Long QT Syndrome Type 3 (LQT3) is an inherited channelopathy associated with a high-risk of life-threating cardiac events across the entire age spectrum from infancy through adolescence to adults and seniors with unclear therapeutics. The central theme of our Multiple-PI LQT3 R01 grant is that joint collaborative investigations into the clinical, phenotype, genotype, and mechanistic aspects of LQT3 will yield novel insights and innovative targets for existing (beta- blocker) and new (sodium/calcium channel blockers) therapeutic approaches for this incompletely studied disorder, with potential extrapolation of the findings to other SCN5A-related medical conditions. This grant application involves three major research activities, each involving genotype-phenotype-therapeutic investigations at different basic and clinical levels involving: 1) Clinical: continue the enrollment and long-term follow-up of patients with LQT3 mutations in our ongoing LQT3 Registry that currently involves over 400 LQT3 patients and carry out population-based LQT3 risk stratification studies involving clinical, phenotype, gender, genotype, and therapy factors, with the information providing lead-ins to mechanistic basic science studies and gene-specific therapies;2) Basic science: conduct biophysical and pharmacological functional investigations on specific LQT3 mutations utilizing: a) innovative, patient-specific induced pluripotent stem cells (iPSC) derived from patients in the LQT3 Registry harboring high-risk LQT3 mutations refractory to conventional therapy;b) relevant LQT3 mouse models investigating genetic risk and therapy in the intact animal;c) specific cellular expression studies to cross-validate the findings from the iPSC and mouse model studies and to evaluate dose-response therapies on disordered sodium-channel kinetics;and d) cardiomyocyte studies to complement beta-blocker and Na+ channel investigation in Aim 2c;and 3) Data management/analysis: provide centralized data management and coordinated biostatistical analyses to optimize the integration and science of the clinical and basic laboratory studies. The successful collaborative efforts of the two PIs (Drs. Moss and Kass) extend over 10 years of professional interactions. This Multiple-PI R01 will be carried out at the University of Rochester Medical Center in Rochester, NY and the Columbia University Medical Center in New York City.
This grant focuses on patients affected with the inherited Type 3 Long QT Syndrome. This research has public health and medical relevance. It will provide new insights into the clinical, basic science, and therapeutic aspects of this disease and will lead to more effective prevention of sudden death for patients with this disorder, and for patients with other genetic and acquired cardiac rhythm disorders.
|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|
|Platonov, Pyotr G; McNitt, Scott; Polonsky, Bronislava et al. (2018) Risk Stratification of Type 2 Long-QT Syndrome Mutation Carriers With Normal QTc Interval: The Value of Sex, T-Wave Morphology, and Mutation Type. Circ Arrhythm Electrophysiol 11:e005918|
|Page, Alex; McNitt, Scott; Xia, Xiaojuan et al. (2017) Population-based beat-to-beat QT analysis from Holter recordings in the long QT syndrome. J Electrocardiol 50:787-791|
|Bohnen, M S; Peng, G; Robey, S H et al. (2017) Molecular Pathophysiology of Congenital Long QT Syndrome. Physiol Rev 97:89-134|
|Zareba, Wojciech; McNitt, Scott; Polonsky, Slava et al. (2017) JT interval: What does this interval mean? J Electrocardiol 50:748-751|
|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|
|Wan, Elaine; Abrams, Jeffrey; Weinberg, Richard L et al. (2016) Aberrant sodium influx causes cardiomyopathy and atrial fibrillation in mice. J Clin Invest 126:112-22|
|Zhang, Claire; Kutyifa, Valentina; McNitt, Scott et al. (2015) Identification of Low-Risk Adult Congenital LQTS Patients. J Cardiovasc Electrophysiol 26:853-858|
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