PROARRHYTHMIC RESPONSE TO POTASSIUM CHANNEL BLOCKADE - NUMERICAL-STUDIES OF POLYMORPHIC TACHYARRHYTHMIAS

Background Prompted by the results of CAST results, attention has shif ted 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 demonstrate d that sodium channel blockade, while antiarrhythmic at the cellular l evel, was inherently proarrhythmic in the setting of a propagating wav e Gent as a result of prolongation of the vulnerable period during whi ch premature stimulation can initiate reentrant activation. From a the oretical perspective, sodium (depolarizing) and potassium (repolarizin g) currents are complementary so that if antiarrhythmic and proarrhyth mic properties are coupled to modulation of sodium currents, then anti arrhythmic 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 excit ation. 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 v ulnerable period (VP). While holding the sodium conductance constant, the potassium conductance (g(K)) was reduced from 1.13 to 0.70 (arbitr ary units), producing a prolongation of the action potential duration (APD). When g(K) was 1.13, the tip of the spiral wave rotated around a small, stationary, unexcited region and the computed ECG was monomorp hic. As g(K) was reduced, the APD was prolonged and the unexcited regi on 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 nons tationary spiral core. Conclusions Torsadelike (polymorphic) ECGs can be derived from spiral wave reentry in a medium of identical cells. Un der normal conditions, the spiral core around which a reentrant wave f ront rotates is stationary. As the balance of repolarizing currents be comes less outward (eg, secondary to potassium channel blockade), the APD is prolonged. When the wavelength (APD velocity) exceeds the perim eter 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), wher eas smaller currents prolong the APD and amplify spiral core instabili ty, resulting in a polymorphic process. We conclude that, similar to s odium channel blockade, the proarrhythmic potential of potassium chann el blockade in the setting of propagation may be directly linked to it s cellular antiarrhythmic potential, ie, arrhythmia suppression result ing from a prolonged APD may, on initiation of a reentrant wave front, destabilize the core of a rotating spiral, resulting in complex motio n (precession) of the spiral tip around a nonstationary region of unex cited cells. In tissue with inhomogeneities, core instability alters t he activation sequence from one reentry cycle to the next and can lead to spiral wave fractionation as the wave front collides with inhomoge neous regions. Depending on the nature of the inhomogeneities, wave fr ont fragments may annihilate one another, producing a nonsustained arr hythmia, or may spawn new spirals (multiple wavelets), producing fibri llation and sudden cardiac death.