A Single-Cell Model of Phase-Driven Control of Ventricular Fibrillation Frequency

The mechanisms controlling the rotation frequency of functional reentry in ventricular fibrillation (VF) are poorly understood. It has been previously shown that Ba2+ at concentrations up to 50 μmol/L slows the rotation frequency in the intact guinea pig (GP) heart, suggesting a role of the inward rectifier current (IK1) in the mechanism governing the VF response to Ba2+. Given that other biological (e.g., sinoatrial node) and artificial systems display phase-locking behavior, we hypothesized that the mechanism for controlling the rotation frequency of a rotor by IK1 blockade is phase-driven, i.e., the phase shift between transmembrane current and voltage remains constant at varying levels of IK1 blockade. We measured whole-cell admittance in isolated GP myocytes and in transfected human embryonic kidney (HEK) cells stably expressing Kir 2.1 and 2.3 channels. The admittance phase, i.e., the phase difference between current and voltage, was plotted versus the frequency in control conditions and at 10 or 50 μmol/L Ba2+ (in GP heart cells) or 1 mM Ba2+ (in HEK cells). The horizontal distance between plots was called the “frequency shift in a single cell” and analyzed. The frequency shift in a single cell was −14.14 ± 5.71 Hz (n = 14) at 10 μM Ba2+ and −18.51 ± 4.00 Hz (n = 10) at 50 μM Ba2+, p < 0.05. The values perfectly matched the Ba2+-induced reduction of VF frequency observed previously in GP heart. A similar relationship was found in the computer simulations. The phase of Ba2+-sensitive admittance in GP cells was −2.65 ± 0.32 rad at 10 Hz and −2.79 ± 0.26 rad at 30 Hz. In HEK cells, the phase of Ba2+-sensitive admittance was 3.09 ± 0.03 rad at 10 Hz and 3.00 ± 0.17 rad at 30 Hz. We have developed a biological single-cell model of rotation-frequency control. The results show that although rotation frequency changes as a result of IK1 blockade, the phase difference between transmembrane current and transmembrane voltage remains constant, enabling us to quantitatively predict the change of VF frequency resulting from IK1 blockade, based on single-cell measurement

Action Potential Duration Restitution Portraits of Mammalian Ventricular Myocytes: Role of Calcium Current

Construction of the action potential duration (APD) restitution portrait allows visualization of multiple aspects of the dynamics of periodically paced myocytes at various basic cycle lengths (BCLs). For the first time, we obtained the restitution portrait of isolated rabbit and guinea pig cardiac ventricular myocytes and analyzed the time constant, τ, of APD accommodation and the slopes of different types of restitution curves, S(dyn) and S(12), measured at varying BCLs. Our results indicate that both τ and the individual slopes are species and pacing dependent. In contrast, the mutual relationship between slopes S(dyn) and S(12) does not depend on pacing history, being a generic feature of the species. In addition, the maximum slope S(12), measured in the restitution portrait at the lowest BCL, predicts the onset of alternans. Further, we investigated the role of the L-type calcium current, I(Ca-L), in the restitution portrait. We found that I(Ca-L) dramatically affects APD accommodation, as well as the individual slopes S(dyn) and S(12) measured in the restitution portrait. However, peak calcium current plays a role only at small values of BCL. In conclusion, the results demonstrate that the restitution portrait is a powerful technique to investigate restitution properties of periodically paced cardiac myocytes and the onset of alternans, in particular. Moreover, the data also show that I(Ca-L) plays a crucial role in multiple aspects of cardiac dynamics measured through the restitution portrait

Ionic Determinants of Functional Reentry in a 2-D Model of Human Atrial Cells During Simulated Chronic Atrial Fibrillation

Recent studies suggest that atrial fibrillation (AF) is maintained by fibrillatory conduction emanating from a small number of high-frequency reentrant sources (rotors). Our goal was to study the ionic correlates of a rotor during simulated chronic AF conditions. We utilized a two-dimensional (2-D), homogeneous, isotropic sheet (5 × 5 cm(2)) of human atrial cells to create a chronic AF substrate, which was able to sustain a stable rotor (dominant frequency ∼5.7 Hz, rosette-like tip meander ∼2.6 cm). Doubling the magnitude of the inward rectifier K(+) current (I(K1)) increased rotor frequency (∼8.4 Hz), and reduced tip meander (∼1.7 cm). This rotor stabilization was due to a shortening of the action potential duration and an enhanced cardiac excitability. The latter was caused by a hyperpolarization of the diastolic membrane potential, which increased the availability of the Na(+) current (I(Na)). The rotor was terminated by reducing the maximum conductance (by 90%) of the atrial-specific ultrarapid delayed rectifier K(+) current (I(Kur)), or the transient outward K(+) current (I(to)), but not the fast or slow delayed rectifier K(+) currents (I(Kr)/I(Ks)). Importantly, blockade of I(Kur)/I(to) prolonged the atrial action potential at the plateau, but not at the terminal phase of repolarization, which led to random tip meander and wavebreak, resulting in rotor termination. Altering the rectification profile of I(K1) also slowed down or abolished reentrant activity. In combination, these simulation results provide novel insights into the ionic bases of a sustained rotor in a 2-D chronic AF substrate