The proposed research is a multidisciplinary, multicenter, collaborative study to investigate the clinical, cardiac, and genetic aspects of the Long QT Syndrome (LQTS) - a heritable disorder with delayed repolarization, episodic malignant arrhythmias with syncope and sudden death, and recently demonstrated gene linkage in a large pedigree. The five-year research plan consists of: l) resolution of the question of genetic heterogeneity in LQTS by testing for Harvey ras-1 gene linkage in the existing well-characterized LQTS families; 2) exploration by segregation analysis of the likelihood that a second gene coexists with the Harvey ras-l gene to explain a more malignant disease process in some LQTS families than in others; 3) establishment of normal standards for 6 quantitative repolarization parameters on a healthy population (n=4,000) using digitized ECG recordings, and biomedical and statistical techniques with adjustment for age, gender, race, and heart rate; 4) continuation of existing LQTS registry with on going enrollment of new families and follow-up of new and existing LQTS pedigrees (n=349 families) in order to provide a central repository for this disorder, especially as it relates to ongoing genetic analyses; 5) investigation of the static (12-lead ECG) and dynamic (24-hour Holter ECG) aspects of ventricular repolarization in LQTS families showing Harvey ras gene linkage to determine if there is a distinctive repolarization abnormality in those with the Harvey ras- 1 gene compared to those without it; and 6) continuation of the prospective longitudinal follow-up study of LQTS families to better understand the long-term clinical course of this disorder; time-dependent survivorship analyses will be performed to evaluate the effects of various clinical features, repolarization severity (QTc length), Harvey ras-l gene linkage, and therapeutic efficacy with antiadrenergic therapy (if data permits) on outcome event rates (syncope and sudden death) in the LQTS population. This integrated research program offers a substantial prospect of: 1) improving the diagnosis and treatment of LQTS; and 2) providing a fundamental understanding of the molecular basis of repolarization-related cardiac arrhythmias.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL051618-01
Application #
3370338
Study Section
Epidemiology and Disease Control Subcommittee 2 (EDC)
Project Start
1993-06-07
Project End
1998-05-31
Budget Start
1993-06-07
Budget End
1994-05-31
Support Year
1
Fiscal Year
1993
Total Cost
Indirect Cost
Name
University of Rochester
Department
Type
Schools of Dentistry
DUNS #
208469486
City
Rochester
State
NY
Country
United States
Zip Code
14627
Kutyifa, Valentina; Daimee, Usama A; McNitt, Scott et al. (2018) Clinical aspects of the three major genetic forms of long QT syndrome (LQT1, LQT2, LQT3). Ann Noninvasive Electrocardiol 23:e12537
Auerbach, David S; Biton, Yitschak; Polonsky, Bronislava et al. (2018) Risk of cardiac events in Long QT syndrome patients when taking antiseizure medications. Transl Res 191:81-92.e7
Wang, Meng; Szepietowska, Barbara; Polonsky, Bronislava et al. (2018) Risk of Cardiac Events Associated With Antidepressant Therapy in Patients With Long QT Syndrome. Am J Cardiol 121:182-187
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
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
Moss, Arthur J (2014) New insights into the arrhythmogenic substrate of the long QT syndrome. Circulation 130:1929-30
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

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