ROME, ITALY. In my first book Lone Atrial Fibrillation: Towards a Cure published 10 years ago, I made the comment "I propose that excessive oxidative stress, caused by reactive oxygen species at the upper part of the left atrium, could be a major cause of ectopic (premature) beats and subsequent atrial fibrillation (AF) episodes. If this is indeed the case, then supplementation with vitamin C and the two most effective dietary neutralizers of reactive oxygen species, gamma-tocopherol and lycopene, may prove beneficial in reducing the frequency of AF episodes."
My conclusion that oxidative stress is an important factor in AF was partly based on the findings of a group of Cleveland Clinic researchers who concluded that AF patients show signs of extensive oxidative injury to their myofibrillar creatine kinase (MM-CK). MM-CK is involved in the control of the contraction of individual heart cells (myocytes). The researchers later followed up their initial findings with an experiment designed to show whether reducing the level of peroxynitrite through the use of an antioxidant (vitamin C) would prevent surgery-induced AF. Their clinical trial involved 50 bypass surgery patients who were given 2 grams of ascorbic acid (extended release) the night prior to their surgery, followed by 500 mg doses twice daily for 5 days following surgery. The incidence of postoperative AF in the vitamin C group was 16.3% as compared to 34.9% in a comparable group not given vitamin C.
Now researchers at the Sapienza University of Rome report that persistent afibbers with high serum levels of vitamin E prior to cardioversion are significantly more likely to remain in normal sinus rhythm (NSR) after cardioversion than are those with low levels. Their clinical trial involved 144 patients with persistent AF (average age of 71 years, 61% male). Almost 90% of study participants had hypertension, 13% had diabetes, and 9% had suffered a heart attack – so not a terribly healthy group. After 4 weeks of anticoagulation with warfarin, all patients underwent biphasic electrical cardioversion starting with a 100 Joule shock. If AF returned within 15 minutes, amiodarone (150 mg) was administered intravenously and the shock was repeated. Patients in whom AF remained even after a 200 J shock, or who experienced immediate recurrence of AF in spite of amiodarone and a second shock were defined as failures and were excluded from the study.
The patients were followed with weekly electrocardiograms and monthly Holter monitoring for 3 months or until first AF recurrence. They were maintained on antiarrhythmics (53% on amiodarone, 32% on flecainide or propafenone, and 11% on sotalol) and 45% also took an ACE inhibitor or angiotensin II receptor blocker. Three months after cardioversion 94 patients (65%) were still in NSR, while 50 patients (35%) had experienced AF recurrence.
The only two variables independently affecting outcome was serum vitamin E level (measured as micromol/mmol cholesterol) and hs-CRP (C-reactive protein). Somewhat surprisingly, the use of antiarrhythmics did not affect outcome. Patients who remained in NSR had an average vitamin E (alpha-tocopherol) level of 5.0 micromol/mmol cholesterol, while those who experienced recurrence had an average level of 3.1. Patients with an alpha-tocopherol level below 4.1 were 2.4 times more likely to experience AF recurrence than were those with a level above 4.1, after adjusting for all other variables that could possibly affect outcome. Vitamin E level was found to be inversely proportional to the levels of urinary 8-isoprostaglandin F2alpha and soluble NOX2-derived peptides, both markers of oxidative stress.
The Italian researchers conclude that low vitamin E levels are associated with AF recurrence in patients undergoing cardioversion. They also suggest that the underlying cause of recurrence is oxidative stress which is, at least partially, counteracted by vitamin E. Thus their recommendation to carry out further trials to see if vitamin E supplementation would be of benefit in the prevention of AF recurrence after electrical cardioversion.
Ferro, D, et al. Serum levels of vitamin E are associated with early recurrence of atrial fibrillation after electrical cardioversion. Circulation Arrhythmia and Electrophysiology, February 23, 2012 [Epub ahead of print]
Editor's comment: It is to be hoped that researchers following up on the above findings will use gamma-tocopherol, in combination with vitamin C, rather than just alpha-tocopherol in any clinical trials to evaluate the benefits of vitamin E supplementation prior to cardioversion. Gamma-tocopherol is the most common form of vitamin E in the diet and constitutes 30-50% of total vitamin E levels in human skin, muscle, and adipose (fat) tissue. Alpha- tocopherol, on the other hand, is much less common in the diet, but is the main and, in many cases, the only component of vitamin E supplements. Dr. Bruce Ames and his colleagues at the University of California suggest that gamma-tocopherol may be significantly more effective in combating cancer, heart disease, and neurodegenerative disease than is alpha-tocopherol. Experimenting on human macrophages (scavenger cells) and cells from human lung tissue (epithelial cells), they found that gamma-tocopherol is at least three times more effective in inhibiting the synthesis of prostaglandin E2 (PGE2) than is alpha-tocopherol. PGE2, a marker of oxidative stress, plays a key role in promoting inflammation and its associated diseases such as cancer and cardiovascular disease. These findings, combined with recent evidence that blood plasma concentrations of gamma-tocopherol, but not alpha-tocopherol, are inversely correlated with the incidence of heart disease, prompt the researchers to speculate that gamma-tocopherol may actually be more important in disease prevention than is alpha-tocopherol. They conclude "It may be that the inclusion of both alpha- and gamma-tocopherols in vitamin E supplements is more effective in human disease prevention, especially considering that alpha-tocopherol supplementation depresses gamma-tocopherol in human plasma and adipose tissue."
Patients awaiting cardioversion are usually placed on warfarin therapy 3 to 4 weeks prior to the procedure. Thus any interaction between warfarin and vitamin E would clearly be of concern. However, there is no evidence that vitamin E affects the level of vitamin K-dependent coagulation factors except in people with certain specific coagulation disorders. There is also no indication that vitamin E alters the coagulation pattern in normal, warfarin-treated patients, so there is no reason to shun vitamin E supplementation when taking warfarin.
 Jiang, Qing, et al. Gamma-tocopherol and its major metabolite, in contrast to alpha-tocopherol, inhibit cyclooxygenase activity in macrophages and epithelial cells. Proceedings of the National Academy of Sciences USA, Vol. 97, No. 21, October 10, 2000, pp. 11494-99
 Kim, JM and White, RH. Effect of vitamin E on the anticoagulant response to warfarin. American Journal of Cardiology, Vol. 77, No. 7, March 1, 1996, pp. 545-46