Irregularly occurring early afterdepolarizations (EADs) in cardiac myocytes are traditionally hypothesized to be caused by random ion channel fluctuations. In this study, we combined 1), patch-clamp experiments in which action potentials were recorded at different pacing cycle lengths from isolated rabbit ventricular myocytes under several experimental conditions inducing EADs, including oxidative stress with hydrogen peroxide, calcium overload with BayK8644, and ionic stress with hypokalemia; 2), computer simulations using a physiologically detailed rabbit ventricular action potential model, in which repolarization reserve was reduced to generate EADs and random ion channel or path cycle length fluctuations were implemented; and 3), iterated maps with or without noise. By comparing experimental, modeling, and bifurcation analyses, we present evidence that noise-induced transitions between bistable states (i.e., between an action potential with and without an EAD) is not sufficient to account for the large variation in action potential duration fluctuations observed in experimental studies. We conclude that the irregular dynamics of EADs is intrinsically chaotic, with random fluctuations playing a nonessential, auxiliary role potentiating the complex dynamics.
2010 Biophysical Society. Published by Elsevier Inc. All rights reserved.