Ventricular arrhythmias are often preceded by beat-to-beat alternation in the action potential duration (APD), called APD alternans, which is a first sign of rhythm instability. Electrical restitution, the functional relationship between APD and previous diastolic interval (DI), is thought by many to govern stability. However, recent evidence suggests that rhythm stability in spatially extended myocardium is determined by many factors, including spatial heterogeneity of restitution and wavefront conduction velocity (CV) dynamics. In order to understand the processes leading to instability, experimental studies were performed to characterize APD restitution and the transition to both APD alternans and conduction alternans throughout the rabbit ventricle.

The spatial profile of transient and steady-state restitution responses was characterized across tissue surfaces and throughout the ventricular wall with a custom-built fiber optic mapping system for recording cardiac action potentials. Intrinsic and pacing-induced heterogeneities were found, particularly across the wall, and were quantified. In opposition to current hypotheses concerning restitution and the onset of alternans, the slopes of the steady-state (dynamic) and transient (S1-S2) restitution curves did not correlate with alternans onset, and neither did the spatial profile of the restitution curves, indicating that APD restitution and spatial gradients in restitution cannot alone determine stability.

Experiments revealed multiple routes to instability, and functional spatial heterogeneity of both APD and CV were destabilizing factors. Spatially discordant APD alternans, in which regions of tissue alternate out of phase, was observed with several phase reversals in a small (15 mm²) area of tissue. Alternation in the inter-beat activation time (local cycle length (CL) alternans), a phenomenon predicted theoretically as being due to APD-CV coupling, was observed for the first time experimentally. Simultaneous discordant APD and discordant local CL alternans combined to create large spatial gradients of repolarization and initiate arrhythmias. Experiments revealed evidence of a new bifurcation that results in APD amplitude modulation patterns and that precedes the period-doubling bifurcation to alternans. A return-map model was developed to describe this new behavior.

This work is a first step toward understanding the role of functional and intrinsic heterogeneities in the formation and evolution of instability throughout three-dimensional myocardium.