title: Up-regulation of the inward rectifier K+ current (I K1) in the mouse heart accelerates and stabilizes rotors.
abstract: 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.affiliation: Institute for Cardiovascular Research and Department of Pharmacology, SUNY Upstate Medical University, Syracuse, NY 13210, USA.
authors.forename: Sami F
authors.initials: SF
authors.lastname: Noujaim
authors.forename: Sandeep V
authors.initials: SV
authors.lastname: Pandit
authors.forename: Omer
authors.initials: O
authors.lastname: Berenfeld
authors.forename: Karen
authors.initials: K
authors.lastname: Vikstrom
authors.forename: Marina
authors.initials: M
authors.lastname: Cerrone
authors.forename: Sergey
authors.initials: S
authors.lastname: Mironov
authors.forename: Michelle
authors.initials: M
authors.lastname: Zugermayr
authors.forename: Anatoli N
authors.initials: AN
authors.lastname: Lopatin
authors.forename: José
authors.initials: J
authors.lastname: Jalife
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000188:drug therapy / Q000503:physiopathology; D001281:Atrial Fibrillation / Q000503:physiopathology; D001282:Atrial Flutter / Q000503:physiopathology; D006332:Cardiomegaly / Q000503:physiopathology; D003198:Computer Simulation; D003645:Death, Sudden; D004562:Electrocardiography; D006321:Heart / Q000502:physiology*; D006327:Heart Block / Q000503:physiopathology; D006329:Heart Conduction System / Q000502:physiology; D006339:Heart Rate / Q000502:physiology; D066298:In Vitro Techniques; D051379:Mice; D008822:Mice, Transgenic; D026902:Potassium Channel Blockers / Q000494:pharmacology; D024661:Potassium Channels, Inwardly Rectifying / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology*; D012032:Refractory Period, Electrophysiological / Q000235:genetics / Q000502:physiology; D015854:Up-Regulation / Q000502:physiology
chemical_list: C489461:Kir2.1 channel; D026902:Potassium Channel Blockers; D024661:Potassium Channels, Inwardly Rectifying