Introduction
It is known that type 2 diabetes mellitus (DM) and coronary artery disease (CAD) are comorbid illnesses [1]. According to traditional concepts and common prognosis scales (Framingham Risk Score and SCORE), DM is an important risk factor for cardiovascular complications [2]. DM has a major impact on prognosis in patients with multivessel atherosclerosis after revascularization. Large randomized trials demonstrated a preference for coronary artery bypass grafting (CABG) over percutaneous interventions and conservative strategy in patients with DM [3-5]. At present, the search for new biomarkers predicting adverse cardiovascular events in patients after CABG is relevant. Visfatin/NAMPT (nicotinamide phosphoribosyltransferase) is an adipocytokine associated with metabolic disorders, endothelial dysfunction, and systemic inflammation [6]. It was previously shown that high levels of visfatin may contribute to vascular inflammation and destabilization of atherosclerotic plaques [7-9].
In connection with the aforementioned, our study aimed to evaluate the prognostic value of type 2 DM and visfatin level in blood serum in patients undergoing CABG.
Material and Methods
Study sample and design
A total of 103 patients with chronic heart failure (CHF) and stable multivessel CAD hospitalized for elective CABG were included in the study. The inclusion criteria were patients with CHF, triple vessel CAD revealed by invasive coronary angiography, atherosclerotic plaques ≥ 50% of the vessel lumen in the anterior descending, circumflex and right coronary arteries, or the presence of left coronary artery stenosis in combination with damage to the right coronary artery. The exclusion criteria were as follows: severe respiratory failure (exacerbation of chronic obstructive pulmonary disease, uncontrolled course of bronchial asthma), diagnosed cancer, acute or aggravated chronic infectious disease, and myocardial infarction or progressive angina less than three months ago.
All patients were examined according to the algorithm including the review of the anamnesis, and clinical examination with determination of body mass index (ratio of body weight in kilograms to the square of height in meters), as well as the symptoms, and signs of heart failure. The instrumental examination included 12-lead electrocardiography (ECG) and transthoracic echocardiography performed by a trained professional [10]. All tests were done before the surgery.
In addition, routine blood tests were performed. The estimated glomerular filtration rate (eGFR) was calculated using the CKD-EPI equation. Coronary angiography was conducted according to clinical indications within two months of inclusion in the study.
DM was diagnosed in compliance with the guidelines [11]. The duration of DM history was analyzed from medical records.
The study was approved by the local institutional Ethics Committee (Protocol No. 188 of September 18, 2018), and all patients signed the written informed consent prior to the study.
The clinical outcomes and adverse cardiovascular events were analyzed 12 months after CABG: the median duration of the follow-up period (Me[IQR]) was (16 [13; 22]) months. The composite endpoints were represented by death due to a cardiovascular event, decompensated heart failure, the need for intravenous diuretic therapy or doubling of the loop diuretics dose, acute ischemic stroke requiring unplanned revascularization, and acute cerebrovascular accident. The patients were distributed between two groups based on registration of composite endpoints: Group 1 (without registration of composite endpoints, n=71), and Group 2 (with the development of composite endpoint, n=32).
Biomarker quantification
The concentration of the N-terminal pro-B-type natriuretic peptide (NT-proBNP) was determined via enzyme immunoassay method using the diagnostic kit by Biomedica Medizinprodukte GmbH (Austria) before CABG and 10 days after it. Creatine kinase myocardial band (CK-MB) activity was determined before CABG and on the first day after it.
The concentration of serum visfatin (ng/mL) was determined by enzyme-linked immunosorbent assay technique using RayBio® Human/Mouse/Rat Visfatin Enzyme Immunoassay Kit before CABG and 10 days after it in all patients. The difference in visfatin levels before and after CABG was calculated using the following formula:
(1)
Statistical data processing
Data were analyzed using the STATISTICA 10.0 and demo version of IBM SPSS software. Continuous variables are presented as median (Me) and interquartile range (IQR) considering their non-normal distributions. Categorical data are presented in absolute and relative values (n [%]). Continuous variables in the independent samples were analyzed using Wilcoxon rank sum test. For categorical variables, statistical significance of differences was determined using Pearson’s χ2 test and the two-sided Fisher’s exact test. The correlation between variables was assessed by calculating the Spearman’s rank correlation coefficient. The survival analysis in the studied groups was carried out using the Kaplan-Meier estimator, and the comparison of the two curves was performed using the log-rank test. The predictive power was calculated using the ROC analysis. Receiver operating characteristic (ROC) curves were drawn for visfatin level and registration of the composite endpoints. The area under the curve (AUC) was measured. The statistical significance was assumed at p <0.05.
Results
Main characteristics of the patients are presented in Table 1. The studied groups did not differ significantly in terms of main clinical characteristics and medical history. However, the patients of Group 2 more often had a history of myocardial infarction (and 81.2% vs. 60.1%, p=0.039).
Table 1. Main characteristics of patients with chronic heart failure and multivessel atherosclerosis of coronary arteries depending on the development of composite endpoints
|
Parameter |
Group 1 (n=71) |
Group 2 (n=32) |
p-value |
|
Men/women, n (%) |
64/7 (90.1; 9.9) |
27/5 (84.4/15.6) |
0.389 |
|
Age, years |
63 (59; 68) |
91 (58; 64) |
0.282 |
|
Smokers, n (%) |
20 (28.1) |
10 (31.3) |
0.750 |
|
Previous acute cerebrovascular accident, n (%) |
3 (4.2) |
2 (6.2) |
0.658 |
|
Previous myocardial infarction, n (%) |
43 (60.1) |
26 (81.2) |
0.039 |
|
Time since last myocardial infarction, months |
32.5 (4.25;158.5) |
20 (5; 131) |
0.889 |
|
Duration of CAD, years |
3 (1; 12) |
3 (1.5; 11) |
0.792 |
|
Angina pectoris, Class I, n (%) |
5 (7) |
1 (3.1) |
0.353 |
|
Angina pectoris, Class II, n (%) |
32 (45.1) |
11 (34.4) |
|
|
Angina pectoris, Class III, n (%) |
34 (47.9) |
20 (62.5) |
|
|
Angina pectoris, Class IV, n (%) |
0 |
0 |
|
|
Heart failure, I sensu NYHA, n (%) |
8 (11.3) |
2 (6.2) |
0.422 |
|
Heart failure, II sensu NYHA, n (%) |
39 (54.9) |
14 (43.8) |
|
|
Heart failure, III sensu NYHA, n (%) |
24 (33.8) |
16 (50) |
|
|
Heart failure, IV sensu NYHA, n (%) |
0 |
0 |
|
|
Heart failure with reduced ejection fraction (LVEF ≤40%) |
21 (29.5) |
13 (40.6) |
0.249 |
|
Heart failure with mildly reduced ejection fraction (LVEF 41-49%) |
11 (15.5) |
3 (9.4) |
|
|
Heart failure with preserved ejection fraction (LVEF≥50%) |
39 (55) |
16 (50) |
|
|
Arrhythmias, n (%) |
36 (50.7) |
11 (34.4) |
0.123 |
|
Body mass index, kg/m2 |
28 (25,1; 31,2) |
29 (25.3;31.8) |
0.491 |
|
Obesity, Grade I |
23 (32.4) |
9 (28.1) |
0.454 |
|
Obesity, Grade II |
2 (2.8) |
2 (6.2) |
|
|
Obesity, Grade III |
1 (1.4) |
2 (6.2) |
|
|
Diabetes mellitus, n (%) |
16 (22.5) |
10 (31.2) |
0.346 |
|
Duration of diabetes mellitus, years |
2 (1.5; 5.75) |
9 (5.5;14.5) |
0.001 |
|
Glomerular filtration rate before CABG (CKD-EPI), mL/min/1.73m2 |
72 (60.5; 79.8) |
67.5 (55.3;75) |
0.204 |
|
Glomerular filtration rate after CABG (CKD-EPI), mL/min/1.73m2 |
74 (64; 85) |
73.2 (58;80.6) |
0.318 |
|
Left ventricular ejection fraction, % |
55 (38; 63.5) |
50 (30.75; 64) |
0.562 |
|
NT-proBNP before CABG, pg/mL |
187.5 (128; 397.2) |
225 (130;626) |
0.321 |
|
NT-proBNP after CABG, pg/mL |
248 (155;461) |
280 (180;650) |
0.409 |
|
Creatine kinase myocardial band before CABG, unit/L |
17 (13; 22.5) |
14 (16.5; 18) |
0.645 |
|
Creatine kinase myocardial band after CABG, unit/L |
25.6 (18;48) |
24.8 (16.3; 51) |
0.782 |
|
Visfatin concentration before CABG, ng/mL |
10.1 (9.49;20.1) |
12.3 (9.7; 26.4) |
0.416 |
|
Visfatin concentration after CABG, ng/mL |
9.49 (9.59; 15.5) |
16.7 (14.4; 21.9) |
0.015 |
|
Δ Visfatin, % |
0.83 (-6; 19.7) |
21.4 (0.03; 45.5) |
0.022 |
The diagnosis of DM was established in 22.5% (n=16) of Group 1 patients vs. 31.2% (n=10) of Group 2 subjects (p=0.346). DM was first diagnosed during the current hospitalization in 6 patients of Group 1 vs. none in Group 2. The duration of DM differed significantly between study groups: 2 (1.5; 5) years in Group 1 and 9 (5.75; 14.5 years) in Group 2 (p=0.001). Kaplan-Meier time-to-event endpoint analysis demonstrated that patients with duration of DM over 5 years experienced significantly earlier and more frequent adverse cardiovascular events after CABG vs. patients without DM and patients with duration of DM less than 5 years (Figures 1A, 1B). At the same time, the endpoint frequencies did not differ between patients without DM and patients with duration of DM less than 5 years (Figure 1C), as well as between all patients with DM and subjects without DM (Figure 1D).
Figure 1. Survival rate of patients after CABG versus the duration of type 2 diabetes mellitus.
1A: 1 – patients with duration of DM less than 5 years (n=13); 2 – patients without DM (n=77); 3 – patients with duration of DM more than 5 years (n=13) (р=0.049).1B: 1 – patients without DM and patients with duration of DM less than 5 years (n=90); 2 – patients with duration of DM more than 5 years (n=13) (р=0.003). 1C: 1 – patients with duration of DM less than 5 years (n=13); 2 – patients without DM (n=77) (р=0.362). 1D: 1 – patients without DM (n=77); 2 – patients with DM (n=26) (р=0.154).
The levels of visfatin in the blood serum before CABG did not differ between the groups (p=0.416), whereas its concentration 10 days after CABG was significantly higher in Group 2 (Table 1). The dynamics of the visfatin level (Δ visfatin) differed significantly between the groups: Δ visfatin indicator was 0.83 (-6; 19.7) % in Group 1 vs. 21.4 (0.03; 45.5) % in Group 2 (p=0.022). ROC analysis revealed that the AUC of visfatin level 10 days after CABG was 0.748 (p=0.016) (Figure 2A), while it was 0.68 (p=0.096) for the Δ visfatin indicator (Figure 2B).
Figure 2. ROC curve for visfatin level and registration of a composite endpoint.
2A: ROC curve of visfatin concentration after CABG and development of endpoints in prospective observation (AUC=0.75; p=0.016); 2B: ROC curve of difference in visfatin concentrations before and after CABG and development of endpoints in prospective observation (AUC=0.68; p=0.096).
The correlation between DM duration and Δ visfatin indicator was calculated (r=0.54, p=0.041) (Figure 3).
Figure 3. Correlation between difference in visfatin concentrations before and after CABG and duration of type 2 diabetes mellitus (r=0.54, p=0.041).
At the same time, the visfatin level did not depend on the presence of DM in the general cohort (Table 2). Furthermore, visfatin levels before and after CABG were not associated with the body mass index (r=-0.07, p=0.653; r=-0.15, p=0.368) and age (0.18, p=0.2; -0.81, p=0.611).
Table 2. Visfatin concentration and its dynamics depending on the presence of diabetes mellitus.
|
Parameter, Me(IQR) |
DM- |
DM+ |
p |
|
Visfatin level before CABG, ng/mL |
11.8(9.8;26.7) |
10.4(9.4;14.8) |
0.184 |
|
Visfatin level after CABG, ng/mL |
9.8(9.5;19.8) |
13.4(9.9;16.8) |
0.526 |
|
Δ Visfatin, % |
-2.5(-23;6.8) |
9.6(-0.9;41.7) |
0.021 |
There was no association of the ejection fraction with endpoint development between groups of patients with different values of left ventricular ejection fraction (p=0.582) (Figure 4).
Figure 4. Survival rate of patients after CABG based on left ventricular ejection fraction
1 – Heart failure with reduced ejection fraction (LVEF ≤40%); 2 – heart failure with mildly reduced ejection fraction (LVEF 41-49%); 3 – heart failure with preserved ejection fraction (LVEF ≥50%).
Discussion
Visfatin is an adipocytokine with some additional properties that are not fully understood yet [6]. The extracellular form of visfatin was shown to be associated with metabolic disorders including obesity and DM. T. Dogru et al. demonstrated that visfatin concentrations increased in patients with DM, but not in patients with impaired carbohydrate tolerance. The authors concluded that visfatin levels did not increase at the early stages of insulin resistance [12]. This finding was confirmed by our results, since the level of visfatin after CABG increased to a lesser extent in patients with DM less than 5 years. There are conflicting data on the relationship between the level of visfatin and the degree of obesity [6]. We did not obtain data on the relationship between the body mass index and visfatin concentration before and after CABG.
It is known that visfatin is one of the key factors in the synthesis of nicotinamide adenine dinucleotide (NAD+). It participates in the pathways of cellular metabolism [13] and possesses proinflammatory effects, including mediating the inflammasome activation [14]. H. Duman et al. established that the level of visfatin, along with the presence of DM, was associated with the severity of coronary atherosclerosis in patients with CAD [15]. In our study, all patients had multivessel coronary artery disease, and therefore their levels of visfatin were initially higher than in the group with less pronounced atherosclerosis, as was shown by H. Duman et al. (8.6 ± 4.2 ng/mL) [15]. However, the dynamics of visfatin level in patients after CABG was not studied to date. According to our results, a significant increase in the concentration of visfatin after CABG is a predictor of adverse cardiovascular events.
Besides, we demonstrated an adverse effect of a longer DM duration on the development of a composite endpoint after CABG, which was consistent with previous data from a cohort of patients with myocardial infarction [16, 17].
At the same time, the concentrations of NT-proBNP and CK-MB did not differ between the groups and were not associated with the endpoint one year after CABG. There was no association of ejection fraction with endpoint development between groups of patients with different values of left ventricular ejection fraction. According to the study by A. Marui et al. (2015) performed on 1,877 patients undergoing CABG (CREDO-Kyoto registry), 236 patients had left ventricular ejection fraction (LVEF) of ≤50% and 152 patients with heart failure had preserved ejection fraction (LVEF>50%). After adjusting for confounding factors, the risk of cardiac arrest and sudden cardiac death did not differ between the groups [18].
The limitation of our study was a small sample size of the patient group with DM, which could affect the level of statistical significance of the assessed differences. Also, we had no data on cardiac troponin concentrations after CABG.
Conclusion
In patients after CABG, the duration of DM had a negative impact on the development of cardiovascular events. With a duration of DM of over 5 years, the risk of adverse events increased significantly. An increase in visfatin level 10 days after CABG was associated with the duration of DM and the development of adverse cardiovascular events in patients. Hence, monitoring the visfatin levels before CABG and 10 days after it and assessing its dynamics can help predicting adverse cardiovascular events in patients.
Data availability
The data used to support the findings of this study are available from the corresponding author upon reasonable request.
Conflict of interest
The authors declare that they have neither apparent or potential conflicts of interest related to the publication of this article.
Funding
This study was supported by the public procurement: FSR # 122020300045-5 (3 February 2022).
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Received 18 October 2022, Revised 13 December 2022, Accepted 9 March 2023
© 2023, Russian Open Medical Journa
Correspondence to Elena A. Kuzheleva. E-mail: kea@cardio-tomsk.ru.
