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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL087055-05
Application #
8090320
Study Section
Electrical Signaling, Ion Transport, and Arrhythmias Study Section (ESTA)
Program Officer
Lathrop, David A
Project Start
2007-08-15
Project End
2012-12-30
Budget Start
2011-07-01
Budget End
2012-12-30
Support Year
5
Fiscal Year
2011
Total Cost
$266,000
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Berenfeld, O; Yamazaki, M; Filgueiras-Rama, D et al. (2014) Surface and intramural reentrant patterns during atrial fibrillation in the sheep. Methods Inf Med 53:314-9
Musa, Hassan; Kaur, Kuljeet; O'Connell, Ryan et al. (2013) Inhibition of platelet-derived growth factor-AB signaling prevents electromechanical remodeling of adult atrial myocytes that contact myofibroblasts. Heart Rhythm 10:1044-51
Yamazaki, Masatoshi; Avula, Uma Mahesh R; Bandaru, Krishna et al. (2013) Acute regional left atrial ischemia causes acceleration of atrial drivers during atrial fibrillation. Heart Rhythm 10:901-9
Yamazaki, Masatoshi; Filgueiras-Rama, David; Berenfeld, Omer et al. (2012) Ectopic and reentrant activation patterns in the posterior left atrium during stretch-related atrial fibrillation. Prog Biophys Mol Biol 110:269-77
Filgueiras-Rama, David; Price, Nicholas F; Martins, Raphael P et al. (2012) Long-term frequency gradients during persistent atrial fibrillation in sheep are associated with stable sources in the left atrium. Circ Arrhythm Electrophysiol 5:1160-7
Filgueiras-Rama, David; Martins, Raphael P; Mironov, Sergey et al. (2012) Chloroquine terminates stretch-induced atrial fibrillation more effectively than flecainide in the sheep heart. Circ Arrhythm Electrophysiol 5:561-70
Avula, Uma Mahesh R; Kim, Gwangseong; Lee, Yong-Eun Koo et al. (2012) Cell-specific nanoplatform-enabled photodynamic therapy for cardiac cells. Heart Rhythm 9:1504-9
Kalifa, Jérôme; Avula, Uma Mahesh R (2012) The Chinese herb extract Wenxin Keli: atrial selectivity from the Far East. Heart Rhythm 9:132-3
Yamazaki, Masatoshi; Mironov, Sergey; Taravant, Clement et al. (2012) Heterogeneous atrial wall thickness and stretch promote scroll waves anchoring during atrial fibrillation. Cardiovasc Res 94:48-57
Kalifa, Jérôme; Yamazaki, Masatoshi (2011) Repolarization alternans in dilated pulsing atria: a preventable ""prelude"" to atrial fibrillation? J Am Coll Cardiol 58:2116-7

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