The candidate is board certified in Cardiology and Cardiac Electrophysiology. He has an extensive background in cardiovascular research including a Doctorate in Pharmacology. He proposes to use his very strong background in Clinical Pharmacology and Clinical Electrophysiology to develop a program to elucidate the molecular basis of atrial fibrillation (AF). Abundant data from Darbar and others supports the underlying hypothesis that genetic factors play a prominent role in the development of AF and its response to therapy. The resources for the candidate to develop as a clinical investigator and to attack this hypothesis are in place. Through this K23 award, the candidate seeks to obtain formal training in human molecular genetics, while developing a vigorous research program combining patient-oriented research and laboratory-based studies. The highly supportive environment at Vanderbilt University coupled to a formal mentoring process, makes it likely the candidate will develop as a nationally and internationally recognized expert in this area. AF, the most common sustained arrhythmia, affects over 2 million Americans and is associated with significant morbidity and mortality. Current therapies for AF are limited partly due to poor understanding of fundamental mechanisms in disease pathogenesis. Identification of gene(s) responsible for AF will provide important insight into the molecular pathways that contribute to AF. There is growing recognition that AF can be a heritable disorder with loci mapped to chromosomes 10 and 6 and an AF-causing mutation in KCNQ1 gene. The candidate has identified multiple extended families with familial AF.
The first aim of this study is to identify and phenotype kindreds with familial AF.
The second aim i s to genotype families with known/candidate AF genes. Most AF is considered secondary to other conditions such as hypertension, hyperthyroidism, cardiomyopathy or valvular disease; however, a substantial minority of patients without obvious cause are said to have """"""""lone"""""""" AF. Preliminary data from Darbar suggest that patients presenting with lone AF in the 4/5 th decades of life have a genetic basis for their condition. Hence, the third aim of this study is investigate the role of genetic factors in patients and their first degree relatives with lone AF while identifying larger kindreds suitable for positional cloning approaches. With this approach, the candidate has identified over 90 probands with lone AF including multiple extended families. This complementary strategy of evaluating individuals and families will enhance our understanding of the molecular pathways of AF and identify novel therapeutic strategies for the prevention and treatment of this common and morbid condition.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Mentored Patient-Oriented Research Career Development Award (K23)
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Special Emphasis Panel (ZHL1-CSR-Q (O1))
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Scott, Jane
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Vanderbilt University Medical Center
Internal Medicine/Medicine
Schools of Medicine
United States
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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
Ritchie, Marylyn D; Rowan, Shane; Kucera, Gayle et al. (2012) Chromosome 4q25 variants are genetic modifiers of rare ion channel mutations associated with familial atrial fibrillation. J Am Coll Cardiol 60:1173-81
Darbar, Dawood; Parvez, Babar; Abraham, Robert (2012) Repolarization recipes for atrial fibrillation: beyond single channel variants. J Am Coll Cardiol 59:1026-8
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) The ""missing"" link in atrial fibrillation heritability. J Electrocardiol 44:641-4
Darbar, Dawood (2010) Genomics, heart failure and sudden cardiac death. Heart Fail Rev 15:229-38
Abraham, Robert L; Yang, Tao; Blair, Marcia et al. (2010) Augmented potassium current is a shared phenotype for two genetic defects associated with familial atrial fibrillation. J Mol Cell Cardiol 48:181-90
Watanabe, Hiroshi; Kaiser, Daniel W; Makino, Seiko et al. (2009) ACE I/D polymorphism associated with abnormal atrial and atrioventricular conduction in lone atrial fibrillation and structural heart disease: implications for electrical remodeling. Heart Rhythm 6:1327-32
Darbar, Dawood (2009) Is it time to develop a ""pathogenicity"" score to distinguish long QT syndrome causing mutations from ""background"" genetic noise? Heart Rhythm 6:1304-5

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