Atrial fibrillation (AF) is the most common heart rhythm disorder, affecting 2.2 million individuals in the United States alone, and is a major cause of morbidity and mortality. Current methods to eliminate AF with anti-arrhythmic drugs and ablation remain suboptimal, reflecting our current lack of understanding of the mechanisms for AF, and how they may differ for patients with presentations such as persistent or paroxysmal AF. This project tests the novel hypothesis that interaction of the dynamic tissue properties of repolarization and conduction with structural heterogeneities provides a direct mechanism for the initiation of human AF and its varying clinical patterns. This project builds upon published work and preliminary observations by our laboratory in patients. We have three specific Aims. 1) To determine whether dynamic tissue properties, including restitution of action potential duration, cause the initiation of atrial fibrillation;2) To determine whether the initiation of atrial fibrillation follows conduction block and reentry;3) To determine whether dynamic tissue properties are required to cause AF in computer models created specifically for each patient, then referenced back to observed AF. We will pursue these aims by acquiring high-resolution electrophysiologic and anatomic data at electrophysiologic study, by performing numerical analysis of activation in both atria, then by developing patient-specific computer models. The computer models that we will create in this project will be among the most detailed and clinically-relevant. This project is significant because it studies a novel mechanism for the development of atrial fibrillation in patients. This mechanism may serve as a method to predict the propensity for AF. Understanding this mechanism may also allow a more rational approach both to drug development and ablation therapy. The performance of this project in patients during electrophysiologic study will also allow its results to be translated directly to practice. Finally, our patient-specific computational models are clinically relevant, and will thus provide a resource for further hypothesis testing in AF.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL083359-05
Application #
8289505
Study Section
Electrical Signaling, Ion Transport, and Arrhythmias Study Section (ESTA)
Program Officer
Rundhaugen, Lynn M
Project Start
2008-07-01
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2014-06-30
Support Year
5
Fiscal Year
2012
Total Cost
$375,129
Indirect Cost
$127,629
Name
University of California San Diego
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
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Zaman, Junaid A B; Baykaner, Tina; Narayan, Sanjiv M (2016) New Mechanism-based Approaches to Ablating Persistent AF: Will Drug Therapy Soon Be Obsolete? J Cardiovasc Pharmacol 67:1-8
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Rappel, Wouter-Jan; Zaman, Junaid A B; Narayan, Sanjiv M (2015) Mechanisms for the Termination of Atrial Fibrillation by Localized Ablation: Computational and Clinical Studies. Circ Arrhythm Electrophysiol 8:1325-33
Zaman, Junaid A B; Narayan, Sanjiv M (2015) Ablating Atrial Fibrillation: Customizing Lesion Sets Guided by Rotor Mapping. Methodist Debakey Cardiovasc J 11:76-81
Zaman, Junaid A B; Narayan, Sanjiv M (2015) Ablation of Atrial Fibrillation: How Can Less Be More? Circ Arrhythm Electrophysiol 8:1303-5
Zaman, Junaid A B; Peters, Nicholas S; Narayan, Sanjiv M (2015) Rotor mapping and ablation to treat atrial fibrillation. Curr Opin Cardiol 30:24-32
Krummen, David E; Hebsur, Shrinivas; Salcedo, Jon et al. (2015) Mechanisms Underlying AF: Triggers, Rotors, Other? Curr Treat Options Cardiovasc Med 17:371

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