More than two million Americans suffer from various forms of atrial fibrillation (AF). AF is a major cause of stroke and an independent risk factor for mortality. Following initiation, AF tends to self-perpetuate, due in part to electrophysiological remodeling of the atria. The high rate activity of the fibrillating atria has multiple electrophysiological, metabolic, and hemodynamic consequences. AF increases atrial oxygen consumption 2-3 fold, and increases the availability of reactive oxygen species (oxidative stress). In post-cardiac surgery patients the increase in oxidative stress is striking, and one-third of these patients develop post- operative AF. The goal of this application is to determine the relationship between oxidative stress and the electrophysiological remodeling that occurs during AF. Oxidative stress modulates the activity of several ion channels (Ca, K, and ryanodine receptor) important for normal atrial function. In preliminary studies, we have demonstrated that rapid pacing of canine atria results in increased oxidative injury, and that treating patients with vitamin C (an antioxidant) can decrease the incidence of post-operative AF. Thus, we propose that increased oxidative stress is a key link between the major risk factors for the development of AF, and that the electrophysiological remodeling accompanying the onset of atrial fibrillation is the result of oxidative stress. To test our hypothesis, parallel studies will be performed in patients and in a rapidly paced canine model of AF.
The aims of this study are: 1) to determine the impact of oxidative stress on action potentials, Ca, K currents, and shortening in isolated atrial myocytes; 2) to assess the oxidative injury in atrial tissue using biochemical and immunohistochemical techniques, and to correlate this with in vivo electrophysiological properties; 3) to correlate plasma levels of oxidative stress markers and anti-oxidant capacity with electrophysiological changes in vivo; 4) to prospectively evaluate antioxidant therapies, with respect to their capacity to decrease levels of markers of oxidative stress and attenuate the electrophysiological remodeling that occurs in fibrillating canine atria; and finally, to directly evaluate the impact of vitamin C on the incidence of post-operative AF in patients. Successful therapies should prevent oxidative Injury, blunting the reduction in atrial effective refractory period that accompanies the onset of AF, minimizing its perpetuation, and facilitating Its termination. We anticipate that these early interventions will prove to be the most effective approach to the long term treatment and prevention of AF.
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