INTRODUCTION

New-onset atrial fibrillation (NOAF) is the most prevalent arrhythmic complication in patients undergoing coronary artery bypass grafting (CABG). While the prevalence of atrial fibrillation (AF) in the general population is 1-2%, the frequency of NOAF development following CABG is 25-40%. Parallel to the improvements in surgery, the prevalence of NOAF development increases even more due to the advanced ages of the operated patients^[1]. Patients with postoperative NOAF have an extended hospitalization and an increased risk of developing various complications such as cardiac events, kidney failure, infection, and cerebral infarction^[2].

It is suggested that many pathophysiological factors during the operation, such as myocardial damage and ischemia, catecholamine discharge, and oxidative stress, cause postoperative NOAF development^[3,4]. However, the underlying reason behind the significant differences in NOAF development in some patients, despite having similar risk factors, is still unknown. After all, many studies report a strong and independent association between the increase in inflammation and various inflammatory markers and NOAF development after CABG^[5,6]. Nevertheless, NOAF development following CABG procedures continues to be a severe complication. Therefore, early risk prediction for postoperative NOAF development before the operation is critical, and new biomarkers are needed to predict it.

Scholars previously showed that the systemic immune-inflammation index (SII), a recently introduced inflammation parameter, can be a strong prognostic indicator of adverse outcomes in various cancer types^[7]. Previous studies suggest that biomarkers, such as neutrophil/lymphocyte ratio (NLR) and platelet/lymphocyte ratio (PLR) — relying on neutrophil, lymphocyte, and platelet counts —, can be used as prognostic indicators in various cardiovascular diseases, as well as for NOAF after CABG^[8]. However, there is no previous study on the relationship between SII levels after CABG and NOAF development. Hence, in this study, we investigated the relationship between SII and NOAF development in patients after CABG, and, to the best of our knowledge, this was the first study exploring such a relationship.

METHODS

RESULTS

In our study, NOAF occurred in 80 (20.4%) of 392 patients. We discovered that 73 (91.3%) of these patients developed AF within the first 2-3 days during ICU follow-up. The mean age of those who developed NOAF was 59 years (52.5-62). Among them, 57 were males and 23 were females. The mean age of patients without NOAF was 53 years (47-62). Among them, 245 were males and 67 were females. Patients who developed NOAF were statistically significantly older (P=0.03). In the group of patients who developed NOAF, while hypertension (HT) history was significantly prevalent, LVEF was significantly lower (P=0.011 and P<0.001, respectively). Other baseline features and preoperative medications did not show statistically significant differences between the groups (Table 1).

Table 1 - Demographic characteristics of the study populations.

Considering the laboratory findings, the platelet count (265 [240-342] vs. 232 [194-255]; P<0.0001) and neutrophil count (7.4 [4.5-8.5] vs. 4.0 [3-6.5]; P<0.001) were significantly higher in the group who developed NOAF. Also, CRP levels were significantly higher in the group developing NOAF (4.7 [2.3-6.4] vs. 2.8 [1.1-4]; P<0.001); PLR levels were significantly higher in patients with NOAF (191 [122-241] vs. 126 [93-207]; P<0.001), and NLR levels were significantly higher (3.9 [3-5.9] vs. 2.6 [1.6-3.3]; P<0.001) in the group developing NOAF. When evaluated in terms of SII, a novel inflammation marker, we discovered SII levels to be statistically higher (1109 [720-2013] vs. 609 [373-754]; P<0.0001) in the group with NOAF (Table 2). The correlation analysis revealed that SII was well associated with CRP levels (r=0.777; P<0.001).

Table 2 - Laboratory findings of the study populations.

On the other hand, there was no significant difference between the groups in the operative and postoperative variables (Table 1). And the groups did not significantly differ in mortality and neurological complications.

In addition, we evaluated the role of various risk factors in NOAF development with the help of a multivariate analysis. We run multivariate logistic regression analysis with variables shown to be associated with NOAF development in the univariate analysis, such as age, HT, LVEF, and SII (Table 3).

Table 3 - Univariate and multivariate logistic regression analyses of independent parameters for atrial fibrillation.

The multivariate logistic regression analysis showed that high SII level (odds ratio [OR]: 1.001, 95% confidence interval [CI]: 1.001-1.002; P<0.001) together with LVEF (OR: 0.922, 95% CI: 0.897-0.947; P<0.001) and high CRP level (OR: 1.108, 95% CI: 0.987-1.244; P=0.046) were independent predictors of NOAF development (Table 3).

The SII levels > 712.8 predicted NOAF with a sensitivity of 85% and a specificity of 61.2% (AUC: 0.781, 95% CI: 0.727-0.835; P<0.001). For NLR, a cutoff value of 2.96 predicted the development of NOAF with a sensitivity of 82.5% and specificity of 57%, and the AUC was 0.724 (95% CI: 0.669-0.780; P<0.001). For CRP, a cutoff value of 4 predicted the development of NOAF with a sensitivity of 57.5% and specificity of 81.7%, and the AUC was 0.634 (95% CI: 0.564-0.704; P<0.001).

ROC curves were compared to assess whether SII had an additional discriminative value over serum CRP and NLR levels. We found that SII had a higher accuracy in predicting NOAF compared with serum NLR alone (SII vs. NLR, AUC: 0.781 vs. 0.724, z=4.117; P<0.0001). Also, the SII value had similar discriminatory power in predicting NOAF when compared with the CRP (SII vs. CRP, AUC: 0.781 vs. 0.634, z =2.824; P=0.0047). However, CRP and NLR had a similar accuracy for predicting NOAF (NLR vs. CRP, AUC: 0.724 vs. 0.634, z=1.732; P=0.0833) (Figure 1).

Fig. 1 - Effect of systemic immune-inflammation index (SII), neutrophil/lymphocyte ratio (NLR), and C-reactive protein (CRP) values on new-onset atrial fibrillation after coronary artery bypass grafting (receiver operating characteristic analysis). AUC=area under the curve; CI=confidence interval; SE=standard error

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Fig. 1 - Effect of systemic immune-inflammation index (SII), neutrophil/lymphocyte ratio (NLR), and C-reactive protein (CRP) values on new-onset atrial fibrillation after coronary artery bypass grafting (receiver operating characteristic analysis). AUC=area under the curve; CI=confidence interval; SE=standard error

In addition, to better evaluate the prognostic significance of SII on NOAF, we selected 153 patients from the non-NOAF group whose characteristics were similar to the group with AF. We discovered that SII levels continued to be statistically higher than those without NOAF. (Table 4). When we re-performed the regression analysis with SII and CRP, which were shown to have an effect on the development of NOAF, high SII level (OR: 1.002, 95% CI: 1.001-1.002; P<0.001) as well as high CRP level (OR: 1.121, 95% CI: 1.013-1.241; P=0.004) were also independent predictors of NOAF development (Table 5).

Table 4 - Demographic characteristics of the study populations (matched group from non-new-onset atrial fibrillation group).

Table 5 - Univariate and multivariate logistic regression analyses of independent parameters for atrial fibrillation.

DISCUSSION

In our study, we focused on the relationship between SII and NOAF development after CABG. Blood samples taken from patients developing NOAF after CABG had dramatically higher CRP, NLR, and SII levels compared to those who did not develop NOAF. The most striking finding of this study was that the SII level was the most effective predictor for patients with NOAF, among all other variables.

Postoperative NOAF is the most prevalent arrhythmic complication after the cardiac operations and is seen almost 50 times more than in the general population^[10]. Postoperative NOAF development increases problems, such as a longer stay in an ICU, morbidity, and higher treatment costs^[11]. Male gender, advanced age, chronic obstructive pulmonary disease, HT, and lower LVEF are the well-known risk factors for NOAF development^[12]. Our findings are consistent with the literature, and low LVEF was found to be an independent predictor of the development of NOAF after CABG^[12].

Although the pathophysiological mechanisms leading to AF development are not fully and accurately revealed, previous studies proved that inflammation, increased inflammatory response, and oxidative stress play an important role in the development and progression of AF^[3,13-14]. Gibson et al.^[15] and Ji et al.^[16] showed a relationship between NLR and CRP levels in the NOAF development in patients undergoing CABG. Gungor et al.^[5] proved that patients with preoperative high PLR levels are at higher risk of NOAF after CABG. In our study, our results on NLR and CRP were consistent with the results of previous studies. However, we could not find a relationship between PLR and NOAF.

It is a prevailed idea that SII can define the immune and inflammatory status in patients more comprehensively than single-component (neutrophils, lymphocytes, and platelets) and two-component (PLR and NLR) inflammatory predictors. Indeed, the results obtained from recent studies showed that high SII levels are superior to NLR and PLR in predicting the risk of adverse clinical outcomes in patients with various diseases^[7]. With its increasing popularity in recent years, its use in the evaluation of cardiovascular diseases has gained substantial momentum.

Huang et al.^[8] found that increased SII levels in ST-elevation myocardial infarction patients treated with percutaneous coronary intervention are associated with both long- and short-term poor clinical outcomes. In addition, Erdoğan et al.^[17] found that SII elevation is an independent predictor for determining functionally significant coronary stenosis detected by fractional flow reserve in patients with chronic coronary syndrome. Our study resulted in a strong relationship between NOAF and SII after CABG. Compared to previous studies, we found that SII was the most robust and independent marker, among others, associated with NOAF development. We also found that the optimal cutoff point for SII was 712.8, which predicted NOAF development after CABG with 85% sensitivity and 61.2% specificity.

We speculate that some mechanisms mediate SII, which leads it to be the most potent predictive marker that contributes to NOAF formation compared to other markers. As it is known, increased neutrophil represents the activation of inflammation, while lymphopenia is an indicator of physiological stress. NLR shows the balance between neutrophil and lymphocyte counts and can be considered as a measure of the response to stress as well as systemic inflammation. There are studies showing that CABG is associated with neutrophil activation and may cause perioperative myocardial damage^[18]. In addition, neutrophils can cause hypercoagulability and are associated with reperfusion injury^[19]. It is obvious that CABG causes serious stress, and it is reasonable to cause a decrease in lymphocyte count. Increased NLR levels are associated with developing arrhythmias^[6,20,21]. Platelets play an important role in hemostasis, which is a physiological response occurring to prevent extravasation of the blood when vascular damage happens. In addition, they have both an inflammatory effect and activate the immune system by releasing chemokines and cytokines^[22]. Moreover, Scott et al.^[23] and Jalife et al.^[24] reported that infiltration of the myocardial tissue of the atrium by leukocytes, as well as some inflammatory cytokines released by both leukocytes and platelets, can cause AF through multiple mechanisms such as promoting atrial electrical, structural, and contractile remodeling.

Our findings are consistent with previous reports highlighting the relationship between inflammation and AF development. The hallmark of the present study was the comparison of several inflammatory markers (neutrophil, lymphocyte, NLR, PLR, and CRP) that were previously shown to be associated with the development of postoperative NOAF in patients.

CONCLUSION

In conclusion, the current study results uncovered that SII, which shows the inflammatory state as a useful, simple, easily measurable, and cheap indicator, is the most robust inflammatory marker that predicts NOAF risk in patients after CABG. More comprehensive and multicenter studies should be conducted to propose a better analysis of all possible predictors of AF.