Introduction

Diseases of the circulatory system, with a observed steady upward trend in the number of cases, remain the leading cause of mortality in developed countries [1]. In the Russian Federation, about one-third of all deaths among individuals over the age of 35 are attributed to coronary artery disease (CAD) [2].

The pathogenesis of CAD, a condition characterized by an imbalance between myocardial oxygen demand and adequate blood supply, is fundamentally linked to atherosclerotic lesions of the coronary arteries. Atherogenesis, as a typical pathological process, is closely associated with the phenomenon of oxidative stress — an imbalance between the release of reactive oxygen species (ROS) and the activity of neutralizing antioxidant defense mechanisms [3]. Despite the possibilities of conservative therapy, in some cases myocardial revascularization is an irreplaceable treatment method for CAD patients, capable of improving both prognosis and quality of life. Surgical treatment of CAD is inevitably accompanied by reperfusion injury, an inflammatory response, and intensified ROS production, collectively contributing to the development of postoperative complications [4, 5].

Adequate assessment of the oxidative status of a macroorganism is a complex task due to the impossibility of direct quantitative measurement of reactive particles in vivo because of their instability, the multitude of interconnections between components of systems responsible for homeostasis, and their dynamic changes. Consequently, in most studies addressing the issue of oxidative stress, the assessment of oxidative balance is carried out using indirect methods [6].

Investigating parameters of induced blood oxidation does not allow for the quantitative measurement of oxidant or antioxidant content. However, it reflects the interaction of a large number of factors influencing free radical oxidation over time, which, it appears, allows for "modeling oxidative stress" and thereby getting closer to in vivo conditions.

Thus, studying induced blood oxidation parameters and their relationship with clinical and laboratory parameters, as well as the revascularization technique, appears to be a promising task. Solving it could personalize the approach to managing CAD patients and predicting possible complications after revascularization.

Materials and methods

The study group consisted of 89 patients with stable coronary artery disease, including 64 patients with a history of myocardial infarction (the PMI group). The control group comprised 24 healthy volunteers, comparable in age and sex to the study group. Coronary artery bypass grafting was performed on 64 patients; indications for revascularization were determined in accordance with current clinical guidelines. All patients in the study group received baseline prognosis-modifying conservative therapy for CAD. Evaluated parameters included anamnestic data, cardiovascular disease risk factors (arterial hypertension, diabetes mellitus, smoking, excess body weight), laboratory findings (complete blood count and biochemical blood analysis), and instrumental parameters (echocardiography, 24-hour electrocardiogram monitoring, coronary angiography). Cognitive status was assessed using the Mini-Mental State Examination (MMSE) questionnaire.

Assessment of induced blood oxidation (IBO) parameters was performed using a YSI 5300 biological oxygen monitor (Yellow Springs Instrument Co., Inc., USA). Free radical oxidation of blood components was induced by the water-soluble initiator AAPH (2,2'-azobis(2-amidinopropane) dihydrochloride). IBO parameters were evaluated upon admission (Time point 1 — B1), 10 days after surgery (Time point 2 — B2), and 6 months after surgery (Time point 3 — B3). It was experimentally established that the oxygen consumption process occurs non-linearly.

Based on the slope of the oxygen concentration curve in the sample, the following were determined:

Statistical data processing was performed using the STATISTICA 10.0 software package (StatSoft Inc., USA). The normality of the distribution of quantitative traits was checked using the Kolmogorov-Smirnov test with the Lilliefors correction. Homogeneity of qualitative traits was assessed based on contingency table analysis. Equality of population variances was tested using Fisher's and Cochran's tests.

Due to the non-normal distribution of the studied quantitative traits, medians and interquartile ranges were calculated. The interquartile range was indicated as the 25th and 75th percentiles. The presented data are expressed as Me (25.0%; 75.0%).

For comparing two independent groups by a single trait, the Mann-Whitney U test, χ² test, and Fisher's exact test were used. Dependent groups were compared using the Wilcoxon signed-rank test. For one-factor comparison of three or more independent groups, ANOVA (analysis of variances) by Kruskal-Wallis, the median test, and the χ² test were used. Nonparametric analysis of variance for three or more dependent groups was performed using Friedman's ANOVA.

To study the relationship between two traits, Spearman's rank correlation analysis was used. The nature of the dependence of a trait on one or more other traits was investigated using logistic regression analysis.

Results and discussion

In a comparative aspect, patients with CAD demonstrated higher (p <0.05) values of induced blood oxidation parameters (Vox, Vinit, Vmax) and the oxidative activity coefficient (KA), and a shorter (p <0.05) initiation period (T) (Table 1) compared to healthy volunteers. This indicates an intensification of free radical oxidation processes in this patient group.

Table 1. Comparative analysis of induced blood oxidation parameters in the group of patients with coronary artery disease compared to healthy individuals

ParameterControl Group (n=24)CAD (n=89)pBlood oxidation rate (Vox), 10-8 mol/L·s1.90 (1.7; 2.2)2.07 (1.8; 2.3)0.049Initiation period time (T), min1.91 (1.3; 2.5)0.97 (0.67; 1.34)0.001Initial oxidation rate (Vinit), 10-8 mol/L·s2.11 (1.6; 2.9)3.29 (2.5; 4.83)0.0001Maximum oxidation rate (Vmax), 10-8 mol/L·s2.54 (2.1; 3.1)3.5 (2.76; 4.83)0.001Oxidative activity coefficient (KA), %5.89 (-11.0; 22.7)40 (15.65; 55.5)0.0001

It was established that patients with CAD exhibit higher values of markers associated with increased ROS production, even in the absence of obstructive lesions [7, 8].

A total of 6 cases of fatal outcomes were recorded. No statistically significant differences in IBO parameters were found in the overall group (n=89) depending on fatal outcome. However, in the group of patients with a history of myocardial infarction (PMI) (n=64), the blood oxidation rate Vox in deceased patients was statistically significantly higher (2.3 (2.3; 2.5) vs. 1.9 (1.7; 2.3), respectively; p = 0.04).

Coronary artery bypass grafting using a cardiopulmonary bypass machine (on-pump) was performed in 31 patients, while off-pump surgery on the beating heart was performed in 33 patients. In a comparative aspect, no statistically significant differences were observed in IBO parameter values during the postoperative period between patients who underwent off-pump surgery and those who underwent surgery with cardiopulmonary bypass. In patients whose surgery was performed under CPB, an increase in time T and a decrease in Vmax values were observed after 6 months (p <0.05). In the off-pump group, 10 days after surgery (B2), a decrease in time T and an increase in Vinit, Vmax, and KA were observed (p <0.05). After 6 months (B3), these parameters were comparable to preoperative values (B1) (Table 2). Thus, it was concluded that changes in parameters characterizing oxidative status during revascularization are transient in nature and do not depend on the chosen method of coronary artery bypass grafting.

Table 2. Dynamics of induced blood oxidation parameters depending on the revascularization technique

ParameterOn-pump (n=31)  Off-pump (n=33)   B1B2B3B1B2B3T0.83 4 (0.63; 1.04)1.04 (0.67; 1.5)1.17 1 (0.9; 1.7)1.14 (0.79; 1.38)0.75 2 (0.57; 1.16)1.17 3 (0.99; 1.44)Vinit3.73 (3.07; 4.5)3.5 (2.3; 4.46)3.08 (2.16; 3.56)2.9 (2.3; 4.06)3.93 2 (2.8; 5.49)2.91 3 (2.41; 3.46)Vmax3.8 (3.1; 4.5)3.73 (2.63; 5.03)3.1 1 (2.3; 3.56)3.03 (2.68; 4.28)4.13 2 (3.03; 5.49)2.96 3 (2.6; 3.53)KA46.15 (21.8; 56.8)39.4 (17.2; 61.95)28.72 (9.24; 45.7)27.6 (9.26; 48.72)38.68 2 (32.14; 68.0)30.98 3 (20.23; 36.56)Notes: 1 ---- On-pump B1-B3 -- p <0.05; 2 ---- Off-pump B1-B2 -- p <0.05;3 ---- Off-pump B2-B3 -- p <0.05; 4 ---- On-pump and Off-pump B1 comparison -- p <0.05.

Inevitable consequences of coronary artery bypass grafting are the systemic inflammatory response and the closely related oxidative stress [9], which are typically transient in nature [10]. One of the mechanisms responsible for increased ROS production after revascularization is the ischemia-reperfusion phenomenon, where restoration of blood flow can even exacerbate myocardial damage [11].

Cardiac arrhythmias (atrial fibrillation, ventricular and supraventricular extrasystole) were registered in the early postoperative period in 45 patients. The results of logistic regression analysis demonstrated a statistically significant (p=0.0001) effect of the blood oxidation rate (Vox) on the development of cardiac arrhythmias. A statistically significant (p=0.013) effect of the terminal blood oxidation rate (Vterm) on the development of supraventricular extrasystole was also registered during off-pump revascularization.

Atrial fibrillation (AF), being one of the most common cardiac arrhythmias in the population, is the most frequent early postoperative complication after coronary artery bypass grafting [12]. It has been established that the intensification of ROS production after revascularization contributes additionally to arrhythmogenesis through cellular calcium overload, resulting from activation of the ryanodine receptor-2 (RYR-2) and mediated effects on fibroblast proliferation with subsequent structural remodeling of atrial tissue [13-15].

Cognitive status was assessed using the MMSE questionnaire. A total of 3 cases of postoperative cognitive dysfunction were registered, occurring exclusively in the group of patients with high Vox values (>2.29×10-8 mol/L·s, p=0.035). The results of logistic regression analysis established a significant effect of Vox value on the development of postoperative cognitive dysfunction (p=0.004).

Oxidative stress, developing in the context of ischemia-reperfusion, exhibits a neurodegenerative effect by inhibiting mitochondrial respiration and thereby promoting the accumulation of free radicals in brain tissue, which is extremely sensitive to harmful effects due to weak endogenous antioxidant defense [16, 17].

Conclusion

Coronary artery disease is accompanied by significant changes in oxidative status, with a shift in balance towards activation of free radical oxidation processes. These processes intensify during myocardial revascularization, which in some cases contributes to the development of complications such as cardiac arrhythmias and cognitive dysfunction. Preoperative monitoring of parameters characterizing oxidative status allows for the identification of a risk group for the development of adverse events during the treatment of patients with CAD.