IK1 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

Research output: Contribution to journalArticle

Abstract

Previous studies have postulated an important role for the inwardly rectifying potassium current (IK1) 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 IK1 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 IK1 heterogeneity, stable high frequency spiral waves were present with IK1 overexpression, whereas lower frequency, meandering spiral waves were observed with IK1 suppression. Our study provides direct evidence for the contribution of IK1 heterogeneity and level to the genesis and stability of spiral waves and highlights the potential importance of IK1 as an antiarrhythmia target.

Original languageEnglish (US)
Pages (from-to)355-364
Number of pages10
JournalCirculation Research
Volume104
Issue number3
DOIs
StatePublished - Feb 13 2009

Fingerprint

Cardiac Myocytes
Muscle Cells
Islands
Action Potentials
Radio Waves
Ventricular Fibrillation
Ventricular Tachycardia
Green Fluorescent Proteins
Membrane Potentials
Potassium
Genes

Keywords

  • Inwardly rectifying potassium current
  • Reentry
  • Spiral waves
  • Ventricular fibrillation
  • Ventricular tachycardia

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

IK1 heterogeneity affects genesis and stability of spiral waves in cardiac myocyte monolayers. / Sekar, Rajesh B.; Kizana, Eddy; Cho, Hee C.; Molitoris, Jared M.; Hesketh, Geoffrey G.; Eaton, Brett P.; Marbán, Eduardo; Tung, Leslie.

In: Circulation Research, Vol. 104, No. 3, 13.02.2009, p. 355-364.

Research output: Contribution to journalArticle

Sekar, RB, Kizana, E, Cho, HC, Molitoris, JM, Hesketh, GG, Eaton, BP, Marbán, E & Tung, L 2009, 'IK1 heterogeneity affects genesis and stability of spiral waves in cardiac myocyte monolayers', Circulation Research, vol. 104, no. 3, pp. 355-364. https://doi.org/10.1161/CIRCRESAHA.108.178335
Sekar, Rajesh B. ; Kizana, Eddy ; Cho, Hee C. ; Molitoris, Jared M. ; Hesketh, Geoffrey G. ; Eaton, Brett P. ; Marbán, Eduardo ; Tung, Leslie. / IK1 heterogeneity affects genesis and stability of spiral waves in cardiac myocyte monolayers. In: Circulation Research. 2009 ; Vol. 104, No. 3. pp. 355-364.
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AU - Sekar, Rajesh B.

AU - Kizana, Eddy

AU - Cho, Hee C.

AU - Molitoris, Jared M.

AU - Hesketh, Geoffrey G.

AU - Eaton, Brett P.

AU - Marbán, Eduardo

AU - Tung, Leslie

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AB - Previous studies have postulated an important role for the inwardly rectifying potassium current (IK1) 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 IK1 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 IK1 heterogeneity, stable high frequency spiral waves were present with IK1 overexpression, whereas lower frequency, meandering spiral waves were observed with IK1 suppression. Our study provides direct evidence for the contribution of IK1 heterogeneity and level to the genesis and stability of spiral waves and highlights the potential importance of IK1 as an antiarrhythmia target.

KW - Inwardly rectifying potassium current

KW - Reentry

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