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CARDIOVASCULAR |
1 Institute for Cardiovascular Research and Department of Pharmacology, SUNY Upstate Medical University, Syracuse, NY, USA
2 Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA
Previous studies have suggested an important role for the inward rectifier K+ current (IK1) 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 µM Ba2+, suggesting an important role for IK1. Moreover, by increasing IK1 density in a two-dimensional computer model having realistic mouse ionic and action potential properties, a highly stable, fast rotor (
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 IK1, compared to other K+ currents. In combination, these results provide the first direct evidence that IK1 up-regulation in the mouse heart is a substrate for stable and very fast rotors.
(Received 20 September 2006;
accepted after revision 3 November 2006;
first published online 9 November 2006)
Corresponding author J. Jalife: Department of Pharmacology, SUNY Upstate Medical University, 750 E. Adams St, Syracuse, NY 13210, USA. Email: jalifej{at}upstate.edu
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