Atrial fibrillation (AF) is the most common cardiac arrhythmia in adults, affecting over 2 million Americans, yet its molecular etiology is poorly understood. Genetic predisposition to AF has been demonstrated in populations and in families segregating specific mutations. These mutations are predicted to confer susceptibility to AF at the cellular level. However, familial AF does not present during childhood suggesting that genetic predisposition alone is not sufficient to cause the disease. Therefore, other factors acquired during life are presumed to interact with the genetically determined cellular substrate for the full expression of the clinical phenotype. The additive or synergistic effects of combined genetic and acquired factors in determining AF susceptibility have not been explored at the mechanistic level. The proposed studies will investigate the cellular consequences of a slow delayed rectifier current (IKs) gain-of-function mutation in KCNQ1 (S140G) linked with familial AF and to explore how the genetic risk is modified by oxidative stress, a common and well- recognized acquired factor in the pathogenesis of AF.
In Specific Aim 1, rabbit atrial myocytes will be transduced with recombinant virus to express either wild-type (WT) or mutant channels. Using whole-cell electrophysiological recording, these studies will test whether gain-of-function characteristics of KCNQ1- S140G observed in vitro translate to increased current density and a shortened APD in atrial myocytes.
In Specific Aim 2, electrophysiological studies will characterize heterologously expressed WT or mutant channels in mammalian cells under acute and prolonged oxidative stress exposure, mimicked by hydrogen peroxide application. These results will disclose the types of functional changes in the channel that occur with oxidative stress exposure.
In Specific Aim 3, experiments will test the hypothesis that oxidative stress in atrial myocytes alters electrophysiology in a manner that potentiates AF-susceptibility conferred by mutant channel expression. Atrial myocytes will be exposed to oxidative stress either acutely during electrophysiological recording or for a prolonged duration in culture. Recordings will be analyzed for APD and action potential perturbations such as early or delayed after depolarizations during different pacing frequencies. These experiments will advance our understanding of how genetic factors and acquired pathophysiological conditions interact to produce AF susceptibility at the cellular level and may lead to better therapies and prevention.

Public Health Relevance

The mechanism for atrial fibrillation (AF), the most common cardiac arrhythmia in adults, is poorly understood, and a better grasp of its molecular basis may lead to improved therapies and prevention. Because AF does not present during childhood, the combination of both genetic predisposition with factors acquired during life may underlie this disorder. These proposed studies will investigate the interaction between a causative AF mutation and oxidative stress, an established AF risk factor that increases with advancing age.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
Project #
5F30HL107066-04
Application #
8802886
Study Section
Special Emphasis Panel (ZRG1-F10A-S (20))
Program Officer
Meadows, Tawanna
Project Start
2013-02-01
Project End
2016-01-31
Budget Start
2015-02-01
Budget End
2016-01-31
Support Year
4
Fiscal Year
2015
Total Cost
$39,720
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Pharmacology
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Ungvari, Zoltan; Csiszar, Anna; Sosnowska, Danuta et al. (2013) Testing predictions of the oxidative stress hypothesis of aging using a novel invertebrate model of longevity: the giant clam (Tridacna derasa). J Gerontol A Biol Sci Med Sci 68:359-67
Campbell, Courtney M; Campbell, Jonathan D; Thompson, Christopher H et al. (2013) Selective targeting of gain-of-function KCNQ1 mutations predisposing to atrial fibrillation. Circ Arrhythm Electrophysiol 6:960-6
Potet, Franck; Lorinc, Amanda N; Chaigne, Sebastien et al. (2012) Identification and characterization of a compound that protects cardiac tissue from human Ether-à-go-go-related gene (hERG)-related drug-induced arrhythmias. J Biol Chem 287:39613-25
Ungvari, Zoltan; Ridgway, Iain; Philipp, Eva E R et al. (2011) Extreme longevity is associated with increased resistance to oxidative stress in Arctica islandica, the longest-living non-colonial animal. J Gerontol A Biol Sci Med Sci 66:741-50
Jorge, Benjamin S; Campbell, Courtney M; Miller, Alison R et al. (2011) Voltage-gated potassium channel KCNV2 (Kv8.2) contributes to epilepsy susceptibility. Proc Natl Acad Sci U S A 108:5443-8