N-acetylcysteine for the prevention of atrial fibrillation: beyond its antioxidant effect

We read with interest the manuscript of Ozaydin et al.1 about the effect of N-acetylcysteine (NAC) for the prevention of postoperative atrial fibrillation. In this prospective, randomized, double-blind, placebo-controlled study, a total of 115 patients undergoing coronary artery bypass and/or valve surgery were included. Patients were randomized to receive NAC or placebo. During follow-up period, 15 patients had atrial fibrillation. The rate of atrial fibrillation was lower in the NAC group compared with the placebo group (three patients vs. 12, odds ratio 0.20, P = 0.019). Notably, in the multivariable logistic regression analysis, the use of NAC was an independent predictor of postoperative atrial fibrillation. Authors considered that oxidative stress play a main role in the development of atrial fibrillation. Since NAC is a free radical scavenger antioxidant agent that reduces cellular oxidative damage, it is possible that the results of this study may in part be explained through this mechanism. However, there are other probable mechanisms of NAC that might explain these data. Hypertension and coronary heart disease are much related with the presence of atrial fibrillation.2 In fact, in the work of Ozaydin et al., ∼54–61% of the patients had hypertension, ∼35–45% stable angina pectoris, ∼31–35% non-ST-elevation myocardial infarction, and ∼21–26% had ST-elevation myocardial infarction. On the other hand, several studies have suggested that angiotensin-system inhibition appears to protect against atrial fibrillation in patients with hypertension or post-myocardial infarction. The majority of patients included in the present study were taking angiotensin-converting enzyme inhibitors (ACEi) (∼66%). It is well known that the antihypertensive effect of ACEi is caused not only by the decrease in angiotensin II production, but also by the decrease in degradation of the kinins. Kinins are vasodilator peptides that stimulate the synthesis of vasoactive substances, such as nitric oxide (NO). In fact, the presence of an NO synthesis inhibitor reduces the antihypertensive effect of ACEi. Therefore, NO could contribute to the activity of ACEi, probably through NO synthesis activation mediated by endogenous kinins. The addition of an SH group donor, such as NAC, may then potentiate the antihypertensive activity of the ACEi through an NO-dependent mechanism.3 Since hypertension and ischaemia are risk factors for postoperative atrial fibrillation and the inhibition of renin–angiotensin system is important in the treatment of these patients, the increase of this inhibition with the addition of NAC may potentiate the preventive effect of ACEi against atrial fibrillation. As a result, the beneficial effects of NAC may be explained not only by its direct antioxidant effect but also by a potentiative synergistic effect on renin–angiotensin system blockade.