxidative stress [21] have been thought to be involved. In addition, cardiovascular risk factors such as diabetes mellitus and hypertension [22, 23], lipid index such as HDL cholesterol and triglyceride, and conventional clinical parameters including fasting glucose, uric acid, etc. were also considered to be associated with CSFP [16, 24, 25]. As in line with previous studies, we also found the prevalence of diabetes mellitus and hypertension and fasting glucose levels were significantly higher in the CSFP group, whereas HDL cholesterol was significantly lower in the CSFP group as compared with the control group.
Inflammation plays an important role in the development of CSFP, neutrophils can infiltrate endothelial tissue and release pro-oxidants and pro-inflammatory mediators, which in turn can form neutrophil extracellular traps (NETs) and promote the formation and development of atherosclerotic plaques [26, 27]. Doğan et al [15] reported NLR as an inflammatory marker to be associated with the presence of CSFP. It has also been reported that high sensitive CRP (hs-CPR) may be an early indicator that could predict the occurrence of CSFP [18]. While SII as an inflammatory marker has been suggested to be related to some cardiovascular diseases, for example, one study showed that SII can act as a circulating immune inflammatory cell to predict major cardiovascular events after coronary intervention in patients with coronary heart disease [9]. Another study concluded that elevated SII may have a predictive value for coronary artery dilation [28]. Similarly, the values of inflammatory indicator such as white blood cell count, NLR, and SII were significantly higher in the CSFP group than in the control group in this study. On the other hand, lymphocyte levels decrease in number during chronic inflammation due to stress response. In addition to increased apoptosis, downregulation of proliferation and redistribution of lymphocytes can lead to low lymphocyte counts [29, 30]. Furthermore, a decrease in lymphocyte counts also has an effect on cardiovascular disease, as found by Major et al [31] in experimental studies in B-cell-deficient mice where a low lymphocyte count promoted atherosclerosis, and another study also showed that low lymphocyte counts were associated with poor prognosis in cardiovascular disease [32]. Similarly, our study showed that patients in the case group had lower lymphocyte counts and higher NLR, PLR and SII. These findings all suggest that SII, an indicator of inflammation, may be a causative factor for CSFP. Platelets play an important connecting role in inflammation, thrombosis, and atherosclerosis formation. Platelets can recruit leukocytes and monocytes to the site of inflammation and secrete inflammatory mediators such as chemokines and cytokines, which can lead to vascular inflammation [33]. At the same time, enhanced thrombosis is related to the development of CSFP as well, and it has been documented that the platelet activation ability is enhanced in CSFP patients, when compared with controls [34]. Akboga et al [22] also found that PLR was not only significantly correlated with CSFP as an inflammatory indicator, but also could lead to the occurrence of CSFP through enhanced pro-systemic coagulant activity. The results of this study also confirmed that platelet, PLR, and SII levels were higher in the CSFP group. In addition, it has been reported that SII is superior to NLR and PLR in predicting the occurrence of certain cardiovascular diseases [10, 11, 30]. The present study also found no significant difference in PLR between the two groups and that NLR was not a predictor of CSFP in the regression model, suggesting that SII could better predict the occurrence of CSFP compared with NLR and PLR.
Diffuse atherosclerosis has also been shown to be an important causative factor in cardiovascular diseases such as CSFP. Avşar et al [35] reported that carotid intima-media thickness (CIMT) was a marker of early atherosclerosis in blood vessels and that CIMT was significantly increased in patients with CSFP. It has also been demonstrated that NLR and SII are significantly associated with atherosclerosis, as in a study by Kaya et al [36] who found NLR to be a predictor of severe coronary atherosclerosis and another study which showed that SII was one of the risk factors for atherosclerosis in predicting the severity of coronary artery lesions [10]. The present study also demonstrated that the NLR and SII levels were significantly higher in the CSFP group compared to the control group, and that SII was positively correlated with mTFC and increased with an increase in the number of coronary arteries involved. Therefore, SII may also assume an important role in the development of CSFP through atherosclerosis.
limitations
Our study has some potential limitations. Firstly, this study was a single-centre study with a relatively small sample size and no long-term follow-up of the patients with CSFP. Secondly, we did not measure C-reactive protein, an inflammatory mediator. Further confirmation is needed in more rigorous large-scale, prospective, and randomized controlled studies.