Heart disease remains the leading cause of death in the United States and other developed countries. Half of these deaths occur suddenly, typically from ventricular tachyarrhythmias that arise in the setting of acute ischemia, acquired heart disease or inherited syndromes including channelopathies and cardiomyopathies. The specialized cardiac conduction system (CCS) comprises a heterogeneous network of cells that orchestrate the initiation and propagation of a wave of electrical excitation throughout the myocardium. Accumulating evidence suggests that dysfunction of the ventricular conduction system (VCS) plays a key mechanistic role triggering a broad range of life-threatening ventricular arrhythmias, however major gaps exist in our understanding of the molecular mechanisms responsible for the formation, function and dysfunction of the VCS. Our laboratory has established new tools and identified novel genes and pathways that we hypothesize are critical for VCS formation, function and dysfunction. In this application we propose a series of experiments designed to test the biological importance of these new genes and pathways.

Public Health Relevance

Heart disease is the leading cause of death in the United States and other developed countries and almost half of these deaths occur suddenly from heart rhythm abnormalities. Our research is directed toward understanding the mechanisms responsible for normal and abnormal heart rhythmicity with a particular focus on arrhythmic diseases that arise from abnormalities in the specialized cardiac conduction system.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL105983-05A1
Application #
9190678
Study Section
Electrical Signaling, Ion Transport, and Arrhythmias Study Section (ESTA)
Program Officer
Lathrop, David A
Project Start
2011-04-01
Project End
2020-04-30
Budget Start
2016-07-01
Budget End
2017-04-30
Support Year
5
Fiscal Year
2016
Total Cost
Indirect Cost
Name
New York University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
Park, David S; Fishman, Glenn I (2018) SCN5A: the greatest HITS collection. J Clin Invest 128:913-915
Shekhar, Akshay; Lin, Xianming; Lin, Bin et al. (2018) ETV1 activates a rapid conduction transcriptional program in rodent and human cardiomyocytes. Sci Rep 8:9944
Fishman, Glenn I (2017) Drug-Induced Arrhythmias, Precision Medicine, and Small Data. Circ Arrhythm Electrophysiol 10:
Park, David S; Fishman, Glenn I (2017) Development and Function of the Cardiac Conduction System in Health and Disease. J Cardiovasc Dev Dis 4:
Park, David S; Shekhar, Akshay; Marra, Christopher et al. (2016) Fhf2 gene deletion causes temperature-sensitive cardiac conduction failure. Nat Commun 7:12966
Shekhar, Akshay; Lin, Xianming; Liu, Fang-Yu et al. (2016) Transcription factor ETV1 is essential for rapid conduction in the heart. J Clin Invest 126:4444-4459
Tsai, Su-Yi; Maass, Karen; Lu, Jia et al. (2015) Efficient Generation of Cardiac Purkinje Cells from ESCs by Activating cAMP Signaling. Stem Cell Reports 4:1089-102
Lin, Xianming; O'Malley, Heather; Chen, Chunling et al. (2015) Scn1b deletion leads to increased tetrodotoxin-sensitive sodium current, altered intracellular calcium homeostasis and arrhythmias in murine hearts. J Physiol 593:1389-407
Park, David S; Cerrone, Marina; Morley, Gregory et al. (2015) Genetically engineered SCN5A mutant pig hearts exhibit conduction defects and arrhythmias. J Clin Invest 125:403-12
Maass, Karen; Shekhar, Akshay; Lu, Jia et al. (2015) Isolation and characterization of embryonic stem cell-derived cardiac Purkinje cells. Stem Cells 33:1102-12

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