AF is a common complication after cardiovascular surgery and often results in prolonged hospital stays and increased morbidity compared with patients who maintain sinus rhythm [2–5]. Approaches to preoperative and postoperative prophylaxis of AF using selective β-blockers [1, 8, 9], amiodarone , and atrial pacing  have achieved varying degrees of clinical success. However, the role of intraoperative β-adrenergic blockers in preventing postoperative AF is unknown. In the present study, patients who received intraoperative landiolol had a significantly lower incidence of postoperative AF (8.8%).
In a study of patients who underwent on-pump CABG, an inhibitory effect on postoperative AF was reported from administering landiolol for 48 h from the start of surgery . The results of our study, which includes not only on-pump CABG, but also off-pump CABG and heart valve surgical patients, suggest that AF occurrences can be suppressed even in these cases. Sezai et al.  reported that postoperative AF was reduced by treatment with landiolol in patients undergoing CABG on cardiopulmonary bypass (10%, 7 of 70 patients). Landiolol infusion was started at the time of central anastomosis during CABG and discontinued after 48 h. In our study, of 57 patients in the landiolol group, β-blocker therapy was continued postoperatively in 41 patients and discontinued after surgery in 16. The incidence of postoperative AF in patients receiving intraoperative and postoperative β-blocker therapy was 9.8%, which was similar to the values in their study. Similarly, the incidence of postoperative AF in patients who received landiolol only during surgery was 6.3%. Most known risk factors were found to be similar among groups. These results suggest a possible role for prophylactic landiolol during cardiac surgery to reduce the incidence of postoperative AF.
In the postoperative heart, multiple factors may potentially predispose a patient to AF through alterations in refractoriness and/or local reentry. These include operative trauma from surgical dissection and manipulation, inflammation, elevation in atrial pressure from postoperative impaired ventricular function, chemical stimulation during perioperative support with catecholamines and other inotropic agents, reflex sympathetic activation from volume loss, anemia or pain, parasympathetic activation, fever from atelectasis or infection, and hypoglycemia or ischemic damage incurred during surgery [17, 18]. Recent studies have shown that markers of oxidative injury and inflammation, such as C-reactive protein, are elevated in patients with AF, indicating that they may have an important role in the pathogenesis of postoperative AF [19, 20]. Landiolol has a lipid peroxidation-reducing effect and suppresses the increase in phospholamban serine phosphorylation in the sarcoplasmic reticulum (SR) in hearts subjected to ischemia-reperfusion (I/R) . Landiolol, as well as propranolol and esmolol, also has cardioprotective effects in isolated guinea pig hearts subjected to I/R injury . Therefore, landiolol may have anti-ischemic properties as an antioxidant and via preservation of SR function during the ischemic period. In addition, preischemic administration of landiolol reduced cardiac cellular damage and improved the recovery of cardiac function in the rat heart through protein kinase C (PKC) epsilon-mediated pathway, similar to that afforded by ischemic preconditioning . Reduction of postoperative AF by landiolol may be due to reduced inflammation or oxidative stress, or pharmacological preconditioning effect, in addition to effective β-blockade.
Cardiac surgery requiring cardiopulmonary bypass results in significant impairment of β-adrenergic receptor (βAR) function . This can cause depressed postoperative myocardial function that results in atrial enlargement, which is a risk for postoperative AF. The possible mechanisms underlying impaired βAR function include myocardial ischemia-reperfusion injury , a hibernating and stunned myocardium , and acute myocardial βAR desensitization [27, 28]. A marked increase in catecholamine levels found during cardiac surgery resulting in agonist-induced desensitization may be a major mechanism behind acute βAR desensitization . Increased myocardial catecholamine concentrations may, at least in part, be the stimulus for the myocardial hyporesponsiveness seen during cardiac surgery. In support of this, blockade of βARs with low-dose βAR antagonist therapy improves myocardial function in congestive heart failure , a clinical setting in which attenuation of chronic βAR desensitization has been postulated as a possible mechanism. In the landiolol group SBP was significantly higher at the start of the operation and SBP and HR were significantly higher at sternotomy, compared to the control group. These results suggested that serum catecholamine levels in the landiolol group may increase during surgery. Nevertheless, we found a marked reduction of postoperative AF in the landiolol group. Landiolol may have the suppressive effect of catecholamine-induced βAR desensitization. Booth et al. reported that intravenous esmolol administration during coronary artery revascularization after acute myocardial ischemia results in improved left ventricular function immediately after cardiopulmonary bypass (CPB) via enhanced βAR signaling , whereas chronic oral ß-adrenergic blocker therapy in patients undergoing CABG surgery does not protect patients from acute βAR desensitization . In addition, Cork et al. demonstrated improved early intermediate outcomes (such as cardiac output) immediately post-CPB in patients receiving an intraoperative β-adrenergic blocker . In a similar manner, improvement of βAR function by intraoperative administration of landiolol may contribute to preserved left ventricular function and fewer inotropic requirements postoperatively, resulting in a reduced incidence of postoperative AF.
The prevalence of AF increases with worsening heart failure from 5% in patients of NYHA class I under drug therapy to as high as 50% in those of NYHA class IV. Structural, electrophysiologic, and neurohumoral mechanisms may play important roles in this effect, but an association of heart failure and AF has not been established in the postoperative setting. Factors predisposing patients to postoperative AF may be unrelated to left ventricular function, and in our study patients who received landiolol intraoperatively experienced less AF than those who did not, despite having similar left ventricular ejection fractions (56.4% vs. 60.5%). However, preoperative left ventricular dysfunction is one of the strongest predictors of mortality after CABG surgery. The use of ultra-short-acting β-blockers has been suggested as a safe and efficacious method for treating patients with accelerated adrenergic drive during and after the postoperative phase of cardiovascular surgery. Landiolol hydrochloride is approximately nine times more potent in β-blocking activity in vivo and eight times more cardioselective in vitro than esmolol . Moreover, the suppressive effects on cardiovascular perforance are significantoly less potent or landiolol than those of esmolol at equipotent β-blocking doses . These properties facilitate a more rapid recovery after drug administration if an adverse effect develops, which should lead to safer perioperative management of patients undergoing cardiac surgery and in other clinical settings.
Our study had several linitations. First, our patients had undergone various cardiac procedures with or without the use of a heart-lung machine. Second, they were not randomly assigned to either group and there was a between-group difference in the number and type of the cardiac surgery that the patients had undergone. Third, the optimum dose for intraoperative landiolol could not be verified, including in our investigations. Therefore, to confirm the preventive effect of intraoperative landiolol on AF after cardiac surgery, a large-scale clinical study is needed.
The main points of our findings are: (1) when landiolol was not administered intraoperatively, the incidence of postoperative AF was lower in the group that received postoperative β-blockers than in the group that did not; (2) even when postoperative β-blockers were used, the incidence of postoperative AF was lower in the group that received intraoperative landiolol; and (3) when landiolol was administered intraoperatively, the incidence of postoperative AF was low regardless of whether or not postoperative β-blockers were used.