Computer model of electrophysiological instability in very small heterogeneous ventricular syncytia

Computer simulations based on a model of transmembrane currents and intracellular Ca2+ flux of an isolated guinea pig myocyte [Nordin, C. Am. J. Physiol. 265 (Heart Circ. Physiol. 34): H2117-H2136, 1993] have previously shown that very small heterogeneous ventricular myocardial syncytia can be constructed in which trains of sustained, nondriven action potentials are initiated and terminated with critically timed premature stimulations by a nonreentrant mechanism. A more detailed examination of the characteristics of such syncytia and the nature of the responses is explored. When cells with the normal configuration of equations were connected by high-resistance gap junctions to other cells in which their configuration was modified to reproduce a myocyte with mild Ca2+ overload and two regenerative levels of diastolic potential, critically timed stimulations shifted the electrical response of the syncytium between a stable phase, in which all myocytes were quiescent until stimulated and generated full action potentials from resting potentials between -90 and -65 mV, and an oscillatory phase, in which all cells generated sustained trains of nondriven action potentials from takeoff potentials between -70 and -30 mV. The following predominant responses were observed in such syncytia: 1) a range of 40-60 ms starting at the refractory period with an inverse relationship between prematurity of the stimulation and time to the first upstroke of nondriven activity, followed by a much shorter period with a direct relationship; 2) a delay shorter than a full compensatory pause following single premature stimulations that do not terminate spontaneous action potentials; and 3) entrainment of nondriven action potentials with short bursts of stimulations at rates just above the intrinsic rate of spontaneous activity and termination at faster rates. The propensity to develop nondriven action potentials was enhanced by Ca2+ loading. Other simulations demonstrated that activity can propagate in syncytia of >100 myocytes from small foci to generate full action potentials in larger regions of normal cells. Analysis of the model shows that these patterns arise primarily from crucial, dynamic relationships among membrane potential, intracellular Ca2+ cycling, and gap junction currents. The results suggest that highly localized interactions between normal and depolarized myocytes in uncoupled heterogeneous syncytia may reproduce many of the characteristic responses of ventricular tachycardia.