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Abstract

Introduction

To investigate the levels of nicotinamide-adenine dinucleotide phosphate oxidase 2 (NOX2) in serum and pericardial drainage samples in the early stage after coronary artery bypass grafting (CABG) and determine whether NOX2 is predictive of postoperative atrial fibrillation (POAF).

Materials and Methods

This prospective pilot study involved 152 adults without history of atrial fibrillation who underwent first-time elective isolated CABG. Serum and pericardial fluid samples were simultaneously obtained from patients at baseline and 4, 12, and 24 h post operation. NOX2 levels were determined using enzyme-linked immunosorbent assays. The heart rhythm of patients was continuously monitored through a Holter monitor until discharge. Logistic regression and receiver-operating characteristic (ROC) curve analyses were performed, as appropriate.

Results

Fifty-one patients (33.6%) experienced in-hospital POAF. NOX2 concentration in serum and pericardial drainage samples was increased after surgery, reached its peak at 12 h, and gradually declined thereafter toward the baseline levels by 24 h. At 12 h, patients with POAF had higher levels of serum NOX2 than those without (3.96 ± 0.35 vs. 3.70 ± 0.75 μg/mL, respectively, p = 0.004). There were no discernible differences in pericardial NOX2 between the 2 groups. Multivariate analysis revealed that serum NOX2 at 12 h post operation was the strongest independent predictor of POAF (odds ratio: 2.179, 95% confidence interval: 1.084–4.377). The area under the ROC curve of the POAF predictive model was 0.732 (95% confidence interval: 0.654–0.801).

Conclusion

Serum NOX2 may be useful in the identification of POAF. Larger studies are warranted to substantiate these findings.

Keywords

coronary artery bypass oxidative stress postoperative atrial fibrillation reactive oxygen species

Introduction

Coronary artery bypass grafting (CABG) surgery has been widely adopted for myocardial revascularization (Glineur et al., 2016). However, despite its benefits, CABG is associated with the development of cardiac- or non-cardiac complications. New-onset postoperative atrial fibrillation (POAF) is one of the most common types of arrhythmias after CABG, with an incidence ranging from 30 to 50% (Filardo et al., 2018; Jawitz et al., 2020; Butt et al., 2019). POAF typically occurs within the first week after the operation, with the peak onset observed at 2–3 days postoperative (Mathew et al., 2004; Seo et al., 2021). Previously, POAF was considered a transient and self-limiting phenomenon. However, emerging studies demonstrated that this complication is linked to substantially worsened outcomes, increasing the risk of cerebrovascular accidents (Seo et al., 2021; Benedetto et al., 2020) and mortality (Woldendorp et al., 2021). Based on its clinical importance, the prevention of POAF is paramount. Although numerous prophylactic and therapeutic measures have been suggested, the prevalence of POAF has not markedly changed over the last few decades (Greenberg et al., 2017). Currently, the etiology of POAF is incompletely understood; nevertheless, a plethora of evidence revealed that oxidative stress plays a crucial role in the initiation of POAF (Dobrev et al., 2019). Oxidative stress indicates an imbalance between the production and neutralization of reactive oxygen species (ROS), which causes cell damage or death (Rodrigo et al., 2021). Research revealed that nicotinamide-adenine dinucleotide phosphate oxidase (NOX) is a major contributor to ROS in the human atrium (Kim et al., 2005). Moreover, significantly increased myocardial NOX activity was found in patients who developed AF after cardiopulmonary bypass (Dudley et al., 2005). Furthermore, previous trials unveiled that the activity of NOX2, a crucial subunit of NOX, was increased in animal models of pacing-induced AF and patients with paroxysmal/persistent AF (Dudley et al., 2005; Reilly et al., 2011; Cangemi et al., 2012). Therefore, NOX2 may be an indicator of POAF.

The studies performed thus far have not investigated the role of NOX2 in the onset of POAF after isolated CABG or the dynamic changes in its levels within 24 h after surgery. Interestingly, there is documented divergence between the incidence rates of POAF following cardiac- and non-cardiac surgeries (Hyun et al., 2021; AlTurki et al., 2020; Kerwin et al., 2020). Therefore, it seems that the complicated focal environment surrounding the heart might contribute to the initiation and perpetuation of POAF. Generally, the pericardium is breached at the time of CABG. Emerging evidence suggests that retained blood after cardiac surgery, which brings highly pro-inflammatory and pro-oxidant molecules to the pericardial space, may trigger POAF (Kramer et al., 2015; St-Onge et al., 2018). Activation of the clotting cascade induced by pericardial retained blood contributes to the inflammatory response that recruits neutrophils from the vasculature lining the pericardium and surface of the heart to the pericardial space and produces cytokines (Szaba & Smiley, 2002). In addition, released methemoglobin through subsequent hemolysis exacerbates the inflammatory environment by activating leukocytes. Ultimately, the white blood cells within the pericardial milieu generate numerous ROS, leading to oxidative stress. Moreover, they prompt lipid peroxidation, thereby damaging atrial cell function. This process is suggested as the potential reason for the development of POAF (Gaudino et al., 2022; Rong et al., 2023). Most previous studies that investigated predisposing factors of POAF focused on the blood or serum. Thus far, evaluations of the effect of pericardial NOX2 on POAF have not been performed. Hence, this pilot study aimed to investigate the levels of NOX2 in serum and pericardial fluid samples during the early period after isolated CABG and test the relationship between NOX2 and the development of POAF.

Materials and Methods

Design and Study Population

The study was performed in accordance with the principles of the Declaration of Helsinki. This investigation was approved (approval code: Z2019SY26) by the ethics review board of Capital Medical University. All patients provided written informed consent for their participation.

This prospective observational pilot study was conducted at the Department of Cardiac Surgery of Anzhen Hospital, a tertiary referral hospital in Beijing, China. Adult patients (age: ≥18 years) with sinus rhythm who were admitted to the department from March 2021 to January 2022 and underwent first-time elective isolated CABG were consecutively recruited. The exclusion criteria were: history of AF or other atrial arrhythmias and inflammatory disorders; occurrence of myocardial infarction and cardiac surgery within the previous 6 months; combination with other cardiac surgery (e.g., valve repair/replacement, or emergent CABG); repeated exploratory thoracotomy, severe heart failure (New York Heart Association Classification Ⅳ); terminal malignancy; and treatment with immunosuppressive and antioxidant medications. Patients with hepatic disease (i.e., more than 3-fold higher alanine aminotransferase or aspartate aminotransferase levels vs. the upper limit of normal) or renal dysfunction (serum creatinine: >2.0 mg/dL) were excluded.

Data Collection

Data including preoperative, intraoperative, and postoperative factors were prospectively recorded by 2 trained investigators. Regular checks of data for missing values or incorrect entries were carried out.

Sample Collection

Preoperative venous blood samples were collected in vacutainer tubes after induction of anesthesia. Baseline pericardial fluid samples were obtained immediately after opening the pericardium using a sterile syringe without a needle. All surgical procedures were performed by a single professional surgical team. Blood samples were maintained at room temperature for 60 min. Samples of serum and pericardial drainage were centrifuged at 3000 r/min for 15 min at 4°C (Centrifuge 5804R, Eppendorf, Germany). Subsequently, the supernatants were collected and frozen at −80°C until analysis. NOX2 levels were determined using an enzyme-linked immunosorbent assay kit (Yanyu Trading Co., Ltd., Shanghai, China) with intra- and inter-assay variability <10% and the lowest detection limit of 0.625 μg/mL. All assays were performed according to the instructions provided by the manufacturers, and the results were analyzed by 2 laboratory technicians who were unaware of the clinical status of patients. The test results became available to the investigators only at the end of the study. Extra blood and pericardial drainage samples were simultaneously obtained from all patients at 4, 12, and 24 h after the operation. To ensure accuracy, the postoperative pericardial drainage tube was maintained empty for at least 1 h prior to sample collection. In almost all patients, the pericardial drainage tubes were removed by 48 h. The pericardial drainage tube was withdrawn when the cumulated volume was <200 mL/24 h.

POAF Monitoring

The primary endpoint was the incidence of POAF, defined as any episode of characteristic AF rhythm (Hindricks et al., 2021) lasting >30 s or requiring medical intervention. Postoperatively, the heart rhythm of patients was continuously monitored using a wearable Holter monitor (RhythmWatch^TM; MicroPort Medical Co., Ltd., Shanghai, China) until discharge from hospital. The accuracy of this equipment for the detection of AF is equivalent to that of a 12-lead electrocardiogram (95% confidence interval [CI]: 94.04–100.00; p = 1.000) (Xiao et al., 2018). Documented electrocardiograms from individual bedside monitors or telemetry were checked daily during the hospital stay. Initially, the identification of POAF was automatically performed by the Holter monitor; next, the data exported from the Holter monitor were manually checked by 2 blinded researchers; any disagreement was resolved through consultation with a senior cardiologist. Thereafter, patients were classified into POAF and non-POAF groups according to the results.

Statistical Analysis

Data are expressed as mean ± standard deviation or median (interquartile range) and percentage of the total (%). The distribution of parameters was examined using the Kolmogorov–Smirnov test. Differences between groups were assessed using Student’s t-test or the Mann–Whitney U test for continuous variables, as appropriate. The chi-squared or Fisher’s exact test was employed for the analysis of categorical variables. Correlation coefficients were determined by Pearson or Spearman’s correlation analyses. Repeated analyses of variance were performed to compare changes in NOX2 levels over time in patients with or without POAF. A logistic regression model using backward stepwise entry of variables was adopted to investigate the association between NOX2 in serum or pericardial fluid and the development of POAF. Only variables with a p-value <0.1 in the univariate analysis were candidates for this model. The receiver operating characteristic (ROC) curve was used to determine the cutoff values of independent variables for POAF identified from the logistic regression. The area under the ROC curve (AUC) was also calculated to investigate the discriminative ability of the prediction models. Analyses were conducted using the SPSS version 25.0 (IBM Corp, Armonk, NY, USA) and MedCalc version 19.7 (MedCalc Software Ltd., Ostend, Belgium) software. The GraphPad prism version 8.0 (GraphPad Software, La Jolla, CA, USA) software was utilized to generate figures. A 2-tailed p-value <0.05 denoted statistically significant differences.

Sample Size Estimation

The sample size was calculated through the logistic regression method using the PASS 15 (NCSS, LLC, Kaysville, UT, USA) software. Previous trials reported that NOX is an independent predictor of AF, with an odds ratio (OR) ranging 1.01–2.41 (Liu et al., 2015; Kim et al., 2008). An OR of 1.90 was adopted in this study to gain a conservative sample size. It was estimated that 121 patients would provide a 2-tailed alpha of 0.05 and a power of 0.90, assuming a 30% rate of POAF (Greenberg et al., 2017).

Results

A total of 152 patients were included in this study; Figure 1 shows the flowchart of patient enrollment. Overall, 51 patients (33.6%) developed in-hospital POAF; in 78.4% (n = 40) of those, POAF occurred within 48–72 h post operation. The demographic and clinical characteristics of the patients are summarized in Table 1. The mean age of the patients was 63.09 ± 8.25 years (80.3% males; 19.7% females). The 2 groups were similar in terms of cardiovascular risk factors, comorbidities, echocardiographic parameters, operative time, laboratory examinations, and numbers of grafts. Nevertheless, patients who developed POAF were older and had larger left atrial diameter than those who remained in sinus rhythm after CABG.

Figure 1.

Flowchart of patient enrollment. POAF, postoperative atrial fibrillation.

Table 1.

Baseline Characteristics of Included Patients.

	POAF (n = 51)	Non-POAF (n = 101)	t/χ²	p-value
Age, mean ± SD (years)	66.55 ± 7.11	61.34 ± 8.27	−3.842	< 0.001
Gender, n (%)			0.697	0.404
Male	39 (76.5)	83 (82.2)
Female	12 (23.5)	18 (17.8)
BMI (kg/m²)	25.62 ± 2.76	25.81 ± 3.22	0.347	0.729
Smoking, n (%)			2.582	0.275
No	21 (41.2)	49 (48.5)
Active smoker	17 (33.3)	37 (36.6)
Ex-smoker	13 (25.5)	15 (14.9)
NYHA classification, n (%)			4.175	0.124
I	10 (19.6)	11 (10.9)
II	34 (66.7)	64 (63.4)
III	7 (13.7)	26 (25.7)
Medical history, n (%)
Diabetes mellitus	19 (37.3)	34 (33.7)	0.192	0.661
Hypertension	32 (62.7)	63 (62.4)	0.002	0.965
Hyperlipemia	10 (19.6)	26 (25.7)	0.706	0.401
COPD	1 (2.0)	—	0.122	0.727
Hypothyroidism	—	3 (3.0)	0.391	0.532
Unstable angina	16 (31.4)	39 (38.6)	0.770	0.380
Myocardial infarction	6 (11.8)	16 (15.8)	0.455	0.500
Stroke	8 (15.7)	17 (16.8)	0.032	0.867
History of PCI, n (%)	9 (17.6)	20 (19.8)	0.102	0.750
Medication, n (%)
Calcium channel blocker	23 (45.1)	46 (45.5)	0.003	0.958
β-blocker	10 (19.6)	18 (17.8)	0.072	0.789
ARB	18 (35.3)	27 (26.7)	1.192	0.275
Statin	28 (54.9)	49 (48.5)	0.553	0.457
Echocardiography
Left atrial diameter (mm)	38 (36, 41)	36 (34, 38)	−3.056	0.002
LVEF, n (%)			0.261	0.610
30–49%	7 (13.7)	11 (10.9)
≥50%	44 (86.3)	90 (89.1)
E/A ratio, n (%)			0.756	0.385
<1	46 (90.2)	86 (85.1)
≥1	5 (9.8)	15 (14.9)
Preoperative laboratory parameters
White blood cells (×10⁹)	6.66 (5.97, 8.41)	7.19 (6.09, 8.15)	−0.663	0.507
C-reactive protein (pg/mL)	3.02 (0.99, 3.02)	1.78 (0.86, 3.02)	−1.353	0.176
K⁺ (mmol/L)	3.90 (3.75, 4.30)	3.98 (3.75, 4.16)	−0.146	0.884
Mg²⁺ (mmol/L)	0.65 (0.56, 0.82)	0.64 (0.57, 0.80)	−0.316	0.752
Hemoglobin	139 (130, 146)	142 (131, 150)	−1.503	0.133
Surgery type, n (%)			1.562	0.211
Off-pump	49 (96.1)	101 (100.0)
On-pump	2 (3.9)	—
Surgery incision, n (%)			0.246	0.620
Large	50 (98.0)	100 (99.0)
Small	1 (2.0)	1 (1.0)
Number of grafts, n (%)			0.205	1.000
1	1 (2.0)	2 (2.0)
2	10 (19.6)	20 (19.8)
≥3	40 (78.4)	79 (78.2)
Use of vasoactive drugs, n (%)	48 (94.1)	93 (92.1)	0.016	0.899
IABP, n (%)	3 (5.9)	1 (1.0)	1.602	0.206
Operative time (h)	3.25 (2.58, 3.65)	3.30 (3.05, 3.78)	−1.296	0.195
Blood loss (mL)	700 (500, 1000)	800 (600, 800)	−0.249	0.804
Pericardial fluid volume (mL)	174.08 ± 167.92	141.33 ± 113.74	−0.664	0.507
Duration of mechanical ventilation (h)	18.17 (14.17, 22.17)	18.08 (13.38, 20.49)	−0.769	0.442
Length of ICU stay (h)	22.00 (16.92, 42.25)	21.83 (17.08, 25.54)	−0.439	0.661
Initiation of treatment with a β-blocker (h)	27.67 (22.83, 48.08)	28.00 (22.28, 43.25)	−0.152	0.879

Note. ARB, angiotensin II receptor blocker; BMI, body mass index; COPD, chronic obstructive pulmonary disease; E/A, late mitral valve inflow velocity/early mitral valve inflow velocity; IABP, intra-aortic balloon counter-pulsation; ICU, intensive care unit; LVEF, left ventricular ejection infarction; NYHA, New York Heart Association; PCI, percutaneous coronary intervention; POAF, postoperative atrial fibrillation.

Trends of NOX2 Levels During the Early Postoperative Stage

In all patients undergoing CABG, the concentration of NOX2 in both serum and pericardial drainage samples was continuously increased post operation, reached its peak at 12 h, and gradually declined thereafter toward the baseline levels by 24 h. NOX2 activity was apparently elevated in the serum compared with pericardial drainage samples at the corresponding time points (Figure 2).

Figure 2.

Trends of NOX2 levels measured in serum and PD samples within 24 h post operation in patients who underwent CABG. CABG, coronary artery bypass grafting; NOX2, nicotinamide-adenine dinucleotide phosphate oxidase 2; PD, pericardial drainage.

Comparison of NOX2 Activity in Serum and Pericardial Drainage Samples After CABG in Patients With and Without POAF

Repeated analyses of variance revealed significant differences in between-subject effects (F = 7.683, p = 0.006) with respect to the levels of serum NOX2; there were no group-by-time effects in pericardial drainage samples over time (Supplemental Table 1). The levels of NOX2 in serum and pericardial drainage samples at different time points were higher in patients with POAF versus those without; the difference noted in the serum samples reached statistical significance at 12 h after surgery (3.96 ± 0.35 vs. 3.70 ± 0.75 μg/mL, respectively, p = 0.004) (Figure 3 and Supplemental Table 1). Weak relationships between serum and pericardial NOX2 levels were revealed only at baseline and 12 h after the operation (Figure 4). These findings implied that pericardial NOX2 may have originated from intrapericardial production. This hypothesis requires further investigation.

Figure 3.

Comparison of NOX2 levels in serum and PD samples obtained from patients with and without POAF at different time points. (A) Patients who developed POAF had higher concentration of NOX2 in the serum across the 24-h time course (P_{between-group} = 0.006), particularly at 12 h (P_{12 h} = 0.004), compared with those who did not. (B) There were no statistically significant differences in the levels of pericardial NOX2 between the 2 groups. In patients who developed POAF, the levels of NOX2 were numerically higher in serum versus pericardial drainage samples. NOX2, nicotinamide-adenine dinucleotide phosphate oxidase 2; POAF, postoperative atrial fibrillation; PD, pericardial drainage; ^*p < 0.05; ^**p < 0.01.

Figure 4.

Correlation analyses of NOX2 levels between serum and pericardial drainage samples at different time points. (A) Before operation. (B) 4 h post operation. (C) 12 h post operation. (D) 24 h post operation. NOX2, nicotinamide-adenine dinucleotide phosphate oxidase 2; PD, pericardial drainage.

NOX2 was an Independent Risk Factor for POAF

A multivariable logistic analysis performed after a univariable analysis with p < 0.10 (except for the variable of serum NOX2 at 12 h post operation) confirmed that age and left atrial diameter were risk factors for POAF (Supplementary Table 2). Thereafter, the postoperative serum concentration of NOX2 at 12 h was added to the analysis. Ultimately, age (OR: 1.092, 95% CI: 1.037–1.149), left atrial diameter (OR: 1.112, 95% CI: 1.009–1.225), and serum NOX2 levels at 12 h post operation (OR: 2.179, 95% CI: 1.084–4.377) were independently associated with the development of POAF (Table 2). The AUC was 0.732 (95% CI: 0.654–0.801); this was slightly higher than the AUC of model 1 (0.712 [95% CI: 0.634–0.783]; ΔAUC, 0.020 [95% CI: −0.20–0.059]; p = 0.33) (Figure 5). The ROC curve demonstrated that the cutoff value of NOX2 was 3.53 μg/mL, and the sensitivity and specificity rates were 98.04% and 35.64%, respectively (Supplemental Table 3).

Table 2.

Results of Logistic Regression Analyses.

Variable	Univariate Analysis		Multivariate Analysis
Variable	OR (95% CI)	p-value	OR (95% CI)	p-value
Model 1
Age	1.094 (1.041–1.150)	<0.001	1.088 (1.035–1.144)	0.001
Left atrial diameter	1.137 (1.035–1.248)	0.007	1.120 (1.016–1.233)	0.022
NYHA classification-III	0.296 (0.090–0.979)	0.046	0.393 (0.110–1.399)	0.149
Model 2
Age	1.088 (1.035–1.144)	0.001	1.092 (1.037–1.149)	0.001
Left atrial diameter	1.120 (1.016–1.233)	0.022	1.112 (1.009–1.225)	0.032
Serum NOX2 at 12 h after surgery	2.063 (1.106–3.847)	0.023	2.179 (1.084–4.377)	0.029

Note. NOX2, nicotinamide‑adenine dinucleotide phosphate oxidase 2; NYHA, New York Heart Association.

Figure 5.

ROC curve analysis for the predictive models of POAF. (A) ROC containing the variables of age and left atrial diameter (model 1). (B) ROC after adding the variable of serum NOX2 at 12 h after surgery based on the results of model 1 (model 2). NOX2, nicotinamide-adenine dinucleotide phosphate oxidase 2; POAF, postoperative atrial fibrillation.

Discussion

We uncovered that NOX2 activity measured in serum and pericardial drainage samples was dynamically altered in the early postoperative stage. Moreover, the levels of NOX2 were higher in patients who developed POAF after first-time elective isolated CABG compared with those who did not, implying that oxidative stress was immediately involved following surgery. Our preliminary data further suggests that the concentration of serum NOX2 at 12 h after surgery is an independent predictor of POAF.

Emerging evidence proposed the role of oxidative stress in the onset of POAF (Jayaram et al., 2022; Anderson et al., 2014). To the best of our knowledge, this is the first study investigating the association of NOX2 activity in serum and pericardial drainage samples with the occurrence of AF after isolated CABG surgery, particularly focusing on time-dependent changes. Experimental and clinical studies have shown that increased NOX2 activity is strongly linked to AF. More recently, researchers verified that transgenic mice with NOX2 overexpression displayed a 2- to 2.5-fold higher content of NOX2 protein in the atrium, along with a prominent elevation of NOX2-mediated superoxide production in atrial tissue homogenates compared with the control; these transgenic mice were more prone to develop AF in response to a rapid burst (p = 0.037; Mighiu et al., 2021). Similarly, Yoo et al. (2020) observed greater NOX2 activity in a canine model of AF. Conversely, treatment with a specific NOX2 inhibitor markedly prolonged the effective refractory period and attenuated the development of AF. Additionally, elevated levels of NOX2 in the serum of patients with pneumonia were linked to an increased risk of AF in the early phase of hospitalization (OR: 1.038, 95% CI: 1.007–1.069; p = 0.014; Violi et al., 2015).

The time at which NOX2 levels reached their peak in our study, reflecting the strongest degree of oxidative stress, was consistent with that reported in a previous investigation (Kramer et al., 2015). Specifically, the concentration of NOX2 in serum at 12 h post operation was identified as a predictive factor for POAF, suggesting that NOX2 plays a functional role in the early initiation of POAF. This hypothesis has been supported by several previous studies (Reilly et al., 2011; Cangemi et al., 2012; Kim et al., 2008). Reilly et al. (2011) reported that the duration of AF varies depending on the source of ROS. In that study, the levels of NOX2 were significantly increased in goats after 14 days of AF and in right atrial tissue obtained from patients who developed POAF. However, these findings cannot account for the changes in atrial ROS noted in patients with longstanding AF. Moreover, the association between NOX2 and stages of AF was further explained and extended by subsequent data indicating that the levels of serum NOX2 were increased only in paroxysmal/persistent AF; statistically significant changes were not observed in patients with permanent AF and controls (Cangemi et al., 2012). Consistent with the current results, NOX2-generated superoxide from the human right atrial appendage at the time of cardiac surgery has been independently associated with the development of POAF (Kim et al., 2008). In the present study, there was no statistically significant difference between the AUC models (0.732 vs. 0.712, DeLong test; p = 0.33); while these data continue to indicate an improved discriminatory ability (ΔAUC = 0.020).

We were unable to recognize the influence of local NOX2 on the occurrence of POAF. Nevertheless, patients who developed POAF had numerically higher levels of pericardial NOX2 at measured points compared with those who did not.

In this study, the concentration of NOX2 at all time points after surgery was lower in pericardial drainage than in serum samples. A possible reason for this observation may be that local NOX2 was released from recruited leukocytes. Evidence has shown that oxidative stress in the postoperative pericardial space is largely attributed to the migration of inflammatory cells, particularly neutrophils and monocytes (St-Onge et al., 2018; Gaudino et al., 2022). These 2 types of leukocytes are primed for oxidative burst through activation of NOX2, followed by the release of hydrogen peroxide into this milieu (Kramer et al., 2015; St-Onge et al., 2018). As observed in Figure. 2, NOX2 levels in pericardial drainage samples were low under basal conditions; however, NOX2 activity gradually increased over time. Physiologically, NOX2 is mainly expressed in endothelial cells and cardiomyocytes (Bendall et al., 2002). Nevertheless, in the setting of CABG, activation of systemic NOX2 may be more relevant to the course of POAF versus activation in the pericardial environment. Although this hypothesis warrants further investigation, it may explain the lower concentration of NOX2 detected in the pericardial drainage versus serum samples. In agreement with previous data, patients who developed POAF were older and had longer left atrial diameter compared with those who did not. These characteristics are perceived as the basis of atrial fibrosis, possibly reflecting a preexisting susceptible atrial substrate that is indispensable for the generation of POAF (Corradi et al., 2020; Axtell et al., 2020; Akintoye et al., 2018; Yang et al., 2022).

Limitations

Due to the limitations of this study, the present findings should be interpreted with caution. Firstly, this study included a relatively small population. However, the total number of patients who were enrolled in the present study with 90% power was sufficient for the evaluation of differences between the 2 groups. Secondly, sample collection was terminated by 24 h after CABG based on the practical reality that the overwhelming majority of pericardial drainage tubes are removed by 48 h post-surgery. However, NOX2 exhibited predictive value for POAF as early as 12 h post-surgery. Thirdly, approximately 99% of patients underwent off-pump CABG surgery; hence, the present results might not be generalizable to other clinical situations. Fourthly, only a single ROS marker was measured. Although NOX2 is a promising factor, associations of POAF with other biomarkers of oxidative stress should be evaluated in future studies. Fifthly, the pericardial concentration of NOX2 only partly reflects the degree of oxidative stress surrounding the heart; thus, the role of other biomarkers should be further investigated. Sixthly, although we did not identify remarkable correlations between serum and pericardial NOX2, we observed an unexpected weak relationship at baseline and 12 h after surgery. Nevertheless, the identification of factors that may be involved in this relationship were beyond the scope of this study. Lastly, we cannot exclude the possibility that the inflammatory status, an established factor interweaved with oxidative stress, complicates the course of POAF.

Conclusion

This preliminary evidence suggests a possible role of serum NOX2 in the predication of POAF. Studies with larger samples are needed to evaluate these results further.

Supplemental Material

Supplemental Material - Association Between Serum Levels of Nicotinamide-Adenine Dinucleotide Phosphate Oxidase 2 and the Development of Atrial Fibrillation After Isolated Coronary Artery Bypass Grafting: A Prospective Pilot Study

Supplemental Material for Association Between Serum Levels of Nicotinamide-Adenine Dinucleotide Phosphate Oxidase 2 and the Development of Atrial Fibrillation After Isolated Coronary Artery Bypass Grafting: A Prospective Pilot Study by Hui Yan, JiaYing Zhang, Fang Qin Wu, and Gui Fang Du in Biological Research For Nursing

Data Availability Statement

The data underlying this study are available from the corresponding author on reasonable request.

Footnotes

Acknowledgments

The authors thank all participants and the clinical staff involved in this study for their valuable support.

Author Contribution

Hui Yan: conceptualization, design; acquisition, analysis, and interpretation of data; drafting and critical revision of the manuscript. Jia-Ying Zhang: design; acquisition of data; drafting of the manuscript. Fang-Qin Wu: conceptualization, design; analysis and interpretation of data; critical revision of the manuscript. Gui-Fang Du: design, acquisition of data; critical revision of the manuscript. All authors approved the final version of the manuscript and agree to be accountable for all aspects of work in terms of data integrity and accuracy.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was supported by the National Natural Science Foundation of China (grant number 81970279).

ORCID iD

Hui Yan

Supplemental Material

Supplemental material for this article is available online.

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