Atrial fibrillation is the most prevalent sustained cardiac arrhythmia, affecting over 2 million Americans. Post-operative atrial fibrillation, leading to significant morbidity and to prolongation of hospital stay, complicates 20 40% of surgical procedures requiring cardiopulmonary bypass. While recent randomized clinical trials indicate interruption of the renin-angiotensin-aldosterone system by either ACE inhibition or ATi receptor antagonism decreases the incidence of atrial fibrillation following myocardial infarction or cardioversion, the effect of interruption of the renin-angiotensin-aldosterone system on the incidence of post-operative atrial fibrillation has not been investigated in a randomized, prospective study. Studies in both animal models and humans suggest that inflammation-induced atrial remodeling plays an important role in the pathogenesis of this arrhythmia. At the same time, emerging data provide evidence that activation of the renin-angiotensin-aldosterone system induces inflammation, myocyte injury, proarrhythmic electrical remodeling and fibrosis through aldosterone. The current proposal derives from data from our laboratory that indicate that activation of the renin-angiotensin-aldosterone system increases markers of inflammation and oxidation, whereas ACE inhibition or aldosterone receptor antagonism decreases markers of inflammation under a variety of conditions including following cardiopulmonary bypass. Thus, this proposal tests the central hypothesis that interruption of the renin-angiotensin-aldosterone system by ACE inhibition or aldosterone receptor antagonism will decrease the frequency of post-operative atrial fibrillation by decreasing inflammation.
In SPECIFIC AIM 1 we will use mechanistic GCRC-based protocols to test the hypothesis that increases in angiotensin II and aldosterone induce oxidation and inflammation through a mineralocorticoid receptor-dependent pathway.
In SPECIFIC AIM 2, we will conduct a randomized clinical trial to test the hypothesis that ACE inhibition or aldosterone receptor antagonism will decrease inflammation and atrial fibrillation following cardiopulmonary bypass. These studies are expected to generate important new information to advance our understanding of the inflammatory effects of the renin-angiotensinaldosterone system on adverse electrical remodeling and fibrosis in patients at risk for atrial fibrillation.
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