Dynamics of early afterdepolarization-mediated triggered activity in cardiac monolayers

Marvin G. Chang, Connie Y. Chang, Enno De Lange, Linmiao Xu, Brian O'Rourke, Hrayr S. Karagueuzian, Leslie Tung, Eduardo Marbán, Alan Garfinkel, James N. Weiss, Zhilin Qu, M. Roselle Abraham

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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.

Original languageEnglish (US)
Pages (from-to)2706-2714
Number of pages9
JournalBiophysical Journal
Volume102
Issue number12
DOIs
Publication statusPublished - Jun 20 2012

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ASJC Scopus subject areas

  • Biophysics

Cite this

Chang, M. G., Chang, C. Y., De Lange, E., Xu, L., O'Rourke, B., Karagueuzian, H. S., ... Abraham, M. R. (2012). Dynamics of early afterdepolarization-mediated triggered activity in cardiac monolayers. Biophysical Journal, 102(12), 2706-2714. https://doi.org/10.1016/j.bpj.2012.05.011