title: Mechanisms underlying the antifibrillatory action of hyperkalemia in Guinea pig hearts.
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 (I(K1)). We hypothesized that hyperkalemia-mediated depolarization of the reversal potential of I(K1) (E(K1)) 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(+)](o)) 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(+)](o), 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 E(K1) 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potential duration, depolarization of E(K1) increased refractoriness, leading to a slowing of VF, which effectively superseded the influence of I(K1) conductance differences on VF organization.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.
authors.affiliation: Center for Arrhythmia Research, University of Michigan, Ann Arbor, Michigan, USA. sanpandi@med.umich.edu
authors.forename: Sandeep V
authors.initials: SV
authors.lastname: Pandit
authors.forename: Mark
authors.initials: M
authors.lastname: Warren
authors.forename: Sergey
authors.initials: S
authors.lastname: Mironov
authors.forename: Elena G
authors.initials: EG
authors.lastname: Tolkacheva
authors.forename: Jérôme
authors.initials: J
authors.lastname: Kalifa
authors.forename: Omer
authors.initials: O
authors.lastname: Berenfeld
authors.forename: José
authors.initials: J
authors.lastname: Jalife
mesh_terms: D000200:Action Potentials / Q000502:physiology*; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000209:etiology*; D001683:Biological Clocks; D001783:Blood Flow Velocity; D002304:Cardiac Pacing, Artificial / Q000379:methods; D004195:Disease Models, Animal; D004562:Electrocardiography / Q000379:methods; D004594:Electrophysiology / Q000379:methods; D006168:Guinea Pigs; D006321:Heart / Q000503:physiopathology; D006329:Heart Conduction System / Q000502:physiology*; D006947:Hyperkalemia / Q000150:complications*; D008564:Membrane Potentials / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D008955:Models, Cardiovascular; D032383:Myocytes, Cardiac; D011188:Potassium / Q000097:blood*; D026902:Potassium Channel Blockers / Q000627:therapeutic use; D024661:Potassium Channels, Inwardly Rectifying / Q000378:metabolism; D015222:Sodium Channels; D014693:Ventricular Fibrillation / Q000503:physiopathology*
chemical_list: D026902:Potassium Channel Blockers; D024661:Potassium Channels, Inwardly Rectifying; D015222:Sodium Channels; D011188:Potassium