Atrial fibrillation (AF) is the most prevalent heart rhythm disorder in the U.S., affecting 2-5 million individuals in whom it may cause stroke, palpitations, heart failure, and even death. Unfortunately, therapy for AF is limited. Anti-arrhythmic or rate-controlling drugs are poorly tolerated, with frequent side effects and do not reduce stroke risk. Ablation is an emerging minimally invasive therapy that has attracted considerable attention because it may eliminate AF. Unfortunately, AF ablation is technically challenging, with a success of only 50-70 % (versus >90% for other arrhythmias), and serious risks. A major cause of these limitations is that the mechanisms for human AF are not known and thus ablation cannot be directed to them. As a result, AF ablation is empiric and results in extensive destruction of the atrium. In this Mid-Career Mentoring Award in Patient Oriented Research, the applicant proposes a mentored training program for clinician-scientists, applying bioengineering principles to address mechanistic hypotheses on the maintenance of human AF. From a training perspective, each mentee will receive continuous mentoring by the applicant and an interdisciplinary research committee comprising experts in heart rhythm medicine, bioengineering, computer modeling and biological physics. Through formalized collaborations, mentees will also be able to train in cellular electrophysiology. Structured didactic training is also outlined. Scientifically, our central hypothesis is that human AF is maintained by localized sources, as opposed to widely dispersed mechanisms (multi-wavelet reentry). We will create detailed maps of atrial activation and recovery (repolarization) in AF in patients at ablation, and then use computational analysis and pharmacologic interventions in near-real-time to study mechanisms that maintain AF. Personalized computer models will be unique in that predictions will be tested directly against observed AF in the same patient, with discrepancies used to directly design further clinical studies. Because the project is performed at ablation, results will be easily translated to practice. The candidate has a track-record of using bioengineering principles, signal processing and computer models to address mechanistic hypotheses in arrhythmia-focused patient oriented research. He also has a track record of training clinician-scientists who continue to pursue patient oriented research, many of whom have secured extramural funding. Proposed studies address three Aims: 1) To determine if localized sources maintain human AF;2) To determine if repolarization alternant, conduction slowing or anatomic factors explain disorganization to fibrillation;3) to determine the impact on AF of ablating at potential localized sources. Successful completion of our Aims will lead to a paradigm-change in the mechanistic understanding of human AF, and approaches to its ablation. Mentees will be trained in a rich interdisciplinary environment and, on completing this program, will be well prepared to embark upon careers in patient-oriented research in heart rhythm disorders.

Public Health Relevance

fibrillation (AF) is an enormous public health problem that affects 2-5 million Americans, causing morbidity or death from stroke, rapid heartbeats and heart failure. Through this Mid-Career Mentoring Award in Patient Oriented Research, the applicant will perform research and train junior physician-researchers to better understand AF, and determine if abnormal activity in small regions or more widespread regions of the heart cause AF. By performing these studies in patients during clinical procedures, this project may lead to a paradigm-shift in understanding and treating AF.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Midcareer Investigator Award in Patient-Oriented Research (K24)
Project #
5K24HL103800-04
Application #
8516570
Study Section
Special Emphasis Panel (ZHL1-CSR-R (M1))
Program Officer
Carlson, Drew E
Project Start
2010-09-01
Project End
2015-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
4
Fiscal Year
2013
Total Cost
$188,897
Indirect Cost
$13,992
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
Zaman, Junaid A B; Baykaner, Tina; Clopton, Paul et al. (2017) Recurrent Post-Ablation Paroxysmal Atrial Fibrillation Shares Substrates With Persistent Atrial Fibrillation : An 11-Center Study. JACC Clin Electrophysiol 3:393-402
Zaman, Junaid A B; Kowalewski, Christopher A B; Narayan, Sanjiv M (2017) Mapping Ripples or Waves in Atrial Fibrillation? J Cardiovasc Electrophysiol 28:383-385
Vidmar, David; Krummen, David E; Hayase, Justin et al. (2017) Spatiotemporal Progression of Early Human Ventricular Fibrillation. JACC Clin Electrophysiol 3:1437-1446
Baykaner, Tina; Trikha, Rishi; Zaman, Junaid A B et al. (2017) Electrocardiographic spatial loops indicate organization of atrial fibrillation minutes before ablation-related transitions to atrial tachycardia. J Electrocardiol 50:307-315
Hammond, H Kirk; Penny, William F; Traverse, Jay H et al. (2016) Intracoronary Gene Transfer of Adenylyl Cyclase 6 in Patients With Heart Failure: A Randomized Clinical Trial. JAMA Cardiol 1:163-71
Vidmar, David; Narayan, Sanjiv M; Krummen, David E et al. (2016) Determining conduction patterns on a sparse electrode grid: Implications for the analysis of clinical arrhythmias. Phys Rev E 94:050401
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
Narayan, Sanjiv M; Zaman, Junaid A B (2016) Mechanistically based mapping of human cardiac fibrillation. J Physiol 594:2399-415
Lalani, Gautam G; Coysh, Thomas; Baykaner, Tina et al. (2016) Organized Sources Are Spatially Conserved in Recurrent Compared to Pre-Ablation Atrial Fibrillation: Further Evidence for Non-Random Electrical Substrates. J Cardiovasc Electrophysiol 27:661-9
Bayer, J D; Lalani, G G; Vigmond, E J et al. (2016) Mechanisms linking electrical alternans and clinical ventricular arrhythmia in human heart failure. Heart Rhythm 13:1922-31

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