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potential duration, depolarization of EK1 increased refractoriness, leading to a slowing of VF, which effectively superseded the influence of lK1 conductance differences on VF organization.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.
Bibliographical noteFunding Information:
This work was supported by National Heart, Blood and Lung Institute grants PO1-HL039707, PO1-HL070074, and RO1-HL080159 (J.J.); a Heart Rhythm Society Michael Mirowski International Fellowship (M.W.); and an American Heart Association postdoctoral fellowship and Scientist Development Grant (S.V.P.).