The main findings of our study are that new onset AF was significantly associated with an inflammatory response in multivariate analysis as indicated by increased CRP concentration, whereas fluid overload was significantly associated with postoperative AF only in univariate analyses. Reduced postoperative plasma phosphate concentration represented a unique risk factor for intermittent/permanent AF in a multiple logistic regression.
Clinical outcomes
New onset and intermittent/permanent AF significantly impacted clinical outcomes of cardiac surgery patients. Patients of both AF groups had a median increase in ICU length of stay of approx. 2 days and required prolonged mechanical ventilation, which leads to increased hospital resource utilisation and higher costs for treatment [
3]. Furthermore, new onset AF was significantly associated with an increased rate of dialysis (8.2% vs. 1.9% in the no AF group). In line with this finding, Tsai and co-workers and Aranki et al. previously described a significantly higher incidence of renal failure in subjects who developed AF after CABG [
3,
10]. The hospital mortality rate was also significantly higher in patients with new onset AF compared to subjects without this arrhythmia. While Villareal and colleagues also identified postoperative AF as a significant risk factor for hospital mortality [
11], more studies have reported lower long-term survival rates for patients who developed AF after surgery [
10,
11,
14,
16,
18].
Postoperative AF and inflammation
CRP concentration was the most significant predictor of new onset AF in multiple logistic regression analysis, pointing out a strong link between AF and inflammation. The effect was present even after accounting for the impact of age, which is reported to be the most powerful predictor of new onset AF [
3‐
5,
7,
8,
11‐
14,
18‐
20]. Elevated levels of CRP as a rough marker for systemic inflammation have been reported in nonsurgical patients with atrial arrhythmias [
22]. In line with our data, preoperative CRP concentration over 3.0 mg/dL significantly increased the risk for AF following CABG in a sample of 152 patients [
23]. In supplement to these previous reports, we managed to demonstrate that higher postoperative CRP concentration as well is a significant predictor of new onset AF in our larger sample of 779 patients.
White blood cell count was significantly higher in patients with new onset AF compared to no AF patients on days 2 and 3 and in patients with intermittent/permanent AF relative to the disappeared AF group on days 4 and 5 (Fig.
3). These results are in line with the findings by Abdelhadi and associates, who reported elevated white blood cell count in patients with AF following CABG or valve surgery. The difference between the two groups was statistically significant on postoperative days 3 to 5 [
24]. Notably, Abdelhidi et al. investigated the association between higher leukocyte concentration and new onset AF only. The new finding of our study is the observation that patients with intermittent/permanent AF also have significantly increased white blood cell count.
Patients with new onset AF had significantly more positive fluid balance on the day of surgery and postoperative days 1 and 2 (Fig.
2). This finding is in agreement with previous reports, which strongly implies fluid overload as a key player in the initiation of postoperative AF [
8,
19,
25]. In a prospective observational cohort study in critically ill nonsurgical patients, Shaver and associates reported that new onset AF was associated with a more pronounced positive fluid balance as compared to fluid balance in patients with recurrent AF [
26]. The authors postulated that new onset AF occurs in the context of prolonged hypotension and insufficient oxygen delivery and clinical management of these conditions may contribute to developing new onset AF. In contrast, a recurrent arrhythmic episode in patients with previous history is more likely the result of underlying structural changes in the atrial myocardium [
26].
Interestingly, more positive fluid balance and leukocyte concentration were not significantly associated with new onset AF in the multivariable model despite significant differences in the univariate analyses, which might be due to other confounding factors.
Indeed, the connection between inflammation and AF indicated by CRP, positive fluid-balance, and leukocyte count is striking. The pathophysiology of AF is a multifactorial process and the exact role of inflammation has not been elucidated yet. However, it is generally believed that the inflammatory response promotes electrical and structural remodelling of the myocardium thereby increasing the risk for AF [
27]. For example, membrane potential fluctuations might be a direct consequence of inflammation [
28]. Furthermore, fibrosis or scarring of the myocardium might lead to heterogeneous electrical conduction which in turn might contribute to the emergence of ectopic beats, late potentials or wavelet re-entry [
28]. In this context, the specific association between increased CRP levels and AF might be explained by the fact that CRP is just a marker for systemic inflammation. Another possibility is that CRP is involved in modulating the local inflammatory response by binding to phosphocholine and thus identifying phospholipid components of damaged cells and activating the complement system [
29]. This molecular mechanism might suggest a more direct impact of CRP on the initiation of AF. Additionally, Watanabe and colleagues reported that CRP levels correlated with larger left atrial diameter in patients with paroxysmal AF [
30], which is also a recognized risk factor for AF [
4,
7]. Fluid overload might contribute to the development of postoperative arrhythmias in a similar manner, since Shaver and colleagues reported increased left atrial size in their study in critically ill patients with new onset AF who were also associated with more positive fluid balance [
26]. However, it is difficult to distinguish between cause and consequence in our study. Positive fluid balance might have been the therapeutic attempt to tackle AF-induced hypotension and as such a consequence of AF. Another possibility is that inflammation might have led to positive fluid balance and AF is a cardiac facet of this pathophysiology without a causal link between both observations. Nevertheless, our findings give reason to prospective trials to reduce systemic inflammation with the aim of mitigating severe complications like AF which impair patient’s outcome.
Potential risk factors for new onset and intermittent/permanent AF
Higher creatinine concentration was another significant predictor for new onset AF in multivariable regression analysis. This had already been suggested by Zaman and colleagues in a univariate analysis in CABG patients [
12]. Conversely, higher Horowitz index values were associated with reduced occurrence of new onset AF. In this context, Haïssaguerre and colleagues reported in 45 patients that the majority of ectopic beats triggering AF originate in the pulmonary veins [
31]. Impaired pulmonary function may thus induce ectopic beats and thereby promote the occurrence of AF [
32]. Therefore, Horowitz index as marker for impaired pulmonary function might be a useful indicator for patients at high risk for developing new onset AF. Finally, a combined procedure of CABG and valve surgery significantly increased the risk for postoperative new onset AF compared to CABG alone. It is noteworthy that the more complex combined procedure is associated with longer CPB and ischemia time and thus an increased surgical injury, fostering inflammation following cardiac surgery [
33,
34] Increased inflammatory response compared to an isolated CABG procedure might in turn lead to a higher incidence of postoperative new onset AF after a combined intervention.
In the multiple logistic regression analysis, higher creatinine and lower phosphate concentrations were significantly associated with postoperative intermittent/permanent AF (Table
4). Shwartz et al. conducted a study in this setting and reported a significant association between hypophosphatemia and increased incidence of newly occurring cardiac arrhythmias including AF in septic patients [
35,
36]. In addition, Švagždienė and Širvinskas described significantly reduced postoperative phosphate concentrations in patients who developed new onset AF after CABG compared to patients who remained in sinus rhythm [
37]. Interestingly, lower phosphate concentration only predicted intermittent/permanent AF but not new onset AF in our study. Notably, we managed to demonstrate this association in a multivariable regression analysis whereas previous reports on the link between hypophosphatemia and new onset AF were only derived from univariate analyses.
Limitations of the analysis
The main limitation of our study is its retrospective nature. Therefore, unobserved confounding effects on the results we obtained cannot be excluded. This limitation is, however, offset by the explorative nature of the analysis. Furthermore, there were missing values in the data set regarding the daily fluid balance and clinical chemistry parameters. However, in the logistic regression analyses, this limitation was overcome by applying the multiple imputation methodology. Additionally, there might be more sophisticated parameters to describe inflammation with higher precision, e.g. interleukins or tumour necrosis factors. Since they were not part of routine laboratory testing, we could not include them in our analysis. Ultimately, we believe that investigating these variables would not have altered the message of this paper.