Atrial fibrillation (AF) is the commonest arrhythmia for which drug therapy is currently prescribed. Many of the antiarrhythmic drugs used to suppress AF however, may cause marked QT prolongation and polymorphic ventricular tachycardia (torsades de pointes). Furthermore, this variability is not confined to antiarrhythmic drugs alone: in fact the risk of proarrhythmia related to excessive QT prolongation has been the single leading cause of drug withdrawal in the last decade. The goal of the present research is to study mechanisms underlying a well-recognized but incompletely understood behavior of the QT interval: following conversion of AF, QT interval transiently and variably prolongs and this can trigger torsades de pointes. We have accumulated evidence that following conversion of AF, the QT interval prolongs in a rate-independent fashion, and that the period following conversion of AF is one of high risk for torsades de pointes in some patients. These data support the working hypothesis in this research that AF generates signals that influence QT behavior and arrhythmia susceptibility following conversion. Such signals may be neurohormonal or rate- related and these will be evaluated in the specific experiments proposed.
In Specific Aim 1, we will relate RR- QT variability prior to and following elective DC-cardioversion of AF to candidate biomarkers of the complex inflammatory, pro-oxidant, and autonomic environment mediating the clinical course of AF.
In Specific Aim 2, we test the hypothesis that rapid antecedent rates, for minutes to days, contribute to RR-QT remodeling by studying the effects of atrial pacing on RR-QT relationship in patients with permanent pacemakers. Common genetic variants can modulate ion currents or the environment in which these currents accomplish normal or abnormal repolarization. Accordingly, in Specific Aim 3, the role of a set of such polymorphisms in modulating QT variability (as determined in Specific Aims 1 and 2) in AF will be determined. These studies will infer mechanisms that will be widely useful in furthering an understanding of arrhythmia risk, particularly as it applies to abnormal ventricular repolarization, and also has the potential to assist in new drug development. Project narrative: In this study, we are trying to better understand the risk factors that predispose a patient to this arrhythmia. The results of this work may help us develop new and better to treat atrial fibrillation.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Clinical and Integrative Cardiovascular Sciences Study Section (CICS)
Program Officer
Boineau, Robin
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Vanderbilt University Medical Center
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
McCauley, Mark; Vallabhajosyula, Sharath; Darbar, Dawood (2016) Proarrhythmic and Torsadogenic Effects of Potassium Channel Blockers in Patients. Card Electrophysiol Clin 8:481-93
Parvez, Babar; Shoemaker, M Benjamin; Muhammad, Raafia et al. (2013) Common genetic polymorphism at 4q25 locus predicts atrial fibrillation recurrence after successful cardioversion. Heart Rhythm 10:849-55
Parvez, Babar; Vaglio, Joseph; Rowan, Shane et al. (2012) Symptomatic response to antiarrhythmic drug therapy is modulated by a common single nucleotide polymorphism in atrial fibrillation. J Am Coll Cardiol 60:539-45
Darbar, Dawood; Parvez, Babar; Abraham, Robert (2012) Repolarization recipes for atrial fibrillation: beyond single channel variants. J Am Coll Cardiol 59:1026-8
Savio-Galimberti, Eleonora; Gollob, Michael H; Darbar, Dawood (2012) Voltage-gated sodium channels: biophysics, pharmacology, and related channelopathies. Front Pharmacol 3:124
Monahan, Ken; Brewster, Jordan; Wang, Li et al. (2012) Relation of the severity of obstructive sleep apnea in response to anti-arrhythmic drugs in patients with atrial fibrillation or atrial flutter. Am J Cardiol 110:369-72
Gbadebo, T David; Okafor, Henry; Darbar, Dawood (2011) Differential impact of race and risk factors on incidence of atrial fibrillation. Am Heart J 162:31-7
Parvez, Babar; Darbar, Dawood (2011) Novel ECG markers for ventricular repolarization: Is the QT interval obsolete? Heart Rhythm 8:1044-5
Yang, Tao; Yang, Ping; Roden, Dan M et al. (2010) Novel KCNA5 mutation implicates tyrosine kinase signaling in human atrial fibrillation. Heart Rhythm 7:1246-52
Darbar, Dawood (2010) Genomics, heart failure and sudden cardiac death. Heart Fail Rev 15:229-38

Showing the most recent 10 out of 21 publications