Cardiac Surgery and the Risk of Atrial Fibrillation: an Intervention Trial Evaluating Melatonin

Atrial fibrillation is the most common arrhythmia to occur after coronary artery bypass graft
(CABG) surgery. This arrhythmia occurs in approximately 1 in every 3 patients in this setting
and the rate is even higher after valve or combined valve and CABG procedures. The majority
of episodes of atrial fibrillation occur within the first 3 days after cardiac surgery and
for those who have an initial episode of atrial fibrillation, the majority will go on to have
another recurrence within 2 days of the first episode. Postoperative atrial fibrillation has
been associated with an increase in neurological, renal and infectious complications as well
as prolonged hospitalization and a significant increase in overall healthcare costs.

There is a considerable amount of emerging data indicating that inflammation and oxidative
stress, by way of reactive oxygen species (ROS), associated with cardiac surgery and
cardiopulmonary bypass (CPB) may play an important role in the in the development of
postoperative atrial fibrillation. Prior animal studies have demonstrated that ROS may lead
to electroanatomical remodeling and increase the vulnerability to atrial fibrillation by
promoting progressive fibrosis and subsequent alteration of the extracellular matrix. A few
randomized controlled trials have demonstrated the beneficial effects of pre-treatment with
anti-inflammatory medications such as statins for the prevention of post-operative atrial
fibrillation. With this in mind, other anti-inflammatory therapies may also be effective in
preventing postoperative atrial fibrillation.

Melatonin (N - acetyl - 5 - methoxytryptamine) is the main product secreted from the pineal
gland and has been shown to be a powerful scavenger of ROS and is regarded as the most potent
endogenous antioxidant. In fact, melatonin is more effective than other antioxidants in
removing free radicals and it has both lipophilic and hydrophilic properties contributing to
its more consistent penetration through cellular membranes. In addition to being a naturally
synthesized hormone, melatonin has been shown to have a very favorable safety profile when
administered in the clinical setting.

For these reasons, investigators have designed a randomized, double-blind, placebo-controlled
trial where patients who are to undergo cardiac surgery and CPB, will be randomized to
melatonin or placebo and the investigators will determine the incidence of post operative
atrial fibrillation in both groups. Additionally, the investigators will measure ROS from
serum as well as right atrial appendage samples of subjects and assess the effects of
melatonin on ROS levels as compared to placebo.

Inclusion Criteria:

1. Age over the age of 18.

2. Scheduled for elective cardiac surgery (coronary artery bypass grafting, valvular
surgery or combined procedures)

3. Enroll at least 48 hours before surgery is scheduled

4. Presence of normal sinus rhythm on screening electrocardiogram.

5. Be willing to provide informed consent (which may be provided by a legally authorized
representative if the patient is not able to do so).

Exclusion Criteria:

1. History of prior atrial fibrillation

2. Inability to give informed consent.

3. Use of anti-arrhythmic drugs other than beta-blockers

4. Chronic NSAID or antioxidant use

5. History of severe autoimmune disorders with the need for autoimmune medications.

6. History of epilepsy.

7. Compromised hepatic function (aminotransferase levels > 1.5 times the upper limit of
normal)

8. Current pregnancy (determined by either serum or urine pregnancy test, as ordered by
the primary team)

9. Non-English Speakers

10. Current use of warfarin, nifedipine, fluvoxamine.