Dynamics of Early Afterdepolarization-Mediated Triggered Activity in Cardiac Monolayers

Abstract

Early afterdepolarizations (EADs) are voltage oscillations that occur during the repolarizing phase of the cardiac action potential and cause cardiac arrhythmias in a variety of clinical settings. EADs occur in the setting of reduced repolarization reserve and increased inward-over-outward currents, which intuitively explains the repolarization delay but does not mechanistically explain the time-dependent voltage oscillations that are characteristic of EADs. In a recent theoretical study, we identified a dual Hopf-homoclinic bifurcation as a dynamical mechanism that causes voltage oscillations during EADs, depending on the amplitude and kinetics of the L-type Ca(2+) channel (LTCC) current relative to the repolarizing K(+) currents. Here we demonstrate this mechanism experimentally. We show that cardiac monolayers exposed to the LTCC agonists BayK8644 and isoproterenol produce EAD bursts that are suppressed by the LTCC blocker nitrendipine but not by the Na(+) current blocker tetrodoxin, depletion of intracellular Ca(2+) stores with thapsigargin and caffeine, or buffering of intracellular Ca(2+) with BAPTA-AM. These EAD bursts exhibited a key dynamical signature of the dual Hopf-homoclinic bifurcation mechanism, namely, a gradual slowing in the frequency of oscillations before burst termination. A detailed cardiac action potential model reproduced the experimental observations, and identified intracellular Na(+) accumulation as the likely mechanism for terminating EAD bursts. Our findings in cardiac monolayers provide direct support for the Hopf-homoclinic bifurcation mechanism of EAD-mediated triggered activity, and raise the possibility that this mechanism may also contribute to EAD formation in clinical settings such as long QT syndromes, heart failure, and increased sympathetic output.

Nonlinear and stochastic dynamics in the heart

“…This feature can be clearly seen in Fig.32b. This behavior was also demonstrated in an experimental system in a recent study [324], which shows that the frequency decreases during the oscillations (Fig.32c). …”

“…Recent studies [166, 253, 322–324] have developed a nonlinear dynamical theory for EADs and showed that EADs arise from a dual Hopf-homoclinic bifurcation, and that chaos is responsible for the irregular appearance of EADs. This theory is summarized in the following sections.…”

Calcium-Voltage Coupling in the Genesis of Early and Delayed Afterdepolarizations in Cardiac Myocytes

“…S2 C) If voltage quickly decays into window voltage for oscillations and then outward current increases very slowly through the Hopf-homoclinic bifurcation window, a very long EAD burst can result. As demonstrated in our previous simulations (57), the slow accumulation of [Na] i causing a very slow increase of I NaK can be a candidate for finally terminating the long-lasting EAD burst.…”

“…For example, [Na] i accumulates very slowly, causing a very slow increase in I NaK , which can also initiate the Hopf-homoclinic bifurcation, as shown in our previous simulations (57). Late I Na is another candidate because it may slowly inactivate (58).…”

“…Depending on the stability of the quasi-equilibrium state, the decay rate of voltage, and the activation speed of the slowly increasing net outward current, as well as Cavoltage coupling, different EAD patterns can occur. Based on the bifurcation theory and results in previous simulations (21,44,(55)(56)(57) and the observations in this study, we summarize below the mechanisms underlying six characteristic patterns of EAD behaviors:…”