Low-grade inflammation plays an important role in the development and progression of coronary and heart failure [11]. It has been demonstrated in experimental and clinical studies that atherosclerosis is an inflammatory disease [31–33. ].
Exposure to cardiovascular risk factors leads to loss of protective endothelium and accumulation of low-density lipoproteins in the subendothelial space of the vascular wall, which causes a low inflammatory response [34]. At the same time, an increase in the concentration of certain inflammatory biomarkers, including immune cell populations and inflammasomes, allows the prediction of the progression of CAD regardless of traditional risk factors [35–37]. In our study, the content of highly sensitive C-reactive protein (CRP), as well as traditional inflammatory parameters of general blood analysis (leukocytes, erythrocyte sedimentation rate (ESR)), was not associated with the development of MACE. This was probably because the study included patients with planned cardiac surgery, which excluded patients with inflammation. Recently, the literature has focused on inflammatory index reflecting low-grade systemic inflammation, such as the NLR, platelet-to-lymphocyte ratio (PLR), and neutrophil*platelet/lymphocyte ratio, which is a systemic immune-inflammation index (SII) [38–39].
The neutrophil-to-lymphocyte ratio is one of the foremost considered, widely available indicators reflecting the processes of systemic inflammation. It is now widely used in almost all branches of medicine as an easily accessible and informative marker of the immune response to communicable and noncommunicable agents. The pathogenetic meaning of this marker is explained by the fact that the NLR reflects a dynamic relationship between congenital (neutrophils) and adaptive (lymphocytes) cell immune responses during the development and progression of disease. The normal range of NLR values is 1–2, and values above 3.0 and below 0.7 in adults are pathological. A slight increase in NLR between 2.3 and 3.0 may be an early sign of disease, including atherosclerotic genesis [40].
According to the literature, broadly accessible markers that demonstrate associations with the closest prognosis in patients after CABG. For example, an increase in NLR above 8.34 in patients after CABG was associated with PPS [16], and an increase in NLR above 2.13 in any period (before or after CABG) was associated with a high risk of developing or relapsing AF [18].
In addition, the NLR value above 2.675 prior to the CABG operation was associated with the insolvency of the subcutaneous vein transplant, but this study [22] failed to achieve the required level of statistical significance (p = 0.075). In another study [24], increases in NLR > 6.4 and 31.8 in the first hour and day after surgery, respectively, were closely related to mortality.
In patients with chronic total occlusion of coronary arteries, the NLR and its dynamics after PCI were associated with the development of MACE for 9–12 months of observation [41]. However, we have not been able to find such data in the literature for patients who have undergone CABG with artificial circulation.
Thus, its role in predicting delayed outcomes in patients after CABG has not been determined to date. In our cohort, the NLR value was not associated with the development of MACE at the prospective one-year observation (AUC = 0,565; р=0,368). This may be partly because NLR is affected by many conditions, including age, the presence of chronic diseases, including DM, obesity, psychiatric diagnosis, cancer, anemia and stress [42].
Growth differentiation factor 15, or macrophage inhibitory cytokine-1, acts as a marker of inflammation and plays a role in cardiovascular pathogenesis, metabolic disorders and neurodegenerative processes. Levels of GDF-15 in serum also increase with aging and in response to cell stress and mitochondrial dysfunction [43]. Recently, the role of GDF-15 in aging and metabolic disorders has been actively discussed by the scientific community. Notably, the GDF-15 receptor, its underlying signaling pathways and biological effects are poorly understood [44].
Some studies have demonstrated the role of GDF-15 in predicting adverse outcomes in CHF, both with a reduced fraction of the left ventricle ejection [45] and with a preserved fraction of the left ventricle ejection [46]. At the same time, the dynamics of GDF-15 concentration in patients with decompensation of heart failure reflected the increased risk of repeated hospitalization and death in the RELAX-AHF study [47].
However, GDF-15 remains a relatively poorly studied marker for CABG patients. There is conflicting evidence in the literature regarding the association of GDF-15 with the development of adverse cardiovascular events in CABG patients. Bouchot O. et al. [27] showed that low GDF-15 values are associated with the development of postoperative AF. However, other studies have demonstrated that high GDF-15 values are unfavorable and associated with the development of AKI [43].
In addition, a study by Matthias Heringlake et al. [30] showed that the plasma GDF-15 level prior to CABG is an independent predictor of postoperative mortality and morbidity in cardiac patients. This is an important addition to known scales for risk stratification in these patients.
In our cohort, there was also no statistically significant association with the development of MACEs during the one-year observation period (AUC = 0,621; р=0,096).
However, given the wide variety of immune processes and the lack of evidence for a correlation between GDF-15 and NLR, we performed a correlation analysis between GDF-15 and NLR. No significant linear correlation was found (r= -0,184, p = 0.102). At the same time, a visual examination of the scattering diagram (Fig. 3) led us to conclude that there was a nonlinear relationship between these parameters. This relationship, according to the distribution of points on the scattering graph, could be a hyperbola. In this case, the product of NLR and GDF-15 would have a separate predictive value. The literature does not describe such data, so we propose a scientific hypothesis. According to the ROC analysis, the AUC for predicting MACEs was 0.648 (p = 0.011). The cutoff point for the NLR*GDF-15 product was found to be 3216. It predicts the development of MACE with a sensitivity of 68% and a specificity of 52%.
It is crucial to note that the statistically significant association of the product NLR*GDF-15 with the development of MACE in patients who underwent CABG remained after the introduction of amendments to sex, age, presence of DM, and LVEF. Therefore, this indicator was an independent predictor of adverse cardiovascular events. The results are new and have not been previously obtained in other studies. This could be the basis for new scientific hypotheses and new large-scale studies.
Study limitations: the main limitation is the small sample size, which is partially offset by the high homogeneity of the group, excluding any additional cardiac surgery, severe associated pathology, including inflammatory etiology. More studies are needed to confirm these results.