Document Detail


Up-regulation of the inward rectifier K+ current (I K1) in the mouse heart accelerates and stabilizes rotors.
MedLine Citation:
PMID:  17095564     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Previous studies have suggested an important role for the inward rectifier K+ current (I K1) in stabilizing rotors responsible for ventricular tachycardia (VT) and fibrillation (VF). To test this hypothesis, we used a line of transgenic mice (TG) overexpressing Kir 2.1-green fluorescent protein (GFP) fusion protein in a cardiac-specific manner. Optical mapping of the epicardial surface in ventricles showed that the Langendorff-perfused TG hearts were able to sustain stable VT/VF for 350 +/- 1181 s at a very high dominant frequency (DF) of 44.6 +/- 4.3 Hz. In contrast, tachyarrhythmias in wild-type hearts (WT) were short-lived (3 +/- 9 s), and the DF was 26.3 +/- 5.2 Hz. The stable, high frequency, reentrant activity in TG hearts slowed down, and eventually terminated in the presence of 10 mum Ba2+, suggesting an important role for I K1. Moreover, by increasing I K1 density in a two-dimensional computer model having realistic mouse ionic and action potential properties, a highly stable, fast rotor (approximately 45 Hz) could be induced. Simulations suggested that the TG hearts allowed such a fast and stable rotor because of both greater outward conductance at the core and shortened action potential duration in the core vicinity, as well as increased excitability, in part due to faster recovery of Na+ current. The latter resulted in a larger rate of increase in the local conduction velocity as a function of the distance from the core in TG compared to WT hearts, in both simulations and experiments. Finally, simulations showed that rotor frequencies were more sensitive to changes (doubling) in I K1, compared to other K+ currents. In combination, these results provide the first direct evidence that I K1 up-regulation in the mouse heart is a substrate for stable and very fast rotors.
Authors:
Sami F Noujaim; Sandeep V Pandit; Omer Berenfeld; Karen Vikstrom; Marina Cerrone; Sergey Mironov; Michelle Zugermayr; Anatoli N Lopatin; José Jalife
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Publication Detail:
Type:  In Vitro; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2006-11-09
Journal Detail:
Title:  The Journal of physiology     Volume:  578     ISSN:  0022-3751     ISO Abbreviation:  J. Physiol. (Lond.)     Publication Date:  2007 Jan 
Date Detail:
Created Date:  2007-01-01     Completed Date:  2007-02-26     Revised Date:  2009-11-18    
Medline Journal Info:
Nlm Unique ID:  0266262     Medline TA:  J Physiol     Country:  England    
Other Details:
Languages:  eng     Pagination:  315-26     Citation Subset:  IM    
Affiliation:
Institute for Cardiovascular Research and Department of Pharmacology, SUNY Upstate Medical University, Syracuse, NY 13210, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Arrhythmias, Cardiac / drug therapy,  physiopathology
Atrial Fibrillation / physiopathology
Atrial Flutter / physiopathology
Cardiomegaly / physiopathology
Computer Simulation
Death, Sudden
Electrocardiography
Heart / physiology*
Heart Block / physiopathology
Heart Conduction System / physiology
Heart Rate / physiology
Mice
Mice, Transgenic
Potassium Channel Blockers / pharmacology
Potassium Channels, Inwardly Rectifying / biosynthesis*,  genetics,  physiology*
Refractory Period, Electrophysiological / genetics,  physiology
Up-Regulation / physiology
Grant Support
ID/Acronym/Agency:
P01 HL039707/HL/NHLBI NIH HHS; R01 HL060843/HL/NHLBI NIH HHS; R01 HL070074/HL/NHLBI NIH HHS; R01 HL69052/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Kir2.1 channel; 0/Potassium Channel Blockers; 0/Potassium Channels, Inwardly Rectifying
Comments/Corrections

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