Atrial fibrillation (AF) is the most common arrhythmia in adults and is associated with atrial dilatation which may be acute or chronic. However, the precise mechanisms linking atrial distension to AF initiation and/or maintenance are unknown. Recent data suggest that the posterior left atrium (PLA) and the pulmonary veins (PV) region play different roles in paroxysmal vs. chronic AF patients who have dilated atria. Our general objective is to investigate the role of chronic structural remodeling of the PLA as a substrate controlling the effects of acute and/or chronic atrial stretch on the electrophysiological mechanisms of AF maintenance in isolated sheep hearts. In addition, we will investigate whether myocardial stretch-activated channels (SACs) in the PLA-PV region are specifically involved in the initiation and maintenance of acute or chronic stretch- related episodes of AF.
Specific Aim 1 is to determine the evolution of AF drivers at the PLA over prolonged AF episodes under conditions of acute atrial stretch. We will utilize a well-characterized Langendorff-perfused sheep heart model of acute atrial stretch and a novel endoscope-coupled optical mapping set-up to visualize the electrical activity on the endocardial surface of the PLA and other intact left atrial sites. We hypothesize that, if intra-atrial pressure is acutely increased, AF sources accelerate, become more stable and are confined to a limited area of the PLA near a junction with a PV.
In Specific Aim 2, we will use a similar mapping technique to investigate the effects of chronic atrial dilatation in a mitral regurgitation (MR) sheep heart model. We postulate that atrial remodeling secondary to chronic atrial dilatation leads to an increase in the number of potential AF sources, which may be widely distributed across the left atrium.
In Specific Aim 3, we will utilize a model of tachypacing-induced chronic congestive heart failure (HF) to characterize the dynamics of left atrial sources in chronically stretched and structurally (extensive fibrosis) remodeled atria. We hypothesize that the extensive interstitial fibrosis in chronically dilated HF atria reduces the frequency of AF sources, contributes to their stabilization at the PLA. However, because of an increased propensity of triggered activity in HF, we expect an increase of the complexity of fibrillatory conduction of waves emerging from such sources. The results obtained from our proposed experiments should help advance the understanding of the mechanisms of AF in the dilated atria and could lead to therapeutic improvements for patients.
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