Antioxidant therapy for AF

CHICAGO, ILLINOIS. In my first book Lone Atrial Fibrillation: Towards A Cure, I suggested that oxidative stress, caused by an imbalance between reactive oxygen species (ROS) and the body’s natural antioxidant defences, could be a precipitating factor for atrial fibrillation (AF) episodes. The majority of paroxysmal episodes originate in the pulmonary veins, which are constantly exposed to highly oxygenated blood flowing through relatively narrow veins, and thus creating substantial shear stress. The combination of a high oxygen pressure and shear stress is a potent breeding ground for ROS. The superoxide anion, singlet oxygen, nitrogen dioxide (peroxynitrite), and hydroxyl radicals are all members of the ROS family. They share the dubious distinction of being able to cause inflammation and inflict considerable damage in tissues, cells and individual DNA strands.

The oxidative stress would be magnified in endurance athletes who also happen to have a 5 times higher incidence of lone AF as compared to the general population. Under normal circumstances any ROS attacking the heart lining or adjacent lung tissue would quickly be rendered harmless by the body’s own antioxidants, or by antioxidants obtained through the diet. However, if antioxidant defenses are inadequate, the immune system is compromised, or if the autonomic nervous system is highly dysfunctional or stressed, it is likely that the ROS could get the upper hand and initiate an inflammatory response and subsequent arrhythmia. Researchers at the Cleveland Clinic and Ohio State University have found 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 also determined that the oxidative damage was caused by peroxynitrite, a highly potent free radical. They conclude that peroxynitrite-induced oxidative stress can damage individual heart cells to such an extent that their normal function is disrupted and atrial fibrillation results[1].

The Cleveland Clinic researchers later followed up these initial findings by an experiment designed to show whether reducing the level of peroxynitrite through the use of an antioxidant (vitamin C) would prevent surgery-induced atrial fibrillation. Their clinical trial involved 50 bypass surgery patients who were given 2 grams of ascorbic acid (extended release) the night before surgery, followed by 500 mg doses twice daily for 5 days after 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. The researchers conclude that AF episodes are sustained by oxidative stress and increased peroxynitrite generation caused by the rapid heart rate[2].

Drs. Sovari and Dudley at the University of Illinois at Chicago now provide further evidence supporting the idea that oxidative stress may be a significant cause of AF. They found that the concentration of ROS derivatives and the ratios of oxidized to reduced glutathione and cysteine are increased in the blood of patients with AF. Other researchers have reported that oxidative stress is associated with abnormal intracellular handling of calcium ions and a decrease in connexin43. There is also evidence that ROS can increase cardiac fibrosis.

The University of Illinois researchers claim that strengthening antioxidant defences using currently available antioxidants is unlikely to be successful in eliminating AF and suggest that a more fruitful approach may be to develop drugs that target the sources of ROS. Among the more important of these are mitochondria, the enzyme nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, and uncoupled nitric oxide synthase (NOS). NADPH oxidase produces large amounts of superoxide radicals and its activity has been shown to be increased in AF patients. The authors conclude that developing drugs targeting NADPH oxidase and/or drugs that will activate natural antioxidant defense mechanisms of individual heart cells (myocytes) may be an effective approach to preventing AF.
Sovari, AA and Dudley, SC. Antioxidant therapy for atrial fibrillation: lost in translation? Heart, August 15, 2012 [Epub ahead of print]

Editor’s comment: It is known that vitamin C helps to regenerate the body’s natural antioxidant, glutathione peroxidase, which also requires selenium for its synthesis. Gamma-tocopherol is highly effective in trapping reactive nitrogen dioxide specimens, while lycopene is very effective in neutralizing (quenching) a highly reactive form of oxygen called singlet oxygen. Finally, ubiquinol (ubiquinone or coenzyme Q10) is another very effective antioxidant which specifically targets ROS originating in mitochondria. Thus, there would seem to be no lack of natural antioxidants which, in the optimum form and combination, might help prevent AF. Several of them have been evaluated for preventing post-operative AF and vitamins C and E have been found to be effective as has N-acetylcysteine. I am not aware of any clinical trials aimed at evaluating the effect of natural antioxidants on the prevention of lone AF.

[1] Mihm, Michael J., et al. Impaired myofibrillar energetics and oxidative injury during human atrial fibrillation. Circulation, Vol. 104, July 10, 2001, pp. 174-80
[2] Carnes, Cynthia A., et al. Ascorbate attenuates atrial pacing-induced peroxynitrite formation and electrical remodelling and decreases the incidence of postoperative atrial fibrillation. Circulation Research, Vol. 89, September 14, 2001, pp. e32-e38