Our proposal is designed to characterize the electrical heterogeneity intrinsic to the atrial and ventricular myocardium, to which our group has contributed significantly over the past many years.
Our specific aims are to: 1) probe differences in sodium channel and action potential characteristics of atrial vs. ventricular cells isolated from the canine heart and assess how these distinctions contribute to atrial-selective sodium channel inhibition and suppression of atrial fibrillation by INa blockers;2) determine to what extent the electrical and pharmacologic heterogeneities uncovered in the canine right atrium exist in the left atrium;3) determine to what extent electrical and pharmacologic heterogeneities uncovered in canine right and left atria of normal dogs differ from those of respective tissues and cells isolated from heart failure dogs (HF); 4) assess the propensity for the development of atrial fibrillation in atria isolated from heart failure dogs and define the substrate and triggers that underlie arrhythmogenesis. 5) assess the effectiveness of different classes of sodium channel blockers in terminating and suppressing re-induction of AF, determine to what extent these agents are atrial-selective, and the mechanisms involved;6) probe the basis for atrial-selective sodium channel block responsible for the anti-AF effects of sodium channel blockers in HF dogs;and 7) assess the influence of parasympathetic agonists on the development of AF in atria isolated from normal and heart failure dogs. The principal goals of our proposal are to probe the extent to which electrical heterogeneities exist between the right and left atrium and ventricles of the canine heart and examine how amplification of these heterogeneities contributes to the development of atrial and ventricular arrhythmias in the normal heart as well as in structurally compromised hearts isolated from dogs with pacing-induced dilated cardiomyopathy. The proposed project is a clinically relevant research inquiry designed to advance our understanding of atrial arrhythmia development and approach to therapy. The central focus involving a test of the hypothesis that atrial-selective modulation of the sodium channel can prevent AF without significantly altering ventricular electrophysiology is innovative and exciting and has the potential to produce a paradigm shift in the pharmacologic approach to therapy of AF, one of the greatest unmet medical needs facing our society. Successful completion of the project will also identify the ionic and cellular mechanisms that contribute to atrial selectivity, thus creating a unique platform for the development of novel therapies that could potentially find their way to the bedside.

Public Health Relevance

Atrial fibrillation (AF) is the most common sustained arrhythmia encountered in the clinic, affecting an estimated 2.5 million Americans. Its prevalence is age-related and is increasing sharply with aging of the population, to the point where the term epidemic has been applied. AF is a major complication associated with congestive heart failure (CHF), which affects an estimated 5 million patients in the United States and is a major cause of hospitalization and mortality. Currently available therapeutic options all have intrinsic limitations and new approaches to the pharmacologic management of atrial fibrillation are critically needed. Safe and effective pharmacologic treatment for AF is one of the greatest unmet medical needs facing our society. Successful completion of the studies proposed in this competing renewal will significantly advance this goal and lead to the development of innovative and effective pharmacologic treatments for AF.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL047678-17A2
Application #
8021311
Study Section
Electrical Signaling, Ion Transport, and Arrhythmias Study Section (ESTA)
Program Officer
Lathrop, David A
Project Start
1993-05-01
Project End
2014-11-30
Budget Start
2010-12-15
Budget End
2011-11-30
Support Year
17
Fiscal Year
2011
Total Cost
$437,500
Indirect Cost
Name
Masonic Medical Research Laboratory, Inc
Department
Type
DUNS #
077307437
City
Utica
State
NY
Country
United States
Zip Code
13501
Hu, Dan; Barajas-Martínez, Hector; Burashnikov, Alexander et al. (2016) Mechanisms underlying atrial-selective block of sodium channels by Wenxin Keli: Experimental and theoretical analysis. Int J Cardiol 207:326-34
Antzelevitch, Charles; Yan, Gan-Xin; Ackerman, Michael J et al. (2016) J-Wave syndromes expert consensus conference report: Emerging concepts and gaps in knowledge. Heart Rhythm 13:e295-324
Antzelevitch, Charles; Patocskai, Bence (2016) Brugada Syndrome: Clinical, Genetic, Molecular, Cellular, and Ionic Aspects. Curr Probl Cardiol 41:7-57
Antzelevitch, Charles; Yan, Gan-Xin; Ackerman, Michael J et al. (2016) J-Wave syndromes expert consensus conference report: Emerging concepts and gaps in knowledge. J Arrhythm 32:315-339
Sroubek, Jakub; Probst, Vincent; Mazzanti, Andrea et al. (2016) Programmed Ventricular Stimulation for Risk Stratification in the Brugada Syndrome: A Pooled Analysis. Circulation 133:622-30
Chorin, Ehud; Hu, Dan; Antzelevitch, Charles et al. (2016) Ranolazine for Congenital Long-QT Syndrome Type III: Experimental and Long-Term Clinical Data. Circ Arrhythm Electrophysiol 9:
Patocskai, Bence; Barajas-Martinez, Hector; Hu, Dan et al. (2016) Cellular and ionic mechanisms underlying the effects of cilostazol, milrinone, and isoproterenol to suppress arrhythmogenesis in an experimental model of early repolarization syndrome. Heart Rhythm 13:1326-34
Antzelevitch, Charles; Yan, Gan-Xin (2015) J-wave syndromes: Brugada and early repolarization syndromes. Heart Rhythm 12:1852-66
Betzenhauser, Matthew J; Pitt, Geoffrey S; Antzelevitch, Charles (2015) Calcium Channel Mutations in Cardiac Arrhythmia Syndromes. Curr Mol Pharmacol 8:133-42
Burashnikov, Alexander; Belardinelli, Luiz; Antzelevitch, Charles (2015) Inhibition of IKr potentiates development of atrial-selective INa block leading to effective suppression of atrial fibrillation. Heart Rhythm 12:836-44

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