This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 104/3/355    most recent CIRCRESAHA.108.178335v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Sekar, R. B. Articles by Tung, L. Search for Related Content PubMed PubMed Citation Articles by Sekar, R. B. Articles by Tung, L. Related Collections Arrythmias-basic studies

(Circulation Research. 2009;104:355.)
© 2009 American Heart Association, Inc.

Cellular Biology

I_K1 Heterogeneity Affects Genesis and Stability of Spiral Waves in Cardiac Myocyte Monolayers

Rajesh B. Sekar, Eddy Kizana^*, Hee C. Cho^*, Jared M. Molitoris, Geoffrey G. Hesketh, Brett P. Eaton, Eduardo Marbán, Leslie Tung

From the Departments of Biomedical Engineering (R.B.S., J.M.M., B.P.E., L.T.) and Biological Chemistry (G.G.H.) and Division of Cardiology (E.K., E.M.), The Johns Hopkins University School of Medicine; and Excigen Inc (H.C.C.), Baltimore, Md.

Correspondence to Leslie Tung, PhD, Department of Biomedical Engineering, The Johns Hopkins University School of Medicine, 720 Rutland Ave, Traylor 703, Baltimore, MD 21205. E-mail ltung{at}jhu.edu

Previous studies have postulated an important role for the inwardly rectifying potassium current (I_K1) in controlling the dynamics of electrophysiological spiral waves responsible for ventricular tachycardia and fibrillation. In this study, we developed a novel tissue model of cultured neonatal rat ventricular myocytes (NRVMs) with uniform or heterogeneous Kir2.1expression achieved by lentiviral transfer to elucidate the role of I_K1 in cardiac arrhythmogenesis. Kir2.1-overexpressed NRVMs showed increased I_K1 density, hyperpolarized resting membrane potential, and increased action potential upstroke velocity compared with green fluorescent protein–transduced NRVMs. Opposite results were observed in Kir2.1-suppressed NRVMs. Optical mapping of uniformly Kir2.1 gene-modified monolayers showed altered conduction velocity and action potential duration compared with nontransduced and empty vector-transduced monolayers, but functional reentrant waves could not be induced. In monolayers with an island of altered Kir2.1 expression, conduction velocity and action potential duration of the locally transduced and nontransduced regions were similar to those of the uniformly transduced and nontransduced monolayers, respectively, and functional reentrant waves could be induced. The waves were anchored to islands of Kir2.1 overexpression and remained stable but dropped in frequency and meandered away from islands of Kir2.1 suppression. In monolayers with an inverse pattern of I_K1 heterogeneity, stable high frequency spiral waves were present with I_K1 overexpression, whereas lower frequency, meandering spiral waves were observed with I_K1 suppression. Our study provides direct evidence for the contribution of I_K1 heterogeneity and level to the genesis and stability of spiral waves and highlights the potential importance of I_K1 as an antiarrhythmia target.

Key Words: Kir2.1 • inwardly rectifying potassium current • reentry • spiral waves • ventricular tachycardia • ventricular fibrillation

This article has been cited by other articles:

				D. M. Pedrotty, R. Y. Klinger, R. D. Kirkton, and N. Bursac Cardiac fibroblast paracrine factors alter impulse conduction and ion channel expression of neonatal rat cardiomyocytes Cardiovasc Res, September 1, 2009; 83(4): 688 - 697. [Abstract] [Full Text] [PDF]

				C. A. Remme, B. P. Scicluna, A. O. Verkerk, A. S. Amin, S. van Brunschot, L. Beekman, V. H.M. Deneer, C. Chevalier, F. Oyama, H. Miyazaki, et al. Genetically Determined Differences in Sodium Current Characteristics Modulate Conduction Disease Severity in Mice With Cardiac Sodium Channelopathy Circ. Res., June 5, 2009; 104(11): 1283 - 1292. [Abstract] [Full Text] [PDF]