The proposed research is a multidisciplinary, multicenter, collaborative study to continue the investigation of the clinical, cardiac, and genetic aspects of the Long QT Syndrome (LQTS) - a heritable channelopathy with delayed ventricular repolarization and episodic life-threatening ventricular tachyarrhythmias manifest by syncope and sudden death. This research project will investigate the phenotype and genotype risk factors and biophysical electrophysiologic risk mechanisms in LQT1 and LQT2 -- the two most common forms of LQTS. This five-year project will: 1) continue to collect: a) detailed annual clinical data throughout the life-span of genotype-identified LQT1 and LQT2 subjects enrolled in the U.S. portion of the LQTS Registry, and b) blood samples on LQTS Registry subjects who are possible carriers of LQT1 and LQT2 mutations by liberal ECG-QTc criteria for thorough genotyping in order to expand the number of identified subjects with LQT1 and LQT2 genotypes;2) carry out comprehensive genotyping for known and novel mutations in the LQT1 and LQT2 genes to identify: a) all patients with LQT1 or LQT2 mutations in the Registry;and b) the presence of two or more ion-channel mutations that may occur in these genes in 10-15% of subjects with these two forms of LQTS;3) perform uniform mammalian expression studies of identified LQT1 and LQT2 mutations to determine the biophysical electrophysiologic functional effects of the mutations on ion-channel currents;and 4) Risk stratify affected individuals with LQT1 and LQT2 mutations for life-threatening arrhythmic events using genotype and phenotype covariates and biophysical electrophysiologic functional data to better identify arrhythmic risk mechanisms in patients with these two inherited LQTS disorders. Functionally, the project has six sections: a Clinical Center for follow-up of the multigenerational LQT1 and LQT2 subjects;a Genetic Pathology Lab for cell-line preparation/storage;a Functional Genomics Center for genotype studies;an Ion-channel Expression center for cellular electrophysiological studies;a Biostatistical Section involved in sophisticated time-to-event analyses;and a Coordination and Data Center for centralized data management and program coordination. Our central hypothesis is that the location of the mutation in the ion-channel and the biophysical dysfunctional effects of the mutations are important risk factors in arrhythmic-related cardiac events independent of clinical covariates and LQTS therapies in patients with LQT1 and LQT2 genotypes. This integrated phenotype-genotype research program has important clinical and basic science implications for improved insight into arrhythmogenic risk mechanisms.

Public Health Relevance

Identification of the relationship between mutant LQTS genes that encode for dysfunctional ion channels and life-threatening ventricular tachyarrhythmias should provide more complete knowledge into the genetic and electrophysiologic factors involved in repolarization disorders. These studies into altered ventricular repolarization should contribute important new insights into sudden cardiac death mechanisms associated with acquired cardiac disorders that accompany ischemic and nonischemic cardiomyopathy and QT-prolonging drugs. This enhanced knowledge should lead to more effective strategies for prevention of sudden death in a broad spectrum of genetic and acquired cardiac disorders with meaningful public health benefits.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Cardiovascular and Sleep Epidemiology (CASE)
Program Officer
Sholinsky, Phyliss
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University of Rochester
Internal Medicine/Medicine
Schools of Dentistry
United States
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Wilde, Arthur A M; Moss, Arthur J; Kaufman, Elizabeth S et al. (2016) Clinical Aspects of Type 3 Long-QT Syndrome: An International Multicenter Study. Circulation 134:872-82
Zhang, Claire; Kutyifa, Valentina; Moss, Arthur J et al. (2015) Long-QT Syndrome and Therapy for Attention Deficit/Hyperactivity Disorder. J Cardiovasc Electrophysiol 26:1039-44
Zhang, Claire; Kutyifa, Valentina; McNitt, Scott et al. (2015) Identification of Low-Risk Adult Congenital LQTS Patients. J Cardiovasc Electrophysiol 26:853-858
Olde Nordkamp, Louise R A; Ruwald, Martin H; Goldenberg, Ilan et al. (2014) Syncope in genotype-negative long QT syndrome family members. Am J Cardiol 114:1223-8
Abu-Zeitone, Abeer; Peterson, Derick R; Polonsky, Bronislava et al. (2014) Oral contraceptive use and the risk of cardiac events in patients with long QT syndrome. Heart Rhythm 11:1170-5
Abu-Zeitone, Abeer; Peterson, Derick R; Polonsky, Bronislava et al. (2014) Efficacy of different beta-blockers in the treatment of long QT syndrome. J Am Coll Cardiol 64:1352-8
Mullally, Jamie; Goldenberg, Ilan; Moss, Arthur J et al. (2013) Risk of life-threatening cardiac events among patients with long QT syndrome and multiple mutations. Heart Rhythm 10:378-82
Nawathe, Pooja A; Kryukova, Yelena; Oren, Ronit V et al. (2013) An LQTS6 MiRP1 mutation suppresses pacemaker current and is associated with sinus bradycardia. J Cardiovasc Electrophysiol 24:1021-7
Mathias, Andrew; Moss, Arthur J; Lopes, Coeli M et al. (2013) Prognostic implications of mutation-specific QTc standard deviation in congenital long QT syndrome. Heart Rhythm 10:720-5
Moss, Arthur J (2012) Selection of high-risk patients for device intervention with the new advances in technology. J Electrocardiol 45:670-2

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