Subcellular metabolic transients and mitochondrial redox waves in heart cells.

Precise matching of energy supply with demand requires delicately balanced control of the enzymes involved in substrate metabolism. In response to a change in substrate supply, the nonlinear properties of metabolic control may induce complex dynamic behavior. Using confocal imaging of flavoprotein redox potential and mitochondrial membrane potential, we show that substrate deprivation leads to subcellular heterogeneity of mitochondrial energization in intact cells. The complex spatiotemporal patterns of redox and matrix potential included local metabolic transients, cell-wide coordinated redox transitions, and propagated metabolic waves both within and between coupled cells. Loss of metabolic synchrony during mild metabolic stress reveals that intra- and intercellular control of mitochondrial function involves diffusible cytoplasmic messengers.

[Slow excitation waves and mechanisms of polymorphic ventricular tachycardia in an experimental model: isolated walls of the right ventricle from rabbit and squirrel]. / Medlennye volny vozbuzhdeniia i mekhanizmy polimorfnoi zheludochkovoi takhikardii v éksperimental'noi modeli: izolirovannye stenki pravogozheludochka krolika i suslika.

The mechanism of polymorphic disturbances of the heart rhythm is studied on an experimental model, isolated ventricular preparations of ground squirrel and rabbit. Polymorphic arrhythmias are identified from habitus of the isolated preparation pseudoECGs mathematically derived from electrograms registered simultaneously at 32 endocardial and 32 epicardial points. The same electrograms allow one to visualize the excitation wave propagation along each of the preparation surfaces. The comparison of excitation wave pictures and corresponding pseudoECGs enabled us to reveal the conditions necessary and sufficient for polymorphism in heart rhythm disturbances. Polymorphic arrhythmias are due to changes in wave pictures in the regions of retarded excitation propagation.

[A system for computer visualization of excitation wave propagation in the myocardium]. / Sistema komp'iuternoi vizualizatsii rasprostraneniia voln vozbuzhdeniia v miokarde.

A method of computer-aided visualization of autowave vortices on the cardiac tissue surface is developed. The software for research into autowave vortex evolution is designed, which allowed an adequate presentation of excitation propagation along complex trajectories and the detection of the most essential features of excitation source behavior.

Functional consequences of lidocaine binding to slow-inactivated sodium channels.

Na channels open upon depolarization but then enter inactivated states from which they cannot readily reopen. After brief depolarizations, native channels enter a fast-inactivated state from which recovery at hyperpolarized potentials is rapid (< 20 ms). Prolonged depolarization induces a slow-inactivated state that requires much longer periods for recovery (> 1 s). The slow-inactivated state therefore assumes particular importance in pathological conditions, such as ischemia, in which tissues are depolarized for prolonged periods. While use-dependent block of Na channels by local anesthetics has been explained on the basis of delayed recovery of fast-inactivated Na channels, the potential contribution of slow-inactivated channels has been ignored. The principal (alpha) subunits from skeletal muscle or brain Na channels display anomalous gating behavior when expressed in Xenopus oocytes, with a high percentage entering slow-inactivated states after brief depolarizations. This enhanced slow inactivation is eliminated by coexpressing the alpha subunit with the subsidiary beta 1 subunit. We compared the lidocaine sensitivity of alpha subunits expressed in the presence and absence of the beta 1 subunit to determine the relative contributions of fast-inactivated and slow-inactivated channel block. Coexpression of beta 1 inhibited the use-dependent accumulation of lidocaine block during repetitive (1-Hz) depolarizations from -100 to -20 mV. Therefore, the time required for recovery from inactivated channel block was measured at -100 mV. Fast-inactivated (alpha + beta 1) channels were mostly unblocked within 1 s of repolarization; however, slow-inactivated (alpha alone) channels remained blocked for much longer repriming intervals (> 5 s). The affinity of the slow-inactivated state for lidocaine was estimated to be 15-25 microM, versus 24 microM for the fast-inactivated state. We conclude that slow-inactivated Na channels are blocked by lidocaine with an affinity comparable to that of fast-inactivated channels. A prominent functional consequence is potentiation of use-dependent block through a delay in repriming of lidocaine-bound slow-inactivated channels.

Proarrhythmic response to potassium channel blockade. Numerical studies of polymorphic tachyarrhythmias.

BACKGROUND: Prompted by the results of CAST results, attention has shifted from class I agents that primarily block sodium channels to class III agents that primarily block potassium channels for pharmacological management of certain cardiac arrhythmias. Recent studies demonstrated that sodium channel blockade, while antiarrhythmic at the cellular level, was inherently proarrhythmic in the setting of a propagating wave front as a result of prolongation of the vulnerable period during which premature stimulation can initiate reentrant activation. From a theoretical perspective, sodium (depolarizing) and potassium (repolarizing) currents are complementary so that if antiarrhythmic and proarrhythmic properties are coupled to modulation of sodium currents, then antiarrhythmic and proarrhythmic properties might similarly be coupled to modulation of potassium currents. The purpose of the present study was to explore the role of repolarization currents during reentrant excitation. METHODS AND RESULTS: To assess the generic role of repolarizing currents during reentry, we studied the responses of a two-dimensional array of identical excitable cells based on the FitzHugh-Nagumo model, consisting of a single excitation (sodium-like) current and a single recovery (potassium-like) current. Spiral wave reentry was initiated by use of S1S2 stimulation, with the delay timed to occur within the vulnerable period (VP). While holding the sodium conductance constant, the potassium conductance (gK) was reduced from 1.13 to 0.70 (arbitrary units), producing a prolongation of the action potential duration (APD). When gK was 1.13, the tip of the spiral wave rotated around a small, stationary, unexcited region and the computed ECG was monomorphic. As gK was reduced, the APD was prolonged and the unexcited region became mobile (nonstationary), such that the tip of the spiral wave inscribed an outline similar to a multipetaled flower; concomitantly, the computed ECG became progressively more polymorphic. The degree of polymorphism was related to the APD and the configuration of the nonstationary spiral core. CONCLUSIONS: Torsadelike (polymorphic) ECGs can be derived from spiral wave reentry in a medium of identical cells. Under normal conditions, the spiral core around which a reentrant wave front rotates is stationary. As the balance of repolarizing currents becomes less outward (eg, secondary to potassium channel blockade), the APD is prolonged. When the wavelength (APD.velocity) exceeds the perimeter of the stationary unexcited core, the core will become unstable, causing spiral core drift. Large repolarizing currents shorten the APD and result in a monomorphic reentrant process (stationary core), whereas smaller currents prolong the APD and amplify spiral core instability, resulting in a polymorphic process. We conclude that, similar to sodium channel blockade, the proarrhythmic potential of potassium channel blockade in the setting of propagation may be directly linked to its cellular antiarrhythmic potential, ie, arrhythmia suppression resulting from a prolonged APD may, on initiation of a reentrant wave front, destabilize the core of a rotating spiral, resulting in complex motion (precession) of the spiral tip around a nonstationary region of unexcited cells. In tissue with inhomogeneities, core instability alters the activation sequence from one reentry cycle to the next and can lead to spiral wave fractination as the wave front collides with inhomogeneous regions. Depending on the nature of the inhomogeneities, wave front fragments may annihilate one another, producing a nonsustained arrhythmia, or may spawn new spirals (multiple wavelets), producing fibrillation and sudden cardiac death.

Metabolic oscillations in heart cells.

Oscillatory rhythms underlie biological processes as diverse and fundamental as neuronal firing, secretion, and muscle contraction. We have detected periodic changes in membrane ionic current driven by intrinsic oscillations of energy metabolism in guinea pig heart cells. Withdrawal of exogenous substrates initiated oscillatory activation of ATP-sensitive potassium current and cyclical suppression of depolarization-evoked intracellular calcium transients. The oscillations in membrane current were not driven by pacemaker currents or by alterations in intracellular calcium and thus represent a novel cytoplasmic cardiac oscillator. The linkage to energy metabolism was demonstrated by monitoring oscillations in the oxidation state of pyridine nucleotides. Interventions which altered the rate of glucose metabolism modulated the oscillations, suggesting that the rhythms originated at the level of glycolysis. The metabolic oscillations produced cyclical changes in electrical excitability, underscoring the potential importance of this intrinsic oscillator in the genesis of cardiac arrhythmias.

Vulnerability in an excitable medium: analytical and numerical studies of initiating unidirectional propagation.

Cardiac tissue can display unusual responses to certain stimulation protocols. In the wake of a conditioning wave of excitation, spiral waves can be initiated by applying stimuli timed to occur during a period of vulnerability (VP). Although vulnerability is well known in cardiac and chemical media, the determinants of the VP and its boundaries have received little theoretical and analytical study. From numerical and analytical studies of reaction-diffusion equations, we have found that 1) vulnerability is an inherent property of Beeler-Reuter and FitzHugh-Nagumo models of excitable media; 2) the duration of the vulnerable window (VW) the one-dimensional analog of the VP, is sensitive to the medium properties and the size of the stimulus field; and 3) the amplitudes of the excitatory and recovery processes modulate the duration of the VW. The analytical results reveal macroscopic behavior (vulnerability) derived from the diffusion of excitation that is not observable at the level of isolated cells or single reaction units.