This project aims at developing, validating and using novel mapping approaches to enhance the understanding of excitation dynamics in atrial fibrillation (AF) and to improve its treatment. AF is the most common sustained arrhythmia in humans afflicting more than 2.5 million Americans and is the leading cause of embolic stroke. For patients with AF, anti-arrhythmic drugs perform poorly and ablation, with controversial success rate and long-term effects, is often the only therapy available. Thus, advancing our understanding of the mechanisms of the arrhythmia and how to device better therapies for it are of paramount importance. It is generally accepted that fibrillation is a common end-pathway of various insults to the heart with multi-factorial alterations in the electrophysiology of the substrate and its activation patterns. It is also acceptable that the alterations promoting the onset and controlling the maintenance of fibrillation have significant regional as well as inter-patient heterogeneity. It is therefore the general objective of this proposal to develop a set of novel mapping approaches that will improve the capability of characterizing the patterns of electrical activation specific to underlying ionic heterogeneities. The proposed study will include full-view (panoramic) intracardiac optical/electrical recordings in isolated sheep hearts and electrical recordings in-vivo sheep. We will take advantage of our previous developments in fluorescence endoscopic imaging of the electrical activity of the heart and singularity value decomposition (SVD) algorithms to design and test a novel approach that in its final form will enable a better correlation between the space-time and frequency properties of the fibrillating atria, with direct possible applicability to individual patients. Our approach builds on a novel SV factorization into ranked space, time and frequency interrelated components to better localize and track potential drivers of AF. This numerical scheme will be included in 3 specific aims as follows: (i) To develop increasingly detailed computer models of the atria to simulate different AF scenarios and validate the SVD ability to point to a driver location, or whether such a driver exists. (ii) To apply the SVD approach to panoramic optical mapping data from two intact atria of isolated sheep heart. The panoramic high resolution optical mapping will be used as a reference for the SVD analysis performed on electrical intracadiac recordings. (iii) To apply the validated electrical mapping algorithms to AF in-vivo in the sheep. Reversible atrial lesions induced by cryoablation will be used to test successful localization of drivers and termination of AF. Accomplishing the aims of the study will provide a solid framework for mapping AF dynamics in patients to improve its understanding and therapy.

Public Health Relevance

Atrial fibrillation (AF) is afflicting over 2.5 million Americans to date and its prevalence is expected to increase sharply in the future. Our understanding of the mechanisms underlying AF and how to treat it is poor. This proposal aims at studying new modalities for mapping the AF in computer and sheep models of AF in-vivo to enable later translation into efficient mapping of patients. Accomplishment of the proposal aims will enhance our understanding of AF and possibly lead to improved risk stratification and guide therapeutic interventions.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Study Section
Modeling and Analysis of Biological Systems Study Section (MABS)
Program Officer
Lathrop, David A
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University of Michigan Ann Arbor
Internal Medicine/Medicine
Schools of Medicine
Ann Arbor
United States
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Pedrón-Torrecilla, Jorge; Rodrigo, Miguel; Climent, Andreu M et al. (2016) Noninvasive Estimation of Epicardial Dominant High-Frequency Regions During Atrial Fibrillation. J Cardiovasc Electrophysiol 27:435-42
Quintanilla, Jorge G; Pérez-Villacastín, Julián; Pérez-Castellano, Nicasio et al. (2016) Mechanistic Approaches to Detect, Target, and Ablate the Drivers of Atrial Fibrillation. Circ Arrhythm Electrophysiol 9:e002481
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Atienza, Felipe; Climent, Andreu M; Guillem, María S et al. (2015) Frontiers in noninvasive cardiac mapping rotors in atrial fibrillation-body surface frequency-phase mapping. Card Electrophysiol Clin 7:59-69
Calvo, David; Atienza, Felipe; Saiz, Javier et al. (2015) Ventricular Tachycardia and Early Fibrillation in Patients With Brugada Syndrome and Ischemic Cardiomyopathy Show Predictable Frequency-Phase Properties on the Precordial ECG Consistent With the Respective Arrhythmogenic Substrate. Circ Arrhythm Electrophysiol 8:1133-43
Jalife, José; Filgueiras Rama, David; Berenfeld, Omer (2015) Letter by Jalife et al Regarding Article, ""Quantitative Analysis of Localized Sources Identified by Focal Impulse and Rotor Modulation Mapping in Atrial Fibrillation"". Circ Arrhythm Electrophysiol 8:1296-8

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