Advanced Methods for Assessing the Stability and Control of Alternans

It is now widely accepted that rotating action potential waves propagating within the heart cause several types of abnormal rapid cardiac rhythm patterns. Many of these rotating waves are sustained purely through the electrical dynamics of the cardiac tissue, without the benefit of a clear anatomical obstacle around which to rotate, a phenomenon known as functional reentry. There have been several types of functional reentry described as possible causes of rapid cardiac rhythm, including leading circle reentry,¹ spiral wave reentry,³² anisotropic reentry,⁸ and figure-of-eight reentry.¹⁰

The onset of ventricular fibrillation (VF) may well be linked to factors that tend to break up these functionally reentrant waves into additional waves. One major theory suggests that a strong dependence of the action potential duration (APD) on the preceding diastolic interval (DI),¹⁸ a phenomenon called steep electrical restitution, is closely correlated with the tendency for a reentrant wave to experience breakup.³⁸ In this theory, the steep restitution creates alternans, the beat-to-beat alternation of action potential parameters such as the APD or DI. When alternans is present during spiral wave rotation, the DI out in front of the rotating wave can become very short during every other rotation. As illustrated in Fig. 1, this short DI can cause a portion of the wave to block, allowing remaining segments of the wave to form additional spiral waves. The first studies of alternans on reentrant action potential waves took place in one-dimensional ring geometry.^7,14,24 This system exhibited a variation of alternans behavior called the oscillating pulse instability, which was found to be caused by an interaction between the dynamics associated with electrical restitution and variations in the conduction velocity, which was also assumed to depend on DI. Such was also the case when alternans was studied in finite length fibers subjected to rapid pacing.¹³ In this case, in both simulation and Purkinje fiber experiments, constant rapid pacing applied to one end of the fiber resulted in alternans behavior that was either in phase throughout the system (concordant alternans) or arranged into regions that were out of phase with one another (discordant alternans). The latter were often seen to lead subsequently to block of some of the propagating action potentials. A hypothesis was subsequently put forward that the presence of discordant alternans leaves the tissue open to the block of segments of propagating wavefronts, leading to the formation of reentrant waves, subsequent block of those waves, electrical turbulence, and finally self-sustaining rapid cardiac rhythm. Substantial evidence for this theory exists; for example, it has been shown that the induction of VF can be prevented or converted into a periodic rhythm when drugs that flatten the restitution function are administered.^16,35 Pastore et al.³¹ have also observed that discordant alternans degenerates into VF upon slight acceleration of the pacing frequency in guinea pig ventricular muscle.