Mechanisms underlying the antifibrillatory action of hyperkalemia in guinea pig hearts

Sandeep V. Pandit, Mark Warren, Sergey Mironov, Alena Talkachova, Jérôme Kalifa, Omer Berenfeld, José Jalife

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Abstract

Hyperkalemia increases the organization of ventricular fibrillation (VF) and may also terminate it by mechanisms that remain unclear. We previously showed that the left-to-right heterogeneity of excitation and wave fragmentation present in fibrillating guinea pig hearts is mediated by chamber-specific outward conductance differences in the Inward rectifier potassium current (lK1). We hypothesized that hyperkalemia-mediated depolarization of the reversal potential of lK1 (EK1) would reduce excitability and thereby reduce VF excitation frequencies and left-to-right heterogeneity. We induced VF In Langendroff-perfused guinea pig hearts and increased the extracellular K+ concentration ([K+] 0) from control (4 mM) to 7 mM (n = 5) or 10 mM (n = 7). Optical mapping enabled spatial characterization of excitation dominant frequencies (DFs) and wavebreaks, and identification of sustained rotors (>4 cycles). During VF, hyperkalemia reduced the maximum DF of the left ventricle (LV) from 31.5 ± 4.7 Hz (control) to 23.0 ± 4.7 Hz (7.0 mM) or 19.5 ± 3.6 Hz (10.0 mM; p < 0.006), the left-to-right DF gradient from 14.7 ± 3.6 Hz (control) to 4.4 ± 1.3 Hz (7 mM) and 3.2 ± 1.4 Hz (10 mM), the number of DF domains, and the incidence of wavebreak in the LV and Interventricular regions. During 10 mM [K+]0, the rotation period and core area of sustained rotors in the LV increased, and VF often terminated. Two-dimensional computer simulations mimicking experimental VF predicted that clamping EK1 to normokalemic values during simulated hyperkalemia prevented all of the hyperkalemia-induced VF changes. During hyperkalemia, despite the shortening of the action potential duration, depolarization of EK1 increased refractoriness, leading to a slowing of VF, which effectively superseded the influence of lK1 conductance differences on VF organization. This reduced the left-to-right excitation gradients and heterogeneous wavebreak formation. Overall, these results provide, to our knowledge, the first direct mechanistic insight into the organization and/or termination of VF by hyperkalemia.

Original languageEnglish (US)
Pages (from-to)2091-2101
Number of pages11
JournalBiophysical Journal
Volume98
Issue number10
DOIs
StatePublished - May 19 2010

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Hyperkalemia
Ventricular Fibrillation
Guinea Pigs
Heart Ventricles
Constriction
Computer Simulation
Action Potentials
Potassium

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Pandit, S. V., Warren, M., Mironov, S., Talkachova, A., Kalifa, J., Berenfeld, O., & Jalife, J. (2010). Mechanisms underlying the antifibrillatory action of hyperkalemia in guinea pig hearts. Biophysical Journal, 98(10), 2091-2101. https://doi.org/10.1016/j.bpj.2010.02.011

Mechanisms underlying the antifibrillatory action of hyperkalemia in guinea pig hearts. / Pandit, Sandeep V.; Warren, Mark; Mironov, Sergey; Talkachova, Alena; Kalifa, Jérôme; Berenfeld, Omer; Jalife, José.

In: Biophysical Journal, Vol. 98, No. 10, 19.05.2010, p. 2091-2101.

Research output: Contribution to journalArticle

Pandit, SV, Warren, M, Mironov, S, Talkachova, A, Kalifa, J, Berenfeld, O & Jalife, J 2010, 'Mechanisms underlying the antifibrillatory action of hyperkalemia in guinea pig hearts', Biophysical Journal, vol. 98, no. 10, pp. 2091-2101. https://doi.org/10.1016/j.bpj.2010.02.011
Pandit, Sandeep V. ; Warren, Mark ; Mironov, Sergey ; Talkachova, Alena ; Kalifa, Jérôme ; Berenfeld, Omer ; Jalife, José. / Mechanisms underlying the antifibrillatory action of hyperkalemia in guinea pig hearts. In: Biophysical Journal. 2010 ; Vol. 98, No. 10. pp. 2091-2101.
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